Contrasting C- and O-Atom Reactivities of Neutral Ketone and Enolate

Subscriber access provided by READING UNIV

Article

Contrasting C- and O-Atom Reactivities of Neutral Ketone and Enolate Forms of 3-Sulfonyloxyimino-2-Methyl-1-Phenyl-1-Butanones Yingtang Ning, Yuko Otani, and Tomohiko Ohwada J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02573 • Publication Date (Web): 30 Nov 2017 Downloaded from http://pubs.acs.org on December 1, 2017

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

The Journal of Organic Chemistry is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

Contrasting C- and O-Atom Reactivities of Neutral Ketone and Enolate Forms of 3-Sulfonyloxyimino-2-Methyl-1-Phenyl-1Butanones Yingtang Ning, Yuko Otani, Tomohiko Ohwada* Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan E-mail: [email protected] Supporting Information Placeholder

Abstract The mechanisms of intramolecular cyclization of 3-sulfonyloxyimino-2-methyl1-phenyl-1-butanones (1) under basic (DABCO and tert-BuOK) and acidic (AcOH and TFA) conditions were investigated by means of experimental and computational methods. The ketone, enol and enolate forms of 1 can afford different intramolecular cyclization products (2, 3, 4), depending on the conditions. The results of the reaction of 1 under basic conditions suggest intermediacy of neutral enol (DABCO) and anionic enolate (tert-BuOK), while the results under acidic conditions (AcOH and TFA) indicate involvement of neutral ketones, which exhibit reactivities arising from both the oxygen lone-pair electrons (O-atom reactivity) and carbon σ-electrons (Catom reactivity). The neutral enol in DABCO afforded 2H-azirine 4. On the other hand, the products (isoxazole 2 and oxazole 3) generated from the ketone form and from the enolate form are the same, but the reaction mechanisms are apparently different. The results demonstrate ambident-like reactivity of neutral ketone in the 3sulfonyloxyimino-2-methyl-1-phenyl-1-butanone system.

1

ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 53

Introduction Ambident reactivity refers to the situation where a compound possesses two strongly interacting reactive centers, either of which may form a chemical bond, accompanied with loss of reactivity at the other site.1 Several ideas have been proposed to explain the different reaction preferences of typical ambident nucleophiles (Figure 1) under different conditions, including the hard and soft acids and bases (HSAB) theory,2 charge and orbital control of organic reactions,3 and the Marcus theory.4 a E X Y

E X-attack

X Y

E Y-attack

X Y E

b E

X

Z

Y

E X-attack

X

Z

Y

E Y-attack

X

Z

Y

E

Figure 1. Examples of different reactivities of ambident nucleophiles. a: CN–, sulfoxides and hydrazines. b: SCN–, phenols and enolates.

Among ambident reactive species, enols and enolates are of particular interest because of their importance in synthetic chemistry.5 Enolate anions generated under basic conditions can react at either the oxygen atom (O-attack) or the carbon atom (Cattack) (Scheme 1a).6 The reaction selectivity depends upon many factors, including the nature of the enolate, the electrophilic counterpart, the reaction solvent and the counterion. For example, metal-cation coordination can lead to a preference for the C-attack product by blocking the O-nucleophilicity.7 In the gas phase without a counterion, O-attack is favored, because the O-nucelophilicity was not blocked by the counterions and solvent, and resonance effects significantly increase the barrier for Catom reactivity.8

2


Page 3 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


a

O

E R

b

O

E

+ E O-attack

E+

R

O

E R

R

E

+

+

O E

C-attack

R

OH R enol

O

E+

O E

C-attack

– H+

nO

R

O-attack

nO

E

enolate

O-attack

– H+

c +

– O

σC-R

E+ C-attack

σC-R

R

O

+ E

R

ketone

Scheme 1. Ambident-like reactions of a: enolate anion, b: enol and c: neutral ketone. Tautomerization of ketones to corresponding enols is relatively facile.

In contrast to the interest in ambident reactivity of anionic enolates and neutral enols, the closely related C-atom and O-atom reactivities of neutral ketones have been little studied. Neutral ketones may have potential for dual reactivities based on the oxygen lone-pair electrons (Scheme 1c, O-atom reactivity) and carbon σ-electrons (C-atom reactivity). O-Attack reactions of ketones occur under acidic conditions.9, 10 However, it is difficult to study the nucleophilic reactivity at the C atom of ketones, because of the inductive effect of the proximate oxygen and the inherent difficulty of breaking an sp3 C-C or C-H bond at the α position.11 Modern synthetic chemistry generally utilizes enolate and enamine intermediates to activate the α-position of carbonyl functionalities.12 In addition, tautomerization of ketones to the corresponding enols is relatively facile under both acidic and basic conditions,13 and C-attack on the enol form predominates over C-attack on the ketone form, even if the equilibrium constant is small (Scheme 1b). Indeed, organic chemistry textbooks state that the

3



Page 4 of 53

tautomerization of ketones to enols explains why "substitution reactions [at carbon] do not occur from the carbonyl form".14

Scheme 2. Model compounds 1a and 1b and the O-attack/C-attack reactivity of the ketone form of 1a. + O

N

O-attack

(E)-oxime OR O N C-attack

O

•+ N

1a, R=Ms 1b, R=Ts

To study the nucleophilic reactivities of the C- and O-atoms of ketones, we designed 3-sulfonyloxyimino-2-methyl-1-phenyl-1-butanones 1a and 1b as model molecules. (Scheme 2) The oxime functionality (C=NOR) can undergo Beckmann rearrangement,15 which can lead to cleavage of the C–C σ bond, even in the case of the electron-deficient C–C σ bond，exemplified in p-nitroacetophenone oxime (Supporting Information, Scheme S1a).16 Oxime compounds are also able to react with a C anion,17 which is known as Neber rearrangement (Scheme S1b).18 These different reactivities of oxime compounds with C–C bonds and C anions, together with the potent reactivity of oximes with heteroatoms via 5-membered ring formation (Scheme S1),19-21 make 1a and 1b suitable for the study of ambident-like reactivity of ketones. In this study, we investigated the reactivities of the C and O atoms of neutral ketone form in the specially designed 3-sulfonyloxyimino-2-methyl-1-phenyl-1butanone system, in comparison with those of the corresponding enol and anionic enolate forms, focusing on intramolecular substitution reaction with the oxime

4


Page 5 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


nitrogen atom. Notably, different distributions of products, and sometimes different products, were obtained. Reactivities of the ketone form and enolate (enol) form are favored under acidic and basic conditions, respectively. We also show that chemoselective synthesis of isoxazoles22 and 2H-azirines,23 which are important synthons in organic chemistry, can be achieved from the same substrate under different conditions through control of the selectivity for O-attack and C-attack.

Results and Discussion Divergent

reactivity

of

2-methyl-3-(((methylsulfonyl)oxy)imino)-1-

phenylbutan-1-one 1a and 1b. Compounds 1a and 1b possess both a carbonyl group (C=O) and hydroxyimino group (C=N–OR) in a single molecule. In all reaction substrates, the oxime N-O bonds are anti-periplanar with the carbonyl groups (i.e., Eoximes). We performed the reactions of 1a and 1b under Brønsted basic conditions (Scheme 3, reactions 1 and 2) and acidic conditions (Scheme 3, reactions 3 and 4). High selectivity for C-attack (C-N bond formation) was observed in the reaction of 1a with a relatively mild base, 1,4-diazabicyclo[2.2.2]octane (DABCO), yielding the 2Hazirine 4a (Scheme 3, reaction 1). Previous reports24 have described the transformation of 4a into 3a by strong bases, and we found that when 1a was treated with tert-BuOK, 2a and 3a were obtained in comparable yields (Scheme 3, reaction 2). Product 2a contains a new O–N bond, which indicates O-atom reactivity. Our mechanistic studies (vide infra) strongly suggest that these reactions under basic conditions occurred from the enol (DABCO) and enolate (tert-BuOK) forms of 1a. On the other hand, a preference for O-attack, leading to the formation of an O-N bond, was observed under acidic conditions using AcOH (Scheme 3, reaction 3). When stronger trifluoroacetic acid (TFA) was used, the reaction again gave a mixture

5



Page 6 of 53

of 2a and oxazole 3a (Scheme 3, reaction 4). The intermediacy of 2H-azirine 4a under acidic conditions was excluded, since 4a in AcOH and TFA did not produce either 2a or 3a, and 4a was recovered after aqueous work-up. Under acidic conditions, 1a and 1b react preferentially as the ketone form, without tautomerizing to the corresponding enol, and provide rare examples of ambident-like reactivities of ketones. Specifically, 2a originates from intramolecular O-attack in 1a (1b), which is highly favored in AcOH. On the other hand, the formation of 4a and 3a reflects Catom reactivity, which is favored in the reaction with DABCO. Dual O- and Creactivities, that is, formation of both 2a and 3a, occurred in the reactions with TFA and tert-BuOK. To understand what reactive species are responsible for these reactions, we carried out a series of mechanistic studies of these transformations. O-attack O (1)

N

OMs

C H

Ph

CH2Cl2 20 ºC 1hr

1a

O

N

O

DABCO

N C

Ph

C-attack O

2a

Ph

O

N

N

1a 1b

O (3) Ph

N

N

C

THF 20 ºC 15 min

2a

Ph

37% 30%

R=Ms, R=Ts,

C H 1a

O (4) Ph

Ph

C H

OMs

O

AcOH MeCN 50 ºC 8 hr OR

C Ph 20 ºC 1hr H 1a R=Ms, 1b R=Ts,

2a

Ph

enolate

N 3a

C

N

AcOH x

ketone

TFA x

ketone

3a

( < 3%)

N C

C

O

91%

O TFA

tert-BuOK ref. (24)

41% 43%

N C

Ph

4a

O

tert-BuOK (2) Ph

enol

C 88 %

(4.1 %)

OR

reactive species

O

2a

65% 51%

Ph

C

N 3a

23% 32%

Scheme 3. Reactions of 1a and 1b under Brønsted basic (reactions 1 and 2) and acidic conditions (reactions 3 and 4). Yields in parentheses were calculated from 1H NMR signals of the crude product, using 1,2-dichloroethane as internal standard.

6


Page 7 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Base-catalyzed

Reactions

of


phenylbutan-1-one 1a. Reaction of 1a with DABCO: C-attack reaction of enol (reaction 1) (Scheme 3). We first studied the reaction of 1a with DABCO. This transformation from 1a to 4a is a familiar Neber-type rearrangement reaction of oxime compounds. The general mechanism of Neber rearrangement is not fully understood,18 and may depend on the nature of the substrate.25 Surprisingly few reaction kinetics data or computational results are available, despite recent advances in application of the Neber rearrangement during the construction of complex molecules.23, 26 For 1a, we found that the best yield was obtained with DABCO in dichloromethane (Table S1, supporting information), although the reaction also proceeded smoothly with other bases including triethylamine and DBU. Therefore, mechanistic study was conducted employing DABCO in CH2Cl2. When an optically active sample of 1a (82: 18 e.r.) was treated with DABCO, the racemic form of 4a was obtained (Figure 2, a). This excludes the possibility of a concerted mechanism for the Neber rearrangement.25b, 27 The reaction showed first-order kinetics for DABCO over the range from 1 to 10 equivalents (Supporting information, Figure S1). The hydrogen/deuterium kinetic isotope effect (KIE) was next studied, and a KIE of kH/kD = 5.2 was observed at -4 ºC (Figure

2,

b.

Also

see the details of kinetic measurements in Supporting

Information). These results suggest that C-attack probably occurred in the enol form (5a). The deprotonation should be the rate-determining step (RDS), and the enolate intermediate can react either intramolecularly to afford 4a directly or generate the enol after proton transfer. This mechanism involved the formation of the carbanion intermediate as the rate-limiting step, as in the E1cB mechanism. 28 This is also in

7



Page 8 of 53

agreement with the results of 13C KIE measurement at natural abundance. Overall, it appears that bond cleavage at the C atom occurred in the RDS (KIE = 1.015, Figure 2c and Figure S2).29 a

c O

N

C* H

OMs DABCO (2.0 eq.)

O

N

1 (meta-, ref.)

1a 82 : 18 e.r.

N

C H

C

CH2Cl2 20 ºC

O

4a racemate

OMs

1.003 1.015

1.004

1b

b O

N

OMs DABCO (10.0 eq.)

C

O

L

kH / kD = 5.2 (-4 ºC)

C

CH2Cl2 -4 ºC

1a

N

4a

Figure 2. Mechanistic studies of Neber-type reaction of 1a.

When the reaction was monitored by means of 1H NMR, the enol/enolate (5a/5a–, Scheme 4) intermediate was too unstable to be observed. The addition of 0.5 equivalent of hydrochloride salt of DABCO ([DABCO-H+]), in the presence of 2 equivalents of DABCO, had the effect of slowing the reaction by about 30% at –4 ºC.30 This result is as would be expected if the enol/enolate intermediate (5a/5a–) is less stable than the starting ketone (1a) and if k-1 is comparable to k2, although the cyclization step is not rate-determining (Eq. 1). This situation is supported by the following computational studies.

O

N

OMs

Ph

k1 k -1

H 1a

O

HO

Ph 5a –

𝑟𝑎𝑡𝑒 =

N OMs

&' &( [*+,-.][𝟏𝐚] &2' [*+,-.345 ]6&( [*+,-.]

k2

Ph 5a

N OMs

(Eq. 1)

Scheme 4. Enol intermediate formed from ketone.

8


4a

Page 9 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


We also conducted DFT calculations on the putative transformation at the M062X/def2-TZVPP/CPCM//M06-2X/6-31+G(d,p)/CPCM level, which has been reported to be compatible with an E1cB-type reaction.31 This calculation method was also used in the computational studies of other reactions of 1a for the sake of consistency and comparability. In these computational studies, NH3 was used as a base instead of DABCO for simplicity. In the first step of the transformation, the 3sulfonyloxyimino-1-ketone 1a is deprotonated by NH3 to form the intermediate NC2 in a slightly endergonic reaction (Figure 3, a, ΔG0 = +2.9 kcal/mol). This step suggests a barrier of 19.6 kcal/mol for the transition state, which is assigned as the rate-determining step (NC1 to NC2). This value was confirmed experimentally: the linear Eyring plot suggests an activation barrier of ΔGexp‡ = 19.7 kcal/mol (Figure S1, Supporting information). The proton transfer from ammonia to the carbonyl oxygen of NC1 was observed, which occurred simultaneously with the deprotonation (i.e., direct formation of NC2 from NC1); and for the reaction with DABCO, it is more likely that the enol intermediate is formed with a stepwise mechanism (Scheme S4). The intermediate NC2 shows a strong enol character (Mayer bond order32 of C(11)C(22) = 1.64; Figure 3b), with negative charge located predominantly on the oxygen atom (ChelpG and NPA, Table S2). The deprotonation occurs in the trans-form of 1a, and thus the hydroxyimino group (C=NOMs) is located anti-periplanar to the oxygen atom in the resultant enol ((E)-enol, NC2). Further cyclization by O-attack to afford isoxazole 2a is not favored (NC2 to NO3) by the s-trans geometry, and instead cyclization occurred in a three-membered transition state (NCT2) to give the 2Hazirine (NC2 to NC3, ΔG0 = -14.2 kcal/mol, ΔG‡ = 16.5 kcal/mol).33 The C-attack on nitrogen atom occurred in a concerted manner with cleavage of the N-O bond in the

9



Page 10 of 53

hydroxylimine group, resembling the SN2 reaction mechanism (NCT2, Figure 3c). Therefore, the Neber rearrangement reaction of 1a can be considered as the result of C-attack (C11) on the intramolecular hydroxyimino N atom after formation of the enol intermediate, reflecting the C-atom reactivity of enols. Under the same reaction conditions, a small amount of isoxazole product was also obtained (Scheme 3). We also studied this transformation computationally (Figure 3a, NO1 to NO3), and found that the reaction is most likely to occur through a (Z)-enol intermediate (NO2).34 The formation of NO2 is both kinetically and thermodynamically disfavored, in accordance with the experimental reaction selectivity. a NH 3 H

O

ΔG ‡

= 19.6 kcal/mol ΔG 0 = +2.9 kcal/mol

Deprotonation N OMs

Ph

ΔG ‡

= 16.5 kcal/mol ΔG 0 = –14.2 kcal/mol

O Ph

N OMs NC2

N Ph

OMs

NC3

X

NH 3

NH 3 H

Cyclization NCT2

O

(E)–Enol

NC1

0 kcal/mol

O

NH 3

H

NH 3

H

‡ OMs ΔG = 24.3 kcal/mol N ΔG 0 = + 6.7 kcal/mol

Deprotonation

Ph

H

NH 4

OMs ΔG ‡ = 17.8 kcal/mol N ΔG 0 = – 39.6 kcal/mol

O

Cyclization

Ph (Z)–Enol

NO1

O N

OMs

Ph NO3

NO2

-2.1 kcal/mol b

Mayer Bond Order O(21)

C(11)

C(22)

N(2)

C(1)

O(21)–C(22)

1.17

C(22)–C(11)

1.64

C(11)–C(1)

1.02

C(1)–N(2)

1.69

c

1.984 Å 1.951 Å

NCT2

NC2

Figure 3. Computational results for the reaction of 1a with NH3. a. Energy profile for C-attack reaction (NC1 to NC3, major) and O-attack reaction (NO1 to NO3, minor); b. Calculated geometry for the (E)-enol intermediate NC2; Calculated geometry for NCT2.

10


Page 11 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Reaction of 1a with tert-BuOK: C-attack and O-attack reactions of enolates (reaction 2) (Scheme 3). The reaction of 1a with tert-BuOK affords a mixture of isoxazole 2a and oxazole 3a in a ratio that is close to 1: 1. As regards the formation of oxazole 3a, which is attributable to C-atom reactivity, a previous mechanistic study has indicated that 4a can be transformed into 3a with tert-BuOK by a deprotonationinitiated mechanism (Scheme S2).24b

Table 1. The effect of counterions on the reaction selectivity of 1a under basic conditions.a O-attack O Ph

OMs Base N (4.0 equiv.) C H 1a

Solvent 20 ºC

O Ph

O

C

Ph

2a

C

N

3a

Entry

Base

Solvent

1

tert-BuOK

THF

2a 42%

3a 44%

49

:

51

2

tert-BuONa

THF

2a 35%

3a 41%

47

:

53

3

tert-BuOK 18-crown-6

THF

2a 38%

3a 35%

52

:

48

4

tert-BuOK NEt 3 (10 equiv.)

THF

2a 38%

3a 41%

48

:

52

2a 41%

3a 43%

49

:

51

tert-BuOK 5 NEt (10 equiv.) Toluene 3 a

C-attack

N

Product

O-attack : C-attack

All yields were determined based on 1H NMR signals of the crude products,

with 1,2-dichloroethane as an internal standard.

Generally, enolate can react at both the C atom and the O atom. The reaction selectivity has been extensively studied, and it is well established that it is influenced

11



Page 12 of 53

by the counterion.7 To study whether K+ is important for the reaction selectivity, we conducted a series of reactions of 1a under basic conditions (Table 1). The reaction of 1a with tert-BuOK is extremely fast and could not be monitored with NMR even at – 20 ºC. Changing the counterion from K+ to Na+ caused little difference in the reaction selectivity (Entry 2). When the reaction was conducted in the presence of 18-crown6,35 the reaction still gave both 2a and 3a in a similar ratio (Entry 3). The presence of NEt3 and toluene enhanced the E/Z selectivity of Li+-enolate by affecting the aggregation state, which changes the anti/syn preference in aldol condensation. 36 As O-attack can only occur from the Z-enol (Figure 3b), one might expect that the addition of NEt3 would affect the O-attack(2a)/C-attack(3a) selectivity. However, NEt3/toluene had little influence on the reaction selectivity (entries 4 and 5). Therefore, the interaction of enolates with metal ions is probably not directly related to the difference in reaction selectivity of 1a with DABCO and tert-BuOK. Me O O

H

Deprotonation N OMs

Ph

K O Ph

ΔG ‡ = 9.0 kcal/mol ΔG 0 = –27.7 kcal/mol

H

N OMs

BC1

(E)–Enolate BC2

O

K

OMe

0 kcal/mol

K

Ph

K

ΔG ‡ = 1.3 kcal/mol ΔG 0 = –17.7 kcal/mol

Cyclization

O N Ph

H OMe OMe K ‡ OMs ΔG = 2.2 kcal/mol OMs ΔG ‡ = 12.1 kcal/mol N O N ΔG 0 = –16.8 kcal/mol ΔG 0 = – 47.7 kcal/mol H Ph Deprotonation Cyclization Ph BO1

-1.6 kcal/mol

(Z)–Enol

OMs

BC3

K O N

OMs

BO3

BO2

Scheme 5. Energy profile of the reaction of 1a with MeOK, leading to isoxazole BO3 and 2H-azirine BC3.

Further scrutiny was conducted using computational methods, with MeOK as a base.37 It should be noted that the E/Z isomerization of oximes (C=N–OMs) would be possible under the reaction conditions due to the resonance in the enolate

12


Page 13 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


intermediates (BC2 and BO2); but this isomerization was not further studied in the current study, considering the fast transformation of 1a with tert-BuOK. The energy profiles for the transformation of 1a into 4a (BC1 to BC3) and 2a (BO1 to BO3) are shown in Scheme 5. In both reaction pathways, the deprotonation step leads to the formation of an enolate intermediate (BC2 or BO2) prior to the cyclization step. The (E)-enolate (BC2) gives the 2H-azirine product (BC2 to BC3), which can be further transformed into oxazole, while the (Z)-enolate undergoes cyclization reaction to give the isoxazole product (BO2 to BO3). As in the case of the reaction with DABCO, the configurations of the enolates (Z and E) are directly related to the reaction selectivity, and the reaction of 1a with tert-BuOK reflects both C-atom reactivity and O-atom reactivity of the enolates. For both reactions, the deprotonation to generate the enolates BC238 and BO239 is highly exothermic (-16.8 kcal/mol and -17.7 kcal/mol), and the reactions are more favorable than those with DABCO. These low-lying intermediates may block the backward trajectory, since the barrier is greater than 19 kcal/mol (back to BC1 and BO1, respectively) compared to the low barriers needed for the extrusion of products. The C-attack cyclization and formation of 2H-azirine (BC3) follows a similar mechanism to the reaction with NH3 (Figure 3), although the energy profile is very different. The O-attack cyclization also occurs in a concerted manner (BO2 to BO3, ΔG‡ = 12.1 kcal/mol), and the construction of the isoxazole ring is thermodynamically favorable (ΔG0 = –47.7 kcal/mol). Nucleus-independent chemical shift (NICS)40 computations for the forming isoxazole ring on the corresponding transition state (BOT2, form BO2 to BO3, vide infra) suggest that a polar mechanism is favored over an electrocyclic pathway.41

13



The difference between the activation barriers leading to irreversible formation of BC2 (E-enolate) and BO2 (Z-enolate) is smaller than 1 kcal/mol. This energy profile can account for the similar yields of 2a and 3a obtained in the reaction of 1a with tertBuOK. Since both of these energy barriers are smaller than 3 kcal/mol, the selectivity is likely to be controlled by the diffusion process, which reduces the O-attack and Cattack selectivity.42

Acid-catalyzed

Reactions

of


phenylbutan-1-one 1a. Reaction of 1a with AcOH: O-attack reaction of neutral ketone (reaction 3) (Scheme 3). The reaction of 1a in a solution of MeCN/AcOH shows a preference for isoxazole formation (2a, 91%), which is a result of O-atom reactivity (Table S3). The intermediacy of 2H-azirine 4a in the formation of 2a was excluded: 4a in AcOH did not produce 2a, and 4a was recovered after aqueous work-up. Considering the potential for ketone-enol tautomerization under acidic conditions, the cyclization reaction (O–N bond formation) could occur in either ketone or enol form. Next, it is of interest to know whether the cyclization reaction occurs concertedly with the cleavage of the oxime N–OMs bond (Scheme S1, SN2) or via an iminyl cationic intermediate (SN1).43

14


Page 14 of 53

Page 15 of 53

O

a

N

OMs

O

N

H ‡ =21.1 kcal•mol -1 S ‡ = –10.6 cal•mol-1•K -1

AcOH/MeCN 1a

2a

b.

Hamme+ Rela-onship 1.5

p-OMe (1c)

1

0.5

p-Me (1d)

H (1a)

lnk/k0

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


0 -0.6

-0.4

-0.2

0

0.2

-0.5

0.4

0.6

p-Cl (1e)

ρ = -3.1 -1

y = -3.1056x + 0.1353 R² = 0.96488

p-COOMe (1f) -1.5

-2

c.

MeO

O

N

OMs

MeO

ko-OMe AcOH/MeCN 56 ºC

1g O

σ

N

O

N

2g

ko-OMe k p-OMe

OMs

O

= 2.20

N

k p-OMe MeO

1c

AcOH/MeCN 56 ºC MeO

2c

Figure 4. Linear energy relationship for the reaction in AcOH/MeCN. a. Activation entropy and activation enthalpy of the reaction of 1a in AcOH/MeCN; b. Hammett relationship (at 56 ºC) for 1a and para-substituted derivatives (1c-1f). c. Reaction rate of o-OMe substituted 1g and p-OMe substituted 1c.

15



Page 16 of 53

The experimental results indicate that the energy barrier for the reaction of 1a in AcOH/MeCN solution is ΔGexp‡ = 24.3 kcal/mol at 298 K (Figure 4a). The Hammett relationship (Figure 4b) for substituents at the para-position of the benzene ring shows a negative value of the Hammett constant (ρ= -3.1), which can be interpreted as reflecting the accumulation of positive charge during the RDS. a O

N

OMs

O

AcOD/MeCN = 1: 1 0.1 M

Ph

O

NOMs

c

OMs

L 39% 1a (recovery)

52% 2a

1a

b

N

Ph

Ph

60 ºC, 30 min

H

O

N

O

N

>99% H

OMs 1.007

1.002

L kH /kD = 1.12

1.004 1.000(ref)

Figure 5. Isotope-labeling experiments for reaction of 1a in AcOH/MeCN

A series of isotope-labeling experiments offers conclusive evidence for the involvement of the ketone form (Scheme S3a and c), but not the enol form (Scheme S3b) of 1a during the cyclization step. The results of isotope-labeling experiments are summarized in Figure 5. When 1a was treated with AcOD at 60 ºC for 30 min, hydrogen-deuterium exchange was not observed in the recovered 1a (Figure 5a). Preequilibration between ketone and enol is therefore not likely to occur, and the reaction appears to proceed either in the ketone form 1a, or in the enol form 1a with enolization as the RDS. Direct measurement of hydrogen/deuterium KIE gave a KIE value of 1.12 at 56 ºC (Figure 5b). These results exclude the possibility of cyclization reaction in the enol form or a concerted cyclization mechanism similar to the Paal-

16


Page 17 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Knorr furan synthesis reaction (Scheme S3d). Therefore, the cyclization reaction can only occur at the ketone form to generate a cationic intermediate, indicating O-atom reactivity of ketones. The nucleophilic substitution reaction on the hydroxyimino nitrogen may occur via either a concerted mechanism (SN2-like, Scheme S3a) or a stepwise mechanism (SN1-like, Scheme S3c). The result of 13C KIE measurement under natural abundance (at 50 ºC) is shown in Figure 5c. Both the carbonyl carbon and iminyl carbon of 1a exhibit secondary 13C KIEs (1.004 and 1.007, respectively; Figure 5c and Figure S2). These KIEs suggest that the cyclization step involving both the C=O and C=NOMs groups is probably rate-limiting. Common-ion depression of the reaction rate was not observed at 56 ºC, since the reaction rate was almost unchanged upon reacting 1b (NOTs) in AcOH/MeCN in the presence of 5 equivalents of TsONa. Furthermore, orthoOMe substitution (1g) increased the reaction rate, which is indicative of a SN2 reaction (Figure 4c).44 These results are all consistent with a SN2-like mechanism, in which formation of the new O–N bond occurs concertedly with cleavage of the hydroxyimino N–OMs bond. AcOH O

OMs ΔG ‡ = 25.1 kcal/mol N ΔG 0 = – 3.3 kcal/mol Cyclization SOT1

Ph H SO1

AcOH O

OMs N

Ph H Oxonium intermediate SO2

MsOH ΔG ‡ = 6.2 kcal/mol ΔG 0 = – 17.1 kcal/mol Deprotonation SOT2

O N AcOH Ph SO3

1.454 Å

2.036 Å 2.072 Å

SOT1

SO2

1.307 Å SOT2

Figure 6. Energy profiles and calculated geometries for the reaction of 1a with AcOH. SOT1: transition state for the cyclization step; SOT2: transition state for the deprotonation step.

17



Page 18 of 53

The results of computational study also support a concerted, SN2-like reaction mechanism from the ketone form of 1a. The free energy profile for the reaction of 1a with AcOH is shown in Figure 6. The reaction is initiated by substitution of the carbonyl oxygen atom on the oximo nitrogen, forming the oxonium intermediate (SO1 to SO2). The transition state for this substitution step (SOT1) shows a strong SN2 character, and possesses an activation energy barrier of 25.1 kcal/mol, in reasonable accordance with the experimental value of 24.3 kcal/mol; this is the RDS of the putative transformation. The following deprotonation reaction (SO2 to SO3) is relatively facile (ΔG‡ =6.2 kcal/mol) with the assistance of acetic acid (SOT2). The developing aromaticity in the transition state accounts for the low activation barrier of deprotonation, in both the isoxazole formation and oxazole formation reactions (vide infra).45 This is in line with the exothermic character of the reaction (ΔG0 =-17.1 kcal/mol), which generates a thermodynamically stable isoxazole product. Reaction of 1a with TFA: O-attack and C-attack reactions of neutral ketone (reaction 4) (Scheme 3). 1a and 1b react in TFA solution to give a mixture of isoxazole 2a and oxazole 3a.46 The intermediacy of 2H-azirine 4a in the formation of 2a and 3a was excluded: 4a in TFA did not produce 3a, and 4a was recovered after aqueous work-up (vide infra). In this context, the formation of 3a under acidic conditions involves a different reaction mechanism from the case of tert-BuOKcatalyzed formation of 4a. We are interested in the origin of the different reaction selectivity

compared

with

the

reaction

using

AcOH.

Also,

ketone-enol

tautomerization of 1a could occur in strongly acidic TFA, and so the reaction might

18


Page 19 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


proceed through the enol form of 1a, as was recognized in the reaction with tertBuOK. Reaction monitoring with NMR at 18 ºC indicated that the rate constants (kobs) for the formation of 2a and 3a from 1b were much smaller than the diffusion limit (Scheme 6a). While the selectivity of the reaction of 1a with tert-BuOK can be explained in terms of the reactivity-selectivity principle and is probably diffusioncontrolled, this cannot be the case for the reaction using TFA. Under basic conditions, the counterion had only a limited influence on reaction selectivity (Table 1). However, the addition of 2.0 equivalents of AcOK to the reaction solution of 1b with TFA changed the reaction selectivity to preferentially afford isoxazole 2a, which is most likely to be explained by the interaction of O and N atoms with K+ (Scheme 7).39 It is therefore inferred that the ketone form selectivity is activation-controlled.

a O

N

OTs O N

Ph

CF 3COOH

H 1b O

N

OTs

O

Ph 2a kH = 8.47x10-4

3a kH = 5.17x10-4

O N

Ph

CF 3COOH

D 1b–D

N

Ph

O

Ph

Ph

N

2a kD = 7.91x10-4

3a kD = 4.35x10-4

kH /kD=1.07

kH /kD=1.19

b. O

N

OAc CF 3COOD (TFA-d)

Ph H 1a–Ac O

N

O

D 1a–Ac–D

CF 3COOH

OAc

Ph D 1a–Ac–D

OAc

Ph

N

O

N

Ph H 1a–Ac

kH = 5.21x10-4

OAc kD = 1.07x10 -4

kH /kD=4.87

Scheme 6. H-D KIEs for 1b and 1b-Ac in TFA. Rate constants are shown as measured observed rate constants (kobs (s-1)) at 18 ºC.

19



O

N

OTs

1b

O

O N TFA

Ph

Page 20 of 53

Ph

N

Ph

Additive

2a

Additive

Isolated Yield

none

3a

51%

32%

AcOH (2.0 equiv.)

50%

35%

AcOK (2.0 equiv.)

88%

(7.5%)

Scheme 7. Effect of AcOK on reaction selectivity. Yields in parentheses were calculated from 1H NMR signals of the crude product, using 1,2-dichloroethane as internal standard.

To study the enolization process of the 3-sulfonyloxyimino-1-ketone derivatives in TFA solution, we synthesized 1a–Ac, which undergoes hydrogen-deuterium exchange in TFA-d solution, but does not afford 2a or 3a (Scheme 6, b). The rate constant for enolization of 1a–Ac at 18 ºC (kobs= 5.21 x 10-4 s-1) is smaller than that of the reaction of 1a with TFA (13.64 x 10-4 s-1). We also observed a primary deuterium KIE of kH/kD = 4.87 for the hydrogen-deuterium exchange at the 2-position of 1a–Ac, and the enolization of 1a–Ac–D was much slower (1.07 x 10-4 s-1). 13, 47 In contrast, the rate constant for reaction of 1b–D with TFA was similar to that for 1b. A secondary deuterium KIE was measured, for both the reaction leading to 2a (KIE = 1.07) and that leading to 3a (KIE = 1.19)(Scheme 6a). The deprotonation at the 2-position is therefore not involved in the rate-limiting step; pre-equilibrium of ketone-enol tautomerization is also unlikely, because the reaction rates for 1b–D to afford 2a and 3a are much faster than the rate of deuterium-hydrogen exchange of 1aAc-D.

20


Page 21 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


The reaction of 2H-azirine 4a in TFA was also carried out. Compound 4a was obtained in the reaction of 1a with DABCO, reflecting the C-atom reactivity of enol (Scheme 3, reaction 1). Treating 4a in TFA for 1 hr at 20 ºC resulted in recovery of the azirine in 77% yield, accompanied with a small amount of decomposition. Considering the different behaviors of 4a and 1a in TFA, it seems plausible that the enol form of 1a was not involved in the reaction of 1a in TFA. It is interesting that Cattack is preferred in the ketone form, though enolization is also viable in TFA. The mechanism of oxime nitrogen insertion into the C–C σ bond at the α-position to the carbonyl moiety is essentially the same as that of Beckmann rearrangement. Intramolecular cyclization of the resultant nitrilium gives the oxazole product 3a (Scheme 8). 48 O Ph

N

OMs

TFA Beckmann rearrangement Ketone form

1a

O N

Ph

•

7a nitrilium intermediate

Ph

O • N

H

3a 8a

Scheme 8. Reaction mechanism of 1a to 3a in TFA.

To understand the difference of reaction selectivity, the energy profiles for the reactions of 1a in TFA solution were calculated (Figure 7). The reaction from 1a to 2a in TFA (SM to AO3), resulting from O-atom reactivity, shows similar behavior to the same transformation in AcOH, except that the substitution step is more facile and exothermic (ΔG‡ = 22.6 kcal/mol, ΔG0 = -7.0 kcal/mol), probably due to the higher acidity of TFA, which activates the oxime functionality.15

21



ΔG (kcal/mol)

2.211 Å

2.027

ACT1 AOT1 23.0 22.6

1.664 Å 2.067

AOT2

ACT2

SM O

Page 22 of 53

-2.1 NOMs

Ph

AOT2

-7.0

+ TFA

1a to 2a (O atom reactivity)

AO2

1a

1a to 3a (C atom reactivity)

-20.3 AO3

-24.9

-29.5

ACT2 -33.5

-34.2 AC2

O atom reactivity: O Ph

F 3COOH

NOMs AOT1

O

OMs N

+ TFA

Ph

Ph

Ph 1a

AO3

H AO2

O

1a

NOMs ACT1 + TFA

-54.6

AC3

C atom reactivity:

CF 3COOH O N MsOH

ACT3

Ph

AC4

F 3COOH O N

•

AC2

OMs Ph

O • N

H F 3COOH

OMs

AC3

O Ph

Figure 7. Energy profiles for the reaction of 1a in TFA. AOT1: Transition state for the O-attack reaction. ACT1: Transition state for the C-attack reaction.

Computational study of the reaction from 1a to 3a was conducted by using 1 molecule of TFA (Figure 7, SM to AC4). It should be noted that a detailed computational study of the Beckmann rearrangement process suggested that multiple acid molecules are required to estimate the influence of solvent,48 and thus the implicit solvent model used in the current computational study would have influenced the energy profile. Fortunately, however, we found that using a single TFA molecule is sufficient to provide valuable insight into the reaction mechanism. A three-step reaction mechanism furnished the oxazole product (SM to AC4) (Figure 7). The first step, forming a nitrilium intermediate (AC2), proceeds via the same reaction mechanism

as

the

Beckmann

rearrangement

reaction,

and

is

highly

thermodynamically favored (ΔG0 = -34.2 kcal/mol). This step is recognized as the RDS of the putative transformation, and the energy barrier (ΔG‡ = 23.0 kcal/mol) is

22


N

MsOH CF 3COOH AC4

Page 23 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


close to that for the reaction of 1a to 2a (ΔG‡ = 22.6 kcal/mol). This is in line with the observed reaction selectivity, i.e., both 2a and 3a are obtained in the reaction. Then, cyclization (AC2 to AC3) and deprotonation (AC3 to AC4) occur stepwise with much lower energy barriers (9.3 kcal/mol and 4.0 kcal/mol, respectively). The transformation is highly thermodynamically favored (ΔG0 = -54.6 kcal/mol, from SM to AC4), generating the oxazole 3a irreversibly. Thus, the different selectivities of 1a in AcOH (only 2a) and in TFA (both 2a and 3a) were well interpreted by computational studies. 49

Similarity of the transition-state geometries of ketone and enolate reactions. The O-attack and C-attack reactivities lead to formation of 3-membered (4a) and 5membered (2a) rings, respectively (Scheme 3). The selectivity in cyclization reactions generating rings of various sizes has been extensively studied and is summarized by Baldwin's rule.50 While the relatively common 5-endo-dig cyclization trajectory occurs during the formation of oxazoles in TFA (7a to 8a, Scheme 8),51a other trajectories, including SN2 type substitution on the hydroxyimino nitrogen atom, have not been extensively discussed in terms of Baldwin's classification. Table 2. Examination of possible involvement of radical intermediate in the reaction.

23



O Ph

N

OTs Conditions

C

20 ºC

O Ph

N C R

R H 1

R=

1i R=

O

O

Ph

C R

2

N

Ph

N C R

3

4

Isolation Yield

Condition

1h

Page 24 of 53

2

3

4

DABCO/CH 2Cl2 AcOH/MeCN TFA

– 83% 46%

– – 43%

89% – –

DABCO/CH 2Cl2 tert-BuOK/THF AcOH/MeCN TFA

– 36% 91% 42%

– 43% – 39%

88% – – –

SN2 type reactions on an sp2 electrophilic center are not rare,52 and both radical and polar mechanisms are possible for substitution at a sulfonyloxyimino nitrogen atom.53 Our experimental observations (Table 2)54 and computational studies suggest that a polar mechanism is most likely for our reactions, without involvement of radical intermediates.55 According to Baldwin's classification, the ring-closure reactions of Cattack (basic conditions) and O-attack (acidic and basic conditions) should be categorized as 3-trig-exo and 5-trig-exo trajectories, though the breaking bonds are hydroxyimino O-N σ-bonds, not the common π-bonds (Figure 8). b.

a. X

X Y Y

3-trig-exo

5-trig-exo

c. N

N OR

x

OR

3-trig-exo

5-trig-exo E+

Figure 8. a. Common trajectories of 3-trig-exo and 5-trig-exo cyclization; b. cyclization on oxime N atom; c. electrophile-promoted cyclization (Also see ref. 51b).

24


Page 25 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


a

OMs Ph HO

N C

149.8º

1.984 Å

Ph HO

OMs

OMs N

Ph

1.951 Å

O

C

48.4º

3-trig (with DABCO) C-attack, enol OMs Ph KO

N C

144.9º

2.087 Å

Ph KO

N

160.5º

N

O

O

2.103 Å 162.1º

N

OMs

O

2.036 Å

O

N

2.072 Å

H 5-trig (with AcOH) O-attack, ketone 160.9

OMs

OMs

Ph H

N

2.211

96.2º

O

N

OMs

2.034 Å

O

96.1º 1.908 Å

Ph

OMs

Ph

K

93.2º

Ph

N

1.856 Å

3-trig (with tert-BuOK) C-attack, enolate K

Ph

OMs N

C 55.5 O C H H 1.664 Å Beckmann Rearrangement (TFA) C-attack, ketone

OMs

C

43.4º

2.019 Å

155.6º

Ph

N

OMs 2.064 Å

Ph H

5-trig (with tert-BuOK) O-attack, enolate

H 5-trig (with TFA) O-attack, ketone

b OMs

OMs Ph KO

N

Ph O

C

3-trig (with tert-BuOK) C-attack, enolate K O

N

N

OMs

C H Beckmann Rearrangement (TFA) C-attack, ketone O

N

OMs

Ph

Ph

H 5-trig (with TFA) O-attack, ketone

5-trig (with tert-BuOK) O-attack, enolate

Figure 9. Geometries of TS (a) and the orbital interactions (b, isovalue = 0.08) in the cyclization steps.

The reaction trajectories are summarized in Figure 9a. During the cyclization reactions, the C=N bond of the electrophilic hydroxyimino group remains inside the forming rings. It has been proposed that the cyclization reactions from an acute attack angle with a π-bond inside the ring system are unfavorable, due to the symmetry mismatch between the n orbital of nucleophiles and the π* orbital of electrophiles51 (Figure 8) and the difficulty in meeting the stereoelectronic requirement (Bürgi–

25



Dunitz attack angle).56 However, this kind of cyclization trajectory becomes feasible for an electrophile-promoted cyclization, which changes the alkyne LUMO symmetry via coordination (Figure 8c),51b and the situation is similar for the cyclization reactions of 1a. The C-attack reaction from both the enolate form (cyclization reaction) and ketone form (Beckmann rearrangement) involves an acute ∠C--N=C angle (around 55º, Figure 9). For the enolate cyclization, the π orbitals of C=N bond and C=C bond are orthogonal (Figure 8).57 This spatial orthogonality can minimize the symmetry mismatch, and the πC=C-π*C=N interaction, which makes the endo cyclization unfavorable, is negligible. The σ*N–OMs orbital is more diffused than the nN orbital (Figure 8), and the acute attack angle also ensures the best overlap of πC=C - σ*N–OMs (enolate) and σC-C - σ*N–OMs (ketone, Figure 9b). For the O-attack 5-trig reactions from the ketone form and enolate form, there is little difference in the geometry of the transition states. In both cases, the attack angles ∠O--N=C are around 95º and there is a large deviation from Bürgi–Dunitz attack. In the transition state, the C–C=O group of ketone (or C=C–O– of enolate) and C=N functionalities stay in the same plane, in order to avoid the symmetry mismatch between nO and π*C=N orbitals (Figure 8). The values of ∠O--N–O are both around 160º, which ensures efficient overlap of nO and σ*N-OMs orbitals and little repulsion between the lone pairs of attacking O atoms and imino N atoms (Figure 8).

26


Page 26 of 53

Page 27 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


a.

NICS(0)zz value of forming ring (O-a8ack, enolate) NICS(0) ZZ / ppm

NICS(0)zz value of forming ring (O-a8ack, ketone) NICS(0) ZZ / ppm

15

15

SOT1

BOT2

10

12 5

0 -8

-4

9 0

4

Reaction Coordinate / 0.1 Bohr b.

K O

N

Ca

Ph

Cb

Cc

OMs

8

-8

amu –0.5

LP(2) O

σ∗Ca-Cb = 9.45

LP(2) O σCb-Cc

π∗Ca-Cb = 3.89 σ∗N-OMs = 11.0

-4

0

4

Reaction Coordinate / 0.1 Bohr

O

N

OMs

Ph H Me

8

amu –0.5

LP(2) O σCb-Cc

σ∗Ca-Cb = 13.9 σ∗N-OMs = 16.2

σCb-Me σCb-Me

π*Ca=O = 5.06 π*Cc=N = 5.26

Figure 10. a. NICS(0)ZZ tensor along the intrinsic reaction coordinate (IRC) at the center of the forming five-membered ring; b. Interaction energy in the transition state of O-attack. LP(2): in-plane lone pair of oxygen atom that participates in the cyclization reaction.

Difference between O-attack reactions from ketone and enolate: On the other hand, the aromaticity properties are quite different between the O-attack reactions from the enolate form and ketone form. We evaluated the NICS(0)ZZ tensor along the intrinsic reaction coordinate (IRC) at the center of the forming five-membered ring; the NICSZZ value represents the contribution perpendicular to the delocalized ring of electrons. For the enolate-form O-attack cyclization, the NICSZZ value steadily decreases along the IRC (Figure 10a, left), and this is consistent with a polar cyclization mechanism.41 The NICS(0)ZZ value of ketone-form cyclization is positive because of the participation of 4π electrons (C=N and C=O), but a minimum value of NICS(0)ZZ = 10.9 ppm appears at the transition state (Figure 10a, right).41c Alabugin et al.41b rationalized a similar trend of aromaticity during 5-endo-trig cyclization as a

27



result of orbital interaction between the n orbital of O atom (lone pair) and adjacent C–C σ* orbital. This was confirmed by natural bond orbital (NBO) analysis58 of the transition state (Figure 10, b), and the O-attack of the ketone form features a stronger interaction (13.9 kcal/mol) than the enolate form (9.45 kcal/mol). A similar trend of in-plane σCb–Cc-σ*N–OMs interaction was also observed. These interactions are significant in the transition state, but are gradually diminished after the transition state of ketone form O-attack reactions, and are responsible for the stabilizing effect in the transition state of ketone form reactions.

Conclusion Experimental and computational studies demonstrated that the ketone, enol and enolate forms of 3-sulfonyloxyimino-2-methyl-1-phenyl-1-butanone 1a can afford different intramolecular cyclization products (2a, 3a, 4a), depending on the conditions. The results of the reaction under basic conditions suggest intermediacy of neutral enol (DABCO) and anionic enolate (tert-BuOK), while the results under acidic conditions (AcOH and TFA) indicate involvement of neutral ketone. The products (2a and 3a) generated from the ketone form and from the enolate form are the same, but the reaction mechanisms are apparently different. Our study on the mechanism of Neber rearrangement of 1a suggested that deprotonation is the ratedetermining step, and 4a arises from the enol form via C-attack. The formation of Cattack (3a) and O-attack (2a) products from enolate in the reaction of 1a with tertBuOK can be explained by the reactivity-selectivity principle. The reactions of 1a under acidic conditions provide unprecedented examples of ambident-like reactivity of ketones. The reactions in AcOH and TFA are activationcontrolled, and the selectivity can be rationalized in terms of the Marcus theory. The

28


Page 28 of 53

Page 29 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


C atom of ketone can react as a nucleophilic site without tautomerization to the corresponding enol, even though the enolization is a possible alternative in TFA. Reactions from the ketone form are similar to the corresponding enolate-form reactions in terms of transition-state geometry, but the aromaticity index of the Oattack reaction is different because of the stronger in-plane interactions from C-C σ bonds. While further aspects of the reactions, such as the role of aggregation of tertBuOK59 and the resulting enolates60, the possibility of an intimate ion pair mechanism,61 and the participation of multiple acid molecules48 remain to be investigated, our results suggest generally preferred trajectories for the 5-trig and 3trig cyclization reactions with an oxime functionality. The synthetic potential of these trajectories is demonstrated by the selective syntheses of isoxazole (2) and azirine (4) from the same starting material (1).62 Experimental Sections General Methods All reactions were carried out under argon atmosphere in oven-dried glassware. All commercially available compounds and solvents were used as received unless otherwise mentioned. Open column chromatography was carried out using Kanto chemical silica gel (silica gel 60 N (100-210 μm)). Melting points were determined with a Yanaco micro melting point apparatus 1

without correction. H (400 MHz) and

13

C (100 MHz) NMR spectra were recorded on a Bruker

Avance 400. Chemical shifts were calibrated with tetramethylsilane and solvent as an internal standard or with the solvent peak, and are shown in ppm (d) values, and coupling constants are shown in Hertz (Hz). The following abbreviations are used: s = singlet, d = doublet, t = triplet, q = quartet, dd = double doublet, dt = double triplet, dq = double quartet, h = hextet, m = multiplet, brs = broad singlet, br = broad signal. Temperature in the NMR experiments was calibrated using signals of methanol according to the reported method.

S3

Electron spray

ionization time-of-flight mass spectra (ESI-TOF MS) were recorded on a Bruker micrOTOF-05 to give high-resolution mass spectra (HRMS). The combustion analyses were carried out in the microanalytical laboratory of this department.

29



Synthesis of compound 1

O

Page 30 of 53

24c

NOMs

1a 1a. To a solution of the oxime 3-(hydroxyimino)-2-methyl-1-phenylbutan-1-one (1.00 g, 5.23 mmol) in 15 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (0.59 g, 5.26 mmol) at 0 ºC followed by addition of a solution of MsCl (0.60 g, 5.23 mmol) in 10 mL of CH2Cl2. The whole was stirred at 0 ºC for 1 hr. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 4: 1) to afford 2-methyl-3-(((methylsulfonyl)oxy)imino)-1phenylbutan-1-one 1a (white solid, 1.29 g, 92%). 1

Mp.: 65-67 ºC. H NMR (CDCl3): δ 8.03 (2H, dd, J=0.8, 8.0 Hz), 7.67-7.63 (1H, m), 7.56-7.52 (2H, m), 4.58 (1H, q, J=6.8 Hz), 3.09 (3H, s), 2.03 (3H, s), 1.51 (3H, d, J=7.2 Hz).

13

C NMR

(CDCl3): δ 197.2, 167.6, 135.6, 133.7, 128.8, 128.6, 47.6, 36.4, 14.1, 13.6. HRMS (ESI-TOF, +

+

[M+Na] ): Calcd. for C12H15NNaO4S , 292.0614. Found: 292.0616. Anal. Calcd. for C12H15NO4S: C, 53.52; H, 5.61; N, 5.20. Found: C, 53.31; H, 5.65; N, 5.19.

O

NOTs

1b 1b. To a solution of the oxime 3-(hydroxyimino)-2-methyl-1-phenylbutan-1-one (2.30 g, 12.01 mmol) in 45 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (1.62 g, 14.42 mmol) at 0 ºC followed by addition of a solution of TsCl (2.75 g, 14.42 mmol) in 15 mL of CH2Cl2. The whole was stirred at 0 ºC for 1 hr. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified by recrystallization

from

hexane/

dichloromethane

to

afford

2-methyl-1-phenyl-3-

((tosyloxy)imino)butan-1-one 1b (white solid, 2.89 g, 70%). 1

Mp.: 90-91 ºC. H NMR (CDCl3): δ 7.85-7.81 (4H, m), 7.55-7.51 (1H, m), 7.35-7.26 (4H, m), 4.41 (1H, q, J=6.8 Hz), 2.45 (3H, s), 1.89 (3H, s), 1.37 (3H, d, J=7.2 Hz).

13

C NMR (CDCl3): δ

196.9, 166.9, 144.9, 135.5, 133.5, 132.8, 129.6, 128.8, 128.7, 128.7, 47.4, 21.7, 14.2, 13.0. +

+

HRMS (ESI-TOF, [M+Na] ): Calcd. for C18H19NNaO4S , 368.0927. Found: 368.0932. Anal. Calcd. for C18H19NO4S C, 62.59; H, 5.54; N, 4.06. Found: C, 62.27; H, 5.64; N, 4.10.

O

NOAc

1a-Ac

30


Page 31 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1a-Ac. To a solution of the oxime 3-(hydroxyimino)-2-methyl-1-phenylbutan-1-one (400.0 mg, 2.092 mmol) in 10 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (260.0 mg, 2.319 mmol) at 0 ºC followed by addition of a solution of AcCl (180.6 mg, 2.300 mmol) in 5 mL of CH2Cl2. The whole was stirred at 0 ºC for 1 hr. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 4: 1) to afford 1a-Ac (colorless oil, 405.6 mg, 83%). 1

H NMR (CDCl3): δ 8.04 (2H, dd, J=0.8, 8.0 Hz), 7.58-7.54 (1H, m), 7.47-7.44 (2H, m), 4.63

(1H, q, J=6.8 Hz), 2.15 (3H, s), 1.91 (3H, s), 1.44 (3H, d, J=7.2 Hz).

13

C NMR (CDCl3): δ

197.9, 168.5, 165.9, 135.7, 133.7, 128.9, 128.8, 47.7, 19.6, 14.6, 12.8. HRMS (ESI-TOF, +

+

[M+Na] ): Calcd. for C13H15NNaO3 , 256.0944. Found: 256.0942. Anal. Calcd. for C13H15NO3: C, 66.94; H, 6.48; N, 6.00. Found: C, 66.83; H, 6.63; N, 5.95.

O

NOMs

1c

MeO

1c. To a solution of the oxime 3-(hydroxyimino)-1-(4-methoxyphenyl)-2-methylbutan-1-one (450.0 mg, 2.034 mmol) in 7.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (DABCO, 240.0 mg, 2.140 mmol) at 0 ºC followed by addition of a solution of MsCl (240.0 mg, 2.095 mmol) in 5 mL of CH2Cl2. The whole was stirred at 0 ºC for 1 hr. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 4: 1) to afford 1c (Colorles oil, 523.7 mg, 86%). 1

H NMR (CDCl3): δ 8.03 (2H, d, J=8.8 Hz), 6.70 (2H, d, J=9.2 Hz), 4.55 (1H, q, J=7.2 Hz),

3.91 (3H, s), 3.13 (3H, s), 2.00 (3H, s), 1.48 (3H, d, J=7.2 Hz).

13

C NMR (CDCl3): δ 195.4, +

167.9, 164.1, 131.0, 128.5, 113.9, 55.6, 47.1, 36.5, 14.2, 13.4. HRMS (ESI-TOF, [M+Na] ): +

Calcd. for C13H17NNaO5S , 322.0720. Found: 322.0722.

O

Me

NOMs

1d

1d. To a solution of the oxime 3-(hydroxyimino)-2-methyl-1-(p-tolyl)butan-1-one (410.0 mg, 1.996 mmol) in 5.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (DABCO, 240.0 mg, 2.140 mmol) at 0 ºC followed by addition of a solution of MsCl (240.0 mg, 2.095 mmol) in 5 mL of CH2Cl2. The whole was stirred at 0 ºC for 1 hr. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 4: 1) to afford 1d (white solid, 513.3 mg, 91%).

31



Page 32 of 53

1

Mp.: 71-72 ºC. H NMR (CD2Cl2): δ 7.93 (2H, d, J=8.0 Hz), 7.34 (2H, d, J=8.0 Hz), 4.56 (1H, q, J=7.2 Hz), 3.11 (3H, s), 2.45 (3H, s), 2.01 (3H, s), 1.49 (3H, d, J=7.2 Hz).

13

C NMR

(CD2Cl2): δ 197.1, 168.1, 145.3, 133.5, 129.9, 129.1, 47.8, 36.9, 21.8, 14.6, 13.9. HRMS +

+

(ESI-TOF, [M+Na] ): Calcd. for C13H17NNaO4S , 306.0770. Found: 306.0779. Anal. Calcd. for C13H17NO4S: C, 55.11; H, 6.05; N, 4.94. Found: C, 54.76; H, 5.99; N, 5.01.

O

NOMs

1e

Cl

1e. To a solution of the oxime 1-(4-chlorophenyl)-3-(hydroxyimino)-2-methylbutan-1-one (572.3 mg, 2.536 mmol) in 10.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (DABCO, 310.0 mg, 2.764 mmol) at 0 ºC followed by addition of a solution of MsCl (310.0 mg, 2.706 mmol) in 5 mL of CH2Cl2. The whole was stirred at 0 ºC for 1 hr. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 4 : 1) to afford 1e (white solid, 694.4 mg, 90%). 1

Mp.: 84-85 ºC. H NMR (CDCl3): δ 7.94 (2H, d, J=8.4 Hz), 7.45 (2H, d, J=8.8 Hz), 4.48 (1H, q, J=7.2 Hz), 3.11 (3H, s), 1.97 (3H, s), 1.47 (3H, d, J=7.2 Hz).

13

C NMR (CDCl3): δ 195.9, +

167.5, 140.5, 133.7, 130.2, 129.3, 47.5, 36.6, 14.3, 13.5. HRMS (ESI-TOF, [M+Na] ): Calcd. +

for C12H14ClNNaO4S ,

326.0224, Found: 326.0227. Anal. Calcd. for

C12H14ClNO4S: C,

47.45; H, 4.65; N, 4.61. Found: C, 47.05; H, 4.59; N, 4.48.

O

MeOOC

N

OMs

1f

1f. To a solution of the oxime methyl 4-(3-(hydroxyimino)-2-methylbutanoyl)benzoate (277.2 mg, 1.113 mmol) in 5.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (DABCO, 140.0 mg, 1.248 mmol) at 0 ºC followed by addition of a solution of MsCl (140.0 mg, 1.222 mmol) in 5.0 mL of CH2Cl2. The whole was stirred at 0 ºC for 1 hr. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 3: 1) to afford 1f (white solid, 308.1 mg, 85%). 1

Mp.: 80-81 ºC. H NMR (CDCl3): δ 8.14 (2H, d, J=8.8 Hz), 8.05 (2H, d, J=8.8 Hz), 4.54 (1H, q, J=6.8 Hz), 3.96 (3H, s), 3.11 (3H, s), 2.00 (3H, s), 1.50 (3H, d, J=7.2 Hz).

13

C NMR (CDCl3): δ

196.7, 167.3, 165.9, 138.6, 134.5, 130.1, 128.6, 52.6, 47.9, 36.6, 14.3, 13.6. HRMS (ESI+

+

TOF, [M+Na] ): Calcd. for C14H17NNaO6S , 350.0669. Found: 350.0662. Anal. Calcd. for C14H17NO6S: C, 51.37; H, 5.23; N, 4.28. Found: C, 51.13; H, 5.06; N, 4.28.

32


Page 33 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


OMe O

N

OMs

1g 1g. To a solution of the oxime 3-(hydroxyimino)-1-(2-methoxyphenyl)-2-methylbutan-1-one (266.8 mg, 1.206 mmol) in 5.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (DABCO, 150.0 mg, 1.337 mmol) at 0 ºC followed by addition of a solution of MsCl (150.0 mg, 1.309 mmol) in 5.0 mL of CH2Cl2. The whole was stirred at 0 ºC for 1 hr. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 4: 1) to afford 1g (colorless oil, 342.1 mg, 95%). 1


(1H, q, J=6.8 Hz), 3.92 (3H, s), 2.97 (3H, s), 2.04 (3H, s), 1.41 (3H, d, J=7.2 Hz).

13

C NMR

(CDCl3): δ 199.5, 168.0, 158.0, 134.1, 130.7, 126.9, 121.0, 111.5, 55.6, 52.0, 36.4, 14.7, +

+

14.0. HRMS (ESI-TOF, [M+Na] ): Calcd. for C13H17NNaO5S , 322.0720. Found: 322.0741

O

N

OTs

1h 1h. To a solution of the oxime 2-(1-(hydroxyimino)ethyl)-1-phenylpent-4-en-1-one (670.6mg, 3.086 mmol) in 10.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (DABCO, 380.0 mg, 3.388 mmol) at 0 ºC followed by addition of a solution of TsCl (650.0 mg, 1.222 mmol) in 10.0 mL of CH2Cl2. The whole was stirred at 0 ºC for 1 hr. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 6: 1) to afford 1h (white solid, 942.9 mg, 83%). 1

Mp.: 82-84 ºC. H NMR (CD2Cl2): δ 7.89-7.86 (2H, m), 7.82-7.79 (2H, m), 7.62-7.58 (1H, m), 7.42-7.38 (2H, m), 7.34 (2H, d, J=8.0 Hz), 5.69-5.59 (1H, m), 5.09-5.04 (1H, m), 4.99-4.96 (1H, m), 4.45 (1H, dd, J=6.8, 8.0 Hz), 2.76-2.69 (1H, m), 2.56-2.43 (4H, m), 1.91 (3H, s).

13

C

NMR (CD2Cl2): δ 196.7, 165.6, 145.2, 135.8, 133.9, 133.5, 132.6, 19.6, 128.7, 128.59, +

+

128.57, 117.4, 52.4, 32.8, 21.4, 12.9. HRMS (ESI-TOF, [M+Na] ): Calcd. for C20H21NNaO4S , 394.1083. Found: 394.1086. Anal. Calcd. for C20H21NO4S: C, 64.67; H, 5.70; N, 3.77. Found: C, 64.54; H, 5.76; N, 3.49.

O

N

OTs

1i

33



Page 34 of 53

1i. To a solution of the oxime 2-(cyclopropylmethyl)-3-(hydroxyimino)-1-phenylbutan-1-one (489.8mg, 2.118 mmol) in 5.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (DABCO, 260.0 mg, 2.318 mmol) at 0 ºC followed by addition of a solution of TsCl (444.0 mg, 2.329 mmol) in 10.0 mL of CH2Cl2. The whole was stirred at 0 ºC for 1 hr. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 6: 1) to afford 1i (white solid, 744.8 mg, 91%). 1

Mp.: 85-86 ºC. H NMR (CD2Cl2): δ 7.91-7.82 (2H, m), 7.83-7.80 (2H, m), 7.63-7.58 (1H, m), 7.44-7.39 (2H, m), 7.34-7.32 (2H, m), 4.48 (1H, dd, J=6.8, 7.6 Hz), 2.46 (3H, s), 1.93 (3H, s), 1.89-1.82 (1H, m), 1.72-1.65 (1H, m), 0.56-0.49 (1H, m), 0.41-0.32 (2H, m), 0.07-0.05 (2H, m).

13

C NMR (CD2Cl2): δ 197.0, 166.6, 145.5, 136.5, 133.8, 133.1, 129.9, 129.02, 128.99, +

+

128.9, 34.3, 21.8, 13.5, 9.2, 4.9, 4.8. HRMS (ESI-TOF, [M+Na] ): Calcd. for C21H23NNaO4S , 408.1240. Found: 408.1230.

O

NOMs

1j

F

1j To a solution of the oxime 1-(4-fluorophenyl)-3-(hydroxyimino)-2-methylbutan-1-one (366.2 mg, 1.750 mmol) in 3.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (DABCO, 220.0 mg, 1.960 mmol) at 0 ºC followed by addition of a solution of MsCl (220.0 mg, 1.927 mmol) in 2 mL of CH2Cl2. The whole was stirred at room temperature for 1 hr. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 4: 1) to afford 1j (white solid, 391.6 mg, 78%). 1

Mp.: 84-86 ºC. H NMR (CDCl3): δ 8.16-8.12 (2H, m), 7.32-7.27 (2H, m), 4.72 (1H, q, J=7.2 Hz), 3.09 (3H, s), 2.01 (3H, s), 1.44 (3H, d, J=7.2 Hz).

13

C NMR (CDCl3): δ 196.6, 168.3,

166.7 (d, JC, F=251.5 Hz), 133.5 (d, JC, F=3.0 Hz), 132.5 (d, JC, F=9.5 Hz), 116.6 (d, JC, F=22.2 +

+

Hz), 48.4, 36.7, 14.5, 14.1. HRMS (ESI-TOF, [M+Na] ): Calcd. for C12H14FNNaO4S , 310.0520. Found: 310.0535. Anal. Calcd. for C12H14FNO4S: C, 50.17; H, 4.91; N, 4.88. Found: C, 49.97; H, 4.82; N, 4.63.

O

NOTs

1k 1k To a solution of the oxime 1-(4-fluorophenyl)-3-(hydroxyimino)-2-methylbutan-1-one (488.0 mg, 2.022 mmol) in 5.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (DABCO,

34


Page 35 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


250.0 mg, 2.224 mmol) at 0 ºC followed by addition of a solution of TsCl (424.0 mg, 2.224 mmol) in 5 mL of CH2Cl2. The whole was stirred at room temperature for 1 hr. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 4: 1) to afford 1k (white solid, 673.9 mg, 84%). 1

Mp.: 121-122 ºC. H NMR (CDCl3): δ 8.43 (1H, s), 7.90-7.76 (6H, m), 7.62-7.51 (2H, m), 7.16 (2H, d, J=8.0 Hz), 4.57 (1H, q, J=7.2 Hz), 2.34 (3H, s), 1.91 (3H, s), 1.41 (3H, d, J=7.2 Hz). 13

C NMR (CDCl3): δ 196.7, 167.2, 144.8, 135.7, 132.8, 132.4, 131.0, 129.9, 129.5, 129.0, +


for C22H21NNaO4S , 418.1083. Found: 418.1102.

O

NOMs

1l

AcO

1l To a solution of the oxime 1-(4-fluorophenyl)-3-(hydroxyimino)-2-methylbutan-1-one (433.1 mg, 1.738 mmol) in 5.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (DABCO, 210.0 mg, 1.873 mmol) at 0 ºC followed by addition of a solution of MsCl (210.0 mg, 1.839 mmol) in 5 mL of CH2Cl2. The whole was stirred at room temperature for 1 hr. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 3: 1) to afford 1l (colorless oil, 374.4 mg, 66%). 1

H NMR (CD2Cl2): δ 8.08 (2H, d, J=8.8 Hz), 7.26 (2H, d, J=8.8 Hz), 4.56 (1H, q, J=6.8 Hz),

3.10 (3H, s), 2.34 (3H, s), 2.03 (3H, s), 1.50 (3H, d, J=7.2 Hz).

13

C NMR (CD2Cl2): δ 195.9,

158.7, 167.5, 154.9, 133.1, 130.3, 122.1, 47.6, 36.5, 20.9, 14.1, 13.5. HRMS (ESI-TOF, +

+

[M+Na] ): Calcd. for C14H17NNaO6S , 350.0669. Found: 350.0680. Note:1l was unstable and gradually decomposed into isoxazole 2l.

O

NOMs

1m 1m To a solution of the oxime 1-(4-fluorophenyl)-3-(hydroxyimino)-2-methylbutan-1-one (706.9 mg, 3.478 mmol) in 10.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (DABCO, 430.0 mg, 3.833 mmol) at 0 ºC followed by addition of a solution of MsCl (430.0 mg, 3.766 mmol) in 5 mL of CH2Cl2. The whole was stirred at room temperature for 1 hr. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 6: 1) to afford 1m (white solid, 863.0 mg, 88%).

35



Page 36 of 53

1

Dec.: 111 ºC. H NMR (CD2Cl2): δ 8.04 (1H, dd, J=1.2, 8.0 Hz), 7.60-7.56 (1H, m), 7.41-7.35 (2H, m), 3.72-.368 (1H, m), 3.22-3.11 (5H, m), 2.47-2.33 (2H, m), 2.10 (3H, s).

13

C NMR

(CD2Cl3): δ 194.8, 167.0, 143.9, 134.1, 131.9, 129.0, 127.2, 126.9, 54.4, 36.5, 28.5, 27.2, 14.2.

HRMS

(ESI-TOF,

+

[M+Na] ):

Calcd.

for

Chemical

Formula:

+

C13H15NNaO4S ,

.

304.0614 Found: 304.0622. Anal. Calcd. for C13H15NO4S: C, 55.50; H, 5.37; N, 4.98. Found C, 55.55; H, 5.37; N, 5.03;

O

NOTs

1n 1n To a solution of the oxime 1-(4-fluorophenyl)-3-(hydroxyimino)-2-methylbutan-1-one (307.3 mg, 1.401 mmol) in 5.0 mL of CH2Cl2 was added 1,4-diazabicyclo[2.2.2]octane (DABCO, 170.0 mg, 1.516 mmol) at 0 ºC followed by addition of a solution of MsCl (170.0 mg, 1.489 mmol) in 5 mL of CH2Cl2. The whole was stirred at room temperature for 1 hr. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 4: 1) to afford 1n (white solid, 479.8 mg, 92%). 1

Mp.: 102-104 ºC. H NMR (CD2Cl2): δ 7.88-7.86 (2H, m), 7.83-7.80 (2H, m), 7.61-7.57 (1H, m), 7.42-7.38 (2H, m), 7.35 (2H, d, J=8.0 Hz), 4.25 (1H, t, J=6.8 Hz), 2.48 (3H, s), 2.45-2.36 (1H, m), 2.31-2.22 (1H, m), 2.06-1.97 (1H, m), 1.84-1.77 (1H, m), 0.96 (3H, t, J=7.6 Hz), 0.86 (3H, t, J=7.6 Hz).

13

C NMR (CD2Cl2): δ 196.3, 169.9, 145.1, 136.3, 133.4, 132.7, 129.5, +


for C20H23NNaO4S , 396.1240. Found: 396.1220.

Synthesis of compound 4 (reaction 1).

O N 4a 4a. To a solution of 1a (134.7 mg, 0.500 mmol) in 5.0 mL of CH2Cl2 was added 1,4diazabicyclo[2.2.2]octane (224.3 mg, 4.0 equiv.) at 20 ºC. The whole was stirred at 20 ºC for 1 hr. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 4: 1) to afford 4a (colorless oil, 76.3 mg, 88%). 1

H NMR (CDCl3): δ 7.63-7.61 (2H, m), 7.48-7.44 (1H, m), 7.40-7.36 (2H, m), 2.47 (3H, s),

1.55 (3H, s).

13

C NMR (CDCl3): δ 202.2, 166.7, 137.4, 131.5, 128.2, 128.2, 42.0, 19.0, 12.9.

The NMR spectral are consistent with the former reports.

36

24c


Page 37 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


O N MeO

4c

4c. To a solution of 1c (149.7 mg, 0.500 mmol) in 5.0 mL of CH2Cl2 was added 1,4diazabicyclo[2.2.2]octane (224.3 mg, 4.0 equiv.) at 20 ºC. The whole was stirred at 20 ºC for 1 hr. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 4: 1) to afford 4c (colorless oil, 94.2 mg, 93%). 1

H NMR (CDCl3): δ 7.65 (2H, d, J=8.8 Hz), 6.89 (2H, d, J=8.4 Hz), 3.85 (3H, s), 2.49 (3H, s),

1.56 (3H, s).

13

C NMR (CDCl3): δ 199.8, 167.4, 162.6, 131.0, 129.4, 113.5, 55.4, 41.6, 19.6,

12.9. The NMR spectral are consistent with the former reports.

24c

O N Me

4d

4d. To a solution of 1d (141.7 mg, 0.500 mmol) in 5.0 mL of CH2Cl2 was added 1,4diazabicyclo[2.2.2]octane (224.3 mg, 4.0 equiv.) at 20 ºC. The whole was stirred at 20 ºC for 1 hr. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 4: 1) to afford 4d (colorless oil, 88.1 mg, 94%). 1


1.56 (3H, s).

13

C NMR (CDCl3): δ 201.6, 166.9, 142.3, 134.4, 128.9, 128.5, 41.8, 21.6, 19.2,

12.9. The NMR spectral are consistent with the former reports.

24c

O N Cl

4e

4e. To a solution of 1e (151.9 mg, 0.500 mmol) in 5.0 mL of CH2Cl2 was added 1,4diazabicyclo[2.2.2]octane (224.3 mg, 4.0 equiv.) at 20 ºC. The whole was stirred at 20 ºC for 1 hr. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 4: 1) to afford 4e (colorless oil, 95.9 mg, 92%). 1

H NMR (CDCl3): δ 7.59 (2H, d, J=8.8 Hz), 7.36 (2H, d, J=8.8 Hz), 2.46 (3H, s), 1.54 (3H, s).

13

C NMR (CDCl3): δ 200.8, 166.9, 138.0, 135.4, 129.9, 128.5, 42.1, 18.8, 12.9. The NMR

spectral are consistent with the former reports.

24c

O N MeOOC

4f

37



Page 38 of 53

4f. To a solution of 1f (163.7 mg, 0.500 mmol) in 5.0 mL of CH2Cl2 was added 1,4diazabicyclo[2.2.2]octane (224.3 mg, 4.0 equiv.) at 20 ºC. The whole was stirred at 20 ºC for 1 hr. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 2: 1) to afford 4f (colorless oil, 106.3 mg, 92%). 1


1.56 (3H, s).

13

C NMR (CDCl3): δ 202.1, 166.4, 166.3, 141.4, 132.3, 129.4, 127.9, 52.4, 42.4,

18.4, 12.9. The NMR spectral are consistent with the former reports.

24c

O N 4h 4h. To a solution of 1h (185.7 mg, 0.500 mmol) in 5.0 mL of CH2Cl2 was added 1,4diazabicyclo[2.2.2]octane (224.3 mg, 4.0 equiv.) at 20 ºC. The whole was stirred at 20 ºC for 1 hr. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 4: 1) to afford 4h (pale yellow oil, 88.9 mg, 89%). 1

H NMR (CDCl3): δ 7.65-7.62 (2H, m), 7.49-7.45 (1H, m), 7.41-7.38 (2H, m), 5.76-5.66 (1H,

m), 5.11-5.06 (2H, m), 2.90-2.84 (1H, m), 2.76-2.71 (1H, m), 2.48 (3H, s).

13

C NMR (CDCl3):

δ 201.4, 166.4, 137.2, 133.4, 131.6, 128.2, 128.2, 118.0, 45.2, 36.3, 13.7. The NMR spectral are consistent with the former reports.

24c

O N 4i

4i. To a solution of 1i (192.7 mg, 0.500 mmol) in 5.0 mL of CH2Cl2 was added 1,4diazabicyclo[2.2.2]octane (224.3 mg, 4.0 equiv.) at 20 ºC. The whole was stirred at 20 ºC for 1 hr. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 4: 1) to afford 4i (colorless oil, 93.9 mg, 88%). 1


(3H, s), 2.08 (1H, dd, J=8.0, 15.2 Hz), 1.98 (1H, dd, J=6.8, 15.2 Hz) 0.62-0.55 (1H, m), 0.500.40 (2H, m), 0.10-0.04 (2H, m).

13

C NMR (CDCl3): δ 202.1, 166.5, 137.3, 131.6, 128.24,

128.22, 46.3, 36.4, 14.0, 7.7, 4.8, 4.6. The NMR spectral are consistent with the former reports.

2

38


Page 39 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


O N 4j

F

4j. To a solution of 1j (143.7 mg, 0.500 mmol) in 5.0 mL of CH2Cl2 was added 1,4diazabicyclo[2.2.2]octane (224.3 mg, 4.0 equiv.) at 20 ºC. The whole was stirred at 20 ºC for 1 hr. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 4: 1) to afford 4j (colorless oil, 86.8 mg, 91%). 1

H NMR (CDCl3): δ 7.74-7.71 (2H, m), 7.10-7.06 (2H, m), 2.49 (3H, s), 1.56 (3H, s).

13

C NMR

(CDCl3): δ 200.3, 167.1, 164.7 (d, JC, F=251.7 Hz), 133.2 (d, JC, F=3.5 Hz), 131.1 (d, JC, F=8.9 Hz), 115.3 (d, JC, F=21.7 Hz), 42.0, 19.0, 12.9. The NMR spectral are consistent with the former reports.

24c

O N 4k 4k. To a solution of 1k (197.7 mg, 0.500 mmol) in 5.0 mL of CH2Cl2 was added 1,4diazabicyclo[2.2.2]octane (224.3 mg, 4.0 equiv.) at 20 ºC. The whole was stirred at 20 ºC for 1 hr. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 4: 1) to afford 4k (colorless oil, 103.9 mg, 93%). 1

H NMR (CDCl3): δ 8.21 (1H, s), 7.93 (1H, d, J=8.0 Hz), 7.88-7.86 (2H, m), 7.74 (1H, dd,

J=1.6, 8.4 Hz), 7.61-7.53 (2H, m), 2.51 (3H, s), 1.63 (3H, s).

13

C NMR (CDCl3): δ 201.9,

167.0, 134.7, 134.5, 132.3, 129.4, 129.3, 128.1, 128.0, 127.7, 126.7, 124.6, 42.1, 19.2, 12.9. The NMR spectral are consistent with the former reports.

24c

O N

AcO

4l

4l. To a solution of 1l (163.7 mg, 0.500 mmol) in 5.0 mL of CH2Cl2 was added 1,4diazabicyclo[2.2.2]octane (224.3 mg, 4.0 equiv.) at 20 ºC. The whole was stirred at 20 ºC for 1 hr. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 4: 1) to afford 4l (colorless oil, 87.5 mg, 76%). 1

H NMR (CDCl3): δ 7.74 (1H, d, J=8.8 Hz), 7.14 (1H, d, J=8.8 Hz), 7.88-7.86 (2H, m), 2.49

(3H, s), 2.33 (3H, s), 1.56 (3H, s).

13

C NMR (CDCl3): δ 200.6, 168.9, 167.0, 153.2, 134.5,

39



Page 40 of 53

+

+

130.1, 121.4, 42.0, 21.2, 19.1, 12.9. HRMS (ESI-TOF, [M+H] ): C13H14NO3 , 232.0968. Found: 232.0972.

O

N 4m

4m. To a solution of 1m (140.6 mg, 0.500 mmol) in 5.0 mL of CH2Cl2 was added 1,4diazabicyclo[2.2.2]octane (224.3 mg, 4.0 equiv.) at 20 ºC. The whole was stirred at 20 ºC for 1 hr. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 4: 1) to afford 4m (colorless oil, 83.5 mg, 90%). 1

H NMR (CDCl3): δ 8.02 (1H, d, J=8.0 Hz), 7.55-7.51 (1H, m), 7.38-7.32 (2H, m), 3.30-3.13

(1H, m), 3.13-3.05 (1H, m), 2.54 (3H, s), 2.22-2.09 (2H, m).

13

C NMR (CDCl3): δ 197.1, 162.3,

143.8, 133.8, 133.6, 128.5, 127.2, 126.8, 41.3, 30.2, 28.6, 12.3. The NMR spectral are consistent with the former reports.

2

O N

4n

4n. To a solution of 1n (186.7 mg, 0.500 mmol) in 5.0 mL of CH2Cl2 was added 1,4diazabicyclo[2.2.2]octane (224.3 mg, 4.0 equiv.) at 20 ºC. The whole was stirred at 20 ºC for 1 hr. The reaction was quenched with water and the mixture was extracted with CH2Cl2. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 4: 1) to afford 4n (colorless oil, 90.2 mg, 90%). f 1

H NMR (CDCl3): δ 7.67 (2H, d, J=8.0 Hz), 7.50-7.46 (1H, m), 7.42-7.38 (2H, m), 2.84-2.77

(2H, m), 2.24-2.17 (1H, m), 2.01-1.92 (1H, m), 1.26 (3H, t, J=7.2 Hz), 0.87 (3H, t, J=7.2 Hz). 13

C NMR (CDCl3): δ 201.9, 170.4, 137.4, 131.5, 128.3, 128.2, 47.8, 24.7, 21.7, 10.1, 8.7. The

NMR spectral are consistent with the former reports.

24c

Synthesis of compound 2 (reaction 3).

O N 2a 2a. A solution of 1a (134.7 mg, 0.500 mmol) in 5.0 mL of AcOH/MeCN (v/v= 1: 1) was stirred at 50 ºC for 8 hr. The reaction was diluted dichloromethane and washed with water, saturated aqueous NaHCO3 solution and brine. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 9: 1) to afford isoxazole 2a (white solid, 78.6 mg, 91%).

40


Page 41 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1

Mp.: 46-48 ºC. H NMR (CDCl3): δ 7.70 (2H, dd, J=1.6, 7.6 Hz), 7.50-7.26 (3H, m), 2.29 (3H, s), 2.17 (3H, s).

13

C NMR (CDCl3): δ 164.2, 161.0, 129.3, 128.79, 128.75, 126.7, 109.2, 10.2, +

+

8.2. HRMS (ESI-TOF, [M+Na] ): Calcd. for C11H11NNaO , 196.0733. Found: 196.0723. Anal. Calcd. for C11H11NO: C, 76.28; H, 6.40; N, 8.09. Found: C, 76.20; H, 6.46; N, 8.09.

O N 2c MeO 2c. A solution of 1c (149.7 mg, 0.500 mmol) in 5.0 mL of AcOH/MeCN (v/v= 1: 1) was stirred at 50 ºC for 4 hr. The reaction was diluted dichloromethane and washed with water, saturated aqueous NaHCO3 solution and brine. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 6: 1) to afford isoxazole 2a (white solid, 92.8 mg, 91%). 1

Mp.: 73-75 ºC. H NMR (CDCl3): δ 7.64 (2H, d, J=8.8 Hz), 6.98 (2H, d, J=9.2 Hz), 3.85 (3H, s), 2.26 (3H, s), 2.13 (3H, s).

13

C NMR (CDCl3): δ 165.2, 160.9, 160.3, 128.1, 121.5, 114.2, +

+

107.9, 55.4, 10.2, 8.2. HRMS (ESI-TOF, [M+Na] ): Calcd. for C12H13NNaO2 , 226.0838. Found: 226.0828. Anal. Calcd. for C12H13NO2 C, 70.92; H, 6.45; N, 6.89. Found: C, 70.77; H, 6.53; N, 6.85.

O N 2d 2d. A solution of 1d (141.7 mg, 0.500 mmol) in 5.0 mL of AcOH/MeCN (v/v= 1: 1) was stirred at 50 ºC for 4 hr. The reaction was diluted dichloromethane and washed with water, saturated aqueous NaHCO3 solution and brine. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 6: 1) to afford isoxazole 2d (white solid, 80.7 mg, 86%). 1

Mp.: 77-79 ºC H NMR (CDCl3): δ 7.59 (2H, d, J=8.4 Hz), 7.27 (2H, d, J=8.4 Hz), 2.40 (3H, s), 2.27 (3H, s), 2.14 (3H, s).

13

C NMR (CDCl3): δ 164.3, 160.9, 139.4, 129.5, 126.5, 126.0, +

+

108.7, 21.4, 10.2, 8.2. HRMS (ESI-TOF, [M+Na] ): Calcd. for C12H13NNaO , 210.0889. Found: 210.0894. Anal. Calcd. for C12H13NO: C, 76.98; H, 7.00; N, 7.48. Found: C, 77.37; H, 7.11; N, 7.39.

O N 2e Cl 2e. A solution of 1e (151.9 mg, 0.500 mmol) in 5.0 mL of AcOH/MeCN (v/v= 1: 1) was stirred at 50 ºC for 8 hr. The reaction was diluted dichloromethane and washed with water, saturated

41



Page 42 of 53

aqueous NaHCO3 solution and brine. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 6: 1) to afford isoxazole 2e (colorless oil, 92.3 mg, 89%). 1

Mp.: 89-90 ºC. H NMR (CDCl3): δ 7.67 (2H, d, J=8.8 Hz), 7.47 (2H, d, J=8.4 Hz), 2.31 (3H, s), 2.18 (3H, s).

13

C NMR (CDCl3): δ 163.1, 161.1, 135.3, 129.1, 127.8, 127.2, 109.6, 10.2, +

+

8.2. HRMS (ESI-TOF, [M+Na] ): Calcd. for C11H10ClNNaO , 230.0343. Found: 230.0342. Anal. Calcd. for C11H10ClNO: C, 63.62; H, 4.85; N, 6.75. Found: C, 63.67; H, 5.05; N, 6.52.

O N 2f MeOOC 2f. A solution of 1f (163.7 mg, 0.500 mmol) in 5.0 mL of AcOH/MeCN (v/v= 1: 1) was stirred at 50 ºC for 12 hr. The reaction was diluted dichloromethane and washed with water, saturated aqueous NaHCO3 solution and brine. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 4: 1) to afford isoxazole 2f (white solid, 96.5 mg, 83%). 1


13

C NMR (CDCl3): δ 166.5, 163.0, 161.2, 132.6, 130.5, 130.1, +

+

126.4, 110.8, 52.3, 10.2, 8.3. HRMS (ESI-TOF, [M+Na] ): Calcd. for C13H13NNaO3 , 254.0788. Found: 254.0792. Anal. Calcd. for C13H13NO3: C, 67.52; H, 5.67; N, 6.06. Found: C, 67.70; H, 6.04; N, 5.79

OMe O N 2g 2g. A solution of 1g (149.7 mg, 0.500 mmol) in 5.0 mL of AcOH/MeCN (v/v= 1: 1) was stirred at 50 ºC for 4 hr. The reaction was diluted dichloromethane and washed with water, saturated aqueous NaHCO3 solution and brine. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 6: 1) to afford isoxazole 2g (colorless oil, 91.7 mg, 90%). 1

H NMR (CDCl3): δ 7.45-7.42 (2H, m), 7.07-6.99 (2H, m), 3.86 (3H, s), 2.29 (3H, s), 1.95 (3H,

s).

13

C NMR (CDCl3): δ 160.4, 156.8, 131.2, 130.7, 120.6, 117.8, 111.5, 111.4, 100.0, 55.5, +

+

10.3, 7.9. HRMS (ESI-TOF, [M+Na] ): Calcd. for C12H13NNaO2 , 226.0838 Found: 226.0831.

O N 2h

2h. A solution of 1h (185.7 mg, 0.500 mmol) in 5.0 mL of AcOH/MeCN (v/v= 1: 1) was stirred at 50 ºC for 4 hr. The reaction was diluted dichloromethane and washed with water, saturated

42


Page 43 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


aqueous NaHCO3 solution and brine. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 6: 1) to afford isoxazole 2h (colorless oil, 82.9 mg, 83%). 1

H NMR (CDCl3): δ 7.68-7.65 (2H, m), 7.48-7.42 (3H, m), 6.02-5.93 (1H, m), 5.14 (1H, dd,

J=1.6, 10.0 Hz), 5.02 (1H, dd, J=1.6, 17.2 Hz), 3.32-3.30 (2H, m), 2.27 (3H, s).

13

C NMR

(CDCl3): δ 165.4, 161.0, 134.4, 129.6, 128.8, 128.3, 126.8, 116.2, 110.9, 26.8, 10.1. HRMS +

+

(ESI-TOF, [M+Na] ): Calcd. for C13H13NNaO , 222.0889. Found: 222.0867. Anal. Calcd. for C13H13NO: C, 78.36; H, 6.58; N, 7.03. Found: C, 78.12; H, 6.72; N, 6.98.

O N 2i

2i. A solution of 1i (192.7 mg, 0.500 mmol) in 5.0 mL of AcOH/MeCN (v/v= 1: 1) was stirred at 50 ºC for 4 hr. The reaction was diluted dichloromethane and washed with water, saturated aqueous NaHCO3 solution and brine. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 6: 1) to afford isoxazole 2i (colorless oil, 96.9 mg, 91%). 1

H NMR (CDCl3): δ 7.73-7.71 (2H, m), 7.49-7.40 (3H, m), 2.57 (1H, d, J=6.4 Hz), 2.33 (3H, s),

0.98-0.88 (1H, m), 0.51-0.47 (2H, m), 0.16-0.12 (2H, m).

13

C NMR (CDCl3): δ 164.8, 160.8, +


for C14H15NNaO , 236.1046. Found: 236.1039.

O N 2j F 2j. A solution of 1j (143.7 mg, 0.500 mmol) in 5.0 mL of AcOH/MeCN (v/v= 1: 1) was stirred at 50 ºC for 8 hr. The reaction was diluted dichloromethane and washed with water, saturated aqueous NaHCO3 solution and brine. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 6: 1) to afford isoxazole 2j (off-white solid, 88.3 mg, 92%). 1

Mp.: 48-50 ºC. H NMR (CDCl3): δ 7.70-7.65 (2H, m), 7.18-7.14 (2H, m), 2.28 (3H, s), 2.14 (3H, s).

13

C NMR (CDCl3): δ 163.3, 163.1 (d, JC, F=248.5 Hz), 161.0, 128.6 (d, JC, F=8.2 Hz), +

125.4 (d, JC, F=3.4 Hz), 115.7 (d, JC, F=21.8 Hz), 109.0,10.2, 8.1. HRMS (ESI-TOF, [M+Na] ): +

Calcd. for C11H10FNNaO , 214.0639. Found: 214.0657.

O N 2k

43



Page 44 of 53

2k. A solution of 1k (197.8 mg, 0.500 mmol) in 5.0 mL of AcOH/MeCN (v/v= 1: 1) was stirred at 50 ºC for 8 hr. The reaction was diluted dichloromethane and washed with water, saturated aqueous NaHCO3 solution and brine. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 4: 1) to afford isoxazole 2k (white solid, 106.5 mg, 95%). 1

Mp.: 105-108 ºC. H NMR (CDCl3): δ 8.19 (1H, s), 7.97-7.84 (4H, m), 7.58-7.55 (2H, m), 2.35 (3H, s), 2.28 (3H, s).

13

C NMR (CDCl3): δ 164.2, 161.1, 133.4, 133.1, 128.6, 128.5, 127.8, +

127.1, 126.7, 126.3, 126.1, 123.8, 109.6, 10.3, 8.4. HRMS (ESI-TOF, [M+Na] ): Calcd. for +

C15H13NNaO , 246.0889 Found: 246.0878. Anal. Calcd. for C15H13NO: C, 80.69; H, 5.87; N, 6.27. Found: C, 80.92; H, 6.02; N, 6.29.

O N 2l AcO 2l. A solution of 1l (163.7 mg, 0.500 mmol) in 5.0 mL of AcOH/MeCN (v/v= 1: 1) was stirred at 50 ºC for 8 hr. The reaction was diluted dichloromethane and washed with water, saturated aqueous NaHCO3 solution and brine. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 4: 1) to afford isoxazole 2l (white solid, 103.8 mg, 90%). 1


13

C NMR (CDCl3): δ 169.2, 163.4, 161.0, 151.2, 127.8, 126.4, +

+

122.1, 109.3, 21.1, 10.2, 8.1. HRMS (ESI-TOF, [M+Na] ): Calcd. for C13H13NNaO3 , 254.0788. Found: 254.0795.

O N 2m 2m. A solution of 1m (140.7 mg, 0.500 mmol) in 5.0 mL of AcOH/MeCN (v/v= 1: 1) was stirred at 50 ºC for 4 hr. The reaction was diluted dichloromethane and washed with water, saturated aqueous NaHCO3 solution and brine. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 6: 1) to afford isoxazole 2m (pale yellow oil, 61.7 mg, 66%). 1

H NMR (CDCl3): δ 7.68-7.66 (1H, m), 7.32-7.29 (3H, m), 3.06 (2H, t, J=7.2 Hz), 2.70 (2H, t,

J=8.0 Hz), 2.32 (3H, s).

13

C NMR (CDCl3): δ 165.0, 157.9, 136.4, 129.4, 128.3, 127.0, 125.4, +

+

121.9, 112.4, 29.0, 17.9, 10.0. HRMS (ESI-TOF, [M+Na] ): Calcd. for C12H11NNaO , 208.0733. Found: 208.0735.

O N 2n

44


Page 45 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


2n. A solution of 1j (186.7 mg, 0.500 mmol) in 5.0 mL of AcOH/MeCN (v/v= 1: 1) was stirred at 50 ºC for 4 hr. The reaction was diluted dichloromethane and washed with water, saturated aqueous NaHCO3 solution and brine. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 6: 1) to afford isoxazole 2j (colorless oil, 85.4 mg, 85%). 1

H NMR (CDCl3): δ 7.72-7.70 (2H, m), 7.51-7.42 (3H, m), 2.73 (2H, q, J=7.2 Hz), 2.63 (2H, q,

J=7.6 Hz), 1.39 (3H, t, J=7.6 Hz), 1.24 (3H, t, J=7.6 Hz).

13

C NMR (CDCl3): δ 165.2, 164.2, +


for C13H15NNaO , 224.1046. Found: 224.1050. Reaction of 1 with tert-BuOK (reaction 2). (1) To a solution of 1a (134.7 mg, 0.500 mmol) in 5.0 mL of THF was added tert-BuOK (224.4 mg, 4.0 equiv.) at 20 ºC. The whole was stirred at 20 ºC for 15min. The reaction was quenched with 0.5 ml of AcOH and diluted with ethyl acetate. The reaction mixture was and washed with water, saturated aqueous NaHCO3 solution and brine. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 6: 1 to 2: 1) to afford isoxazole 2a (colorless oil, 32.2 mg, 37%) and oxazoe 3a (white solid, 35.7 mg, 41% ).

O

N 3a 1

3a. Mp.: 44-45 ºC. H NMR (CDCl3): δ 7.59 (2H, dd, J=1.6, 8.0 Hz), 7.46-7.42 (2H, m), 7.3313 7.28 (1H, m), 2.50 (3H, s), 2.40 (3H, s). C NMR (CDCl3): δ 159.4, 145.1, 131.6, 129.3, + + 128.7, 127.3, 125.1, 13.9, 13.2. HRMS (ESI-TOF, [M+Na] ): Calcd. for C11H11NNaO , 196.0733. Found: 196.0714. (2) To a solution of 1i (192.7 mg, 0.500 mmol) in 5.0 mL of THF was added tert-BuOK (224.4 mg, 4.0 equiv.) at 20 ºC. The whole was stirred at 20 ºC for 15min. The reaction was quenched with 0.5 ml of AcOH and diluted with ethyl acetate. The reaction mixture was and washed with water, saturated aqueous NaHCO3 solution and brine. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 9: 1 to 4: 1) to afford isoxazole 2i (colorless oil, 38.6 mg, 36%) and oxazoe 3i (colorless oil, 46.0 mg, 43% ).

O

N 3i

1

3i. H NMR (CDCl3): δ 7.61-7.59 (2H, m), 7.45-7.42 (2H, m), 7.34-7.30 (1H, m), 2.71 (2H, d, 13 J=6.8 Hz), 2.53 (3H, s), 1.19-1.12 (1H, m), 0.56-0.51 (2H, m), 0.29-0.26 (2H, m). C NMR (CDCl3): δ 159.6, 145.2, 135.4, 129.2, 128.7, 127.5, 125.4, 31.2, 14.1, 10.1, 4.3. HRMS (ESI+ + + TOF, [M+Na] ): HRMS (ESI-TOF, [M+Na] ): Calcd. for C14H15NNaO , 236.1046. Found: 236.1042. Reaction of 1 with TFA (reaction 4) (1) 1a (134.7 mg, 0.500 mmol) was added to 5.0 ml of TFA at 20 ºC. The whole was stirred at 20 ºC for 1 hr and diluted dichloromethane. The reaction mixture was and washed with water, saturated aqueous NaHCO3 solution and brine. The solvent was evaporated and the residue

45



was purified with column chromatography (Hexane: EtOAc= 6: 1 to 2: 1) to afford isoxazole 2a (colorless oil, 56.0 mg, 65%) and oxazoe 3a (white solid, 20.1 mg, 23%). (2) 1h (185.7 mg, 0.500 mmol) was added to 5.0 ml of TFA at 20 ºC. The whole was stirred at 20 ºC for 1 hr and diluted dichloromethane. The reaction mixture was and washed with water, saturated aqueous NaHCO3 solution and brine. The solvent was evaporated and the residue was purified with column chromatography (Hexane: EtOAc= 8: 1 to 2: 1) to afford isoxazole 2h (colorless oil, 45.4 mg, 46%) and oxazoe 3h (white solid, 43.2 mg, 43%).

O

N 3h

1

3h. H NMR (CDCl3): δ 7.56 (2H, dd, J=1.2, 8.0 Hz), 7.44-7.41 (2H, m), 7.34-7.30 (1H, m), 13 6.09-5.99 (1H, m), 5.19-5.14 (2H, m), 3.50-3.48 (2H, m), 2.50 (3H, s). C NMR (CDCl3): δ 159.9, 145.8, 134.5, 133.5, 128.9, 128.8, 127.7, 125.4, 116.5, 31.5, 14.0. HRMS (ESI-TOF, + + [M+Na] ): Calcd. for C13H13NNaO , 222.0889. Found: 222.0881.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI Kinetic measurements, DFT calculation data and NMR spectral for 1, isoxazole 2, oxazole 3 and 2H-azirine 4.

Corresponding Author * E-mail: [email protected] ORCID Tomohiko Ohwada: 0000-0001-5390-0203 Notes The authors declare no competing financial interest. ACKNOWLEDGMENTS This work was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (15K14927) to T. O.. The computations were performed at the Research Center for Computational Science, Okazaki, Japan. We thank the computational facility for generous allotments of computer time.

Notes and References

46


Page 46 of 53

Page 47 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1. Muller, P. Pure Appl. Chem. 1994, 66, 1077-1184. 2. (a). Pearson, R. G. J. Am. Chem. Soc. 1963, 85, 3533-3539. (b). Pearson, R. G. Science 1966, 151, 172-177. (c). Ho, T. Chem. Rev. 1975, 75, 1-20. (d). Pearson, R. G. Chemical Hardness; Wiley-VCH: Weinheim, 1997. 3. (a). Klopman, G. J. Am. Chem. Soc. 1968, 90, 223. (b). Fleming, I. Molecular Orbitals and Organic Chemical Reactions, student ed.; Wiley: Chichester, 2009. 4. (a). Breugst, M.; Zipse, H.; Guthrie, J. P.; Mayr, H. Angew. Chem., Int. Ed. 2010, 49, 5165. (b) Mayr, H.; Breugst, M.; Ofial, A. R. Angew. Chem., Int. Ed. 2011, 50, 6470-6505. (c). Mayr, H.; Ofial, A. R. Acc. Chem. Res. 2016, 49, 952-965. (d) Marcus, R. A. Annu. Rev. Phys. Chem. 1964, 15, 155-196. (e) Marcus, R. A. J. Phys. Chem. 1968, 72, 891-899. (f). Albery, W. J.; Kreevoy, M. M. Adv. Phys. Org. Chem. 1978, 16, 87-157. (g) Albery, W. J. Annu. Rev. Phys. Chem. 1980, 31, 227-263. (e) Marcus, R. A. Angew. Chem., Int. Ed. 1993, 32, 1111-1121. (h) Marcus, R. A. Pure Appl. Chem. 1997, 69, 13-29. 5. Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry, 5th ed.; Part A: Structure and Mechanisms; Springer: 2007 6. (a). Jones, M. E.; Kass, S. R.; Filley, J.; Barkley, R. M.; Ellison, G. B. J. Am. Chem. Soc. 1985, 107, 109-115. (b). Zimmerman, H. E. Acc. Chem. Res. 1987, 20, 263-268. (c). Zhong, M.; Brauman, J. I. J. Am. Chem. Soc. 1996, 118, 636-641. 7. (a). Kurts, A. L.; Macias, A.; Beletskaya, I. P.; Reutov, O. A. Tetrahedron 1971, 27, 4759 – 4767. (b). Houk, K. N.; Paddon-Row, N. J. Am. Chem. Soc. 1986, 108, 2659-2662. (c). Sakata, T.; Seki, N.; Yomogida, K.; Yamagishi, H.; Otsuki, A.; Inoh, C.; Yamataka, H. J. Org. Chem. 2012, 77, 10738-10744. 8. (a). Bernasconi, C. F.; Wenzel, P. J. J. Am. Chem. Soc. 1994, 116, 5405. (b). Seitz, C. G.; Zhang, H.; Mo, Y.; Karty, J. M. J. Org. Chem. 2016, 81, 3711−3719. 9. (a) Stewart, R.; Yates, K. J. Am. Chem. Soc. 1958, 80, 6355-6359. (b) Fischer, A.; Grigor, B. A.; Packer, J.; Vaughan, J. J. Am. Chem. Soc. 1961, 83, 4208-4210. (c) Levy, G. C.; Cargioli, J. D.; Racela, W. J. J. Am. Chem. Soc. 1970, 92, 6238-6246. (d) Lee, D. G. Can. J. Chem. 1970, 48, 1919-192. 10. Amarnath, V.; Amarnath, K. J. Org. Chem. 1995, 60, 301−307 11. Hudzik, J. M.; Bozzelli, J. W. J. Phys. Chem. A. 2012, 116, 5707− 5722. 12. (a). Dénès, F.; Pérez-Luna, A.; Chemla, F. Chem. Rev. 2010, 110, 2366-2477. (b). Huang, Z.; Lim, H. N.; Mo, F.; Young, M. C.; Dong, G. Chem. Soc. Rev. 2015, 44,

47



7764-7786 (c). Shaw, M. H.; Twilton, J.; MacMillan, D. W. C. J. Org. Chem. 2016, 81, 6898. 13. (a). Capon, B.; Guo, B.; Kwok, F. C.; Siddhanta, A. K.; Zucco, C. Acc. Chem. Res. 1988, 21, 135-140 (b). Toullec, J. Adv. Phys. Org. Chem. 1982, 18, 1-77. (c) Hegarty, A. F.; Dowling, J. P.; Eustace, S. J.; McGarraghy, M. J. Am. Chem. Soc. 1998, 120, 2290-2296. 14. See ref. 5, page 601 15. Chandrasekhar, S. The Beckmann and Related Reactions. In Comprehensive Organic Synthesis, 2nd ed; Knochel, P. Molander, G. A., Eds.; Elsevier: Amsterdam, 2014. 16. Pearson, D. E.; Bruton, J. D. J. Org. Chem. 1954, 19, 957. 17. Pedras, M. S. C.; To Q. H.; Schatte, G. Chem. Commun. 2016, 52, 2505–2508. 18. (a). Berkowitz, W. F. Org. React. 2012, 78, 321-410. (b). Uyanik, M.; Ishihara, K. Functional Group Transformations via Carbonyl Derivatives. In Comprehensive Organic Synthesis, 2nd ed; Knochel, P. Molander, G. A., Eds.; Elsevier: Amsterdam, 2014. 19. Ohwada, T.; Tani, N.; Sakamaki, Y.; Kabasawa, Y.; Otani, Y.; Kawahata, M.; Yamaguchi, K. Proc. Natl. Acad. Sci. U. S. A. 2013, 110, 4206−4211. 20. (a). Stokker, G. J. Org. Chem. 1983, 48, 2613-2615. (b). Counceller, C. M.; Eichman, C. C.; Wray, B. C.; Stambuli, J. P. Org. Lett. 2008, 10, 1021-1023. (c). Wray, B. C.; Stambuli, J. P. Org. Lett. 2010, 12, 4576-4579. 21. (a). Bode, J. W.; Uesuka, H.; Suzuki, K. Org. Lett. 2003, 5, 395. (b). Jones, R. C. F.; Chatterley, A.; Marty, R.; Owton, W. M.; Elsegood, M. R. J. Chem. Commun. 2015, 51, 1112-1115. 22. Hu, F.; Szostak, M. Adv. Synth. Catal. 2015, 357, 2583− 2614 23. (a). Khlebnikov, A. F.; Novikov, M. S. Tetrahedron 2013, 69, 3363− 3401. (b). Huang, C.-Y.; Doyle, A. G. Chem. Rev. 2014, 114, 8153− 8198. 24 (a). Ullman, E. F.; Singh, B. J. Am. Chem. Soc. 1966, 88, 1844. (b). Singh, B.; Ullman, E. F. J. Am. Chem. Soc. 1967, 89, 6911. (c). Ning, Y.; Otani, Y.; Ohwada, T.; J. Org. Chem. 2017, 82, 6313-6326. 25. (a). O’Brien, C. Chem. Rev. 1964, 64, 81-89. (b). Ooi, T.; Takahashi, M.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2002, 124, 7640

48


Page 48 of 53

Page 49 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


26. (a). Callebaut, G.; Meiresonne, T.; De Kimpe, N.; Mangelinckx, S. Chem. Rev. 2014, 114, 7954−8015. (b). Choi, S.; Ha, S.; Park, C.-M. Chem. Commun. 2017, 53, 6054. 27. Friis, P.; Larsen, P. O.; Olsen, C. E. J. Chem. Soc. Perkin Trans. 1 1977, 661 – 665. 28. (a). Bordwell, F. G. Acc. Chem. Res. 1972, 5, 374. (b). Fishbein, J. C.; Jencks, W. P. J. Am. Chem. Soc. 1988, 110, 5075-5086. (c). Ryberg, P.; Matsson, O. J. Am. Chem. Soc. 2001, 123, 2712–2718. (d). Alunni, S.; De Angelis, F.; Ottavi, L.; Papavasileiou, M.; Tarantelli, F. J. Am. Chem. Soc. 2005, 127, 15151–15160. (e). Itoh, S.; Yamataka, H. Chem. -Eur. J. 2011, 17, 1230-1237. (f). Kudavalli, J. S.; Rao, S. N.; Bean, D. E.; Sharma, N. D.; Boyd, D. R.; Fowler, P. W.; Gronert, S.; Kamerlin, S. C.; Keeffe, J. R.; More O’Ferrall, R. A. J. Am. Chem. Soc. 2012, 134, 1405614069. 29. (a). Singleton, D. A.; Thomas, A. A. J. Am. Chem. Soc. 1995, 117, 9357−9358. (b). Singleton, D. A.; Szymanski, M. J. J. Am. Chem. Soc. 1999, 121, 9455 −9456 30. Plata, R. E.; Singleton, D. A. J. Am. Chem. Soc. 2015, 137, 3811-3826 31. Kim, Y.; Mohrig, J. R.; Truhlar, D. G. J. Am. Chem. Soc. 2010, 132, 11071−11082. 32. Mayer, I. Chem. Phys. Lett. 1983, 97, 270−274. 33. These values are comparable to the barriers of E1cb elimination in base-catalyzed aldol condensation reactions. Perrin, C. L.; Chang, K.-L. J. Org. Chem. 2016, 81, 5631-5635. 34. Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc. 1976, 98, 28682877. 35. Jackman, L. M.; Lange, B. C. J. Am. Chem. Soc. 1981, 103, 4494-4499. 36. (a) Zhao, P.; Collum, D. B. J. Am. Chem. Soc. 2003, 125, 4008-4009, (b). Godenschwager, P.; Collum, D. B. J. Am. Chem. Soc. 2008, 130, 8726-8732. 37. The reaction of 1a with MeOK also gave a 1:1 mixture of 2a and 3a, in a total yield of 57%. 38. (a). The stability of E-enolate BC2 is partially attributable to dipole minimization: Kwan, E. E.; Scheerer, J. R.; Evans, D. A. J. Org. Chem. 2013, 78, 175-203. (b). The E-enolate is also stabilized by K+-π interaction (see Figure S3): Houk, R. J. T.; Anslyn, E. V.; Stanton, J. F. Org. Lett. 2006, 8, 3461– 3463.

49



39. The chelation of BO2 with K+ stabilizes the enolate by ΔΔG = –2.9 kcal/mol. See Figure S4 for details. 40. (a). Chen, Z.; Wannere, C. S.; Corminboeuf, C.; Puchta, R.; Schleyer, P. v. R. Chem. Rev. 2005, 105, 3842−3888. (b). Schleyer, P. V. R.; Wu, J. I.; Cossío, F. P.; Fernández, L. Chem. Soc. Rev. 2014, 43, 4909−4921. 41. (a). Arrieta, A.; de Cózar, A.; Cossío, F. P. Curr. Org. Chem. 2011, 15, 35943608. (b). Gilmore, K.; Manoharan, M.; Wu, J. I.-C.; Schleyer, P. V. R.; Alabugin, I. V. J. Am. Chem. Soc. 2012, 134, 10584-10594. (c). Johnston, C. P.; Kothari, A.; Sergeieva, T.; Okovytyy, S. I.; Jackson, K. E.; Paton, R. S.; Smith, M. D. Nat. Chem. 2015, 7, 171−177. (d). Sharma, K.; Wolstenhulme, J. R.; Painter, P. P.; Yeo, D.; Grande-Carmona, F.; Johnston, C. P.; Tantillo, D. J.; Smith, M. D. J. Am. Chem. Soc. 2015, 137, 13414−13424. (e). Peng, Q.; Paton, R. S. Acc. Chem. Res. 2016, 49, 10421051. 42. (a). Mayr, H.; Ofial, A. R. Angew. Chem., Int. Ed. 2006, 45, 1844−1854. (b). Beaver, M. G.; Woerpel, K. A. J. Org. Chem. 2010, 75, 1107-1118. (c). Read, J. A.; Woerpel, K. A. J. Org. Chem. 2017, 82, 2300-2305. 43. Byrne, P. A.; Kobayashi, S.; Würthwein, E.-U.; Ammer, J.; Mayr, H. J. Am. Chem. Soc. 2017, 139, 1499–1511. 44. Examples of stabilization of the transition state of SN2 reaction by electrostatic interaction and HOMO-HOMO interaction: (a). Wladkowski, B. D.; Lim, K. F.; Allen, W. D.; Brauman, J. I. J. Am. Chem. Soc. 1992, 114, 9136-9153 (b). Galabov, B.; Nikolova, V.; Wilke, J. J.; Schaefer, H. F.; Allen, W. D. J. Am. Chem. Soc. 2008, 130, 9887−9896. (c). Wu, C.-H.; Galabov, B.; Wu, J. I-C.; Ilieva, S.; Schleyer, P.v.R.; Allen, W. D. J. Am. Chem. Soc. 2014, 136, 3118−3126. (d). Erden, I.; Gronert, S.; Keeffe, J. R.; Ma, J.; Ocal, N.; Gärtner, C.; Soukup, L. L. J. Org. Chem. 2014, 79, 6410-6418. (e). Garcia, A.; Otte, D. A. L.; Salamant, W. A.; Sanzone, J. R.; Woerpel, K. A. Angew. Chem., Int. Ed. 2015, 54, 3061−3064. (f). Robiette, R.; Trieu-Van, T.; Aggarwal, V. K.; Harvey, J. N. J. Am. Chem. Soc. 2016, 138, 734−737. (g). Ning, Y.; Fukuda, T.; Ikeda, H.; Otani, Y.; Kawahata, M.; Yamaguchi, K.; Ohwada, T. Org. Biomol. Chem. 2017, 15, 1381-1392. (h). Inagaki, S.; Fujimoto, H.; Fukui, K. J. Am. Chem. Soc. 1976, 98 (16), 4693–4701. 45. Bernasconi, C. F.; Wenzel, P. J. J. Org. Chem. 2010, 75, 8422-8434.

50


Page 50 of 53

Page 51 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


46. The ratio of 2a/3a formation is dependent on the amount of TFA. See Table S4 in Supporting information for details. 47. (a). Lienhard, G. E.; Wang, T. C. J. Am. Chem. Soc. 1969, 91, 1146-1153. (b). Lammertsma, K. Bharatam, P. V. J. Org. Chem. 2000, 65, 4662. (c). J. A. Long, N. J. Harris and K. Lammertsma, J. Org. Chem. 2001, 66, 6762-6767. (d). Roca-Lopez, D.; Daru, A.; Tejero, T.; Merino, P. RSC Adv. 2016, 6, 22161-22173. 48. Yamabe, S.; Tsuchida, N.; Yamazaki, S. J. Org. Chem. 2005, 70, 10638−10644. 49. A similar trend of intrinsic barrier was also reported for the reaction of enolates with various electrophiles. For examples, see (a) Gompper, R.; Wagner, H.-U.; Angew. Chem., Int. Ed. 1976, 15, 321–333. (b). Kurts, A. L.; Genkina, N. K.; Macias, A.; Beletskaya, L. P.; Reutov, O. A. Tetrahedron 1971, 27, 4777–4785. 50. (a). Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734-736. (b). Baldwin, J. E.; Kruse, L. I.; J. Chem. Soc., Chem. Commun. 1977, 233-235. (c). Alabugin, I. V.; Gilmore, K. Chem. Commun. 2013, 49, 11246-11250. 51. (a). Gilmore, K.; Alabugin, I. V. Chem. Rev. 2011, 111, 6513-6556. (b). Alabugin, I. V.; Gilmore, K.; Manoharan, M. J. Am. Chem. Soc. 2011, 133, 12608-12623. (c). Alabugin, I. V.; Timokhin, V. I.; Abrams, J. N.; Manoharan, M.; Ghiviriga, I.; Abrams, R. J. Am. Chem. Soc. 2008, 130, 10984-10995, (c) Alabugin, I. V.; Manoharan, M.; Breiner, B.; Lewis, F. J. Am. Chem. Soc. 2003, 125, 9329-9342. 52. For examples of susbtitution reactions on sp2 C atom (SNVσ), see (a). Rappoport, Z. Tetrahedron Lett. 1978, 19, 1073–1076. (b). Ando, K.; Kitamura, M.; Miura, K.; Narasaka, K. Org. Lett. 2004, 6, 2461–2463. (c). Shiers, J. J.; Shipman, M.; Hayes, J.; Slawin, A. M. Z. J. Am. Chem. Soc. 2004, 126, 6868–6869. (d). Bernasconi, C. F.; Rappoport, Z. Acc. Chem. Res. 2009, 42, 993−1003. (e). Godoi, B.; Schumacher, R. F.; Zeni, G. Chem. Rev. 2011, 111, 2937-2980. (f). Fernández, I.; Bickelhaupt, F. M.; Uggerud, E. J. Org. Chem. 2013, 78, 8574-8784. (g). Ochiai, M.; Okubo, T.; Miyamoto, K. J. Am. Chem. Soc. 2011, 133, 3342-3344. 53. (a). Narasaka, K.; Kitamura, M. Eur. J. Org. Chem. 2005, 2005, 4505-4519. (b). Huang, H.; Ji, X.; Wu, W.; Jiang, H. Chem. Soc. Rev. 2015, 44, 1155-1171. (c). Li, J.; Hu, Y.; Zhang, D.; Liu, Q.; Dong, Y.; Liu, H. Adv. Synth. Catal. 2017, 359, 710-771. 54. Reaction of 1g with tert-BuOK was complex, due to migration of the double bond, which generated a mixture of E- and Z- isomers. Also see ref. 24b.

51



55. (a). Bodineau, N.; Mattalia, J. -M.; Thimokin, V.; Handoo, K.; Négrel, J. -C.; Chanon, M. Org. Lett. 2000, 2303-2306. (b). Tanko, J. M.; Li, X.; Chahma, M.; Jackson, W. F.; Spencer, J. N. J. Am. Chem. Soc. 2007, 129, 4181-4192. (c). Otte, D. A. L.; Woerpel, K. A. Org. Lett. 2015, 17, 3906−3909. 56. (a). Bürgi, H. B.; Dunitz, J. D. Acc. Chem. Res. 1983, 16, 153-161. (b). Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985, 41, 3925-3941, 57. Alabugin, I. V.; Gold, B. J. Org. Chem. 2013, 78, 7777-7784. 58. Glendening, E. D.; Reed, A. E.; Carpenter, J. E.; Weinhold, F. NBO, version 3.1; University of Wisconsin: Madison, WI. 59. Chisholm, M. H.; Drake, S. R.; Naiini, A. A.; Streib, W. E. Polyhedron 1991, 10, 337−345. 60. Algera, R. F.; Gupta, L.; Hoepker, A. C.; Liang, J.; Ma, Y.; Singh, K. J.; Collum, D. B. J. Org. Chem. 2017, 82, 4513–4532. 61. Winstein, S.; Clippinger, E.; Fainberg, A. H.; Heck, R.; Robinson, G. C. J. Am. Chem. Soc. 1956, 78, 328−335. 62. Reaction generality of 1 with DABCO and AcOH is summarized in Table S5. Further studies are continuing on reaction generality.

52


Page 52 of 53

Page 53 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table of contents Contrasting C- and O-Atom Reactivities of Neutral Ketone and Enolate Forms of 3-Sulfonyloxyimino-2-Methyl-1-Phenyl-1-Butanones Yingtang Ning, Yuko Otani, Tomohiko Ohwada

O

N

Ph

O–N formation

OH

Ph

O–N formation O-attack

C–N formation

Ph

Acid N

O Ph

OMs

C–N formation C-attack

Ketone

O N

C-attack

Enol Base

N

OMs

Ph

O-attack

O

N

53


O Ph

N

Contrasting C- and O-Atom Reactivities of Neutral Ketone and Enolate

Recommend Documents