Acetylene-Triggered Reductive Incorporation of Phosphine

Subscriber access provided by ROBERT GORDON UNIVERSITY

Article

Acetylene-triggered reductive incorporation of phosphine chalcogenides into quinoline scaffold: toward SNHAr reaction Boris A. Trofimov, Pavel A. Volkov, Kseniya O. Khrapova, Anton A. Telezhkin, Nina I. Ivanova, Alexander I. Albanov, Nina K. Gusarova, Alexandra M. Belogolova, and Alexander B. Trofimov J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00519 • Publication Date (Web): 19 Apr 2019 Downloaded from http://pubs.acs.org on April 21, 2019

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 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 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.

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 15 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

1

Acetylene-triggered reductive incorporation of phosphine chalcogenides into quinoline scaffold: toward SNHAr reaction Boris A. Trofimov*, Pavel A. Volkov, Kseniya O. Khrapova, Anton A. Telezhkin, Nina I. Ivanova, Alexander I. Albanov, Nina K. Gusarova, Alexandra M. Belogolova and Alexander B. Trofimov A.E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, 1 Favorsky St., Irkutsk 664033, Russian Federation E-mail: [email protected] Supporting Information R1 R1

P

O

R1

N

N

R3

R5 60-80% 9 examples 1

R8

R4

R5

O R4

20-25 °C, 4.5-17 h MeCN

R1

P

X

R7

R3

H

3

R7

R6

O

N 20-75 °C, 3-72 h MeCN

X = O; R2 = H 2

R8

N

O

+ R2

R6

R1 P R1

R3

R2 X

51-91% 18 examples

4

5

6

7

8

X = O, S; R = Ar, ArAlk; R = H, Ar; R = Ar, HetAr; R , R = H, Me, OMe; R , R , R = H, Me, Br, NO2

ABSTRACT: Quinolines react with acylacetylenes and secondary phosphine chalcogenides at 20–75 °C to afford N-acylvinyl2(1)-chalcogenophosphoryldihydroquinolines in good and excellent yields. Unlike the pyridine-derived similar intermediates, which eliminate E-alkenes to give aromatic chalcogenophosphorylpyridines, thereby completing SNHAr reaction, with quinolines, the reaction stops at formation of the above phosphorylated N-acylvinyl-dihydroquinolines, thus representing a pendant SNHAr process. This reaction opens a one-pot atom-economic single-step access to pharmaceutically-targeted phosphorylated functionalized dihydroquinolines and isoquinolines.

INTRODUCTION Nucleophilic substitution of hydrogen in aromatic or heteroaromatic systems (SNHAr reaction), usually proceeding via dihydro intermediates, is now rapidly growing into a mainstream of modern organic chemistry.1 Pioneered mostly by Chupakhin et al1c,2 these reactions allow avoiding the preliminary functionalization (commonly, halogenation) for further introduction of the desired substituents into aromatic or heteroaromatic rings that is inevitably accompanied by the formation of hazardous (often halogen-containing) waste. In the SNHAr reactions, commonly completed after the initial nucleophilic addition to the aromatic system, eventually, the C-H bond behaves as an active functional group thereby securing ecologically friendly (green) organic synthesis. Since in these processes hydrogen formally leaves as a hydride-ion (often as H+/2e) and carbanionic or dihydro intermediates are formed in order to complete the substitution, an oxidant (chloranil,1a DDQ,1c O2,1c KMnO4,1c Br2,1a dimethyl dioxirane1a), frequently quite aggressive, is usually required.1,2 Sometimes, electrochemical oxidation of the intermediates is applied.3 Recently, we have found a new type of SNHAr reaction, in which electron-deficient acetylenes play the role of an oxidative agent being selectively reduced to the corresponding E-alkenes.4 So, when pyridine is treated with

benzoylphenylacetylene and diphenylphosphine oxide without catalyst at 70 °C for 24 h, regioselective substitution of hydrogen at position 4 occurs to give diphenylphosphorylpyridine in 57% yield along with Ebenzoylphenylethene (Scheme 1). It has been shown that substitution proceeds via the intermediate N-acylvinyl-4-phosphoryldihydropyridines, sometimes isolable in minor quantities, which are readily convertible to the final products.4 However, similar intermediates obtained with propiolates remain stable.5 Scheme 1. Regioselective nucleophilic substitution in pyridine by diphenylphosphine oxide in the presence of benzoylphenylacetylene as oxidant Previous work O

Ph + Ph

N

Ph

ACS Paragon Plus Environment

H

Ph

P

O N Ph

70 °C, 24 h MeCN

Ph

O

Ph

O

+ Ph

P

Ph

O

O

P

+ N

Ph 57%

Ph

Ph

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 15

2 RESULTS AND DISCUSSION Here we report on peculiarities of this reaction in the quinoline series. At first glance, the expected SNHAr substitution will face no obstacles. However, the reaction took another direction. Indeed, when quinolines 1a-d were allowed to contact secondary phosphine oxides 2a-c and terminal acylacetylenes 3a,b without catalysts at room temperature, instead of the substitution, reductive incorporation of phosphine oxides 2a-c into the quinoline scaffold occurred to deliver N-acylvinyl-2-phosphoryldihydroquinolines 4a-i in 60–80% yield. The synthetically suitable reactant molar ratio was optimized to be 1:2:3 = 1.2:1:1.2 (Scheme 2). These small excesses of quinolines and acetylenes relative to phosphine oxides were required due to side transformations of the primary quinoline/acetylene zwitterions. Reaction completion was monitored by 31P NMR spectroscopy, up to the exhaustive conversion of a starting phosphine oxide that corresponds to the full disappearance of the phosphine oxide 31P signals in the reaction mixture. Scheme 2. Tandem regio- and stereoselective addition of acylacetylenes and secondary phosphine oxides to quinolinesa R3 R1 +

R2 N 1a-d

R

3

R3

O P

O 20-25 °C, 4.5-17 h

+

Ph

N

Ph

P

Ph

Ph

N

4a, 75% (5 h)

Ph

P

Ph

O

Ph

N

Furyl

Me

O

O P

Ph

N

P

Ph Ph

N OMe

O

O 4g, 75% (10 h)

N

+ N

P

Ph

O + Ph

H

Ph Ph

MeCN

Ph

2a

1a

O 70-75 °C, 50 h

Ph

+

N

P

P N

H

6

O

O

O

Ph

P

Ph

5a

Ph Ph

7

The reaction of isoquinolines 8a-d with secondary phosphine oxides 2a,b,d and terminal acylacetylenes 3a,b proceeded faster (3–12 h) and provided better yields (65–91%) as compared to the quinoline series (Scheme 4). Scheme 4. Tandem regio- and stereoselective addition of acylacetylenes and secondary phosphine oxides to isoquinolinesa

Ph

P

Ph

R3

Ph

Me

R

1

R

+

N

4

R4

P

O H

Me

R5

R4 P O

3a,b

O

R4 9a-k Br

O P

Me

R1 N

MeCN

R5

2a,b,d

8a-d

R2

20-25 °C, 3-12 h

O

+

N N

Ph

N

4h, 77% (9 h)

P

O 4f, 70% (8 h)

O

O

O

R3

R2

Ph

4e, 74% (8 h)

Furyl

Furyl

O Me

O

Ph

Ph

4c, 80% (4.5 h)

O

Furyl

4d, 76% (7 h) Ph

R2

O

O 4b, 78% (7 h)

O Ph

P

4a-i

Scheme 3. Reaction of benzoylphenylacetylene and diphenylphosphine oxide with quinoline

Furyl

Furyl

Ph

N

O O

Ph

P

O R1

P

R4

3a,b

O

Ph

MeCN

R4

H

2a-c

R

3

The narrow range of the product yields (60–80%) evidences a weak substituent effect on the reaction course albeit the process is much faster with 3-methylquinoline (4.5 h vs 5–17 h for other cases, Scheme 2). The longest reaction time (17 h) and the lowest yield (60%) were observed for phosphine oxide 2c with the bulkiest substituent, PhCH(Me)CH2, that hints at a steric hindrance. The importance of sterics in this reaction was manifested with an internal acylacetylene, benzoylphenylacetylene 5a, which demanded 50 h at 70 °C to give a mixture (1.1:1) of a target N-benzoylvinyl-2-diphenylphosphoryldihydroquinoline 6 and 2,4-bis(diphenylphosphoryl)tetrahydroquinoline 7. The latter (Scheme 3) was shown to form almost quantitatively when phosphine oxide 2a with quinoline 1a were heated at 70 °C for 18 h (see Experimental section).

N

Ph

Ph P O Ph

Ph P O Ph

O

Furyl

Furyl

Ph P O O Ph 9c, 91% (8 h)

O

9b, 91% (5 h)

9a, 87% (3 h)

Me N

N

Br

N

N N

Ph

aReagents and conditions: quinoline 1a-d (1.2 mmol), secondary phosphine oxide 2a-c (1.0 mmol), acylacetylene 3a,b (1.2 mmol), MeCN (3 mL), 20–25 °C.

Thus, the following differences from reaction of the same reactants with pyridines feature the process with quinolines: (i) in no caseswere substitution products detected; (ii) regioselective 1,2-addition of acylacetylenes and phosphine oxides to quinolines took place, 1,4-addition being not observed at all; (iii) 100% E-stereoselectivity of the aminoenone moiety on the adduct was attained; (iv) much milder conditions of the reaction (20 °C vs 70 °C, 4.5–17 h vs 20–70 h) were required. Eventually, the reaction stops at the stage of the intermediate dihydroderivatives which appear to be quite stable and do not undergo aromatization with elimination of alkenes. This is in a sharp contrast to the pyridine series. In other words, here we have faced a delayed SNHAr reaction.

O

9d, 74% (4 h)

NO2

O 4i, 60% (17 h)

Furyl

Ph P O Ph

Furyl

Ph P O Ph

Ph

O

P O

N

Ph O

O

Ph

Ph 9f, 82% (6 h)

9e, 87% (7 h)

Furyl

P O

Ph

9g, 70% (8 h)

N

Furyl

P O

Ph

O

Ph 9h, 80% (10 h)

NO2 N

N Ph

P O

Furyl O

Ph 9i, 87% (12 h)

p-ClC6H4

P O p-ClC6H4 9j, 78% (7 h)

N

Ph O

p-ClC6H4

P O

Furyl O

p-ClC6H4 9k, 65% (10 h)

aReagents and conditions: isoquinoline 8a-d (1.2 mmol), secondary phosphine oxide 2a,b,d (1.0 mmol), acylacetylene 3a,b (1.2 mmol), MeCN (3 mL), 20–25 °C.

The slowest process (10, 12 h) is observed for 4-bromo- and 5-nitroisoquinolines 8b,d, especially in combination with more voluminous bis(2-phenylethyl)phosphine oxide 2b (Scheme 4, 9h and 9i), that clearly indicates the importance of nitrogen atom basicity and steric shielding of the phosphorus atom. Evidently, the reaction accelerates as isoquinoline basicity increases and steric constrains from the phosphine oxide side reduce.

ACS Paragon Plus Environment

Page 3 of 15 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

3 Noteworthy, in the case of bis(2-phenylethyl)phosphine sulfide 10a, along with the predicted N-acylvinyl-1phosphorylated dihydroisoquinolines 11a,b, the adducts of this phosphine chalcogenide to acylacetylenes are formed, approximately in equal ratio yields (according to 31P NMR spectra of the reaction mixture) with the yields being 51, 40% for 11a,b and 45, 35% for 12a,b, respectively (Scheme 5). Scheme 5. Reaction of isoquinoline, bis(2phenylethyl)phosphine sulfide and acylacetylenes Ph

+

N

P

Ph

10a

8a

S H

N

3a,b

20-25 °C, 3-4 h MeCN

R

Ph

R

P S

Ph

O

+

P

Ph

+

S R

O

O

Ph 11a, R = Ph (51%) 11b, R = Furyl (40%)

12a, R = Ph (45%) 12b, R = Furyl (35%)

Obviously, this side formation of P-acylvinylphosphine sulfides 12a,b results from the higher nucleophilicity of phosphine sulfide 10a as compared to the corresponding oxide 2b. This also agrees well with the two-fold faster formation (3, 4 h vs 6, 8 h for corresponding phosphine oxide, Scheme 4, 9f and 9g) of dihydroisoquinolines. The key steric effect role on this tandem vinylation/phosphorylation of isoquinoline is especially manifested when internal acetylenes 5a,b are involved in this reaction (Scheme 6). Scheme 6. Tandem addition of acylphenylacetylenes and secondary phosphine chalcogenides 2b, 10a,b to isoquinolinea R1 N

+

R1

X

P

+ Ph

H

70-75 °C, 45-72 h

R2

MeCN

O

O O Ph

P

N Ph

O N Ph R1 P X 1 R 13a-e

5a,b

2b, 10a,b

8a

O

Ph

O

P

Ph

Ph 13a, 51% (72 h)

N Ph

O Furyl

S

Ph

P

Ph 13d, 66% (45 h)

Ph

Ph 13c, 62% (50 h) O

O S

P

N Ph

Ph

Ph

13b, 65% (65 h) N Ph

R2

Furyl

S p-ClC6H4

P

N Ph

Furyl

p-ClC6H4

13e, 60% (50 h)

aReagents and conditions: isoquinoline 8a (1.5 mmol), secondary phosphine chalcogenide 2b, 10a,b (1.0 mmol), acylphenylacetylene 5a,b (1.5 mmol), MeCN (3 mL), 70–75 °C.

As seen from Scheme 6, even at a much higher temperature (70–75 °C) the process proceeds about ten times slower, providing yields ~20–30% less relative to the corresponding terminal acylacetylenes. Although the regioselectivity of this tandem addition is retained for both quinolines and isoquinolines, the stereochemistry is changed. In all cases, the reaction mixture contains mainly (70–75%) the Z-isomers, but after column chromatography (silica) purification, the content of E-isomer increases up to ~60%. This implies that the Zisomer is a kinetic product. Similar to all the above cases, the aromatization of dihydroquinolines and isoquinolines to the anticipated

phosphorylated derivatives with elimination of acylalkenes (to complete SNHAr reaction) does not occur. As 1H NMR analysis shows, the crude products have minor admixture (~up to 10%) of adducts of phosphine chalcogenides to acetylenes6 and enols resulted from trace water addition to the starting acylacetylenes.7 Our attempts to force the elimination of acylalkenes from the N-benzoylethenyl-1-bis(2-phenylethyl)phosphoryldihydroisoquinoline 9f have led to the starting isoquinoline 8a and secondary phosphine oxide 2b, together with polymeric products. This backward process takes place upon heating (105–110 °C), or with acids (CF3COOH, room temperature, 3 h; CH3COOH, 70–75 °C, 20 h) or copper halides (CuBr2, CuI). The ease of the backward process is obviously due to vicinal disposition of the chalcogenophosphoryl and acylethenyl groups that facilitates the elimination of both moieties via a six-membered transition state (Scheme 7). The acylacetylenes thus released can form the adducts with the eliminated phosphine chalcogenides, trace water and undergo oligomerization. Scheme 7. Backward aromatization of dihydroisoquinoline 9f in the presence of acids or copper (II) halides O Ph

N P

+

Ph

H

Ph

2+

H (Cu )

O Ph

O

9f

+N

2+ + N H (Cu )

P

O

Ph + 2+

H (Cu )

Ph Ph

O P 2b

H

Ph

H

O

+

Ph

With conventional oxidants like chloranil or DDQ, the same backward aromatization to give isoquinolines and adducts8 of phosphine oxide 2b to carbonyl groups of the quinones is detected. Also, under the action of a strong base (t-BuOK in THF) on dihydroisoquinoline 13a, elimination of bis(2phenylethyl)phosphine oxide 2b to restore the starting isoquinoline occurs. However, a positive result in these attempts to complete the expected SNHAr reaction has been achieved, when dihydroisoquinoline 13a has been treated with the combined system t-BuOK/DDQ: in the reaction mixture, along with the initial compound 13a, the aromatic bis(2phenylethyl)phosphorylisoquinoline 14, the product of the expected SNHAr reaction, is detected (31P, 1H NMR), Scheme 8. Scheme 8. Aromatization of dihydroisoquinoline 13a by tBuOK/DDQ system O O Ph

P

N Ph

13a

Ph

Ph

t-BuOK/DDQ, THF

Ph

o

Ph

20-25 C, 2 h

O P

+ 13a N

14 14:13a (3:1)

Eventually, we have developed a one-pot atom-economic single-step synthesis of novel pharmaceutically prospective compounds, which meets the PASE9 paradigm. Considering the mechanism of the reaction investigated, it is assumed that the driving force of the process is activation of the pyridine ring in 1,3(4)-dipolar intermediate A reversibly resulted from nucleophilic attack of the nitrogen atom of the

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 4 of 15

4 quinolines (isoquinolines) at the triple bond of the acylacetylenes, which therefore act as triggers of the follow up tandem transformation. It includes hydrogen transfer from phosphine chalcogenides to the carbanionic center of intermediate A, giving the carbocationic intermediate B, further accepting the phosphorus-centered anion onto position 2 of the pyridine moiety (Scheme 9). Scheme 9. Plausible mechanism of tandem addition of acylacetylenes and secondary phosphine chalcogenides to (iso)quinolines + N

O

+

-

-

Ph

N

Ph

Ph

O A

Ph

P

H

N

+

O H

+

-P

B Ph

Ph

Ph Ph

O O

Ph

O

Ph

+

N

P N

Ph

O

O

It is likely that the tandem Nvinylation/phosphorylation process proceeds simultaneously via six-membered cyclic transition state C (Scheme 10) that is geometrically predetermined by the 1,2-disposition of acylethenyl and chalcogenophosphoryl functions. In turn, this geometrical background is probably the reason for the easy reverse aromatization of the dihydroderivatives 4, 9, 13 towards the starting quinolines or isoquinolines (Scheme 7). Scheme 10. Alternative plausible mechanism of tandem addition of acylacetylenes and secondary phosphine chalcogenides to (iso)quinolines

+

+ N

O

Ph

Ph

O A

O

Ph Ph

P

H

N

+ -

Ph

O

Ph P H Ph

O C

+

Figure 1. Charge distribution and LUMO localization (in brackets) in pyridine and zwitterionic adducts of pyridine and quinoline with benzoylphenylacetylene

-

-

Ph

N

N

internal acetylenes) is rendered by steric requirements. The reaction regioselectivity is understood in terms of an anticipated stronger positive charge at the α-position relative to the nitrogen atom, provided the process is a chargecontrolled one. Thus, the question arises: why do pyridines, when treated with phosphine chalcogenides and acylarylacetylenes, undergo smooth SNHAr reaction at the γ(4)-position of the heterocyclic ring, while nucleophilic attack, in the case of quinolines and isoquinolines, is directed at the α-position (2 or 1, respectively) and the process remains a pendant on dihydroderivative step? In other words, why, in the quinoline series, does the electron-deficient acetylene trigger only nucleophilic addition and is not further eliminated as the corresponding alkene to free the aromatic phosphorylated quinolines thereby playing an oxidant role and completing the SNHAr reaction? Our quantum chemical calculations (HF/6311G**//B3LYP/6-311G**, see Supporting Information for details) show (Figure 1) that α-positions to the nitrogen atom both in pyridine- and quinoline-derived zwitterions bear positive charges (0.17 and 0.23, respectively), while the γpositions are almost neutral (-0.06 and -0.02, respectively). However, the LUMO localization at the γ-position of pyridine zwitterion is higher than that in the quinoline zwitterion (0.34 and 0.29, respectively), so the α-positions have a much lower LUMO localization (0.18). Consequently, nucleophilic attack at the pyridine zwitterion is not charge- but orbital-controlled, whereas for quinoline or isoquinoline cases charge-control is in effect, which well agrees with the experiment. Comparison of charge distribution in free pyridine and in zwitterions (Figure 1) confirms the polarization, and hence activation of the heterocyclic ring in the latter, as well as polarization of the acylvinyl moiety (the carbanionic character of β-carbon relative to the nitrogen atom).

O

Ph Ph

O

P

-0.27 (0.09) 0.10 (0.11)

-0.13 (0.36)

N -0.49 (0.24)

N

-0.27 (0.09)

-0.26 (0.08)

0.10 (0.11)

0.21 (0.14)

-0.06 (0.34)

-0.39 (0.17)

Ph

N

-0.27 (0.03) 0.17 (0.18)

-0.18 (0.04)

-0.75

O (0.01)

0.56 -0.02 (0.01) -0.24 (0.00) (0.01)

Ph

-0.13 (0.08)

-0.02 -0.15 (0.09) -0.12 (0.29) (0.01)

-0.29 (0.05) 0.23

0.26

-0.18 (0.04) (0.06)

-0.74 N-0.38(0.18) O (0.00) (0.13)

0.56 -0.04 Ph (0.00) -0.24 (0.00) Ph (0.01)

Ph O

The above mechanism is in good agreement with experimentally observed structural effects. Indeed, it well explains why the reaction with isoquinolines is more facile than that with quinolines: this predictably results from a higher basicity of isoquinoline (pKa values 5.46 and 4.93, respectively),10 thus providing a greater concentration of intermediate A (Scheme 9). Consequently electronwithdrawing substituents in the isoquinoline ring slow down the reaction (Scheme 4). Also, in accord with the suggested mechanism, the voluminous phosphine oxide 2b (with phenylethyl substituents) and internal acylacetylene substantially hinder the process due to steric restriction for the formation of intermediates A and B or cyclic transition state C. Obviously, the observed stereochemistry (E-configuration of the adducts for terminal acylacetylenes and kinetic Z-isomers in case of

CONCLUSION Quinolines and isoquinolines react in a tandem manner with acylacetylenes and secondary phosphine chalcogenides under catalyst-free conditions at 20–75 °C to afford N-acylvinyl2(1)-chalcogenophosphoryldihydroquinolines in good and excellent yields. This contrasts with pyridines, wherein similar intermediates eliminate E-alkenes to give aromatic chalcogenophosphorylpyridines, thus finishing an SNHAr reaction. The above results for quinolines represent a pendant SNHAr process. Another peculiar feature of this reaction is phosphorylation of the 2(1)-position of quinoline ring, while pyridines are phosphorylated at position 4. This difference has been rationalized by quantum chemical analysis, which showed the phosphorylation step to be charge-controlled for quinolines while orbital-controlled for pyridines. The reaction developed opens a one-pot atom-economic single-step access to novel families of phosphorylated functionalized

ACS Paragon Plus Environment

Page 5 of 15 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

5 dihydroquinolines and isoquinolines, intermediates for pharmaceuticals.

prospective

Experimental Section General information. All reactions were carried out under an argon atmosphere. Quinolines 1a-d, isoquinolines 8a-d and diphenylphosphine oxide 2a are commercial reagents (Aldrich). Secondary phosphine chalcogenides 2b-d, 10a,b were prepared from styrene, 4-chlorostyrene, α-methylstyrene and elemental phosphorus as previously described.11 Acylacetylenes 3a,b, 5a,b were prepared by reported methods.12 The reaction was monitored using 31P NMR monitoring the disappearance of peaks of the initial secondary phosphine chalcogenides. The 1H, 13C, 15N and 31P NMR spectra were recorded on Bruker DPX 400 and Bruker AV400 spectrometers (400.13, 100.62, 40.56 and 161.98 MHz, respectively) in CDCl3 and DMSO-d6 solutions and referenced to HMDS (1H, 13C), MeNO2 (15N) and H3PO4 (31P). The assignment of signals in 1H spectra was performed using 2D homonuclear correlation method COSY. Resonance signals of 13C were assigned with application of 2D heteronuclear correlation methods HSQC and HMBC. The values of the δ 15N were measured through the 2D 1H-15N HMBC experiment. FT-IR spectra were obtained with a Varian 3100 FT-IR spectrometer. The C, H, N microanalyses were performed on a Flash EA 1112 Series elemental analyzer. The Br, Cl, P and S content were determined by combustion method. Reaction of secondary phosphine oxides 2a-c with quinolines 1a-d and terminal acylacetylenes 3a,b: General procedure. To a solution of secondary phosphine oxide 2a-c (1.0 mmol) in MeCN (3 mL), quinoline 1a-d (1.2 mmol) and terminal acylacetylene 3a,b (1.2 mmol) were added in three portions at regular intervals. The mixture was stirred under an argon atmosphere at 20–25 °C for 4.5–17 h (see also Scheme 2). After completion of the reaction (31P NMR monitoring), the solvent was removed under reduced pressure. The obtained residue was purified by column chromatography on SiO2 (eluent: toluene/ethyl acetate, 1:1) with subsequent reprecipitation of the crude product from CHCl3 to hexane to yield the target 1,2-dihydroquinolines 4a-i. (2E)-3-[2-(diphenylphosphoryl)quinolin-1(2H)-yl]-1phenylprop-2-en-1-one (4a). Yield: 346 mg (75%); brown powder, mp 175–178 °С (reprecipitated from CHCl3 to hexane). 1H NMR (400.13 MHz, CDCl3): δ 5.53 (dd, 1H, H-2, quinoline, 3J2-3 = 5.9 Hz, 2JPH = 11.7 Hz); 5.93 (br s, 1H, H-3, quinoline); 6.34 (d, 1H, =CHC(O)Ph, 3Jtrans = 12.7 Hz); 6.45 (dd, 1H, H-4, quinoline, 3J4-3 = 8.2 Hz, 4J4-P = 3.6 Hz); 6.78 (d, 1H, H-8, quinoline, 3J8-7 = 7.2 Hz); 6.91 (t, 1H, H-7, quinoline, 3J 3 3 7-8 ≈ J7-6 = 7.2 Hz); 6.98 (d, 1H, H-5, quinoline, J5-6 = 7.2 Hz); 7.15 (t, 1H, H-6, quinoline, 3J6-5 ≈ 3J6-7 = 7.2 Hz); 7.32– 7.46 (m, 9H, Hm,p, PhC(O); Hm,p, PhP); 7.69–7.73 (m, 4H, Ho, PhP); 7.83–7.88 (m, 2H, Ho, PhC(O)); 7.93 (d, 1H, =CHN, 3J 13 1 trans = 12.7 Hz). C{ H} NMR (100.62 MHz, CDCl3): δ 60.0 (d, C-2, quinoline, 1JCP = 71.0 Hz); 98.8 (=CHC(O)Ph); 117.9 (C-8, quinoline); 120.1 (C-6, quinoline); 124.2 (С-7, quinoline); 125.2 (d, C-4a, quinoline, 4JCP = 3.1 Hz); 126.7 (C-3, quinoline); 127.6 (Со, PhC(O)); 127.7 (d, C-4, quinoline, 3J CP = 8.4 Hz); 127.9 (Сm, PhC(O)); 128.1, 128.2 (2d, Cm, PhP, 3J 3 1 CP = 11.4 Hz, JCP = 11.6 Hz); 128.5, 129.8 (d, Ci, PhP, JCP = 93.1 Hz); 129.2 (C-5, quinoline); 131.2, 131.7 (2d, Co, PhP, 2J 2 CP = 8.8 Hz, JCP = 9.4 Hz); 131.4 (Сp, PhC(O)); 132.1, 132.2 (d, Сp, PhP, 4JCP = 2.8 Hz); 135.9 (Сi, PhC(O)); 139.0 (С-8a,

quinoline); 148.7 (=CHN); 188.8 (C=O). 31P NMR (161.98 MHz, CDCl3): δ 26.2. IR (KBr): νmax = 3058, 2926, 1646, 1582, 1542, 1493, 1445, 1334, 1305, 1240, 1212, 1181, 1117, 1051, 1022, 969, 915, 731, 700, 664, 539, 502 cm-1. Anal. Calcd for С30Н24NO2P: С, 78.08; Н, 5.24; N, 3.04; P, 6.71. Found: С, 78.26; Н, 5.18; N, 3.09; P, 6.50. (2E)-3-[2-(diphenylphosphoryl)quinolin-1(2H)-yl]-1(furan-2-yl)prop-2-en-1-one (4b). Yield: 352 mg (78%); brown powder, mp 173–175 °С (reprecipitated from CHCl3 to hexane). 1H NMR (400.13 MHz, CDCl3): δ 5.53 (dd, 1H, H-2, quinoline, 3J2-3 = 5.6 Hz, 2JPH = 11.4 Hz); 5.96 (br s, 1H, H-3, quinoline); 6.21 (d, 1H, =CHC(O)Furyl, 3Jtrans = 13.1 Hz); 6.48–6.51 (m, 2H, H-4, quinoline; H-4, furyl); 6.81 (d, 1H, H8, quinoline, 3J8-7 = 7.2 Hz); 6.95 (dd, 1H, H-7, quinoline, 3J7-8 ≈ 3J7-6 = 7.2 Hz); 7.00–7.03 (m, 2H, H-5, quinoline; H-3, furyl); 7.18 (dd, 1H, H-6, quinoline, 3J6-5 ≈ 3J6-7 = 7.2 Hz); 7.33–7.45 (m, 6H, Hm,p, PhP); 7.52 (m, 1H, H-5, furyl); 7.72, 7.87 (m, 4H, Ho, PhP); 7.92 (d, 1H, =CHN, 3Jtrans = 13.1 Hz). 13C{1H} NMR (100.62 MHz, CDCl ): δ 60.2 (d, C-2, 3 quinoline, 1JCP = 70.5 Hz); 98.4 (=CHC(O)Furyl); 112.1 (C-4, furyl); 115.1 (C-3, furyl); 118.3 (C-8, quinoline); 120.4 (C-6, quinoline); 124.7 (С-7, quinoline); 125.7 (d, C-4a, quinoline, 4J CP = 3.1 Hz); 127.1 (C-3, quinoline); 128.2 (d, C-4, quinoline, 3JCP = 8.4 Hz); 128.4, 128.5 (2d, Cm, PhP, 3JCP = 10.3 Hz, 3JCP = 11.1 Hz); 129.3 (d, Ci, PhP, 1JCP = 114.6 Hz); 129.5 (C-5, quinoline); 131.5, 132.0 (2d, Co, PhP, 2JCP = 8.8 Hz, 2JCP = 9.2 Hz); 132.4, 132.5 (d, Сp, PhP, 4JCP = 2.3 Hz); 139.2 (С-8a, quinoline); 145.2 (C-5, furyl); 148.1 (=CHN); 154.1 (C-2, furyl); 177.7 (C=O). 15N NMR (40.56 MHz, CDCl3): δ -279.6. 31P NMR (161.98 MHz, CDCl3): δ 26.9. IR (KBr): νmax = 3057, 2926, 2856, 1643, 1545, 1483, 1465, 1384, 1334, 1305, 1249, 1203, 1165, 1115, 1091, 1067, 1018, 970, 921, 837, 729, 700, 645, 534, 502 cm-1. Anal. Calcd for С28Н22NO3P: С, 74.49; Н, 4.91; N, 3.10; P, 6.86. Found: С, 74.38; Н, 4.97; N, 3.16; P, 6.61. (2E)-3-[2-(diphenylphosphoryl)-3-methylquinolin-1(2H)yl]-1-(furan-2-yl)prop-2-en-1-one (4c). Yield: 372 mg (80%); yellow powder, mp 180–182 °С (reprecipitated from CHCl3 to hexane). 1H NMR (400.13 MHz, CDCl3): δ 1.95 (s, 3H, Me); 5.21 (d, 1H, H-2, quinoline, 2JPH = 12.7 Hz); 6.05 (d, 1H, =CHC(O)Furyl, 3Jtrans = 12.9 Hz); 6.21 (br s, 1H, H-4, quinoline); 6.46 (dd, 1H, H-4, furyl, 3J4-3 = 3.5 Hz, 3J4-5 = 1.8 Hz); 6.79 (d, 1H, H-5, quinoline, 3J5-6 = 7.4 Hz); 6.91 (d, 1H, H-8, quinoline, 3J8-7 = 8.1 Hz); 6.95–6.98 (m, 2H, H-6, quinoline; H-3, furyl); 7.15 (dd, 1H, H-7, quinoline, 3J7-8 ≈ 3J76 = 8.1 Hz); 7.19–7.22, 7.33–7.43 (m, 6H, Hm,p, PhP); 7.50 (d, 1H, H-5, furyl, 3J5-4 = 1.8 Hz); 7.51–7.57, 7.83–7.88 (m, 4H, Ho, PhP); 7.76 (d, 1H, =CHN, 3Jtrans = 12.9 Hz). 13C{1H} NMR (100.62 MHz, CDCl3): δ 22.2 (Me); 64.8 (d, C-2, quinoline, 1J CP = 66.9 Hz); 98.0 (=CHC(O)Furyl); 111.9 (C-4, furyl); 114.8 (C-3, furyl); 117.7 (C-8, quinoline); 123.6 (d, C-4, quinoline, 3JCP = 7.8 Hz); 124.7 (C-6, quinoline); 126.1 (C-5, quinoline); 126.6 (d, C-4a, quinoline, 4JCP = 2.8 Hz); 127.8, 128.3 (2d, Cm, PhP, 3JCP = 11.4 Hz, 3JCP = 11.8 Hz); 128.2 (С7, quinoline); 129.2, 129.7 (2d, Ci, PhP, 1JCP = 90.1 Hz, 1JCP = 93.7 Hz); 130.6 (d, C-3, quinoline, 2JCP = 1.2 Hz); 131.3, 131.5 (2d, Co, PhP, 2JCP = 9.0 Hz, 2JCP = 9.6 Hz); 132.0, 132.3 (d, Сp, PhP, 4JCP = 2.4 Hz); 137.1 (С-8a, quinoline); 144.9 (C5, furyl); 147.0 (=CHN); 153.8 (C-2, furyl); 177.2 (C=O). 15N NMR (40.56 MHz, CDCl ): δ -273.9. 31P NMR (161.98 3 MHz, CDCl3): δ 29.1. IR (KBr): νmax = 3057, 2982, 1644,

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 6 of 15

6 1547, 1484, 1468, 1443, 1383, 1334, 1304, 1243, 1205, 1164, 1110, 1093, 1066, 1014, 969, 935, 875, 838, 753, 698, 667, 570, 513 cm-1. Anal. Calcd for С29Н24NO3P: С, 74.83; Н, 5.20; N, 3.01; P, 6.65. Found: C, 74.73; Н, 5.13; N, 2.95; P, 6.38. (2E)-3-[2-(diphenylphosphoryl)-6-methylquinolin-1(2H)yl]-1-(furan-2-yl)prop-2-en-1-one (4d). Yield: 354 mg (76%); brown powder, mp 189–190 °С (reprecipitated from CHCl3 to hexane). 1H NMR (400.13 MHz, CDCl3): δ 1.94 (s, 3H, Me); 5.54 (br s, 1H, H-2, quinoline); 5.92 (d, 1H, H-3, quinoline, 3J 3 3-4 = 9.5 Hz); 6.29 (d, 1H, =CHC(O)Furyl, Jtrans = 12.9 Hz); 3 3 6.46 (dd, 1H, H-4, furyl, J4-3 = 3.5 Hz, J4-5 = 1.7 Hz); 6.79– 6.81 (m, 2H, H-4,5, quinoline); 6.87–6.90 (m, 1H, H-3, furyl); 7.05–7.10 (m, 2H, H-7,8, quinoline); 7.27–7.31 (m, 4H, Hm, PhP); 7.38–7.43 (m, 2H, Hp, PhP); 7.51 (d, 1H, H-5, furyl, 3J 5-4 = 1.7 Hz); 7.62–7.68 (m, 4H, Ho, PhP); 7.76 (d, 1H, =CHN, 3Jtrans = 12.9 Hz). 13C{1H} NMR (100.62 MHz, CDCl3): δ 20.4 (Me); 60.1 (d, C-2, quinoline, 1JCP = 70.2 Hz); 97.5 (=CHC(O)Furyl); 111.8 (C-4, furyl); 114.7 (C-3, furyl); 118.1 (C-8, quinoline); 120.1 (C-3, quinoline); 125.4 (d, C-4a, quinoline, 4JCP = 3.1 Hz); 127.5 (C-5, quinoline); 128.1 (d, C4, quinoline, 3JCP = 8.4 Hz); 128.2, 128.3 (d, Cm, PhP, 3JCP = 11.5 Hz); 128.8, 129.8 (d, Ci, PhP, 1JCP = 93.1 Hz); 129.8 (С7, quinoline); 131.3, 131.7 (2d, Co, PhP, 2JCP = 8.7 Hz, 2JCP = 9.7 Hz); 132.1, 132.2 (2d, Сp, PhP, 4JCP = 2.6 Hz, 4JCP = 2.9 Hz); 134.1 (C-6, quinoline); 136.7 (С-8a, quinoline); 144.8 (C-5, furyl); 148.0 (=CHN); 153.9 (C-2, furyl); 177.5 (C=O). 15N NMR (40.56 MHz, CDCl ): δ -279.2. 31P NMR (161.98 3 MHz, CDCl3): δ 27.1. IR (KBr): νmax = 3057, 2980, 2926, 2863, 1644, 1561, 1548, 1492, 1469, 1386, 1334, 1304, 1246, 1212, 1163, 1118, 1092, 1062, 1018, 968, 934, 885, 804, 754, 702, 669, 585, 534 cm-1. Anal. Calcd for С29Н24NO3P: С, 74.83; Н, 5.20; N, 3.01; P, 6.65. Found: С, 74.66; Н, 5.25; N, 3.06; P, 6.41. (2E)-3-[2-(diphenylphosphoryl)-6-methoxyquinolin-1(2H)yl]-1-(furan-2-yl)prop-2-en-1-one (4e). Yield: 356 mg (74%); beige powder, mp 164–166 °С (reprecipitated from CHCl3 to hexane). 1H NMR (400.13 MHz, CDCl3): δ 3.76 (s, 3H, OMe); 5.49 (dd, 1H, H-2, quinoline, 3J2-3 = 6.0 Hz, 2JPH = 11.5 Hz); 6.02 (ddd, 1H, H-3, quinoline, 3J3-4 = 9.7 Hz, 3J3-2 = 6.0 Hz, 3J 3 PH = 2.8 Hz); 6.12 (d, 1H, =CHC(O)Furyl, Jtrans = 12.9 Hz); 6.41 (d, 1H, H-5, quinoline, 4J5-7 = 2.7 Hz); 6.47–6.51 (m, 2H, H-4, quinoline; H-4, furyl); 6.75 (dd, 1H, H-7, quinoline, 3J7-8 = 8.6 Hz, 4J7-5 = 2.7 Hz); 6.97 (d, 1H, H-8, quinoline, 3J8-7 = 8.6 Hz); 7.01 (d, 1H, H-3, furyl, 3J3-4 = 3.5 Hz); 7.33–7.50 (m, 6H, Hm,p, PhP); 7.52 (d, 1H, H-5, furyl, 3J5-4 = 1.8 Hz); 7.69–7.75, 7.85–7.91 (m, 4H, Ho, PhP); 7.89 (d, 1H, =CHN, 3J 13 1 trans = 12.9 Hz). C{ H} NMR (100.62 MHz, CDCl3): δ 55.2 (OMe); 60.1 (d, C-2, quinoline, 1JCP = 68.9 Hz); 97.0 (=CHC(O)Furyl); 111.6 (C-4, furyl); 112.1 (C-5, quinoline); 114.2 (С-7, quinoline); 114.4 (C-3, furyl); 119.3 (C-8, quinoline); 120.9 (C-3, quinoline); 126.5 (C-4a, quinoline); 127.9, 128.2 (2d, Cm, PhP, 3JCP = 11.6 Hz, 3JCP = 11.2 Hz); 128.1 (d, C-4, quinoline, 3JCP = 8.2 Hz); 128.6, 129.6 (2d, Ci, PhP, 1JCP = 91.0 Hz, 1JCP = 90.7 Hz); 131.2, 131.5 (2d, Co, PhP, 2JCP = 8.8 Hz, 2JCP = 9.6 Hz); 132.0, 132.2 (2d, Сp, PhP, 4J 4 CP = 2.4 Hz, JCP = 2.8 Hz); 132.3 (С-8a, quinoline); 144.5 (C-5, furyl); 148.2 (=CHN); 153.8 (C-2, furyl); 156.4 (C-6, quinoline); 177.3 (C=O). 15N NMR (40.56 MHz, CDCl3): δ 276.1. 31P NMR (161.98 MHz, CDCl3): δ 27.0. IR (KBr): νmax = 3056, 2984, 2837, 1641, 1546, 1496, 1469, 1436, 1379, 1337, 1306, 1220, 1163, 1117, 1094, 1066, 1043, 1017, 974, 929, 851, 801, 752, 701, 590, 533 cm-1. Anal. Calcd for

С29Н24NO4P: С, 72.34; Н, 5.02; N, 2.91; P, 6.43. Found: С, 72.21; Н, 5.09; N, 2.97; P, 6.13 (2E)-3-{2-[bis(2-phenylethyl)phosphoryl]quinolin-1(2H)yl}-1-phenylprop-2-en-1-one (4f). Yield: 362 mg (70%); brown powder, mp 144–145 °С (reprecipitated from acetone to hexane). 1H NMR (400.13 MHz, CDCl3): δ 1.75–1.97 (m, 4H, CH2P); 2.66–2.88 (m, 4H, CH2Ph); 5.06 (dd, 1H, H-2, quinoline, 3J2-3 = 6.1 Hz, 2JPH = 14.3 Hz); 5.86 (ddd, 1H, H-3, quinoline, 3J3-4 = 9.7 Hz, 3J3-2 = 6.1 Hz, 3JPH = 2.4 Hz); 6.54 (dd, 1H, H-4, quinoline, 3J4-3 = 9.7 Hz, 4JPH = 4.2 Hz); 6.74 (d, 1H, =CHC(O)Ph, 3Jtrans = 12.7 Hz); 6.77–6.78 (m, 2H, Hp, PhCH2); 6.98–7.16 (m, 11H, Ho,m, PhCH2; H-5,7,8, quinoline); 7.18–7.22 (m, 1H, H-6, quinoline); 7.33–7.36 (m, 2H, Hm, PhC(O)); 7.39–7.43 (m, 1H, Hp, PhC(O)); 7.86–7.88 (m, 2H, Ho, PhC(O)); 8.05 (d, 1H, =CHN, 3Jtrans = 12.7 Hz). 13C{1H} NMR (100.62 MHz, CDCl3): δ 27.3, 27.5 (d, CH2Ph, 2JCP = 3.4 Hz); 27.9, 28.5 (2d, CH2P, 1JCP = 55.5 Hz, 1JCP = 56.6 Hz); 58.7 (d, C-2, quinoline, 1JCP = 64.3 Hz); 99.7 (=CHC(O)Ph); 118.3 (C-8, quinoline); 120.5 (C-3, quinoline); 124.8 (С-7, quinoline); 126.3, 126.6 (Cp, PhCH2); 127.3 (C-4a, quinoline); 127.4 (C-4, quinoline); 127.7, 127.8 (Co, PhCH2); 128.0 (Сm, PhC(O)); 128.2 (C-6, quinoline); 128.3 (Со, PhC(O)); 128.4, 128.6 (Cm, PhCH2); 130.1 (C-5, quinoline); 131.8 (Сp, PhC(O)); 139.1 (С-8a, quinoline); 139.2 (Сi, PhC(O)); 140.2, 140,3 (2d, Ci, PhCH2, 3JCP = 12.2 Hz, 3JCP = 13.4 Hz); 148.9 (=CHN); 189.4 (C=O). 15N NMR (40.56 MHz, CDCl3): δ 280.3. 31P NMR (161.98 MHz, CDCl3): δ 49.2. IR (neat): νmax = 3059, 3030, 2922, 2855, 1646, 1579, 1544, 1492, 1452, 1333, 1305, 1238, 1213, 1174, 1049, 1022, 966, 914, 760, 733, 702, 659 cm-1. Anal. Calcd for С34Н32NO2P: С, 78.90; Н, 6.23; N, 2.71; P, 5.98. Found: С, 78.81; Н, 6.18; N, 2.80; P, 5.72. (2E)-3-{2-[bis(2-phenylethyl)phosphoryl]quinolin-1(2H)yl}-1-(furan-2-yl)prop-2-en-1-one (4g). Yield: 381 mg (75%); beige powder, mp 159–161 °С (reprecipitated from acetone to hexane). 1H NMR (400.13 MHz, CDCl3): δ 1.77–2.06 (m, 4H, CH2P); 2.79–2.94 (m, 4H, CH2Ph); 5.18 (dd, 1H, H-2, quinoline, 3J2-3 = 6.5 Hz, 2JPH = 14.1 Hz); 6.00 (ddd, 1H, H-3, quinoline, 3J3-4 = 9.9 Hz, 3J3-2 = 6.5 Hz, 3J3-P = 2.4 Hz); 6.48 (dd, 1H, H-4, furyl, 3J4-3 = 3.5 Hz, 3J4-5 = 1.8 Hz); 6.62 (dd, 1H, H-4, quinoline, 3J4-3 = 9.9 Hz, 4JPH = 4.3 Hz); 6.69 (d, 1H, =CHC(O)Furyl, 3Jtrans = 13.1 Hz); 6.90–6.91 (m, 2H, Ho, PhCH2); 7.03–7.28 (m, 13H, Ho,m,p, PhCH2; H-5,6,7,8, quinoline; H-3, furyl); 7.49 (d, 1H, H-5, furyl, 3J5-4 = 1.8 Hz); 8.10 (d, 1H, =CHN, 3Jtrans = 13.1 Hz). 13C{1H} NMR (100.62 MHz, CDCl3): δ 27.3, 27.5 (d, CH2Ph, 2JCP = 3.4 Hz); 28.2, 28.5 (2d, CH2P, 1JCP = 57.2 Hz, 1JCP = 55.1 Hz); 58.2 (d, C-2, quinoline, 1JCP = 64.0 Hz); 98.6 (=CHC(O)Furyl); 112.1 (C-4, furyl); 115.3 (C-3, furyl); 118.4 (C-8, quinoline); 120.9 (C-6, quinoline); 125.0 (С-7, quinoline); 125.1 (d, C-4a, quinoline, 4JCP = 2.5 Hz); 126.3, 126.5 (Cp, PhCH2); 127.3 (d, C-4, quinoline, 3JCP = 7.8 Hz); 127.4 (C-3, quinoline); 127.8, 127.9 (Cm, PhCH2); 128.4, 128.6 (Co, PhCH2); 130.1 (C-5, quinoline); 139.1 (С-8a, quinoline); 140.3 (d, Ci, PhCH2, 3JCP = 13.3 Hz); 145.2 (C-5, furyl); 148.2 (=CHN); 154.0 (C-2, furyl); 177.8 (C=O). 15N NMR (40.56 MHz, CDCl3): δ -280.0. 31P NMR (161.98 MHz, CDCl ): δ 49.8. IR (neat): ν 3 max = 3060, 3027, 2960, 2866, 1645, 1575, 1548, 1489, 1463, 1386, 1335, 1307, 1247, 1162, 1066, 1019, 967, 934, 835, 754, 702, 668, 590 cm-1. Anal. Calcd for С32Н30NO3P: С, 75.72; Н, 5.96; N, 2.76; P, 6.10. Found: С, 75.61; Н, 5.89; N, 2.66; P, 5.91.

ACS Paragon Plus Environment

Page 7 of 15 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

7 (2E)-3-{2-[bis(2-phenylethyl)phosphoryl]-6-methylquinolin1(2H)-yl}-1-(furan-2-yl)prop-2-en-1-one (4h). Yield: 402 mg (77%); yellow powder, mp 168–169 °С (reprecipitated from acetone to hexane). 1H NMR (400.13 MHz, CDCl3): δ 1.76– 2.10 (m, 4H, CH2P); 2.32 (s, 3H, Me); 2.83–2.95 (m, 4H, CH2Ph); 5.19 (dd, 1H, H-2, quinoline, 3J2-3 = 6.0 Hz, 2JPH = 13.7 Hz); 6.06 (ddd, 1H, H-3, quinoline, 3J3-4 = 9.9 Hz, 3J3-2 = 6.3 Hz, 3J3-P = 2.2 Hz); 6.52 (dd, 1H, H-4, furyl, 3J4-3 = 3.2 Hz, 3J4-5 = 1.5 Hz); 6.62 (dd, 1H, H-4, quinoline, 3J4-3 = 9.9 Hz, 4JPH = 4.0 Hz); 6.66 (d, 1H, =CHC(O)Furyl, 3Jtrans = 12.9 Hz); 6.92 (s, 1H, H-5, quinoline); 6.96, 7.05 (m, 4H, Ho, PhCH2); 7.11–7.28 (m, 9H, Hm,p, PhCH2; H-7,8, quinoline; H3, furyl); 7.52 (d, 1H, H-5, furyl, 3J5-4 = 1.5 Hz); 8.13 (d, 1H, =CHN, 3Jtrans = 12.9 Hz). 13C{1H} NMR (100.62 MHz, CDCl3): δ 20.6 (Me); 27.5, 27.7 (2d, CH2Ph, 2JCP = 3.6 Hz, 2J 1 1 CP = 2.6 Hz); 28.3, 28.8 (2d, CH2P, JCP = 55.7 Hz, JCP = 1 56.7 Hz); 58.2 (d, C-2, quinoline, JCP = 63.7 Hz); 98.0 (=CHC(O)Furyl); 112.2 (C-4, furyl); 115.2 (C-3, furyl); 118.4 (C-8, quinoline); 121.1 (C-3, quinoline); 125.2 (C-4a, quinoline); 126.4, 126.6 (Cp, PhCH2); 127.6 (d, C-4, quinoline, 3J CP = 7.2 Hz); 127.9, 128.0 (Cm, PhCH2); 128.1 (C-5, quinoline); 128.5, 128.7 (Co, PhCH2); 130.6 (С-7, quinoline); 135.0 (C-6, quinoline); 136.8 (С-8a, quinoline); 140.4, 140.5 (2d, Ci, PhCH2, 3JCP = 14.4 Hz, 3JCP = 11.4 Hz); 145.2 (C-5, furyl); 148.4 (=CHN); 154.2 (C-2, furyl); 177.9 (C=O). 15N NMR (40.56 MHz, CDCl3): δ -279.8. 31P NMR (161.98 MHz, CDCl3): δ 49.5. IR (neat): νmax = 3058, 3029, 2923, 2864, 1644, 1567, 1549, 1494, 1469, 1384, 1334, 1305, 1247, 1164, 1065, 1019, 972, 914, 811, 753, 731, 646, 587 cm-1. Anal. Calcd for С33Н32NO3P: С, 75.99; Н, 6.18; N, 2.69; P, 5.94. Found: С, 75.81; Н, 6.08; N, 2.75; P, 5.81. (2E)-3-{2-[bis(2-phenylpropyl)phosphoryl]quinolin-1(2H)yl}-1-phenylprop-2-en-1-one (4i). Yield: 327 mg (60%); waxy product. The product is a mixture of four stereoisomers in a ratio of 1.7:1.4:1.1:1 (1H and 31P NMR data). IR (neat): νmax = 3060, 3031, 2965, 2927, 2877, 1648, 1583, 1546, 1492, 1453, 1400, 1331, 1307, 1240, 1213, 1175, 1048, 1022, 965, 913, 846, 765, 731, 704, 656, 536 cm–1. Anal. Calcd for С36Н36NO2P: С, 79.24; Н, 6.65; N, 2.57; P, 5.68. Found: С, 79.10; Н, 6.78; N, 2.51; P, 5.43. R,R(S,S)-stereoisomer (major). 1H NMR (400.13 MHz, CDCl3): δ 1.22, 1.65 (m, 4H, CH2P); 1.23 (d, 6H, MeCH, 3JHH = 7.0 Hz); 2.99 (m, 2H, CHMe); 4.42 (dd, 1H, H-2, quinoline, 3J2-3 = 5.8 Hz, 2JPH = 14.4 Hz); 5.47 (ddd, 1H, H-3, quinoline, 3J3-4 = 10.0 Hz, 3J3-2 = 5.8 Hz, 3JPH = 2.0 Hz); 6.42 (dd, 1H, H-4, quinoline, 3J4-3 = 10.0 Hz, 4JPH = 4.0 Hz); 6.62–6.75 (m, 19H, Ph, Ar); 6.72 (d, 1H, =CHC(O)Ph, 3Jtrans = 13.1 Hz); 7.98 (d, 1H, =CHN, 3Jtrans = 13.1 Hz). 13C{1H} NMR (100.62 MHz, CDCl3): δ 24.8 (d, MeCH, 3JCP = 11.7 Hz); 34.1 (d, CHMe, 2JCP = 3.0 Hz); 35.1 (d, CH2P, 1JCP = 56.5 Hz); 59.1 (d, C-2, quinoline, 1JCP = 63.6 Hz); 101.1 (=CHC(O)Ph); 118.4 (C-8, quinoline); 120.4 (C-3, quinoline); 124.4 (С-7, quinoline); 125.5 (C-4a, quinoline); 127.1 (C-4, quinoline); 126–129 (Со,m,p, Ph; C-6, quinoline); 129.9 (C-5, quinoline); 139.6 (С-8a, quinoline); 145.6 (d, Ci, PhCH2, 3JCP = 7.3 Hz); 146.3 (Сi, PhC(O)); 149.2 (=CHN); 189.8 (C=O). 15N NMR (40.56 MHz, CDCl3): δ -281.1. 31P NMR (161.98 MHz, CDCl3): δ 47.5. R,S(S,R)Rp- and R,S(S,R)Sp-stereoisomers (medium). 1H NMR (400.13 MHz, CDCl3): δ 1.36 (d, 6H, MeCH, 3JHH = 7.0 Hz); 1.87, 2.02 (m, 4H, CH2P); 3.47 (m, 2H, CHMe); 4.18 (dd, 1H, H-2, quinoline, 3J2-3 = 5.8 Hz, 2JPH = 14.8 Hz); 5.31 (ddd, 1H, H-3, quinoline, 3J3-4 = 10.0 Hz, 3J3-2 = 5.8 Hz, 3JPH = 2.2 Hz); 6.39

(dd, 1H, H-4, quinoline, 3J4-3 = 10.0 Hz, 4JPH = 4.2 Hz); 6.62– 6.75 (m, 19H, Ph, Ar); 6.72 (d, 1H, =CHC(O)Ph, 3Jtrans = 12.7 Hz); 8.06 (d, 1H, =CHN, 3Jtrans = 12.7 Hz). 13C{1H} NMR (100.62 MHz, CDCl3): δ 23.7 (d, MeCH, 3JCP = 4.6 Hz); 33.9 (d, CHMe, 2JCP = 3.2 Hz); 36.4 (d, CH2P, 1JCP = 56.1 Hz); 58.8 (d, C-2, quinoline, 1JCP = 63.8 Hz); 101.3 (=CHC(O)Ph); 118.3 (C-8, quinoline); 120.1 (C-3, quinoline); 124.4 (C-4a, quinoline); 125.0 (С-7, quinoline); 127.0 (C-4, quinoline); 126–129 (Со,m,p, Ph; C-6, quinoline); 130.1 (C-5, quinoline); 139.5 (С-8a, quinoline); 145.0 (d, Ci, PhCH2, 3JCP = 11.1 Hz); 146.4 (Сi, PhC(O)); 149.0 (=CHN); 189.8 (C=O). 15N NMR (40.56 MHz, CDCl3): δ -280.9. 31P NMR (161.98 MHz, CDCl3): δ 49.3. Two pairs of diastereomers with meso configuration of phenylalkyl substituents (minor). 1H NMR (400.13 MHz, CDCl3): δ 1.10, 1.16, 1.30, 1.33 (d, 6H, MeCH, 3J HH = 7.0 Hz); 1.64, 1.66, 1.68, 1.80, 1.88, 1.98 (m, 4H, CH2P); 2.92, 3.16, 3.32, 3.35 (m, 2H, CHMe); 4.80, 5.00 (dd, 1H, H-2, quinoline, 3J2-3 = 6.2 Hz, 2JPH = 11.7 Hz, 2JPH = 13.7 Hz); 5.84, 6.01 (ddd, 1H, H-3, quinoline, 3J3-4 = 9.7 Hz, 3J3-2 = 6.2 Hz, 3JPH = 2.5 Hz); 6.61, 6.62 (m, 1H, H-4, quinoline); 6.75–7.50 (m, 19H, Ph, Ar); 6.63, 6.70 (d, 1H, =CHC(O)Ph, 3J 3 trans = 12.6 Hz); 8.01, 8.13 (d, 1H, =CHN, Jtrans = 12.6 Hz). 13C{1H} NMR (100.62 MHz, CDCl ): δ 23.9, 24.3, 24.6, 24.9 3 (4d, MeCH, 3JCP = 3.7 Hz, 3JCP = 7.1 Hz, 3JCP = 11.7 Hz, 3JCP = 11.3 Hz); 33.5, 33.6, 33.7, 34.3 (4d, CHMe, 2JCP = 3.7 Hz, 2JCP = 4.6 Hz, 2JCP = 3.5 Hz, 2JCP = 4.0 Hz); 36.4 (d, CH2P, 1JCP = 56.1 Hz); 58.9, 59.4 (2d, C-2, quinoline, 1JCP = 63.8 Hz, 1JCP = 63.1 Hz); 98.9, 99.5 (=CHC(O)Ph); 118.5, 118.7 (C-8, quinoline); 120.3, 121.4 (C-3, quinoline); 124.1, 125.3 (C-4a, quinoline); 124.5, 124.8 (С-7, quinoline); 127.3, 127.4 (C-4, quinoline); 126–129 (Со,m,p, Ph; C-6, quinoline); 129.9, 130.0 (C-5, quinoline); 139.6, 139.7 (С-8a, quinoline); 145.7, 145.8, 145.8, 145.9 (4d, Ci, PhCH2, 3JCP = 12.5 Hz, 3JCP = 10.9 Hz, 3J 3 CP = 15.0 Hz, JCP = 14.0 Hz); 146.5, 146.6 (Сi, PhC(O)); 149.4, 149.6 (=CHN); 189.5, 189.6 (C=O). 15N NMR (40.56 MHz, CDCl3): δ -279.1, -280.4. 31P NMR (161.98 MHz, CDCl3): δ 48.7, 49.2. Reaction of diphenylphosphine oxide 2a with quinoline 1a and benzoylphenylacetylene 5a. To a solution of diphenylphosphine oxide 2a (1.0 mmol, 202 mg) in MeCN (4 mL), quinoline 1a (1.5 mmol) and benzoylphenylacetylene 5a (1.5 mmol) were added in two portions at regular intervals. The mixture was stirred under an argon atmosphere at 70–75 °C for 50 h (see also Scheme 3). After completion of the reaction (31P NMR monitoring), the solvent was removed under reduced pressure. The obtained residue was purified by column chromatography on SiO2 (eluent: toluene/Et2O, 1:2) to yield a mixture of the target N-benzoylvinyl-2diphenylphosphoryldihydroquinoline 6 and 2,4bis(diphenylphosphoryl)-tetrahydroquinoline 7 in a ratio of ~ 1.1:1 (1Н and 31Р NMR data). The latter was shown to form almost quantitatively when phosphine oxide 2a with quinoline 1a were heated at 70 °C for 18 h. 2,4-Bis(diphenylphosphoryl)-1,2,3,4-tetrahydroquinoline (7).13 Yield: 517 mg (97%); white powder, mp 175–177 °С (reprecipitated from CHCl3 to hexane). 1H NMR (400.13 MHz, CDCl3): δ 2.05–2.20, 2.43–2.49 (m, 2H, H-3, quinoline); 3.73 (ddd, 1H, H-4, quinoline, 2JPΗ = 9.1 Hz, 3J4-3 = 5.8 Hz, 3J4-3 = 1.8 Hz); 4.12 (br s, 1H, NH); 4.90 (ddd, 1H, H2, quinoline, 2JPΗ = 12.5 Hz, 3J2-3 = 2.5 Hz, 3J2-3 = 2.8 Hz); 6.05 (d, 1H, H-5, quinoline, 3J5-6 = 7.6 Hz); 6.26 (dd, 1H, H-6, quinoline, 3J6-5 ≈ 3J6-7 = 7.6 Hz); 6.47 (d, 1H, H-8, quinoline,

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 8 of 15

8 3J 8-7

= 8.1 Hz); 6.90 (dd, 1H, H-7, quinoline, 3J7-8 = 8.1 Hz, 3J7= 7.6 Hz); 7.31–7.56 (m, 12H, Hm,p, PhP); 7.63–7.68, 7.79– 6 7.84 (m, 8H, Ho, PhP). 13C{1H} NMR (100.62 MHz, CDCl3): δ 22.1 (C-3, quinoline); 38.1 (dd, C-4, quinoline, 1JCP = 68.1 Hz, 3JCP = 12.6 Hz); 47.3 (d, C-1, quinoline, 1JCP = 81.3 Hz); 113.3 (d, C-4a, quinoline, 2JCP = 5.2 Hz); 115.7 (C-8, quinoline), 116.8 (C-6, quinoline); 127.9 (C-7, quinoline); 128.2, 128.4, 128.6, 128.8 (4d, Cm, PhP, 3JCP = 11.4 Hz, 3JCP = 11.6 Hz); 129.8 (d, Ci, PhP-C-4, 1JCP = 158.0 Hz); 129.9 (d, Ci, PhP-C-2, 1JCP = 173.5 Hz); 130.0 (C-5, quinoline), 131.2, 131.3, 131.4, 131.6 (4d, Со, PhP, 2JCP = 8.4 Hz, 2JCP = 9.3 Hz); 131.7, 131.9, 132.2 (Сp, PhP); 144.3 (dd, C-8a, quinoline, 3J 3 31P NMR (161.98 C8a-N-C2-P = 8.8 Hz, JC8a-C4a-C4-P = 4.1 Hz). MHz, CDCl3): δ 31.4 (PhP-C-2); 32.8 (PhP-C-4). IR (KBr): νmax = 3050, 2914, 2859, 1682, 1487, 1437, 1317, 1253, 1185, 1115, 1029, 998, 917, 827, 732, 705, 637, 570 sh, 540, 522 cm-1. Anal. Calcd for С33Н29NO2P2: С, 74.29; Н, 5.48; N, 2.63; P, 11.61. Found: С, 74.10; Н, 5.43; N, 2.55; P, 11.40. Reaction of secondary phosphine oxides 2a,b,d with isoquinolines 8a-d and terminal acylacetylenes 3a,b: General procedure. To a solution of secondary phosphine oxide 2a,b,d (1.0 mmol) in MeCN (4 mL), isoquinoline 8a-d (1.2 mmol) and terminal acylacetylene 3a,b (1.2 mmol) were added in two portions at regular intervals. The mixture was stirred under an argon atmosphere at 20–25 °C for 3–12 h (see also Scheme 4). After completion of the reaction (31P NMR monitoring), the solvent was removed under reduced pressure. The product obtained was purified as follows: in the case of the compounds 9a,b,f,g,j,k, the residue was reprecipitated from CHCl3 to hexane; for dihydroisoquinolines 9с,e,i, acetone (3 mL) was added to the residue, the precipitate was filtered off and washed with Et2O; compounds 9d,h were purified by column chromatography on SiO2 (eluent: toluene/ethyl acetate, 1:1) with subsequent reprecipitation of the crude product from CHCl3 to hexane. (2E)-3-[1-(diphenylphosphoryl)isoquinolin-2(1H)-yl]-1phenylprop-2-en-1-one (9a). Yield: 401 mg (87%); yellow powder, mp 224–226 °С (reprecipitated from CHCl3 to hexane). 1H NMR (400.13 MHz, CDCl3): δ 5.66 (d, 1H, H-4, isoquinoline, 3J4-3 = 7.4 Hz); 5.76 (br s, 1H, H-1, isoquinoline); 6.17 (d, 1H, =CHC(O)Ph, 3Jtrans = 13.0 Hz); 6.40 (d, 1H, H-3, isoquinoline, 3J3-4 = 7.4 Hz); 6.81 (br s, 1H, H-8, isoquinoline); 6.90 (d, 1H, H-5, isoquinoline, 3J5-6 = 7.6 Hz); 7.00 (dd, 1H, H-6, isoquinoline, 3J6-5 ≈ 3J6-7 = 7.6 Hz); 7.15 (dd, 1H, H-7, isoquinoline, 3J7-8 ≈ 3J7-6 = 7.6 Hz); 7.34– 7.49 (m, 10H, Hm,p, PhP; Hm,p, PhC(O); =CHN); 7.67–7.71 (m, 4H, Ho, PhP); 7.76–7.78 (m, 2H, Ho, PhC(O)). 13C{1H} NMR (100.62 MHz, CDCl3): δ 65.1 (br s, C-1, isoquinoline); 98.0 (=CHC(O)Ph); 110.6 (C-4, isoquinoline); 124.6 (C-4a, isoquinoline); 125.2 (C-5, isoquinoline); 127.2 (C-6,8, isoquinoline); 127.8 (Со, PhC(O)); ≈128.0 (C-3, isoquinoline, overlapped by other signals); 128.2 (Сm, PhC(O)); 128.3, 128.4 (2d, Cm, PhP, 3JCP = 11.5 Hz, 3JCP = 12.0 Hz); 128.8 (С7, isoquinoline); 129.9 (d, Ci, PhP, 1JCP = 95.3 Hz); 131.3 (С-8a, isoquinoline); 131.6, 132.1 (2d, Co, PhP, 2JCP = 8.5 Hz, 2J CP = 8.9 Hz); 132.2 (Сp, PhP); 139.3 (Сi, PhC(O)); 148.6 (=CHN); 188.8 (C=O). 31P NMR (161.98 MHz, CDCl3): δ 29.2. IR (KBr): νmax = 2964, 2921, 2875, 2823, 1644, 1575, 1547, 1452, 1435, 1389, 1357, 1311, 1206, 1181, 1117, 1047, 1020, 964, 927, 745, 697, 541 cm-1. Anal. Calcd for С30Н24NO2P: С, 78.08; Н, 5.24; N, 3.04; P, 6.71. Found: С, 77.98; Н, 5.12; N, 3.11; P, 6.56.

(2E)-3-[1-(diphenylphosphoryl)isoquinolin-2(1H)-yl]-1(furan-2-yl)prop-2-en-1-one (9b). Yield: 411 mg (91%); yellow powder, mp 218–220 °С (reprecipitated from CHCl3 to hexane). 1H NMR (400.13 MHz, CDCl3): δ 5.70 (d, 1H, H-4, isoquinoline, 3J4-3 = 7.5 Hz); 5.77 (br s, 1H, H-1, isoquinoline); 6.12 (d, 1H, =CHC(O)Furyl, 3Jtrans = 12.9 Hz); 6.43 (d, 1H, H-3, isoquinoline, 3J4-3 = 7.6 Hz); 6.52 (dd, 1H, H-4, furyl, 3J4-3 = 3.3 Hz, 3J4-5 = 1.7 Hz); 6.84 (br s, 1H, H-8, isoquinoline); 6.94 (d, 1H, H-5, isoquinoline, 3J5-6 = 7.6 Hz); 7.04 (dd, 1H, H-6, isoquinoline, 3J6-5 ≈ 3J6-7 = 7.6 Hz); 7.10 (d, 1H, H-3, furyl, 3J3-4 = 3.3 Hz); 7.20 (dd, 1H, H-7, isoquinoline, 3J7-8 ≈ 3J7-6 = 7.6 Hz); 7.36–7.43 (m, 4H, Hm, PhP); 7.47–7.51 (m, 2H, Hp, PhP); 7.55 (d, 1H, =CHN, 3Jtrans = 12.9 Hz); 7.69–7.76 (m, 4H, Ho, PhP). 13C{1H} NMR (100.62 MHz, CDCl3): δ C-1 was not detected due to broadening; 97.3 (=CHC(O)Furyl); 111.0 (C-4, isoquinoline); 112.1 (C-4, furyl); 115.0 (C-3, furyl); 124.5 (C-4a, isoquinoline); 125.3 (d, C-5, isoquinoline, 4JCP = 1.9 Hz); 127.3 (m, C-6,8, isoquinoline); ≈128 (C-3, isoquinoline, overlapped by other signals); 128.3, 128.5 (d, Cm, PhP, 3JCP = 11.4 Hz); 128.9 (d, С-7, isoquinoline, 4JCP = 2.6 Hz); 128.2, 129.9 (2d, Ci, PhP, 1J 1 CP = 92.5 Hz, JCP = 91.5 Hz); 131.5 (C-8a, isoquinoline); 131.8, 132.4 (2d, Co, PhP, 2JCP = 8.6 Hz, 2JCP = 9.4 Hz); 132.3 (Сp, PhP); 145.1 (C-5, furyl); 147.9 (=CHN); 154.1 (C-2, furyl); 177.2 (C=O). 31P NMR (161.98 MHz, CDCl3): δ 28.8. IR (KBr): νmax = 3059, 2927, 2856, 1640, 1546, 1461, 1427, 1358, 1311, 1277, 1234, 1195, 1161, 1115, 1092, 1057, 1015, 968, 925, 833, 775, 729, 699, 540 cm-1. Anal. Calcd for С28Н22NO3P: С, 74.49; Н, 4.91; N, 3.10; P, 6.86. Found: С, 74.39; Н, 4.85; N, 3.02; P, 6.71. (2E)-3-[4-bromo-1-(diphenylphosphoryl)isoquinolin-2(1H)yl]-1-(furan-2-yl)prop-2-en-1-one (9c). Yield: 483 mg (91%); yellow powder, mp 214–215 °С (washed with Et2O). 1H NMR (400.13 MHz, CDCl3): δ 5.69 (d, 1H, H-1, isoquinoline, 2JPH = 6.4 Hz); 6.14 (d, 1H, =CHC(O)Furyl, 3Jtrans = 13.1 Hz); 6.52 (dd, 1H, H-4, furyl, 3J4-3 = 3.3 Hz, 3J4-5 = 1.6 Hz); 6.75 (br s, 1H, H-8, isoquinoline); 6.90 (dd, 1H, H-7, isoquinoline, 3J7-8 ≈ 3J 3 7-6 = 7.7 Hz); 7.11 (d, 1H, H-3, furyl, J4-3 = 3.3 Hz); 7.14– 7.18 (m, 1H, H-3, isoquinoline); 7.27–7.31 (m, 2H, H-5,6, isoquinoline); 7.37–7.55 (m, 7H, Hm,p, PhP; H-5, furyl); 7.53 (d, 1H, =CHN, 3Jtrans = 13.1 Hz); 7.66–7.73 (m, 4H, Ho, PhP). 13C{1H} NMR (100.62 MHz, CDCl +DMSO-d ): δ 61.3 (br s, 3 6 C-1, isoquinoline); 97.2 (=CHC(O)Furyl); 111.6 (C-4, furyl); 115.0 (C-3, furyl); 124.4 (C-5, isoquinoline); 124.5 (C-4a, isoquinoline); 126.5 (C-4, isoquinoline); 126.7 (C-3, isoquinoline); 127.3 (C-8, isoquinoline); 127.8, 128.2 (2d, Cm, PhP, 3JCP = 11.5 Hz, 3JCP = 11.5 Hz); 127.9, 128.6 (2d, Ci, PhP, 1JCP = 90.6 Hz, 1JCP = 93.1 Hz); 128.4 (С-6,7, isoquinoline); 130.8 (d, C-8a, isoquinoline, 2JCP = 2.7 Hz); 131.4, 131.7 (2d, Co, PhP, 3JCP = 8.4 Hz, 3JCP = 10.0 Hz); 131.9, 132.0 (d, Сp, PhP, 4JCP = 2.3 Hz); 145.1 (C-5, furyl); 147.0 (=CHN); 153.4 (C-2, furyl); 176.0 (C=O). 31P NMR (161.98 MHz, CDCl3+DMSO-d6): δ 27.3. IR (KBr): νmax = 3060, 2982, 2935, 2855, 1644, 1548, 1471, 1443, 1405, 1375, 1316, 1277, 1235, 1200, 1159, 1112, 1092, 1055, 1014, 953, 914, 814, 752, 698, 548 cm-1. Anal. Calcd for С28Н21BrNO3P: С, 63.41; Н, 3.99; Br, 15.07; N, 2.64; P, 5.84. Found: С, 63.25; Н, 3.91; Br, 15.34; N, 2.58; P, 5.61. (2E)-3-[1-(diphenylphosphoryl)-3-methylisoquinolin-2(1H)yl]-1-(furan-2-yl)prop-2-en-1-one (9d). Yield: 344 mg (74%); yellow powder, mp 212–214 °С (reprecipitated from CHCl3 to hexane). 1H NMR (400.13 MHz, CDCl3): δ 2.04 (s, 3H, Me);

ACS Paragon Plus Environment

Page 9 of 15 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

9 5.63 (s, 1H, H-4, isoquinoline); 5.96 (d, 1H, H-1, isoquinoline, 2J 3 PH = 9.5 Hz); 6.34 (d, 1H, =CHC(O)Furyl, Jtrans = 12.9 Hz); 6.54 (dd, 1H, H-4, furyl, 3J4-3 = 3.3 Hz, 3J4-5 = 1.4 Hz); 6.89 (d, 2H, H-5,8, isoquinoline, 3J8(5)-7(6) = 7.6 Hz); 6.98 (dd, 1H, H-6, isoquinoline, 3J5-6 = 7.6 Hz); 7.13–7.17 (m, 2H, H-7, isoquinoline; H-3, furyl); 7.33–7.41 (m, 4H, Hm, PhP); 7.45– 7.51 (m, 2H, Hp, PhP); 7.59 (d, 1H, H-5, furyl, 3J5-4 = 1.4 Hz); 7.67–7.77 (m, 4H, Ho, PhP); 7.83 (d, 1H, =CHN, 3Jtrans = 12.9 Hz). 13C{1H} NMR (100.62 MHz, CDCl3): δ 19.7 (Me); 63.7 (d, C-1, isoquinoline, 1JCP = 67.3 Hz); 97.6 (=CHC(O)Furyl); 110.5 (C-4, isoquinoline); 111.9 (C-4, furyl); 114.8 (C-3, furyl); 124.1 (d, C-5, isoquinoline, 4JCP = 2.2 Hz); 124.4 (C-4a, isoquinoline); 126.2 (d, C-6, isoquinoline, 5JCP = 2.4 Hz); 126.5 (d, C-8, isoquinoline, 3JCP = 4.0 Hz); 127.9, 128.1 (d, Cm, PhP, 3JCP = 12.0 Hz); 128.5 (d, С-7, isoquinoline, 4JCP = 2.8 Hz); 128.8, 129.9 (2d, Ci, PhP, 1J 1 2 CP = 92.7 Hz, JCP = 91.5 Hz); 131.3, 132.8 (2d, Co, PhP, JCP 2 2 = 9.0 Hz, JCP = 9.2 Hz); 131.7 (d, C-8a, isoquinoline, JCP = 3.4 Hz); 132.0 (Сp, PhP); 136.5 (C-3, isoquinoline); 144.0 (=CHN); 144.9 (C-5, furyl); 154.0 (C-2, furyl); 177.1 (C=O). 15N NMR (40.56 MHz, CDCl ): δ -266.4. 31P NMR (161.98 3 MHz, CDCl3): δ 30.2. IR (KBr): νmax = 3059, 2983, 1643, 1546, 1468, 1440, 1387, 1310, 1237, 1170, 1113, 1091, 1047, 1015, 959, 912, 872, 804, 753, 699, 596, 540 cm-1. Anal. Calcd for С29Н24NO3P: С, 74.83; Н, 5.20; N, 3.01; P, 6.65. Found: С, 74.69; Н, 5.31; N, 3.10; P, 6.45. (2E)-3-[1-(diphenylphosphoryl)-5-nitroisoquinolin-2(1H)yl]-1-(furan-2-yl)prop-2-en-1-one (9e). Yield: 432 mg (87%); orange powder, mp 252–254 °С (washed with Et2O). 1H NMR (400.13 MHz, CDCl3): δ 5.83 (d, 1H, H-1, isoquinoline, 2JPH = 3.6 Hz); 6.16 (d, 1H, =CHC(O)Furyl, 3Jtrans = 13.0 Hz); 6.42 (d, 1H, H-4, isoquinoline, 3J4-3 = 8.3 Hz); 6.54 (dd, 1H, H-4, furyl, 3J4-3 = 3.4 Hz, 3J4-5 = 1.6 Hz); 6.63 (d, 1H, H-3, isoquinoline, 3J3-4 = 8.3 Hz); 7.11–7.15 (m, 3H, H-6,7,8, isoquinoline); 7.38–7.57 (m, 8H, Hm,p, PhP; H-3,5, furyl); 7.71–7.86 (m, 5H, Ho, PhP; =CHN). 13C{1H} NMR (100.62 MHz, CDCl3+DMSO-d6): δ 61.8 (br s, C-1, isoquinoline); 98.6 (=CHC(O)Furyl); 104.4 (C-4, isoquinoline); 112.2 (C-4, furyl); 116.0 (C-3, furyl); 124.7 (C-6, isoquinoline); 126.6 (С7, isoquinoline); 126.7 (C-4a, isoquinoline); 127.5 (C-8a, isoquinoline); 128.3, 129.8 (2d, Ci, PhP, 1JCP = 89.7 Hz, 1JCP = 93.9 Hz); 128.4, 128.7 (2d, Cm, PhP, 3JCP = 11.5 Hz, 3JCP = 11.9 Hz); 131.6, 131.9 (2d, Co, PhP, 2JCP = 8.8 Hz, 2JCP = 9.6 Hz); 132.1 (C-8, isoquinoline); 132.5 (Сp, PhP); 133.6 (C-3, isoquinoline); 143.8 (C-5, isoquinoline); 146.4 (C-5, furyl); 146.9 (=CHN); 153.3 (C-2, furyl); 175.8 (C=O). 15N NMR (40.56 MHz, CDCl3): δ -275.1 (isoquinoline); -6.1 (NO2). 31P NMR (161.98 MHz, CDCl3): δ 29.3. IR (KBr): νmax = 3086, 3058, 2919, 2853, 1644, 1568, 1522, 1463, 1426, 1353, 1335, 1258, 1235, 1171, 1115, 1090, 1059, 1018, 961, 912, 809, 764, 730, 699, 537 cm-1. Anal. Calcd for С28Н21N2O5P: С, 67.74; Н, 4.26; N, 5.64; P, 6.24. Found: С, 67.58; Н, 4.19; N, 5.55; P, 6.01. (2E)-3-{1-[bis(2-phenylethyl)phosphoryl]isoquinolin2(1H)-yl}-1-phenylprop-2-en-1-one (9f). Yield: 424 mg (82%); yellow powder, mp 214–216 °С (reprecipitated from CHCl3 to hexane). 1H NMR (400.13 MHz, CDCl3): δ 1.78– 2.15 (m, 4H, CH2P); 2.37–2.90 (m, 4H, CH2Ph); 5.35 (br s, 1H, H-1, isoquinoline); 5.88 (d, 1H, H-4, isoquinoline, 3J4-3 = 7.6 Hz); 6.38 (d, 1H, =CHC(O)Ph, 3Jtrans = 12.6 Hz); 6.48 (d, 1H, H-3, isoquinoline, 3J3-4 = 7.6 Hz); 6.94–7.23 (m, 14H,

Ho,m,p, PhCH2; H-5,6,7,8, isoquinoline); 7.39–7.43 (m, 2H, Hm, PhC(O)); 7.41 (m, 1H, Hp, PhC(O)); 7.63 (d, 1H, =CHN, 3Jtrans = 12.6 Hz); 7.81–7.84 (m, 2H, Ho, PhC(O)). 13C{1H} NMR (100.62 MHz, CDCl3): δ 27.4, 27.9 (2d, CH2Ph, 2JCP = 3.5 Hz, 2J 1 1 CP = 3.1 Hz); 28.7, 29.2 (2d, CH2P, JCP = 54.2 Hz, JCP = 55.6 Hz); 67.0 (C-1, isoquinoline); 98.1 (=CHC(O)Ph); 112.5 (C-4, isoquinoline); 124.5 (C-6, isoquinoline); 124.6 (C-4a, isoquinoline); 125.4 (C-5, isoquinoline, 4JCP = 1.9 Hz); 126.5 (Cp, PhCH2); 127.5 (d, С-7, isoquinoline, 4JCP = 3.5 Hz); 127.8 (Со, PhC(O)); 128.0, 128.1 (Co, PhCH2); 128.2 (d, C-8, isoquinoline, 3JCP = 1.9 Hz); 128.4 (Сm, PhC(O)); 128.7 (Cm, PhCH2); 129.3 (d, C-3, isoquinoline, 5JCP = 2.5 Hz); 130.5 (d, С-8a, isoquinoline, 2JCP = 2.8 Hz); 131.9 (Сp, PhC(O)); 139.2 (Сi, PhC(O)); 140.4, 140.7 (d, Ci, PhCH2, 3JCP = 12.9 Hz); 148.6 (=CHN); 189.0 (C=O). 15N NMR (40.56 MHz, CDCl3): δ -276.2. 31P NMR (161.98 MHz, CDCl3): δ 49.9. IR (neat): νmax = 3060, 3028, 2922, 2855, 1645, 1579, 1545, 1494, 1453, 1426, 1359, 1316, 1277, 1206, 1045, 1023, 928, 775, 701, 656 cm-1. Anal. Calcd for С34Н32NO2P: С, 78.90; Н, 6.23; N, 2.71; P, 5.98. Found: С, 78.79; Н, 6.13; N, 2.65; P, 5.75. (2E)-3-{1-[bis(2-phenylethyl)phosphoryl]isoquinolin2(1H)-yl}-1-(furan-2-yl)prop-2-en-1-one (9g). Yield: 355 mg (70%); brown powder, mp 186–188 °С (reprecipitated from CHCl3 to hexane). 1H NMR (400.13 MHz, CDCl3): δ 1.89– 2.25 (m, 4H, CH2P); 2.47–3.02 (m, 4H, CH2Ph); 5.48 (br s, 1H, H-1, isoquinoline); 5.99 (d, 1H, H-4, isoquinoline, 3J4-3 = 7.4 Hz); 6.43 (d, 1H, =CHC(O)Furyl, 3Jtrans = 13.3 Hz); 6.53 (dd, 1H, H-4, furyl, 3J4-3 = 3.3 Hz, 3J4-5 = 1.7 Hz); 6.57 (d, 1H, H-3, isoquinoline, 3J3-4 = 7.4 Hz); 7.05–7.30 (m, 15H, Ho,m,p, PhCH2; H-5,6,7,8, isoquinoline; H-3, furyl); 7.54 (d, 1H, H-5, furyl, 3J5-4 = 1.7 Hz); 7.74 (d, 1H, =CHN, 3Jtrans = 13.3 Hz). 13C{1H} NMR (100.62 MHz, CDCl3): δ 27.6, 28.0 (d, CH2Ph, 2JCP = 3.5 Hz); 28.7, 29.3 (d, CH2P, 1JCP = 54.4 Hz); 64.8 (br s, C-1, isoquinoline); 97.5 (=CHC(O)Furyl); 111.1 (C-4, isoquinoline); 112.4 (C-4, furyl); 115.5 (C-3, furyl); 124.8 (C-4a, isoquinoline); 125.5 (d, C-5, isoquinoline, 4J CP = 1.9 Hz); 126.5 (Cp, PhCH2); 127.7 (d, C-8, isoquinoline, 3J CP = 3.5 Hz); 128.1, 128.2 (Cm, PhCH2); 128.3 (d, C-3, isoquinoline, 3JCP = 1.9 Hz); 128.7, 128.8 (Co, PhCH2); 129.1 (C-6,7, isoquinoline); 130.6 (d, С-8a, isoquinoline, 2JCP = 2.3 Hz); 140.6, 140.8 (d, Ci, PhCH2, 3JCP = 13.0 Hz); 145.4 (C-5, furyl); 148.0 (=CHN); 154.1 (C-2, furyl); 177.5 (C=O). 15N NMR (40.56 MHz, CDCl3): δ -274.9. 31P NMR (161.98 MHz, CDCl3): δ 27.0. IR (neat): νmax = 3118, 3058, 2928, 2845, 1643, 1570, 1545, 1483, 1465, 1385, 1334, 1305, 1249, 1201, 1165, 1092, 1066, 1018, 970, 914, 836, 742, 701, 646, 538, 503 cm-1. Anal. Calcd for С32Н30NO3P: С, 75.72; Н, 5.96; N, 2.76; P, 6.10. Found: С, 75.61; Н, 5.89; N, 2.69; P, 5.98. (2E)-3-{1-[bis(2-phenylethyl)phosphoryl]-4bromoisoquinolin-2(1H)-yl}-1-(furan-2-yl)prop-2-en-1-one (9h). Yield: 469 mg (80%); brown powder, mp 90−92 °С (reprecipitated from CHCl3 to hexane). 1H NMR (400.13 MHz, CDCl3+DMSO-d6): δ 1.90–2.23 (m, 4H, CH2P); 2.44– 3.02 (m, 4H, CH2Ph); 5.45 (br s, 1H, H-1, isoquinoline); 6.45 (d, 1H, =CHC(O)Furyl, 3Jtrans = 12.9 Hz); 6.54 (dd, 1H, H-4, furyl, 3J4-3 = 3.2 Hz, 3J4-5 = 1.4 Hz); 6.96 (br s, 1H, H-3, isoquinoline); 7.08–7.45 (m, 14H, Ho,m,p, PhCH2; H-6,7,8, isoquinoline; H-3, furyl); 7.55–7.57 (m, 2H, H-5, isoquinoline; H-5, furyl); 7.66 (d, 1H, =CHN, 3Jtrans = 12.9 Hz). 13C{1H} NMR (100.62 MHz, CDCl3+DMSO-d6): δ 27.2, 27.7 (2d, CH2Ph, 2JCP = 4.0 Hz, 2JCP = 3.6 Hz); 28.6, 28.8 (2d, CH2P, 1JCP = 54.9 Hz, 1JCP = 56.6 Hz); 61.5 (br s, C-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 10 of 15

10 isoquinoline); 98.1 (=CHC(O)Furyl); 112.3 (C-4, furyl); 115.7 (C-3, furyl); 125.2 (C-4a, isoquinoline); 125.5 (C-5, isoquinoline); 126.5 (Cp, PhCH2); 127.3 (C-4, isoquinoline); 128.0, 128.1 (2d, Co, PhCH2, 3JCP = 8.4 Hz, 3JCP = 10.0 Hz); 128.2 (C-6,7, isoquinoline); 128.6, 128.6 (Cm, PhCH2); 129.4 (C-3, isoquinoline); 129.5 (C-8, isoquinoline); 129.9 (d, С-8a, isoquinoline, 2JCP = 2.4 Hz); 140.2, 140.4 (d, Ci, PhCH2, 3JCP = 12.9 Hz); 145.4 (C-5, furyl); 146.6 (=CHN); 153.7 (C-2, furyl); 177.1 (C=O). 15N NMR (40.56 MHz, CDCl3+DMSOd6): δ -273.5. 31P NMR (161.98 MHz, CDCl3+DMSO-d6): δ 49.4. IR (neat): νmax = 3063, 3027, 2929, 2863, 1646, 1569, 1550, 1462, 1394, 1368, 1317, 1277, 1230, 1211, 1158, 1086, 1055, 1015, 955, 913, 753, 700, 585 cm-1. Anal. Calcd for С32Н29BrNO3P: С, 65.54; Н, 4.98; Br, 13.62; N, 2.39; P, 5.28. Found: С, 65.38; Н, 4.86; Br, 13.45; N, 2.29; P, 5.01. (2E)-3-{1-[bis(2-phenylethyl)phosphoryl]-5nitroisoquinolin-2(1H)-yl}-1-(furan-2-yl)prop-2-en-1-one (9i). Yield: 481 mg (87%); orange powder, mp 96−97 °С (washed with Et2O). 1H NMR (400.13 MHz, CDCl3): δ 1.92–2.26 (m, 4H, CH2P); 2.50–3.07 (m, 4H, CH2Ph); 5.55 (d, 1H, H-1, isoquinoline, 2JPH = 10.4 Hz); 6.56 (dd, 1H, H-4, furyl, 3J4-3 = 3.5 Hz, 3J4-5 = 1.5 Hz); 6.52 (d, 1H, =CHC(O)Furyl, 3Jtrans = 13.3 Hz); 6.78 (m, 2H, H-3,4, isoquinoline); 7.04–7.30 (m, 11H, Ho,m,p, PhCH2; H-3, furyl); 7.40 (dd, 1H, H-7, isoquinoline, 3J7-8 ≈ 3J7-6 = 8.3 Hz); 7.53 (d, 1H, H-5, furyl, 3J 3 5-4 = 1.5 Hz); 7.56 (d, 1H, H-8, isoquinoline, J8-7 = 8.3 Hz); 3 7.70 (d, 1H, =CHN, Jtrans = 13.3 Hz); 8.00 (d, 1H, H-6, isoquinoline, 3J6-7 = 8.3 Hz). 13C{1H} NMR (100.62 MHz, CDCl3): δ 27.5, 27.7 (2d, CH2Ph, 2JCP = 3.8 Hz, 2JCP = 4.0 Hz); 28.7, 29.2 (d, CH2P, 1JCP = 54.5 Hz); 61.5 (br s, C-1, isoquinoline); 99.0 (=CHC(O)Furyl); 104.8 (C-4, isoquinoline); 112.4 (C-4, furyl); 116.0 (C-3, furyl); 125.5 (C-6, isoquinoline); 125.7 (d, C-4a, isoquinoline, 3JCP = 2.4 Hz); 126.5, 126.6 (Cp, PhCH2); 127.0 (С-8a, isoquinoline); 127.6 (С-7, isoquinoline); 127.9, 128.0 (Co, PhCH2); 128.6, 128.7 (Cm, PhCH2); 132.7 (d, C-8, isoquinoline, 2JCP = 3.2 Hz); 133.4 (C-3, isoquinoline); 140.0, 140.2 (d, Ci, PhCH2, 3JCP = 13.0 Hz); 144.5 (C-5, isoquinoline); 145.6 (C-5, furyl); 146.5 (=CHN); 153.6 (C-2, furyl); 177.0 (C=O). 15N NMR (40.56 MHz, CDCl3): δ -276.8. 31P NMR (161.98 MHz, CDCl3): δ 50.4. IR (neat): νmax = 3083, 3063, 3026, 2932, 2864, 1649, 1565, 1550, 1526, 1464, 1421, 1352, 1256, 1216, 1175, 1084, 1054, 1016, 977, 914, 827, 757, 703, 671, 589 cm-1. Anal. Calcd for С32Н29N2O5P: С, 69.56; Н, 5.29; N, 5.07; P, 5.61. Found: С, 69.48; Н, 5.21; N, 5.18; P, 5.45. (2E)-3-[1-{bis[2-(4chlorophenyl)ethyl]phosphoryl}isoquinolin-2(1H)-yl]-1phenylprop-2-en-1-one (9j). Yield: 457 mg (78%); beige powder, mp 192−194 °С (reprecipitated from CHCl3 to hexane). 1H NMR (400.13 MHz, CDCl3): δ 1.64–2.19 (m, 4H, CH2P); 2.31–2.95 (m, 4H, CH2Ar); 5.45 (br s, 1H, H-1, isoquinoline); 5.97 (d, 1H, H-4, isoquinoline, 3J4-3 = 7.4 Hz); 6.45 (d, 1H, =CHC(O)Ph, 3Jtrans = 13.1 Hz); 6.55 (d, 1H, H-3, isoquinoline, 3J3-4 = 7.4 Hz); 6.92, 6.99 (2d, 4H, Ho, p-ClC6H4, 3J 3 2(6)-3(5) = 8.0 Hz); 7.10 (d, 1H, H-5, isoquinoline, J5-6 = 6.3 Hz); 7.15, 7.20 (2d, 4H, Hm, p-ClC6H4, 3J3(5)-2(6) = 8.0 Hz); 7.27–7.33 (m, 3H, H-6,7,8, isoquinoline); 7.41–7.46 (m, 2H, Hm, PhC(O)); 7.49–7.53 (m, 1H, Hp, PhC(O)); 7.72 (d, 1H, =CHN, 3Jtrans = 13.1 Hz); 7.89–7.92 (m, 2H, Ho, PhC(O)). 13C{1H} NMR (100.62 MHz, CDCl ): δ 26.8, 27.3 (2d, 3 CH2Ar, 2JCP = 3.4 Hz, 2JCP = 3.6 Hz); 28.6, 29.1 (2d, CH2P, 1J 1 CP = 54.5 Hz, JCP = 54.9 Hz); 61.7 (br s, C-1, isoquinoline);

98.0 (=CHC(O)Ph); 110.9 (C-4, isoquinoline); 124.5 (C-4a, isoquinoline); 125.4 (C-5, isoquinoline); 127.5, 127.6 (C-6,8, isoquinoline); 127.8 (Со, PhC(O)); 128.2 (С-7, isoquinoline); 128.4 (Сm, PhC(O)); 128.7 (Cm, p-ClC6H4); 129.3, 129.4 (Co, p-ClC6H4); 129.3 (d, C-3, isoquinoline, 3JCP = 2.4 Hz); 130.5 (С-8a, isoquinoline); 132.0 (Сp, PhC(O)); 132.2 (Cp, pClC6H4); 138.9, 139.1 (d, Ci, p-ClC6H4, 3JCP = 12.8 Hz); 139.1 (Сi, PhC(O)); 148.6 (=CHN); 188.8 (C=O). 15N NMR (40.56 MHz, CDCl3): δ -274.6. 31P NMR (161.98 MHz, CDCl3): δ 49.4. IR (neat): νmax = 3062, 3030, 2923, 2856, 1645, 1578, 1546, 1492, 1454, 1425, 1360, 1316, 1276, 1208, 1182, 1092, 1045, 1020, 915, 810, 774, 740, 653 cm-1. Anal. Calcd for С34Н30Cl2NO2P: С, 69.63; Н, 5.16; Cl, 12.09; N, 2.39; P, 5.28. Found: С, 69.48; Н, 5.09; N, 2.35; P, 5.05. (2E)-3-[1-{bis[2-(4chlorophenyl)ethyl]phosphoryl}isoquinolin-2(1H)-yl]-1(furan-2-yl)prop-2-en-1-one (9k). Yield: 375 mg (65%); brown powder, mp 126−128 °С (reprecipitated from CHCl3 to hexane). 1H NMR (400.13 MHz, CDCl3): δ 1.77–2.20 (m, 4H, CH2P); 2.35–2.97 (m, 4H, CH2Ar); 5.48 (br s, 1H, H-1, isoquinoline); 5.98 (d, 1H, H-4, isoquinoline, 3J4-3 = 7.4 Hz); 6.41 (d, 1H, =CHC(O)Furyl, 3Jtrans = 13.4 Hz); 6.53–6.57 (m, 2H, H-3, isoquinoline; H-4, furyl); 6.94, 7.01 (2d, 4H, Ho, pClC6H4, 3J2(6)-3(5) = 8.3 Hz); 7.12 (d, 1H, H-5, isoquinoline, 3J53 6 = 6.3 Hz); 7.18, 7.22 (2d, 4H, Hm, p-ClC6H4, J3(5)-2(6) = 8.3 3 Hz); 7.20 (d, 1H, H-3, furyl, J3-4 = 3.3 Hz); 7.31–7.34 (m, 3H, H-6,7,8, isoquinoline); 7.54 (d, 1H, H-5, furyl, 3J5-4 = 1.4 Hz); 7.73 (d, 1H, =CHN, 3Jtrans = 13.4 Hz). 13C{1H} NMR (100.62 MHz, CDCl3): δ 26.7, 27.2 (2d, CH2Ar, 2JCP = 3.4 Hz, 2J 1 1 CP = 3.8 Hz); 28.5, 29.0 (2d, CH2P, JCP = 55.5 Hz, JCP = 56.3 Hz); 61.1 (br s, C-1, isoquinoline); 98.3 (=CHC(O)Furyl); 110.9 (C-4, isoquinoline); 112.2 (C-4, furyl); 115.3 (C-3, furyl); 124.4 (C-4a, isoquinoline); 125.3 (C-5, isoquinoline); 127.6 (d, C-8, isoquinoline, 3JCP = 3.5 Hz); 128.2 (d, C-3, isoquinoline, 3JCP = 1.9 Hz); 128.6 (Cm, pClC6H4); 128.7 (С-7, isoquinoline); 129.3, 129.4 (Co, pClC6H4); 129.4 (C-6, isoquinoline); 130.4 (С-8a, isoquinoline); 132.1 (Cp, p-ClC6H4); 138.8, 139.0 (Ci, pClC6H4, 3JCP = 13.0 Hz); 145.2 (C-5, furyl); 147.6 (=CHN); 153.8 (C-2, furyl); 177.2 (C=O). 15N NMR (40.56 MHz, CDCl3): δ -275.4. 31P NMR (161.98 MHz, CDCl3): δ 49.4. IR (neat): νmax = 3071, 3033, 2927, 2864, 1642, 1566, 1548, 1485, 1463, 1423, 1358, 1309, 1277, 1230, 1205, 1160, 1091, 1055, 1014, 914, 808, 771, 732, 648, 512, 487 cm-1. Anal. Calcd for С32Н28Cl2NO3P: С, 66.67; Н, 4.90; Cl, 12.30; N, 2.43; P, 5.37. Found: С, 66.52; Н, 4.81; Cl, N, 2.53; P, 5.15. Reaction of secondary phosphine sulfide 10a with isoquinoline 8a and terminal acylacetylenes 3a,b: General procedure. A solution of secondary phosphine sulfide 10a (1.0 mmol), isoquinoline 8a (1.1 mmol) and terminal acylacetylene 3a,b (1.1 mmol) in MeCN (3 mL) was stirred under an argon atmosphere at 20–25 °C for 3–4 h (see also Scheme 5). After completion of the reaction (31P NMR monitoring), the solvent was removed under reduced pressure. The obtained residue was purified by column chromatography on SiO2 (eluent: toluene/ Et2O, 7:1) to yield adduct 12a,b of phosphine sulfide to acetylene. Then SiO2 was washed with Et2O to obtain the target phosphorylated 1,2dihydroisoquinoline 11a,b. (2E)-3-[1-[bis(2-phenylethyl)phosphorothioyl]isoquinolin2(1H)-yl]-1-phenylprop-2-en-1-one (11a). Yield: 272 mg (51%); yellow powder, mp 81–83 °С (reprecipitated from

ACS Paragon Plus Environment

Page 11 of 15 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

11 CCl4 to hexane). 1H NMR (400.13 MHz, CDCl3): δ 1.97–2.27 (m, 4H, CH2P); 2.45–3.05 (m, 4H, CH2Ph); 5.43 (br s, 1H, H1, isoquinoline); 6.06 (d, 1H, H-4, isoquinoline, 3J4-3 = 7.5 Hz); 6.48 (d, 1H, =CHC(O)Ph, 3Jtrans = 12.9 Hz); 6.67 (d, 1H, H-3, isoquinoline, 3J3-4 = 7.5 Hz); 7.05–7.09 (m, 4H, Ho, PhCH2); 7.16–7.42 (m, 10H, Hm,p, PhCH2; H-5,6,7,8, isoquinoline); 7.46–7.49 (m, 2H, Hm, PhC(O)); 7.52–7.56 (m, 1H, Hp, PhC(O)); 7.74 (d, 1H, =CHN, 3Jtrans = 12.9 Hz); 7.97 (m, 2H, Ho, PhC(O)). 13C{1H} NMR (100.62 MHz, CDCl3): δ 28.7, 29.1 (2d, CH2Ph, 2JCP = 2.2 Hz, 2JCP = 2.8 Hz); 31.1, 31.2 (2d, CH2P, 1JCP = 39.7 Hz, 1JCP = 40.1 Hz); 66.5 (d, C-1, isoquinoline, 1JCP = 47.9 Hz); 98.7 (=CHC(O)Ph); 111.5 (C-4, isoquinoline); 124.5 (C-4a, isoquinoline); 125.4 (C-5, isoquinoline); 126.5, 126.6 (Cp, PhCH2); 127.8 (C-6, isoquinoline); 127.9 (d, С-7, isoquinoline, 4JCP = 2.4 Hz); 128.0 (Со, PhC(O)); 128.2, 128.3 (Co, PhCH2); 128.5 (Сm, PhC(O)); 128.7, 128.7 (Cm, PhCH2); 128.8 (d, C-8, isoquinoline, 3JCP = 3.7 Hz); 129.6 (d, C-3, isoquinoline, 3JCP = 2.5 Hz); 130.6 (d, С-8a, isoquinoline, 2JCP = 3.0 Hz); 132.0 (Сp, PhC(O)); 139.2 (Сi, PhC(O)); 140.5, 140.6 (2d, Ci, PhCH2, 3JCP = 12.7 Hz, 3JCP = 12.5 Hz); 149.1 (=CHN); 189.1 (C=O). 15N NMR (40.56 MHz, CDCl3): δ -272.1. 31P NMR (161.98 MHz, CDCl3): δ 60.7. IR (neat): νmax = 3061, 3028, 2923, 2863, 1646, 1578, 1546, 1493, 1452, 1424, 1357, 1313, 1276, 1206, 1123, 1044, 1023, 915, 773, 740, 700, 655, 607, 554 cm-1. Anal. Calcd for С34Н32NOPS: С, 76.52; Н, 6.04; N, 2.62; P, 5.80; S, 6.01. Found: С, 76.35; Н, 6.13; N, 2.78; P, 5.60; S, 5.77. (2E)-3-[1-[bis(2-phenylethyl)phosphorothioyl]isoquinolin2(1H)-yl]-1-(2-furyl)prop-2-en-1-one (11b). Yield: 209 mg (40%); yellow powder, mp 75–76 °С (reprecipitated from CCl4 to hexane). 1H NMR (400.13 MHz, CDCl3): δ 1.93–2.25 (m, 4H, CH2P); 2.43–3.03 (m, 4H, CH2Ph); 5.42 (br s, 1H, H1, isoquinoline); 6.06 (d, 1H, H-4, isoquinoline, 3J4-3 = 7.4 Hz); 6.41 (d, 1H, =CHC(O)Furyl, 3Jtrans = 12.9 Hz); 6.55 (dd, 1H, H-4, furyl, 3J4-3 = 3.5 Hz, 3J4-5 = 1.7 Hz); 6.65 (d, 1H, H3, isoquinoline, 3J3-4 = 7.4 Hz); 7.06–7.42 (m, 15H, Ho,m,p, PhCH2; H-5,6,7,8, isoquinoline; H-3, furyl); 7.57 (d, 1H, H5, furyl, 3J5-4 = 1.7 Hz); 7.74 (d, 1H, =CHN, 3Jtrans = 12.9 Hz). 13C{1H} NMR (100.62 MHz, CDCl3): δ 28.6, 28.9 (2d, CH2Ph, 2JCP = 2.9 Hz, 2JCP = 1.7 Hz); 30.9 (d, CH2P, 1JCP = 39.8 Hz); 66.4 (br s, C-1, isoquinoline); 97.8 (=CHC(O)Furyl); 111.5 (C-4, isoquinoline); 112.2 (C-4, furyl); 115.4 (C-3, furyl); 124.4 (C-4a, isoquinoline); 125.3 (d, C-5, isoquinoline, 4JCP = 1.9 Hz); 126.3, 126.4 (Cp, PhCH2); 127.8 (C-8, isoquinoline); 127.8 (C-3, isoquinoline); 128.1 (С-7, isoquinoline); 128.1, 128.2 (Cm, PhCH2); 128.5, 128.6 (Co, PhCH2); 129.4 (d, C-6, isoquinoline, 5JCP = 2.3 Hz); 130.4 (d, С-8a, isoquinoline, 2JCP = 2.3 Hz); 140.4, 140.5 (d, Ci, PhCH2, 3JCP = 14.2 Hz); 145.3 (C-5, furyl); 148.0 (=CHN); 153.9 (C-2, furyl); 177.2 (C=O). 31P NMR (161.98 MHz, CDCl3): δ 60.9. IR (neat): νmax = 3084, 3028, 2926, 2857, 1643, 1569, 1549, 1461, 1424, 1357, 1309, 1275, 1233, 1202, 1158, 1125, 1086, 1053, 1014, 917, 770, 733, 701, 651, 602, 554 cm-1. Anal. Calcd for С32Н30NO2PS: С, 73.40; Н, 5.77; N, 2.67; P, 5.92; S, 6.12. Found: С, 73.21; Н, 5.85; N, 2.77; P, 5.69; S, 5.95. (2E)-3-[bis(2-phenylethyl)phosphorothioyl]-1-phenylprop2-en-1-one (12a). Yield: 182 mg (45%), waxy product. The product is characterized from a mixture with the product of double nucleophilic addition of secondary phosphine sulfide to benzoylacetylene14 (9:1 ratio). However, due to its low

concentration, the assignment of signals is impossible. 1H NMR (400.13 MHz, CDCl3): δ 2.26–2.37 (m, 4H, CH2P); 2.82–3.12 (m, 4H, CH2Ph); 7.12–7.32 (m, 11H, Ho,m,p, PhCH2; =CHP); 7.52–7.56 (m, 2H, Hm, PhC(O)); 7.63–7.67 (m, 1H, Hp, PhC(O)); 8.00 (dd, 1H, =CHC(O)Ph, 3Jtrans = 16.0 Hz, 2JPH = 20.0 Hz); 8.03–8.04 (m, 2H, Ho, PhC(O)). 13C{1H} NMR (100.62 MHz, CDCl3): δ 28.4 (d, CH2Ph, 2JCP = 2.6 Hz); 34.0 (d, CH2P, 1JCP = 53.2 Hz); 126.7 (Cp, PhCH2); 128.4, 128.7 (Co,m, PhCH2); 128.9, 129.0 (Со,m, PhC(O)); 133.9 (Сp, PhC(O)); 135.8 (d, =CHP, 1JCP = 66.8 Hz); 136.5 (Сi, PhC(O)); 140.2 (d, Ci, PhCH2, 3JCP = 14.2 Hz); 141.6 (d, =CHC(O)Ph, 2JCP = 4.5 Hz); 187.7 (d, C=O, 3JCP = 17.0 Hz). 31P NMR (161.98 MHz, CDCl ): δ 43.3. IR (neat): ν 3 max = 3060, 3028, 2923, 2860, 1665, 1600, 1534, 1495, 1449, 1401, 1326, 1279, 1251, 1180, 1137, 1073, 1005, 968, 911, 864, 741, 697, 655, 602, 554, 494 cm-1. (2E)-3-[bis(2-phenylethyl)phosphorothioyl]-1-(furan-2yl)prop-2-en-1-one (12b). Yield: 138 mg (35%); white powder, mp 69–70 °С (reprecipitated from CCl4 to hexane). 1H NMR (400.13 MHz, CDCl ): δ 2.21–2.28 (m, 4H, CH P); 3 2 2.76–3.07 (m, 4H, CH2Ph); 6.60 (dd, 1H, H-4, furyl, 3J4-3 = 3.6 Hz, 3J4-5 = 1.7 Hz); 7.12–7.25 (m, 11H, Ho,m,p, PhCH2; =CHP); 7.39 (d, 1H, H-3, furyl, 3J3-4 = 3.6 Hz); 7.68 (d, 1H, H-5, furyl, 3J5-4 = 1.7 Hz); 7.75 (dd, 1H, =CHC(O)Furyl, 3J 2 13 1 trans = 16.0 Hz, JPH = 20.0 Hz). C{ H} NMR (100.62 MHz, CDCl3): δ 28.0 (d, CH2Ph, 2JCP = 3.0 Hz); 33.7 (d, CH2P, 1JCP = 53.0 Hz); 112.6 (C-4, furyl); 119.7 (C-3, furyl); 126.3 (Cp, PhCH2); 128.0, 128.3 (Co,m, PhCH2); 135.4 (d, =CHP, 1JCP = 66.8 Hz); 139.8 (d, Ci, PhCH2, 3JCP = 14.4 Hz); 140.5 (d, =CHC(O)Furyl, 2JCP = 5.2 Hz); 147.7 (C-5, furyl); 152.3 (C2, furyl); 174.6 (d, C=O, 3JCP = 18.3 Hz). 31P NMR (161.98 MHz, CDCl3): δ 43.1. IR (neat): νmax = 3060, 3028, 2922, 2858, 1659, 1605, 1564, 1493, 1460, 1393, 1306, 1274, 1218, 1185, 1138, 1085, 1038, 1007, 969, 913, 849, 758, 702, 648, 600, 554, 494 cm-1. Anal. Calcd for С23Н23O2PS: С, 70.03; Н, 5.88; P, 7.85; S, 8.13. Found: С, 70.25; Н, 5.79; P, 7.67; S, 8.36. Reaction of secondary phosphine chalcogenides 2b, 10a,b with isoquinoline 8a and internal acylacetylenes 5a,b: General procedure. To a solution of secondary phosphine chalcogenide 2b, 10a,b (1.0 mmol) in MeCN (3 mL), isoquinoline 8a (1.5 mmol) and internal acylacetylene 5a,b (1.5 mmol) were added in three portions at regular intervals. The mixture was stirred under an argon atmosphere at 70–75 °C for 45–72 h (see also Scheme 6). After completion of the reaction (31P NMR monitoring), the target dihydroisoquinolines 13a-e were purified by column chromatography on SiO2 (for phosphine oxides 13a,b: toluene/Et2O, 1:2; for phosphine sulfides 13c,d: toluene/Et2O, 7:1; for phosphine sulfide 13e: toluene). 3-[1-[bis(2-phenylethyl)phosphoryl]isoquinolin-2(1H)-yl]1,3-diphenylprop-2-en-1-one (13a). Yield: 303 mg (51%); waxy product. The product is a mixture of two stereoisomers in a ratio of 1.24:1 (1H and 31P NMR data). Anal. Calcd for С40Н36NO2P: С, 80.92; Н, 6.11; N, 2.36; P, 5.22. Found: С, 80.77; Н, 6.23; N, 2.26; P, 4.97. E-isomer (major). 1H NMR (400.13 MHz, CDCl3): δ 2.00–2.45 (m, 4H, CH2P); 2.73–3.05 (m, 4H, CH2Ph); 5.88 (d, 1H, H-1, isoquinoline, 2JPH = 11.3 Hz); 5.96 (d, 1H, H-4, isoquinoline, 3J4-3 = 7.8 Hz); 6.50 (s, 1H, =CHC(O)Ph); 6.73 (d, 1H, H-3, isoquinoline, 3J3-4 = 7.8 Hz); 7.11–7.57 (m, 20H, Ar; H-5,6,7,8, isoquinoline); 7.97 (m, 4H, Ho,m, PhC(O)). 13C{1H} NMR (100.62 MHz, CDCl3): δ

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 12 of 15

12 27.0, 27.3 (2d, CH2Ph, 2JCP = 3.5 Hz, 2JCP = 4.0 Hz); 28.4, 29.5 (2d, CH2P, 1JCP = 54.3 Hz, 1JCP = 53.0 Hz); 62.7 (d, C-1, isoquinoline, 1JCP = 64.7 Hz); 102.8 (=CHC(O)Ph); 107.4 (C4, isoquinoline); 124.0 (C-4a, isoquinoline); 124.3 (d, C-5, isoquinoline, 4JCP = 1.4 Hz); 125.9, 126.0 (Cp, PhCH2); 127.5 (d, С-7, isoquinoline, 4JCP = 2.6 Hz); 127.6 (Со, PhC(O)); 127.8, 127.8, 127.9, 128.3 (Co,m, PhCH2); 128.3 (Сm, PhC(O)); 128.3 (C-6, isoquinoline); 129.1 (C-8, isoquinoline); 129.6 (C3, isoquinoline); 131.1 (Сo,m, =C(N)Ph); 131.2 (С-8a, isoquinoline); 131.8 (Сp, PhC(O)); 134.3 (Сi, =C(N)Ph); 134.5 (Сp, =C(N)Ph); 139.9 (Сi, PhC(O)); 140.9, 141.3 (2d, Ci, PhCH2, 3JCP = 13.3 Hz, 3JCP = 13.7 Hz); 159.8 (=C(N)Ph); 186.4 (C=O). 31P NMR (161.98 MHz, CDCl3): δ 53.4. Zisomer (minor). 1H NMR (400.13 MHz, CDCl3): δ 2.00–2.45 (m, 4H, CH2P); 2.73–3.05 (m, 4H, CH2Ph); 5.63 (d, 1H, H-1, isoquinoline, 2JPH = 12.8 Hz); 5.87 (d, 1H, H-4, isoquinoline, 3J 3 4-3 = 7.8 Hz); 6.34 (d, 1H, H-3, isoquinoline, J3-4 = 7.8 Hz); 7.11–7.57 (m, 20H, Ar; H-5,6,7,8, isoquinoline); 8.08 (m, 4H, Ho,m, PhC(O)). 13C{1H} NMR (100.62 MHz, CDCl3): δ 26.2, 28.7 (2d, CH2P, 1JCP = 55.8 Hz, 1JCP = 56.8 Hz); 27.2, 27.7 (2d, CH2Ph, 2JCP = 3.5 Hz, 2JCP = 4.0 Hz); 62.5 (d, C-1, isoquinoline, 1JCP = 63.6 Hz); 107.5 (=CHC(O)Ph); 109.4 (C4, isoquinoline); 124.8 (C-4a, isoquinoline); 124.8 (C-5, isoquinoline); 126.2, 126.4 (Cp, PhCH2); 127.4 (С-7, isoquinoline); 127.7, 128.3, 128.5, 128.5 (Co,m, PhCH2); 128.0 (Со, PhC(O)); 128.1 (Сm, PhC(O)); 128.1 (C-6, isoquinoline); 128.8 (C-8, isoquinoline); 129.5 (C-3, isoquinoline); 130.2 (Сo,m, =C(N)Ph); 131.1 (С-8a, isoquinoline); 131.6 (Сp, PhC(O)); 136.6 (Сi, =C(N)Ph); 140.0 (Сi, PhC(O)); 140.4, 140.6 (2d, Ci, PhCH2, 3JCP = 13.9 Hz, 3JCP = 14.1 Hz); 158.8 (=C(N)Ph); 188.9 (C=O). 31P NMR (161.98 MHz, CDCl3): δ 50.7. 3-[1-[bis(2-phenylethyl)phosphoryl]isoquinolin-2(1H)-yl]1-(2-furyl)-3-phenylprop-2-en-1-one (13b). Yield: 379 mg (65%); waxy product. The product is a mixture of two stereoisomers in a ratio of 1.28:1 (1H and 31P NMR data). Anal. Calcd for С38Н34NO3P: С, 78.20; Н, 5.87; N, 2.40; P, 5.31. Found: С, 78.03; Н, 5.79; N, 2.34; P, 5.01. E-isomer (major). 1H NMR (400.13 MHz, CDCl3): δ 1.62–2.19 (m, 4H, CH2P); 2.45–2.82 (m, 4H, CH2Ph); 5.64 (d, 1H, H-1, isoquinoline, 2JPH = 10.0 Hz); 5.72 (d, 1H, H-4, isoquinoline, 3J 4-3 = 7.7 Hz); 6.24 (s, 1H, =CHC(O)Furyl); 6.35 (dd, 1H, H4, furyl, 3J4-3 = 3.4 Hz, 3J4-5 = 1.7 Hz); 6.52 (d, 1H, H-3, isoquinoline, 3J3-4 = 7.7 Hz); 6.96 (d, 1H, H-3, furyl, 3J3-4 = 3.4 Hz); 6.85–7.34 (m, 19H, Ar; H-5,6,7,8, isoquinoline); 7.24 (d, 1H, H-5, furyl, 3J5-4 = 1.7 Hz). 13C{1H} NMR (100.62 MHz, CDCl3): δ 27.2, 27.4 (d, CH2Ph, 2JCP = 3.4 Hz); 28.6, 29.7 (2d, CH2P, 1JCP = 54.4 Hz, 1JCP = 53.5 Hz); 63.4 (d, C-1, isoquinoline, 1JCP = 64.7 Hz); 106.7 (=CHC(O)Furyl); 107.5 (C-4, isoquinoline); 112.3 (C-4, furyl); 115.4 (C-3, furyl); 124.3 (d, C-4a, isoquinoline, 3JCP = 1.8 Hz); 124.4 (d, C-5, isoquinoline, 4JCP = 1.4 Hz); 126.0, 126.1 (Cp, PhCH2); 127.6 (d, С-7, isoquinoline, 4JCP = 2.6 Hz); 127.7 (d, C-8, isoquinoline, 3JCP = 4.6 Hz); 127.9, 127.9, 128.0, 128.1 (Co,m, PhCH2); 128.6, 128.7, 128.8, 129.2 (Сo,m, =C(N)Ph); 128.9 (C6, isoquinoline); 131.3 (Сp, =C(N)Ph); 131.4 (d, С-8a, isoquinoline, 2JCP = 2.8 Hz); 134.3 (Сi, =C(N)Ph); 134.8 (C-3, isoquinoline); 141.1, 141.4 (2d, Ci, PhCH2, 3JCP = 13.3 Hz, 3J CP = 14.2 Hz); 145.5 (C-5, furyl); 154.7 (C-2, furyl); 159.8 (=C(N)Ph); 174.7 (C=O). 15N NMR (40.56 MHz, CDCl3): δ 281.3. 31P NMR (161.98 MHz, CDCl3): δ 53.7. Z-isomer (minor). 1H NMR (400.13 MHz, CDCl3): δ 1.62–2.19 (m, 4H,

CH2P); 2.45–2.82 (m, 4H, CH2Ph); 5.42 (br s, 1H, H-1, isoquinoline); 5.69 (d, 1H, H-4, isoquinoline, 3J4-3 = 7.7 Hz); 6.12 (d, 1H, H-3, isoquinoline, 3J3-4 = 7.7 Hz); 6.26 (dd, 1H, H-4, furyl, 3J4-3 = 3.4 Hz, 3J4-5 = 1.7 Hz); 6.74 (s, 1H, =CHC(O)Furyl); 6.96 (d, 1H, H-3, furyl, 3J3-4 = 3.4 Hz); 6.85–7.34 (m, 19H, Ar; H-5,6,7,8, isoquinoline); 7.35 (d, 1H, H-5, furyl, 3J5-4 = 1.7 Hz). 13C{1H} NMR (100.62 MHz, CDCl3): δ 26.6, 29.4 (2d, CH2P, 1JCP = 54.4 Hz, 1JCP = 53.5 Hz); 27.4, 27.9 (d, CH2Ph, 2JCP = 3.4 Hz); 62.0 (d, C-1, isoquinoline, 1JCP = 62.0 Hz); 100.0 (=CHC(O)Furyl); 110.2 (C-4, isoquinoline); 112.1 (C-4, furyl); 115.7 (C-3, furyl); 125.0 (d, C-5, isoquinoline, 4JCP = 1.8 Hz); 125.4 (d, C-4a, isoquinoline, 3JCP = 1.8 Hz); 126.4, 126.5 (Cp, PhCH2); 127.6 (d, С-7, isoquinoline, 4JCP = 2.6 Hz); 127.7 (d, C-8, isoquinoline, 3JCP = 4.6 Hz); 127.9, 128.0, 128.1, 128.4 (Co,m, PhCH2); 128.6, 128.7, 128.8, 129.2 (Сo,m, =C(N)Ph); 129.5 (C6, isoquinoline); 129.8 (C-3, isoquinoline); 129.9 (Сp, =C(N)Ph); 131.2 (d, С-8a, isoquinoline, 2JCP = 2.8 Hz); 136.7 (Сi, =C(N)Ph); 140.7, 140.8 (2d, Ci, PhCH2, 3JCP = 13.3 Hz, 3J CP = 14.1 Hz); 144.7 (C-5, furyl); 155.1 (C-2, furyl); 158.6 (=C(N)Ph); 176.6 (C=O). 31P NMR (161.98 MHz, CDCl3): δ 50.4. 3-[1-[bis(2-phenylethyl)phosphorothioyl]isoquinolin-2(1H)yl]-1,3-diphenylprop-2-en-1-one (13c). Yield: 377 mg (62%); waxy product. The product is a mixture of two stereoisomers in a ratio of 1.12:1 (1H and 31P NMR data). Anal. Calcd for С40Н36NOPS: С, 78.79; Н, 5.95; N, 2.30; P, 5.08; S, 5.26. Found: С, 78.55; Н, 5.88; N, 2.21; P, 4.88; S, 5.01. E-isomer (major). 1H NMR (400.13 MHz, CDCl3): δ 1.93–2.54 (m, 4H, CH2P); 2.56–3.13 (m, 4H, CH2Ph); 5.94 (d, 1H, H-1, isoquinoline, 2JPH = 8.2 Hz); 6.02 (d, 1H, H-4, isoquinoline, 3J 4-3 = 7.8 Hz); 6.52 (s, 1H, =CHC(O)Ph); 6.84 (d, 1H, H-3, isoquinoline, 3J3-4 = 7.8 Hz); 7.00–8.09 (m, 24H, Ar; H5,6,7,8, isoquinoline). 13C{1H} NMR (100.62 MHz, CDCl3): δ 28.3, 28.6 (2d, CH2Ph, 2JCP = 2.7 Hz, 2JCP = 3.5 Hz); 29.6, 32.4 (2d, CH2P, 1JCP = 39.1 Hz, 1JCP = 41.0 Hz); 66.9 (d, C-1, isoquinoline, 1JCP = 46.0 Hz); 102.8 (=CHC(O)Ph); 108.3 (C4, isoquinoline); 122.8 (C-4a, isoquinoline); 123.9 (C-5, isoquinoline); 126.4 (Cp, PhCH2); 127.5 (С-7, isoquinoline); 127.8, 127.9, 128.1, 128.3 (Co,m, PhCH2); overlapped by other signals: C-3,6, isoquinoline; Со,m, PhC(O); Со,m, =C(N)Ph; 129.1 (C-8, isoquinoline); 131.4 (d, С-8a, isoquinoline, 2JCP = 2.7 Hz); 131.8 (Сp, PhC(O)); 132.1 (Сp, =C(N)Ph); 136.6 (Сi, =C(N)Ph); 140.1 (Сi, PhC(O)); 140.9, 141.3 (2d, Ci, PhCH2, 3J 3 CP = 15.0 Hz, JCP = 15.3 Hz); 160.1 (=C(N)Ph); 186.7 (C=O). 15N NMR (40.56 MHz, CDCl3): δ -281.5. 31P NMR (161.98 MHz, CDCl3): δ 65.5. Z-isomer (minor). 1H NMR (400.13 MHz, CDCl3): δ 1.93–2.54 (m, 4H, CH2P); 2.56–3.13 (m, 4H, CH2Ph); 5.43 (d, 1H, H-1, isoquinoline, 2JPH = 8.2 Hz); 5.94 (d, 1H, H-4, isoquinoline, 3J4-3 = 7.8 Hz); 6.33 (d, 1H, H-3, isoquinoline, 3J3-4 = 7.8 Hz); 7.00–8.09 (m, 24H, Ar; H-5,6,7,8, isoquinoline). 13C{1H} NMR (100.62 MHz, CDCl3): δ 27.7, 32.3 (2d, CH2P, 1JCP = 42.9 Hz, 1JCP = 37.6 Hz); 28.7, 29.1 (2d, CH2Ph, 2JCP = 3.5 Hz, 2JCP = 3.1 Hz); 66.6 (d, C-1, isoquinoline, 1JCP = 42.2 Hz); 108.3 (=CHC(O)Ph); 110.0 (C-4, isoquinoline); 124.8 (C-5, isoquinoline); 125.1 (C4a, isoquinoline); 126.1 (Cp, PhCH2); 127.7 (С-7, isoquinoline); 128.3, 128.4, 128.5, 128.6 (Co,m, PhCH2); overlapped by other signals: C-3,6, isoquinoline; Со,m, PhC(O); Со,m,p, =C(N)Ph; 128.8 (C-8, isoquinoline); 130.9 (d, С-8a, isoquinoline, 2JCP = 2.7 Hz); 131.4 (Сp, PhC(O)); 134.4 (Сi, =C(N)Ph); 140.2 (Сi, PhC(O)); 140.6, 140.7 (2d, Ci,

ACS Paragon Plus Environment

Page 13 of 15 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

13 PhCH2, 3JCP = 15.0 Hz, 3JCP = 15.3 Hz); 158.7 (=C(N)Ph); 188.6 (C=O). 15N NMR (40.56 MHz, CDCl3): δ -268.6. 31P NMR (161.98 MHz, CDCl3): δ 58.9. 3-[1-[bis(2-phenylethyl)phosphorothioyl]isoquinolin-2(1H)yl]-1-(2-furyl)-3-phenylprop-2-en-1-one (13d). Yield: 396 mg (66%); waxy product. The product is a mixture of two stereoisomers in a ratio of 3.48:1 (1H and 31P NMR data). Anal. Calcd for С38Н34NO2PS: С, 76.10; Н, 5.71; N, 2.34; P, 5.16; S, 5.35. Found: С, 76.29; Н, 5.63; N, 2.23; P, 4.85; S, 5.12. E-isomer (major). 1H NMR (400.13 MHz, CDCl3): δ 1.96–2.50 (m, 4H, CH2P); 2.50–3.06 (m, 4H, CH2Ph); 5.43 (br s, 1H, H-1, isoquinoline); 6.01 (d, 1H, H-4, isoquinoline, 3J4-3 = 8.2 Hz); 6.49 (s, 1H, =CHC(O)Furyl); 6.59 (dd, 1H, H-4, furyl, 3J4-3 = 3.5 Hz, 3J4-5 = 1.7 Hz); 6.87 (d, 1H, H-3, isoquinoline, 3J3-4 = 8.2 Hz); 7.04–7.61 (m, 21H, Ar; H5,6,7,8, isoquinoline; H-3,5, furyl). 13C{1H} NMR (100.62 MHz, CDCl3): δ 28.1, 28.5 (d, CH2Ph, 2JCP = 2.6 Hz); 29.5, 32.1 (2d, CH2P, 1JCP = 37.4 Hz, 1JCP = 39.3 Hz); 66.4 (d, C-1, isoquinoline, 1JCP = 46.0 Hz); 100.1 (=CHC(O)Furyl); 108.0 (C-4, isoquinoline); 112.3 (C-4, furyl); 115.6 (C-3, furyl); 122.6 (C-4a, isoquinoline); 123.9 (d, C-5, isoquinoline, 4JCP = 2.3 Hz); 125.9 (d, С-7, isoquinoline, 4JCP = 3.1 Hz); 126.3 (Cp, PhCH2); 127.7 (C-3, isoquinoline); 127.8, 127.9, 127.9, 128.1, 128.2, 128.2, 128.5, 128.5, 128.6, 129.1, 129.3 (Co,m, PhCH2; Сo,m, =C(N)Ph); 128.9 (C-6, isoquinoline); 129.6 (C-8, isoquinoline); 131.2 (d, С-8a, isoquinoline, 2JCP = 2.7 Hz); 131.3 (Сp, =C(N)Ph); 133.9 (Сi, =C(N)Ph); 140.5, 140.7, 141.1 (3d, Ci, PhCH2, 3JCP = 15.3 Hz, 3JCP = 15.7 Hz, 3JCP = 14.9 Hz); 145.6 (C-5, furyl); 154.5 (C-2, furyl); 159.8 (=C(N)Ph); 174.7 (C=O). 15N NMR (40.56 MHz, CDCl3): δ 280.2. 31P NMR (161.98 MHz, CDCl3): δ 66.1. Z-isomer (minor). 1H NMR (400.13 MHz, CDCl3): δ 1.96–2.50 (m, 4H, CH2P); 2.50–3.06 (m, 4H, CH2Ph); 5.93 (d, 1H, H-4, isoquinoline, 3J4-3 = 8.2 Hz); 5.97 (br s, 1H, H-1, isoquinoline); 6.32 (d, 1H, H-3, isoquinoline, 3J3-4 = 8.2 Hz); 6.50 (s, 1H, =CHC(O)Furyl); 6.59 (dd, 1H, H-4, furyl, 3J4-3 = 3.5 Hz, 3J4-5 = 1.7 Hz); 7.04–7.61 (m, 21H, Ar; H-5,6,7,8, isoquinoline; H-3,5, furyl). 13C{1H} NMR (100.62 MHz, CDCl3): δ 27.7, 32.4 (2d, CH2P, 1JCP = 37.4 Hz, 1JCP = 39.3 Hz); 28.5, 28.9 (d, CH2Ph, 2JCP = 2.6 Hz); 66.0 (d, C-1, isoquinoline, 1JCP = 46.0 Hz); 108.0 (=CHC(O)Furyl); 110.4 (C-4, isoquinoline); 112.0 (C-4, furyl); 115.1 (C-3, furyl); 124.9 (d, C-5, isoquinoline, 4JCP = 2.3 Hz); 125.1 (C-4a, isoquinoline); 126.5 (Cp, PhCH2); 126.8 (d, С-7, isoquinoline, 4J CP = 3.8 Hz); 127.7 (C-3, isoquinoline); 127.8, 127.9, 127.9, 128.1, 128.2, 128.2, 128.5, 128.5, 128.6, 129.1, 129.3 (Co,m, PhCH2; Сo,m, =C(N)Ph); 129.2 (C-8, isoquinoline); 129.4 (C-6, isoquinoline); 130.6 (d, С-8a, isoquinoline, 2JCP = 3.1 Hz); 134.6 (Сp, =C(N)Ph); 136.3 (Сi, =C(N)Ph); 140.5, 140.7, 141.1 (3d, Ci, PhCH2, 3JCP = 15.3 Hz, 3JCP = 15.7 Hz, 3JCP = 14.9 Hz); 144.8 (C-5, furyl); 154.9 (C-2, furyl); 158.3 (=C(N)Ph); 176.1 (C=O). 15N NMR (40.56 MHz, CDCl3): δ 267.3. 31P NMR (161.98 MHz, CDCl3): δ 59.9. 3-[1-{bis[2-(4chlorophenyl)ethyl]phosphorothioyl}isoquinolin-2(1H)-yl]-1(2-furyl)-3-phenylprop-2-en-1-one (13e). Yield: 401 mg (60%); waxy product. The product is a mixture of two stereoisomers in a ratio of 2.76:1 (1H and 31P NMR data). Anal. Calcd for С38Н32Cl2NO2PS: С, 68.26; Н, 4.82; Cl, 10.60; N, 2.09; P, 4.63; S, 4.80. Found: С, 68.45; Н, 4.77; N, 2.17; P, 4.35; S, 5.01. E-isomer (major). 1H NMR (400.13 MHz, CDCl3): δ 1.86–2.45 (m, 4H, CH2P); 2.45–2.87 (m, 4H,

CH2Ar); 5.35 (br s, 1H, H-1, isoquinoline); 5.99 (d, 1H, H-4, isoquinoline, 3J4-3 = 7.9 Hz); 6.48 (s, 1H, =CHC(O)Furyl); 6.61 (dd, 1H, H-4, furyl, 3J4-3 = 3.5 Hz, 3J4-5 = 1.7 Hz); 6.79 (d, 1H, H-3, isoquinoline, 3J3-4 = 7.9 Hz); 6.98–7.53 (m, 18H, Ar; H-5,6,7,8, isoquinoline; H-3, furyl); 7.62 (d, 1H, H-5, furyl, 3J5-4 = 1.7 Hz). 13C{1H} NMR (100.62 MHz, CDCl3): δ 27.7, 28.0 (2d, CH2Ar, 2JCP = 2.3 Hz, 2JCP = 2.7 Hz); 27.7, 29.4 (2d, CH2P, 1JCP = 43.7 Hz, 1JCP = 37.6 Hz); 66.7 (d, C-1, isoquinoline, 1JCP = 46.4 Hz); 100.2 (=CHC(O)Furyl); 108.0 (C-4, isoquinoline); 112.5 (C-4, furyl); 115.9 (C-3, furyl); 122.5 (C-4a, isoquinoline); 124.1 (d, C-5, isoquinoline, 4JCP = 2.3 Hz); 126.7 (d, С-7, isoquinoline, 4JCP = 2.3 Hz); 128.5, 129.3, 129.3, 129.6 (Co,m, p-ClC6H4); 128.8 (Сo, =C(N)Ph); 128.8 (Сp, =C(N)Ph); 129.6 (C-6, isoquinoline); 129.7 (d, C-8, isoquinoline, 3JCP = 3.5 Hz); 129.7 (Сm, =C(N)Ph); 131.2 (Cp, p-ClC6H4); 131.6 (C-3, isoquinoline); 131.8 (d, С-8a, isoquinoline, 2JCP = 4.2 Hz); 136.2 (Сi, =C(N)Ph); 139.3, 139.7 (d, Ci, p-ClC6H4, 3JCP = 15.3 Hz); 145.9 (C-5, furyl); 154.6 (C-2, furyl); 159.9 (=C(N)Ph); 174.9 (C=O). 31P NMR (161.98 MHz, CDCl3): δ 65.9. Z-isomer (minor). 1H NMR (400.13 MHz, CDCl3): δ 1.86–2.45 (m, 4H, CH2P); 2.45–2.87 (m, 4H, CH2Ar); 5.92 (d, 1H, H-4, isoquinoline, 3J4-3 = 7.8 Hz); 6.31 (d, 1H, H-1, isoquinoline, 2JPH = 12.8 Hz); 6.51 (dd, 1H, H-4, furyl, 3J4-3 = 3.5 Hz, 3J4-5 = 1.7 Hz); 6.83 (s, 1H, =CHC(O)Furyl); 6.91 (d, 1H, H-3, isoquinoline, 3J3-4 = 7.8 Hz); 6.98–7.53 (m, 19H, Ar; H-5,6,7,8, isoquinoline; H-3,5, furyl). 13C{1H} NMR (100.62 MHz, CDCl3): δ 28.0, 28.5 (d, CH2Ar, 2JCP = 2.3 Hz); 32.0, 32.5 (2d, CH2P, 1JCP = 39.9 Hz, 1J 1 CP = 40.6 Hz); 66.3 (d, C-1, isoquinoline, JCP = 42.9 Hz); 107.6 (=CHC(O)Furyl); 110.4 (C-4, isoquinoline); 112.2 (C4, furyl); 115.3 (C-3, furyl); 125.0 (d, C-5, isoquinoline, 4JCP = 2.3 Hz); 125.1 (C-4a, isoquinoline); 127.0 (d, С-7, isoquinoline, 4JCP = 4.2 Hz); 127.9 (Сp, =C(N)Ph); 128.5, 129.3, 129.3, 129.6 (Co,m, p-ClC6H4); 129.0 (d, C-8, isoquinoline, 3JCP = 3.8 Hz); 129.4 (Сo, =C(N)Ph); 129.5 (C-6, isoquinoline); 129.5 (Сm, =C(N)Ph); 130.8 (Cp, p-ClC6H4); 132.3 (d, С-8a, isoquinoline, 2JCP = 3.8 Hz); 133.9 (Сi, =C(N)Ph); 134.8 (C-3, isoquinoline); 139.0 (d, Ci, p-ClC6H4, 3J CP = 15.0 Hz); 144.9 (C-5, furyl); 155.0 (C-2, furyl); 158.4 (=C(N)Ph); 176.2 (C=O). 31P NMR (161.98 MHz, CDCl3): δ 59.7. Aromatization of 3-[1-[bis(2phenylethyl)phosphoryl]isoquinolin-2(1H)-yl]-1,3diphenylprop-2-en-1-one 13a. A solution of 3-[1-[bis(2phenylethyl)phosphoryl]isoquinolin-2(1H)-yl]-1,3diphenylprop-2-en-1-one 13a (0.2 mmol, 118 mg), t-BuOK (0.2 mmol, 22 mg) and DDQ (0.2 mmol, 46 mg) in THF (2 mL) was stirred under an argon atmosphere at 20–25 °C for 2 h. The solvent was removed under the reduced pressure. The obtained residue was passed through chromatographic column (SiO2, eluent: toluene/Et2O, 1:2) to yield the mixture of the starting dihydroisoquinoline 13a and the expected aromatized product, 1-[bis(2-phenylethyl)phosphoryl]isoquinoline 14 in a ratio of ~ 1:3 (1Н and 31Р NMR data). The latter, without isolation, was characterized by 1Н and 31Р NMR spectra. 1-[bis(2-phenylethyl)phosphoryl]isoquinoline (14). 1H NMR (400.13 MHz, CDCl3): δ 7.69–7.76 (m, 3H, H-4,6,7, isoquinoline); 7.86 (d, 1H, H-5, isoquinoline, 3J5-6 = 8.1 Hz); 8.60 (d, 1H, H-8, isoquinoline, 3J8-7 = 5.3 Hz); 9.57 (d, 1H, H3, isoquinoline, 3J4-3 = 8.2 Hz). All these spectral patterns closely correspond to those of the known15 analog, 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 14 of 15

14 (diphenylphosphoryl)isoquinoline. In 31P NMR (161.98 MHz, CDCl3) spectrum of 14 the signal at 47.8 ppm was observed. Quantum chemical calculations. The geometrical parameters of pyridine and benzoylphenylacetylene zwitterionic adducts to pyridine (ZAP) and quinoline were obtained by means of the full geometry optimization procedure using the density functional theory (DFT) approach with the B3LYP functional and the 6-311G** basis set.16 The calculations were performed using the Gaussian program package.17 In the case of the ZAP, the thermodynamic stability of the Z- and E-isomers were additionally investigated at the level of second-order Møleer-Plesset perturbation theory (MP2) which was used in the combination with the 6-311G** basis set. The Mulliken and natural bond orbital (NBO)18 analysis of the electronic density was accomplished using results of the Hartree-Fock (HF) calculations performed using the GAMESS program package19 and the 6-311G** basis set. The basis set effect on the calculated atomic charges was studied in the case of ZAP by comparing the results for the 6-311G** and ccpVDZ20 basis sets.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Quantum chemical calculations and NMR spectral data (PDF).

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT This work was supported by the Russian Scientific Foundation (Grant No. 18-73-10080). The main results were obtained using the equipment of the Baikal Analytical Center of Collective using SB RAS.

REFERENCES (1) (a) Makosza, M.; Wojciechowski, K. Nucleophilic Substitution of Hydrogen in Heterocyclic Chemistry. Chem. Rev. 2004, 104, 2631–2666. (b) Gulevskaya, A. V.; Pozharskii, A. F. Nucleophilic Aromatic Substitution of Hydrogen as a Tool for Heterocyclic Ring Annulation. Adv. Heterocycl. Chem. 2007, 93, 57–115. (c) Charushin, V. N., Chupakhin, O. N., Eds. Metal Free C-H Functionalization of Aromatics. In Top. Heterocycl. Chem.; Springer International Publishing: Switzerland, 2014; Vol. 37. (2) (a) Charushin, V. N.; Chupakhin, O. N. Nucleophilic aromatic substitution of hydrogen and related reactions. Mendeleev Commun. 2007, 17, 249–254. (b) Chupakhin, O. N.; Charushin, V. N. Recent advances in the field of nucleophilic aromatic substitution of hydrogen. Tetrahedron Lett. 2016, 57, 2665–2672. (c) Manna, S.; Serebrennikova, P. O.; Utepova, I. A.; Antonchick, A. P.; Chupakhin, O. N. Hypervalent Iodine(III) in Direct Oxidative Amination of Arenes with Heteroaromatic Amines. Org. Lett. 2015, 17, 4588–4591. (d) Chupakhin, O. N.; Charushin, V. N. Nucleophilic C-H functionalization of arenes: A new logic of organic synthesis Expanding the scope of nucleophilic substitution of hydrogen in aromatics. Pure Appl. Chem. 2017, 89, 1195–1208. (3) (a) Cruz, H.; Gallardo, I.; Guirado, G. Electrochemical Synthesis of Organophosphorus Compounds through Nucleophilic

Aromatic Substitution: Mechanistic Investigations and Synthetic Scope. Eur. J. Org. Chem. 2011, 7378–7389. (b) Shchepochkin, A. V.; Chupakhin, O. N.; Charushin, V. N.; Petrosyan, V. A. Direct nucleophilic functionalization of C(sp2)−H bonds in (hetero)arenes by electrochemical methods. Usp. Khim. 2013, 82, 747–771. (c) Chupakhin, O. N.; Shchepochkin, A. V.; Charushin, V. N. Atom- and step-economical nucleophilic arylation of azaaromatics via electrochemical oxidative cross C–C coupling reactions. Green Chem. 2017, 19, 2931–2935. (4) Trofimov, B. A.; Volkov, P. A.; Khrapova, K. O.; Telezhkin, A. A.; Ivanova, N. I.; Albanov, A. I.; Gusarova, N. K.; Chupakhin, O. N. Metal-free site selective cross-coupling of pyridines with secondary phosphine chalcogenides using acylacetylenes as oxidants. Chem. Commun. 2018, 54, 3371–3374. (5) (a) Gusarova, N. K.; Volkov, P. A.; Ivanova, N. I.; Arbuzova, S. N.; Khrapova, K. O.; Albanov, A. I.; Smirnov, V. I.; Borodina, T. N.; Trofimov, B. A. One-pot reductive N-vinylation and C(4)phosphorylation of pyridines with alkyl propiolates and secondary phosphine chalcogenides. Tetrahedron Lett. 2015, 56, 4804–4806. (b) Gusarova, N. K.; Volkov, P. A.; Ivanova, N. I.; Khrapova, K. O.; Albanov, A. I.; Afonin, A. V.; Borodina, T. N.; Trofimov, B. A. Onepot regio- and stereoselective synthesis of tertiary phosphine chalcogenides with (E)-N-ethenyl-1,2-dihydroquinoline functionalities. Tetrahedron Lett. 2016, 57, 3776–3780. (6) Glotova, T. E.; Dvorko, M. Yu.; Gusarova, N. K.; Arbuzova, S. N.; Ushakov, I. A.; Kazantseva, T. I.; Trofimov, B. A. Chemo- and Regiospecific Monoaddition of Secondary Phosphine Sulfides to 1-Acyl-2-phenylacetylenes. Phosphorus, Sulfur Silicon Relat. Elem. 2008, 183, 1396–1401. (7) Bartlett, S. L.; Beaudry, C. M. High-Yielding Oxidation of βHydroxyketones to β-Diketones Using o-Iodoxybenzoic Acid. J. Org. Chem. 2011, 76, 9852–9855. (8) Ramirez, F.; Dershowitz, S. Reaction of Dialkyl Phosphites with Quinones. J. Org. Chem. 1957, 22, 1282–1283. (9) Clarke, P. A.; Santos, S.; Martin, W. H. C. Combining pot, atom and step economy (PASE) in organic synthesis. Synthesis of tetrahydropyran-4-ones. Green Chem. 2007, 9, 438–440. (10) Lokov, M.; Tshepelevitsh, S.; Heering, A.; Plieger, P. G.; Vianello, R.; Leito, I. On the Basicity of Conjugated Nitrogen Heterocycles in Different Media. Eur. J. Org. Chem. 2017, 4475– 4489. (11) (a) Trofimov, B. A.; Вrandsma, L.; Arbuzova, S. N.; Malysheva, S. F.; Gusarova, N. K. Nucleophilic addition of phosphine to aryl- and hetarylethenes a convenient synthesis of bis(2-arylalkyl)and bis(2-hetaralkyl)phosphine. Tetrahedron Lett. 1994, 35, 7647– 7650. (b) Gusarova, N. K.; Bogdanova, M. V.; Ivanova, N. I.; Chernysheva, N. А.; Sukhov, B. G.; Sinegovskaya, L. M.; Kazheva, O. N.; Alexandrov, G. G.; D’yachenko, O. A.; Trofimov, B. A. Hydrothiophosphorylation of Vinyl Sulfoxides: First Examples. Synthesis 2005, 3103–3106. (c) Sukhov, B. G.; Gusarova, N. K.; Ivanova, N. I.; Bogdanova, M. V.; Kazheva, O. N.; Alexandrov, G. G.; D’yachenko, O. A.; Sinegovskaya, L. M.; Malysheva, S. F.; Trofimov, B. A. Synthesis and structure of bis(2-phenylethyl) phosphine selenide. J. Struct. Chem. 2005, 46, 1066–1071. (d) Malysheva, S. F.; Artem’ev, A. V.; Gusarova, N. K.; Timokhin, B. V.; Tatarinova, A. A.; Trofimov, B. A. Synthesis of new secondary phosphine chalcogenides with bulky substituents from aryl(hetaryl)ethenes, red phosphorus, sulfur, and selenium. Russ. J. Gen. Chem. 2009, 79, 1617–1621. (e) Trofimov, B. A.; Gusarova, N. K. Elemental phosphorus in strongly basic media as phosphorylating reagent: a dawn of halogen-free ‘green’ organophosphorus chemistry. Mendeleev Commun. 2009, 19, 295–302. (f) Artem’ev, A. V.; Malysheva, S. F.; Gusarova, N. K.; Korocheva, A. O.; Timokhina, L. V.; Trofimov, B. A. Nucleophilic addition of phosphine to 4chlorostyrenes in the KOH-DMSO system. Russ. Chem. Bull. 2013, 62, 2495–2497. (12) (a) Zanina, A. S.; Shergina, S. I.; Sokolov, I. E.; Myasnikova, R. N. A new route for the synthesis of 1,3-diketones. Russ. Chem. Bull. 1995, 44, 689–694. (b) Zhang, X.; Lu, Z.; Fu, C.; Ma, S. Synthesis of highly substituted allylic alcohols by a regio- and stereo-

ACS Paragon Plus Environment

Page 15 of 15 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

15 defined CuCl-mediated carbometallation reaction of 3-aryl-substituted secondary propargylic alcohols with Grignard reagents. Org. Biomol. Chem. 2009, 7, 3258–3263. (c) Tomilin, D. N.; Petrova, O. V.; Sobenina, L. N.; Mikhaleva, A. I.; Trofimov, B. A. A convenient synthesis of hetarylethynyl ketones from hetarylcarbaldehydes and acetylene. Chem. Heterocycl. Compd. 2013, 49, 341–344. (d) Whittaker, R. E.; Dermenci, A.; Dong, G. Synthesis of Ynones and Recent Application in Transition-Metal-Catalyzed Reactions. Synthesis 2016, 48, 161–183. (13) Luo, K.; Chen, Y.-Z.; Chen, L.-X.; Wu, L. Autoxidative C(sp2)–P Formation: Direct Phosphorylation of Heteroarenes under Oxygen, Metal-Free, and Solvent-Free Conditions. J. Org. Chem. 2016, 81, 4682–4689. (14) Glotova, T. E.; Dvorko, M. Yu.; Arbuzova, S. N.; Ushakov, I. A.; Verkhoturova, S. I.; Gusarova, N. K.; Trofimov, B. A. Base Catalyzed Double Addition of Secondary Phosphine Chalcogenides to Benzoylacetylene. Lett. Org. Chem. 2007, 4, 109–111. (15) Zhang, H.-Y.; Sun, M.; Ma, Y.-N.; Tiana, Q.-P.; Yang, S.-D. Nickel-catalyzed C-P cross-coupling of diphenylphosphine oxide with aryl chlorides. Org. Biomol. Chem. 2012, 10, 9627–9633. (16) Krishnan, R.; Binkley, J. S.; Seeger, R.; Pople, J. A. Self‐consistent molecular orbital methods. XX. A basis set for correlated wave functions. J. Chem. Phys. 1980, 72, 650–654. (17) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Petersson, G. A.; Nakatsuji, H.; Li, X.; Caricato, M.; Marenich, A.; Bloino, J.; Janesko, B. G.; Gomperts, R.; Mennucci, B.; Hratchian, H. P.; Ortiz, J. V.; Izmaylov, A. F.; Sonnenberg, J. L.; Williams-Young, D.; Ding, F.; Lipparini, F.; Egidi, F.; Goings, J.; Peng, B.; Petrone, A.; Henderson, T.; Ranasinghe, D.; Zakrzewski, V. G.; Gao, J.; Rega, N.; Zheng, G.; Liang, W.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Throssell, K.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.;

Staroverov, V. N.; Keith, T.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Millam, J. M.; Klene, M.; Adamo, C.; Cammi, R.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Farkas, O.; Foresman, J. B.; Fox, D. J. Gaussian 09, Revision C.01; Gaussian, Inc.: Wallingford, CT, 2010. (18) (a) Foster, J. P.; Weinhold, F. Natural hybrid orbitals. J. Am. Chem. Soc. 1980, 102, 7211–7218. (b) Weinhold, F.; Landis, C. R. Discovering Chemistry with Natural Bond Orbitals; Wiley-VCH: Hoboken, 2012. (c) Glendening, E. D.; Badenhoop, J. K.; Reed, A. E.; Carpenter, J. E.; Bohmann, J. A.; Morales, C. M.; Landis, C. R.; Weinhold, F. NBO 6.0; Theoretical Chemistry Institute, University of Wisconsin: Madison, 2013. (d) Glendening, E. D.; Landis, C. R.; Weinhold, F. NBO 6.0: Natural bond orbital analysis program. J. Comput. Chem. 2013, 34, 1429–1437. (19) (a) Schmidt, M. W.; Baldridge, K. K.; Boatz, J. A.; Elbert, S. T.; Gordon, M. S.; Jensen, J. H.; Koseki, S.; Matsunaga, N.; Nguyen, K. A.; Su, S.; Windus, T. L.; Dupuis, M.; Montgomery, J. A. General atomic and molecular electronic structure system. J. Comp. Chem. 1993, 14, 1347–1363. (b) Gordon, M. S.; Schmidt, M. W. Advances in Electronic Structure Theory: GAMESS a decade later. In Theory and Applications of Computational Chemistry: The First Forty Years; Dykstra, C. E., Frenking, G., Kim, K. S., Scuseria, G. E., Eds.; Elsevier: Amsterdam, 2005; pp 1167–1189. (20) (a) Dunning, T. H, Jr. Gaussian basis sets for use in correlated molecular calculations. I. The atoms boron through neon and hydrogen. J. Chem. Phys. 1989, 90, 1007–1023. (b) Kendall, R. A.; Dunning, T. H., Jr.; Harrison, R. J. Electron affinities of the first-row atoms revisited. Systematic basis sets and wave functions. J. Chem. Phys. 1992, 96, 6796–6806.

ACS Paragon Plus Environment