Dearomatizing Radical Cyclizations and Cyclization Cascades

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Dearomatizing radical cyclizations and cyclization cascades triggered by electron-transfer reduction of amide-type carbonyls Huan-Ming Huang, and David J. Procter J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b12077 • Publication Date (Web): 20 Dec 2016 Downloaded from http://pubs.acs.org on December 20, 2016

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Journal of the American Chemical Society

Dearomatizing radical cyclizations and cyclization cascades triggered by electron-transfer reduction of amide-type carbonyls Huan-Ming Huang and David J. Procter* School of Chemistry, Oxford Road, University of Manchester, Manchester, M13 9PL, United Kingdom ABSTRACT: Highly selective dearomatizing radical cyclizations and cyclization cascades, triggered by single electrontransfer to amide-type carbonyls by SmI2-H2O-LiBr provide efficient access to unprecedented spirocyclic scaffolds containing five stereocenters with high diastereocontrol. The first dearomatizing radical cyclizations involving radicals derived from the amide carbonyls by single electron-transfer take place under mild conditions and engage a range of aromatic and heteroaromatic systems present in the barbiturate substrates. The radical cyclizations deliver new polycyclic hemiaminals or enamines selectively, depending on the conditions employed, that are based on a medicinally proven scaffold and can be readily manipulated.

1. INTRODUCTION Dearomatization is a powerful strategy for the construction of diverse three dimensional structures, including complex, polycyclic scaffolds and natural products, from simple aromatic starting materials.1 Successful approaches to dearomatization involve, for example, oxidation, cycloaddition, alkylation, arylation and C-H activation.2 Radical cyclizations can also be used to achieve dearomatization,3 and, although major advances have been made in this field, the development of new strategies for dearomatization by radical addition, particular those that deliver novel heterocyclic architectures, is an important goal.1-3 SmI2 is a highly versatile, commercially available or readily-prepared electron transfer (ET) reductant.4 SmI2-mediated dearomatizing cyclizations and cyclization cascades have recently been developed, with seminal contributions coming from the teams of Schmalz,5 Reissig,6 Fang,7 Tanaka,8 Yamashita,9 Wang and Li.10 Of particular note, Reissig has exploited an impressive SmI2-induced dearomatizing cyclization cascade in a concise total synthesis of Strychnine.6p,s,v Despite the progress made, until now, SmI2-mediated dearomatizing reactions are limited to radicals derived from ketone or aldehyde substrates (Scheme 1A). Furthermore, few examples of radical cascade cyclizations involving dearomatization have been reported.6d,f,p,q,s,v,9 The amide functional group is widely found in biological molecules, pharmaceuticals, natural products and functional materials.11 However, because of their resistance to reduction, developing cyclizations and cascades involving ET reduction of amide carbonyls is challenging.12 Herein, we demonstrate the feasibility of SmI2-mediated dearomatizing cyclizations and cyclization cascades involving radicals 1 formed by ET reduction of amide-type carbonyls (Scheme 1B).

Scheme 1. (A) Known dearomatizating radical cyclizations of aldehydes and ketones. Unknown dearomatizating radical cyclizations of amides. (B) Dearomatizing radical cyclizations and cyclization cascades of barbiturates. (C) The importance of spiro-heterocyclic scaffolds. A. Dearomatizing radical cyclizations: R = alkyl/H – known; R = NR 2 – unknown Ar/HetAr

O

Y

Ar/HetAr

X

1 e

Y

O

R

X

1 e 2 H+

R

X

HO

Y

R

B. This work: dearomatizing radical cyclizations and cyclization cascades of amides n first amide dearomatizing radical cyclizations XH

Ar/HetAr

O Me

N

O

Y

1 e X

O

1 e

Me

N R 2 H+ N O N O 1 Me Me n first amide dearomatizing radical cyclization cascades R O

Y HO Me N N Me

O

R O

H X O X

SmIIIO X

1 e

N

Y

1 e

N

R O

R O

HO N

R Y 2 H+ N O Ar/HetAr N O N O R' R' R' • 2 electron cascades • 2 new C–C bonds • 4 stereocentres • highly diastereoselective Y

Ar/HetAr

O

C. The importance of spirocyclic scaffolds

Me

Me Me Me H

H

OMe O Me

Me N

H O

O NH

O Me

stachybotrylactam

MeO 2C

O

MeO

N

Cl MeO griseofulvin O MeO 2C

N

O

HO O H

NH N H

CO 2Me N CO 2Me

grandilodine A

ACS Paragon Plus Environment

N CO 2Me CO 2Me

grandilodine B

H OH

morphine

O OMe

phosphodiesterase (PDE4) Inhibitor


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The processes involve two ET events, and thus require approximately two equivalents of the commercial reagent, and construct complex medicinally-relevant, polycyclic barbiturates containing up to five stereocenters with high diastereoselectivity.13 The spirocyclic scaffolds accessible are related to those found in biologically active products, drug targets and natural products (Scheme 1C).14

2. RESULTS AND DISCUSSION Optimization of the first dearomatizing radical cyclizations of amides – the key role of LiBr. Barbiturate 2a is available in three steps from commercially available 1,3dimethylbarbituric acid and was selected as a model substrate for optimization studies. Treatment of 2a with SmI2 in THF returned only starting material (Table 1, entry 1). Upon activation of SmI2 by H2O,15 the desired product of dearomatizing cyclization 3a was obtained in 20% yield, with 32% of 2a recovered (entry 2). The addition of LiBr to SmI216 gave 3a in 40% NMR yield (entry 3). However, when LiBr was added to SmI2 and H2O, the reaction delivered cyclized product 3a in 78% isolated yield with excellent diastereocontrol (> 95:5 dr) (entry 4). Increasing the amount of H2O did not have a beneficial effect on the reaction (entry 5). Table 1. Optimizating the dearomatizing radical cyclization of amide 2aa,b Me O

O

Me O

N N Me

O

see table

Me O

Me

1

3

–

100

0

2

3

100

32

20

c

3

–

-

40

5

3

200

H

Me

O

Me

–

80 (78)

-

73

Me N OH Me O

O

3f 75% > 95:5 dr

Cy

N OH Me S

N OH Me O

3e 83% > 95:5 dr X-ray Ph O Me N

N

O

N

O

3d 72% > 95:5 dr X-ray

Me NH

Ph O

N

iBu

N OH Me S

N OH Me O

O

O

N

d

Cy

N

Ph

Ph

X

3b 84% > 95:5 dr X-ray

N OH Me O

O

n

N OH Y Me 3

O

3c 76% > 95:5 drc X-ray Me

R

N

O

X-ray crystal structure of 3a

N

O

b

3a

THF, rt, 2 h

2

iBu

O

N OH Me O

Yield/% 2a

100

O

N

O

SmI2–H2O–LiBr

Me

3a

3

N Me

O

(equiv)

c

Me Y

O

N OH O Me

(equiv)

4

X

n

N

O

Me

O R

3a 78% > 95:5 dr X-ray

H2O

c

Me

Me

SmI2

3

O

N

2a

Entry

reduction to the anion under the SmI2-H2O/LiBr conditions and radical cyclization is more efficient. A hindered approach of Sm(II), in the modified reagent system, to the radicals may result in a slower outer-sphere ET process. Scope of dearomatizing radical cyclizations of amides. We next examined the scope of the dearomatizing radical cyclization of amides 2 (Scheme 2). Benzofuran substrates bearing hindered alkyl groups, such as isobutyl (3a) and methylcyclohexyl (3b), and aryl-containing substituents (3c-e) on the barbituric acid ring, exhibited excellent reactivity and dearomatized spirocyclic products were isolated in good yield and essentially as single diastereoisomers. The relative stereochemistry in 3a-e was confirmed by Xray crystallographic analysis.20 Scheme 2. Scope of the dearomatizing radical cyclization of amides.a,b

Me

Me O

Page 2 of 10

NH

O

3g 78% > 95:5 dr

N OH Me S

NH

3h 47% > 95:5 dr

Ph

a

Reaction conditions: 2a (0.1 mmol, in 2 mL THF) at room temperature under N2, was added H2O, followed by SmI2 and b 1 the reaction quenched after 2 h. Yield was determined by H NMR spectroscopy using 2,3,5,6-tetrachloronitrobenzene as an c d internal standard. LiBr (20 equiv wrt SmI2) was used. isolat1 ed yield. > 95:5 dr - determined by H NMR on the crude product mixture.

Flowers has proposed that the combination of SmI2 and LiBr generates a soluble form of SmBr2 in situ.17 Thus, the addition of LiBr may generate SmBr2-H2O or the ate complex SmBr3–Li+-H2O.18,19 SmBr2 (approx. –1.55 V vs SCE) has a higher reduction potential than SmI2 (–0.9 V vs SCE).17,18 It is therefore surprising that the radical intermediates in dearomatizing cyclizations (cf. 1 in Scheme 1) and cyclization cascades (cf. 13 in Scheme 7) appear less susceptible to

O

O Me O

Me

N N OH Me S

NH

3i 47% > 95:5 dr

a

O

iBu

N

OH N O Me 3j 27% > 95:5 dr X-ray

X-ray crystal structure of 3j

Reaction conditions: To a solution of 2a (0.1 mmol), in THF (2 mL) at room temperature under N2, was added H2O, followed by a mixture of SmI2 and LiBr. The reaction was b quenched after 2 h. Isolated yields, > 95:5 dr - determined by 1 c H NMR on the crude product mixtures. major product 3c is a 75:25 mixture of diastereoisomers at the remote stereocenter.


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Benzothiazole-containing substrates also underwent smooth dearomatizing radical spirocyclization to give 3f-i in moderate to high yield and high diastereocontrol. The relative stereochemistry in 3f was assigned by nOe studies and inferred for analogous products.21 Finally, barbiturate 3j, the product of a 6-exo-trig amide dearomatizing radical cyclization was isolated in modest yield and as a single diastereoisomer. The structure of 3j was confirmed by X-ray crystallographic analysis (Scheme 2).20 Proposed mechanism for the dearomatizing radical cyclizations of amides. A mechanism for the dearomatizing radical cyclization of amides is shown in Scheme 3. Radical 4 is formed by ET to the amide-type carbonyl from Sm(II). Subsequent 5-exo-trig dearomatizing radical cyclization, via transition structure 5, and a second ET gives dianion 6, which, after protonation, gives 3 (Scheme 3). For benzofuran substrates (Y = O, X = CH) the preference for transition structure 5 may arise from the minimization of dipole-dipole interactions. For benzothiazole substrates (Y = S, X = N) coordination of Sm(III) to nitrogen may lead to a preference for transition structure 5. To date our studies have focused specifically on the chemistry of activated amide-type carbonyls in medicinally-relevant barbituric acid substrates although we expect the process to extend to other cyclic imides.12c,d Analogous chemistry of simple amides and lactams will likely require the future development of more-reducing Sm(II) reagent systems.12f Scheme 3. Proposed mechanism for the dearomatizing radical cyclizations of amides.

complex scaffolds in a single operation (Table 2).22 Treatment of 7a with SmI2 returned only starting material (entry 1), thus confirming the importance of H2O and LiBr for activation of the reductant. Addition of H2O (100 equiv.) to SmI2 and 7a led to formation of the desired cascade product 9a (60% NMR yield), after acid-mediated dehydration of hemiaminal product 8a, but little diastereocontrol was observed (45:55 dr) (entry 2). Addition of LiBr to SmI2 gave 9a in 40% NMR yield (entry 3). However, when LiBr was added to SmI2 and H2O at room temperature, both the yield and diastereoselectivity of the reaction were increased (71%, 63:27 dr) (entry 4). We next investigated the effect of temperature on the radical cascade. The use of SmI2-H2OLiBr at 0 °C delivered optimal results and the cascade product 9a was obtained in good yield and with high diastereocontrol (80% isolated yield, 92:8 dr) and only 10% of monocyclization byproduct 10 (entry 5). Lower reaction temperatures gave lower yields of 9a and a greater proportion of 10 (entry 6). Without acidic work up, the corresponding hemiaminal product 8a was isolated in 76% yield and 93:7 dr (entry 7). X-ray crystallographic analysis confirmed the structure of major diastereoisomer 9a and the corresponding minor diastereoisomer 9a’ (not shown).2o

Table 2. Optimization of the dearomatizing radical cyclization cascade of amide 7a.a H

see iPr Table O

O N

OH O

iPr O

N

N O

7a

N O

Me

R'

8a

iPr O

N [R' = benzofuran-2-yl] O Me

X

R

O Y

N

O

N Me

Me

X

R

O

OSmIII

N Me

2

O

R

O N N Me

O Y

when X= CH 2

O Me O

N

O dipoles near antiparallel

5

N Me

entry

T/°C

c

O

1 N

Y

d

when X=N

O

R

N OH Y Me 3

H X

2 x H+

Me

8a

9a

10

rt

100

-

-

-

chelation control

2

rt

24

-

3

e

rt

-

-

4

rt

-

-

5

0

-

-

6

−15

-

-

g

0

-

60 (45:55) 40 (48:52)

R

N

O

Yield/% (dr)

SmIII

1 e

N

N O 10 R'

7a

R

O

Me

SmIII

9a

b

4

5-exo-trig

Me

R'

Y

N

1e

O

O

iPr O

N

N R'

O O

O

N O Y Me SmIII 6

SmIII X

71 (63:27)

20 15 7

f

Optimization of the dearomatizing radical cascade cyclizations of amides. Having established the feasibility of dearomatizing radical cyclizations involving radical anions derived from amides by ET, we sought to develop related radical-radical cyclization cascades involving dearomatization of aryl and heteroaryl substituents. Model substrate 7a, readily synthesized from diethyl-2methylmalonate in three steps, was used to explore novel dearomatizing radical cascades capable of delivering more

7

85 (80) (92:8) 57 (95:5) f

a

80 (76)

7

(93:7)

(93:7)

10 34 8

Reaction conditions: To 7a (0.1 mmol), in THF (2 mL) under N2, was added H2O (100 equiv), followed by a mixture of SmI2 (3 equiv) and LiBr (20 equiv wrt SmI2). After 2 h, HCl (2 b M, 1 mL) was added and the reaction stirred for 20 min. Yield


Journal of the American Chemical Society 1

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determined by H NMR spectroscopy using 2,3,5,6tetrachloronitrobenzene as internal standard. dr was deter1 c mined by H NMR on crude product mixtures. Without H2O d e f g and LiBr. Without LiBr. Without H2O. Isolated yield. Without HCl. T = temperature.

Scheme 4. Scope of the dearomatizing radical cyclization cascade.a,b

Condition A SmI2-H2O-LiBr R' THF, 0 oC, 2 h

R1 O O

N N

7

Page 4 of 10

O O

R2

H OH O

Condition B R2 SmI2-H2O-LiBr THF, 0 oC, 2 h then HCl (2 M, 1 mL) 20 min

R1 O

N N O

8

R2

O

N O

R'

Condition A

R1 O

N

R'

9 Condition B

Condition A H

H OH O

N

O

N O 8d 73% 93:7 dr [R' = 5-Br-benzofuran-2-yl]

R'

O

R'

H OH O

iPr O

N N

N R' R' 8f O 8e O 59% 91:9 dr 80% 94:6 dr [R' = 5-Me-benzofuran-2-yl] [R' = 5-F-benzofuran-2-yl] H

H OH

OH iPr O

N

iBu O

8c O 52% 89:11 dr [R' = benzofuran-2-yl]

iPr O

N

H

O

N

Me

OH

iPr O

N

R'

H

F

OH

Me O

OH O

N

8b O 73% 69:31 dr [R' = benzofuran-2-yl]

R'

H

O

N

Me O

N

N 8a O 76% 92:8 dr [R' = benzofuran-2-yl]

Br

H OH

iPr O

O

O Me

OH iPr O

N

O

iPr O

N

N

N

N Br R' R' R' 8g O 8h O 8i O 72% 91:9 dr 66% 96:4 dr 68% > 95:5 dr [R' = 5-MeO-benzofuran-2-yl] [R' = 6-MeO-benzofuran-2-yl] [R' = 7-Br-benzofuran-2-yl] H OH O

iPr O

N

N R' 8j O 81% 91:9 dr [R' = naphtho[2,1-b]furan-2-yl] X-ray

X-ray crystal structure of 8j

Condition B

O

iPr O

N

N 9a O 80% 92:8 dr [R' = benzofuran-2-yl] X-ray

O

Me O

N

N 9b O 74% 69:31 dr [R' = benzofuran-2-yl]

R'

O

iPr O

N

N 9d O 80% 93:7 dr [R' = 5-Br-benzofuran] X-ray

R'

iBu O

N

N O 9c 54% 89:11 dr [R' = benzofuran-2-yl] X-ray

R'

R'

Me

F

Br

O

O

iPr O

N

N O 9e 85% 94:6 dr [R' = 5-F-benzofuran] X-ray

O

R'

iPr O

N

N R' 9f O 65% 91:9 dr [R' = 5-Me-benzofuran]

Me O O

iPr O

N

N R' 9g O 74% 91:9 dr [R' = 5-MeO-benzofuran-2-yl]

O

iPr O

N N

R' 9j O 85% 91:9 dr [R' = naphtho[2,1-b]furan-2-yl] X-ray

a

O Me

O

N

iPr O

O

iPr O

N N

N Br R' 9i O R' 9h O 79% > 95:5 dr 68% 95:5 dr [R' = 6-MeO-benzofuran-2-yl] [R' = 7-Br-benzofuran-2-yl] X-ray X-ray

X-ray crystal structure of 9i

Reaction conditions A: To a solution of 7 (0.1 mmol), in THF (2 mL) under N2, was added H2O, followed by a mixture of SmI2 and LiBr, the reaction was quenched after 2 h. Reaction


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conditions B: To a solution of 7 (0.1 mmol), in THF (2 mL) under N2, was added H2O, followed by a mixture of SmI2 and LiBr, after 2 h, HCl (2 M, 1 mL) was added and stirred for 20 b 1 min. Isolated yield. Dr determined from H NMR of crude product mixtures.

Scheme 5. Radical cyclization cascades involving dearomatization of various heteroaromatic and aromatic rings.a,b Condition A SmI2-H2O-LiBr R' THF, 0 oC, 2 h

R1 O O

N O

Y

7

X R2

OH

Y

Condition B R2 SmI2-H2O-LiBr o THF, 0 C, 2 h then HCl (2 M, 1 mL) 20 min

N

H X

H

H X

R1 O

N N 8

O

R2

Y

R1 O

N N O

R'

R'

9

Condition A

Condition B

H

H

OH

OH S

iPr O

N

N

N O

O

R'

8k 35% > 95:5 dr [R' = benzo[b]thiophen-2-yl] X-ray H H OH N iPr F O

N

O

H

H N

H N

OH iPr O Cl

N

H OH

O

iPr O

N

H N S

O

H OH N

iPr O

N O R' 8o 43% > 95:5 dr [R' = 6-Cl-benzo[d]oxazol-2-yl]

N O R' O R' 8m 8n 52% > 95:5 dr 47% > 95:5 dr [R' = benzo[d]oxazol-2-yl] [R' = 5-F-benzo[d]oxazol-2-yl] H N

R'

8l 40% > 95:5 dr [R' = naphthalen-1-yl]

X-ray crystal structure of 8k

O

N

Br

iPr O

N

H OH N

iPr O

N N O R' O R' 8p 8q 49% > 95:5 dr 30% > 95:5 dr [R' = 5-Br-benzo[d]oxazol-2-yl] [R' = benzo[d]thiazol-2-yl]

S

N

iPr O

N O R' 9k 40% > 95:5 drc [R' = benzo[b]thiophen-2-yl] X-ray

iPr O

N N O

R'

9l 43% > 95:5 drc [R' = naphthalen-1-yl] X-ray

X-ray crystal structure of 9l

a

Reaction conditions A: To a solution of 7 (0.1 mmol), in THF (2 mL) under N2, was added H2O, followed by a mixture of SmI2 and LiBr, the reaction was quenched after 2 h. Reaction conditions B: To a solution of 7 (0.1 mmol), in THF (2 mL) under N2, was added H2O, followed by a mixture of SmI2 and LiBr, , after 2 h, HCl (2 M, 1 mL) was added and stirred for 20 b 1 min. Isolated yield. Dr determined by H NMR of crude c product mixtures. Prepared using Condition B.

the barbituric acid ring were tolerated, including bulky isopropyl and isobutyl substituents, and the corresponding cascade products (8a-c and 9a-c) were obtained in good yield. Substrates bearing the hindered isopropyl substituent gave the highest yields and diastereoselectivities. Next we investigated the scope with regards to the benzofuran motif undergoing dearomatization. Benzofurans bearing bromo (8d, 8i and 9d, 9i), fluoro (8e and 9e), methyl (8f and 9f) and methoxy (8g, 8h and 9g, 9h) groups, as well as naphthylfused furans (8j and 9j) were compatible with the cascade process and gave polycyclic products in good to excellent isolated yield (59-85%) and with excellent diastereocontrol (91:9 to 95:5 dr). The relative stereochemistry of the major products 8j and 9a, 9c-e, 9h-j was confirmed by X-ray crystallographic analysis.20 We further investigated the scope of the radical cyclization cascade by varying the aromatic moiety undergoing dearomatization (Scheme 5). Pleasingly, benzothiophene (8k and 9k), naphthalene (8l and 9l), benzoxazole (8m-p), benzothiazole (8q) were compatible with the process and provided diverse barbiturates bearing spiro-heterocyclic motifs with essentially complete diastereocontrol (> 95:5 dr). Attempts to engage simple benzene substituents in the dearomatizing process have so far proved unsuccessful. Again, fluoro (8n), chloro (8o) and bromo (8p) substituents on the heterocyclic ring were tolerated in the process. The relative stereochemistry in 8o was assigned by nOe studies and inferred for analogous products.21 Attempted cascade reactions involving two dearomatization events were unsuccessful. We believe that the high stability and ease of reduction of the benzylic radicals formed during the first dearomatization event (factors that are also key to driving the dearomatization event), rule out trapping of the radical by a second radical acceptor, whether it be another aromatic unit or a simple alkene or alkyne. Dearomatizing cyclization cascades of amides involving 7-endo-trig processes. When a benzofuran and benzothiophene moiety were attached to nitrogen of the barbituric acid unit through the 3-position of the heterocycle, dearomatizing radical-radical cyclization cascades involving 5-exo-trig and 7-endo-trig processes were observed and azepine-containing products 11a and 11b were obtained in moderate yield with excellent diastereocontrol (Scheme 6). Scheme 6. Dearomatizing radical cyclization cascades involving 7-endo-trig processes.a,b

Scope of the dearomatizing radical cyclization cascade of amides. With optimal conditions established, the generality of the dearomatizing radical cascade cyclization for the construction of tetracyclic hemiaminals 8 or enamines 9 was investigated (Scheme 4). Focusing initially on the dearomatization of benzofurans, various alkyl groups on



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iPr O

SmI2–H2O–LiBr THF, rt, 2 h

R' O X

N

iPr O

SmI2–H2O–LiBr THF, rt, 2 h

H HO H

iPr

O

N

N

N O

11a (from 10a) 45% > 95:5 dr [R' = benzofuran-3-yl]

R'

R'

N

1e

III Sm

N

X

O

O

N N

X

O

O

7 or 10

H S

HO H

12 5-exo-trig

H O

iPr O R'

10a X = O 10b X = S H O

Page 6 of 10

iPr N

N

O

iPr

H R'

heterocycle attached via C2

O

III Sm

X

O

N

N

6-exo-trig

R'

O

dearomatizing spirocyclization

11b (from 10b) 38% > 95:5 dr [R' = benzo[b]thiophen-3-yl] X-ray

O

13 heterocycle attached via C3

7-endo-trig

dearomatizing cyclization X-ray crystal structure of 11b

X

Reaction conditions: To a solution of 10 (0.1 mmol), in THF (2 mL) under N2, was added H2O, followed by a mixture of b SmI2 and LiBr. The reaction was quenched after 2 h. Isolated 1 yield. Dr was determined by H NMR of the crude product mixture.

In dearomatizing radical cyclization cascades, ET from Sm(II) to the amide-type carbonyl forms radicals 12. 5-Exotrig cyclization then forms radical intermediates 13 which undergo either 6-exo-trig or 7-endo-trig dearomatizing cyclization, depending on the site of attachment of the heteroaryl unit to the barbituric acid scaffold. When the heteroaromatic group is attached via C2, spirocyclization takes place via chair transition structure 14 in which dipoledipole interactions are minimized. Further ET reduction and protonation then delivers 8. In contrast, when the heteroaryl unit is attached via C3, 7-endo-trig radical cyclization via transition structure 15 leads to 11 (Scheme 7). Scheme 7. Proposed mechanisms for the dearomatizing radical cyclization cascades.

N

N

OSmIII

H H

15

iPr N

O N

1 e 2 x H+

O

R'

H

OH iPr O

N

H X

N

8

SmIII

X

H

X

O

R'

O

1 e 2 x H+

a

iPr O

H

14

O

R'

HO

iPr O N

N

H 11

O

R'

Manipulation of the products of dearomatizing amide radical cyclizations and cyclization cascades. The dearomatizing radical cyclizations and cyclization cascades can be carried out on larger scale to deliver products such as 3b and 9a with excellent diastereocontrol in good isolated yield (Scheme 8). Scheme 8. Larger scale dearomatizing radical cyclizations and cyclization cascades of amides. O Me

O

Cy

Me O

N

O

N Me

SmI2–H2O–LiBr

O

N OH Me O

R' O

N N O

O

0.62 g

3b 78% > 95:5 dr

SmI2–H2O–LiBr THF, 0 °C, 2 h

iPr O

7a

N

O

THF, rt, 2 h 2 mmol, 0.80 g

2b

Cy

then HCl (2 M, 15 mL) 1h

1 mmol, 0.48 g

O

iPr O

N N O

0.34 g

R'

9a 70% 92:8 dr

[R' = benzofuran-2-yl]

The unusual hemiaminal products arising from dearomatizing amide radical cyclization can be readily manipulated. For example, iminium ion generation, upon exposure of 3b to BF3•OEt2, and addition of various carbon nucleophiles, delivers complex tertiary amine products 16a-c with high stereocontrol (Scheme 9).23 Scheme 9. Manipulation of the hemiaminal products of the dearomatizing radical cyclization of amides.


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Journal of the American Chemical Society O

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

Me

Cy

O

O

N OH Me O

CH 2Cl 2, rt Nucleophile (Nu – )

3b

O Me O

Me

BF 3•Et 2O

N

O

Cy Me

N N Me

O

O

16a 96% > 95:5 dr (with allylTMS)

O Me

N Me

N Nu Me O

Cy

O

AUTHOR INFORMATION

Cy

Corresponding Author

N

O

N Me

•

*[email protected]

O

Cl

16b 66% > 95:5 dr (with propargylTMS) O

Me

O 16a–d major

N

Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Experimental details, characterization data and spectra, X-ray structures, and NOE studies (PDF).

Cy

N

16c 55% > 95:5 dr (with 2-chloromethylallylTMS)

X-ray crystal structure of major diastereoisomer of 16d

N

O

N H O Me 16d 99% 68:32 dr (with Et3SiH)

O

9a

N N O

R'

iPr O

CAN (6 equiv) CH3CN:H 2O 45%

O

N

17

O

N R'

[R' = benzofuran-2-yl] DIBAL-H (3 equiv) oC

O

N

9a

O

iPr O N R'

We thank the EPSRC (EPSRC Established Career Fellowship to D. J. P.), the Leverhulme Trust (Research Fellowship to D. J. P.), and the University of Manchester (President’s Scholarship to H. H.).

REFERENCES

Similarly, the products of dearomatizing amide radical cyclization cascades can be further elaborated. For example, selective allylic oxidation of tetracyclic enamine 9a gave ketone 17 in moderate yield (Scheme 10).24 The cyclic urea moiety in the cascade products can be reduced. For example, reduction of 9a with DIBALH gave new hemiaminal 18 which can be reduced further by excess reagent to give polycyclic aminal 19. Scheme 10. Manipulation of the novel polycyclic spirobarbiturates. O

The authors declare no competing financial interest.

ACKNOWLEDGMENT

Cy

iPr O

Notes

THF, –78 68%

to rt

DIBAL-H (8 equiv) THF, –78 oC to rt 95%

O

N

18

O

O

N

iPr OH N R'

iPr

19

N R'

3. CONCLUSION The first dearomatizing radical cyclizations and cyclization cascades triggered by ET reduction of amide-type carbonyls provide access to unprecedented polycyclic molecular architectures containing up to five stereocenters with high diastereocontrol. The mild process exploits activation of SmI2 with H2O and LiBr, exhibits wide scope with regard to the aromatic system undergoing dearomatization, and delivers novel scaffolds based on a medicinally-proven structural platform. While the current method is limited to amide-type carbonyls in cyclic imides, future studies will focus on extending the method to simple lactam substrates.

ASSOCIATED CONTENT

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J. 2015, 21, 18394. (l) Chciuk, T. V.; Anderson, W. R.; Flowers, II, R. A. Angew. Chem., Int. Ed. 2016, 6033. (m) Chciuk, T. V.; Anderson, W. R.; Flowers, II, R. A. J. Am. Chem. Soc. 2016, 138, 8738. (16) For the beneficial effect of LiBr (and LiCl) on SmI2mediated carbon-carbon bond-forming processes, see: (a) Peltier, H. M.; McMahon, J. P.; Patterson, A. W.; Ellman, J. A. J. Am. Chem. Soc. 2006, 128, 16018. (b) Asano, Y.; Suzuki, S.; Aoyama, T.; Shimizu, K.; Kajitani, M.; Yokoyama, Y. Synthesis 2007, 2007, 1309. (c) Iwasaki, H.; Eguchi, T.; Tsutsui, N.; Ohno, H.; Tanaka, T. J. Org. Chem. 2008, 73, 7145. (d) Zörb, A.; Brückner, R. Eur. J. Org. Chem. 2010, 4785. (e) J. Y. Cha, J. T. S. Yeoman, S. E. Reisman, J. Am. Chem. Soc. 2011, 133, 14964. (f) Gilles, P.; Py, S. Org. Lett. 2012, 14, 1042. (g) Yeoman, J. T. S.; Mak, V. W.; Reisman, S. E. J. Am. Chem. Soc. 2013, 135, 11764. For examples using SmI2-H2O-LiBr, see: ref. 6t, 6u and 12b. (17) (a) Fuchs, J. R.; Mitchell, M. L.; Shabangi, M.; Flowers, II, R. A. Tetrahedron Lett. 1997, 38, 8157. (b) Miller, R. S.; Sealy, J. M.; Shabangi, M.; Kuhlman, M. L.; Fuchs, J. R.; Flowers, II, R. A. J. Am. Chem. Soc. 2000, 122, 7718. (c) Knettle, B. W.; Flowers, II, R. A. Org. Lett. 2001, 3, 2321. (18) For the effective redox potential of SmBr2-H2O, see: Szostak, M.; Spain, M.; Procter, D. J. J. Org. Chem. 2014, 79, 2522. (19) (a) Yuan, F.; Qian, H.; Min, X. Inorg. Chem. Commun. 2006, 9, 391. (b) Deacon, G. B.; Forsyth, C. M.; Junk, P. C.; Wang, J. Inorg. Chem. 2007, 46, 10022. (c) Evans, W. J.; Anwander, R.; Ansari, M. A.; Ziller, J. W. Inorg. Chem. 1995, 34, 5. (20) See Supporting Information for X-ray structures and CCDC numbers (CCDC 1517640 for 3a, CCDC 1517641 for 3b, CCDC 1517642 for 3c, CCDC 1517643 for 3d, CCDC 1517644 for 3e, CCDC 1517645 for 3j, CCDC 1517646 for 8j, CCDC 1517647 for 8k, CCDC 1517649 for 9a, CCDC 1517648 for 9a’, CCDC 1517650 for 9c, CCDC 1517651 for 9d, CCDC 1517652 for 9e, CCDC 1517653 for 9h, CCDC 1517654 for 9i, CCDC 1517655 for 9j, CCDC 1517656 for 9k, CCDC 1517657 for 9l, CCDC 1517638 for 11b, CCDC 1517639 for 16d). (21) See Supporting Information for nOe studies on 3f, 8o and 18. (22) For selected reviews on cascade reactions, see: (a) Anderson, E. A. Org. Biomol. Chem. 2011, 9, 3997. (b) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134. (c) Nicolaou, K. C.; Chen, J. S. Chem. Soc. Rev. 2009, 38, 2993. (d) Tietze, L. F. Chem. Rev. 1996, 96, 115. (23) For selected reviews on iminium chemistry, see: (a) Royer, J.; Bonin, M.; Micouin, L. Chem. Rev. 2004, 104, 2311. (b) Maryanoff, B. E.; Zhang, H. C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem. Rev. 2004, 104, 1431. (c) Yazici, A.; Pyne, S. Synthesis. 2009, 2009, 339. (d) Yazici, A.; Pyne, S. Synthesis. 2009, 2009, 513. (24) Nair, V.; Deepthi, A. Chem. Rev. 2007, 107, 1862.

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n dearomatizing radical cyclizations & cascades n amides n high stereocontrol n up to 5 stereocenters



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10 ACS Paragon Plus Environment

Dearomatizing Radical Cyclizations and Cyclization Cascades

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