Sulfonamide Directivity Enables Ni-Catalyzed 1,2-Diarylation of Diverse Alkenyl Amines

Omar Apolinar‡, Van T. Tran‡, Michael A. Schmidt†, Joseph Derosa‡, Keary M. Engle‡,*

Background: Engle Lab & 1,2-Dicarbofunctionalization1

Substrate Scope Table

References

1. For representative reviews on conjunctive cross-coupling, see: (a) R. Giri, S. KC, J. Org. Chem. 2018,83, 3013–3022. (b) J. Derosa, O. Apolinar, T. Kang, V. T. Tran; K. M. Engle, Chem. Sci. 2020, 11,4287–4296. (v) X. Qi, T. Diao, ACS Catal. 2020, DOI: 10.1021/acscatal.0c02115.

2. (a) J.-W. Gu, Q.-Q. Min, L.-C. Yu, X. Zhang, Angew. Chem. Int. Ed. 2016, 55, 12270–12274 (b) B.Shrestha, P. Basnet, R. K. Dhungana, S. KC, S. Thapa, J. M. Sears, R. Giri, J. Am. Chem. Soc. 2017,139, 10653–10656. (c) W. Li, J. K. Boon, Y. Zhao, Chem. Sci. 2018, 9, 600–607. (d) J. Derosa, R.Kleinmans, V. T. Tran, M. K. Karunananda, S. R. Wisniewski, M. D. Eastgate, K. M. Engle, J. Am.Chem. Soc. 2018, 140, 17878–17883. (e) V. T. Tran, Z.-Q. Li, T. J. Gallagher, J. Derosa, P. Liu, K. M.Engle, Angew. Chem. Int. Ed. 2020, 59, 7029–7034; Angew. Chem. 2020, 132, 7095–7100. (f) J.Derosa, T. Kang, V. T. Tran, S. R. Wisniewski, M. K. Karunananda, T. C. Jankins, K. L. Xu, K.M. Engle, Angew. Chem. Int. Ed. 2020, 59, 1201–1205.

3. M. A. Schmidt, R. W. Stokes, M. L. Davies, F. Roberts, J. Org. Chem. 2017, 82, 4550−4560.4. (a) C. Q. O’Broin, P. Fernández, C. Martínez, K. Muñiz, Org. Lett. 2016, 18, 436–439. (b) M. Shang, K.

S. Feu, J. C. Vantourout, L. M. Barton, H. L. Osswald, N. Kato, K. Gagaring, C. W. McNamara, G.Chen, L. Hu, S. Ni, P. Fernández-Canelas, M. Chen, R. R. Merchant, T. Qin, S. L. Schreiber, B. Melillo,J.-Q. Yu, P. S. Baran, Proc. Natl. Acad. Sci. USA 2019, 116, 8721–8727.

Control Experiments, Alkenyl Chain Length Effects, and Proposed Mechanism

Previous Reports on 1,2-Dicarbofunctionalization of Alkenyl Amines2

Optimization Table

• Various N-functionalizations of1,2-diarylated product 2ai, suchas Mitsunobu, propargylation,etc. are demonstrated.

• Recently reported by BMS,3 the4-cyano-phenyl-sulfonyl (4-Cs)group is cleavable under mildconditions.

• 4-(Trifluoromethyl)-phenyl-sulfonyl group determined to beuncleavable under theconditions.

• Highly functionalized secondaryamines are obtained with thislinchpin strategy.

Linchpin Technology: Diversification of a 1,2-Diarylated Product

‡Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037. †Process Chemistry Development, Bristol Myers Squibb, One Squibb Drive, New Brunswick, New Jersey 08903.

NS

O

OO

HN

[Engle, 2019]

[Engle, 2018]ON

[Zhang, 2016]

N

[Giri, 2017]

previous alkenyl amine substrates

this work

R

DGn

cat. Ni

[C–M], [C–X]DG

n[C]

[C]

HNRO2S

1–3R

• remote alkenes compatible• proposed chelation via nitrogen atom• removable –SO2R

HN

[Zhao, 2018]

N

N

O R

Ar–B(OH)2RF–X Ar–ZnX

Ar–X

Ar–B(nep)Ar–X

Ar–B(OH)2Alkynyl–XAlkenyl–X

[Me2Zn]Allyl–X

Ar–B(nep)Ar–X

Ar S N

O ONiII

Ar1 Ar S N

O ONiII

4 6 Ar1

OSAr N

SAr

OOO O

Me

1o, n.r. 1p, n.r.

B. tether length effects

A. control experiments

C. proposed catalytic cycle

via

n = 1 (2af): 68%, 7:1 r.r.n = 2 (2a): 82%, >20:1 r.r.n = 3 (2ag): 82%, >20:1 r.r.n = 4: (2ah): n.d.

Php-tolH

NArO2S n

Ar S N

O ONiII5

Ar1

oxidativeaddition/alkene

coordination

migratory insertion

transmetalation

reductiveelimination

Ar1 I

Ar2 B(nep)

Ni0HN

ArO2S

Ar S N

O ONiII

Ar1

ArO2S NH

Ar2

Ar1

Ar S N

O ONiIIL Ar1

RO B(nep) LL

L

Ar S N

NaO ONiII

Ar1

Ar2L

NaOR

Ar = p-CF3C6H4

S NH

O O

NC

Ph CF3

Br

K2CO3, DMF, 100 ˚C

BnCl, K2CO3

DMF, 60 ˚C

K2CO3, DMF, 100 ˚C

N

Ph CF3

4-Cs

N

Ph CF3

4-Cs

Bn

N

Ph CF3

4-Cs

Ar

3b, 66%

3c, 75%

3d, 77%

NH

Ph CF3

NH

Ph CF3

Bn

NH

Ph CF3

4b, 32%

4c, 60%

4d, 83%

Boc2O, DMAP

DCM, rt

N

Ph CF3

4-Cs

Ph 4

PPh3, DEAD4-phenyl-1-butanol

DCM, rt

N

Ph CF3

4-Cs

BocNH

Ph CF3

Boc

4e, 68%

NH

Ph CF3

Ph4a, 88%

4

1-dodecanethiolDBU, DMF, rt

3e, 65%

3a, 75%

2ai, 87% (1 mmol scale)

Ar FAr = p-NO2C6H4

Ar

Synthesis of 1,2-Diarylated Pyrrolidines via Hofmann–Löffler–Freytag (HLF) Cyclization

S NH

NIS (2 equiv)LEDs (400 nm)

DCM, rt, 6 h

2z

O O

NC

Ph

Me

S N

(±)-3f, 70%

O O

NC

PhMe

• Violet light initiates the Hofmann–Löffler–Freytag (HLF) cyclization of a 2z, furnishing 4-Cs-protected pyrrolidine (±)-3f in good yield as a single diastereomer, with the two aryl groupsin a trans configuration.4

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O

O

Ot-Bu

OMe

MeMe

O

SF3C

O O SO

F3Cn.d. n.d. n.d. 16% 2a, 90 (82)

R NH

20 mol% Ni(cod)215 mol% DMFUNaOH (3 equiv)

R NH

(3 equiv)

s-BuOH, rt, 12 h(3 equiv)

Ph I

p-tol B(nep)

p-tolPh

R =

>20:1 r.r. [X-ray]

entry deviation from standard conditions %Yield 2a

conditions from alkenyl amide diarylationconditions from alkenyl carboxylate diarylation

1

4

no ligand

6

5

7

p-tol-B(OH)2 instead of p-tol-B(nep) 54p-tol-B(pin) instead of p-tol-B(nep)

Ph-Br instead of Ph-INi(cod)(DQ), NiCl2, Ni(acac)2, or NiBr2•glyme

instead of Ni(cod)2

50n.d.n.d.

3

30

n.d.60

2

1 2

10 mol% Ni(cod)2 instead of 20 mol%8 901.5 equiv of PhI, p-tolB(nep), NaOH instead of 3 equiv9 90

S NH

O O

F3C

Ph Me

R1 S NH

O O20 mol% Ni(cod)215 mol% DMFUNaOH (3 equiv)

(3 equiv) s-BuOH (0.2 M)rt, 12–40 h(3 equiv)

Ar1 I Ar2 B(nep)

S NH

O O

F3C

Ph

S NH

O O

F3C

Ph i-Pr

S NH

O O

F3C

Ph

Me

Me

S NH

O O

F3C

Ph CF3

2e, 70%p-F (2c), 88%o-F (2d), 91%

2l, 74%2m, 90%

2b, 99% (96%)

S NH

O O

F3C

PhS N

H

O O

F3C

Ph N

2k, 74%

F

S NH

O O

F3C

PhS N

H

O O

F3C

Ph

CF3

2n, 82%

S NH

O O

F3C

Ph

2s, 89%

t-Bu

S NH

O O

F3C

Ph

2t, 91%

F3C CF3

S NH

O O

F3C

Ph

2v, 96%

OPh

S NH

O O

F3C

Ph

2u, 67%

NHBoc

S NH

O O

F3C

Ph

2w, 69%

Me

O

S NH

O O

F3C

Ph

p-OMe (2f), 78% m-OMe (2g), 99%o-OMe (2h), 81%

p-Cl (2i), 96%o-Cl (2j), 89%

electrophile scope

F OMe

Cl

nucleophile scope

S NH

O O

F3C

Ph

OMe

2r, 70%

p-F (2o), 89% m-F (2p), 91%o-F (2q), 99%

F

1a–i 2b–ad

S NH

O O

F3C

p-tolPh

(±)-2ab, 70%(>20:1 d.r.)

(from Z)

Me

S NH

O O

F3C

p-tol

Me(±)-2ac, 86%(>20:1 d.r.)

(from E)

Ph

S NH

O O

F3C

R2S NH

O O

F3C

Ph

2ad, 50%

Me

R1 S NH

O O p-tolPh

R1 = p-OMeC6H4 (2x), 90%R1 = p-MeC6H4 (2y), 74%R1 = p-CNC6H4 (2z), 90%R1 = Me (2aa), 79%

[X-ray]

alkene scope unreactive substrates

R2

R3R1 S N

H

O O Ar2 R2

R3

Ar1

PhO S NH

O O

O2N

sulfonamide scope

R2 = Me, CO2Me

R1 R2

[Ni]

[C]

[C] Y

Z

[C]

R1 R2

[C]

R1 R2

[C]

[Ni]

[C]

R1 R2R1 R2

[C]

+[C]

[C] Y

Z

cat. [Ni]

alkenestarting material

coupling partner

Ni-catalyzed intermolecular1,2-dicarbofunctionalization

coupling partner

product

[C]–Y, [C]–Z = organometallic reagent, organohalide, or related coupling partner

R

[C][Ni]β-hydride

eliminationdicarbo-

functionalization

R

[C] [C]

R[C]

alkyl

non-conjugated

[Ni][C]

DG

directing groupcoordination

Alkene Substrate

Stabilization Strategy

NNH

8-AQ auxiliary

Directing Group (DG) Examples

NH

OR

native amide DG