Catalytic Asymmetric Synthesis of α-Arylpyrrolidines and Benzo-fused Nitrogen Heterocycles

Article abstract of DOI:10.1002/anie.201814331

Herein, we report a practical two-step synthetic route to α-arylpyrrolidines through Suzuki–Miyaura cross-coupling and enantioselective copper-catalyzed intramolecular hydroamination reactions. The excellent stereoselectivity and broad scope for the transformation of substrates with pharmaceutically relevant heteroarenes render this method a practical and versatile approach for pyrrolidine synthesis. Additionally, this intramolecular hydroamination strategy facilitates the asymmetric synthesis of tetrahydroisoquinolines and medium-ring dibenzo-fused nitrogen heterocycles.

Full text of DOI:10.1002/anie.201814331

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Catalytic Asymmetric Synthesis of α-Arylpyrrolidines and Benzo-
fused Nitrogen Heterocycles
Authors: Xi-Jie Dai, Oliver D. Engl, Thierry León, and Stephen L.
Buchwald
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201814331
Angew. Chem. 10.1002/ange.201814331
Link to VoR: http://dx.doi.org/10.1002/anie.201814331
http://dx.doi.org/10.1002/ange.201814331

10.1002/anie.201814331
Angewandte Chemie International Edition
COMMUNICATION
Catalytic Asymmetric Synthesis of α-Arylpyrrolidines and Benzo-fused
Nitrogen Heterocycles
Xi-Jie Dai, Oliver D. Engl, Thierry León, and Stephen L. Buchwald*
Dedicated to Professor Ronald Raines in celebration of his 60th birthday
Abstract: Herein we report a practical two-step synthetic route to α-
arylpyrrolidines consisting of Suzuki-Miyaura cross-coupling and
enantioselective copper-catalyzed intramolecular hydroamination
reactions. The excellent stereoselectivity and broad scope for the
transformation of substrates with pharmaceutically relevant
heteroarenes render this method a practical and versatile approach
for pyrrolidine synthesis. Additionally, this intramolecular
hydroamination strategy facilitates the asymmetric synthesis of
tetrahydroisoquinolines and medium ring dibenzo-fused nitrogen
heterocycles.
Saturated nitrogen heterocycles are among the most prevalent
structural subunits in medicinal agents[1] and bioactive alkaloids[2].
In particular, enantioenriched α-aryl-substituted pyrrolidines are a
common class of therapeutics[3], as well as useful chiral controllers[4]
in asymmetric catalysis. For example, the recent emergence of
enantiopure α-arylpyrrolidines in treatments for hepatitis C[5] and
mantle cell lymphoma[6] highlights their value in this regard (Figure
1, A). The predominance of α-heteroaryl substituents in these
pyrrolidine substructures is due, in part, to the well-known
therapeutic and physicochemical properties provided by these
fragments.[7] Therefore, the development of synthetic routes that are
capable of incorporating diverse heteroaryl substituents into
stereodefined α-arylpyrrolidines is of great interest.
The asymmetric synthesis of α-arylpyrrolidines has been the
subject of considerable effort.[9] Important strategies to accomplish
this include directed C–H arylation,[9a] hydrogenation of cyclic
enamines,[9c]
[3+2]
cycloaddition,[9g]
arylation/cyclization
cascades[9i] and reductive cyclization reactions[9j]. Further, based on
the carbamate-directed asymmetric lithiation method pioneered by
Hoppe[10] and Beak[11], Campos and colleagues at Merck developed
the first enantioselective α-arylation of N-Boc-pyrrolidines. Their
impressive protocol featured
a
(–)-sparteine-mediated[12]
asymmetric α-lithiation and the subsequent transmetallation with
ZnCl2, followed by a Negishi coupling with an aryl bromide (Figure
1, B-a).[13] In 2018, Zhang disclosed an elegant enantioselective
cobalt-catalyzed radical cyclization of preformed N-
tosylhydrazones to furnish α-arylpyrrolidines (Figure 1, B-b).[14] To
date, these two reports are the only catalytic examples that enable
the installation of heteroaryl substituents with precise
stereochemical control at the α-position of pyrrolidines. While the
industrial manufacture of enantioenriched α-arylpyrrolidine
compounds typically relies on chiral pool synthesis from proline via
Figure 1. A) Recent examples of pharmaceuticals bearing enantiopure α-
heteroarylpyrrolidines. B) Current synthetic approaches to enantiopure α-
heteroarylpyrrolidines. C) Our protocol features Pd-catalyzed Suzuki-Miyaura
coupling and enantioselective Cu-catalyzed intramolecular hydroamination. Boc
= tert-butyloxycarbonyl; rt = room temperature; cat. = catalytic; FG = functional
groups; TS = toluenesulfonyl; pin = pinacolato; piv = pivalate; Bn = benzyl.
substrate-controlled asymmetric induction,[15] more versatile and
catalytic methods that are amenable to the preparation of molecules
with drug-like structural features would be useful for early-stage
drug research development.
In 2013, Hirano and Miura[16] and our laboratory[17] reported the
enantioselective copper-catalyzed hydroamination of olefins, in
which C–N bonds are formed by the reaction of chiral alkylcopper(I)
[a]
Dr. X.-J. Dai, Dr. O. D. Engl, Dr. T. León, Prof. Dr. S. L. Buchwald
Department of Chemistry, Room 18–490
Massachusetts Institute ofTechnology, Cambridge, MA 02139 (USA)
E-mail: sbuchwal@mit.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
This article is protected by copyright. All rights reserved.

10.1002/anie.201814331
Angewandte Chemie International Edition
COMMUNICATION
Table 1. Optimization of Enantiopure α-Arylpyrrolidine Synthesis[a]
chiral bisphosphine ligands and found that (R,R)-Ph-BPE (L3)
offered the best reactivity and enantioselectivity (entry 5-7).[22] The
use of other ligands such as (R,R)-iPr-DUPHOS (L2) and (S)-
DTBM-BIPHEP (L6) was less successful (entries 4 and 10).
Switching from phenyl to isopropryl or ethyl substituents on the
phospholane backbone led to a significant attenuation of reactivity
(entries 8 and 9).
Having optimized the intramolecular C–N bond-forming step, we
evaluated several routes for the preparation of the hydroxylamine
pivalate substrates. It was important that the selected method can
easily: (1) incorporate a range of heteroaryl substituents, and (2) start
from a common building block that can be prepared on a large scale.
The most efficient strategy was determined to entail a Suzuki-
Miyaura cross-coupling of a vinylboronate ester precursor 3. This
was prepared by the Zr-catalyzed syn-hydroboration of the terminal
alkyne,[23] which left the N–O bond intact. Intermediate 3 was used
in cross-coupling reactions with a wide range of aryl bromides
(Table 2, left column, 1ac, 1b-o). [24] Although oxidative addition of
N–O bonds has been noted in other palladium-catalyzed cross-
coupling reactions,[25] the corresponding hydroxylamine pivalates
were successfully obtained. Among the heteroaryl bromides tested,
a pyrazole (1f), pyrimidines (1g, 1h), azaindoles (1i, 1j), a furan (1k),
and a pyridine (1l) gave higher yields than a thiazole (1m) or
imidazoles (1n, 1o).[8b, 26]
Like the Pd-catalyzed cross coupling reaction, the subsequent
enantioselective copper-catalyzed intramolecular hydroamination
proved to be tolerant of a wide range of functional groups and α-
heteroaryl substituents.[27] Good yields (62–83%) and excellent
enantioselectivities (97.5: 2.5–99.5: 0.5 er) were obtained for most
α-arylpyrrolidine products (Table 2, right column, 2a-l). Two
exceptions were substrates bearing an N-Boc indole (2e) or an N-Ts
azaindole (2j), for which moderate yields were observed, along with
a slight increase in the quantity of substrate lost to reduction of the
N–O bonds. The absolute stereochemistry of pyrrolidine product 2l
was determined as R by single crystal X-ray crystallography (see the
SI for details). While the conversion of five-membered azoles such
as a thiazole (2m) and imidazoles (2n, 2o) was comparable to that
of other examples, significant erosion of the enantioselectivity was
observed.[28] In these cases, we found that the use of L3 and
dimethoxy(methyl)silane (DMMS) not only improved the
enantioselectivity, but also led to higher yields.[29]
Our efforts next focused on exploring the asymmetric synthesis of
nitrogen heterocycles with other ring sizes. In comparison with α-
arylpyrrolidines, the synthesis of four- and six-membered nitrogen
heterocycles proceeded slowly.[30] For example, the synthesis of α-
phenylpiperidine 5 resulted in a lower yield (Scheme 1, A) than the
corresponding α-phenylpyrrolidine 2a (45% vs 95 %).[31] Varying a
number of reaction parameters (ligand, solvent, temperature and
concentration) did not further improve the results. Aiming to
facilitate the cyclization process, we introduced a geometric
constraint into the linear carbon chain of the starting material by
introducing an aryl group between the olefin and the hydroxylamine-
O-pivalate-containing side chain. This modification restored the
high reactivity in the catalytic event, providing chiral
tetraisohydroquinoline 7 in excellent yield and enantioselectivity
(86% yield, 99.5: 0.5 er, Scheme 1, B).
[a] 1aa, R1 = phenyl; 1ab, R1 = 4-dimethylaminophenyl; 1ac, R1 = tert-butyl.
Reaction conditions: 0.20 mmol 1 (1.0 equiv), Cu(OAc)2 (4.0 mol%), chiral
bisphosphine ligands (4.4 mol%), diethoxy(methyl)silane (2.5 equiv), THF (0.40
mL), see details in the Supplementary Information. [b] Yields were determined
by 1H NMR using 1,2-dibromoethane as an internal standard. [c] Enantiomeric
ratio (er) was determined by supercritical fluid chromatography (SFC). [d] With
4.4 mol% Ph3P. [e] With 2.2 mol% Ph3P. THF = tetrahydrofuran; er =
enantiomeric ratio.
species (generated in situ through the hydrocupration of olefins)
with an electrophilic aminating reagent. Many variants of the
intermolecular hydroamination reactions have since been
reported,[18] including a regioselective, intramolecular reaction used
to synthesize chiral aziridines.[19] We decided to see whether this
chemistry could be utilized for the preparation of other
enantiomerically enriched nitrogen heterocycles. Herein, we report
a versatile two-step synthesis of enantioenriched α-arylpyrrolidines
that is compatible with a broad range of heteroaryl substituents
(Figure 1, C). Furthermore, we describe the asymmetric synthesis of
enantiopure benzo-fused nitrogen heterocycles bearing six- to nine-
membered rings.
Initially, hydroxylamine benzoate 1aa was evaluated as a model
substrate in the copper-catalyzed hydroamination reaction. Upon
subjecting 1aa to a THF solution of CuH catalyst (formed from
Cu(OAc)2, (S)-DTBM-SEGPHOS (L1), and diethoxy(methyl)silane
(DEMS)) at ambient temperature, the desired pyrrolidine product
2a[20] was obtained in 78% yield with 97.5:2.5 er (Table 1, entry 1).
A significant quantity of a byproduct, derived from the reductive
cleavage of the N–O bond of the substrate, was observed. To
minimize this undesired process, the reactivity of the N–O bond in
the electrophilic amine source was varied through modification of
the hydroxylamine ester.[21] While the use of electron-rich p-(N,N-
dimethylamino)benzoate 1ab provided 2a in higher yield (entry 2),
employing pivalate 1ac further improved both yield and
enantioselectivity (entry 3). We next investigated the use of various
Successful
construction
of
the
enantioenriched
tetraisohydroquinoline led us to examine dibenzo-fused nitrogen
heterocycles with medium ring sizes,[32] as many compounds with
This article is protected by copyright. All rights reserved.

10.1002/anie.201814331
Angewandte Chemie International Edition
COMMUNICATION
Table 2. Scope of Enantiopure α-Arylpyrrolidines[a, b]
[a] Unless noted, standard reaction conditions of the Suzuki-Miyaura coupling: 1.50-2.50 mmol arylbromides (1.0 equiv), 3 (1.3 equiv), SPhos-G3 (5.0 mol%), K2CO3
(3.0 eqiuv), THF/H2O = 3/1 (0.30 M), 60 °C, see the SI for details. [b] Unless noted, standard reaction conditions of the intramolecular hydroamination: 0.50 mmol
1a-o (1.0 equiv), Cu(OAc)2 (4.0 mol%), (S)-DTBM-SEGPHOS (4.4 mol%), DEMS (2.5 equiv), THF (1.0 mL), see the SI for details. Isolated yields are reported as
the average of two runs. er was determined by SFC. [c] dioxane/H2O = 3/1 (0.30 M), 80 °C. [d] Cu(OAc)2 (8.0 mol%), (R,R)-Ph-BPE (8.8 mol%), DMMS (2.5 equiv).
[e] (R,R)-Ph-BPE (4.4 mol%), DMMS (2.5 equiv).
these structural elements are found in pharmaceuticals and bioactive
alkaloids (Scheme 2, A).[33] Our approach to access the core
structural scaffolds requires either a four- or a five-step synthetic
sequence, all of which culminated with the enantioselective Cu-
catalyzed intramolecular hydroamination. For instance, oxazonine
10 was prepared in five steps in excellent yield and
enantioselectivity, starting from salicylaldehyde (Scheme 2, B).
Similar efficiency and selectivity were observed in the synthesis of
azepine 11 and oxazocine 12 (Scheme 2, C). [34]
Moreover, we applied this intramolecular hydroamination strategy
to asymmetric syntheses of six- to nine-membered benzo-fused
nitrogen heterocycles. While (S)-DTBM-SEGPHOS worked well
for most α-arylpyrrolidines, (R,R)-Ph-BPE provided better results
for substrates containing five-membered azoles as well as for the
synthesis of medium ring benzo-fused nitrogen heterocycles.
In conclusion, we have developed a practical two-step synthetic
route to enantiopure α-arylpyrrolidines comprising Suzuki-Miyaura
cross-coupling
and
enantioselective
copper-catalyzed
intramolecular hydroamination reactions. This approach provides an
efficient method to prepare pyrrolidines bearing pharmaceutically
relevant α-heteroaryl substituents including pyrazoles, pyrimidines,
azaindoles, pyridines, furans, thiazoles and fused imidazoles with
high levels of enantiomeric purity under very mild conditions.
This article is protected by copyright. All rights reserved.

10.1002/anie.201814331
Angewandte Chemie International Edition
COMMUNICATION
Scheme
1.
Synthesis
of
Enantiopure
α-Arylpiperidine
and
TecnioSpring funding (TECSPR13-1-0040). We are grateful to Dr.
Peter Mꢀller for crystallographic analysis and Dr. Bruce Adams
(MIT) for assistance with NMR structure-determination. We
acknowledge Dr. Andy Thomas, Dr. Scott McCann, Richard Liu and
Dr. Christine Nguyen for assistance in the preparation of this
manuscript.
Tetraisohydroquinoline[a]
Keywords: asymmetric synthesis• copper • hydroamination •
pyrrolidines • benzo-fused nitrogen heterocycles
[1] a) E. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem. 2014, 57,
10257−10274; b) M. E. Welsch, S. A. Snyder, B. R. Stockwell, Curr.
Opin. Chem. Biol. 2010, 14, 347−361. c) R. D. Taylor, M. MacCoss,
A. D. G. Lawson, J. Med. Chem. 2014, 57, 5845−5859.
[2] C. V. Galliford, K. A. Scheidt, Angew. Chem. Int. Ed. 2007, 46,
8748−8758; Angew. Chem. 2007, 46, 8902−8912.
[3] a) J. E. Sieser, M. T. Maloney, E. Chisowa, S. J. Brenek, S. Monfette,
J. J. Salisbury, N. M. Do, R. A. Singer, Org. Process Res. Dev. 2018,
22, 527−534; b) M. Baumann, I. R. Baxendale, C. Kuratli, S. V. Ley,
R. E. Martin, J. Schneider, ACS Comb. Sci. 2011, 13, 405−413.
[4] a) S. M. Banik, A. Levina, A. M. Hyde, E. N. Jacobsen, Science 2017,
358, 761−764; b) S. E. Reisman, A. G. Doyle, E. N. Jacobsen, J. Am.
Chem. Soc. 2008, 130, 7198−7199; c) A. M. d. A. R. Gonsalves, M. E.
d. S. Serra, M. R. Silva, A. M. Beja, J. A. Paixão, L. A. d. Veiga, J.
Mol. Catal. A: Chem. 2001, 168, 53−59.
[a] Isolated yields are reported as the average of two runs. Reaction conditions:
0.50 mmol 4 or 6 (1.0 equiv), Cu(OAc)2 (4.0 mol%), (R,R)-Ph-BPE (4.4 mol%),
DMMS (2.5 equiv), THF (1.0 mL), see the SI for details. [b] No product was
observed using (S)-DTBM-SEGPHOS as the ligand.
Scheme 2. Synthesis of Enantiopure Dibenzo-fused Nitrogen Heterocycles[a]
[5] F. Poordad, F. Felizarta, A. Asatryan, M. S. Sulkowski, R. W.
Reindollar, C. S. Landis, S. C. Gordon, S. L. Flamm, M. W. Fried, D.
E. Bernstein, C.-W. Lin, R. Liu, S. S. Lovell, T. I. Ng, J. Kort, F. J.
Mensa, Hepatology 2017, 66, 389−397.
[6] M. Wang, S. Rule, P. L. Zinzani, A. Goy, O. Casasnovas, S. D. Smith,
G. Damaj, J. Doorduijn, T. Lamy, F. Morschhauser, C. Panizo, B.
Shah, A. Davies, R. Eek, J. Dupuis, E. Jacobsen, A. P. Kater, S. Le
Gouill, L. Oberic, T. Robak, T. Covey, R. Dua, A. Hamdy, X. Huang,
R. Izumi, P. Patel, W. Rothbaum, J. G. Slatter, W. Jurczak, Lancet
2018, 391, 659−667.
[7] a) T. J. Ritchie, S. J. F. Macdonald, S. Peace, S. D. Pickett, C. N.
Luscombe, MedChemComm 2012, 3, 1062−1069; b) C. K. Prier, D.
W. C. MacMillan, Chem. Sci. 2014, 5, 4173−4178.
[8] a) D. C. Blakemore, L. Castro, I. Churcher, D. C. Rees, A. W. Thomas,
D. M. Wilson, A. Wood, Nat. Chem. 2018, 10, 383−394; b) P. S.
Kutchukian, J. F. Dropinski, K. D. Dykstra, B. Li, D. A. DiRocco, E.
C. Streckfuss, L.-C. Campeau, T. Cernak, P. Vachal, I. W. Davies, S.
W. Krska, S. D. Dreher, Chem. Sci. 2016, 7, 2604−2613.
[a] Isolated yields are reported as the average of two runs. Reaction conditions:
0.50 mmol 4 or 6 (1.0 equiv), Cu(OAc)2 (4.0 mol%), (R,R)-Ph-BPE (4.4 mol%),
DMMS (2.5 equiv), THF (1.0 mL), see the SI for details. [b] See SI for detailed
synthetic sequences of azepine and oxazocine analogs. PG = protecting groups.
[9] a) P. Jain, P. Verma, G. Xia, J.-Q. Yu, Nat. Chem. 2017, 9, 140−144;
b) C. J. Cordier, R. J. Lundgren, G. C. Fu, J. Am. Chem. Soc. 2013,
135, 10946−10949; c) G.-H. Hou, J.-H. Xie, P.-C. Yan, Q.-L. Zhou,
J. Am. Chem. Soc. 2009, 131, 1366−1367; d) R. L. LaLonde, B. D.
Sherry, E. J. Kang, F. D. Toste, J. Am. Chem. Soc. 2007, 129,
2452−2453; e) M. C. Wood, D. C. Leitch, C. S. Yeung, J. A. Kozak,
L. L. Schafer, Angew. Chem. Int. Ed. 2007, 46, 354−358; Angew.
Chem. 2007, 119, 358−362; f) A. R. Brown, C. Uyeda, C. A.
Brotherton, E. N. Jacobsen, J. Am. Chem. Soc. 2013, 135, 6747−6749;
g) B. M. Trost, S. M. Silverman, J. Am. Chem. Soc. 2012, 134,
4941−4954; h) N. S. Sheikh, D. Leonori, G. Barker, J. D. Firth, K. R.
Campos, A. J. H. M. Meijer, P. O’Brien, I. Coldham, J. Am. Chem.
Soc. 2012, 134, 5300−5308; i) Z. Cui, H.-J. Yu, R.-F. Yang, W.-Y.
Gao, C.-G. Feng, G.-Q. Lin, J. Am. Chem. Soc. 2011, 133,
12394−12397; j) L. Rajender Reddy, S. G. Das, Y. Liu, M. Prashad,
J. Org. Chem. 2010, 75, 2236−2246; k) For a recent review focus on
the racemic synthesis of saturated N-heterocycles, see: C.-V. T. Vo, J.
W. Bode, J. Org. Chem. 2014, 79, 2809−2815.
Acknowledgements
The authors acknowledge the National Institutes of Health under
Award No. R35-GM122483 for support of the research reported in
this publication and R01-GM058160-17S1 supplemental grant for
the purchase of supercritical fluid chromatography (SFC) equipment.
The content of this publication is solely the responsibility of the
authors and does not necessarily represent the official views of the
National Institutes of Health. X.-J.D. thanks the Canadian National
Science and Engineering Research Council (NSERC) for a
postdoctoral fellowship. O.D.E. thanks the Swiss National Science
Foundation (SNSF) for a postdoctoral fellowship (P2EZP2_175140).
T.L. thanks the Generalitat de Catalunya and ACCIÓ for the
[10] a) D. Hoppe, A. Carstens, T. Krämer, Angew. Chem. Int. Ed. 1990, 29,
1424−1425; Angew. Chem. 1990, 102, 1455−1456; b) D. Hoppe, T.
This article is protected by copyright. All rights reserved.

10.1002/anie.201814331
Angewandte Chemie International Edition
COMMUNICATION
Hense, Angew. Chem. Int. Ed. 1997, 36, 2282−2316; Angew. Chem.
1997, 109, 2376−2410.
CuH system, see: B. H. Lipshutz, K. Noson, W. Chrisman, A. Lower,
J. Am. Chem. Soc. 2003, 125, 8779−8789.
[11] a) S. T. Kerrick, P. Beak, J. Am. Chem. Soc. 1991, 113, 9708−9710;
b) P. Beak, S. T. Kerrick, S. Wu, J. Chu, J. Am. Chem. Soc. 1994, 116,
3231−3239; c) P. O'Brien, Chem. Commun. 2008, 655−667; d) P.
O'Brien, J. L. Bilke, Angew. Chem. Int. Ed. 2008, 47, 2734−2736;
Angew. Chem. 2008, 120, 2774−2776.
[12] Only one enantiomer of α-arylpyrrolidines is assessible using the
commercially available (−)-sparteine. A (+)-sparteine surrogate was
developed preceding the commercial availbility of (+)-sparteine, see:
M. J. Dearden, C. R. Firkin, J.-P.R. Hermet, P. O'Brien, J. Am. Chem.
Soc. 2002, 124, 11870−11871.
[13] a) K. R. Campos, A. Klapars, J. H. Waldman, P. G. Dormer, C.-y.
Chen, J. Am. Chem. Soc. 2006, 128, 3538−3539; b) A. Klapars, K. R.
Campos, J. H. Waldman, D. Zewge, P. G. Dormer, C.-Y. Chen, J. Org.
Chem. 2008, 73, 4986−4993.
[23] The stereochemistry of β-substituted olefins has
a significant
influence on the reaction efficiency, see refs. [19] and [21].
[24] N. C. Bruno, N. Niljianskul, S. L. Buchwald, J. Org. Chem. 2014, 79,
4161−4166.
[25] D. T. Ahneman, J. G. Estrada, S. Lin, S. D. Dreher, A. G. Doyle,
Science 2018, 360, 186−190.
[26] Conditions developed to conduct aryl-aryl coupling of unprotected,
nitrogen-rich heterocycles failed to improve efficiency in these azole
cases, see: M. A. Düfert, K. L. Billingsley, S. L. Buchwald, J. Am.
Chem. Soc. 2013, 135, 12877−12885.
[27] Although (R,R)-Ph-BPE provided the best results in Table 1, (S)-
DTBM-SEGPHOS was chosen as the ligand to examine the scope of
α-arylpyrrolidines because of cost, availability and stability.
[28] It is currently unclear whether the erosion of selectivity is due to
epimerization of the alkylcopper species before the C–N bond
formation. For mechanistic discussions on enantioselective
hydrocupration and subsequent epimerization relevant to the
hydroboration of alkenes, see: Y. Xi, J. F. Hartwig, J. Am. Chem. Soc.
2017, 139, 12758−12772.
[29] Improved yields were also observed in synthesis of six- to nine-
membered ring nitrogen heterocycles by switching to (R,R)-Ph-BPE
and DMMS.
[30] Our attempts to synthesize an enantioenriched α-phenylazetidine
resulted in a 30% isolated yield. 1H NMR analysis indicated the
formation of several byproducts; see the SI for details.
[14] Y. Wang, X. Wen, X. Cui, X. P. Zhang, J. Am. Chem. Soc. 2018, 140,
4792−4796.
[15] a) J. A. Kozlowski, et al. (Merck Sharp & Dohme Corp.), World Pat.,
WO2012040923A1. 2012; b) J. Liu, et al. (Merck Sharp & Dohme
Corp.), US Pat., 066238, 2016.
[16] Y. Miki, K. Hirano, T. Satoh, M. Miura, Angew. Chem. Int. Ed. 2013,
52, 10830−10834; Angew. Chem. 2013, 125, 11030−11034.
[17] S. Zhu, N. Niljianskul, S. L. Buchwald, J. Am. Chem. Soc. 2013, 135,
15746−15749.
[18] a) S. Zhu, S. L. Buchwald, J. Am. Chem. Soc. 2014, 136,
15913−15916; b) N. Niljianskul, S. Zhu, S. L. Buchwald, Angew.
Chem. Int. Ed. 2015, 54, 1638−1641; Angew. Chem. 2015, 127,
1658−1661; c) D. Niu, S. L. Buchwald, J. Am. Chem. Soc. 2015, 137,
9716−9721; d) S. Zhu, N. Niljianskul, S. L. Buchwald, Nat. Chem.
2016, 8, 144−150; e) S.-L. Shi, S. L. Buchwald, Nat. Chem. 2015, 7,
38−44; f) S. Ichikawa, S. Zhu, S. L. Buchwald, Angew. Chem. Int. Ed.
2018, 57, 8714−8718; Angew. Chem. 2018, 130, 8850−8854; For a
minireview on the enantioselective copper-catalyzed hydroamination
reactions, see: g) M. T. Pirnot, Y.-M. Wang, S. L. Buchwald, Angew.
Chem. Int. Ed. 2016, 55, 48−57; Angew. Chem. 2016, 128, 48−57.
[19] H. Wang, J. C. Yang, S. L. Buchwald, J. Am. Chem. Soc. 2017, 139,
8428−8431.
[31] (R,R)-Ph-BPE and DMMS replaced (S)-DTBM-SEGPHOS and
DEMS. However, under our standard hydroamination conditions
(footnote b, Table 2), formation of 2-phenylpiperidine 5 was not
detected from 4 (footnote b, Scheme 1) while 2-phenylpyrrolidine 2a
was isolated in 83% yield from 1ac.
[32] C.-V. T. Vo, M. U. Luescher, J. W. Bode, Nat. Chem. 2014, 6,
310−314.
[33] a) J. L. Kenwright, W. R. J. D. Galloway, D. T. Blackwell, A. Isidro-
Llobet, J. Hodgkinson, L. Wortmann, S. D. Bowden, M. Welch, D. R.
Spring, Chem. Eur. J. 2011, 17, 2981−2986; b) P. Mestichelli, M. J.
Scott, W. R. J. D. Galloway, J. Selwyn, J. S. Parker, D. R. Spring, Org.
Lett. 2013, 15, 5448−5451; c) A. Joncour, A. Décor, S. Thoret, A.
Chiaroni, O. Baudoin, Angew. Chem. Int. Ed. 2006, 45, 4149−4152;
Angew. Chem. 2006, 118, 4255−4158.
[20] The absolute stereochemistry of α-arylpyrrolidines 2a-k was assigned
by analogy to that of 2l (see Table 2).
[21] J. S. Bandar, M. T. Pirnot, S. L. Buchwald, J. Am. Chem. Soc. 2015,
137, 14812−14818.
[22] No further improvement was observed by the addition of Ph3P (entries
5 and 7). For the reactivity increase caused by adding Ph3P in another
[34] The absolute stereochemistry of nitrogen heterocycles 2m-o, 5, 7, 11,
12 was assigned by analogy to that of 10. See SI for details.
This article is protected by copyright. All rights reserved.

10.1002/anie.201814331
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Xi−Jie Dai, Oliver D. Engl, Thierry León,
and Stephen L. Buchwald*
Page No. – Page No.
Catalytic Asymmetric Synthesis of α-
Arylpyrrolidines and Benzo-fused
Nitrogen Heterocycles
Here, it is shown that an enantioselective copper-catalyzed intramolecular
hydroamination reaction can be used jointly with the Suzuki-Miyaura cross-coupling
to yield a diverse array of α-arylpyrrolidine scaffolds that contain pharmaceutically
relevant heteroarenes with excellent enantiomeric purity under very mild conditions.
Further, this intramolecular hydroamination strategy is applicable to the asymmetric
syntheses of six- to nine-membered benzo-fused nitrogen heterocycles.
This article is protected by copyright. All rights reserved.