Enantioselective Synthesis of anti-1,2-Diamines by Cu-Catalyzed Reductive Couplings of Azadienes with Aldimines and Ketimines

Article abstract of DOI:10.1021/jacs.8b04750

Here we report highly efficient and chemoselective azadiene-imine reductive couplings catalyzed by (Ph-BPE)Cu-H that afford anti-1,2-diamines. In all cases, reactions take place with either aldimine or ketimine electrophiles to deliver a single diastereom

Full text of DOI:10.1021/jacs.8b04750

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Communication
Enantioselective Synthesis of anti-1,2-Diamines by Cu-Catalyzed
Reductive Couplings of Azadienes with Aldimines and Ketimines
Xinxin Shao, Kangnan Li, and Steven J. Malcolmson
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 18 May 2018
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Enantioselective Synthesis of anti-1,2-Diamines by Cu-Catalyzed Re-
ductive Couplings of Azadienes with Aldimines and Ketimines
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Xinxin Shao, Kangnan Li, and Steven J. Malcolmson*
Department of Chemistry, Duke University, Durham, NC 27708, United States
Supporting Information Placeholder
C bond formation (versus imine reduction12).
ABSTRACT: Here we report highly efficient and chemoselec-
tive azadiene–imine reductive couplings catalyzed by (Ph-
BPE)Cu–H that afford anti-1,2-diamines. In all cases, reactions
take place with either aldimine or ketimine electrophiles to
deliver a single diastereomer of product in >95:5 er. The prod-
ucts’ diamines are easily differentiable, facilitating down-
stream synthesis.
Within the last several years, enantioselective Cu-catalyzed
reductive couplings13,14 of unsaturated hydrocarbons with var-
ious C-electrophiles has rapidly emerged as an effective way
for preparing myriad chemical motifs, often comprised of vic-
inal stereogenic centers. Vinylarenes,10c,d,15 vinylboronic es-
ters,16 allenes,11e,17 and conjugated enynes18 and dienes15g,18 have
comprised the substrates for these processes, yet none has es-
tablished vicinal heteroatom-substituted stereogenic centers.
Our recent disclosure of the Cu-catalyzed reductive coupling
of 2-azadienes and ketones shows the promise these reagents
hold for achieving such a goal.9 In this work, we demonstrate
that 2-azadienes participate in chemoselective Cu-catalyzed
reductive couplings with N-diphenylphosphinoyl (Dpp)
imines. Both aldimines and ketimines react to furnish anti-
1,2-diamines19 with vicinal stereogenic centers, in most cases
as a single stereoisomer. The two N-groups of the products,
one an imine and the other a phosphinamide, are readily dis-
criminated, enabling their subsequent divergent elaboration.
The catalytic enantioselective preparation of vicinal dia-
mines is an important goal in synthetic chemistry owing to the
large number of pharmaceuticals, natural products, and chiral
ligands that contain this motif.1 Although several approaches
to this moiety have been reported by a number of researchers,
significant shortcomings in scope or the ability to differentiate
the products’ two amino groups constrain their utility
(Scheme 1). One major strategy has utilized intermolecular
olefin diamination2 to afford either the anti- or syn-1,2-dia-
mines.3 In nearly all such cases, the two introduced amino
groups have identical substituents, making their differentia-
tion challenging to achieve.4 Another strategy has employed
N-substituted enolates or nitroalkanes in Mannich-type reac-
tions;5–7 either diastereomer may be selectively formed. How-
ever, in the former case, the requirement of an electron with-
drawing group reduces the scope of diamines that may be pre-
pared. In the latter, nitro group reduction is needed to secure
the diamine.8 In both cases, when tetrasubstituted amine-
containing stereogenic centers are formed, one of that center’s
other substituents has been limited to a carbonyl-like group.
Scheme 1. Catalytic Enantioselective Methods for Pre-
paring Vicinal Diamines and Proposed Strategy
To address these limitations, we sought to develop a
method that would unite two N-containing reagents via cata-
lytic enantioselective C–C bond formation such that: 1) a
greater diversity of 1,2-diamines, including those with N-con-
taining tetrasubstituted stereogenic centers, might be gar-
nered; 2) the nitrogen groups of the products would be easily
differentiated in order to assist in subsequent derivatizations;
and 3) either free amine could be obtained without the need
for harsh reducing conditions. We envisioned that the reduc-
tive coupling of 2-azadienes9 and suitably activated imines
could allow us to realize this goal (Scheme 1). However, cata-
lytic enantioselective reductive couplings with imines are
rare.10,11 Successful implementation of our proposed strategy
would require high catalyst efficiency and control over dia-
stereo-, and enantio-, and chemoselectivity for the desired C–
We initially explored addition of terminal 2-azadiene 1a to
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Dpp-aldimine 2a (Table 1). Optimal conditions employ
more sterically hindered aldimines do not affect reaction effi-
ciency: o-tolyl 3p is furnished in 89% yield (entry 15). Het-
eroaryl aldimines can be coupled efficiently with the terminal
azadiene as well to generate diamines 3q–s in 83–94% yield
(entries 16–18).
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3.0 equivalents of azadiene, DMMS as the reducing agent, t-
BuOH as additive, a Cu-based catalyst with (S,S)-Ph-BPE as
the ligand, and 5 C (ice bath) reaction temperature (entry 1).
After 1 h under these conditions, the desired diamine 3a can
be obtained in 82% yield, solely as the anti-diastereomer and
as a single enantiomer. Accompanying 3a is ca. 15% reduction
product 4a. Utilizing imine activating groups other than Dpp
(e.g., Ts, Boc, etc.) results in <2% conversion to 3a (entry
2).10d,12 Conducting the reaction at 22 C results in poorer
chemoselectivity, delivering more of the unwanted 4a; how-
ever, stereoselectivity remains unaffected (entry 3). Omitting
t-BuOH not only lowers catalyst efficiency but also adversely
affects chemoselectivity (entry 4), similar to observations
made by the Buchwald lab in styrene–imine couplings.10d The
identity of the alcohol additive is also critical for the selective
formation of 3a (entry 5). Although an i-Pr-BPE–Cu complex
fails to furnish any product (entry 6), switching to i-Pr-
DuPHOS generates 3a in 40% yield, 10:1 dr, and 99:1 er but ac-
Unsaturated imines also undergo efficient coupling with
azadiene 1a (entries 19–20). Allylic amine 3t, bearing a trisub-
stituted olefin, is formed in 71% yield. The less hindered cin-
namyl 3u is isolated in 61% yield but the reductive coupling
also affords ca. 15% of saturated diamine. An alkyl-substituted
imine leads to 52% yield of saturated diamine 3v in >99:1 er
(entry 21). An alkynyl aldimine failed to deliver the desired
diamine product.
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Table 2. Aldimine Scope in Couplings with Azadiene 1a
companied by a substantial quantity of 4a (entry 7).
A
QuinoxP-derived catalyst, although highly selective for C–C
bond formation coupling over imine reduction (8:1), generates
3a in only 4:1 dr (entry 8).20
Table 1. Impact of Reaction Conditions in Azadiene–Imine
Reductive Couplingsa
aReaction under N2 with 0.1 mmol imine 2a. bDetermined by 400 MHz
1H NMR spectroscopy of the unpurified mixture. cIsolated yield of pu-
rified 3a. dDetermined by HPLC analysis of purified 3a major diastere-
omer. eYield of the major/minor diastereomer of 3a.
aReaction under N2 with 0.2 mmol imine 2. Dr measured by 400 MHz
1H NMR spectroscopy of the unpurified mixture. bIsolated yield of pu-
c
rified 3. Determined by HPLC analysis of purified 3. d5.0 equiv 1a.
e4.0 equiv 1a. fFormed as a 4:1 mixture of 3u:3v; yield of isolated 3u.
Several aldimines undergo coupling with azadiene 1a, lead-
ing to anti-diamines 3 as a single diastereomer (Table 2). In
most cases, only a single enantiomer of product is generated.
A variety of aryl-substituted imines participate in the reaction
with the more electron rich substrates affording the highest
yields (64–93%, entries 1–5, 13, 15). Halogen substituents are
tolerated with diamines 3g–i and 3o isolated in 55–73% yield
(entries 6–8, 14). More electron poor imines also yield the de-
sired diamines 3j–l (entries 9–11) but in somewhat diminished
yields (41–59%). The observed trend is due to increasingly
competitive imine reduction as the imine partner becomes
more electron deficient;21 however, boronic ester 3m is iso-
lated in 75% yield as a single stereoisomer (entry 12). Notably,
We also examined the coupling of 4-substituted 2-azadi-
enes with aldimines to deliver diamines comprised of -alkyl
groups other than methyl. As typified in eq. 1, the added steric
hindrance of azadiene 1b leads to slower Cu–H insertion and
a more competitive reduction, which adversely affects the
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diamine yield. An electron rich aldimine, such as 2c, and an
imine (red) and the other mono-protected as the phosphina-
mide (blue). Either may be transformed to the amine by hy-
drolysis (i.e., without reduction). These qualities allow for se-
lective functionalization of either product nitrogen. For ex-
ample, deprotonation of the phosphinamide N–H of 3a ena-
bles alkylation to deliver 7 in 84% yield while retaining the
imine. Alternatively, the imine may be hydrolyzed under
mildly acidic conditions and the resulting free amine then
functionalized, such as in the formation of benzyl carbamate
8 (85% yield over two steps). The phosphinamide may then
be cleaved with stronger acid, enabling functionalization of
the liberated amine: phosphinamide 8 is converted to t-butyl
carbamate 9 in 80% yield (two steps).
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extended reaction time (6 h) are required to obtain good yield
of 3w. Increasing to 5.0 equivalents of azadiene improves the
reaction as well with the product then isolated in 56% yield
(versus 42% with 3.0 equiv 1b), >20:1 dr, and >99:1 er.
We next sought to test whether azadiene couplings with
ketimines would enable the synthesis of 1,2-diamines wherein
one stereogenic center is fully substituted. Reactions that
form such motifs wherein both amines are bound to stereo-
genic centers, each with a variety of substituents, are rare and
challenging to achieve. Therefore, we were pleased to find
that terminal azadiene 1a reacts with aryl–alkyl and diaryl
ketimines to generate diamines 6a–h in 84–92% yield (Table
3). With the exception of the less electrophilic, electron rich
imine 5b (entry 2), which requires higher temperature and
longer reaction time, reactions proceed efficiently at 5 C
within 2 h. Transformations occur with >98% chemoselectiv-
ity for the reductive coupling regardless of imine identity. Re-
markably, in all cases, the diamines are obtained in >20:1 dr
(entries 1–7) and with high enantioselectivity. Notably, in ad-
dition to tolerating several aryl groups, the coupling is also
permissible with longer chain alkyl groups (entry 7). The ste-
rically encumbered benzophenone imine reacts smoothly to
give diamine 6h in 86% yield (entry 8).
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Table 4. Addition of 4-Substituted Azadienes to
Ketiminesa
Table 3. Couplings of Azadiene 1a with Ketiminesa
aReaction under N2 with 0.2 mmol imine 5. b–cSee Table 2.
Scheme 2. Utilizing the Products’ Differentiated
Amines
aReaction under N2 with 0.1 mmol imine 5. b–cSee Table 2. dReaction at
22 C for 24 h.
Furthermore, ketimines also participate in reductive cou-
plings with 4-substituted 2-azadienes, proceeding with ca. 60–
70% chemoselectivity to furnish diamines 6i–r as a single dia-
stereomer and with high enantioselectivity (Table 4). Despite
the steric congestion, reactions proceed to completion within
6 h at 5 C. Product yields are improved with 10 mol % catalyst
loading.22 Variation of the ketimine’s aryl substituent, includ-
ing both electron rich and electron poor arenes, is tolerated in
couplings with azadiene 1b (entries 1–5). The azadiene may
contain several functional groups, including heterocycles,
ethers, esters, and halides that are preserved in the products
(44–63% yield, entries 6–10). The versatility of the reaction
partners should enable the assembly of a range of complex
molecules from these diamine building blocks.
In this work, we have shown that reductive couplings of 2-
azadienes with imines are an efficient and highly stereoselec-
tive way to construct vicinal diamines, several of which are dif-
ficult to access through existing protocols and have not before
succumbed to enantioselective synthesis. The methodology
The developed azadiene–imine reductive couplings have
the advantage that the amines within the products are readily
differentiated (Scheme 2) as one is doubly protected as an
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Zhao, B.; Shi, Y. “Synthesis of (+)-CP-99,994 via Pd(0)-Catalyzed
Asymmetric Allylic and Homoallylic C–H Diamination of Terminal
Olefin,” J. Org. Chem. 2009, 74, 7577.
represents a rare example of enantioselective reductive cou-
plings of imines as well as Cu-catalyzed reductive couplings to
set vicinal heteroatom-substituted stereogenic centers. Our
future efforts will concentrate on the further development of
azadienes and their applications to chiral amine synthesis.
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(5) For a review on Mannich reactions with N-substituted nucleo-
philes, see: (a) Arrayás, R. G.; Carretero, J. C. “Catalytic Asymmetric
Direct Mannich Reaction: A Powerful Tool for the Synthesis of ,-
Diamino Acids,” Chem. Soc. Rev. 2009, 38, 1940. For enantioselective
examples, see: (b) Kobayashi, S.; Yazaki, R.; Seki, K.; Yamashita, Y.
“The Fluorenone Imines of Glycine Esters and Their Phosphonic Acid
Analogues,” Angew. Chem., Int. Ed. 2008, 47, 5613. (c) Hernández-
Toribio, J.; Arrayás, R. G.; Carretero, J. C. “Direct Mannich Reaction of
Glycinate Schiff Bases with N-(8-Quinoyl)sulfonyl Imines: A Catalytic
Asymmetric Approach to anti-,-Diamino Esters,” J. Am. Chem. Soc.
2008, 130, 16150. (d) Kano, T.; Sakamoto, R.; Akakura, M.; Maruoka, K.
“Stereocontrolled Synthesis of Vicinal Diamines by Organocatalytic
Asymmetic Mannich Reaction of N-Protected Aminoacetaldehydes:
Formal Synthesis of (–)-Agelastatin A,” J. Am. Chem. Soc. 2012, 134,
7516. (e) Zhang, W.-Q.; Cheng, L.-F.; Yu, J.; Gong, L.-Z. “A Chiral
Bis(betaine) Catalyst for the Mannich Reaction of Azlactones and Al-
iphatic Imines,” Angew. Chem., Int. Ed. 2012, 51, 4085. (f) Lin, S.; Ka-
wato, Y.; Kumagai, N.; Shibasaki, M. “Catalytic Asymmetric Mannich-
Type Reaction of N-Alkylidene--Aminoacetonitrile with Ketimines,”
Angew. Chem., Int. Ed. 2015, 54, 5183. (g) Kondo, M.; Nishi, T.; Hat-
anaka, T.; Funahashi, Y.; Nakamura, S. “Catalytic Enantioselective Re-
action of -Aminoacetonitriles Using Chiral Bis(imidazoline) Palla-
dium Catalysts,” Angew. Chem., Int. Ed. 2015, 54, 8198. (h) Kano, T.;
Kobayashi, R.; Maruoka, K. “Versatile In Situ Generated N-Boc-
Imines: Application to Phase-Transfer-Catalyzed Asymmetric Man-
nich-Type Reactions,” Angew. Chem., Int. Ed. 2015, 54, 8471.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures, analytical data for new compounds,
and X-ray crystallographic data. This material is available free
of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*steven.malcolmson@duke.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We are grateful for financial support of this research from the
NIH (GM124286), ACS Petroleum Research Fund (56575-
DNI1), and Duke University. We thank Dr. Roger Sommer
(NC State) for X-ray crystallographic analysis.
(6) For enantioselective vinylogous Mannich reactions to prepare
this motif, see: (a) Ranieri, B.; Curti, C.; Battistini, L.; Sartori, A.; Pinna,
L.; Casiraghi, G.; Zanardi, F. “Diastereo- and Enantioselective Catalytic
Vinylogous Mukaiyama-Mannich Reactions of Pyrrole-Based Silyl
Dienolates with Alkyl-Substituted Aldehydes,” J. Org. Chem. 2011, 76,
10291. (b) Silverio, D. L.; Fu, P.; Carswell, E. L.; Snapper, M. L.; Hov-
eyda, A. H. “N-Substituted Tertiary and O-Substituted Quaternary
Carbon Stereogenic Centers by Site-, Diastereo- and Enantioselective
Vinylogous Mannich Reactions,” Tetrahedron Lett. 2015, 56, 3489.
(7) For examples of enantioselective nitro-Mannich reactions, see:
(a) Yamada, K.-i.; Harwood, S. J.; Gröger, H.; Shibasaki, M. “The First
Catalytic Asymmetric Nitro-Mannich-Type Reaction Promoted by a
New Heterobimetallic Complex,” Angew. Chem., Int. Ed. 1999, 38,
3504. (b) Yamada, K.-i.; Moll, G.; Shibasaki, M. “The First Enantiose-
lective and Diastereoselective Catalytic Nitro-Mannich Reaction: A
New Entry to Chiral Vicinal Diamines,” Synlett 2001, SI, 980. (c) Knud-
sen, K. R.; Risgaard, T.; Nishiwiki, N.; Gothelf, K. V.; Jørgensen, K. A.
“The First Catalytic Asymmetric Aza-Henry Reaction of Nitronates
with imines: A Novel Approach to Optically Active -Nitro--Amino
Acid- and ,-Diamino Acid Derivatives,” J. Am. Chem. Soc. 2001, 123,
5843. (d) Nugent, B. M.; Yoder, R. A.; Johnston, J. N. “Chiral Proton
Catalysis: A Catalytic Enantioselective Direct Aza-Henry Reaction,” J.
Am. Chem. Soc. 2004, 126, 3418. (e) Yoon, T. P.; Jacobsen, E. N. “Highly
Enantioselective Thiourea-Catalyzed Nitro-Mannich Reactions,” An-
gew. Chem., Int. Ed. 2005, 44, 466. (f) Singh, A.; Yoder, R. A.; Shen, B.;
Johnston, J. N. “Chiral Proton Catalysis: Enantioselective Brønsted
Acid Catalyzed Additions of Nitroacetic Acid Derivatives as Glycine
Equivalents,” J. Am. Chem. Soc. 2007, 129, 3466. (g) Trost, B. M.;
Lupton D. W. “Dinuclear Zinc-Catalyzed Enantioselective Aza-Henry
Reaction” Org. Lett. 2007, 9, 2023. (h) Singh, A.; Johnston, J. N. “A Di-
astereo- and Enantioselective Synthesis of -Substituted syn-,-Dia-
mino Acids,” J. Am. Chem. Soc. 2008, 130, 5866. (i) Uraguchi, D.; Ko-
shimoto, K.; Ooi, T. “Chiral Ammonium Betaines: A Bifunctional Or-
ganic Base Catalyst for Asymmetric Mannich-Type Reaction of -Ni-
trocarboxylates,” J. Am. Chem. Soc. 2008, 130, 10878. (j) Davis, T. A.;
Wilt, J. C.; Johnston, J. N. “Bifunctional Asymmetric Catalysis: Ampli-
fication of Brønsted Basicity Can Orthogonally Increase the Reactivity
of a Chiral Brønsted Acid,” J. Am. Chem. Soc. 2010, 132, 2880. (k)
Handa, S.; Gnanadesikan, V.; Matsunaga, S.; Shibasaki, M. “Heterobi-
metallic Transition Metal/Rare Earth Metal Bifunctional Catalysis: A
Cu/Sm/Schiff Base Complex for Syn-Selective Catalytic Asymmetric
REFERENCES
(1) For a review, see: Lucet, D.; Le Gall, T.; Mioskowski, C. “The
Chemistry of Vicinal Diamines,” Angew. Chem., Int. Ed. 1998, 37, 2580.
(2) For a review on enantioselective olefin diamination, see: (a)
Zhu, Y.; Cornwall, R. G.; Du, H.; Zhao, B.; Shi, Y. “Catalytic Diamina-
tion of Olefins via N–N Bond Activation,” Acc. Chem. Res. 2014, 47,
3665. For examples of enantioselective intermolecular reactions, see:
(b) Du, H.; Yuan, W.; Zhao, B.; Shi, Y. “Catalytic Asymmetric Diamina-
tion of Conjugated Dienes and Triene,” J. Am. Chem. Soc. 2007, 129,
11688. (c) Du, H.; Zhao, B.; Shi, Y. “Catalytic Asymmetric Allylic and
Homoallylic Diamination of Terminal Olefins via Formal C–H Activa-
tion,” J. Am. Chem. Soc. 2008, 130, 8590. (d) Cornwall, R. G.; Zhao, B.;
Shi, Y. “Catalytic Asymmetric Synthesis of Cyclic Sulfamides from
Conjugated Dienes,” Org. Lett. 2013, 15, 796. (e) Muñiz, K.; Barreiro,
L.; Romero, R. M.; Martínez, C. “Catalytic Asymmetric Diamination of
Styrenes,” J. Am. Chem. Soc. 2017, 139, 4354.
(3) For ring-forming (intramolecular) enantioselective cases, see:
(a) Sequeira, F. C.; Turnpenny, B. W.; Chemler, S. R. “Copper-Pro-
moted and Copper-Catalyzed Intermolecular Alkene Diamination,”
Angew. Chem., Int. Ed. 2010, 49, 6365. (b) Ingalls, E. L.; Sibbald, P. A.;
Kaminsky, W.; Michael, F. E. “Enantioselective Palladium-Catalyzed
Diamination of Alkenes Using N-Fluorobenzenesulfonimide,” J. Am.
Chem. Soc. 2013, 135, 8854. (c) Turnpenny, B. W.; Chemler, S. R. “Cop-
per-Catalyzed Alkene Diamination: Synthesis of Chiral 2-Aminome-
thyl Indolines and Pyrrolidines,” Chem. Sci. 2014, 5, 1786. (d) Mizar,
P.; Laverny, A.; El-Sherbini, M.; Farid, U.; Brown, M.; Malmedy, F.;
Wirth, T. “Enantioselective Diamination with Novel Chiral Hyperva-
lent Iodine Catalysts,” Chem. – Eur. J. 2014, 20, 9910. (e) Fu, S.; Yang,
H.; Li, G.; Deng, Y.; Jiang, H.; Zeng, W. “Copper(II)-Catalyzed Enanti-
oselective Intramolecular Cyclization of N-Alkenylureas,” Org. Lett.
2015, 17, 1018. (f) Wang, F.-L.; Dong, X.-Y.; Lin, J.-S.; Zeng, Y.; Jiao, G.-
Y.; Gu, Q.-S.; Guo, X.-Q.; Ma, C.-L.; Liu, X.-Y. “Catalytic Asymmetric
Radical Diamination of Alkenes,” Chem. 2017, 3, 979.
(4) For intermolecular diaminations where the two amines may be
differentiated, see: (a) Simmons, B.; Walji, A. M.; MacMillan, D. W. C.
“Cycle-Specific Organocascade Catalysis: Application to Olefin Hy-
droamination, Hydro-oxidation, and Amino-oxidation, and to Natural
Product Synthesis,” Angew. Chem., Int. Ed. 2009, 48, 4349. (b) Fu, R.;
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Nitro-Mannich Reaction,” J. Am. Chem. Soc. 2010, 132, 4925. (l) Spra-
J.-R.; Cho, C.-W.; Krische, M. J. “Hydrogen-Mediated Reductive Cou-
pling of Conjugated Alkynes with Ethyl (N-Sulfinyl)iminoacetates:
Synthesis of Unnatural -Amino Acids via Rhodium-Catalyzed C–C
Bond Forming Hydrogenation,” J. Am. Chem. Soc. 2005, 127, 11269. (c)
Komanduri, V.; Grant, C. D.; Krische, M. J. “Branch-Selective Reduc-
tive Coupling of 2-Vinyl Pyridines and Imines via Rhodium Catalyzed
C–C Bond Forming Hydrogenation,” J. Am. Chem. Soc. 2008, 130,
12592. (d) Zhu, S.; Lu, X.; Luo, Y.; Zhang, W.; Jiang, H.; Yan, M.; Zeng,
W. “Ruthenium(II)-Catalyzed Regioselective Reductive Coupling of
-Imino Esters with Dienes,” Org. Lett. 2013, 15, 1440. (e) Liu, R. Y.;
Yang, Y.; Buchwald, S. L. “Regiodivergent and Diastereoselective CuH-
Catalyzed Allylation of Imines with Terminal Allenes,” Angew. Chem.,
Int. Ed. 2016, 55, 14077. (f) Lee, K. N.; Lei, Z.; Ngai, M.-Y. “-Selective
Reductive Coupling of Alkenylpyridines with Aldehydes and Imines
via Synergistic Lewis Acid/Photoredox Catalysis,” J. Am. Chem. Soc.
2017, 139, 5003. For related redox neutral processes, see: (g) Schmitt,
D. C.; Lee, J.; Dechert-Schmitt, A.-M. R.; Yamaguchi, E.; Krische, M. J.
“Ruthenium Catalyzed Hydroaminoalkylation of Isoprene via Trans-
fer Hydrogenation: Byproduct-Free Prenylation of Hydantoins,”
Chem. Commun. 2013, 49, 6096. (h) Chen, T.-Y.; Tsutsumi, R.; Mont-
gomery, T. P.; Volchkov, I.; Krische, M. J. “Ruthenium-Catalyzed C–C
Coupling of Amino Alcohols with Dienes via Transfer Hydrogenation:
Redox-Triggered Imine Addition and related Hydroaminoalkyla-
tions,” J. Am. Chem. Soc. 2015, 137, 1798. (i) Oda, S.; Sam, B.; Krische,
M. J. “Hydroaminomethylation Beyond Carbonylation: Allene–Imine
Reductive Coupling by Ruthenium-Catalyzed Transfer Hydrogena-
tion,” Angew. Chem., Int. Ed. 2015, 54, 8525.
(12) For enantioselective Cu-catalyzed imine hydrosilylation, see:
Lipshutz, B. H.; Shimizu, H. “Copper(I)-Catalyzed Asymmetric Hy-
drosilylations of Imines at Ambient Temperatures,” Angew. Chem.,
Int. Ed. 2004, 43, 2228.
(13) For Cu–H reviews, see: (a) Rendler, S.; Oestreich, M. “Polishing
a Diamond in the Rough: “Cu–H” Catalysis with Silanes,” Angew.
Chem., Int. Ed. 2007, 46, 498. (b) Lipshutz, B. H. “Rediscovering Or-
ganocopper Chemistry Through Copper Hydride. It’s All About the
Ligand,” Synlett 2009, 509. (c) Jordan, A. J.; Lalic, G.; Sadighi, J. P.
“Coinage Metal Hydrides: Synthesis, Characterization, and Reactiv-
ity,” Chem. Rev. 2016, 116, 8318.
(14) For reviews of catalytic reductive couplings with metals other
than Cu, see: (a) Montgomery, J. “Nickel-Catalyzed Reductive Cycli-
zations and Couplings,” Angew. Chem., Int. Ed. 2004, 43, 3890. (b)
Hassan, A.; Krische, M. J. “Unlocking Hydrogenation for C–C Bond
Formation: A Brief Overview of Enantioselective Methods,” Org. Pro-
cess Res. Dev. 2011, 15, 1236. (c) Standley, E. A.; Tasker, S. Z.; Jensen, K.
L.; Jamison, T. F. “Nickel Catalysis: Synergy between Method Devel-
opment and Total Synthesis,” Acc. Chem. Res. 2015, 48, 1503. (d) Ngu-
yen, K. D.; Park, B. Y.; Luong, T.; Sato, H.; Garza, V. J.; Krische, M. J.
“Metal-Catalyzed Reductive Coupling of Olefin-Derived Nucleo-
philes: Reinventing Carbonyl Addition,” Science 2016, 354, No.
aah5133. (e) Kim, S. W.; Zhang, W.; Krische, M. J. “Catalytic Enantiose-
lective Carbonyl Allylation and Propargylation via Alcohol-Mediated
Hydrogen Transfer: Merging the Chemistry of Grignard and Sabatier,”
Acc. Chem. Res. 2017, 50, 2371.
(15) (a) Saxena, A.; Choi, B.; Lam, H. W. “Enantioselective Copper-
Catalyzed Reductive Coupling of Alkenylazaarenes with Ketones,” J.
Am. Chem. Soc. 2012, 134, 8428. (b) Wang, Y.-M.; Bruno, N. C.;
Placeres, A. L.; Zhu, S.; Buchwald, S. L. “Enantioselective Synthesis of
Carbo- and Heterocycles through a CuH-Catalyzed Hydroalkylation
Approach,” J. Am. Chem. Soc. 2015, 137, 10524. (c) Wang, Y.-M.; Buch-
wald, S. L. “Enantioselective CuH-Catalyzed Hydroallylation of Vi-
nylarenes,” J. Am. Chem. Soc. 2016, 138, 5024. (d) Bandar, J. S.; Ascic,
E.; Buchwald, S. L. “Enantioselective CuH-Catalyzed Reductive Cou-
pling of Aryl Alkenes and Activated Carboxylic Acids,” J. Am. Chem.
Soc. 2016, 138, 5821. (e) Friis, S. D.; Pirnot, M. T.; Buchwald, S. L.
“Asymmetric Hydroarylation of Vinylarenes Using a Synergistic Com-
bination of CuH and Pd Catalysis,” J. Am. Chem. Soc. 2016, 138, 8372.
(f) Zhou, Y.; Bandar, J. S.; Buchwald, S. L. “Enantioselective CuH-Cat-
alyzed Hydroacylation Employing Unsaturated Carboxylic Acids as
Aldehyde Surrogates,” J. Am. Chem. Soc. 2017, 139, 8126. (g) Gui, Y.-Y.;
Hu, N.; Chen, X.-W.; Liao, L.-L.; Ju, T.; Ye, J.-H.; Zhang, Z.; Li, J.; Yu,
gue, D. J.; Singh, A.; Johnston, J. N. “Diastereo- and Enantioselective
Additions of -Nitro Esters to Imines for anti-,-Diamino Acid Syn-
thesis with -Alkyl-Substitution,” Chem. Sci. 2018, 9, 2336.
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(8) For other enantioselective approaches to vicinal diamines, see:
(a) Ooi, T.; Sakai, D.; Takeuchi, M.; Tayama, E.; Maruoka, K. “Practical
Asymmetric Synthesis of Vicinal Diamines through the Catalytic
Highly Enantioselective Alkylation of Glycine Amide Derivatives,” An-
gew. Chem., Int. Ed. 2003, 42, 5868. (b) Kitagawa, O.; Yotsumoto, K.;
Kohriyama, M.; Dobashi, Y.; Taguchi, T. “Catalytic Asymmetric Syn-
thesis of Vicinal Diamine Derivatives through Enantioselective N-Al-
lylation Using Chiral -Allyl Pd-Catalyst,” Org. Lett. 2004, 6, 3605. (c)
Trost, B. M.; Fandrick, D. R.; Brodmann, T.; Stiles, D. T. “Dynamic Ki-
netic Asymmetric Allylic Amination and Acyl Migration of Vinyl Aziri-
dines with Imido Carboxylates,” Angew. Chem., Int. Ed. 2007, 46, 6123.
(d) Arai, K.; Lucarini, S.; Salter, M. M.; Ohta, K.; Yamashita, Y.; Koba-
yashi, S. “The Development of Scalemic Multidentate Niobium Com-
plexes as Catalysts for the Highly Stereoselective Ring Opening of
meso-Epoxides and meso-Aziridines,” J. Am. Chem. Soc. 2007, 129,
8103. (e) Yu, R.; Yamashita, Y.; Kobayashi, S. “Titanium(IV)/Tridentate
BINOL Derivative as Catalyst for meso-Aziridine Ring-Opening Reac-
tions: High Enantioselectivity, Strong Positive Non-Linear Effect and
Structural Characterization,” Adv. Synth. Catal. 2009, 351, 147. (f) Mac-
Donald, M. J.; Hesp, C. R.; Schipper, D. J.; Pesant, M.; Beauchemin, A.
M. “Highly Enantioselective Intermolecular Hydroamination of Allylic
Amines with Chiral Aldehydes as Tethering Catalysts,” Chem. – Eur. J.
2013, 19, 2597. (g) Wu, B.; Gallucci, J. C.; Parquette, J. R.; RajanBabu,
T. V. “Bimetallic Catalysis in the Highly Enantioselective Ring-Open-
ing Reactions of Aziridines,” Chem. Sci. 2014, 5, 1102. (h) Uraguchi, D.;
Kinoshita, N.; Kizu, T.; Ooi, T. “Synergistic Catalysis of Ionic Brønsted
Acid and Photosensitizer for a Redox Neutral Asymmetric -Coupling
of N-Arylaminomethanes with Aldimines,” J. Am. Chem. Soc. 2015, 137,
13768. (i) Izumi, S.; Kobayashi, Y.; Takemoto, Y. “Catalytic Asymmetric
Synthesis of anti-,-Diamino Acid Derivatives,” Org. Lett. 2016, 18,
696. (j) Chai, Z.; Yang, P.-J.; Zhang, H.; Wang, S.; Yang, G. “Synthesis
of Chiral Vicinal Diamines by Silver(I)-Catalyzed Enantioselective
Aminolysis of N-Tosylaziridines,” Angew. Chem., Int. Ed. 2017, 56, 650.
(k) Dumoulin, A.; Bernadat, G.; Masson, G. “Enantioselective Three-
Component Amination of Enecarbamates Enables the Synthesis of
Structurally Complex Small Molecules,” J. Org. Chem., 2017, 82, 1775.
(l) Mwenda, E. T.; Nguyen, H. N. "Enantioselective Synthesis of 1,2-
Diamines Containing Tertiary and Quaternary Centers through Rho-
dium-Catalyzed DYKAT of Racemic Allylic Trichloroacetimidates,"
Org. Lett. 2017, 19, 4814. (m) Perrotta, D.; Wang, M.-M.; Waser, J.
“Lewis Acid Catalyzed Enantioselective Desymmetrization of Donor–
Acceptor meso-Diaminocyclpropanes,” Angew. Chem., Int. Ed. 2018,
57, 5120.
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(9) Li, K.; Shao, X.; Tseng, L.; Malcolmson, S. J. “2-Azadienes as Re-
agents for Preparing Chiral Amines: Synthesis of 1,2-Amino Tertiary
Alcohols by Cu-Catalyzed Enantioselective Reductive Couplings with
Ketones,” J. Am. Chem. Soc. 2018, 140, 598.
(10) For enantioselective examples see: (a) Ngai, M.-Y.; Barchuk, A.;
Krische, M. J. “Enantioselective Iridium-Catalyzed Imine Vinylation:
Optically Enriched Allylic Amines via Alkyne–Imine Reductive Cou-
pling Mediated by Hydrogen,” J. Am. Chem. Soc. 2007, 129, 12644. (b)
Zhou, C.-Y.; Zhu, S.-F.; Wang, L.-X.; Zhou, Q.-L. “Enantioselective
Nickel-Catalyzed Reductive Coupling of Alkynes and Imines,” J. Am.
Chem. Soc. 2010, 132, 10955. (c) Ascic, E.; Buchwald, S. L. “Highly Dia-
stereo- and Enantioselective CuH-Catalyzed Synthesis of 2,3-Disubsti-
tuted Indolines,” J. Am. Chem. Soc. 2015, 137, 4666. (d) Yang, Y.; Perry,
I. B.; Buchwald, S. L.” Copper-Catalyzed Enantioselective Addition of
Styrene-Derived Nucleophiles to Imines Enabled by Ligand-Con-
trolled Chemoselective Hydrocupration,” J. Am. Chem. Soc. 2016, 138,
9787. For a related redox neutral process, see: (e) Oda, S.; Franke, J.;
Krische, M. J. “Diene hydroaminomethylation via Ruthenium-Cata-
lyzed C–C Bond Forming Transfer Hydrogenation: Beyond Carbonyl-
ation,” Chem. Sci. 2016, 7, 136.
(11) For non-enantioselective examples, see: (a) Townes, J. A.; Ev-
ans, M. A.; Queffelec, J.; Taylor, S. J.; Morken, J. P. “Stereoselective
Synthesis of trans -Lactams through Iridium-Catalyzed Reductive
Coupling of Imines and Acrylates,” Org. Lett. 2002, 4, 2537. (b) Kong,
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D.-G. “Highly Regio- and Enantioselective Copper-Catalyzed Reduc-
(18) Yang, Y.; Perry, I. B.; Lu, G.; Liu, P.; Buchwald, S. L. “Copper-
Catalyzed Asymmetric Addition of Olefin-Derived Nucleophiles to
Ketones,” Science 2016, 353, 144.
tive Hydroxymethylation of Styrenes and 1,3-Dienes with CO2,” J. Am.
Chem. Soc. 2017, 139, 17011. (h) Gribble, Jr., M. W.; Guo, S.; Buchwald,
S. L. “Asymmetric Cu-Catalyzed 1,4-Dearomatization of Pyridines and
Pyridazines without Preactivation of the Heterocycle or Nucleophile,”
J. Am. Chem. Soc. 2018, 140, 5057.
(16) (a) Han, J. T.; Jang, W. J.; Yun, J. “Asymmetric Synthesis of
Borylalkanes via Copper-Catalyzed Enantioselective Hydroallylation,”
J. Am. Chem. Soc. 2016, 138, 15146. (b) Lee, J.; Torker, S.; Hoveyda, A.
H. “Versatile Homoallylic Boronates by Chemo- SN2'-, Diastereo- and
Enantioselective Catalytic Sequence of Cu–H Addition to Vinyl-
B(pin)/Allylic Substitution,” Angew. Chem., Int. Ed. 2017, 56, 821.
(17) Tsai, E. Y.; Liu, R. Y.; Yang, Y.; Buchwald, S. L. “A Regio- and
Enantioselective CuH-Catalyzed Ketone Allylation with Terminal Al-
lenes,” J. Am. Chem. Soc. 2018, 140, 2007.
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(19) For azaallyl anion additions to imines that afford syn-1,2-dia-
mines, see: (a) Chen, Y.-J.; Seki, K.; Yamashita, Y.; Kobayashi, S. “Cat-
alytic Carbon–Carbon Bond-Forming Reactions of Aminoalkane De-
rivatives with Imines,” J. Am. Chem. Soc. 2010, 132, 3244. (b) Matsu-
moto, M.; Harada, M.; Yamashita, Y.; Kobayashi, S. “Catalytic Imine–
Imine Cross-Coupling Reactions,” Chem. Commun. 2014, 50, 13041.
(20) For additional screening data, see the Supporting Information.
(21) See the Supporting Information for further details.
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(22) For example, with 5 mol % Cu and 6 mol % Ph-BPE, diamine
6i in Table 4, entry 1 is isolated in only 50% yield after 12 h.
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