Highly Enantioselective Iridium-Catalyzed Coupling Reaction of Vinyl Azides and Racemic Allylic Carbonates

Article abstract of DOI:10.1021/jacs.0c01766

The iridium-catalyzed enantioselective coupling reaction of vinyl azides and allylic electrophiles is presented and provides access to β-chiral carbonyl derivatives. Vinyl azides are used as acetamide enolate or acetonitrile carbanion surrogates, leading to γ,δ-unsaturated β-substituted amides as well as nitriles with excellent enantiomeric excess. These products are readily transformed into chiral N-containing building blocks and pharmaceuticals. A mechanism is proposed to rationalize the chemoselectivity of this coupling reaction.

Full text of DOI:10.1021/jacs.0c01766

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Article
Highly Enantioselective Iridium-Catalyzed Coupling
Reaction of Vinyl Azides and Racemic Allylic Carbonates
Min Han, Min Yang, Rui Wu, Yang Li, Tao Jia, Yuanji Gao, Hai-Liang Ni, Ping Hu, Bi-Qin Wang, and Peng Cao
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c01766 • Publication Date (Web): 13 Jul 2020
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Highly Enantioselective Iridium-Catalyzed Coupling Reaction of Vinyl
Azides and Racemic Allylic Carbonates
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Min Han,‡ Min Yang,‡ Rui Wu, Yang Li, Tao Jia, Yuanji Gao, Hai-Liang Ni, Ping Hu, Bi-Qin Wang, and
Peng Cao*
College of Chemistry and Materials Science, Sichuan Normal University, Chengdu 610068, China
ABSTRACT: The Iridium-catalyzed enantioselective coupling reaction of vinyl azides and allylic electrophiles is presented
and provides access to -chiral carbonyl derivatives. Vinyl azides are used as acetamide enolate or acetonitrile carbanion
surrogates, leading to ,-unsaturated -substituted amides as well as nitriles with excellent enantiomeric excess. These prod-
ucts are readily transformed into chiral N-containing building blocks and pharmaceuticals. A mechanism was proposed to
rationalize the chemoselectivity of this coupling reaction.
Owing to the recent development of more convenient syn-
INTRODUCTION
Transition metal-catalyzed asymmetric allylic alkylation
thetic approaches,11c the vinyl azide chemistry has received
increasing interests of synthetic chemists.11 Since the semi-
(AAA) reaction represents a powerful and appealing tool for
nal work by Chiba,12b Lewis/Brønsted acid-promoted cou-
construction of nonracemic compounds.1 The Ir-catalyzed
pling reactions of vinyl azides and C-electrophiles (i.e. alde-
asymmetric allylation of carbonyl compounds is one of the
hydes, imines, propargylic alcohols, p-quinone methides)
most important methods for generating a stereocenter, par-
have been developed and become a straightforward ap-
ticularly, in the  position of carbonyl derivatives. (Scheme
proach towards amides and nitriles.12 We envisioned that
the cooperative Lewis acid and chiral transition metal catal-
1a) Pioneered by Takeuchi2a and Helmchen,2b a variety of
“soft” or stabilized carbanions (e.g. malonic esters, malono-
ysis might facilitate the asymmetric coupling of vinyl azides
nitrile, sulfonylacetic esters and disulfones) have been used
and C-electrophiles. Herein, the Lewis acid-promoted and
in this reaction.3 However, simple carbonyl compounds
with weak  C-H acidity are challenging nucleophiles. The
difficulty is attributed to the formed “hard” unstabilized
Ir-catalysed AAA13 with vinyl azides was demonstrated,
wherein vinyl azides were used as the acetamide enolate as
well as acetonitrile carbanion surrogates (Scheme 1c). The
enolates, which are fairly basic and not compatible with the
method represents the first catalytic enantioselective ap-
allylic electrophiles or adducts. A desirable solution is to
proach towards synthesis of enantioenriched amides and
seek appropriate enolates surrogates (Scheme 1b).4 As the
nitriles with the use of vinyl azides.
seminal work, Hartwig demonstrated the highly efficient al-
lylation reaction of ketones4a
and
4e, ,-unsaturated ke-
tones,4b-d and aliphatic esters4f by using their silyl enol
ethers. Meanwhile, the elegant Ir-catalyzed AAA of -keto-
carboxylates,5 ketene acetal6a and ketene aminal6b were re-
ported, respectively, by You and Carreira, providing access
to a variety of enantioenriched carbonyl compounds.
Scheme 1. Ir-Catalyzed Enantioselective Allylations of
Unstabilized Enolates
Amides and nitriles are extremely useful not only in the
organic chemistry but also in the bio-chemistry and mate-
rial science.7 Nevertheless, few allylation reactions ap-
peared regarding the use of amide enolates or -carbanion
of nitriles as nucleophiles,8 probably because of side reac-
tions caused by the extremely “hard” property. For example,
in the studies on Pd-catalyzed AAA, Hou and coworkers
found that the -carbanion of acetonitrile (pKa ≈ 31 in
DMSO)9 couldn’t react with allylic electrophiles but at-
tacked another acetonitrile to form enamine (Thorpe reac-
tion).10 Thus, the highly general and enantioselective alkyl-
ation of acetonitrile is still elusive.
Vinyl azides, molecules that contain conjugate alkene and
azide moieties, have been known for around a century.
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groups. On the other hand, -alkyl or alkenyl-substituted vi-
nyl azides were also tested, but had no reactivity.
RESULTS AND DISCUSSION
1
2
In initial studies, the enantioselective coupling of (1-az-
idovinyl)benzene (2a) and branched allylic alcohols or car-
bonates was tested with [Ir(cod)Cl]2 (2.5 mol%), (R)-L1 (10
mol%) and BF3·OEt2 (10 mol%) in dichloromethane. The
tert-butyl (1-phenylallyl) carbonate (1a) was found to be
the optimal allylic electrophile, producing the desired prod-
uct 3aa in 40% yield and 93% ee at 15 oC. (See the support-
ing information for full optimization details) Through sys-
tematic optimization of the Lewis acid, solvent and temper-
ature, a promising result was achieved. (entry 1, Table 1)
We then turned our attention to the study of salt effects, in
an attempt to accelerate isomerization of intermediary π-
allyliridium complexes.14 Indeed, the use of halide salts as
additives improved the catalytic efficiency. Inorganic salts
(e.g. LiCl, LiBr, ZnBr2) improved the yield of 3aa, albeit with
erosion of ee value (entries 2-5). Pleasingly, Bu4NCl or
Bu4NBr as the additive significantly improved the dynamic
kinetic asymmetric transformation (DYKAT) of 1a to afford
3aa in moderate yields (68% and 65%) with high enantio
enrichment (entries 6 and 7). By increasing the loading of
BF3.Et2O to 50 mol% and lowering the temperature to 10 oC,
3aa was obtained in good yield (74%) and excellent enanti-
opurity (entry 9). The dosage of 2a could be further reduced
to 1.2 equiv. without loss of yield or ee (entry 10), indicating
that vinyl azides were relatively stable and robust amide
enolate surrogates. When changing the chiral ligand or Ir
catalyst precursor, the reaction gave worse results. (entries
11-13) Control experiments confirm that no product was
observed in the absence of [Ir(cod)Cl]2, the ligand or Lewis
acid, (entries 14 and 15) indicating the necessity of each cat-
alyst.
3
4
5
6
7
8
9
Table 1. Development of the Vinyl Azide-Allyl Coupling
Reaction.a
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entry
changes of reaction conditions
yield
(%)b
63
ee
(%)c
90
1
2
3
4
5
6
none
LiCl (10 mol%) as the additive
LiBr (10 mol%) as the additive
ZnCl2 (10 mol%) as the additive
ZnBr2 (10 mol%) as the additive
Bu4NCl (10 mol%) as the
additive
74
88
73
84
63
56
77
50
68
98
7
8
Bu4NBr (10 mol%) as the
additive
65
34
74
76
99
99
99
99
Bu4NI (10 mol%) as the
additive
9d
Bu4NBr (10 mol%) as the
additive
With optimal conditions in hand, various (hetero)aryl
substituted allylic alcohol carbonates were tested with 2a
to give the corresponding products with good to high yields
and nearly all in absolute stereochemical control. (Table 2)
The stereo- and electronic nature of the aryl groups on the
allylic substrates had little effect on the yields and enanti-
10d,e
Bu4NBr (10 mol%) as the
additive
11d,e
12d,e
13d,e
14d,e
15d,e
(R)-L2 as the ligand
(R)-L3 as the ligand
C1 as the Ir catalyst
without BF3.Et2O
59
trace
trace
0
99
/
i
oselectivities. Aryl units bearing alkyl (Me and Pr), phenyl,
/
CF3 and halo (Cl and Br) substituents were successfully in-
corporated into -aryl ,-unsaturated amides (3ab-aj). The
(R)-configuration of 3aj was confirmed by the X-ray diffrac-
tion of single crystal. The allylic carbonates with 3,4- or 2,6-
dichloro substituted aryl groups were also reactive to pro-
duce 3ak and 3al in moderate yields (69% and 63%) with
excellent ees (>99% and 97%). Fused ring- (- or -naph-
thyl) and hetero-aryl (3-thienyl or 3-indolyl) substituted al-
lylic carbonates were readily transformed into enantiopure
amides (3am-ap). And the asymmetric transformation of
alkyl-substituted allylic electrophiles was demonstrated by
synthesis of 3aq in 37% yield with 99% ee. However, 2-phe-
nylbut-3-en-2-ol or 2-methyl-1-phenylprop-2-en-1-ol de-
rived carbonates had no reactivity, probably due to the ste-
ric hindrance. In order to get insights into the electronic ef-
fects of vinyl azides on the allylic substitution as well as
Schmidt rearrangement process, the scope of vinyl azides
was evaluated. The catalysis was tolerant of alkyl, aryl,
alkoxyl, halo, carbonyl, nitro, ester, CF3 and cyano groups
(for 3ba-3ma) installed on the p- or m-position of -aryl
unit of vinyl azides, but not tolerant of o-substituents on aryl
/
without Ir or (R)-L1
0
/
a The reaction was performed with 1a (0.2 mmol), 2a (0.3
mmol), [Ir(COD)Cl]2 (2.5 mol%), (R)-L1 (10 mol%), BF3.Et2O
b
c
(30 mol%) in toluene (2.0 mL). The isolated yield of 3aa.
Determined by chiral HPLC. d The reaction was performed at
10 oC with 50 mol% of BF3.Et2O. e 1.2 equiv. of 2a and 4.0 mL
of toluene were used.
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Table 2. Synthesis of Enantioenriched -Substituted ,-Unsaturated Amidesa
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a The reaction was performed with 1 (0.20 mmol), 2 (0.24 mmol), [Ir(COD)Cl]2 (2.5 mol%), (R)-L1 (10 mol%), BF3.Et2O (50 mol%)
b
c
d
and Bu4NBr (10 mol%) in toluene (4.0 mL). Isolated yield. Determined by chiral HPLC. The absolute configuration of 3aj was
e
o
confirmed by the X-ray diffraction (CCDC 1950457). The reaction was performed at 35 C. f The dosage of vinyl azide 2 was 0.30
mmol.
Next, the method was applied to synthesize chiral nitriles
with -hydroxypropan-2-yl substituted vinyl azide (4)15 as
acetonitrile carbanion surrogate. Initially, the coupling of
1a and 4 failed with the standard conditions of Table 2.
None of product was formed, while both substrates were
decomposed. ( entry 1, Table 3) The effect of Lewis acid was
then evaluated and zinc salts were found to promote the re-
action. (entries 3, 6 and 9) The strong Lewis acids would de-
compose the vinyl azide to erode the yield (entries 2 and 4),
while the weak Lewis acids couldn’t facilitate the catalytic
process (entries 5 and 8). Finally, the reaction, promoted
both by ZnBr2 (15 mol%) and Ir/(R)-L1 (5 mol%), gave the
enantiopure (R)-3-phenylpent-4-enenitrile (5a) in
excellent yield (entry 10), the absolute configuration deter-
mined by the comparison of its specific rotation with that in
the literature.16 Under the optimized reaction conditions
(ZnCl2 or ZnBr2 as the Lewis acid), an array of racemic aryl-
substituted allylic carbonates were efficiently transformed
into enantiopure -(hetero)aryl pent-4-enenitriles. As de-
picted in Table 4, a wide range of functional groups, includ-
ing alkyl, alkynyl, aryl, halo, carbonyl, carbonate, on the aryl
units of allylic carbonates were tolerated and provided the
enantioenriched homoallylic nitriles (5b-5p) in moderate
to high yields with excellent ees. Meanwhile, fused ring- (-
or -naphthyl) and hetero-aryl (3-thienyl or 3-indolyl) sub-
stituted allylic carbonates were readily transformed into
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nearly enantiopure nitriles. (5q-5t) Although the
is the first catalytic method for asymmetric synthesis of -
substituted pent-4-enenitriles, which are difficult to pre-
pare through other methods, for example unavailable by en-
antioselective allylation of acetonitrile or asymmetric con-
jugated addition of -unsaturated nitriles.17
1
2
3
4
5
6
alkoxyl(MeO or BnO)-aryl derived allylic carbonate was un-
stable and unable to provide the desired product, the corre-
sponding allylic alcohol was appropriate to participate in
the catalytic asymmetric coupling (the transformation of 13
into 14 in the Scheme 2). To the best of our knowledge, this
Table 3. The Enantioselective Coupling Reaction of -Hydroxypropan-2-yl Substituted Vinyl Azide (4)a
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Entry Lewis acid yield (%)b ee (%)c Entry Lewis acid yield (%)b ee (%)c
1
2
3
4
5
BF3.Et2O
Sc(OTf)3
Zn(OTf)2
In(OTf)3
Mg(OTf)2
trace
trace
45
nd
nd
99
99
--
6
7
ZnCl2
InCl3
86
69
n.r.
93
95
99
99
--
8
MgCl2
ZnBr2
ZnBr2
38
9
10d
98
99
8
a The reaction was performed with 1 (0.20 mmol), 4 (0.24 mmol), [Ir(COD)Cl]2 (2.5 mol%), (R)-L1 (10 mol%) and the Lewis
acid (10 mol%) in toluene (2 mL). b The isolated yield. c Determined by chiral HPLC. d 15 mol% of ZnBr2 was used.
Table 4. Synthesis of Enantioenriched -Substituted ,-Unsaturated Nitriles a
a The reaction was performed with 1 (0.20 mmol), 4 (0.24 mmol), [Ir(COD)Cl]2 (2.5 mol%), (R)-L1 (10 mol%) and the Lewis
acid (15 mol%) in toluene (2 mL). b The isolated yield. c Determined by chiral HPLC. d ZnCl2 as the Lewis acid. e ZnBr2 as the
Lewis acid.
To demonstrate the utility of this catalytic approach, syn-
thetic transformations of products were carried out.
(Scheme 2) The reduction of enantiopure 3aa by LiAlH4 en-
abled access to N-phenyl pent-4-enylamine (6) (68% yield,
98% ee), which underwent an intramolecular alkene-carbo-
amination to obtain 2,3-bissubstituted pyrrolidine (7) in
moderate yield with excellent stereoselectivity. The se-
quential N-allylation and ring-closing metathesis was suc-
cessful to transform 3aa into a seven membered lactam 8 in
57% yield and 99% ee. In addition, a Pd-catalyzed
intramolecular cyclization of 3aj via the C-N bond formation
was demonstrated to obtain 3,4-dihydroquinolinone (9) in
95% yield with no detriment to the enantiomeric excess.
Enantioenriched homoallylic nitrile products were readily
transformed into important N-containing building blocks.
For example, the enantiopure 5a underwent the hydrolysis,
in the presence of hydrogen peroxide and base,8 to afford
free amide 10 in high yield and conservation of enantio-
meric excess. The selective reduction of 5a by LiAlH4 gave
11 without loss of ee value. Meanwhile, the Ni-mediated
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reduction system enable hydrogenation of both cyano and
alkenyl moieties to afford 12 in moderate yield with excel-
lent ee.
desired isomer (16a) in 64% yield. Finally, a sequential
three-step transformation of 16a successfully gave the en-
antiopure 17 in high yield.22 The absolute configuration of
(S,S)-17 was confirmed by the X-ray diffraction (CCDC
2012123) and found consistent with that of the target.19
1
2
3
4
Scheme 2. Synthetic Transformations of Products
5
6
7
8
Mechanistic Considerations. The mechanism was pro-
posed to explain chemo- and stereoselectivity of the cata-
lytic coupling reaction. (Scheme 3) In the presence of Lewis
acid (i.e. BF3·OEt2 or Zn(II) salt), the chiral Ir(I) complex ac-
tivates allylic carbonate (1a) through oxidative addition to
form an Ir(III) intermediate (I) and [LA-OtBu]-. An enanti-
oselective C-C bond coupling of I and vinyl azide follows to
generate enantioenriched iminodiazonium ion (II). When
bearing a 2-hydroxypropan-2-yl group at the  position (i.e.,
from 4), the intermediate II undergoes a fragmentation pro-
cess to give 5a. When R is a phenyl group, the 1,2-phenyl
migration (Schmidt rearrangement) leads to the highly re-
active nitrilium ion (III), the latter immediately trapped by
[LA-OtBu]- to form tert-butyl imidate (IV)23 or directly hy-
drolyzed to the amide product. High resolution mass spec-
trum (HRMS) study on the reaction system indicated a ma-
jor species matching the imidate intermediate IV with a pro-
ton. (For the detail, see SI) And the control experiment
demonstrated that trace of water would lead to the ketone
product (3a’) formation (Chart 1), probably via direct hy-
drolysis of the iminodiazonium intermediate II. These re-
sults indicate that, in the coupling reaction of -aromatic-
substituted vinyl azides and allyl tert-butyl carbonates, the
desired amide products are obtained through the Schmidt
rearrangement/alcoholysis pathway.
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Chart 1. Water Effect on the Coupling Reaction
100
3aa
3a'
80
60
40
20
0
Moreover, the asymmetric method was successfully ap-
plied to prepare a potent GluN2B inhibitor (BMS-986169),
which is used to treat major depressive disorder.18 The pre-
vious synthetic method for this chiral molecule relies on chi-
ral HPLC resolution of the racemic piperidine intermedi-
ate.19 Herein, the first asymmetric and formal synthetic pro-
tocol was realized. The synthetic route began with the (R)-
L1/Ir-catalyzed allylic coupling with 1-(4-(benzyloxy)phe-
nyl)prop-2-en-1-ol (13) as the allylic electrophile, due to
the incompetence of corresponding allylic carbonate. Fortu-
nately, the catalytic reaction proceeded smoothly with InCl3
as the Lewis acid and afforded the enantiopure homoallylic
nitrile (14) in 76% yield. And the N-Boc homoallylic amine
(15) was obtained through a LiAlH4 reduction and N-Boc
protection sequence in 80% yield. Followed by the asym-
metric Sharpless dihydroxylation20 and then the selective
sulfonylation of primary hydroxyl group,21 both 16a and
16a’ were given with moderate ratio (4/1). The mixture
could be separated by column chromatography to afford the
0
0.1
0.2
0.5
1
2
H2O (equiv.)
Scheme 3. A Proposed Mechanism
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(3) For selective examples of malonic acid derivatives as pronu-
CONCLUSIONS
cleophiles, see: (a) Kinoshita, N.; Marx, K. H.; Tanaka, K.; Tsubaki,
K.; Kawabata, T.; Yoshikai, N.; Nakamura, E.; Fuji, K. Enantioselec-
tive allylic substitution of cinnamyl esters catalyzed by irid-
ium−chiral aryl phosphite complex:ꢀ Conspicuous change in the
mechanistic spectrum by a countercation and solvent. J. Org. Chem.
2004, 69, 7960-7964. (b) Alexakis, A.; Polet, D. Very Efficient
Phosphoramidite ligand for asymmetric iridium-catalyzed allylic
alkylation. Org. Lett. 2004, 6, 3529-3532. (c) Polet, D.; Alexakis, A.;
Tissot-Croset, K.; Corminboeuf, C.; Ditrich, K. Phosphoramidite
ligands in iridium-catalyzed allylic substitution. Chem.-Eur. J. 2006,
12, 3596-3609. (d) Lipowsky, G.; Miller, N.; Helmchen, G. Regio-and
enantioselective iridium-catalyzed allylic alkylation with in situ
activated P, C-chelate complexes. Angew. Chem. Int. Ed. 2004, 43,
1
2
3
4
5
6
7
8
In summary, vinyl azides were explored in the transition
metal-catalyzed coupling reaction, for the first time, as the
equivalent of acetamide enolate and acetonitrile carbanion.
The amide/nitrile moiety and the chiral center were gener-
ated simultaneously in a single step. The utility of products
was demonstrated through transformations into several
pharmaceutical cores, including chiral pyrrolidine and pi-
peridine (the key intermediate of BMS-986169). Prelimi-
nary evidence suggests that the nitrilium ion (IV) is trapped
by an alkoxyl group (i.e. -OtBu) en route to the desired am-
ide products. The method complements significantly the
catalytic asymmetric alkylation reactions with vinyl azides.
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
4595-4597. (e) Schelwies, M.;
Dübon, P.; Helmchen, G.
Enantioselective modular synthesis of 2, 4-disubstituted
cyclopentenones by iridium-catalyzed allylic alkylation. Angew.
Chem. Int. Ed. 2006, 45, 2466-2469. (f) Giacomina, F.; Riat, D.;
Alexakis, A. ω-Ethylenic allylic substrates as alternatives to cyclic
substrates in copper-and iridium-catalyzed asymmetric allylic
alkylation. Org. Lett. 2010, 12, 1156-1159. (g) Xia, J.; Zhuo, C.; You,
S. Synthesis of cyclopropane-containing building blocks via Ir-
catalyzed enantioselective allylic substitution reaction. Chin. J.
Chem. 2010, 28, 1525-1528. (h) Peng, F.; Hall, D. G. Preparation of
α-substituted allylboronates by chemoselective iridium-catalyzed
asymmetric allylic alkylation of 1-propenylboronates. Tetrahedron
Lett. 2007, 48, 3305-3309. (i) Butcher, T. W.; Hartwig, J. F.
Enantioselective synthesis of tertiary allylic fluorides by iridium-
catalyzed allylic fluoroalkylation. Angew. Chem., Int. Ed. 2018, 130,
13125-13129. For selective examples of malononitrile and masked
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ASSOCIATED CONTENT
Supporting Information. Experimental procedures and char-
acterization data are available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* cao_peng@outlook.com
Author Contributions
‡These authors contributed equally.
ACKNOWLEDGMENT
We thank the NSFC (grant No. 21572218, 21901176 and
21901177) for financial support. The authors also thank Prof.
Zhang-Jie Shi (University of Fudan) and Dr Gregory Perry (Uni-
versity of Manchester) for helpful comments.
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