CuH-Catalyzed Asymmetric Hydroamidation of Vinylarenes

Article abstract of DOI:10.1002/anie.201802797

A CuH-catalyzed enantioselective hydroamidation reaction of vinylarenes has been developed using readily accessible 1,4,2-dioxazol-5-ones as electrophilic amidating reagents. This method provides a straightforward and efficient approach to synthesize chiral amides in good yields with high levels of enantiopurity under mild conditions. Moreover, this transformation tolerates substrates bearing a broad range of functional groups.

Full text of DOI:10.1002/anie.201802797

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Accepted Article
Title: CuH-Catalyzed Asymmetric Hydroamidation of Vinylarenes
Authors: Yujing Zhou, Oliver D Engl, Jeffrey S Bandar, Emma D Chant,
and Stephen L. Buchwald
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10.1002/anie.201802797
Angewandte Chemie International Edition
COMMUNICATION
CuH-Catalyzed Asymmetric Hydroamidation of Vinylarenes
Yujing Zhou†, Oliver D. Engl†, Jeffrey S. Bandar, Emma D. Chant, and Stephen L. Buchwald*[a]
optically active amine products. We envisioned that the
hydrocupration-electrophilic trapping sequence described above
could also be exploited to synthesize amides. Herein we
describe the realization of this strategy using readily accessible
1,4,2-dioxazol-5-ones[8] as the electrophilic amidating reagents.
This operationally simple procedure allows for direct access to
chiral amides from vinylarenes in good yields and high levels of
enantioselectivity under mild conditions (Scheme 1C).
Abstract:
A
CuH-catalyzed enantioselective hydroamidation
reaction of vinylarenes has been developed using readily accessible
1,4,2-dioxazol-5-ones as electrophilic amidating reagents. This
method provides
a straightforward and efficient approach to
synthesize chiral amides in good yields with high levels of
enantiopurity under mild conditions. Moreover, this transformation
tolerates substrates bearing a broad range of functional groups.
A. General approach to access chiral amides
The enantioselective synthesis of chiral amides with
a
stereogenic center adjacent to the nitrogen atom is of great
importance due to the presence of this substructure in many
natural products and biologically active molecules.[1] Commonly
used synthetic strategies involves the coupling of an activated
carboxylic acid with an enantioenriched amine[2] (Scheme 1A,
path a), as well as the asymmetric hydrogenation of enamides
(Scheme 1A, path b).[3] An attractive alternative is the
asymmetric hydroamidation of olefins, in which an olefin is
formally inserted into an amide N-H bond (Scheme 1A, path c).
This transformation allows direct access to complex amides from
simple achiral precursors, and is typically catalyzed by Brønsted
acids or transition metals.[4] However, few enantioselective
intermolecular variants have been reported (Scheme 1B).[5] In
one example, an asymmetric coupling of cyclic urea derivatives
with unactivated terminal olefins using a chiral gold complex was
developed by Widenhoefer.[5a] Later, Hartwig disclosed an Ir-
R3
path a
path b
O
NH
+
O
O
R2
N
R4
X
R1
R3
R1
R2
+
X
R4
R2
path c
R1
N
R4
N
R3
O
R3
R1
R4
R2
X = H or LG
chiral amide
B. Asymmetric intermolecular hydroamidation reactions (previous work)
Widenhoefer et al., 2009
O
O
Me
*
n = 4-8
Me
L*AuCl, AgSbF6
+
Me
RN
NH
RN
N
1,4-dixoane, 100 °C
n = 4-8
(10-60 equiv)
Hartwig et al., 2012
O
[Ir(coe)2Cl]2
catalyzed
hydroamidation
of
aliphatic
alkenes,
and
O
(S)-DTBM-SEGPHOS
Ar
NH
+
enantioselective examples were shown when norbornene or
norbornadiene was used as the olefin.[5b] In 2015, Liu reported
that styrene derivatives react with N-fluorobenzenesulfonimide in
the presence of palladium acetate and a pyridine-oxazoline type
ligand to afford chiral sulfonamides.[5c] Despite the progress in
this field, existing methods often require the use of high reaction
temperatures, activated substrates, or large excesses of the
alkene. In order to expand the synthetic utility of this
transformation, highly enantioselective and general olefin
hydroamidation reactions that proceed under mild conditions are
highly desirable.
Ar
NH2
toluene, 120 °C
(4 equiv)
Liu et al., 2015
PhO2S
Ar
SO2Ph
Me
PhO2S
SO2Ph
Pd(OAc)2, L*
N
N
F
+
Ar
EtOAc, 30 °C
(2.5-3 equiv)
C. CuH-catalyzed asymmetric hydroamidation of alkenes (this work)
Advantages
O
Ar
n
n
n
n
broad scope of vinylarenes
high levels of enantioselectivity
mild reaction conditions
L*CuH
R3SiH
HN
R
+
Recently, the CuH-catalyzed asymmetric hydroamination of
olefins has been developed as a general and efficient method to
access chiral amines with high regio- and enantioselectivity.[6,7]
The key step in these protocols involves the catalytic generation
of enantioenriched alkylcopper nucleophiles via the addition of a
L*CuH species across an alkene. This species can be then
intercepted by an electrophilic amination reagent to produce
O
N
Ar
Me
O
up to 97% ee
O
readliy accessible starting materials
R
Scheme 1. A) General approaches to enantioenriched amides, B) Previous
and C) Current work on asymmetric hydroamidation of alkenes.
Initially, we evaluated the effectiveness of N-benzoyloxy
benzamide (E1) as an electrophile under typical CuH-catalyzed
hydroamination conditions (Table 1, entry 1).[7] Only a trace
amount of the desired product was detected by GC-MS analysis.
Instead, decomposition of the electrophile was primarily
observed. Changing the leaving group on the electrophile from
benzoate (E1) to pivalate (E2) did not circumvent the undesired
decomposition process (Table 1, entry 2). We also evaluated
several electrophilic amidating reagents originally employed in
C-H amidation reactions by Chang.[8] Among these, 3-phenyl-
1,4,2-dioxazol-5-one (2a) demonstrated increased stability in the
presence of L*CuH species and provided a moderate yield of
desired hydroamidation product 3a with good enantioselectivity
(40% yield, 88% ee, Table 1, entry 4). The choice of Ph-BPE as
the supporting ligand[9] and diphenylsilane as the hydride source
was based on an examination of common chiral phosphine
[a]
Y. Zhou[†], Dr. O. D. Engl[†], Dr. J. S. Bandar, E. D. Chant, Prof. Dr.
S. L. Buchwald
Department of Chemistry, Room 18-490
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
E-mail: sbuchwal@mit.edu
These authors contributed equally.
[†]
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201802797
Angewandte Chemie International Edition
COMMUNICATION
ligands and hydrosilane reagents. At higher temperature, the
decomposition of the electrophile is more rapid, resulting in
lower yield of the desired product (Table 1, entry 5). Therefore,
the reaction was conducted at 4 °C, which significantly increased
the yield (Table 1, entry 6). Further optimization of the reaction
conditions revealed that the employment of 1,4-dioxane as
solvent led to the improvement of enantioselectivity (Table 1,
entries 8-10). Since a lower reaction temperature had been
observed to be beneficial for the reaction yield, mixtures of THF
and 1,4-dioxane were tested in order to allow the reaction to be
achieve high conversion (3e).[11] Functional groups, including
esters (3d, 3h), amides (3i), and aryl halides (3g, 3k), remained
intact under the reaction conditions. Moreover, styrenes bearing
ortho substituents (3j, 3k, 3l) were all efficiently converted to the
desired amide products in good yields and with high levels of
enantiopurity. Vinylarenes that contain heterocycles such as a
benzofuran (3m), an N-Boc protected indazole (3n), and a
quinoline (3o), were also accommodated. However, β-
substituted styrenes, which are less reactive towards
hydrocupration, failed to engage in this hydroamidation
reaction.[12]
°
performed at 4 C without freezing the solvent.[10] A 4:1 ratio of
1,4-dioxane: THF provided the best results, affording the amide
product in 75% isolated yield and 94% ee (Table 1, entry 11). It
is notable from a practical perspective that only one equivalent
of the electrophile was needed to achieve high yields.
Table 2. Vinylarene scope of the hydroamidation reaction.[a,b]
Table 1. Optimization of hydroamidation reaction conditions.[a]
Entry
E
Temp., °C
Solvent
THF
Yield 3a, %[b]
ee, %
ND
ND
ND
88
1
2
E1
E2
E3
2a
2a
2a
2a
2a
2a
2a
rt
rt
trace
trace
0
THF
3
rt
THF
4
rt
THF
40
5
45
4
THF
23
88
6
THF
85
87
7
–15
4
THF
51
84
8
MTBE
toluene
1,4-dioxane
15
86
9
4
10
93
10
rt
57
96
[a] Conditions: 0.50 mmol alkene (1.0 equiv), 2a (1.0 equiv), copper(II) acetate
(4 mol%), (S,S)-Ph-BPE (4.4 mol%), Ph2SiH2 (2.0 equiv) in 1,4-dioxane/THF
(4/1, 0.5 M), see the Supporting Information for details. [b] Average isolated
yield from two experiments. [c] 4 mol% + 2 mol% catalyst was used. [d] 4
mol% + 4 mol% catalyst was used.
1,4-dioxane
/THF (4/1)
11
12
13
2a
2a
2a
4
4
4
80 (75)[c]
77
94
93
92
1,4-dioxane
/THF (3/2)
1,4-dioxane
/THF (1/1)
A range of aromatic amide electrophiles was examined in this
reaction using styrene as the alkene component (Table 3).
Regardless of the substitution pattern on the benzene ring of the
electrophile, the corresponding amide products 3p-3v were
obtained in moderate to good yields (44–77%) and with
excellent enantioselectivity (90–94% ee). Based on experimental
observations, we conclude that the electron-deficient
electrophiles are more prone to decompose than their electron-
rich counterparts. We hypothesized that an unidentified species
is slowly generated and attenuates the reactivity of the CuH
catalyst, resulting in poor conversion of starting materials.[13] In
order to solve this problem, a second batch of L*CuH solution
was added to improve the conversion for these substrates,
thereby enabling the formation of the corresponding amides in
60
[a] Conditions: 0.25 mmol styrene (1.0 equiv), 3-phenyl-1,4,2-dioxazol-5-
one (1.0 equiv), copper(II) acetate (4 mol%), (S,S)-Ph-BPE (4.4 mol%),
diphenylsilane (2.0 equiv), in solvent (0.50 mL), see the Supporting
Information for further details. E = amide electrophile. [b] Yield determined
by 1H NMR using 1,1,2,2-tetrachloroethane as an internal standard. [c]
Isolated yield in parenthesis.
synthetically useful yields. We found that
a heterocyclic
electrophile was also effective in this transformation (3w). In
contrast, an electrophile bearing an alkyl 3-substituent (2j, R =
Bn) provides the corresponding amide 3x in poor yield due to
the rapid nonproductive consumption of 2j. However, when 2j
was slowly added over 2 h to the reaction mixture, the amide
Having identified the optimal reaction conditions, the reactivity of
a range of vinylarenes was next investigated (Table 2). Both
electron-rich and electron-deficient styrenes reacted smoothly
with 2a to form 3a-o in good yields (61–80%) and
enantioselectivity (64–97% ee), although a slightly higher
catalyst loading was required for the electron-rich derivatives to
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10.1002/anie.201802797
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COMMUNICATION
product was obtained in moderate yield (54%) and with useful
enantioselectivity (75% ee).
In conclusion,
a
highly enantioselective hydroamidation
reaction of vinylarenes is reported using 1,4,2-dioxazol-5-ones
as electrophilic amidating reagents. Since these reagents can
be readily prepared from the corresponding carboxylic acids[8a,
8b], this protocol provides a straightforward and efficient method
to access chiral amides from readily accessible achiral
coupling partners. Products with diverse substitution patterns
and various functional groups were afforded in good yields and
high levels of enantiopurity. Efforts towards developing
hydroamidation protocols with broader alkene scope are
ongoing.
Table 3. Electrophile scope of the hydroamidation reaction.[a,b]
Acknowledgements
Research reported in this publication was supported by the
National Institutes of Health (GM58160, GM122483). We also
thank the NIH for a supplemental grant for the purchase of
supercritical
fluid
chromatography
(SFC)
equipment
(GM058160-17S1) and for a postdoctoral fellowship for J. S. B.
(GM112197). Dr. O. D. Engl thanks the Swiss National Science
Foundation
(SNSF)
for
a
postdoctoral
fellowship
(P2EZP2_175140). We acknowledge Richard Liu, Dr. Andy
Thomas, and Dr. Christine Nguyen for advice on the preparation
of this manuscript.
Keywords: amides • alkenes • copper • enantioselectivity •
[a] Conditions: 0.50 mmol 1a (1.0 equiv), 1,4,2-dioxazol-5-ones (1.0 equiv),
copper(II) acetate (4.0 mol%), (S,S)-Ph-BPE (4.4 mol%), Ph2SiH2 (2.0 equiv)
in 1,4-dioxane/THF (4/1, 0.5 M), see the Supporting Information for details. [b]
Average isolated yield from two experiments. [c] 4 mol% + 2 mol% catalyst
was used. [d] 4 mol% + 4 mol% catalyst was used. [e] Slow addition of the
amide electrophile solution was required; see the Supporting Information for
details.
amidation
[1]
For selected examples, see: a) V. S. Ananthanarayanan, S. Tetreault,
A. Saint-Jean, J. Med. Chem. 1993, 36, 1324; b) A. A. Patchett, J. Med.
Chem. 1993, 36, 2051; c) R. Naito, Y. Yonetoku, Y. Okamoto, A.
Toyoshima, K. Ikeda, M. Takeuchi, J. Med. Chem. 2005, 48, 6597; d) S.
K. Branch, I. Agranat, J. Med. Chem. 2014, 57, 8729; e) S. Mikami, S.
Sasaki, Y. Asano, O. Ujikawa, S. Fukumoto, K. Nakashima, H. Oki, N.
Kamiguchi, H. Imada, H. Iwashita, T. Taniguchi, J. Med. Chem. 2017,
60, 7658.
Based
on
previously
reported
CuH-catalyzed
hydrofunctionalization reactions,[14] a mechanism was postulated
for this transformation, which is shown in Scheme 2. Initially, the
styrene undergoes stereoselective migratory insertion into a Ph-
BPE-ligated copper hydride, which produces chiral benzylcopper
intermediate I. This intermediate participates in oxidative
insertion into the N-O bond in electrophile 2a, followed by the
extrusion of CO2 and reductive elimination to form species III.[15]
Subsequent metathesis with a hydrosilane regenerates the
L*CuH catalyst, as well as releasing the desired amidation
product.
[2]
For reviews on chiral amine synthesis, see: a) Chiral Amine Synthesis
(Ed.: T. C. Nugent), Wiley, Weinheim, 2010; b) Stereoselective
Formation of Amines, Vol. 343 of Topics in Current Chemistry (Eds.: W.
Li, X. Zhang), Springer, Berlin, 2014.
[3]
[4]
For a recent review on the asymmetric hydrogenation of enamides,
see: J.-H. Xie, S.-F. Zhu, Q.-L. Zhou, Chem. Soc. Rev. 2012, 41, 4126.
For selected reviews on alkene hydroamination and hydroamidation,
see: a) L. Huang, M. Arndt, K. Gooßen, H. Heydt, L. J. Gooßen, Chem.
Rev. 2015, 115, 2596; b) E. Bernoud, C. Lepori, M. Mellah, E. Schulz, J.
Hannedouche, Catal. Sci. Technol. 2015, 5, 2017; c) J. Hannedouche,
E. Schulz, Chem. Eur. J. 2013, 19, 4972; d) J. S. Yadav, A. Antony, T.
S. Rao, B. V. S. Reddy, J. Organomet. Chem. 2011, 696, 16; e) T. E.
Müller, K. C. Hultzsch, M. Yus, F. Foubelo, M. Tada, Chem. Rev. 2008,
108, 3795; f) K. C. Hultzsch, Adv. Synth. Catal. 2005, 347, 367.
For examples of enantioselective intermolecular hydroamidation
reactions of olefins, see: a) Z. Zhang, S. D. Lee, R. A. Widenhoefer, J.
Am. Chem. Soc. 2009, 131, 5372; b) C. S. Sevov, J. Zhou, J. F.
Hartwig, J. Am. Chem. Soc. 2012, 134, 11960; c) F. Yu, P. Chen, G.
Liu, Org. Chem. Front. 2015, 2, 819.
[5]
[6]
[7]
For reviews on the CuH-catalyzed hydroamination reactions, see: a) M.
T. Pirnot, Y.-M. Wang, S. L. Buchwald, Angew. Chem. Int. Ed. 2016, 55,
48; b) A. J. Jordan, G. Lalic, J. P. Sadighi, Chem. Rev. 2016, 116, 8318.
For selected examples of CuH-catalyzed asymmetric hydroamination
reactions, see: a) Y. Miki, K. Hirano, T. Satoh, M. Miura, Angew. Chem.
Int. Ed. 2013, 52, 10830; b) S. Zhu, N. Niljianskul, S. L. Buchwald, J.
Am. Chem. Soc. 2013, 135, 15746; c) D. Niu, S. L. Buchwald, J. Am.
Chem. Soc. 2015, 137, 9716; d) Y. Yang, S.-L. Shi, D. Niu, P. Liu, S. L.
Buchwald, Science 2015, 349, 62; e) H. Wang, J. C. Yang, S. L.
Buchwald, J. Am. Chem. Soc. 2017, 139, 8428. Also see reference 6a
and references therein.
Scheme 2. Proposed mechanism of CuH-catalzyed hydroamidation reaction.
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[8]
a) Y. Park, K. T. Park, J. G, Kim, S. Chang, J. Am. Chem. Soc. 2015,
137, 4534; b) Y. Park, S. Jee, J. G, Kim, S. Chang, Org. Process Res.
Dev. 2015, 19, 1024; c) J. Park, S. Chang, Angew. Chem. Int. Ed. 2015,
54, 14103; d) H. Wang, G. Tang, X. Li, Angew. Chem. Int. Ed. 2015, 54,
13049; e) V. Bizet, L. Buglioni, C. Bolm, Angew. Chem. Int. Ed. 2014,
53, 5639.
[9]
For applications of BPE ligands, see: a) M. J. Burk, Acc. Chem. Res.
2000, 33, 363; b) I. C. Lennon, C. J. Pilkington, Synthesis 2003, 11,
1639.
[10] The melting point of 1,4-dioxane is 12 °C.
[11] The hydrocupration step is slower for the electron-rich alkenes
compared to the electron-deficient ones. Thus, the decomposition of
the amide electrophiles, as well as the deactivation of the catalyst, was
more pronounced in the cases of electron-rich substrates.
[12] Other substrates, including terminal alkyl-substituted and 1,1-
disubstituted olefins, did not afford the desired hydroamidation products
in this protocol. We believe that sluggish hydrocupration of these
substrates under the current conditions accounts for the failure of these
transformations.
[13] Both starting materials, as well as diphenylsilane, remained in the
reaction mixture after 24 h. Prolonged reaction time did not lead to
further increase in conversion.
[14] a) J. S. Bandar, M. T. Pirnot, S. L. Buchwald, J. Am. Chem. Soc. 2015,
137, 14812; b) S. Tobisch, Chem. Eur. J. 2016, 22, 8290; c) Y. Xi, J. F.
Hartwig, J. Am. Chem. Soc. 2017, 139, 12758; d) J. Lee, S. Radomkit,
S. Torker, J. del Pozo, A. H. Hoveyda, Nat. Chem. 2018, 10, 99.
[15] At this point, we are not able to determine the precise position of the
decarboxylation step in the mechanism. Although significant bubbling is
observed during the MeOH workup, this can be ascribed to either the
generation of H2 from R3Si-H species or the release of CO2 from some
compounds, or both.
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10.1002/anie.201802797
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COMMUNICATION
COMMUNICATION
Yujing Zhou, Oliver D. Engl, Jeffrey S.
Bandar, Emma D. Chant, Stephen L.
Buchwald*
Page No. – Page No.
CuH-Catalyzed Asymmetric
Hydroamidation of Vinylarenes
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