A Modified System for the Synthesis of Enantioenriched N-Arylamines through Copper-Catalyzed Hydroamination

Article abstract of DOI:10.1002/anie.201803026

Despite significant recent progress in copper-catalyzed enantioselective hydroamination chemistry, the synthesis of chiral N-arylamines, which are frequently found in natural products and pharmaceuticals, has not been realized. Initial experiments with N-arylhydroxylamine ester electrophiles were unsuccessful and, instead, their reduction in the presence of copper hydride (CuH) catalysts was observed. Herein, we report key modifications to our previously reported hydroamination methods that lead to broadly applicable conditions for the enantioselective net addition of secondary anilines across the double bond of styrenes, 1,1-disubstituted olefins, and terminal alkenes. NMR studies suggest that suppression of the undesired reduction pathway is the basis for the dramatic improvements in yield under the reported method.

Full text of DOI:10.1002/anie.201803026

Angewandte
Communications
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International Edition: DOI: 10.1002/anie.201803026
German Edition: DOI: 10.1002/ange.201803026
Asymmetric Catalysis Very Important Paper
A Modified System for the Synthesis of Enantioenriched N-Arylamines
through Copper-Catalyzed Hydroamination
Saki Ichikawa, Shaolin Zhu, and Stephen L. Buchwald*
[
9]
Abstract: Despite significant recent progress in copper-cata-
lyzed enantioselective hydroamination chemistry, the synthesis
of chiral N-arylamines, which are frequently found in natural
products and pharmaceuticals, has not been realized. Initial
experiments with N-arylhydroxylamine ester electrophiles were
unsuccessful and, instead, their reduction in the presence of
copper hydride (CuH) catalysts was observed. Herein, we
report key modifications to our previously reported hydro-
amination methods that lead to broadly applicable conditions
for the enantioselective net addition of secondary anilines
across the double bond of styrenes, 1,1-disubstituted olefins,
and terminal alkenes. NMR studies suggest that suppression of
the undesired reduction pathway is the basis for the dramatic
improvements in yield under the reported method.
In light of our previous studies, we began our inves-
tigation by exploring the reactivity of N-arylhydroxylamine
esters using styrene as the model substrate, (S)-DTBM-
SEGPHOS/Cu(OAc) as the precatalyst, and (MeO)2
2
[
10]
MeSiH
as the stoichiometric reductant. We chose to
employ the 4-diethylaminobenzoate ester of phenylbenzylhy-
droxylamine (2a) as the electrophilic amine source. In the
case of aliphatic amines, reagents bearing this modified
leaving group were found to possess better stability and
enhanced reactivity relative to the benzoate esters (Scheme
Under these conditions, a small amount of the desired
product 3a (17%) was formed in a moderately enantioselec-
tive manner (41% ee; Scheme 1a). A significant amount of N-
[
9e,f]
1a).
E
nantiomerically enriched N-arylamines are important
synthetic targets in organic chemistry due to their prevalence
in a variety of pharmaceuticals, agrochemicals, and functional
[1]
materials. Consequently, their synthesis has been actively
investigated over the past few decades, leading to the
development of a number of useful approaches, including
the addition of nucleophiles to imines, reductive amina-
tion, and late-transition-metal-catalyzed hydroamination.
[2]
[
3]
[4]
In particular, the enantioselective hydroamination of alkenes
and alkynes has received considerable attention due to the
conceptual simplicity of this method, although the substrate
scope is quite limited.
The use of copper hydride (LCuH) catalysts has recently
been demonstrated as a useful approach for the synthesis of
[
5]
chiral secondary and tertiary alkylamines. In reactions using
these catalysts, an alkylcopper intermediate, generated
through hydrocupration of an alkene, reacts with a N-
alkylhydroxylamine ester to furnish the amine product. N-
alkylhydroxylamine esters have previously been employed by
several research groups as electrophilic nitrogen sources in
[6–8]
transition-metal-catalyzed processes.
In contrast, to the
best of our knowledge, N-arylhydroxylamine esters have not
been used in these transformations. The extension of the
copper-catalyzed asymmetric hydroamination reaction to
these electrophilic amine reagents would provide a versatile
and flexible approach for the preparation of a-chiral aryl-
amines.
[
*] S. Ichikawa, Dr. S. Zhu, Prof. Dr. S. L. Buchwald
Department of Chemistry, Massachusetts Institute of Technology
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:
https://doi.org/10.1002/anie.201803026.
Scheme 1. Initial result of the copper-catalyzed hydroamination of
styrene 1a with N-arylhydroxylamine ester 2a.
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benzylaniline was also formed through reductive cleavage of
petent coupling partners using this method. Furthermore, the
reaction could be applied to trans-b-substituted (1d) and cis-
b-substituted (1e) styrenes, hindered b,b-disubstituted sty-
renes (1 f), and 1,1-disubstituted alkenes (1h). Both cis- and
trans-b-substituted olefins yielded the corresponding
the NÀO bond of 2a (Scheme 1b).
To improve upon this result, we conducted an extensive
evaluation of reaction conditions and additives (Table 1). We
[
a,b,c]
products in similar yields and in a stereoselective
Table 1: Reaction Optimization.
[9a]
manner as we previously reported. Moreover, the
reaction with 3-vinylpyridine provided 3g in an
efficient manner. The catalyst system also achieved
high levels of diastereoselectivity in the hydroami-
nation of (R)-limonene (3i, 3i’). Terminal alkenes
(
1j–1l), which are relatively less reactive compared
[
b]
[c]
Entry
X
PR3
Additive
Yield [%]
ee [%]
to styrene derivatives, were also competent sub-
strates and gave the desired products in moderate
yield under the reaction conditions. This method
tolerated terminal alkenes containing a terminal
epoxide (1k) and an indole (1l)
We also surveyed the scope with respect to N-
arylamine benzoate electrophiles (2b–2j; Table 3).
Electron-poor substituents on the aryl ring of the
1
2
3
4
5
6
7
8
9
OC(O)C H NEt
OC(O)C H NEt
OC(O)C H NEt
OC(O)C H NEt
OC(O)C H NEt
OC(O)C H NEt
OC(O)C H NEt
OC(O)C H NEt
OC(O)C H NEt
OC(O)C H NEt
OAc
OPiv
PPh3
PPh3
none
PCy3
PCyPh2
none
71
97
39
45
81
77
48
76
19
87
91
82
30
80
89
92
87
89
86
84
84
88
6
4
2
2
2
2
2
2
2
2
2
2
tBuOH
tBuOH
tBuOH
tBuOH
6
4
6
4
6
4
6
4
P(2-anisyl) Ph tBuOH
2
6
4
PPh3
PPh3
PPh3
PPh3
iPrOH
LiOtBu
NaOtBu
6
4
6
4
amine electrophile, including a trifluoromethyl
6
4
10
11
12
13
Mg(OtBu)2 62
group (2b), a fluorine (2c), and an ester (2d), were
compatible with our method. Additionally, those
containing an aryl chloride (2e) and bromide (2 f)
were suitable substrates for this process. Unfortu-
nately, we were unable to prepare amine electro-
philes in which the aryl group of the aniline had
electron-donating substituents, such as a methoxy
6
4
PPh3
tBuOH
tBuOH
tBuOH
88
88
95
PPh3
OC(O)1,3-OMeC H3 PPh3
6
[
(
(
a] Reaction conditions: 0.2 mmol 1a (1.0 equiv), 2 (1.2 equiv), Cu(OAc)2
3.0 mol%), (S)-DTBM-SEGPHOS (3.3 mol%), PR (6.0 mol%), additive
3
1.0 equiv), (MeO) MeSiH (3.0 equiv) in THF (0.1 mL) at 608C; see the Supporting
Information for details. [b] The yield was determined by GC analysis using n-
dodecane as an internal standard. [c] The enantioselectivity was determined by
chiral HPLC analysis.
2
[13,14]
group.
Substrates bearing heterocycles, includ-
ing a pyridine (2c) and a thiophene (2g), were
successfully converted into the desired products.
Additionally, using arylhydroxylamine esters with
primary (2h) and cyclic secondary (2i) alkyl groups or an allyl
group (2j) led to good results. We also examined the reaction
in the presence of a TIPS-protected propargyl substrate and
1-methyl-1H-imidazole. In the former case, the reaction
proceeded well, and the latter case, no product was formed
(see the Supporting Information for details).
Next, we were interested in ascertaining the origin of the
beneficial effect of adding tBuOH and PPh to the reaction
mixture. We suspected that these additives attenuate the
unproductive reduction of the hydroxylamine ester reagent.
N-arylhydroxylamine ester 2a was treated with solutions of
(MeO) MeSiH and copper catalyst in [D ]THF either with or
without tBuOH/PPh , and the consumption of 2a was
monitored by H NMR spectroscopy (Figure 1). We found
that if the amount of added PPh was kept constant, the
addition of tBuOH resulted in significantly slower consump-
tion of 2a. The same trend was observed when comparing the
presence and absence of PPh while the amount of added
tBuOH was kept constant. We speculate that the degradation
pattern in the presence of tBuOH without PPh resulted from
found that the addition of a catalytic amount of PPh as
led to a dramatic and unexpected
enhancement in yield and enantioselectivity (71% yield, 87%
ee, entry 1). A non-chiral HCu-PPh species is presumably
generated and does not compete with the desired hydro-
amination catalyzed by the DTBM-SEGPHOS-bound copper
3
[
11]
a secondary ligand
3
[
11]
species.
a stoichiometric amount of tBuOH (1 equiv). In this way,
a was obtained in high yield and with a high level of
Further improvements were made by adding
[12]
3
3
enantiomeric purity (97% yield, 91% ee, entry 2). The
inclusion of both PPh and tBuOH were necessary to achieve
3
these results (entry 3). The use of other phosphines as
additives resulted in considerably lower yields and/or enan-
tioselectivity (entries 4–6), while the inclusion of other
alcohols lowered the yield of 3a (entry 7). Alkoxides, such
as LiOtBu, were also investigated and were less effective
compared to tBuOH (entries 8–10). A number of electro-
philic amine reagents with different leaving groups also
provided the desired product with slightly lower levels of
enantioselectivity (entries 11–13).
2
8
3
1
[15]
3
3
3
With optimized conditions in hand, we sought to explore
the substrate scope of this asymmetric hydroamination
process. A variety of olefins could be effectively transformed
into the corresponding enantiomerically enriched amines in
good to excellent yields (Table 2). Products from styrene (1a)
as well as from styrenes bearing both electron-donating (1b)
and electron-withdrawing (1c) ring substituents were com-
the fact that tBuOH was consumed before the reduction of 2a
proceeded (see the Supporting Information for details).
Taken together, these data suggest that both additives play
an important role in suppressing the undesired reduction of
the hydroxylamine ester, 2. With both additives, less than
10% of 2 was consumed over 1 hour. In comparison, when
2
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[
a,b]
[a,b]
Table 2: Scope with respect to olefins.
Table 3: Scope with respect to N-arylamine benzoate electrophiles.
[a] Reaction conditions: 0.5 mmol olefin (1.0 equiv), N-arylamine ben-
zoate (1.2 equiv), Cu(OAc) (3.0 mol%), (R)-DTBM-SEGPHOS
2
(3.3 mol%), PPh (6.0 mol% equiv), tBuOH (1.0 equiv), (MeO) MeSiH
3 2
(3.0 equiv) in THF (0.25 mL) at 608C; see the Supporting Information for
details. [b] N-arylamine benzoate electrophiles bearing ortho substitu-
ents on the aryl ring did not give products.
[a] Reaction conditions: 0.5 mmol olefin (1.0 equiv), 2a (1.2 equiv),
Cu(OAc) (3.0 mol%), (R)-DTBM-SEGPHOS (3.3 mol%), PPh
2
3
(
(
6.0 mol%), tBuOH (1.0 equiv), (MeO) MeSiH (3.0 equiv) in THF
0.25 mL) at 608C; see the Supporting Information for details. [b] After
was critical for enabling the use of N-arylhydroxylamine
esters as the electrophilic nitrogen source. This method was
successfully applied to the synthesis of a- and b-chiral
arylamines with a variety of functional groups from a diverse
range of olefin substrate classes.
2
recrystallization. [c] (Æ)-DTBM-SEGPHOS was used. Both starting
materials were fully converted after the reaction time.
either additive was omitted, less than 10% of the 2 remained
after 50 minutes.
Acknowledgements
Additionally, we monitored the CuH-catalyzed hydro-
amination of styrene using 2a in the presence or absence of
Research reported in this publication was supported by the
National Institutes of Health (R01-GM58160 and R35-
GM122483). 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. S.I. thanks the Japan Student Services Organization
(JASSO) for a graduate fellowship. We are grateful to Drs.
Michael Pirnot, Yi-Ming Wang, Mycah Uehling, Koji Kubota,
Andy Thomas, Scott McCann, and Christine Nguyen for their
advice on the preparation of this manuscript. We thank Dr.
Nootaree Niljianskul for her early work on this project.
1
tBuOH/PPh through H NMR spectroscopy. We observed
3
that the reaction rate was also significantly enhanced by the
addition of tBuOH/PPh (Figure 2), which is consistent with
3
[
12,16]
the previously proposed
role of tBuOH and PPh3 in
promoting turnover of the catalyst. It is also possible that
PPh3 prevents the coordination of amine electrophiles to
LCuH, thereby helping to suppress its undesired reduction.
In summary, we have developed a copper-catalyzed
hydroamination of alkenes with arylamine O-benzoates for
the preparation of enantioenriched tertiary arylamines. The
use of tBuOH, in conjunction with a catalytic amount of PPh3,
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(
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Keywords: asymmetric synthesis · copper ·
homogeneous catalysis · hydroamination · N-arylamines
4
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Communications
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1
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2
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LCuOR species III to LCuH I instead of protonating the chiral
alkyl copper intermediate II, to give the reduced styrene.
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Manuscript received: March 12, 2018
Revised manuscript received: April 27, 2018
Accepted manuscript online: May 30, 2018
Version of record online: && &&, &&&&
Angew. Chem. Int. Ed. 2018, 57, 1 – 6
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Asymmetric Catalysis
S. Ichikawa, S. Zhu,
S. L. Buchwald*
&&&& — &&&&
A Modified System for the Synthesis of
Enantioenriched N-Arylamines through
Copper-Catalyzed Hydroamination
Winds of change: An efficient method for
the preparation of enantioenriched N-
arylamines was developed by making key
modifications to a previously reported
hydroamination. The reaction is medi-
ated by a copper(I)-hydride (CuH) cata-
lyst, and wide range of olefins and N-
arylhydroxylamines are compatible under
the optimized conditions. Key to the
successful development of this method
was the addition of tBuOH and PPh to
3
the reaction mixture.
6
www.angewandte.org
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2018, 57, 1 – 6
These are not the final page numbers!