Gold(I)/chiral br??nsted acid catalyzed enantioselective hydroamination-hydroarylation of alkynes: The effect of a remote hydroxyl group on the reactivity and enantioselectivity

Article abstract of DOI:10.1002/chem.201405061

The catalytic enantioselective hydroamination-hydroarylation of alkynes under the catalysis of (R₃P)AuMe/(S)-3,3a?2-bis(2,4,6-triisopropylphenyl)-1,1a?2-bi-naphthyl-2,2a?2-diyl hydrogenphosphate ((S)-TRIP) is reported. The alkyne was reacted with a range of pyrrole-based aromatic amines to give pyrrole-embedded aza-heterocyclic scaffolds bearing a quaternary carbon center. The presence of a hydroxyl group in the alkyne tether turned out to be very crucial for obtaining products in high yields and enantioselectivities. The mechanism of enantioinduction was established by carefully performing experimental and computational studies.

Full text of DOI:10.1002/chem.201405061

DOI: 10.1002/chem.201405061
Communication
&
Synthetic Methods
Gold(I)/Chiral Brønsted Acid Catalyzed Enantioselective
Hydroamination–Hydroarylation of Alkynes: The Effect of
a Remote Hydroxyl Group on the Reactivity and Enantioselectivity
Valmik S. Shinde,[a] Manoj V. Mane,[b] Kumar Vanka,[b] Arijit Mallick,[c] and Nitin T. Patil*[a]
Abstract: The catalytic enantioselective hydroamination–
hydroarylation of alkynes under the catalysis of
(R3P)AuMe/(S)-3,3’-bis(2,4,6-triisopropylphenyl)-1,1’-bi-
naphthyl-2,2’-diyl hydrogenphosphate ((S)-TRIP) is report-
ed. The alkyne was reacted with a range of pyrrole-based
aromatic amines to give pyrrole-embedded aza-heterocy-
clic scaffolds bearing a quaternary carbon center. The
presence of a hydroxyl group in the alkyne tether turned
out to be very crucial for obtaining products in high
yields and enantioselectivities. The mechanism of enan-
tioinduction was established by carefully performing ex-
Scheme 1. Enantioselective addition of HÀNu to CÀC multiple bonds.
perimental and computational studies.
imines. We envisaged that the hydroamination of alkynes with
aromatic amines would occur in the presence of a chiral Au
catalyst[4] to form imines, which would then undergo an intra-
The hydroamination of allenes, olefins, and alkynes catalyzed
by transition-metal complexes is a fundamentally important re-
action, which has been widely used in organic synthesis.[1] The
addition of amines to allenes and/or olefins generates chiral
amines, and a large number of reports on catalytic enantiose-
lective variants exist (Scheme 1a and b).[2] We envisioned a dif-
ferent approach involving the addition of amines and electron
rich aromatic compounds to alkynes, leading to chiral sec-
ondary amines (Scheme 1c). The process is a catalytic enantio-
selective hydroamination–hydroarylation, which could be of
great importance since chiral aza-heterocycles bearing a quater-
nary carbon center can be generated. To our surprise, there
have been no reports on catalytic enantioselective versions of
such processes to date.[3]
molecular attack with the tethered aromatic compound to pro-
duce an enantioenriched double-addition product
(Scheme 1c). A crucial aspect for the success of the proposed
reaction would be the formation of a tight ion pair[5] between
the imine nitrogen atom and the chiral Au catalyst. Based on
the available knowledge on enantioselective gold catalysis,[6]
two strategies could be easily envisaged. The first strategy in-
volves the use of L*AuX complexes.[5] However, the enantiose-
lective addition of nucleophiles to imines under the catalysis
of L*AuX complexes has rarely been reported.[7] We assumed
that the shortage of such reports might be due to the inability
of Au complexes to coordinate strongly with imines[8]—the
phenomenon can be well understood with the HSAB principle
and relativistic effects.[4k,9] The alternate strategy involves the
use of LAuX* complexes, generated in situ from LAuMe and
HÀX* (X*=chiral phosphate anion).[10] This strategy is support-
ed by two facts: 1) a chiral phosphate counter ion acts as
a ligand bonded to the gold species, thus facilitating the hy-
droamination reaction[10n,11] and 2) the residual X*H generated
in situ can act as a catalyst for the addition of HÀNu to
imines.[12] This hypothesis was supported by the pioneering
work of Gong and co-workers who reported a consecutive AuI-
catalyzed intramolecular hydroamination of alkynes and chiral
Brønsted acid catalyzed enantioselective transfer hydrogena-
tion.[10q] Herein, for the first time, we report the catalytic enan-
tioselective hydroamination–hydroarylation of alkynes under
the catalysis of a AuI/B*ÀH binary system to generate optically
active pyrrole-containing aza-heterocyclic scaffolds bearing
a quaternary carbon center.
The reason for the slow progress in developing a catalytic
enantioselective hydroamination–hydroarylation might be the
requirement of a catalyst that can perform a hydroamination
as well as an enantioselective addition of HÀNu to transient
[a] V. S. Shinde, Dr. N. T. Patil
Organic Chemistry Division, CSIR-National Chemical Laboratory
Dr. Homi Bhabha Road, Pune 411 008 (India)
E-mail: n.patil@ncl.res.in
[b] M. V. Mane, Dr. K. Vanka
Physical Chemistry Division, CSIR-National Chemical Laboratory
Dr. Homi Bhabha Road, Pune 411 008 (India)
[c] A. Mallick
Polymer and Advance Material Laboratory
CSIR-National Chemical Laboratory
Dr. Homi Bhabha Road, Pune 411 008 (India)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405061.
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used instead of 5a (entry 8). The use of the bulky gold catalyst
4a-AuMe or 4b-AuMe in combination with 5a gave 3a in 80
and 81% yield with 98 and 95% ee, respectively (entries 9 and
10). Next, we screened chiral phosphoric acid catalysts 5 bear-
ing various types of substituents at the 3,3’ position on the bi-
naphthyl backbone (Figure 1). As shown in entries 11–15, all of
the chiral catalysts 5 performed satisfactory in terms of the
yield (except entry 13); however, the ee values were found to
be strongly dependent on the C-3 substituent. We further ex-
tensively studied the effect of the solvent, catalyst loading,
and temperature on the reaction outcome.[14] The study re-
vealed that the best conditions are treating 1b and 2a in pres-
ence of 5 mol% 4a-AuMe and 10 mol% 5a in DCE at room
temperature (entry 9).
Table 1. Optimization of the reaction conditions.[a]
Entry
1
2
AuI
BH (5)
Yield [%][b]
22
ee [%][c]
2a R=H
R1 =nHex
Ph3PAuMe
5a
4.7
2
3
4
5
6
7
2a
2a
2a
2a
4a-AuMe
4b-AuMe
4a-AuMe
4a-AuMe
4a-AuMe
Ph3PAuMe
5a
5a
5b
5c
5d
5a
27
31
48
56
57
76
5.3
4.4
3.2
3.0
6.2
91
2a
2b R=H
R1 =(CH2)3OH
With the optimized conditions in hand, we explored the
generality of the catalytic enantioselective hydroamination–hy-
droarylation reaction by using various 2-(2-aminoaryl)pyrroles
and alkynes (Table 2). 4-Pentyn-1-ol reacted smoothly with vari-
ous 2-(2-aminophenyl)pyrroles (bearing OMe, Cl, and Me sub-
stituents) under the established conditions to obtain the de-
sired products 3a–d in yields ranging from 73–83% and ee
values ranging from 95–99% (C2ÀC3 cyclization). When the
8
9
2b
2b
2b
2b
2b
2b
2b
2b
Ph3PAuMe
4a-AuMe
4b-AuMe
4a-AuMe
4a-AuMe
4a-AuMe
4a-AuMe
4a-AuMe
5b
5a
5a
5b
5c
5d
5e
5 f
84
80
81
76
69
57
83
83
78
98
95
39
57
41
63
29
10
11
12
13
14
15
[a] Reaction conditions: 1a (0.15 mmol), 2 (0.15 mmol), AuI (5 mol%), HÀ
B*(10 mol%), DCE (2.0 mL), RT, 24 h. [b] Isolated yields. [c] The ee was de-
termined by HPLC analysis on a chiral stationary phase.
Table 2. Reaction of 2-(2-aminophenyl)pyrroles and alkynols.[a]
Since chiral pyrroles are prevalent building blocks in a variety
of natural products and pharmaceuticals, we started our inves-
tigation by using 2-(2-aminophenyl)pyrrole (1a) as a bis-nucle-
ophile (Table 1). Initially, the reaction was performed by using
octyne 2a and 2-(1-methyl-1H-pyrrol-2-yl) aniline (1a) in the
presence of 5 mol% [PPh3AuMe] and 10 mol% 5a (Figure 1).
Figure 1. Catalyst employed for the optimization.
Pleasingly, product 3a was obtained in 22% yield; however,
the ee was found to be only 4.7% (entry 1). To investigate the
effect of the phosphine ligand, Au complexes 4a and 4b were
tested regarding their catalytic efficiency; however, none of
them was found to be beneficial (entries 2 and 3). When chiral
Brønsted acids 5b, 5c, and 5d were used in the presence of
4a-AuMe, a slight increase in yield was observed; however, the
ee still remained low (entries 4–6). Based on our previous
report,[13] we decided to use an alkyne that bears an ÀOH
group in the tether. When 4-pentyn-1-ol (2b) was reacted with
1a in the presence of 5 mol% [PPh3AuMe] and 10 mol% 5a,
the reaction proceeded smoothly to afford 3a in 76% yield
with 91% ee (entry 7). The ee dropped to 78% when 5b was
[a] Reaction conditions: 1 (0.15 mmol), 2 (0.15 mmol), 4a-AuMe (5 mol%),
(S)-5a (10 mol%), DCE (2.0 mL), RT, 72 h. All yields are isolated yields; the
ee values were determined by HPLC analysis on a chiral stationary phase.
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methyl group on the pyrrole nitrogen atom was replaced by
a benzyl group, the ee dropped down to 55% (3d vs. 3e). It is
worth noting that the carbon-chain length between the OH
group and the alkyne moiety has a major effect because the
use of 5-hexyn-1-ol provided 3 f with only 30% ee. Internal aro-
matic alkynols bearing a halogen, methoxy, trifluoromethyl, or
methyl group at the meta and para positions were well tolerat-
ed to afford the corresponding dihydropyrolo[3,2-c]quinolines
in yields ranging from 60 to 82% and ee values higher than
90% in all cases.
not necessary and even protected pyrrole derivatives work
equally well to give the corresponding products in good yields
and enantioselectivities.
Next, we endeavored to study the applicability of the 2-
amino phenyl pyrroles for the catalytic enantioselective hyro-
amination–hydroarylation reaction (Table 4). In all cases exam-
ined, pyrrolo[1,2-a]quinoxalines (NÀC2 cyclization) were ob-
tained in good yields with excellent ee values (>90%).
Table 4. Reaction of N-(2-aminophenylpyrroles) and alkynols.[a]
Next, we turned our attention to 3-(2-aminophenyl)pyrroles
(Table 3). Lowering the reaction temperature turned out to be
beneficial to obtain dihydropyrolo[2,3-c]quinolines in good
yields and high enantiomeric purities (C3ÀC2 cyclization).[14]
A
variety of substrates were examined to understand the scope
and limitations of the reaction. Notably, 4-pentyn-1-ol and in-
ternal alkynols bearing an aromatic ring with various steric and
electronic modifications were well tolerated. As can be judged
from 7a/7b and 7c/7d, the free NH group of the pyrrole is
Table 3. Reaction of 3-(2-aminophenyl)pyrroles and alkynols.[a]
[a] Reaction conditions: 8 (0.15 mmol), 2 (0.15 mmol), 4a-AuMe (5 mol%),
(S)-5a (10 mol%), DCE (2.0 mL), À258C, 72 h. All yields are isolated yields;
the ee values were determined by HPLC analysis on a chiral stationary
phase.
The scalability and practicality of the developed method is
demonstrated by the gram-scale asymmetric synthesis of 3g
(82% yield, 94.5% ee) from 1a and 2g. Because of the impor-
tance of pyrrole-containing heterocycles in pharmaceutical
chemistry, the present reaction can provide an efficient access
to such molecules in enantiomerically pure form. Moreover,
the hydroxyl group in the product provides a versatile handle
for further transformations to access additional molecular
complexity.
The absolute configuration of products 9a (Table 4) and 3g
(after dehydrative cyclization) was determined by single-crystal
X-ray analysis[14] and that of the other products was assigned
by analogy. It is worth noting that the absolute configuration
in the products varies depending on the type of alkyne used
(4-pentyn-1-ol vs. 4-arylbut-3-yn-1-ols); however, the mode of
enantioinduction remains the same.[15]
Control experiments have been performed carefully, which
led us to conclude that the OH group in the alkyne is essential
to provide the products in good yields and enantioselectivities
(Scheme 2). The reaction of benzyl-protected 4-pentyn-1-ol
with 1a under the optimized reaction conditions gave 10 only
with 25% ee (Scheme 2a). In this case, the product might have
been formed through a direct hydroamination–hydroarylation
[a] Reaction conditions: 6 (0.15 mmol), 2 (0.15 mmol), 4a-AuMe (5 mol%),
(S)-5a (10 mol%), DCE (2.0 mL), À258C, 72 h. All yields are isolated yields;
the ee values were determined by HPLC analysis on a chiral stationary
phase. [b] Reaction performed at À158C.
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concurrent activation of both the imine nitrogen atom and the
tethered hydroxyl group through hydrogen-bonding interac-
tions, which creates a chiral environment and exhibits products
with very high enatioselectivities.
A literature analysis revealed that the organocatalytic enan-
tioselective condensation reaction between aromatic amines
with carbonyl compounds (or equivalent) is an important
method for accessing enantiopure scaffolds. However, all these
methods lead to the generation of asymmetric tertiary carbon
centers.[16] Since the formation of asymmetric quaternary
carbon centers[17] is very important, recent focus of many re-
search groups is devoted to the development of catalytic
asymmetric variants that generate quaternary carbon cen-
ters.[18,19] However, most of these reactions require either cyclic
imines[18] or specially designed substrates.[19] In this regard, the
newly developed method is valuable. Moreover, the hydroxyl
group could provide a functional handle for further functionali-
zations.
Scheme 2. Control experiments.
reaction, as previously reported by our research group.[3a]
When commercially available 2-methylenetetrahydrofuran was
treated with 1a under conditions A and B, 3a was obtained in
almost identical yield and ee (Scheme 2b, conditions A and B).
The use of preformed gold phosphate, generated in situ from
4a-AuMe and (S)-5a, delivered 3a only in 51% yield, although
the reaction time was prolonged to 100 h. However, the ee of
the product remained almost identical (95% ee; Scheme 2b,
conditions C). All these observations clearly indicate the impor-
tance of the tethered hydroxyl group in the alkyne. It can also
be concluded that the hydroalkoxylation is catalyzed by the in
situ generated gold phosphate, while the condensation is pro-
moted only by (S)-5a. The formation of the product in low
yield (Scheme 2b, conditions C) can be attributed to of a small
amount of phosphoric acid (S)-5a, which is generated by deg-
radation of gold phosphate in the presence of substrates bear-
ing OH and NH2 groups. The involvement of a gold phosphate
in the condensation reaction can be ruled out based on com-
putational studies.[14]
In summary, we have discovered the catalytic enantioselec-
tive hydroamination–hydroarylation of alkynes under the catal-
ysis of a AuI/chiral Brønsted acid binary system. The method is
very general and works well for a range of pyrrole-based aro-
matic amines and, therefore, may open unprecedented oppor-
tunities in diversity-oriented synthesis (DOS) for the develop-
ment of enantioselective relay[20] catalytic branching cascade
reactions.[21] In addition, the work presented herein could be
considered as an advanced complement to Pictet–Spengler
(type) reactions, because the formation of quaternary carbon
centers through the condensation of aromatic amines with car-
bonyl compound is highly challenging and mostly limited to
tryptamines.[19,22] Further investigations on expanding the
scope of this reaction are currently underway in our laboratory.
To clearly understand the role of the tethered OH group and
the mode of enantioinduction, DFT calculations were per-
formed by using the Turbomole 6.4 suite of programs and the
TZVP/PBE/B3LYP approach. The studies indicate that the “Re-
face” attack of the nucleophile is kinetically preferred over the
“Si-face” attack by 5.8 (DG) and 3.6 kcalmolÀ1 (DE; Figure 2).
Clearly, the highest level of enantioinduction can be accounted
by the transition state involving the H-bonding interaction be-
tween the transient imino alcohol and B*ÀH. The bifunctional
nature of the chiral phosphoric acid[12] is responsible for the
Experimental Section
Representative procedure
At room temperature, (S)-TRIP (10 mol%) and (Johnphos)AuMe
(5 mol%) in DCE (2 mL) were added to a flame-dried screw-capped
vial equipped with a magnetic stir bar, and the reaction mixture
was stirred for 30 min. To this reaction mixture, alkynol (0.15 mmol)
was added followed by the aromatic amine (0.15 mmol) under
argon atmosphere. The reaction vial was fitted with a cap, evacuat-
ed, back-filled with argon, and stirred at a specified temperature
(72 h). The reaction mixture was diluted with ethyl acetate and fil-
tered through a plug of silica gel. The filtrate was concentrated
and thus the obtained residue was purified by silica gel column
chromatography using petroleum ether/EtOAc as an eluent to
afford analytically pure final compounds. All racemic samples were
synthesized by using (Johnphos) AuCl (5 mol%) and AgOTf
(5 mol%) catalysts following the same reaction conditions (reaction
time of 24 h).
Acknowledgements
Generous financial support by the DST-New Delhi (No. SB/S1/
OC-17/2013) and CSIR-New Delhi (CSC0108 and CSC0130) is
gratefully acknowledged. V.S.S. thanks UGC-New Delhi for the
Figure 2. “Si-face” attack versus “Re-face” attack.
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Keywords: Brønsted acids
· enantioselectivity · gold ·
hydroamination · hydroarylation
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Received: August 30, 2014
Revised: October 7, 2014
Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
&
Synthetic Methods
V. S. Shinde, M. V. Mane, K. Vanka,
A. Mallick, N. T. Patil*
&& – &&
Gold(I)/Chiral Brønsted Acid Catalyzed
Enantioselective Hydroamination–
Hydroarylation of Alkynes: The Effect
of a Remote Hydroxyl Group on the
Reactivity and Enantioselectivity
Enantioinduction: The catalytic enan-
tioselective hydroamination–hydroaryla-
tion of alkynes by using a (R3P)AuMe/
(S)-3,3’-bis(2,4,6-triisopropylphenyl)-1,1’-
binaphthyl-2,2’-diyl hydrogenphosphate
((S)-TRIP) binary catalyst system is re-
ported (see scheme). The OH group in
the alkyne tether is essential to obtain
the pyrrole-embedded aza-heterocyclic
scaffolds bearing a quaternary carbon
center in high yields and enantioselec-
tivities.
&
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!