Enantioselective N-H functionalization of indoles with α,β- unsaturated γ-lactams catalyzed by chiral Bronsted acids

Article abstract of DOI:10.1002/anie.201102046

Nitrogen revives: Cyclic N-acyliminium ions were generated from α,β-unsaturated γ-lactams (1) and underwent intermolecular addition by indole nucleophiles (2) under the catalysis of a chiral Bronsted acid (3). A variety of N-functionalized indole derivatives containing a pyrrolidinone moiety (4) were assembled with high enantioselectivity. Bn=benzyl. Copyright

Full text of DOI:10.1002/anie.201102046

Communications
DOI: 10.1002/anie.201102046
Asymmetric Catalysis
Enantioselective N–H Functionalization of Indoles with
a,b-Unsaturated g-Lactams Catalyzed by Chiral Brønsted Acids**
Yinjun Xie, Yingwei Zhao, Bo Qian, Lei Yang, Chungu Xia, and Hanmin Huang*
Chiral indole motifs are privileged heterocyclic structures in
drug discovery and widely exist in synthetic bioactive com-
pounds and natural products.[1] Therefore, intense effort has
been devoted to the direct enantioselective functionalization
of indole cores for the synthesis of optically active indole
derivatives.[2] While many asymmetric alkylation methods
exist for the functionalization of indoles at the C3 or C2
atom,[3] the asymmetric functionalization of indoles at the N
atom is limited.[4] This limitation probably results from the
intrinsic lower reactivity of the N atom compared to the C3
and C2 atoms of the indole core. One way to circumvent this
problem is to use a base as a catalyst to facilitate the cleavage
of the acidic proton on the N atom and make the N atom
prone to alkylation.[4b–c] The conjugate base of a chiral
phosphoric acid could be produced by the abstraction of the
acidic proton by another substrate.[5] As such, a chiral
phosphoric acid would function as a catalyst to promote the
N alkylation of an indole under the appropriate reaction
conditions. Herein we report a Brønsted acid catalyzed
enantioselective N-alkylation reaction of indoles that selec-
tively affords chiral N-alkylated indole derivatives with
excellent enantioselectivity (up to 95% ee).
alkaloid natural product targets.[8] The a,b-unsaturated g-
lactam 1 could also act as a surrogate for the cyclic N-
acyliminium ion since it could be easily converted into the N-
acyliminium ion upon accepting an acidic proton from an
appropriate Brønsted acid.[9] This interesting and unique
feature prompted us to surmise that the use of a chiral
phosphoric acid, instead of an achiral Brønsted acid, would
give rise to a chiral conjugate base/N-acyliminium ion pair A
by protonation of the a,b-unsaturated g-lactam. In this case,
À
the acidic N H atom of the indole would interact with the
conjugate base of the chiral Brønsted acid through hydrogen
bonding, thus activating the N atom to react with the cyclic N-
acyliminium ion. The N-selective asymmetric functionaliza-
tion of indoles would be expected to provide facile access to
chiral indole derivatives that contain pyrrolidinone moieties,
which are prominent features of many natural products and
pharmaceuticals (Scheme 1).[8a,b,10]
The cyclic N-acyliminium ions are highly reactive electro-
philes and are extensively utilized for the construction of
À
nitrogen-containing ring systems by C C bond-formation
reactions.[6] By using this strategy, the research groups of
Jacobsen and Dixon have successfully installed pyrrolidinone
moieties at the C2- and C3-positions of an indole using cyclic
N-acyliminium ions as electrophiles.[7] However, to the best of
our knowledge, the enantioselective N alkylation of an indole
with this type of reactive species has never been explored,
despite the fact that the structural motifs of the corresponding
products could act as useful precursors to more complex
Scheme 1. Enantioselective N functionalization of indoles.
[*] Y. Xie, Y. Zhao, B. Qian, Dr. L. Yang, Prof. Dr. C. Xia,
Prof. Dr. H. Huang
To explore our hypothesis, the reaction of a,b-unsaturated
g-lactam 1a with indole 2a catalyzed by phosphoric acids 4
was examined (Table 1) for the optimization of the reaction
conditions. In the presence of 5 mol% of 4a in toluene at
room temperature, the reaction of 1a with 1.2 equivalents of
indole gave the desired product 3a in 29% yield and 22% ee,
together with a trace amount of the C3-alkylation by-product
(less than 5% yield). Under these reaction conditions several
phosphoric acids (4; Scheme 1), which have a variety of
substituents at the 3- and 3’-positions of the binaphthyl
scaffold, were tested, and the results are listed in Table 1. The
sterically congested phosphoric acid catalysts were found to
be crucial for the activity and enantioselectivity, with the
catalyst 4g, which bears bulky 2,4,6-triisopropylphenyl groups
State Key Laboratory for Oxo Synthesis and Selective Oxidation
Lanzhou Institute of Chemical Physics
Chinese Academy of Sciences, Lanzhou, 730000 (China)
Fax: (+86)931-496-8129
E-mail: hmhuang@licp.cas.cn
Prof. Dr. H. Huang
State Key Laboratory of Applied Organic Chemistry
Lanzhou University, Lanzhou, 730000 (China)
Y. Xie, Y. Zhao
Graduate School of the Chinese Academy of Sciences (China)
[**] This work was supported by the Chinese Academy of Sciences and
the National Natural Science Foundation of China (20802085). We
are grateful to Prof. A. Lei for providing the in situ IR instrument.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201102046.
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Angew. Chem. Int. Ed. 2011, 50, 5682 –5686

Table 1: Optimization of the reaction conditions.[a]
Table 2: Substrate scope of indoles.[a]
R1, R2
R3
Yield [%][b]
ee [%][c]
Entry
Cat.
Solvent
Yield [%][b]
ee [%][c]
Entry
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4 f
4g
4g
4g
4g
4g
4g
4h
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2ClCH2Cl
Et2O
benzene
o-xylene
toluene
toluene
29
21
15
53
50
80
75
65
80
60
66
85
65
22
0
19
9
11
56
87
66
81
60
82
87
90
1
2
3
4
5
6
7
8
H, H
H, H
H, H
H, H
H, H
H, H
H, H
Me, H
H
3a,65(85)
3b,44(82)
3c,71(72)
3d,38(71)
3e,25(72)
3 f, 24(87)
3g,25(65)
3h,38(81)
3i, 42
3j, 95
3k, 98
3l, 96
3m,96
3n, 91
3o, 91
3p, 94
3q, 90
3r, 94
3s, 92
3t, 94
90(87)
90(83)
90(86)
86(80)
88(80)
90(83)
90(86)
93(93)
91
82
94
91
95
92
87
93
92
86
86
90
5-Me
5-OMe
5-F
5-Br
4-Br
6-Cl
H
H
H
H
H
9
9
2-MePh, H
H, Me
10
11
12[d]
13[e]
10
11
12
13
14
15
16
17
18
19
20
Me, Me
–(CH2)3–
–(CH2)4–
–(CH2)5–
–(CH2)6–
Et, Me
Me, (CH2)4CH3
–(CH2)4–
–(CH2)4–
Me, Me
H
H
H
H
[a] Reaction conditions:
4 (5 mol%), 1a (0.2 mmol), indole 2a
(0.24 mmol), toluene (1.5 mL), at room temperature (15–208C) for
24 h. [b] Yield of the isolated product. [c] Determined by HPLC analysis
using a chiral stationary phase. [d] Reaction time was 36 h. [e] 10 mol%
of 4h was used and the reaction time was 36 h. Bn=benzyl.
H
5-Me
5-Cl
5-Cl
[a] Reaction conditions:
1
(0.2 mmol), indole
2
(0.24 mmol), 4h
at the 3- and 3’-positions, being the most active and
enantioselective (Table 1, entry 7). A screen of the solvents
revealed that the reaction proceeded with significantly higher
yields and stereoselectivities in aprotic solvents (toluene,
Et2O, and THF) than protic solvents, which could form
hydrogen bonds with either the catalyst or the substrates.
Toluene was the best choice of solvent amongst the solvents
examined (Table 1, entries 7–11; see the Supporting Informa-
tion for details), and up to 85% yield and 87% ee of product
3a could be obtained when the reaction time was prolonged
to 36 hours (Table 1, entry 12). We realized that a more rigid
or tighter ion pair might increase the enantioselectivity. Thus,
the Brønsted acid 4g, which contains the larger sulfur atom in
the corresponding conjugate base and therefore would lead to
a more rigid ion pair, was employed in this reaction. For this
reaction an excellent enantioselectivity of up to 90% ee was
obtained,[11] albeit with a relatively lower yield (Table 1,
entry 13).
With the optimized reaction conditions in hand, the
reactions of a variety of indoles were carried out using either
catalyst 4g or 4h (Table 2). For indoles 2a–2h, both 4g and 4h
were used (Table 2, entries 1-8), whereas only 4h was used for
the C2-substituted, C3-substituted, and C2,C3-disubstituted
indoles 2i–2t (Table 2, entries 9–20). The reactions of 2a–2g
revealed that a change in the substitution pattern on the
benzene ring of the indole core had no pronounced effect on
the yield and enantioselectivity. The yields for the reactions of
2a–2g were generally higher when 4g was used as a catalyst,
but the enantioselectivities were relatively lower than those
obtained with 4h (Table 2, entries 1–7). The substituents at
the C2- and C3-positions of the indole had a great influence
on the reactivity when 4h was used. For example, the
introduction of a substituent at the C2-position of the indole
core gave the corresponding N-alkylation products with
(10 mol%), toluene (1.5 mL), at room temperature for 36 h. [b] Yield
of the isolated product. The data in parentheses was obtained using 4g
(5 mol%) instead of 4h as the catalyst. [c] Determined by HPLC analysis
using a chiral stationary phase.
higher enantioselectivities but lower yields (Table 2, entries 8
and 9 versus entry 1. In contrast, for indole substrate 2j, which
has a substituent at the C3-position, the use of 4h as a catalyst
led to the formation of product 3j in 95% yield with moderate
enantioselectivity (Table 2, entry 10 versus 8). Gratifyingly,
the 2,3-disubstituted indoles 2k–2t proved to be suitable
substrates for the present reaction and the desired products
3k–3t were afforded in 90–98% yields and 86-95% ee
(Table 2, entries 11–20). Remarkably, a range of 2,3-fused
indoles, with a variety of ring sizes, could be tolerated to give
the corresponding adducts without affecting the yields and
ee values (Table 2, entries 12–15, 18, and 19). In further
experiments, the amide protection group of 1 was varied and
the results revealed that only the C3-alkylation product was
obtained with low ee values when the phenyl or Boc was used
as a protection group instead of benzyl.[12] The reason for this
result is not clear at the present stage. The absolute config-
uration of the N-alkylation product 3 f was determined to be S
by single-crystal X-ray analysis (Figure 1).[13] The absolute
configurations of other products obtained by this method
were tentatively assigned by analogy.
The N-alkylation product 3m could be converted into
pyrrolidinone 5 by the cleavage of the benzyl group upon
exposure to Na/NH3 in THF (85% yield; Scheme 2). Protec-
tion and then reduction of the amide moiety in 5 afforded
pyrrolidine 6 in 45% yield over two steps. In addition, the
functionalized indole structure 3 could be used as the starting
material for the efficient construction of some N-fused ring
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Figure 1. X-ray structure of the enantiomerically pure 3 f (left) and 8
(right). Thermal ellipsoids are set at 30% probability.
systems. The brominated compound 7 was readily prepared
by the treatment of 3j with NBS. The subsequent palladium-
catalyzed intramolecular C-H functionalization of 7 afforded
the desired structurally N-fused polycyclic compound 8,
which could potentially find valuable applications in medic-
inal chemistry.[14] The structure of 8 was also confirmed
unambiguously by single-crystal X-ray analysis.[13]
The nonlinear effect studies of the current reaction rule
out the possibility that two or more molecules of the catalyst
Scheme 3. Deuterium-labeling experiments.
yield upon isolation (Scheme 3b). In contrast, when the
undeuterated 4g and deuterated indole [D1]-2j were used
under identical reaction conditions, the corresponding
adduct was obtained in 87% yield almost without any
deuterium incorporation (Scheme 3c). This result clearly
shows that the Brønsted acid acts as a proton source to
react with the a,b-unsaturated g-lactam 1a for the gener-
ation of the N-acyliminium ion, and the ion-formation step
is prior to the indole alkylation step. Furthermore, when
this reaction was conducted in one pot with [D1]-2j, 1a, and
a stoichiometric amount of [D1]-4g as the reactants, we
observed that only the 3- and 4-positions of the pyrrolidi-
none ring were extensively deuterated in the desired
product 3j, as shown in Scheme 3d. This lack of deuterium
scrambling in the 5 position suggests that the indole
alkylation step may not be the turnover-limiting step in
our catalytic system.
Scheme 2. Transformations of the N functionalized products. Boc=tert-
butyloxycarbonyl, DMA=dimethylacetamide, DMAP=4-dimethylamino-
pyridine, NBS=N-bromosuccinimide, Piv=trimethylacetyl, THF=tetrahy-
drofuran.
are involved in the transition state of the present catalytic
system (see the Supporting Information). Bocchi et al. have
proposed a mechanism for the formation of an N-acyliminium
ion from an a,b-unsaturated g-lactam under acidic reaction
conditions.[9c] To rationalize the reaction pathway and eluci-
date the effect of the Brønsted acid we carried out labeling
experiments. As depicted in Scheme 3a, after treatment of 1
Further insights into the mechanism were obtained from
in situ FTIR experiments. The stoichiometric reaction of
phosphoric acid 4g with 1a was monitored by using in situ
FTIR to detect the formation of the ion pair A. We were
delighted to observe that the kinetic profiles clearly revealed
the consumption of 1a and the formation of a new species.
The specific IR spectra of the newly formed species revealed
that the enol-type N-acyliminium ion B (Figure 2) was most
likely involved in the contact ion pair (see the Supporting
Information for details). Moreover, the results of HRMS
(ESI) analysis also supported the formation of the contact ion
pair A.[16]
On the basis of the above results, a plausible working
model for the present reaction is proposed in Figure 2. The
free hydroxy group in the enol-type cyclic N-acyliminium ion
B captures the conjugate Brønsted base of the phosphoric
acid 4g in the contact ion pair, presumably by intermolecular
hydrogen bonding. Assisted by the conjugate base, the acidic
1
with DCO2D at room temperature the H NMR analysis of
the recovered starting material revealed extensive deuterium
incorporation at the 3-, 4-, and 5-positions of lactam 1a. This
H/D scrambling suggests that the protonation of the lactam in
the formation of the N-acyliminium ion is reversible. Further
experiments were carried out with deuterium-labeled phos-
phoric acid [D1]-4g and indole [D1]-2j, respectively. After
treatment of 1a with 1.0 equivalent of deuterated Brønsted
acid [D1]-4g at room temperature for 2.5 hours, the resulting
intermediate reacted with the 3-methylindole 2j, to afford the
corresponding product 3j with H/D scrambling[15] in 90%
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À
N H group of the indole 2a is prone to nucleophilic addition
to the cyclic N-acyliminium ion. As shown in Figure 2, the
chiral environment created by the 1,1’-binaphthyl backbone,
and the congested 3- and 3’-substitutents of the catalyst 4g[13]
cause the indole to approach from the Re face of the N-
acyliminium ion B to stereoselectively furnish the corre-
sponding S-configured product.
In summary, we have developed a novel and efficient
Brønsted acid catalyzed intermolecular enantioselective
N alkylation of indoles with a,b-unsaturated g-lactams as
electrophiles, thus providing a highly enantioselective method
for the synthesis of chiral pyrrolidinones containing indole
moieties from simple starting materials. The approach opens a
new application of chiral Brønsted acids toward enantiose-
lective N functionalization of indoles. Further studies to
extend the reaction scope are in progress.
Received: March 23, 2011
Published online: May 17, 2011
Keywords: asymmetric catalysis · Brønsted acids · indoles ·
.
N-acyliminium ions · N functionalization
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[15] The full assignment of the proton signals of 3j was obtained by
2D NMR techniques, see the Supporting Information for details.
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