Enantioselective oxidative cross-coupling reaction of 3indolylmethyl c-h bonds with 1, 3-dicarbonyls using a chiral lewis acid-bonded nucleophile to control stereochemistry

Article abstract of DOI:10.1002/anie.201002108

(Figure Presented) A highly enantioselective C-H-activationbased oxidative coupling reaction of 3arylmethylindole derivatives with dibenzyl malonate by using chiral Lewis acid bonded nucleophiles provided an approach to indole derivatives (see scheme; DDQ = 2, 3-dichloro-5, 6-dicyano1, 4-benzoquinone, OTf=trifluoromethanesulfonate).

Full text of DOI:10.1002/anie.201002108

Communications
DOI: 10.1002/anie.201002108
À
C H Activation
Enantioselective Oxidative Cross-Coupling Reaction of 3-
À
Indolylmethyl C H Bonds with 1,3-Dicarbonyls Using a Chiral Lewis
Acid-Bonded Nucleophile to Control Stereochemistry**
Chang Guo, Jin Song, Shi-Wei Luo, and Liu-Zhu Gong*
Dedicated to Professor You-Cheng Liu on the occasion of his 90th birthday
À
Cross-coupling reactions using C H activa-
tion have emerged as robust alternatives to
conventional transformations for the creation
[1]
À
of new C C bonds. The enantioselective
variants hold great potential in synthetic
application,[2] but continue to present formi-
dable challenges. These reactions may be
limited by the absence of binding sites in
hydrocarbon compounds that enable the for-
mation of a stereochemically defined transi-
tion state for achieving high enantioselectiv-
ity. Furthermore, there are few examples of
appropriate chiral ligands that tolerate the
highly oxidizing conditions that are com-
3
À
Scheme 1. General concept for the creation of sp C H bond-activation-based enantiose-
À
monly used for C H activation. In particular,
the sp3 C H-activation-based asymmetric
lective oxidative coupling.
À
À
C C bond-forming reaction has largely
relied on metal carbenoid insertion,[3]
although recent efforts have been directed toward enantio-
tetrahydroisoquinoline with malonate by using a chiral
palladium catalyst and DDQ as the oxidant, which provided
the desired compound in 86% ee.[7] Very recently, an organo-
catalytic asymmetric oxidative coupling of benzylic com-
pounds with aldehydes was established with up to 86% ee.[8]
However, to the best of our knowledge, no highly enantio-
selective analogues of the oxidative coupling of 3-indolyl-
3
À
selective cross-coupling reactions involving sp C H activa-
tion.[4]
1,3-Dicarbonyl compounds of type 1 are able to coordi-
nate to a variety of chiral Lewis acids to form chiral
nucleophiles (I) that have been employed in various trans-
formations with high levels of stereoselectivity.[5] Inspired by
these successes, we envisioned the control of the stereochem-
À
methyl C H bonds with malonates are available. Indole
À
istry in the C H-activation-based oxidative coupling reac-
derivatives have widespread applications in organic synthe-
sis;[9] therefore, the titled reaction holds great importance in
organic synthesis. Herein, we report the highly enantioselec-
tions (cross-dehydrogenative coupling)[6] of dicarbonyls with
arylmethyl compounds (2) by means of a similar chiral
nucleophile to induce the stereochemistry (Scheme 1).
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) has
been used in efficient oxidative coupling reactions involving
À
tive oxidative coupling of 3-indolylmethyl C H bonds with
3
À
malonates by sp C H-activation using a chiral Lewis acid
bonded nucleophile to control stereochemistry.
3
[6]
À
sp C H activation. Sodeoka and co-workers reported the
We initially focused on the DDQ-oxidized coupling
reaction of dimethyl malonate (1a) with 3-benzylindole
(2a) in the presence of 10 mol% of Cu(OTf)2 and 12 mol%
of a chiral bis(oxazoline) ligand 4a.[10] The reaction gave good
enantioselectivity but a very low yield (Table 1, entry 1). The
replacement of 4a with 4b provided a clean reaction to afford
the desired product 3a in 80% yield, albeit with 31% ee
(Table 1, entry 2). The stereoselectivity was further enhanced
by using 5a as the ligand (64% ee; Table 1, entry 3). However,
the substitution of metal triflates other than copper led to
less-satisfactory reactions (Table 1, entries 4 and 5). Dibenzyl
malonate showed comparably higher enantioselectivity than
other counterparts (Table 1, entries 3, 6–7). However, 5b and
5c gave even lower levels of stereoselectivity than 5a under
asymmetric oxidative coupling reaction of N-Boc-protected
[*] C. Guo, J. Song, S.-W. Luo, Prof. L.-Z. Gong
Hefei National Laboratory for Physical Sciences at the Microscale
and Department of Chemistry
University of Science and Technology of China
Hefei, 230026 (China)
Fax: (+86)551-360-6266
E-mail: gonglz@ustc.edu.cn
Homepage: http://staff.ustc.edu.cn/~gonglz/index.htm
[**] We are grateful for financial support from MOST (973 project
2009CB825300) and the Ministry of Education.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201002108.
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Chemie
Table 1: Seeking optimal chiral Lewis acids and optimization of reaction
Table 2: Investigating the scope of the procedure.[a]
conditions.[a]
Entry
R, Ar, Ar’ (3)
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
H, 4-BrC6H4, Ph (3d)
H, 4-ClC6H4, Ph (3e)
H, 4-FC6H4, Ph (3 f)
H, 4-MeOC6H4, Ph (3g)
H, 4-MeC6H4, Ph (3h)
H, 4-NO2C6H4, Ph (3i)
H,4-CNC6H4,Ph(3j)
H, 3-BrC6H4, Ph (3k)
H, 3-MeC6H4, Ph (3l)
H, 3-MeOC6H4, Ph (3m)
97
82
99
74
97
98
81
72
96
97
93
Entry R(1)
Metal
L* Solvent t [h]
3
Yield
[%][b]
ee
91
[%][c]
90[d]
86
1
Me(1a) Cu(OTf)2 4a CH2Cl2 18 3a
6
85
31
64
44
60
63
75
59
2
3
Me(1a) Cu(OTf)2 4b CH2Cl2
Me(1a) Cu(OTf)2 5a CH2Cl2
5
6
3a
3a
80
84
34
56
81
90
90
86
95
73
41
99
91
90[e]
90[e,f]
93
4
5
6
7
Me(1a) Mg(OTf)2 5a CH2Cl2 17 3a
Me(1a) Zn(OTf)2 5a CH2Cl2 22 3a
Et (1b) Cu(OTf)2 5a CH2Cl2 15 3b
Bn(1c) Cu(OTf)2 5a CH2Cl2 16 3c
94
94
8
9
Bn(1c) Cu(OTf)2 5b CH2Cl2
Bn(1c) Cu(OTf)2 5c CH2Cl2
5
5
3c
3c
11
84
90
53
10
11
12
13
Bn(1c) Cu(OTf)2 5a CH2Cl2 13 3c
Bn(1c) Cu(OTf)2 5a CHCl3 15 3c
Bn(1c) Cu(OTf)2 5a PhCH3 16 3c
80[d]
90[d]
94[d]
94[d]
12
13
14
15
16
17
18
H, Ph, 4-FC6H4 (3o)
99
99
92
88
70
88
78
93
92
94
92
94
95
96
H, Ph, 4-ClC6H4 (3p)
H, 4-BrC6H4, 4-FC6H4 (3q)
H, 4-BrC6H4, 4-ClC6H4 (3r)
H, Ph, 4-MeC6H4 (3s)
5-Cl, Ph, Ph (3t)
[e]
Bn(1c) Cu(OTf)2 5a
–
21 3c
[a] The reaction of 1 (0.1 mmol) with 2a (0.1 mmol) was conducted at
258C. [b] Yield of isolated product. [c] Determined by HPLC. [d] At 08C.
[e] Using CHCl3/PhCH3 =1:15 as solvent.
5-Cl, 4-BrC6H4, Ph (3u)
[a] Unless indicated otherwise, the reaction was performed on a
0.1 mmol scale. [b] Yield of isolated product. [c] Determined by HPLC
(see Supporting Information). [d] At À108C. [e] The reaction was
performed on a 0.2 mmol scale. [f] At À58C.
these conditions (Table 1, entries 8 and 9). Optimization of
reaction parameters, including solvent and reaction temper-
ature, revealed that halogenated solvents provided higher
yields than toluene, whereas the use of nonpolar solvent and
conducting the reaction at 08C gave higher levels of
stereoselectivity (Table 1, entries 10–12). The best outcomes
of conversion and enantioselectivity were achieved when the
reaction was performed at 08C in a chloroform/toluene
solvent mixture (1:15; Table 1, entry 13).
A variety of structurally diverse 3-arylmethylindole deriv-
atives were able to participate in the asymmetric oxidative
cross-coupling reaction (Table 2). This procedure was effec-
tive and highly enantioselective for either electronically rich
or poor 3-arylmethyl substituted substrates (up to 99% yield
and 94% ee; Table 2, entries 1–11). The electronic properties
of the aryl substituent imposed no apparent influences on the
stereoselectivity (86–94% ee), but had a great effect on the
reaction conversion. Notably, variation of the 2-aryl substitu-
ent still provided a good reaction and excellent enantiomeric
purity (Table 2, entries 12–16). The introduction of substitu-
ents onto the indole moiety was well-tolerated and resulted in
excellent levels of enantioselectivity (95% and 96% ee,
respectively; Table 2, entries 17 and 18). The configuration of
3t was assigned as R by X-ray analysis (see the Supporting
Information).
Besides malonates, 1,3-diketones were also tolerated
under the reaction conditions. For example, acetyl acetone
(1d) and propionyl butanone (1e) both underwent oxidative
coupling reactions with 2a in good yields and high enantio-
selectivity [70% and 83% ee, respectively; Eq. (1)]. How-
ever, benzylic compounds, other than 3-indolylmethyl, failed
to undergo the reaction. Despite this setback, the synthetic
importance of indole derivatives gives this reaction great
potential in asymmetric organic synthesis.
Oxindoles bearing a quaternary stereogenic center at the
3-position have great importance as building blocks in the
synthesis of alkaloids.[11] The products obtained from this
asymmetric cross-dehydrogenative coupling can be readily
transformed into oxindoles (Scheme 2). Removal of the
benzyl group on 3c (94% ee) by hydrogenation on Pd/C
and followed by decarboxylation with copper(I) oxide
produced 6 in 74% yield.[12] Methylation of 6 furnished 7 in
79% yield. Following a known procedure,[13] compound 7 was
converted into oxindole 9,[14] which contained an all-carbon
quaternary stereogenic center, in 72% overall yield whilst
retaining the 94% ee. The configuration of 9 was determined
by X-ray analysis after it was transformed into N-benzylic
derivative 10. Notably, Michael addition of 3-aryl oxindoles to
cinnamates to giving highly enantioenriched oxindole 9 has
not been reported.
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Scheme 2. Synthetic utility of the procedure and determination of
stereochemistry. Reagents and conditions: a) Pd/C, H2, MeOH, 258C,
then Cu2O, CH3CN, 658C, 74% yield. b) SOCl2, CH3OH, 0–258C, 79%,
94% ee. c) Oxone, NaHCO3, acetone/H2O, 08C, 92%. d) Sc(OTf)3,
toluene, 1108C, 81%, 94% ee. e) KOtBu, BnBr, THF, 238C, 75%.
THF=tetrahydrofuran.
Scheme 4. Plausible pathway to generate the cation intermediate, and
DFT calculation of its electron distribution.
2,3,4,4a,9,9a-Hexahydro-1H-pyrido[2,3-b]indoles
have
found widespread appearance in natural products.[15] This
skeleton can be enantioselectively accessed using the reaction
reported here. For example, the N-methylation of 9 with
iodomethane in the presence of sodium hydride, followed by
an amidation with methylamine readily produced 11. The
reductive cyclization of 11 with lithuium aluminum hydride
furnished 12 in 75% yield (Scheme 3).
intermediate that participates in the reaction, which indicated
that the positive charge delocalizes and distributes over the
conjugate system, and thus the vinylogous iminium cation is
more likely to be involved in the reaction.
Presumably, the vinylogous iminium cation would
undergo depronation with IV to form a copper complex VI,
which might be attacked by dicarbonyl compounds to give the
final chiral product. However, the DFT calculation of binding
energies of VII with HOTf and of that with Cu(OTf)2 (Va
versus VI’) revealed that the vinylogous iminium cation Va is
easier to form (Scheme 5), and thus Va rather than VI is a
possible reaction intermediate.
On the basis of the experimental and theoretical studies,
the reaction pathway to generate chiral products has been
proposed (Scheme 6). After the copper-catalyzed dehydro-
genation of 3-arylmethylindole to give Va, the resultant
copper phenoxide (IV) serves as a base to deprotonate the
dibenzyl malonate, generating a chiral anion intermediate
VIII, which enantioselectively attacks the vinylogous iminium
cation Va generated from the dehydrogenation to undergo a
conjugate addition, giving the chiral product. Although
chiral-copper-complex-catalyzed Michael addition reactions
are well-established,[5,10,20] the analogous procedure involving
vinylogous iminium cations has not yet been reported.
The observed stereochemistry can be best explained by
the proposed reaction models shown in Figure 1. Because of
the steric repulsion between the Ar group and phenyl ring of
the chiral catalyst, the transition state IXa is more favorably
formed than IXb to preferentially give the desired product
with observed stereochemistry (Figure 1).
Scheme 3. Synthesis of 2,3,4,4a,9,9a-hexahydro-1H-pyrido[2,3-b]indole.
Reagents and conditions: a) NaH, THF, MeI, RT, 81% yield.
b) MeNH2 (30% in MeOH), MeOH, RT, 78% yield. c) LiAlH4, THF,
08C to RT, 75% yield.
To identify the reaction intermediate, we performed ESR
studies while monitoring the reaction. The solution of DDQ
in toluene exhibited a weak ESR signal whereas the addition
of 3-benzylic indole, dibenzyl malonate, and the copper
complex to the solution of DDQ did not show any ESR signal
(see the Supporting Information, Figures S1 and S2), thus
indicating that a cationic rather than radical species was
generated to serve as the key intermediate of the coupling
reaction.[16–18] The presence of a Lewis acid actually enhances
the oxidizing ability,[19] therefore the chiral copper complex
enhances the oxidizing ability by coordinating to the oxygen
of DDQ to facilitate the dehydrogenation of 3-arylmethyl-
indole (Scheme 4). Principally, the resultant cation exists as
either a vinylogous iminium cation (Va) or a carbon cation
(Vb). We then used DFT calculations to address the possible
In conclusion, we have reported the highly enantioselec-
À
tive C H-activation-based oxidative coupling reaction of
3-arylmethylindoles with dibenzyl malonate using chiral
Lewis acid catalysts. Presumably, the reaction proceeded by
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the vinylogous iminium cations. In addition, the protocol also
3
À
represents a unique sp C H-activation-based approach to
access oxindole derivatives bearing quaternary stereogenic
centers with high optical purity.
Received: April 9, 2010
Published online: June 29, 2010
Keywords: asymmetric catalysis · bis(oxazoline) ligands ·
.
À
C H activation · cross-coupling · Lewis acids
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