Rhodium-Catalyzed Chemodivergent Regio- and Enantioselective Allylic Alkylation of Indoles

Article abstract of DOI:10.1002/chem.202004613

The control of C3/N1 chemoselectivity in indole alkylation with the same electrophiles is still challenging. An Rh/bisoxazolinephosphane-catalyzed chemodivergent regio- and enantioselective allylic alkylation of indoles was developed. Chiral C3- and N1-al

Full text of DOI:10.1002/chem.202004613

Accepted Article
Accepted Article
Title: Rhodium-Catalyzed Chemodivergent Regio- and
Enantioselective Allylic Alkylation of Indoles
Authors: Minghe Sun, Min Liu, and Changkun Li
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Rhodium-Catalyzed Chemodivergent Regio- and Enantioselective
Allylic Alkylation of Indoles
[
a]
[a]
[a]
Minghe Sun, Min Liu, and Changkun Li*
[
a]
Mr. M. Sun, Miss M. Liu, Prof. Dr. C. Li
Shanghai Key Laboratory for Molecular Engineering of Chiral, School of Chemistry and Chemical Engineering.
Shanghai Jiao Tong University
800 Dongchuan Road, Shanghai 200240, China
E-mail: chkli@sjtu.edu.cn
Supporting information for this article is given via a link at the end of the document.
benzoate catalyst in the presence of base (Scheme 1, b, right).[13]
No catalyst could realize the chemo-switchable asymmetric C3
and N1 allylation process due to the innate nature of the -allyl-
metal intermediates.[
Abstract: The control of C3/N1 chemo-selectivity with the same
electrophiles is still challenging in the indole alkylation.
A
Rh/bisoxazolinephosphine-catalyzed chemodivergent regio- and
enantioselective allylic alkylation of indoles has been developed.
Chiral C3- and N1-allylindoles can be selectively obtained in high
branch/linear ratio and up to 99% ee by changing the counter anions
of Rh, allylic carbonates, reaction temperatures and ligands.
14]
Our group developed the new catalyst system based on
Rh(I)/bisoxazolinephosphine to solve the regio- and
enantioselective allylation from aliphatic allylic substrates with
[
15,
different nitrogen, carbon, oxygen and sulfur pronucleophiles.
1
6]
The easy modification of the counter anions and ligands as well
as the broad reaction temperature range and the utilization of
released base enables the flexible adjudgment of the
electrophilicity of the -allylrhodium intermediate. In this study,
Introduction
Indole skeleton is one of the privileged heterocycles and exists
in many natural products and synthetic biologically active
molecules.[1] The direct functionalization of indoles provides an
efficient way to prepare valuable chiral indole derivatives.
Because of the innate high nucleophilicity of the C3 position of
unsubstituted indoles, enormous methods have been developed
for the C3 alkylation, such as the asymmetric Friedel-Crafts type
reactions with highly reactive electrophiles.[2] Nevertheless, the
asymmetric N1-functionalization for the C3-unsubstituted indoles
is much more challenging.[3] Careful selection of base, counter
cation, solvent, temperature and additive is usually necessary to
selectively get the N1-allylation products. Moreover, less
activated electrophiles are normally used to avoid the C3
functionalization (Scheme 1, a). The predictable and chemo-
switchable asymmetric C3/N1 alkylation of unsubstituted indoles
with the same alkylation reagent is still very challenging and highly
desirable.
Transition-metal-catalyzed asymmetric allylation[4] of indoles
provides a powerful method to synthesize chiral C3 and N1-allyl
indoles. Despite many reports on the chiral C3-allylindole
synthesis,[5,6] highly branch- and enantioselective allylation of
indoles from monosubstituted allylic precursors could be achieved
by You and coworkers with iridium and -acidic phosphoramidite
ligands,[
7a,b,c]
in which highly reactive Ir(III)/-allyl intermediates
are involved (Scheme 1, b, left). Shen and Dong reported an
asymmetric allylation of indoles with alkynes in the presence of
chiral Rh complex.[7d] On the other hand, the asymmetric N1-
allylation of indoles was successfully developed from either
special indoles with electron-withdrawing groups[8] and C3-
substitutents[9] or oxygen-substituted allylic precursors.[10] Indirect
synthesis of chiral N-allylindoles from indolines, anilines and
arylhydrazines is another solution.[11] Directly from unbiased
indoles, the regio- and enantioselective N1[12]-allylic alkylation has
only been realized recently by Krische group with less
electrophilic neutral tol-BINAP-modified π-allyliridium-C, O-
Scheme 1. Transition-metal-catalyzed enantioselective C3- and N1-allylation of
unsubstituted indoles.
1
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we present the chemo-switchable regio- and enantioselective
allylic alkylation of unbiased indoles. C3-allylindoles could be
obtained exclusively from allyl methyl carbonates in above 20 : 1
could be obtained in 88% yield and 95% ee (entry 5). The
substituents on the ligands have a significant effect on the
selectivities of the products. 3aa was isolated as the main product
when L2 with phenyl as the R groups on the oxazoline rings was
used under otherwise the same condition (entry 6). L3 with
2
branch/linear ratio and up to 99% ee with Rh(cod)
as catalyst at 80 C. While, N1-allyl indoles were prepared from
2
BF
4
and NPNPh,
Ph
o
3 6 4
electron-withdrawing 4-CF C H group lead to lower ratio of the
allyl t-butyl carbonates in normally the same level of regio- and
N1-allylation product 4aa, while the highest 90% yield and 99%
DTBM, i-Pr
at 100 o
enantioselectivity with [Rh(cod)Cl]
Scheme 1, c).
2
and NPN
C
ee were obtained when L4 with 4-MeO-3,5-dit-BuC
group at R position was applied (entries 7 and 8).
6
H
2
(DTBM)
1
(
With the optimized conditions in hand, we firstly investigated
the scope of indoles and allylic methyl carbonates for C3-allylation
Results and Discussion
(
Table 2). Indoles with a halogen substituent at the 5-position
react smoothly to give the C3-allylation products 3ba to 3ea in
high yields and ees. Electron-neutral methyl, phenyl, vinyl and
phenylacetylide groups have neglectable effect on the results of
the reactions (3fa to 3ia). Moderately electron-deficient ester and
aldehyde groups can slow down the C3-allylation reactions (3ja
and 3ka), while only N1-allylation products could be observed
when indoles 1l and 1m with strong electron-withdrawing CN and
nitro groups were used. The absolute configuration of 3ja was
assigned to be R by single crystal X-ray diffraction analysis.[
Electron-donating methoxy group at 5-position also make the
reaction be sluggish, probably due to the lower acidity of the N-H
proton (3na). In addition, electron-withdrawing chloride and
electron-donating MeO groups at 4, 6, and 7 positions of the
indole skeletion have little infleunce on the yields and
enantioselectivities (3oa to 3ta). Under the standard reaction
conditions, indoles with methyl and phenyl groups at the
The research started with allylic methyl carbonate 1a bearing
simple alkyl group and unsubstituted indole 2a as model
substrates (Table 1). Using Rh(cod)
2
BF
4
and NPN-type ligand L1
o
as the catalyst in CH
3
CN at 80 C, C3-allylation product 3aa could
be obtained in 60% yield, above 20 : 1 branch/linear ratio and 98%
ee as the only product (entry 1). The yield could be further
improved to 93% when L2 was applied as the ligand (entry 2). To
2 2 4
our surprise, when [Rh(cod)Cl] was used instead of Rh(cod) BF ,
N1-allylation product 4aa was isolated in 41% yield and 97% ee
as the main product, along with 15% of 3aa (entry 3). This result
inspires us to explore whether the N1-allylation product can be
obtained solely by adjusting the reaction conditions, which is still
a big challenge in the direct functionalization of indoles. The yield
17]
o
of 4aa increased to 51% by carrying out the reaction at 100 C
(
entry 4). When the methyl group in the allyl carbonate 2a was
replaced by t-Bu group, 4aa
[a]
Table 1. Optimization of reaction conditions.
Table 2. Scope of Rh-catalyzed Regio- and Enantioselective C3-Allylation of
Indoles[a]
entry
R
Rh salts
L*
3aa (%)[b]
4aa (%)[b]
1
2
Me
Me
Rh(cod)
2
BF
4
4
2
2
2
2
2
2
L1
L2
L1
L1
L1
L2
L3
L4
60(98)
93(98)
15(98)
15(98)
8(98)
0
Rh(cod)
2
BF
0
3
Me
[Rh(cod)Cl]
[Rh(cod)Cl]
[Rh(cod)Cl]
[Rh(cod)Cl]
[Rh(cod)Cl]
[Rh(cod)Cl]
41(97)
51(95)
88(95)
24(92)
66(93)
90(99)
4
Me
5[c,d]
6[c,d]
7[c,d]
8[c,d]
t-Bu
t-Bu
t-Bu
t-Bu
65(93)
11(99)
6(99)
[
a] All reactions were run with 5 mol% rhodium and 5 mol% ligand on a 0.2 mmol
scale in 1 ml CH CN unless otherwise noted. [b] Yield of isolated product and
3
the numbers in the parentheses were the ee values. [c] The reaction was carried
out at 100 C. [d] 36 hours.
o
3
[a] Conditions: 0.2 mmol 1 and 0.3 mmol 2 in 1 ml CH CN were used as the
standard condition.
2
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2
- position can also be tolerated in the C3-allylation reaction (3ua
enantioselectivities of the products with chlorides and MeO
groups at 4- or 6-positions of the indole phenyl ring are also
excellent (4oa to 4ra). Relatively lower branch/linear ratios were
observed when 7-Chloro and MeO indoles were used, probably
due to the bulky environment at the nitrogen atoms. The reactions
of 2-methyl or 2-phenylindoles are slower under standard reaction
condition (4ua and 4va). A series of 3-substituted indoles can also
undergo the N1-allylation reaction (4wa and 4xa). Protected
tryptophan could be N1-allylated diastereoselectively, with the
Boc-protected amine untouched (4ya). The N1-allylated indole
4za with both 2 and 3 positions blocked can be isolated in 71%
yield and >99% ee. Allylic carbonates with simple methyl and
phenylethyl groups react under the standard condition to give 4ab
and 4ac in high yields and ees. Sterically more hindered isobutyl,
isopropyl, and cyclohexyl groups could be introduced by the allylic
amination to give corresponding N1-allylic indoles in high yields
with excellent enantioselectivities (4ae, 4af and 4ag). It is worth
noting that 51% of ring opening product 4ah' of the cyclopropyl
group by oxidative addition with Rh(I) was observed when allyl
carbonate with a cyclopropyl group was used, along with 41%
regular product 4ah. In addition, phenyl substituted allyl indole 4ai
can also be obtained in 75% yield and 98% ee under standard
condition. The absolute configuration of 4ab to 4ag was assigned
to be R by comparison of their optical rotation to literature reported
values.[12]
and 3va). On the other side, we also investigated the scope of
allyl carbonates. Allylic methyl carbonates with simple methyl,
phenylethyl and TBS-protected hydroxyl group react effciently
with 1a to give 3ab to 3ad in high yields and ees. Sterically more
hindered isobutyl, isopropyl, cyclohexyl and cyclopropyl groups
could be introduced by the allylic substitution to give
corresponding allylic indoles 3ae to 3ah. Phenyl-substituted allylic
carbonate can also react to produce the target product in high
yield, although a slightly reduced 88% ee was obtained (3ai). No
dearomative C3-allylation products were obtained when 3-
methylindole was used.
The reaction scope of N1-allylation was evaluated with the
same indoles and allylic t-butyl carbonates (Table 3). Similar to
the C3-allylation reactions, various indoles with halogens (1b to
1
e), and electron-neutral groups (1f to 1i) react in the presence of
o
[
Rh(cod)Cl]
2
/L4 at 100 C to give the N1-allylation products in high
yields and enantioselectivities. Strong electron-withdrawing ester,
aldehyde, cyano and nitro groups at 5-position can also be
tolerated in 4ja to 4ma. Relatively lower 58% yield of 4na was
obtained when indole 1n with electron-donating MeO group at 5-
position was used. It is gratifying that the yields and
Table 3. Reaction scope of indoles and carbonates for N1-allylation[a]
To demonstrate the practicality of the Rh-catalyzed regio- and
enantioselective indole C3- and N1-allylation reactions, gram-
scale synthesis was conducted (Scheme 2). 8 mmol of 2-
methylindole 1u was converted to 1.86 g of C3-allyl indole 3ua
(
2
(
97% yield, 98% ee) with 12 mmol of allylic carbonate 1a under
.5 mol% catalyst (eq 1). Similarly, 1.59 g of N1-allyl indole 4ca
87% yield, 99% ee) can be prepared from 7 mmol of 5-
chloroindole 1c and 10.5 mmol of allylic carbonate 2a' under the
catalysis of 1.25 mol% of [Rh(cod)Cl] /L4.
2
Scheme 2. Gram-Scale Synthesis.
To understand the counter-anion-switched chemo-selectivity of
indole allylation, several control experiments were conducted.
When N-methylindole 5a was used as the substrate, no C3-
allylation product could be isolated under either the standard C3-
allylation or the N1-allylation condition (eq 3). This result suggests
the -allyl-Rh intermediate is not electrophilic enough for a
Friedel-Crafts type allylation with neutral indole. A deprotonation
of indole may occur in the C3-allylation process. N-deuterated
indole 1a-D was utilized to investigated the mechanism. We found
the deprotonation step can switch the C3/N1 chemoselectivity (eq
[
a] Conditions: 0.2 mmol 1 and 0.3 mmol 2 in 1 ml of CH
3
CN were used as the
4
). 4aa was the major product from normal indole 1a (entry 3,
standard condition. [b] B : L = 10 : 1. [c] B : L = 16 : 1.
3
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Table 1). However, when 1a-D was used, the C3-allylation 3aa
became the main product, which indicates that N1-allylation is
less favored when the deprotonation becomes difficult. The ratio
of 4aa increased when the reaction was conducted at 100 C, at
which the deprotonation is more effective.
be explained by the less efficient deprotonation at lower
temperature during the temperature raising time (eq 6).
Kinetic study for both C3- and N1-allylations was performed
o
(
See the supporting information). The initiate reaction rate of C3-
allylation is zero-order to the allylic carbonate and first order to the
indole and the catalyst. The formation of -allylic-Rh intermediate
is a fast step. While, The initiate reaction rate of N1-allylation is
zero-order to both the allylic carbonate and indole. The C-N bond
formation process is is very likely to be the rate determining step.
Based on the experiments above and our previous study,[16a]
two catalytic cycles were proposed for C3 and N1 allylation
2 4
respectively in Scheme 3. When Rh(cod) BF /L2 is used as the
catalyst, fast oxidative addition of allyl methyl carbonate 2 with
cationic Rh(I) produces the 6-coordinate π-allyl/rhodium/NPN
complex intermediate B, in which methoxide anion is bound to
rhodium (Cycle 1). A concerted deprotonation of N-H by the
bounded MeO group and nucleophilic attack of C3 to the mono-
cationic B via TS-1 leads to the formation of C3-allylation product
A naked N-indole anion was proposed for the formation of N1-
allylation. This possible anion could be trapped as 7 when 1
equivalent of ethyl acrylate 6 was added (eq 5). The formation of
A and releases methanol.[
18]
3
and regenerates the Rh(NPN)BF
4
Alternatively, when [Rh(cod)Cl]
2
/L1 or L4 is utilized as catalyst,
oxidative addition with allyl t-butyl carbonate 2' generates the
mono-cationic π-allyl/rhodium intermediate D with a basic t-BuO
anion in the outer sphere. Fast deprotonation of indole by this t-
BuO anion results in the formation of another intermediate E as
an ionic pair, in which the N-indole anion is located out of the
coordination sphere of Rh, but not bound to Rh. The mono-
cationic -allyl-Rh complex acts as the countercation. Outer-
sphere nucleophilic attack of N-centered indole anion to the
carbon in π-allyl/rhodium complex produces the N1-allylation
product 4 and releases catalyst C (Cycle 2). However, when the
reaction was conducted at lower temperature or with weaker base,
the generation of E is challenging. Small amount of C3-allylation
product 3 could be formed via TS-2.
8
% 3aa under the optimized N1-allylation condition was observed
when the reaction was stopped after 20 minutes. This result could
Scheme 3. Mechanistic Proposal
about the chemoselective funcationalization of indoles. By
changing the catalyst precursors, allylic carbonates, reaction
temperatures and ligands, C3- or N1-allylindoles can be
selectively obtained in high branch/linear ratio and up to 99% ee.
Future work will explore the sophisticated control of various
challenging selectivities for other nucleophiles under the
Rh/bisoxazolinephosphine catalyst system.
Conclusion
We have developed a Rh(I)/bisoxazolinephosphine-catalyzed
chemodivergent regio- and enantioselective allylic alkylation of
unbiased indoles. The easy modification on the -allylrhodium
complex in this catalyst system enables the switchable reactivities
of the indole nucleophiles, which provides a better understanding
4
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Keywords: Allylic Substitutions • Rhodium • Indole • Asymmetric
Catalysis • Chemo-divergent
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15276−15281. c) M. Liu, H. Zhao, C. Li, Chin. Chem. Lett.
doi.org/10.1016/j.cclet.2020.04.009.
[
[
17] CCDC 2015163 (3ja) contains the supplementary crystallographic data
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Cambridge Crystallographic Data Centre.
18] For a proposed interaction between indole N-H and hydrogen bond
acceptor in the -allylmetal complex, see ref. 5h.
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Entry for the Table of Contents
Chemodivergent regio- and enantioselective allylic alkylation of indoles has been developed with rhodium/bisoxazolinephosphine.
C3- or N1 selectivity could be controlled by changing the counter anions of Rh, allylic carbonates, reaction temperatures and ligands.
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