Diastereoselective synthesis of C3-quaternary indolenines using α,β-unsaturated N-aryl ketonitrones and activated alkynes

Article abstract of DOI:10.1002/anie.201200860

New trick for an old dog: C3-Quaternary indolenines were synthesized by combining readily available α,β-unsaturated N-aryl ketonitrones and activated alkynes. This remarkably simple and atom-economical transformation does not require transition-metal cata

Full text of DOI:10.1002/anie.201200860

Angewandte
Chemie
DOI: 10.1002/anie.201200860
Synthetic Methods
Diastereoselective Synthesis of C3-Quaternary Indolenines Using
a,b-Unsaturated N-Aryl Ketonitrones and Activated Alkynes**
C. Bryan Huehls, Tyler S. Hood, and Jiong Yang*
Indole-containing structures are ubiquitous in natural prod-
ucts, medicinal compounds, and organic materials.[1] Given
their biomedical importance, synthetic methods towards
these structural motifs remain relevant even after decades
of innovations.[2] However, despite all the efforts toward the
efficient construction of C3-quaternary indole derivatives,
significant challenges remain.[3] These challenges are found in
the forms of spirooxindole, pyrroloindoline, furoindoline, and
other indole-containing polycycles, which exist in a large
number of alkaloids, such as physovenine,[4] physostigmine,[5]
minfiensine,[6] citrinadin B,[7] communesin B,[8] aspidophyll-
ine A,[9] and mitraphylline[10]. (Scheme 1). Many of the
allows rapid and stereoselective synthesis of these structural
motifs from simple starting materials would be of tremendous
value and provide entry to the structurally diverse family of
indole alkaloids. Herein, we report a remarkably simple and
efficient approach that consists of combining a,b-unsaturated
N-aryl ketonitrones and activated alkynes to form C3-
quaternary indolenines with formation of the heterocycles
and two contiguous quaternary and tertiary chiral centers
from readily available starting materials (Scheme 2).
Scheme 2. Reaction of a,b-unsaturated N-aryl ketonitrones and acti-
vated alkynes.
Our preliminary investigation of the reaction of a,b-
unsaturated N-phenyl ketonitrone 1a, which was readily
prepared from tert-butyl pent-2-enoate by a two-step route
that we have previously described,[16] and diethyl acetylene-
dicarboxylate in methylene chloride showed that they readily
combined to give C3-quaternary indolenine 2a (Table 1,
entry 1; and X-ray structure of Figure 1). In addition to the
formation of a 3H-indole heterocycle, this drastic trans-
formation also led to diastereoselective formation of two
contiguous quaternary and tertiary chiral centers.
The potential of such a transformation as a general entry
to C3-quaternary indolenines prompted us to examine
various reaction parameters in an attempt to improve its
efficiency (Table 1). The reaction was found to give better
yields in nonpolar solvents (CH2Cl2 or toluene; Table 1,
entries 1–6). The addition of both Brønsted and Lewis acids
decreased the reaction efficiency or stopped the reaction
completely (Table 1, entries 7–14). Elevated temperature (40
to 808C) not only accelerated the reaction, but led to
Scheme 1. Some indole alkaloids.
existing methods form the C3 quaternary center by alkyla-
tion,[11] cycloaddition,[12] and rearrangement of 3-substituted
indoles or oxindoles.[13,14] These methods are limited by the
availability or the ease of preparation of the indole and
oxindole starting materials, especially those that have sub-
stituents on the indole benzenoid ring. Indeed, whereas
methods have been developed for syntheses of C2- and C3-
substituted indoles, the selective functionalization of the
indole benzenoid ring remains problematic.[15] A method that
[*] C. B. Huehls, T. S. Hood, Prof. Dr. J. Yang
Department of Chemistry, Texas A&M University
College Station, TX 77843-3255 (USA)
E-mail: yang@mail.chem.tamu.edu
Homepage: http://www.chem.tamu.edu/rgroup/yang
[**] We thank Dr. Joseph H. Reibenspies of the X-ray Diffraction
Laboratory in the Department of Chemistry at Texas A&M
University for X-ray crystallography analysis, Dr. Peddabuddi Gopal
of the same department for some preliminary studies, and
Professors Kevin Burgess and Daniel Singleton of the same
department for helpful discussions. Financial support was provided
by Texas A&M University and the Welch Foundation (A-1700).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201200860.
Figure 1. X-ray based ORTEP drawings of 2a (O red, N blue). Spheres
are drawn at the 50% probability level.[25]
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Table 1: Optimization of conditions for formation of 2a.[a]
Entry
Solvent
Additive[b]
T [8C]
2a[c]
1
2
3
4
5
6
CH2Cl2
THF
ether
–
–
–
–
–
–
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
40
64
48
21
trace
trace
68
7
45
DMF
iPrOH
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
7[d]
8[d,e]
9
10
11
12
13
14
15
16
HOAc
HOAc/H2O
TFA
TfOH
ZnCl2
SnCl4
FeCl3
TiCl4
–
trace
15
trace
trace
trace
trace
73
Scheme 3. Reaction of 1 and activated alkynes. All reactions were
carried out using 1 equivalent of 1 and 3 equivalents of activated
alkynes at 808C in toluene until the reaction was complete by TLC
analysis (8–12 h). The yields are of the isolated products.
–
80
79
[a] All reactions were carried out using 1 equiv of 1a and 3 equiv of
diethyl acetylenedicarboxylate. [b] Unless noted otherwise, 1.2 equiv of
the additive was used. [c] Yield of the isolated product. [d] 0.2 equiv of
HOAc was used. [e] The reaction was carried out in a mixture of toluene/
H2O (10:1). DMF=N,N’-dimethylformamide, Tf=trifluoromethane-
sulfonyl, TFA=trifluoroacetic acid.
phenylacetylene, and diphenylacetylene; not shown) did not
participate in the reaction.
To further explore the generality of this method a series of
N-aryl ketonitrones without b substituents (3) were also
investigated (Scheme 4).[17] Good to moderate yields were
obtained for reactions of a,b-unsaturated N-tolyl ketoni-
trones with diethyl acetylenedicarboxylate: the 6-methyl
indolenine 4i was regioselectively generated from the N-
meta-tolyl ketonitrone and 5- and 7-methyl indolenines (4b
and 4g, respectively) were formed from the N-para-tolyl and
N-ortho-tolyl ketonitrones, respectively. a,b-Unsaturated
ketonitrones with 2’-bromo, 3’-chloro, and 4’-chloro-N-
phenyl groups also reacted to give indolenines (4h, 4j, and
4c) regioselectively. Substitution of the N-phenyl group with
the electron-donating methoxy, dimethylamino, and dime-
thoxy groups was found to be compatible with these reactions
(4d, 4e, and 4k). Significantly reduced yield was observed
when the N-phenyl ring was substituted with the electron-
withdrawing cyano group (4 f). Monoactivated terminal
alkynes in the form of methyl, ethyl, allyl, and benzyl esters
of propiolic acid readily reacted with the a,b-unsaturated N-
4’-anisyl ketonitrone to give C3-quaternary indolenines (4l–
4o). A preliminary study showed that the alkyne with a keto
activating group rather than an ester group was also compat-
ible with the reaction (4p).
improved yields as well (Table 1, entries 15 and 16). Thus, all
subsequent reactions were carried out in toluene at 808C
unless noted otherwise.
The scope of the reaction was investigated under the
optimized reaction conditions using a range of a,b-unsatu-
rated N-phenyl ketonitrones (1) and activated alkynes
(Scheme 3). The yields of 2 were affected by the size of the
alkyl ester groups of both the ketonitrones and the activated
alkynes, but in opposite ways; a better yield was observed
when the ketonitrone with a bulky tert-butyl carboxylate
substituent was used (2a versus 2b and 2c), however, a lower
yield was obtained when an alkyne with an ester of increased
steric bulk was used (2e versus 2c and 2d). The a’-alkyl (R2)
substituent of the a,b-unsaturated ketonitrones also exerted
a slight influence over the reaction efficiency (2 f and 2g). All
these reactions appeared to be stereoselective since only the
anti diastereomer was isolated in each of the examined cases.
Excellent regioselectivity was observed when alkyl pro-
piolates (R4 = H) were used. Only the C3-quaternary indole-
nines (2h, 2i, and 2j) were formed upon reaction of 1a with
unsymmetrical monoactivated alkynes. The steric character-
istics of the ester groups of these monoactivated alkynes had
a more pronounced effect over the reaction yields than that of
the ester groups of the symmetrical diactivated alkynes. For
example, the reaction of 1a with methyl propiolate led to
formation of 2h in 61% yield whereas 2j was obtained in only
32% yield from the reaction of 1a and tert-butyl priopiolate.
A C3-quaternary indolenine (2k) was also formed when the
monoactivated internal alkyne ethyl 3-phenylpriopiolate was
used. Alkynes without activating groups (such as 6-dodecyne,
These C3-quaternary indolenines could be easily manip-
ulated for potential synthetic applications. For example, the
indolenine moiety of 4l could be oxidized with mCPBA to
form oxindole 5 (Scheme 5).[18] Also reduction of 4l with the
Hantzsch ester gave 6 in 76% yield.[19] Complex mixtures
were formed when other reducing agents (such as NaBH4,
NaBH3CN, and NaBH(OAc)3/HOAc) were used. The 3-
substituted indole 7 was quantitatively formed by the retro-
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Scheme 6. Proposed reaction mechanism.
We speculate that formation of the zwitterion (E)-8 is
accompanied by significant reduction of the energy barrier
Scheme 4. Reaction of 3 with activated alkynes. All reactions were
carried out using 1 equivalent of 3 and 3 equivalents of activated
alkynes at 808C in toluene until the reaction was complete by TLC
analysis (8–12 h). The yields are of the isolated products. [a] These
reactions were conducted at RT. Bn=benzyl.
=
for C N bond isomerization to give (Z)-8, which cyclizes to
form 9. The next step involves hydrolysis of 9 to give 10.
Further transformations of 10 through [3,3] sigmatropic
rearrangement,[22] tautomerization, and intramolecular con-
densation lead to formation of the C3-quaternary indolenine
2a.[23] Only a catalytic amount of water is necessary for the
entire process since water is regenerated upon formation of
2a. Such a mechanism is consistent with the stereoselective
formation of the diastereomer illustrated for 2a (Scheme 6).
Specifically, minimization of the 1,3-allylic strain requires 10
to adopt the conformation shown in Scheme 6;[24] this
conformation directs the [3,3] sigmatropic rearrangement to
occur from the sterically less-hindered b face to give 2a
stereoselectively. Since the nucleophilic attack of the oxygen
atom of the nitrone will occur at the b position of the
activated alkyne, this mechanism also rationalizes the regio-
selectivity in the formation of C3-quaternary indolenines
(such as 2i and 2k) when monoactivated alkynes are used.
In conclusion, we have developed an expedient approach
to C3-quaternary indolenines that are potentially applicable
in the synthesis of complex indole alkaloids and related
compounds. It features a topographically dramatic trans-
formation of a,b-unsaturated N-aryl ketonitrones with acti-
vated alkynes that leads to formation of the heterocycles with
concomitant generation of up to two contiguous quaternary
and tertiary stereocenters without transition metal catalysis.
This remarkable transformation is general and proceeds with
good yields considering its complexity. This transformation
also constitutes a rare example of reactions involving a,b-
unsaturated ketonitrones and reveals some insights into the
reactivity of these relatively unexplored species. Studies to
extend the scope of the reaction, develop asymmetric
variants, and validate/elucidate the reaction mechanism are
underway.
Michael cleavage of one of the C3-substituents when 4m was
treated with pyrrolidine. This method provides a unique entry
to substituted indoles by reaction of a,b-unsaturated N-aryl
ketonitrones and activated alkynes.
We propose the reaction mechanism shown in Scheme 6.
The [5+2] cycloaddition of 1a with diethyl acetylenedicar-
boxylate (R = CO2Et) would give a seven-membered hetero-
cycle 9.[20] This transformation possibly proceeds through
a stepwise process initiated by the nucleophilic Michael attack
of the oxygen atom of the nitrone on the activated alkyne.[21]
Scheme 5. Some transformations of 4l and 4m. Hantzsch ester=
Received: February 1, 2012
diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.
Published online: && &&, &&&&
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Keywords: alkynes · diastereoselectivity · nitrogen heterocycles ·
nitrones · quaternary centers
.
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Communications
Synthetic Methods
New trick for an old dog: C3-Quaternary
indolenines were synthesized by com-
bining readily available a,b-unsaturated
N-aryl ketonitrones and activated alkynes.
This remarkably simple and atom-eco-
nomical transformation does not require
transition metal catalysis and involves the
formation of the heterocycles with con-
comitant generation of two contiguous
quaternary and tertiary chiral centers.
C. B. Huehls, T. S. Hood,
J. Yang*
&&&& — &&&&
Diastereoselective Synthesis of C3-
Quaternary Indolenines Using a,b-
Unsaturated N-Aryl Ketonitrones and
Activated Alkynes
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