Dearomative Indole (3 + 2) Reactions with Azaoxyallyl Cations - New Method for the Synthesis of Pyrroloindolines

Article abstract of DOI:10.1021/jacs.5b10221

Herein, we report the first examples of the synthesis of pyrroloindolines by means of (3 + 2) dearomative annulation reactions between 3-substituted indoles and highly reactive azaoxyallyl cations. Computational studies using density functional theory (DFT) (B3LYP-D3/6-311G++) support a stepwise reaction pathway in which initial C-C bond formation takes place at C3 of indole, followed by ring closure to give the observed products. Insights gleaned from these calculations indicate that the solvent, either TFE or HFIP, can stabilize the transition state through H-bonding interactions with oxygen of the azaoxyallyl cation and other relevant intermediates, thereby increasing the rates of these reactions.

Full text of DOI:10.1021/jacs.5b10221

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Dearomative Indole (3 + 2) Reactions with Azaoxyallyl Cations − New
Method for the Synthesis of Pyrroloindolines
Maria C. DiPoto, Russell P. Hughes, and Jimmy Wu*
Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755, United States
S
* Supporting Information
Scheme 1. Synthesis of Pyrroloindolines
ABSTRACT: Herein, we report the first examples of the
synthesis of pyrroloindolines by means of (3 + 2)
dearomative annulation reactions between 3-substituted
indoles and highly reactive azaoxyallyl cations. Computa-
tional studies using density functional theory (DFT)
(B3LYP-D3/6-311G**++) support a stepwise reaction
pathway in which initial C−C bond formation takes place
at C3 of indole, followed by ring closure to give the
observed products. Insights gleaned from these calcu-
lations indicate that the solvent, either TFE or HFIP, can
stabilize the transition state through H-bonding inter-
actions with oxygen of the azaoxyallyl cation and other
relevant intermediates, thereby increasing the rates of
these reactions.
yrroloindolines are important structural motifs found in
Pnumerous families of biorelevant alkaloid natural products.
As a result, considerable resources have been expended to
develop new and improved methods for their syntheses. By far,
the most common way to prepare pyrroloindolines is through
biomimetic pathways starting with either tryptophan, trypt-
amine, or derivatives thereof.1−20 Such a strategy involves the
formation of bonds a and b (Scheme 1a) by alkylation at C3
with various electrophiles to generate an iminium intermediate,
followed by ring closure to give the desired products. The
alternative retrosynthetic disconnection at bonds b and c
(Scheme 1b) would require 3-substituted indole 1 and 1,3-
previous paper of this issue,38 the first examples of dearomative
dipole 2 as synthons. In the forward direction, this approach
constitutes a dearomative indole (3 + 2) annulation reaction
and has been a relatively underexplored option for preparing
pyrroloindolines as compared to the biomimetic strategy
described above. Notable recent examples include Reisman’s
use of 2-amidoacrylates,21−23 Davies’ reports of Rh-catalyzed
annulation reactions,24,25 and annulations with aziridines by
Chai.26
Consistent with our continuing interest in indole annula-
tion27 and alkylation reactions,28 we recently disclosed a new
method for carrying out formal (3 + 2) cycloadditions between
3-substituted indoles and oxyallyl cations 5 (Scheme 1c).29 We
were, therefore, intrigued by Jeffrey and co-workers’ report in
which they described the (4 + 3) cycloaddition reaction
between azaoxyallyl cations and dienes such as furan and
cyclopentadiene,30−32 later expanded to include diamina-
tions.33,34 We postulated that azaoxyallyl cations 9 may also
react with 3-substituted indoles in a fashion analogous to
oxyallyl cations (Scheme 1d).29 In this manuscript and in the
(3 + 2) annulation reactions between indoles and azaoxyallyl
cations is described as a novel means to prepare pyrroloindo-
lines.
We initiated our studies by examining the reaction between
N-benzyl-3-methylindole (11) and bromohaloamide 8 under
conditions we originally developed for the (3 + 2) annulation
reaction of oxyallyl cations.29 Gratifyingly, this led to the
formation of the desired product 12 in 94% isolated yield
(Table 1, entry 1). Under these conditions (first reported by
Fohlisch and co-workers for generating oxyallyl cations),35
̈
formation of the azaoxyallyl cation likely occurs by hydrogen-
bond-mediated tautomerization followed by unimolecular
ionization of bromide. Despite this success, we later discovered
that the use of TFE (2,2,2-trifluoroethanol) leads to
competitive decomposition of haloamide 8 by solvolysis. By
Received: September 29, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b10221
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Journal of the American Chemical Society
Communication
Table 1. Optimization Reactions
Scheme 2. Synthesis of Monosubstituted and Unsubstituted
Pyrroloindolines
a
concn
(M)
temp
(°C)
time
(h)
yield
(%)
entry
base
solvent
1
2
Na2CO3
Na2CO3
Na2CO3
Na2CO3
NEt3
TFE
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.50
rt
0
4
94
TFE
6
61
b
3
TFE
rt
rt
rt
rt
rt
rt
rt
rt
6
91
4
5
6
7
8
THF
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
18
16
8
no rxn
42
K2CO3
40
Cs2CO3
Na2CO3
Na2CO3
Na2CO3
12
4
46
89
b
9
18
6
66
10
39
a
b
Isolated yield. 2 equiv of indole, 1 equiv of haloamide.
a
Table 2. Scope of Dearomative Indole (3 + 2) Reaction
switching to the more sterically hindered solvent hexafluoro-
isopropanol (HFIP), we were able to minimize these solvolysis
byproducts while maintaining high yields of the desired
pyrroloindolines (entry 8).
With optimized reaction conditions in hand, we sought to
delineate the scope of the reaction. Alkylation on the indole
nitrogen could be either methyl or benzyl. The reaction was
compatible with a wide range of functional groups at the C3
position of indole. These include esters, free alcohols, esters,
nitriles, phthalimide, isopropyl, and methyl. We also demon-
strated that substitution at C2 (entry 6), electron-rich groups at
C4/6 (entry 17), and electronegative groups at C5 are well
tolerated (entry 15). For the electron-rich substrate, we
observed significant amounts of byproducts resulting from
electrophilic aromatic substitution with the azaoxyallyl cation at
C7 (entry 17). We were able to overcome this problem by
reversing the stoichiometry of the indole and haloamide
starting materials. N−O bond cleavage could be achieved using
Mo(CO)6 to give 14 (eq 1).
When indole 15 was reacted with monomethyl-substituted α-
haloamide 16a, the expected product 17a was generated in 54%
yield as an inseparable mixture of diastereomers with respect to
the stereocenter bearing the methyl group (Scheme 2). It was
also possible to prepare unsubstituted pyrroloindolines such as
18. We accomplished this by carrying out the annulation
reaction of 15 with dichlorohaloamide 16b to initially give 17b
in a 1:1 diastereomeric ratio with respect to the stereocenter
bearing the chloride. Protodehalogenation using the Zn/Cu
couple provided the desired compound 18.
a
Indole (1 equiv), α-haloamide (2 equiv), Na2CO3 (4 equiv) in HFIP,
b
c
0.25 M. Isolated yield. Significant decomposition products observed.
Several of the yields in Table 2 (entries 1, 7, 11, 12, 13, 15)
and for compound 17 are slightly different from the
corresponding reactions reported in the paper preceding this
one.38 These differences are likely attributable to a combination
of higher reaction concentration (i.e., 1 M versus 0.25 M) and,
in some instances, longer reaction times (entries 1, 11, 15) and
higher temperatures (50 °C versus room temperature for
compound 17) that were utilized by Jeffrey.
The mechanism of this reaction was examined using Density
Functional Theory (DFT) using the dispersion corrected
B3LYP-D3 functional and the 6-311G**++ basis set; this
B
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Journal of the American Chemical Society
Communication
method and basis set have been demonstrated to be competent
in predicting the energetics of reactions of oxyallyl cations with
indoles.29 The model starting materials used were indole 15
and azaoxyallyl cation 9-Me. An implicit solvent correction for
2,2,2-trifluoroethanol (TFE) was used. Full details of all
calculations are provided in the Supporting Information.
Attempts to locate a transition state for a concerted reaction
were unsuccessful, but energy surfaces for various stepwise
processes were found. Formation of the expected product 12
could occur in a stepwise fashion by initial construction of the
C−C bond at C3 of indole 15 to give intermediate 19a as
shown in Figure 1. Alternatively, formation of a C−N bond at
C2 of the indole could occur first to give intermediate 19b. The
energy profiles for these two reactions are illustrated in Figure
2.
none of which shows any interaction of N with C2 of the
indole; likewise conformers essentially isoenergetic with TS1‡
were also located. We were unable to find TS2‡, suggesting that
it is a very low energy process that evolves smoothly during
rotation of the newly formed C−C bond of intermediate 19a.
Our calculations also reveal that the observed regiochemistry
of addition to give 12 is kinetic in origin. The calculated
intermediate 20a en route to the formation of 21 (the
regioisomer of 12) is shown in Figure 3. Product 21 is 1.8 kcal/
Figure 3. Calculated structures of starting materials, product, and
intermediates for stepwise reaction of 15 with 9-Me to give 21 (the
regioisomer of 12). H atoms are not shown.
mol more stable than 12, and intermediate 20a is also 1.8 kcal/
mol more stable than the corresponding intermediate 19a.
However, the transition state leading to 20a lies 2.9 kcal/mol
higher in energy than TS1‡ (leads to 19a). From these data, we
conclude that the preference for the formation of product 12
over 21 is governed by kinetic control.
The strong hydrogen-bonding solvents TFE and HFIP also
play a significant role in this reaction. As an extreme limiting
case, the effect of a very strong H-bonding solvent was modeled
by calculating the energetics of the reaction between a fully O-
protonated azaoxyallyl cation 22 and indole 15 with an implicit
TFE solvent model. Key calculated structures are shown in
Figure 4. O-Protonation dramatically lowers the activation
Figure 1. Calculated structures of starting materials, product and
intermediates for the stepwise reaction of 15 with 9-Me to give 12.
Except for 9-Me and 15, H atoms are not shown.
Figure 4. Calculated structures of protonated oxyallyl cation 22, the
protonated intermediate 19a(H+), and the protonated transition state
TS1‡(H+) for its reaction with indole 15. H atoms are not shown
except for the OH.
barrier of the first step TS1‡(H+) (located 16.4 kcal/mol above
reactants) and also strongly stabilizes the intermediate of the
corresponding protonated intermediate 19a(H+) which lies
only 1.9 kcal/mol higher than the reactants. The energy of
regioisomeric intermediate 20a(H+) becomes 3.4 kcal/mol
higher than that of 19a(H+) with the transition state for
formation of 20a(H+) lying 4.3 kcal/mol above TS1‡(H+),
thereby increasingly favoring the observed regioselectivity.
These calculations suggest that, when strong hydrogen bond-
donor solvents are used, the actual energy of the transition state
should be intermediate between that of TS1‡ and TS1‡(H+).
This should accelerate the rates of these reactions and also
increase their regioselectivity. We and others have seen similar
effects of protonation on the reaction energetics calculated for
Figure 2. Free energy profiles for the stepwise formation of product
12 via intermediates 19a (red) and 19b (blue) with calculated
structures of the transition states for the rate limiting steps. H atoms
are not shown.
The lowest energy stepwise pathway is via intermediate 19a,
which is over 21 kcal/mol more stable than its regioisomer 19b.
Moreover, transition state TS1‡ which leads to 19a is almost 20
kcal/mol lower in energy than TS1A‡ leading to 19b.
Formation of product 12 is downhill by almost 10 kcal/mol
with respect to the starting materials. There are other
conformers of intermediate 19a with essentially equal energies,
C
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Journal of the American Chemical Society
Communication
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In summary, we have disclosed the first report of preparing
pyrroloindolines by means of dearomative (3 + 2) annulation
reactions between indoles and azaoxyallyl cations. DFT
calculations indicate a stepwise reaction mechanism and that
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.5b10221.
■
S
(23) Wang, H.; Reisman, S. E. Angew. Chem., Int. Ed. 2014, 53 (24),
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(26) Chai, Z.; Zhu, Y.-M.; Yang, P.-J.; Wang, S.; Wang, S.; Liu, Z.;
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Experimental details and characterization of all new
compounds; selected NOESY, HMBC, HMQC, COSY
data; details of DFT calculations; final geometry
coordinates for all calculated structures; and larger scale
graphics of Figures 1−4 (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: jimmy.wu@dartmouth.edu.
Present Address
Department of Chemistry, Dartmouth College, 6128 Burke
Laboratories, Hanover, New Hampshire 03755, United States.
■
(30) Jeffrey, C. S.; Barnes, K. L.; Eickhoff, J. A.; Carson, C. R. J. Am.
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
J.W. acknowledges the generous support of the NIH NIGMS
(1R01GM111638). M.C.D. was also supported, in part, by a
GAANN fellowship provided by the United States Department
of Education. We thank Prof. Christopher S. Jeffrey (University
of Nevada, Reno) and his students for helpful discussions.
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