Metal-Free Directed Diastereoselective C2,C3-Cyclopropanation of Substituted Indoles with Diazoesters

Article abstract of DOI:10.1021/acs.orglett.9b01197

A metal-free directed C2,C3-cyclopropanation of suitably substituted indoles with α-diazo esters has been accomplished for the diastereoselective synthesis of cyclopropane-fused indolines in good yield. This method works well with a wide range of differen

Full text of DOI:10.1021/acs.orglett.9b01197

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Metal-Free Directed Diastereoselective C2,C3-Cyclopropanation of
Substituted Indoles with Diazoesters
Jayanta Ghorai and Pazhamalai Anbarasan*
Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, India
S
* Supporting Information
ABSTRACT: A metal-free directed C2,C3-cyclopropanation of suitably substituted indoles with α-diazo esters has been
accomplished for the diastereoselective synthesis of cyclopropane-fused indolines in good yield. This method works well with a
wide range of differently substituted α-diazo esters as well as indole derivatives and shown excellent compatibility for diverse
directing group like pyridyl, pyrimidyl, acyl, and urea derivatives. Furthermore, the preliminary mechanistic investigation
revealed the importance of directing group for the developed transformation.
workers9f reported Cu(II)- or Fe(II)-catalyzed intramolecular
yclopropanes are ubiquitous subunits frequently encoun-
Ctered in various carbo- and heterocycles having wide
cyclopropanation of indoles with high enantioselectivity using
chiral spiro bisoxazolines as the chiral ligand (Scheme 1a).
biological activities.1 In addition, the cyclopropane moiety has
been utilized in the synthesis as key intermediates en route to
accessing complicated structures, such as medium-sized rings
or highly functionalized molecules via ring-opening and/or
ring-expansion strategies.2 Hence, number of strategies for the
construction of cyclopropane has been described in the
literature.3 One of the well-known methods is the
Simmons−Smith cyclopropanation reaction, where a methyl-
ene group is introduced to the olefin via cycloaddition on
treatment of diiodomethane with the zinc−copper couple.4
However, the most important and diversified cyclopropanation
that found tremendous application is the transition-metal-
catalyzed cyclopropanation of olefin with diazo compounds.5
On the other hand, substituted indole is one of the most
widely spread heterocycles in natural products6 and
pharmaceuticals.7 In particular, cyclopropane-fused indoles
have exhibited appreciable toxicity toward B16 melanoma cells
and also reverse multidrug resistance in vincristine-resistant KB
cells.8 Representative examples include lundurines A−D
(Figure 1). The known method for the synthesis of 2,3-
cyclopropane-fused indole skeleton is rather limited to
transition-metal-catalyzed inter- or intramolecular coupling of
indole with diazoesters.9 For instance, Zhou, Zhu, and co-
Scheme 1. Cyclopropanation of Indole with Diazoester
Pirovano and co-workers reported9h the diastereo- and
enantioselective synthesis of 2-vinylcyclopropa[b]indolines
through intermolecular reaction of 2-vinylindoles with diazo
compounds in the presence of Cu(OTf)2·Tol as catalyst and
pyridine-containing macrocycles as ligands (Scheme 1b).
However, all of these methods require a significant amount
of transition-metal catalyst for the successful cyclopropanation
of indoles. Thus, the development of a general and efficient
diastereoselective metal-free10 cyclopropanation of indole is
highly desirable and significant. In continuation of our interest
Received: April 5, 2019
Figure 1. Natural products having 2,3-cyclopropanated indoles.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01197
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Letter
in functionalization of diazo compounds,11 we herein disclose
the first metal-free directed cyclopropanation of indole with
diazoester for the synthesis of cyclopropane-fused indolines
(Scheme 1c).
Scheme 2. Scope of Diazoesters
At the start, 1-(pyridin-2-yl)-1H-indole 1a and methyl 2-
diazo-2-phenylacetate 2a were chosen as model substrates for
the directed C2,C3-cyclopropanation of indole. Gratifyingly,
reaction of 1 equiv of 1a with 1.2 equiv of 2a in toluene at 80
°C gave the expected product 3a in 47% yield as single
diastereomer (Table 1, entry 1). The structure and relative
a
Table 1. Cyclopropanation of 1a with 2a: Optimization
b
entry
solvent
temp (°C)
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
toluene
DCE
MeCN
PhCN
dioxane
PhCl
80
80
80
80
80
80
80
80
70
90
11
11
11
11
11
11
11
11
18
10
47
27
79 (70)
69
48
43
52
65
62
75
c
DMF
MeNO2
MeCN
MeCN
10
a
Reaction conditions: 1a (0.25 mmol, 1 equiv), 2a (0.31 mmol, 1.2
b
c
equiv), solvent (1.5 mL), temp, time. all are isolated yields. yield of
gram scale reaction.
substituted diazoester also led the product 3h in 90% yield.
The formation of readily functionalizable halogen substituted
derivatives 3i−l was also achieved in good yields. Most
interestingly, o-iodo-, m-chloro-, and m,p-dichloro-substituted
diazo esters also gave the products 3n, 3m, and 3o in 49, 56,
and 61% yield, respectively. Furthermore, diazoester derived
from pyridine derivative also underwent a smooth reaction to
furnish the corresponding product 3p in 58% yield. However,
strongly electron-withdrawing nitro- and cyano-substituted
diazo esters did not afford the expected cyclopropanated
product.
Next, relatively electron-deficient the diazo ketone 4 derived
from α-phenylacetone was utilized in place of diazo esters. The
reaction of 1a with 4 under the optimized conditions did not
afford the expected cyclopropanated product; instead,
formation of bicyclic product 5 was observed in 79% yield,
which was confirmed by single-crystal X-ray analysis (eq 1).
stereochemistry of 3a were unambiguously confirmed by X-ray
analysis. Changing the solvent to a chlorinated solvent like
DCE decreased the yield of 3a (27%) (Table 1, entry 2). On
the other hand, using acetonitrile, more polar coordinating
solvent afforded the product 3a in 79% yield after 11 h (Table
1, entry 3), but benzonitrile gave a comparatively low yield
(69%) (Table 1, entry 4). Using other solvents like dioxane,
chlorobenzene, DMF, and nitromethane did not increase the
yield of 3a (Table 1, entries 5−8). Decreasing the temperature
to 70 °C gave a negative influence and reduced the yield to
62% (Table 1, entry 9). Furthermore, increasing the temper-
ature did not have a significant effect and gave the product in
75% yield (Table 1, entry 10). Thus, 1 equiv of 1, 1.2 equiv of
2, acetonitrile as solvent, and 80 °C were chosen as the optimal
reaction conditions for the directed cyclopropanation.
Having the optimized reaction conditions in hand, the
generality of various substituted diazoesters was examined
(Scheme 2). Both methyl and ethyl 2-diazophenylacetate gave
the corresponding C2,C3-cyclopropanated products 3a and 3b
in 79 and 82% yield, respectively. Diazoesters having various
substitutions on the benzene ring also provided the expected
product in good yield. m- and p-tolyl diazoesters provided the
corresponding products 3c and 3d in 76 and 81% yield,
respectively. A p-tert-butyl-substituted diazoester led to the
formation of the product 3e in 79% yield. Electron-donating
substitutions like p-OMe and p-OBn on the phenyl ring had
positive influence on the reaction and afforded the
corresponding cyclopropane-fused indolines 3f and 3g in 89
and 87% yield, respectively. Additionally, m,p-dimethoxy
The formation of 5 can be rationalized through the initial
nucleophilic attack of C3-position of indole to carbene carbon
followed by intramolecular trapping of resultant iminium ion.
The influence of substitutions on the indole moiety and on
the directing group was investigated (Scheme 3). 5-Methyl-
and 5-phenyl-substituted indoles gave the cyclopropanated
products 3q and 3r in 66 and 82% yield, respectively. Electron-
donating methoxy-substituted indole derivative furnished the
B
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Organic Letters
Letter
Scheme 3. Scope of Indole Derivatives
Scheme 4. Scope of Directing Group
substituted and pyridine-containing diazoester also furnished
the products 3am and 3an in good yield.
product 3s in 57% yield. Importantly, 5-halo-substituted
indoles led to the formation of products 3t−v in good yield.
Electron-withdrawing substituents such as methoxycarbonyl,
cyano, and nitro groups at different positions showed good
tolerance under the optimized conditions and gave the
products 3w, 3x, 3y, and 3z in 85, 73, 82, and 80% yield,
respectively. On the other hand, reaction of 3-methylindole
and 7-azaindole derivatives under the optimized conditions did
not afford the expected cyclopropanated products (3aa and
3ab), and most of the starting material was recovered. This
indicated that the present successful cyclopropanation reaction
requires electron-rich and C2,C3-unsubstituted indole deriva-
tives. Unlike N-pyridylindole, N-pyridylpyrrole did not
afforded the cyclopropanated product but rather gave the
C2-alkylated product 3ac in 35% yield.
Subsequently, focus was directed toward the synthetic utility
of the developed transformation. Bisindole 6 having pyridyl at
one nitrogen and methyl at other was subjected to demonstrate
the chemoselectivity of the present transformation. Gratify-
ingly, reaction of 6 under the optimized conditions gave
exclusively the product 7 in 67% yield (Scheme 5), which was
Scheme 5. Synthetic Application
After successful demonstration of the diazoesters and indole
derivatives, the efficiency of various directing groups was
examined (Scheme 4). At first, the effect of substitution on the
directing pyridine group was studied. Methyl- and methoxy-
substituted pyridines afforded the corresponding products 3ad
and 3ae in 72 and 69% yield, respectively. Similar to pyridine,
pyrimidine was also highly effective as a directing group and
led to the formation of 3af in 79% yield. Next, the nitrogen-
based directing group was replaced with an oxygen-based
directing group. Interestingly, N-acetylindole on reaction with
diazoester 2a under the optimized conditions afforded the
cyclopropaned product 3ag in 62% yield, which demonstrates
the wide applicability of the present transformation. Inspired
by the result, next, N,N-dimethyl-1H-indole-1-carboxamide
and (1H-indol-1-yl)(morpholino)methanone were synthesized
and subjected under the optimized reaction conditions, which
led to the corresponding products 3ah and 3ai in 59 and 68%
yield, respectively. Subsequently, applicability of N-acetylin-
dole with other diazoesters was also tested under the
developed conditions. p-Methyl and p-tert-butyl diazoester on
reaction with N-acetylindole afforded the products 3aj and 3ak
in good yield. Biologically important fluorine containing
diazoester underwent smooth reaction and gave the product
3al in 65% yield. Highly electron rich m,p-dimethoxy-
confirmed by 2D NMR. This demonstrates that the reaction
occur in an intramolecular fashion and only at the indole
having directing group. On the other hand, the reaction of
compound 3af with MeOTf in DCM followed by treatment
with aqueous NaOH in methanol at 60 °C did not afford the
expected deprotected product; instead, 3-alkylated indole 8
was observed in 79% yield. The formation of 8 could be
rationalized via the initial deprotection of pyrimidine to form
sodium amide, which led to subsequent cyclopropane ring
opening and aromatization (Scheme 5).
In order to understand the insight into the reaction
mechanism, few control experiments were carried out. In
order to obtain information about the influence of the
directing group, the reaction was performed with N-phenyl-
indole 9a as the substrate (Scheme 6a). Reaction of 9a with 2a
did not afford the expected cyclopropanated product. Similarly,
replacement of a 2-pyridyl group with 3-pyridyl or 4-pyridyl as
the directing group also did not furnish the cyclopropanated
C
DOI: 10.1021/acs.orglett.9b01197
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Organic Letters
Letter
tivity could be rationalized from the stability of two possible
orientations of intermediate C that affords the cyclized
product. As shown in Scheme 7, orientation C2 is relatively
favored compared to the orientation C1, which is possibly due
to the presence of significant steric hindrance in the C1
orientation (the phenyl group and hydrogen as well as the ester
moiety and pyridyl group face each other) and absence of
similar steric problem and presence of favorable π−π
interaction in C2 orientation. Thus, cyclization from C2
orientation would afford the observed diastereomer as the sole
product. On the other hand, amide- and aminocarbonyl-
directed cyclopropanation also could proceed through the
generation of oxygen-based ylide followed by cyclization.
In conclusion, we have successfully developed a metal-free-
directed C2,C3-cyclopropanation method of indole with
diazoesters for the synthesis of cyclopropane-fused indoline
skeleton. The method was well accepted for a wide range of
differently substituted diazoesters as well as indole derivatives,
which results in expected cyclopropanated products in good
yield. Moreover, the method has shown excellent compatibility
for a significant variety of directing groups like pyridyl,
pyrimidyl, acyl, and urea derivatives. A synthetic application of
the method the directing group was removed, but during the
process the cyclopropane ring opened up and 3-alkylated
indole derivative was formed. Additionally, on the basis of
preliminary mechanistic investigation, a plausible reaction
mechanism was proposed.
Scheme 6. Control Experiments
product. These experiments revealed that (1) the directing
group is highly essential for the successful cyclopropanation,
(2) the directing group must be at the ortho position, and (3)
directed cyclopropanation is an intramolecular transformation.
Another experiment was carried out to understand the
influence of the directing group. The same equimolar mixture
of 1a and 1af, having pyridyl (one directing site) and pyrimidyl
(two directing site) directing groups, was treated with 1.2
equiv of 2a under standard reaction conditions (Scheme 6b).
Analysis of the reaction mixture after 5 h afforded the ∼1:1
ratio of the corresponding cyclopropanated products 3a and
3af in 43% overall yield. Similar results were observed even
after 11 h with complete reaction. This experiment implies that
the number of co-ordination sites does not significantly alter
1
the rate of the reaction. Next, variable-temperature H NMR
was recorded for the mixture of 1a and 2a. Interestingly, a
significant amount of downfield shift for the C6-proton of
pyridine was observed (see the Supporting Information),
which further enforced the potential interaction of pyridine
nitrogen with diazo compound.
Based on these preliminary investigations, a plausible
mechanism was proposed for the developed reaction (Scheme
7). At first, the diazo compound 2 would undergo thermal-
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01197.
1
Experimental details, characterization data, and H and
Scheme 7. Plausible Reaction Pathway
13C NMR spectra of isolated compounds (PDF)
Accession Codes
CCDC 1888375 and 1908121 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: anbarasansp@iitm.ac.in.
ORCID
Pazhamalai Anbarasan: 0000-0001-6049-5023
Notes
The authors declare no competing financial interest.
assisted nitrogen extrusion to form the carbene A, which might
coordinate with directing group of indole derivative 1 to give
the ylide intermediate B. Alternatively, direct displacement of
molecular nitrogen in the diazo compound 1 by the directing
group in 2 would also generate the ylide intermediate B.
Intramolecular attack with the assistance of pyrrolic nitrogen
would generate the zwitterion C. Formation of cyclopropanate
product 3 from C could be readily visualized through the
intramolecular cyclization, where the cyclization affords the
exclusively single diastereomer. The observed diastereoselec-
ACKNOWLEDGMENTS
■
We thank the Science and Engineering Research Board
(SERB), New Delhi (Project No.: EMR/2016/003677/OC),
for financial support. J.G. thanks IIT, Madras, for a fellowship.
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