Lewis acid catalyzed indole synthesis via intramolecular nucleophilic attack of phenyldiazoacetates to iminium ions

Article abstract of DOI:10.1021/jo902089e

(Chemical Equation Presented) Lewis acids catalyze the cyclization of methyl phenyldiazoacetates with an ortho-imino group, prepared from o-aminophenylacetic acid, to give 2,3-substituted indoles in quantitative yields.

Full text of DOI:10.1021/jo902089e

pubs.acs.org/joc
SCHEME 1. Copper(II)-Catalyzed Formation of 2,5-Dihydro-
pyrroles
Lewis Acid Catalyzed Indole Synthesis via
Intramolecular Nucleophilic Attack of
Phenyldiazoacetates to Iminium Ions
Lei Zhou and Michael P. Doyle*
Department of Chemistry and Biochemistry, University of
Maryland, College Park, Maryland 20742
of N-aryl amides with ethyl diazoacetate.6 However, efficient
methods for the synthesis of indoles from simple precursors
continue to be of great value. Diazoacetates and aryldiazoa-
cetates have been widely employed under catalytic conditions
for many organic transformations, including cyclopropana-
tion,7 insertion,8 and ylide formation and subsequent reac-
tions.9,10 Aziridination using imine and diazoacetate catalyzed
by either Lewis acids11 or Brønsted acids12 is also well-known.
In 2003, we reported the synthesis of dihydropyrroles from
vinyldiazoacetates and imines, and in that report, we provided
evidence for copper(II)-catalyzed formation of 2,5-dihydro-
pyrroles by activation of the imine toward electrophilic addi-
tion to the diazo carbon of the vinyldiazoacetate (Scheme 1).13
We now report an intramolecular analogue of the imine
diazoacetate reaction that can be performed with a broad
selection of inexpensive Lewis acids with catalyst loadings at/
or below 1.0 mol %.
Methyl N-substituted iminophenyldiazoacetates (2) were
synthesized efficiently by reactions of p-nitrobenzenesulfo-
nylazide (PNBSA), DBU, and methyl 2-arylmethyleneami-
nophenylacetates (1) that were prepared in quantitative yield
from methyl o-aminophenylacetate and aryl and vinyl-sub-
stituted aldehydes (Scheme 2). In the simplest case, methyl
diazo(2-phenylmethyleneaminophenyl)acetate was treated
with a broad spectrum of Lewis acids, each at 1.0 mol %.
Reaction times and product yields are given in Table 1.
Reaction times were determined by monitoring the reaction
solution every 5 min. As can be seen from these results, a wide
variety of catalysts are suitable, but two were selected for
mdoyle3@umd.edu
Received September 28, 2009
Lewis acids catalyze the cyclization of methyl phenyldia-
zoacetates with an ortho-imino group, prepared from
o-aminophenylacetic acid, to give 2,3-substituted indoles
in quantitative yields.
Indoles are referred to as “privileged structures” in drug
discovery because of their capacity to bind to many receptors
with high affinity. The synthesis of indoles has been of con-
siderable interest to organic chemists for more than a century.1
Many powerful methodologies for the synthesis of these
heterocycles have been developed, including the Fisher indole
synthesis,2 heteroannulation and cyclization of 2-alkynylani-
lines,3 a metal-catalyzed cascade reaction,4 intramolecular
C-H amination of azidoacrylates,5 and a domino reaction
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Published on Web 11/11/2009
DOI: 10.1021/jo902089e
r
2009 American Chemical Society

Zhou and Doyle
JOCNote
SCHEME 2. Synthesis of Methyl N-Substituted Iminophenyl-
diazoacetates
TABLE 2. Indole Synthesis via Intramolecular Nucleophilic Attack of
Imines by Phenyldiazoacetates
TABLE 1. Cyclization of Methyl Diazo(2-phenylmethyl-
eneaminophenyl)acetate Catalyzed by Lewis Acids
entry Lewis acid 1 mol % reaction time (min)
yield (%)
1
2
3
4
5
ZnCl2
BF3 Et2O
TiCl4
SnCl4
Mg(OTf)2
Sn(OTf)2
In(OTf)3
Zn(OTf)2
Ni(OTf)2
Cu(OTf)2
Sc(OTf)3
La(OTf)3
Yb(OTf)3
60
10
5
10
60
15
5
40
15
5
very low conversion
100
100
100
no conversion
100
100
100
3
6
7
8a
9
100
100
10
11
12
13
5
60
20
100
very low conversion
100
aReaction was complete in less than 10 min when 5 mol % of
Zn(OTf)2 was used; reaction was complete in 10 h when 0.1 mol % of
Zn(OTf)2 was used.
further investigation. No reaction occurred in the absence of
acid.
No attempt was made to rigorously dry the Lewis acids
employed, so different times could be suitable for complete
reaction dependent on humidity and other relevant condi-
tions. The use of lower amounts of catalyst was investigated.
For instance, reaction was complete within 40 min when
1 mol % of zinc triflate was used but was complete at only
10 min when 5 mol % of zinc triflate was employed. How-
ever, when the reaction is performed in the presence of only
0.1 mol % of zinc triflate, for complete reaction, 10 h was
required.
The scope of the reaction with representative methyl
2-arylmethyleneaminophenylacetates (1) was examined.
The reactant diazo compounds (2) were prepared according
to Scheme 2 in 60-80% overall yields (Table 2). Cyclization
catalyzed by zinc triflate or boron trifluoride etherate furn-
ished indoles 3 in quantitative yields.
Consistent with these observations, the mechanism of
the cyclization involves activation of the imine by the Lewis
acid for electrophilic attack on the diazo carbon to form
a diazonium ion intermediate. Expulsion of N2 and dis-
sociation of the Lewis acid furnishes the product indole
(Scheme 3). The difference in base strength between imine
and indole is the driving force for the highly efficient
catalytic turnover.
aCalculation of overall yield is based on compound 1.
A demonstration of the synthetic utility of this methodol-
ogy is shown in Scheme 4. Indole 3f was converted to
biologically active14 indoloquinolin-2(1H)-one 4 in high
yield following reduction of the nitro group and cyclization
in methanol. This synthetic strategy is highly efficient com-
pared with the published method,15 which starts from the
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Stalhandske, C.; Wallberg, H. Tetrahedron 2003, 59, 1033–1048.
J. Org. Chem. Vol. 74, No. 23, 2009 9223

Zhou and Doyle
JOCNote
SCHEME 3. Mechanism of Lewis Acid Promoted Indole
Synthesis
In summary, we have developed a general and efficient
synthesis of functionalized indoles from Lewis acid pro-
moted intramolecular nucleophilic attack of imines by phe-
nyldiazoacetates. Reaction conditions are mild, and product
yields are good under low catalyst loading with inexpensive,
commercially available Lewis acids. The approach proves to
be very useful for the synthesis of biologically active and
naturally occurring indole derivatives. Efforts are actually
directed toward the extension of this methodology to natural
products and drug synthesis.
Experimental Section
General Procedure for Diazo Compound 2 Synthesis (Table 2).
To a stirred solution of 1 (1 mmol) and PNBSA (2-3 mmol) in
MeCN (5 mL) was added DBU (4-6 mmol) at 0 °C. The
reaction mixture was then allowed to warm to room tempera-
ture. After stirring for 12 h, the reaction mixture was quenched
with aqueous NH4Cl, extracted with diethyl ether, and dried
over anhydrous Na2SO4. The solvent was removed under
reduced pressure and purified by flash column chromatography
on silica gel to give the corresponding diazo compound 2.
General Procedure for Indole 3 Synthesis (Table 2). To a
stirred solution of 2 (0.25 mmol) in DCM (5 mL) was added
boron trifluoride etherate or zinc triflate (1 mol %) at room
temperature. The yellow reaction mixture was stirred until it
turned pale yellow or colorless within 10-30 min. The mixture
was then passed through a silica gel plug to remove the catalyst.
After evaporation of the solvent, pure indole 3 was obtained as a
light yellow solid in quantitative yield.
SCHEME 4. Synthesis of Indoloquinolin-2(1H)-one
Acknowledgment. We gratefully acknowledge the finan-
cial support provided by the National Institutes of Health
(GM46503) and the National Science Foundation.
reaction of hydrozine with 4-hydroxyquinoline-2(1H)-one,
followed by treatment with cyclohexanone, thermal Fischer
indolization, and dehydrogenation to afford indoloquino-
line-2(1H)-one in low yield.
Supporting Information Available: General experimental
procedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
9224 J. Org. Chem. Vol. 74, No. 23, 2009