A flexible synthesis of indoles from ortho -substituted anilines: A direct synthesis of isocryptolepine

Article abstract of DOI:10.1055/s-0029-1218706

The reaction of anilines bearing a benzylic activating group in the ortho position with aromatic aldehydes or α,β-unsaturated aldehydes results in an efficient synthetic route to substituted indoles. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0029-1218706

1386
FEATURE ARTICLE
A Flexible Synthesis of Indoles from ortho-Substituted Anilines:
A Direct Synthesis of Isocryptolepine
S
ynthesis of Indole
e
s
fromorth
o
o
-Substitute
r
d Anilin
g
es e A. Kraus,* Haitao Guo, Ganesh Kumar, Gerald Pollock III, Heather Carruthers, Divya Chaudhary,
Jonathan Beasley
Department of Chemistry, Iowa State University, Ames, IA 50011, USA
Fax +1(515)2940105; E-mail: gakraus@iastate.edu
Received 23 December 2009; revised 1 March 2010
We describe herein not only an expansion of the scope of
this practical and convenient synthetic method to include
additional activating groups but also the application of
this methodology to the efficient synthesis of heterocyclic
indole-containing natural products.
Abstract: The reaction of anilines bearing a benzylic activating
group in the ortho position with aromatic aldehydes or a,b-unsatur-
ated aldehydes results in an efficient synthetic route to substituted
indoles.
Key words: alkaloids, carbanions, electrocyclic reactions, indoles
H
N
base
RCHO
N
R
NH2
Br–
Introduction
Br–
Ph3P
R
Ph3P
1
The indole subunit is found in a wide variety of biologi-
cally active natural products.1 As a consequence, a num-
ber of useful synthetic methods for the preparation of
indoles have been devised. Sundberg collated these meth-
ods.2 Hydrazones and anilines are among the most com-
mon precursors to indoles. Hydrazones are intermediates
in both the Fischer indole synthesis3 and the Japp–
Klingemann indole synthesis.4 ortho-Haloanilines react
with either alkenes or alkynes and a palladium catalyst to
provide substituted indoles5 (Scheme 1). Several research
groups have utilized this strategy for the construction of
indole alkaloids.6
Scheme 2
The method outlined in Scheme 2 permits the synthesis of
a wide range of substitution patterns. The method is com-
patible with both electron-withdrawing groups and elec-
tron-donating groups. Figure 1 shows the indoles that we
have prepared.
Results and Discussion
We prepared a series of anilines shown in Figure 2 to un-
derstand the range of activating groups G that would per-
mit cyclization. All five compounds were considerably
more soluble than phosphonium salt 1 and therefore could
allow a wider range of reaction conditions for both the
imine formation step and the base-mediated cyclization
step.
H
NH2
N
NH2
alkene or
alkyne
aldehyde
R2
X
R1
G
Scheme 1
ortho-Alkylindoles have been less frequently employed.
One example is the Madelung synthesis, in which the di-
anion of an anilide undergoes cyclization at high temper-
atures.7 A second example is the Bischler indolesynthesis,
involving the coupling of anilines and bromoacetophe-
nones. The reported microwave-assisted synthesis8 of 2-
arylindoles is based on this mode of indole synthesis.
The synthesis of imines under microwave conditions in-
volves combining the aniline and the aldehyde with a cat-
alytic amount of acetic acid in methanol and heating in a
sealable tube to 80 °C. The formation of the imine re-
quired only a few minutes to go to completion. After imi-
ne formation was complete, the imine was dissolved in
THF and treated with one equivalent of potassium tert-
butoxide at 0 °C to produce the indole.
Recently, we communicated a flexible synthesis of in-
doles by way of an electrocyclic closure of the anion of an
imine derived from the reaction of a commercially avail-
able phosphonium salt 1 with an aromatic aldehyde
(Scheme 2).9 Our method proceeds under mild conditions
in high yields (81–95%) using readily available reagents.
Sulfone 2 was generated from the corresponding benzylic
alcohol by reaction with benzenesulfinic acid.10 This ap-
pears to be a reasonably general method for aminobenzyl
sulfone synthesis. The reaction of sulfone 2 with represen-
tative aldehydes is depicted below in Table 1.
Commercially available 2-cyanomethylaniline was next
studied. Surprisingly, this compound reacted with alde-
hydes under the standard conditions to generate 3-cy-
SYNTHESIS 2010, No. 8, pp 1386–1393
Advanced online publication: 24.03.2010
DOI: 10.1055/s-0029-1218706; Art ID: Z27809SS
x
x
.
x
x
.2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Biographical Sketches
Synthesis of Indoles from ortho-Substituted Anilines
1387
Dr. George A. Kraus re- in 1976. He is now a Uni- methods and their applica-
ceived a B.S. degree in versity Professor of Chem- tion to the synthesis of natu-
chemistry from the Univer- istry
at
Iowa
State ral products. Dr. Kraus has
sity of Rochester in 1972 University. His research in- over 280 publications in ref-
and a Ph.D. in chemistry terests include the develop- ereed journals.
from Columbia University ment of new synthetic
Dr. Haitao Guo received nology. He obtained his synthesis. He joined the
his B.S. in 1999 and Masters Ph.D. in 2009 from the Iowa AAT Bioquest Inc. in 2009
in 2002 in Chemistry from State University exploring and is involved in fluores-
Dalian University of Tech- complex natural products cent dye chemistry.
Dr. Ganesh Kumar re- Mumbai in 1999. He He is now a postdoctoral
ceived a B.Sc. from Bhar- worked for five years in fellow in UT Southwestern
athidasan University in Hindustan Lever Ltd. before Medical Center with Dr.
1996 followed by a B. Tech going to Iowa State where John Falck.
from the University of he received a Ph.D. in 2009.
Gerald Pollock III re- University. He is currently group of George A. Kraus at
ceived his B.S. in Chemistry studying natural product Iowa State University.
from Saginaw Valley State synthesis in the research
Heather Caruthers earned Chemistry from Iowa State tion at Iowa State Universi-
a B.S. in chemistry from Ce- University in 2009. She is ty.
dar Crest College in 2006 now pursuing her Ph.D.
and an M.S. in Organic course in Chemical Educa-
Divya Chaudhary received (New Delhi, India) in 2005 ate student in the laboratory
a B.S. in chemistry (Honors) and an M.S. from University of Dr. George A. Kraus in
from Sri Venkateswara Col- of Delhi in 2007. She is cur- the Department of Chemis-
lege, University of Delhi rently a second-year gradu- try.
Jonathan Beasley got his University. He is currently a organic chemistry in Dr.
B.S. in chemistry from the graduate student at Iowa Kraus’s research group.
Southeast Missouri State State University, studying
Synthesis 2010, No. 8, 1386–1393 © Thieme Stuttgart · New York

1388
G. A. Kraus et al.
FEATURE ARTICLE
N
H
O
N
H
N
N
H
81%
86%
95%
MeO
Br
N
H
N
H
N
H
95%
100%
81%
MeO
H
NO2
N
H
N
N
H
H
MeO
28%
87%
83%
OMe
N
N
H
N
H
H
93%
84%
100%
F
Cl
N
H
N
H
N
H
84%
90%
88%
O
O
N
H
N
N
H
H
86%
72%
97%
Cl
NH
O
N
H
N
H
N
H
O
OH
100%
100%
76%
Figure 1 Indoles prepared using aniline 1
G
drogen with base followed by reaction with oxygen.
Although this was not the expected product, it represents
a convenient route to 3-cyanoindoles. The results with
representative aldehydes are illustrated below in Table 2.
2: G = SO2Ph, X = Ph
3: G = CN, X = H
X
4: G = PO(OEt)2, X = H
5: G = SPh, X = H
NH2
6: G = SMe, X = SMe
Figure 2 Anilines bearing a benzylic activating group
Phosphonate 4 was prepared from o-nitrobenzyl bromide
by reaction with triethyl phosphite followed by reduction
of the nitro group.11 The reaction of 4 with benzaldehyde
generated the required imine; however, the imine did not
undergo ring closure. We then synthesized the sulfide 5.12
anoindoles in good to excellent yields. Instead of the
elimination of cyanide, oxidation to a 3-cyanoindole oc-
curred, presumably via deprotonation of the benzylic hy-
Synthesis 2010, No. 8, 1386–1393 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of Indoles from ortho-Substituted Anilines
1389
Table 1 Reaction of 2 with Aldehydes to Generate Indoles
H
N
+
RCHO
NH2
R
PhO2S
Ph
Ph
2
7
Entry
1
Aldehyde
Product
Isolated yield (%)
Ph
CHO
7a
7b
7c
85
Ph
N
H
Ph
CHO
CHO
2
3
81
68
Cl
Cl
Br
N
H
Ph
Br
N
H
Ph
HO
CHO
4
5
7d
7e
71
74
OMe
N
MeO
H
OH
Ph
CHO
N
H
Ph
CHO
NH
6
7f
68
N
H
N
H
Although the required intermediate formed readily, the re- Mechanism
action of the imine with base returned the starting imine.
Therefore, lithium diisopropylamide was used in place of We believe that these cyclizations proceed by imine for-
potassium tert-butoxide, resulting in cyclization and elim- mation, followed by a base-mediated electrocyclic ring
ination of the phenylthio group. We then prepared the closure and a 1,5-hydrogen atom shift. Our rationale for
known thioacetal 6 in 68% yield in one step from aniline the generation of two types of products is shown in
by the method of Setzer.13 Imine formation followed by Scheme 4. If G is bulky, it is likely to adopt an orientation
treatment with base afforded 3-methylthio-2-phenylin- perpendicular to the aromatic ring to minimize nonbonded
dole (9)14 in 42% yield. Indole 10 was synthesized from 6 interactions and therefore would be well aligned to elimi-
in 78% yield (Scheme 3).
nate to form an intermediate that would undergo a rapid
1,5-hydrogen atom shift to provide the indole. If G is a
small group such as a nitrile, it is likely to adopt a wider
range of conformations. In the conformation with the cy-
ano group in the plane of the ring, the benzylic hydrogen
alpha to the nitrile would be very acidic, allowing depro-
tonation and oxidation to generate the 3-cyanoindole.
SMe
SMe
CHO
SMe
+
X
N
X
NH2
H
6
9: X = H
10: X = Br
Scheme 3
Synthesis 2010, No. 8, 1386–1393 © Thieme Stuttgart · New York

1390
G. A. Kraus et al.
FEATURE ARTICLE
Table 2 Reaction of 3 with Aldehydes to Generate Indoles
H
N
+
RCHO
NH2
R
CN
CN
3
8
Entry
Aldehydes
Product
Isolated yield (%)
97
H
N
N
N
1
2
3
4
5
8a
8b
8c
8d
8e
CHO
Ph
CN
H
78
83
87
74
MeO
CHO
OMe
CN
H
Br
CHO
Br
CN
H
N
N
N
CHO
CN
H
CHO
CN
H
6
8f
85
O2N
CHO
NO2
CN
base
N
N
N
R
R
G
R
G
G
G perpendicular
to aryl ring
G in plane of
aryl ring
G = PPh3+, SO2Ph
G = CN
H
N
H
N
R
R
CN
H
Scheme 4
number of syntheses of isocryptolepine have been report-
ed.16 The most common approach involves organopalladi-
Extension to Heterocyclic Synthesis
The indolo[2,3-b]quinoline alkaloid, isocryptolepine, was um-mediated coupling of substituted quinolines.17 We
isolated from the roots of Cryptolepis sanguinolenta. This report herein a direct and strategically different approach
compound exhibits potent antiplasmodial activity.15
A
starting from o-nitrobenzaldehyde.
Synthesis 2010, No. 8, 1386–1393 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of Indoles from ortho-Substituted Anilines
1391
NH2
PPh3Br
O
O2N
H
H
Fe
N
N
H
HCl–EtOH
90%
NO2
AcOH, MeOH
72%
H2N
11
(CH2O)n, TFA
MeCN, 80 °C
81%
N
H
N
MeI
toluene
Lit.16 91%
N
N
Me
isocryptolepine
12
Scheme 5
2,3-Disubstituted Indoles from Active 2-Aminobenzyl Com-
pounds; General Procedure
As shown in Scheme 5, the nitro group in the nitrophenyl
indole 11 can be readily reduced using iron and hydro-
chloric acid in aqueous ethanol. Formaldehyde and tri-
fluoroacetic acid introduced the aldehyde group into the
3-position of the indole, which rapidly cyclized to gener-
ate the tetracyclic ring system 12 in 81% yield. Since
Kundu and co-workers have already accomplished the N-
methylation using methyl iodide in toluene,16 the synthe-
sis of indoloquinoline 12 constitutes a formal total synthe-
sis of isocryptolepine.
In a 10 mL microwave reaction vessel (CEM Discover System)
equipped with a magnetic stir bar, the active 2-aminobenzyl com-
pound 3, 6, or the 2-aminobenzyl phosphonium salt 1 (0.5 mmol),
the respective aldehyde (0.5 mmol), and glacial AcOH (11.4 mL, 0.2
mmol) were added to distilled MeOH (3 mL). The vial was capped
properly and placed in the microwave. Microwave irradiation was
carried out at 80 °C for 10 min (temperature fixed). After cooling
the vial to r.t., MeOH was removed under vacuum. All MeOH must
be removed before the next step. THF (4 mL) was added to the mix-
ture, followed by dropwise addition of a 1 M t-BuOK solution in
THF (0.8 mL). The resulting mixture was stirred at 25 °C under ar-
gon for 1 h. Sat. aq NH4Cl (10 mL) was added to quench the reac-
tion and the aqueous layer was extracted with EtOAc (3 × 10 mL).
The organic layers were combined and washed with brine (2 × 10
mL), dried (MgSO4), and filtered. The filtrate was concentrated un-
der vacuum and the residue was purified by silica gel column chro-
matography using a mixture of EtOAc and hexanes as the eluent.
The indolo[2,1-a]isoquinolines are a family of com-
pounds that have shown potent inhibitory activity against
tumors.18 The synthesis of 14 was achieved from aldehyde
13, readily available from indene.19 Indole formation pro-
vided a mixture of the expected indole ester and 14. Treat-
ment of this mixture with PTSA20 afforded 14 in 79%
yield (Scheme 6).
3-Cyano-2-phenyl-1H-indole (8a)
In conclusion, the synthesis of indoles using aminobenzyl
phosphonium salts or sulfones or nitriles is a direct and
flexible strategy. This strategy is compatible with a wide
range of functional groups. It has already been successful-
ly applied to several natural products, including rutae-
carpine, arcyriacyanin A, and isocryptolepine.
1H NMR (400 MHz, CDCl3): d = 8.83 (s, 1 H), 7.89 (d, J = 8 Hz, 2
H), 7.78 (d, J = 8 Hz, 1 H), 7.55–7.45 (m, 4 H), 7.34–7.28 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 148.4, 136.4, 135.9, 128.9, 128.2,
128.1, 124.6, 124.1, 123.8, 122.8, 119.2, 115.9, 112.9, 54.3.
MS: m/z = 218, 190, 164, 96, 83, 71, 69, 57, 52.
HRMS: m/z calcd for C15H10N2 [M+]: 218.084; found: 218.084.
Microwave reactions were conducted in a capped vial using a CEM
Discover System. The reaction temperature was measured by the
build-in temperature control system in CEM Discover Microwave
reactor.
3-Cyano-2-(4-methoxyphenyl)-1H-indole (8b)
1H NMR (400 MHz, CDCl3): d = 8.77 (s, 1 H), 7.84 (d, J = 8 Hz, 2
H), 7.74 (d, J = 8 Hz, 2 H), 7.43 (d, J = 8 Hz, 1 H), 7.33–7.22 (m, 2
H), 7.04 (d, J = 8 Hz, 1 H), 3.88 (s, 3 H).
NH2
MeO
O
O
PPh3Br
CHO
H
PTSA
79%
N
N
CO2Me
AcOH, MeOH
microwave, 80 °C, 10 min
13
62%
14
Scheme 6
Synthesis 2010, No. 8, 1386–1393 © Thieme Stuttgart · New York

1392
G. A. Kraus et al.
FEATURE ARTICLE
13C NMR (100 MHz, CDCl3): d = 161.2, 145.1, 135.1, 129.1, 128.5,
2-(2-Nitrophenyl)indole (11)
122.1, 119.6, 115.1, 111.6, 67.5, 60.1, 55.7.
1H NMR (400 MHz, acetone-d6): d = 10.65 (br s, 1 H), 7.90 (d, J = 8
Hz, 1 H), 7.81 (d, J = 6.8 Hz, 1 H), 7.71 (t, J = 15.2 Hz, 1 H), 7.64
(d, J = 8 Hz, 1 H), 7.57 (t, J = 14 Hz, 1 H), 7.48 (d, J = 8 Hz, 1 H),
7.20 (t, J = 14.4 Hz, 1 H), 7.10 (t, J = 15.6 Hz, 1 H), 6.68 (s 1 H).
MS: m/z = 248, 233, 205, 178, 151, 124, 105, 86, 84, 49.
HRMS: m/z calcd for C16H12N2O [M+]: 248.096; found: 248.095.
13C NMR (acetone-d6): d = 205.8, 149.4, 137.8, 132.9, 132.5, 131.5,
2-(4-Bromophenyl)-3-cyano-1H-indole (8c)
129.1, 129.0, 127.1, 122.8, 120.9, 120.1, 111.6, 102.7.
1H NMR (400 MHz, CDCl3): d = 8.63 (s, 1 H), 7.98 (d, J = 8 Hz, 2
H), 7.73 (d, J = 8 Hz, 2 H), 7.52 (d, J = 8 Hz, 1 H), 7.43 (t, J = 8 Hz,
1 H), 7.32 (t, J = 8 Hz, 1 H), 7.27 (d, J = 8 Hz, 1 H).
HRMS: m/z calcd for C14H10N2O2 [M+]: 238.07422; found:
238.07453.
13C NMR (100 MHz, CDCl3): d = 159.8, 149.5, 135.7, 132.2, 130.9,
Indolo[2,3-b]quinoline (12)
129.6, 129.3, 129.1, 127.0, 126.3, 125.8, 118.4, 118.1, 65.2.
1H NMR (400 MHz, DMSO-d6): d = 12.68 (br s, 1 H), 9.58 (s, 1 H),
8.51 (dd, J = 1.0, 7.5 Hz, 1 H), 8.30 (d, J = 7.7 Hz, 1 H), 8.11 (d,
J = 8.4 Hz, 1 H), 7.75–7.64 (m, 3 H), 7.47 (d, J = 8.2 Hz, 1 H), 7.32
(d, J = 7.1 Hz, 1 H).
MS: m/z = 298, 296, 219, 190, 165, 143, 116, 89.
HRMS: m/z calcd for C15H19BrN2 [M+]: 295.995; found: 295.995.
13C NMR (DMSO-d6): d = 145.8, 145.1, 140.0, 139.3, 130.0, 128.6,
3-Cyano-2-(3-methylphenyl)-1H-indole (8d)
1H NMR (400 MHz, CDCl3): d = 8.61 (s, 1 H), 7.77 (d, J = 8 Hz, 1
H), 7.69 (d, J = 8 Hz, 2 H), 7.46–7.41 (m, 2 H), 7.32–7.29 (m, 3 H),
2.44 (s, 3 H).
126.5, 125.9, 122.3, 122.1, 121.0, 120.6, 117.4, 114.9, 112.0.
HRMS: m/z calcd for C15H10N2 [M+]: 218.0844; found: 218.0854.
13C NMR (100 MHz, CDCl3): d = 145.1, 139.5, 135.1, 129.6, 127.6,
Indolo[2,1-a]isoquinolin-6(5H)-one (14)
1H NMR (400 MHz, CDCl3): d = 8.54 (d, J = 7.6 Hz, 1 H), 7.84 (d,
J = 6.4 Hz, 1 H), 7.59 (d, J = 6.8 Hz, 1 H), 7.31–7.36 (m, 5 H), 7.03
(s, 1 H), 4.10 (s, 2 H).
122.6, 119.8, 116.9, 111.8, 67.2, 21.7.
MS: m/z = 232, 204, 190, 115.
HRMS: m/z calcd for C16H12N2 [M+]. 232.100; found: 232.100.
13C NMR (CDCl3): d = 167.0, 135.3, 134.2, 130.6, 130.2, 129.8,
128.7, 128.1, 127.8, 125.5, 124.8, 124.1, 120.7, 116.8, 103.5, 37.8.
HRMS: m/z calcd for C16H11NO [M+]: 233.08406; found:
233.08431.
3-Cyano-2-(styryl)-1H-indole (8e)
1H NMR (400 MHz, CDCl3): d = 8.71 (s, 1 H), 7.72 (d, J = 8 Hz, 1
H), 7.57 (d, J = 8 Hz, 2 H), 7.43–7.24 (m, 8 H).
13C NMR (100 MHz, CDCl3): d = 143.3, 135.6, 135.5, 133.2, 129.5,
129.2, 128.4, 127.3, 125.0, 122.6, 119.7, 116.2, 115.5, 115.3, 111.6,
86.6.
Acknowledgment
We thank the Iowa State University Department of Chemistry for
support of this work.
MS: m/z = 244, 243, 231, 217, 191, 189, 115, 105, 84, 56, 49.
HRMS: m/z calcd for C17H12N2 [M+]: 244.100; found: 244.101.
3-Cyano-2-(4-nitrophenyl)-1H-indole (8f)
References
1H NMR (400 MHz, CDCl3): d = 8.63 (s, 1 H), 8.49 (d, J = 8 Hz, 2
H), 8.30 (d, J = 8 Hz, 2 H), 7.75 (d, J = 8 Hz, 1 H), 7.62 (d, J = 8
Hz, 1 H), 7.40 (t, J = 8 Hz, 1 H), 7.35 (t, J = 8 Hz, 1 H).
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13C NMR (100 MHz, CDCl3): d = 147.1, 137.6, 135.1, 130.1, 129.5,
129.0, 127.2, 124.3, 122.3, 118.9, 116.5, 112.6, 57.0.
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MS: m/z = 264, 263, 247, 241, 217, 211, 190, 163, 150, 123, 102.
HRMS: m/z calcd for C15H9N3O2 [M+]: 263.069; found: 263.069.
3-(Methylthio)-2-phenyl-1H-indole (9)
1H NMR (300 MHz, CDCl3): d = 8.30 (br s, 1 H), 7.83 (m, 3 H), 7.48
(t, J = 6 Hz, 2 H), 7.39 (m, 2 H), 7.24 (m, 2 H), 2.29 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 139.7, 135.6, 131.9, 130.9, 128.6,
128.3, 128.1, 123.0, 120.6, 119.6, 111.1, 104.9, 19.72, 19.70.
HRMS: m/z calcd for C15H13NS [M+]: 239.07687; found:
239.07719.
2-(4-Bromophenyl)-3-(methylthio)-1H-indole (10)
1H NMR (300 MHz, CDCl3): d = 8.31 (br s, 1 H), 7.80 (dd, J = 6.5,
2.2 Hz, 1 H), 7.71 (dt, J = 8.4, 2.4 Hz, 2 H), 7.59 (dt, J = 8.4, 1.8 Hz,
2 H), 7.37 (dd, J = 6.9, 2.4 Hz, 1 H), 7.24 (m, 2 H), 2.28 (s, 3 H).
(8) Sridharan, V.; Perumal, S.; Avendaño, C.; Menéndez, J. C.
Synlett 2006, 91.
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(10) Koutek, B.; Pavlickova, L.; Soucek, M. Synth. Commun.
1976, 6, 305.
13C NMR (100 MHz, CDCl3): d = 138.4, 135.6, 131.8, 130.82,
130.76, 129.5, 123.3, 122.4, 120.8, 119.7, 111.1, 105.5, 19.7, 19.6.
HRMS: m/z calcd for C15H12BrNS [M+]: 316.98738; found:
316.98779.
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