A novel protocol for construction of indolylmethyl group at aldehydes or ketones

Article abstract of DOI:10.1055/s-2001-16808

A new method for introduction of indolylmethyl group to aldehydes or ketones using diethyl (o-isocyanophenylmethyl) phosphonate through Horner-Wadsworth-Emmons condensation, thiolmediated radical cyclization, and the subsequent desulfurization is described. The Horner-Wadsworth-Emmons reagent was prepared from 2-nitrobenzaldehyde in a concise three-step sequence.

Full text of DOI:10.1055/s-2001-16808

LETTER
1403
A Novel Protocol for Construction of Indolylmethyl Group at Aldehydes or
Ketones
Hidetoshi Tokuyama, Manabu Watanabe, Yuki Hayashi, Toshiki Kurokawa, Ge Peng,1 Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, CREST, The Japan Science and Technology Corporation (JST),
7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
Fax +81(3)58028694; E-mail: fukuyama@mol.f.u-tokyo.ac.jp
Received
PO(OEt)2
Abstract: A new method for introduction of indolylmethyl group to
R
O
R
aldehydes or ketones using diethyl (o-isocyanophenylmethyl)phos-
phonate through Horner-Wadsworth-Emmons condensation, thiol-
mediated radical cyclization, and the subsequent desulfurization is
described. The Horner-Wadsworth-Emmons reagent was prepared
from 2-nitrobenzaldehyde in a concise three-step sequence.
+
NC
H
NC
1
2
Scheme 2
Key words: 3-substituted indoles, diethyl (o-isocyanophenylmeth-
yl)phosphonate, Horner-Wadsworth-Emmons condensation, 2-alk-
enylphenyl isocyanides, thiol-mediated radical cyclization
venient access to a wide variety of 2-alkenylphenyl isocy-
anide 1. Herein, we report a novel strategy for
introduction of indole moiety using diethyl (o-isocy-
anophenylmethyl)phosphonate as an indolylmethylation
reagent.
The indole nucleus is ubiquitous among a wide range of
natural products, and the synthesis of this important struc-
ture have attracted attention of synthetic chemists.2
Among the numerous methods that have been developed
for the synthesis of indoles, there appear to be few practi-
cal and mild procedures available for the synthesis of
3-substituted indoles.3 Although several methods for in-
troduction of substituents at C3-position, namely nucleo-
philic addition to indoleines generated by gramine
fragmentation4 or Pd-catalyzed coupling with 3-
haloindoles5, have been well documented, these proce-
dures have some problems with the versatility of the sub-
stituents and/or the stability of the substrates.
Furthermore, the venerable Fischer indole synthesis using
aldehydes often requires heating in the presence of strong
acid, precluding therefore preparation of indoles with
acid-labile functionalities. 6
A facile route to the requisite Horner-Wadsworth-Em-
mons reagent using Pudovik reaction was established
(Scheme 3).8 2-Nitrobenzaldehyde (3) was condensed
with diethyl phosphite, followed by simultaneous catalyt-
ic hydrogenation of the nitro group and the hydroxy group
at the benzylic position to give the corresponding aniline
5. According to the Ugi’s protocol,9 5 was converted to the
desired isonitrile, diethyl (o-isocyanophenylmethyl)phos-
phonate (2) (47% overall yield from 3). Because of the
simple operations of the sequence, this protocol can be
easily applied to a large-scale preparation.10
OH
HPO(OEt)2
KF
Pd/C, H2
EtOH
CHO
NO2
In our earlier studies, we reported a construction of substi-
tuted indoles by radical cyclization of 2-alkenylphenyl
isocyanide 1 under mild and neutral conditions (Scheme
1).7 The success of this methodology encouraged us to de-
velop a suitable Horner-Wadsworth-Emmons reagents
such as 2 (Scheme 2). This reagent would be condensed
with a variety of aldehydes, which would provide a con-
PO(OEt)2
NO2
THF, 40 °C
750 psi
100 °C
3
4
85%
97%
aq KOH, CHCl3
cat. BnEt3N+Cl-
PO(OEt)2
NH2
PO(OEt)2
CH2Cl2, reflux
57%
NC
5
2
Scheme 3
n-Bu3SnH
AIBN
R
R
NC
CH3CN
N
SnBu3
The new Horner-Wadsworth-Emmons reagent 2 has
proven to be quite useful for the synthesis of a wide range
of 2-alkenylphenyl isocyanides. A typical procedure in-
volves addition of either aliphatic or aromatic aldehyde to
an anion of 2, generated by treatment with LDA at
78 °C, and raising the reaction temperature to 23 °C (Ta-
ble 1, entries 1-3).11 In contrast, glyceraldehyde12 ace-
1
H+
R
R
N
SnBu3
N
H
H
Scheme 1
Synlett 2001, No. 9, 1403–1406 ISSN 0936-5214 © Thieme Stuttgart · New York

1404
H. Tokuyama et al.
LETTER
tonide and the Garner’s aldehyde13 were relatively less (Table 2).14 While only 31% of the desired indole 9a was
reactive, and as a result, an intramolecular attack of the obtained using 1.5 equivalent of ethanethiol and AIBN in
benzylic anion of 2 to the isonitrile occurred to give dieth- acetonitrile at 100 °C for 15 minutes, the use of five
yl 3-indolylphosphonate as a side product. This undesired equivalents of ethanethiol improved the yield to 71% (en-
side reaction could practically be suppressed by the addi- tries 1 and 2). Under these reaction conditions, formation
tion of HMPA (entries 4 vs. 5).
of the corresponding tetrahydroquinoline was not ob-
served. Although the use of other thiols such as thiophenol
or 2-mercaptoethanol also furnished the corresponding 2-
indolyl sulfide in high yields, we chose ethanethiol be-
cause of the higher yields in the subsequent desulfuriza-
tion process (entries 2 vs. 3 or 4). Finally, it was found that
carrying out the cyclization and the desulfurization pro-
cesses without isolation of 2-thioindoles 9 gave 3-substi-
tuted indoles 7 in higher yields.15
Table 1 Horner-Wadsworth-Emmons Condensations with 2
LDA, THF
R
–78 °C;
PO(OEt)2
RCHO, (additive)
–78 °C to rt
NC
NC
6a-e
2
Entry
1
Yield (%)a
RCHO
CHO
CHO
CHO
Additive
87
6a
Table 2 Thiol-Mediated Radical Cyclization
RSH
Bu
93 6b
2
3
4
5
cat. AIBN
Bu
90 6c
CH3CN
100 °C
NC
N
X
H
Raney-Ni
EtOH
6a
9a: X= SR
7a: X= H
41b
6d
80c
O
N
HMPA
(5 eq)
O
O
Yield (%)
6a to 9a 9a to 7a 6a to 7a
CHO
Boc
Entry
Equiv.
RSH
HMPA
(5 eq)
6
78 6e
1
2
3
4
5
EtSH
EtSH
PhSH
1.5
5.0
5.0
5.0
5.0
31
71
50
79
94
94
79
76
29
67
40
60
83a
CHO
a) Only E isomer was obtained unless otherwise noted.
b) E/Z ratio was 11 / 1. c) E/Z ratio was 3.7/1.
SH
HO
Depending on the substituents at the olefin terminus of the
indole precursor 1, there remains a problem in the radical-
induced indole formation. While substrates with radical-
stabilizing substituents generally provide cleanly the de-
sired indoles, isonitriles bearing simple alkyl groups such
as 6a resulted in the formation of a considerable amount
of tetrahydroquinoline 8 due to a 6-endo-trig radical cy-
clization (Scheme 4).7a In order to achieve selective 5-
exo-trig cyclization, we have carefully reinvestigated the
reaction conditions.
EtSH
a) Compound 9a was desulfurized immediately after removal of sol-
vent due to its instability in air.
As summarized in Table 3, a range of 2-alkenylphenyl
isocyanides were converted to the corresponding 3-sub-
stistuted indoles by the optimized reaction conditions
(vide supra).16 In particular, this sequence is compatible
with such acid-labile functionality as acetonide and Boc
group (entries 4 and 5).
A further synthetic application of the present protocol is
demonstrated by the reaction with ketones. Horner-Wad-
sworth-Emmons reaction of 2 with cyclohexanone took
place smoothly in the presence of five equivalents of
HMPA to give olefin 10 in 73% yield. Indole formation
reaction and the subsequent desulfurization afforded 3-in-
dolylcyclohexane 11 in almost quantitative yield (Scheme
5).
n-Bu
n-Bu3SnH
AIBN
NC
6a
CH3CN
100 °C
n-Bu
n-Bu
+
N
H
N
H
7a; 51%
8; 33%
In conclusion, we have demonstrated a facile and versatile
method for introduction of indolylmethyl group using a
new Horner-Wadsworth-Emmons reagent. The facile and
practical preparation of the indolylmethylation reagent
coupled with mild cyclization conditions would make this
protocol a general method for the construction of indolyl-
methyl unit from the structurally complex carbonyl com-
pounds.
Scheme 4
Instead of the standard radical conditions using tri-n-bu-
tyltin hydride, we examined the conditions with a various
thiols, and eventually found that the use of excess
ethanethiol was quite effective for the radical cyclization
Synlett 2001, No. 9, 1403–1406 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Novel Protocol for Construction of Indolylmethyl Group at Aldehydes or Ketones
1405
(6) Reference 3a, Chapter 7.
Table 3 Synthesis of 3-Substituted Indoles
(7) (a) Fukuyama, T.; Chen, X.; Peng, G. J. Am. Chem. Soc. 1994,
116, 3127. (b) Kobayashi, Y.; Fukuyama, T. J. Heterocycl.
Chem. 1998, 35, 1043.
(8) Texier-Boullet, F.; Foucaud, A. Synthesis 1982, 165.
(9) Weber, W. P.; Gokel, G. W.; Ugi, I. K. Angew. Chem. Int. Ed.
Engl. 1972, 11, 530.
EtSH (5 eq)
cat. AIBN
R
Raney-Ni
EtOH
R
CH3CN
100 °C, 15 min
NC
6a-e
Entrya
N
H
7a-e
(10) Preparation of 2. To a solution of 2-nitrobenzaldehyde (3)
(25.0 g, 0.165 mol) and diethyl phosphite (21.0 mL, 0.163
mol) in THF (300 mL) was added KF (56.0 g, 0.963 mol).
After stirring at 40 °C for 2 h, the mixture was filtered, and the
filtrate was evaporated in vacuo to give a crude mixture.
Recrystallization (CH2Cl2-hexane) afforded phosphonate 4 as
colorless crystals (39.5 g, 84%); Mp: 123.5 - 125.4 °C; IR
(film, cm-1) 3243, 2983, 2937, 2912, 2866, 1609, 1577, 1531,
1442, 1394, 1352, 1266, 1234, 1206, 1089, 1040, 970, 844,
786, 741, 710; 1H NMR (400 MHz, CDCl3) 1.22 (t, J = 7.1
Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H), 4.03-4.18 (m, 4H), 5.91 (br
s, 1H), 6.31 (d, J = 13.9 Hz, 1H), 7.43-7.47 (m, 1H), 7.68 (t,
J = 7.6 Hz, 1H), 7.98-8.04 (m, 2H); 13C NMR (100 MHz,
CDCl3) 16.1 (d, J(CP) = 24 Hz), 16.2 (d, J(CP) = 21 Hz),
63.3 (d, J(CP) = 27 Hz), 64.1 (d, J(CP) = 30 Hz), 65.5 (d,
J(CP) = 638 Hz), 124.6, 128.3, 128.9, 133.0, 133.3, 147.5.
Anal. Calcd for C11H16NO6P: C, 45.68; H, 5.58; N, 4.84.
Found: C, 45.64; H, 5.52; N, 4.74.
R
Yield (%)
83
6a
6b
1
2
70
76
61
64
3
6c
6d
6e
4b
5
O
O
Boc
N
O
a) E-isomers of the starting olefins were used.
b) E/Z mixture (3.7/1) of the 6d was used.
A solution of 4 (2.00 g, 6.91 mmol) in ethanol (70 mL) was
hydrogenated over 10% Pd/C (0.40 g) at a hydrogen pressure
of 750 psi at 100 °C for 3 days. Upon completion, the reaction
mixture was filtered through a pad of Celite, and the filter cake
was washed with EtOAc. The filtrate and washings were
combined, and evaporated under reduced pressure to yield
aniline 5 (1.63 g, 97%) as a yellow oil. The crude product was
used for the next transformation without purification; IR (film,
cm-1) 3422, 3356, 3250, 2991, 2911, 1643, 1609, 1576, 1497,
1450, 1390, 1218, 1164, 1058, 1025, 959, 753; 1H NMR (400
MHz, CDCl3) 1.22 (t, J = 7.0 Hz, 6H), 3.10 (d, J = 20.8 Hz,
1H), 3.91-4.00 (m, 4H), 4.24 (s, 2H), 6.67-6.74 (m, 2H), 6.99-
7.08 (m, 2H); 13C NMR (100 MHz, CDCl3) 16.2, 16.3, 29.3,
31.5, 62.2, 62.3, 117.0, 117.0, 117.1, 117.1, 118.9, 118.9,
128.0, 128.1, 131.4, 131.5, 145.8, 145.9.
LDA, HMPA
THF, –78 °C;
PO(OEt)2
cyclohexanone
–78 °C to rt
NC
NC
2
10
73%
EtSH, cat. AIBN
CH3CN;
Raney-Ni
EtOH
N
H
11
97%
To a solution of 5 (5.00 g, 20.6 mmol) in CH2Cl2 (40 mL) were
added CHCl3 (4.13 mL, 51.5 mmol), BnEt3NCl (94 mg, 0.41
mmol), and 50% aq KOH (40 mL). After a short induction
period, the reaction mixture was stirred at reflux. Upon the
completion, it was quenched by addition of water. The
mixture was partitioned between ether and sat NH4Cl. The
aqueous layer was thoroughly extracted with ether. The
extracts were combined and washed with brine, dried over
K2CO3 and evaporated under reduced pressure. The residue
was then purified by flash column chromatography on silica
gel (MeOH-CHCl3, 1:50) to yield isonitrile 2 (2.99 g, 57%);
IR (film, cm-1) 3481, 2991, 2938, 2917, 2121, 1642, 1484,
1450, 1416, 1383, 1257, 1197, 1164, 1051, 1025, 965, 858,
832, 766; 1H NMR (250 MHz, CDCl3) 1.28 (t, J = 7.0 Hz,
6H), 3.33 (d, J = 22.2 Hz, 2H), 4.06 (q, J = 7.0 Hz, 2H), 4.12
(q, J = 7.2 Hz, 2H), 7.25-7.52 (m, 4H); 13C NMR (62.5 MHz,
CDCl3) 16.0, 16.1, 28.6, 30.8, 62.0, 62.2, 126.1, 126.2,
126.2, 126.3, 126.8, 126.8, 126.8, 127.7, 127.7, 128.8, 128.9,
129.1, 129.1, 129.2, 129.2, 130.9, 131.0, 166.6. Anal. Calcd
for C12H16NO3P: C, 56.92; H, 6.37; N, 5.53. Found: C, 56.84;
H, 6.47; N, 5.23.
Scheme 5
Acknowledgement
This work was partially supported by the Ministry of Education,
Culture, Sports, Science, and Technology, Japan. H.T. thanks the
Mitsubishi Chemical Corporation Fund for financial support. T. K.
thanks Eisai Co., Ltd. for financial support.
References and Notes
(1) Current address: Xenoport, 2631 Hanover Street, Palo Alto,
CA 94304, USA
(2) (a) Saxton, J. E. Indoles; Wiley-Interscience: New York 1983;
Part 4. (b) Pindur, U.; Adam, R. J. Hetrocycl. Chem. 1988, 25,
1.
(3) (a) Sundberg, R. J. Indoles; Academic Press: London 1996.
(b) Joule, J. A. Indole and Its Derivatives, in Science of
Synthesis: Houben-Weyl Methods of Molecular
Transformations, Thomas, E. J. Ed., Georg Thieme Verlag:
Stuttgart 2000; Category 2, Vol. 10, Chapter 10.13.
(c) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045.
(4) Reference 3a, Chapter 12.
(11) General Procedure. To a stirred solution of LDA in THF
(prepared from 5.65 mmol of diisopropylamine and 5 mmol
of n-BuLi in hexane) was added Horner-Emmons Reagent 2
(1.10 g, 4.35 mmol) at 78 °C. The mixture was stirred at
78 °C for 30 minutes before addition of aldehydes (3.92
mmol). The resulting mixture was stirred for additional 20
(5) Reference 3a, Chapter 11.
Synlett 2001, No. 9, 1403–1406 ISSN 0936-5214 © Thieme Stuttgart · New York

1406
H. Tokuyama et al.
LETTER
minutes at 78 °C and then allowed to warm to room
temperature and stirred for another 1 hour before it was
quenched by addition of 3 mL of water. The biphasic mixture
was stirred at room temperature for 10 minutes and partitioned
between ethyl ether and sat NH4Cl. The aqueous layer was
thoroughly extracted with ethyl ether. The extracts were
combined and washed with brine, dried over Na2SO4 and
evaporated on a rotary evaporator. Generally the residue was
then purified by flash silica gel chromatography eluting with
5-25% ether in hexane.
(15) We have found that 2-thioethylindole 9 was unstable in air.
See, also; Nakagawa, M.; Yamaguchi, H.; Hino, T.
Tetrahedron Lett. 1970, 47, 4035.
(16) General Procedure. A mixture of isonitrile (1.0 equiv.),
ethanethiol (5.0 equiv.) and AIBN (0.1 equiv.) in dry
acetonitrile in a sealed tube was heated at 100 °C for 15
minutes under an argon atmosphere. Upon cooling to room
temperature, the solution was evaporated under reduced
pressure. After removal of solvent, the residue was dissolved
in ethanol, to which was added Raney-Ni, and then stirred at
room temperature. The reaction mixture was then filtrated
through a pad of Celite. The filtrate was evaporated under
reduced pressure to yield 3-substituted indoles as analytically
pure material.
Isocyanide 6b. IR (film, cm-1) 3384, 2959, 2867, 2118, 1646,
1476, 1455, 1364, 1265, 1090, 1040, 972, 756; 1H NMR (250
MHz, CDCl3) 1.57 (s, 9H), 6.35 (d, J = 16.0 Hz), 6.62 (d,
J = 16.0 Hz, 1H), 7.22 (dd, J = 1.2, 7.4 Hz) 7.29-7.32 (m, 2H)
7.55 (d, J = 7.5 Hz, 1H); 13C NMR (62.5 MHz, CDCl3) 29.2,
33.8, 119.0, 124.4, 125.6, 126.9, 127.2, 129.1, 134.4, 146.3,
166.3; HR-MS (EI) m/z calcd for C13H15N 185.1204, found
185.1203.
7a; IR (film, cm-1) 3316, 3054, 2962, 2850, 1618, 1460, 1423,
1343, 1234, 1101, 1010, 743; 1H NMR (250 MHz, CDCl3)
0.92 (t, J = 6.6 Hz, 3H), 1.14 (m, 4H), 1.74 (sep, J = 7.4 Hz,
1H), 2.77 (t, J = 7.4 Hz, 2H), 6.97 (s, 1H), 7.12 (t, J = 7.1 Hz,
1H), 7.20 (t, J = 7.3 Hz, 1H), 7.36 (d, J = 7.3 Hz, 1H), 7.63 (d,
J = 7.1 Hz, 1H), 7.88 (s, 1H); 13C NMR (62.5 MHz, CDCl3)
14.1, 22.6, 29.8, 30.7, 31.8, 111.0, 117.2, 119.0, 120.9, 121.8,
127.6, 132.2. HR-MS (EI) m/z calcd for C13H17N: 187.1361.
Found: 187.1363.
(12) Schmid, C. R.; Bryant, J. D. Org. Synth. 1993, 72, 6.
(13) Garner, P.; Park, J. M. Org. Synth. 1991, 70, 18.
(14) The reaction of isonitriles with thiol radicals have been
reported. See: (a) Saegusa, T.; Kobayashi, S.; Ito, Y. J. Org.
Chem. 1970, 35, 2118. (b) Bachi, M. D.; Balanov, A.; Bar-
Ner, N. J. Org. Chem. 1994, 59, 7752. (c) Camaggi, C. M.;
Leardini, R.; Nanni, D.; Zanardi, G. Tetrahedron 1998, 54,
5587. (d) Rainier, J. D.; Kennedy, A. R. J. Org. Chem. 2000,
65, 6213.
Article Identifier:
1437-2096,E;2001,0,09,1403,1406,ftx,en;Y12901ST.pdf
Synlett 2001, No. 9, 1403–1406 ISSN 0936-5214 © Thieme Stuttgart · New York