Immobilized α-diazophosphonoacetate as a versatile key precursor for palladium catalyzed indole synthesis on a polymer support

Article abstract of DOI:10.1039/b109987f

Rh(II)-catalyzed N-H insertion reaction of immobilized α-diazophosphonoacetate with 2-haloanilines followed by Horner-Emmons reaction gave immobilized enaminoesters, which were efficiently cyclized to indoles via intramolecular palladium catalyzed reactio

Full text of DOI:10.1039/b109987f

Immobilized a-diazophosphonoacetate as a versatile key precursor for
palladium catalyzed indole synthesis on a polymer support
Kazuo Yamazaki† and Yoshinori Kondo*
Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, Aoba-ku, Sendai 980-8578,
Japan. E-mail: ykondo@mail.pharm.tohoku.ac.jp
Received (in Cambridge, UK) 2nd November 2001, Accepted 7th December 2001
First published as an Advance Article on the web 7th January 2002
Rh(II)-catalyzed N–H insertion reaction of immobilized a-
diazophosphonoacetate with 2-haloanilines followed by
Horner–Emmons reaction gave immobilized enaminoesters,
which were efficiently cyclized to indoles via intramolecular
palladium catalyzed reaction on a polymer support.
was achieved by the treatment of 6 with dodecylbenzenesulfo-
nyl azide using DBU as a base in toluene (Scheme 2). The
resulting polymer-bound a-diazophosphonoacetate showed
2
1
characteristic absorptions at 2124 and 1702 cm in ATR FT-
IR indicating the existence of the diazo and ester functionalities,
respectively. The loading of resin 7 was estimated by elemental
2
1
The insertion reactions of carbene and carbenoid species have
been widely used as one of the important methods in recent
analysis of the polymer beads for nitrogen as 1.1–1.2 mmol g
for each batch and the measured values indicated the smooth
and reasonable progress of the transformation.
1
organic chemistry. Moody and coworkers reported the N–H
insertion reaction of rhodium carbenoids, which allow function-
alization of amides, carbamates and anilines effectively.2
Rhodium carbenoid insertion reactions have already been used
for the construction of several heterocyclic compounds and
cyclopropane derivatives in solid phase chemistry,3 however
the N–H insertion reaction of a-diazophosphonoacetate on a
polymer support has not been reported to our knowledge. In this
communication we present the rhodium catalyzed reaction of
immobilized a-diazophosphonoacetate with anilines and its
application to a new indole synthesis.5
Next, we investigated the reaction conditions of rhodium-
10
catalyzed N–H insertion of resin 7. When the reaction of 7
with 2-iodoaniline (5 equiv.) in the presence of 5 mol% rhodium
acetate was carried out at 80 °C in toluene, a long reaction time
(40 h) was found to be required upon monitoring the complete
,4
2
1
disappearance of the diazo absorption at 2124 cm in ATR FT-
IR. When 20 mol% phenol was used as an additive for the
reaction, a significant rate acceleration was observed. The role
of phenol in the reaction rate enhancement is not clear, however
2c
a previous report also suggested a similar additive effect.
First, we started with a solution phase investigation for our
Similarly, other anilines gave N–H insertion products using the
reaction conditions with retention of the high loading level. The
solid phase Horner–Emmons reaction of 8 with aromatic
aldehyde (3 equiv.) using DBU (3 equiv.) as a base proceeded
smoothly without any problems and a broad range of aryl and
heteroaryl aldehydes were found to be amenable for the
reaction. The progress of the reaction was conveniently
monitored by ATR FT-IR which showed that the ester
6
indole synthesis. Triethyl a-diazophosphonoacetate 1 was
2 4
reacted with iodoaniline in the presence of Rh (OAc) and the
rhodium-catalyzed N–H insertion reaction proceeded smoothly
to give the desired a-anilinophosphonoacetate 3 in 78% yield
7
(
Scheme 1). Subsequent Horner–Emmons reaction of 3 with
benzaldehyde gave a-(2-iodophenyl)amino substituted a,b-
unsaturated ester 4 in almost quantitative yield. Compound 4
was found to be a single isomer but its geometry has not yet
been determined. The palladium-catalyzed intramolecular cy-
2
1
absorption of 8 at 1737 cm disappeared and was replaced by
2
1
a new absorption for the enaminoester at 1702 cm . Polymer-
bound a-anilinophosphonoacetates were found to be useful
precursors for the preparation of immobilized a-anilino-a,b-
unsaturated esters; acid catalyzed condensation of a-keto esters
with aniline on a polymer support as an alternative approach has
not previously been investigated.
8
clization of the enaminoester 4 was carried out to give ethyl
3
-phenyl-2-indolecarboxylate 5 in 56% yield. Based on these
results in the solution phase, we next investigated the solid
phase application of the rhodium-catalyzed N–H insertion
reaction.
Polymer-bound diethylphosphonoacetate 6 was easily syn-
thesized from hydroxymethyl polystyrene resin. The condensa-
tion of hydroxymethyl polystyrene resin (1% DVB) with
diethylphosphonoacetic acid was carried out using the mixed
Finally, palladium-catalyzed intramolecular cyclization was
carried out using similar reaction conditions as for the solution
phase procedure. When 9a was heated at 110 °C for 12 h in the
2 3 3
presence of 15 mol% Pd (dba) , P(o-Tol) and triethylamine in
9
anhydride method. Diazo transfer to the phosphonoacetate 6
DMF followed by the transesterification of polymer-bound
indole carboxylate using MeONa in MeOH–THF, methyl
3
-phenyl-2-indolecarboxylate 10a was obtained in 48% yield
after SiO
2
column chromatography based on the loading of 9a
Scheme 1
†
On leave from the Central Research Laboratories, SSP Co. Ltd., Narita,
Japan.
Scheme 2
2
10
CHEM. COMMUN., 2002, 210–211
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(d) M. C. Bagley, R. T. Buck, S. L. Hind, C. J. Moody and A. M. Z.
Slawin, Synlett, 1996, 825; (e) L. Ferris, D. Haigh and C. J. Moody,
Synlett, 1995, 921; (f) C. J. Moody, L. Ferris, D. Haigh and E. Swann,
Chem. Commun., 1997, 2391.
3
4
(a) B. Clapham, C. Spanka and K. D. Janda, Org. Lett., 2001, 3, 2173;
(
b) Y. Iso, H. Shindo and H. Hamana, Tetrahedron, 2000, 56, 5353; (c)
M. R. Gowravaram and M. A. Gallop, Tetrahedron Lett., 1997, 38,
973; (d) D. L. Whitehouse, K. H. Nelson, S. N. Savinov and D. J.
6
Austin, Tetrahedron Lett., 1997, 38, 7139; (e) T. Nagashima and H. M.
L. Davies, J. Am. Chem. Soc., 2001, 123, 2695; (f) M. Cano, F. Camps
and J. Joglar, Tetrahedron Lett., 1998, 39, 9819.
Recent reviews for solid phase synthesis: (a) R. J. Franzén, J. Comb.
Chem., 2000, 2, 195; (b) B. A. Bunin, The Combinatorial Index,
Academic Press, San Diego, 1998; (c) A. W. Czarnik and S. H. A.
DeWitt, Practical Guide to Combinatorial Chemistry, American
Chemical Society, Washington DC, 1997; (d) in Combinatorial
Chemistry, John Wiley & Sons, ed. S. R. Wilson and A. W. Czarnik,
New York, 1997; (e) S. H. DeWitt and A. W. Czarnik, Acc. Chem. Res.,
Scheme 3
Table 1 Palladium catalyzed cyclization of haloarylenamino esters 9
Loading/mmol
g
1
996, 29, 114; (f) L. A. Thompson and J. A. Ellman, Chem. Rev., 1996,
2
1
9
X
10
R
1
R
2
Yield (%)
9
6, 555.
5
Recently, some applications for aniline insertion to indole synthesis
were reported: (a) C. J. Moody and E. Swann, Synlett, 1998, 135; (b) J.
A. Brown, Tetrahedron Lett., 2000, 41, 1623.
a
b
c
d
e
f
I
Br
I
Br
I
Br
1.00
1.04
0.94
0.90
0.93
0.92
a
a
b
c
d
e
H
H
H
H
H
4-Me
Ph
Ph
48
52
40
54
31
62
6 4
4-MeOC H
6
7
8
S. Takano, S. Tomita, M. Takahashi and K. Ogasawara, Synthesis, 1987,
2-Pyridyl
2-Thienyl
Ph
1
116.
U. Schmidt, H. Griesser, V. Leitenberger, A. Lieberknecht, R. Mangold,
R. Meyer and B. Riedl, Synthesis, 1992, 487.
T. Sakamoto, T. Nagano, Y. Kondo and H. Yamanaka, Synthesis, 1990,
2
15.
(
Scheme 3). In a similar fashion, palladium catalyzed reactions
9 Solid phase Horner–Emmons reaction(a) J. M. Salvino, T. J. Kiesow, S.
Darnbrough and R. Labaudiniere, J. Comb. Chem., 1999, 1, 134; (b) P.
Wipf and T. C. Henninger, J. Org. Chem., 1997, 62, 1586.
for the other substrates were also carried out to give 3-ar-
ylindole-2-carboxylates 10b–e in the yields summarized in
Table 1.
1
0 Typical experimental procedure: a mixture of resin 7 (1.5 g, 1.8 mmol),
2
-iodoaniline (1.97 g, 9.0 mmol), phenol (35 mg, 0.36 mmol),
Rh (OAc) (40 mg, 0.09 mmol) and toluene (15 ml) was heated at 80 °C
for 12 h under argon atmosphere. The resin was washed with toluene (15
Cl
In summary, we have demonstrated the first solid phase
application of rhodium catalyzed N–H insertion into im-
mobilized carbenoids generated from immobilized a-diazo-
phosphonoacetate and a new and efficient method for the
synthesis of 3-arylindole-2-carboxylates was developed. Fur-
ther applications of this strategy toward diverse synthesis of
other heterocyclic systems are currently under investigation.
This work was partly supported by Grant-in Aid for Scientific
Research (No. 12557198) from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
2
4
ml 3 3), DMF (15 ml 3 3), THF (15 ml 3 3), CH
2
2
(15 ml 3 3),
MeOH (15 ml 3 3) and the resin was dried under reduced pressure at 40
°C. The loading of 8a was estimated by elemental analysis for nitrogen
21
as 0.94 mmol g . DBU (0.11 ml, 0.76 mmol) was added to a
suspension of resin 8a (270 mg, 0.25 mmol) in THF (3 ml) and agitated
for 5 min then benzaldehyde (0.077 ml, 0.76 mmol) was added and
agitated for 12 h at rt. The resin was washed with THF (3 ml 3 3), DMF
(
3 ml 3 3), THF (3 ml 3 3), CH
the resin was dried under reduced pressure. A mixture of resin 9a (0.23
g, 0.23 mmol), Pd (dba) (16 mg, 0.017 mmol), P(o-Tol) (21 mg, 0.069
mmol), Et N (0.48 ml, 3.45 mmol) and DMF (2 ml) was heated at 110
C for 12 h under argon atmosphere. The resin was washed with DMF
(3 ml 3 3), DMF+H O = 1+1 (3 ml 3 3), DMF (3 ml 3 3), THF (3 ml
2 2
Cl (3 ml 3 3), MeOH (3 ml 3 3) and
2
3
3
3
Notes and references
°
1
2
T. Ye and M. A. McKervey, Chem. Rev., 1994, 94, 1091.
(a) E. Aller, R. T. Buck, M. J. Drysdale, L. Ferris, D. Haigh, C. J.
Moody, N. D. Pearson and J. B. J. Sanghera, Chem. Soc., Perkin Trans.
2
3 3), MeOH (3 ml 3 3) and the resin was dried under reduced pressure
at 40 °C. The above resin and NaOMe (75 mg, 1.38 mmol) in THF (2
ml) and MeOH (1 ml) was agitated at rt for 6 h to give 28 mg (48%) of
methyl 3-phenyl-2-indolecarboxylate 10a.
1
, 1996, 2879; (b) L. Ferris, D. Haigh and C. J. Moody, J. Chem. Soc.,
Perkin Trans. 1, 1996, 2885; (c) D. Haigh, Tetrahedron, 1994, 50, 3177;
CHEM. COMMUN., 2002, 210–211
211