Construction of heterocyclic compounds by use of α-diazophosphonates: New one-pot syntheses of indoles and isocoumarins

Article abstract of DOI:10.1021/ol025916k

(Matrix Presented) α-Diazophosphonates, which have extremely useful properties from a synthetic point of view, are disclosed as 1,1-ambiphilic one-carbon building blocks for one-pot construction of various heterocyclic compounds. They are easily prepared and have higher stability by the effect of the phosphoryl group than corresponding α-diazocarbonyl compounds. Using this synthon, we have developed a novel, mild, and efficient synthetic method of 2,3-disubstituted indoles and 3,4-disubstituted isocoumarins.

Full text of DOI:10.1021/ol025916k

ORGANIC
LETTERS
2002
Vol. 4, No. 14
2317-2320
Construction of Heterocyclic
Compounds by Use of
r-Diazophosphonates: New One-Pot
Syntheses of Indoles and Isocoumarins
Yoshinori Nakamura* and Tatsuzo Ukita
DiscoVery Research Laboratory, Tanabe Seiyaku Co., Ltd., 3-16-89, Kashima,
Yodogawa, Osaka 532-8505, Japan
y-naka@tanabe.co.jp
Received March 22, 2002
ABSTRACT
r-Diazophosphonates, which have extremely useful properties from a synthetic point of view, are disclosed as 1,1-ambiphilic one-carbon
building blocks for one-pot construction of various heterocyclic compounds. They are easily prepared and have higher stability by the effect
of the phosphoryl group than corresponding r-diazocarbonyl compounds. Using this synthon, we have developed a novel, mild, and efficient
synthetic method of 2,3-disubstituted indoles and 3,4-disubstituted isocoumarins.
It is an attractive and versatile synthetic method to create
several bonds utilizing the multifunctional building blocks
bearing more than one reactive functional group in the same
molecule. In particular, molecules having reaction centers
on the same carbon atom can be employed to construct cyclic
compounds with one carbon homologation. The Simmons-
Smith cyclopropanation1 and isoquinoline syntheses reported
by Sekine2 and Silveira3 are categorized as this type of
reaction.
et al.,5 have been proven to be the most versatile catalysts
for the decomposition of R-diazocarbonyl compounds and
are now widely used in transformations such as C-H
insertion, X-H insertion (X ) NH, O, S), cyclopropanation,
and ylide formation. In contrast to the R-diazocarbonyl
compounds, R-diazophosphonates 1 have been much less
widely studied so far.6 Moody et al. reported a new, efficient
synthesis of cyclic ethers based on the rhodium carbenoids
derived from 1.7 From a synthetic point of view, R-diazo-
phosphonates have extremely useful properties, e.g., unique
structural features having two different kinds of functional
groups on the same carbon atom, higher stability by the effect
of the phosphoryl group than that of corresponding R-dia-
The transition-metal-catalyzed decomposition of diazo
compounds has become a standard method in organic
synthesis.4 Rhodium(II) complexes, first described by Teissie´
(1) (a) Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1958, 80, 5323.
(b) Simmons, H. E.; Cairns, T. L.; Vladuchick, S. A.; Hoiness, C. M. Org.
React. 1973, 20, 1.
(2) Kohno, H.; Sekine, Y. Heterocycles 1996, 42, 141.
(3) Silveira, C. C.; Bernardi, C. R.; Braga, A. L.; Kaufman, T. S.
Tetrahedron Lett. 1999, 40, 4969.
(4) (a) Doyle, M. P. Chem. ReV. 1986, 86, 919. (b) Ye, T.; McKervey,
M. A. Chem. ReV. 1994, 94, 1091. (c) Padwa, A.; Austin, D. J. Angew.
Chem., Int. Ed. Engl. 1994, 33, 1797. (d) Doyle, M. P.; Forbes, D. C. Chem.
ReV. 1998, 98, 911.
(5) Paulissen, R.; Reimlinger, H.; Hayez, A.; Hubert, A. J.; Teyssie´, Ph.
Tetrahedron Lett. 1973, 14, 2233.
(6) (a) Buck, R. T.; Clarke, P. A.; Coe, D. M.; Drysdale, M. J.; Ferris,
L.; Haigh, D.; Moody, C. J.; Pearson, N. D.; Swann, E. Chem. Eur. J. 2000,
6, 2160. (b) Haigh, D. Tetrahedron 1994, 50, 3177. (c) Brown, J. A.
Tetrahedron Lett. 2000, 41, 1623.
(7) (a) Moody, C. J.; Sie, E.-R. H. B.; Kulagowski, J. J. Tetrahedron
Lett. 1991, 32, 6947. (b) Moody, C. J.; Sie, E.-R. H. B.; Kulagowski, J. J.
Tetrahedron 1992, 48, 3991.
10.1021/ol025916k CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/08/2002

Scheme 1
zocarbonyl compounds,8 and ease of preparation. Thus, we
44% yield, no O-H insertion product 11 was obtained from
10. These results are consistent with the previous findings6b
that the yields of the O-H insertion reaction of phenol
derivatives bearing an electron-withdrawing group or a bulky
group on the ortho position are generally low. Surprisingly,
treatment of 2-benzoylbenzoic acid 16a with 1a in the
presence of 1 mol % of rhodium(II) acetate at 80 °C in
toluene afforded the desired compound 17a quantitatively.
To our knowledge, this is the first example of the rhodium-
(II) acetate-catalyzed insertion reaction of diazocompounds
into the O-H bond of the carboxy group. The subsequent
intramolecular HWE reaction of 17a with DBU at room
temperature in toluene smoothly proceeded to give the ethyl
4-phenylisocoumarin-3-carboxylate 18a in 81% yield.
The indole nucleus is widely present in numerous natural
products and biologically active compounds, and the syn-
thesis of indoles has attracted considerable interest in
synthetic organic chemistry for many years.10 However, few
efficient synthetic methods for the construction of 2,3-
disubstituted indoles are available despite many reports for
the synthetic methods of indoles. On the other hand,
isocoumarins, which display a wide range of biological
activities,11 are a class of naturally occurring lactones and
are used as intermediates for the synthesis of isoquinolino-
nes.12 Thus, we selected indole and isocoumarin derivatives
as target compounds in order to exhibit the usefulness of
this synthetic methodology.
planned to utilize R-diazophosphonates 1 as the building
blocks for the construction of various heterocycles via
dirhodium(II) complex catalyzed heteroatom-H insertion and
the subsequent intramolecular Horner-Wadsworth-Emmons
(HWE) reaction.
R-Phosphoryl metallocarbenoid 2, which is easily gener-
ated from 1 in the presence of dirhodium(II) complex, can
be regarded as one carbon synthon 6 that has the potentiality
of reacting with both nucleophiles (X-H) and electrophiles
(El) on the same carbon atom (Scheme 1). Our strategy is
based upon the initial intermolecular X-H insertion reaction
of 1 with the compounds 3 having both X-H and El groups
(step 1) and the subsequent cyclization of phosphonate
stabilized carbanion 5 under the basic conditions (step 2) to
give cyclic compounds.
To make the scope and limitation of this methodology
clear, we examined the reaction of triethyl diazophospho-
noacetate 1a with 2-aminobenzophenone 7a, 2-hydroxyben-
zophenone 10, 2-thiobenzophenone 13, or 2-benzoylbenzoic
acid 16a (Scheme 2). In our initial attempt, rhodium(II)
acetate-catalyzed reaction of 1a with 7a in toluene at 80 °C
gave the corresponding N-H insertion product 8a in 86%
yield. The experimental procedure of 8a was quite simple
since the slow addition of 1a to the reaction mixture was
not necessary, in contrast to the case of cyclic ether formation
reported by Fuchs.9 The subsequent treatment of 8a with
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at room temper-
ature in toluene gave indole 9a quantitatively as shown in
Scheme 2. While the S-H insertion reaction of 1a with 13
and the subsequent cyclization gave benzothiophene 15 in
In the course of our study on the synthesis of indole
derivatives, we next turned our attention to the development
of one-pot procedures without the isolation of 8 in order to
make the procedures as simple as possible and to avoid
Scheme 2
2318
Org. Lett., Vol. 4, No. 14, 2002

Table 1. One-Pot Preparation of Indolesa
compd
product
yieldb
(%)
entry
7
R1
R2
R3
R4
R5
9
1
2
3
4
5
6
7
8
9c
10c
7a
7b
7c
7d
7e
7f
7g
7a
7a
7a
Ph
H
Me
CH2Ph
Ph
Ph
2-thienyl
Ph
Ph
H
H
H
H
Cl
NO2
OMe
H
H
H
H
H
H
H
H
H
OMe
H
H
H
H
H
H
H
H
H
H
H
H
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
CN
9a
9b
9c
9d
9e
9f
9g
9h
9i
86
73
84
84
91
84
72
91
76
56
CONMe2
Ph
H
9j
11d
12
7a
7h
Ph
Ph
H
Cl
H
H
H
Me
Ph
COOEt
9k
9l
14
20
a Rh-catalyzed reactions were run with 1.0 equiv of amino ketone, 1.0 equiv of R-diazophosphonate, and 1.0 mol % of Rh2(OAc)4 in toluene at 80 °C.
Cyclization reactions were run with 1.1 equiv of DBU in toluene at room temperature unless otherwise stated. b Yields are isolated yields. c Cyclization
reaction was carried out at 80 °C. d LiHMDS was employed in the cyclization reaction.
material loss during the workup procedures. As shown in
Table 1, 9a was obtained in 86% yield from the starting
material 7a in one-pot procedures (entry 1), almost the same
yield as with the stepwise procedures (Scheme 2).
these compounds may be decarboxylated on heating.13 In
terms of the substituents of the R-diazophosphonates,
electron-withdrawing groups such as the ester or cyano
groups facilitated the cyclization to indoles enough to proceed
at room temperature (Table 1, entries 1-8), while the
cyclization of the compounds bearing the tertiary amide
group required relatively high temperature. 3-N,N-Dimeth-
ylcarbamoyl and 3-morpholinocarbonyl derivatives (9i and
9j) were obtained by heating at 80 °C in 76% and 56%
yields, respectively. On the other hand, the yield of 2-phe-
nylindole 9k from R-diazobenzylphosphonate 1e was very
low even when treated with a strong base, lithium hexam-
ethyldisilazide (LiHMDS). These results indicate that the
yields of the cyclization reaction are highly dependent upon
the acidity of the active methylene group of the insertion
2-Aminobenzaldehyde was transformed into ethyl indole-
2-carboxylate 9b in 73% yield (Table 1, entry 2). Enolizable
ketones such as methyl and benzyl ketone were successfully
employed to give the desired 3-alkylindoles in good yields
(Table 1, entries 3 and 4). It is noteworthy that both electron-
withdrawing and electron-donating groups on the phenyl ring
of aniline are tolerated in this reaction (Table 1, entries 5-7).
It should be noted that the resultant indole 2-carboxylate
derivatives could be considered to be the stable equivalents
of 2-unsubstituted indoles, since the indoles are stabilized
by the electron-withdrawing effect of the ester group, and
Table 2. One-Pot Preparation of Isocoumarinsa
compd
product
yieldb
(%)
entry
16
R1
R2
R3
18
1
2
3
4
16a
16b
16c
16d
H
H
OMe
H
H
OMe
H
Ph
H
18a
18b
18c
18d
81
54
73
73
3,4,5-(OMe)3Ph
3,4,5-(OMe)3Ph
OCH2Ph
a Rh-catalyzed reactions were run with 1.0 equiv of carboxylic acid, 1.0 equiv of R-diazophosphonate, and 1.0 mol % of Rh2(OAc)4 in toluene at 80 °C.
Cyclization reactions were run with 1.1 equiv of DBU in toluene at room temperature. b Yields are isolated yields.
Org. Lett., Vol. 4, No. 14, 2002
2319

Scheme 3
products. The N-H insertion reaction of 7h having the
derivatives were obtained in good yields (Table 2, entries 3
and 4), but the yield of 4-unsubstituted derivative dropped
off (Table 2, entry 2). It is noteworthy that 4-(3,4,5-
trimethoxyphenyl) derivatives 18c and 18d were successfully
obtained, since the concomitant formation of demethylated
compounds were observed under the Chatterjea’s conditions
(strong acidic conditions), which is the most common method
for the preparation of this class of compounds.14
Then we explored a further application to isocoumarin-
related ring systems (Scheme 3). The thieno[3,2-c]pyran
derivative 20, which could not be synthesized by Chatterjea’s
method in our attempts, was successfully obtained by our
synthetic method. Moreover, highly strained 2-oxa-fluoran-
thene 22 was also formed in 41% yield from 9-fluorenone-
1-carboxylic acid 21 in one-pot procedures.
N-methylamino group was less successful, probably due to
the steric hindrance of the methyl group that prevents the
coordination of the nitrogen atom to the rhodium metal of
the phosphorylcarbenoid (Table 1, entry 12).
Table 2 summarizes the results of the one-pot synthesis
of isocoumarins by the reaction of 1a with carboxylic acids
16. Ethyl 4-phenylisocoumarin-3-carboxylate 18a was ob-
tained in 81% yield by the one-pot procedures without the
isolation of 17a (Table 2, entry 1). In general, 4-aryl
(8) (a) Regitz, M.; Bartz, W. Chem. Ber. 1970, 103, 1477. (b) Regitz,
M. Angew. Chem., Int. Ed. Engl. 1975, 14, 222. (c) Cox, G. G.; Miller, D.
J.; Moody, C. J.; Sie, E.-R. H. B.; Kulagowski, J. J. Tetrahedron 1994, 50,
3195.
(9) Kim, S.; Sutton, S. C.; Guo, C.; LaCour, T. G.; Fuchs, P. L. J. Am.
Chem. Soc. 1999, 121, 2056.
In summary, we have proposed the novel usage of
R-diazophosphonates 1 as one carbon synthon 6 having both
nucleophilic and electrophilic character on the same carbon
for one-pot construction of various heterocycles. Based on
this concept, we have developed the novel, mild, and efficient
synthetic method of 2,3-disubstituted indoles and 3,4-
disubstituted isocoumarins. Application of our method to the
synthesis of other types of heterocycles is currently underway
in our laboratories.
(10) For reviews on indole synthesis, see: (a) Gribble, G. W. J. Chem.
Soc., Perkin Trans. 1 2000, 1045. (b) Grrible, G. W. Contemp. Org. Synth.
1994, 145. (c) Pindur, U.; Adam, R. J. Heterocycl. Chem. 1988, 25, 1.
(11) (a) Barry, R. D. Chem. ReV. 1964, 64, 229. (b) Waters, S. P.;
Kozlowski, M. C. Tetrahedron Lett. 2001, 42, 3567. (c) Larock, R. C.;
Doty, M. J.; Han, X. J. Org. Chem. 1999, 64, 8770. (d) Wang, L.; Shen,
W. Tetrahedron Lett. 1998, 39, 7625.
(12) (a) Ukita, T.; Nakamura, Y.; Kubo, A.; Yamamoto, Y.; Moritani,
Y.; Saruta, K.; Higashijima, T.; Kotera, J.; Takagi, M.; Kikkawa, K.; Omori,
K. J. Med. Chem. 2001, 44, 2204. (b) Natsugari, H.; Ikeura, Y.; Kiyota,
Y.; Ishichi, Y.; Ishimaru, T.; Saga, O.; Shirafuji, H.; Tanaka, T.; Kamo, I.;
Doi, T.; Otsuka, M. J. Med. Chem. 1995, 38, 3106.
(13) (a) Andrew, M.; Birch, A. M.; Bradley, P. A. Synthesis 1999, 1181.
(b) Macleod, J. K.; Ward, A.; Willis, A. C. Aust. J. Chem. 1998, 51, 177.
(c) Murakami, Y.; Takahashi, H.; Nakazawa, Y.; Koshimizu, M.; Watanabe,
T.; Yokoyama, Y. Tetrahedron Lett. 1989, 30, 2099.
(14) (a) Chatterjea, J. N.; Banerjee, B. K.; Jha, H. C. Chem. Ber. 1965,
98, 3279. (b) Thrash, T. P.; Welton, T. D.; Behar, V. Tetrahedron Lett.
2000, 41, 29.
Supporting Information Available: Experimental
procedures and spectral data for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL025916K
2320
Org. Lett., Vol. 4, No. 14, 2002