A new method for the generation of indole-2,3-quinodimethanes and 2-(N-alkoxycarbonylamino)-1,3-dienes. Intramolecular Heck/Diels-Alder cycloaddition cascade starting from acyclic α-phosphono enecarbamates

Article abstract of DOI:10.1039/b704374k

An intramolecular Heck/Diels-Alder cycloaddition cascade starting from acyclic α-phosphono enecarbamates has been developed to prepare nitrogen heterocycles via indole-2,3-quinodimethanes and 2-(N-alkoxycarbonylamino)-1,3- dienes. The Royal Society of Che

Full text of DOI:10.1039/b704374k

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
A new method for the generation of indole-2,3-quinodimethanes and
2-(N-alkoxycarbonylamino)-1,3-dienes. Intramolecular Heck/Diels–
Alder cycloaddition cascade starting from acyclic a-phosphono
enecarbamates{
Haruhiko Fuwa* and Makoto Sasaki*
Received (in Cambridge, UK) 22nd March 2007, Accepted 17th April 2007
First published as an Advance Article on the web 1st May 2007
DOI: 10.1039/b704374k
An intramolecular Heck/Diels–Alder cycloaddition cascade
starting from acyclic a-phosphono enecarbamates has been
developed to prepare nitrogen heterocycles via indole-2,3-
quinodimethanes and 2-(N-alkoxycarbonylamino)-1,3-dienes.
As exemplified by Heck, Stille and Suzuki–Miyaura reactions,
Scheme 1 Concept of the present work.
Pd(0)-catalysed reactions play significant roles in organic synthesis
by virtue of their exceptional chemo- and stereoselectivity, mild
thieno[3,4-b]indole dioxide.11 Furthermore, we envisioned that
reaction conditions and tolerance of sensitive functional groups.
our strategy could be extended to a general synthesis of exocyclic
Organic chemists have put much effort into the development of
2-acylamino-1,3-dienes.
strategies and tactics employing Pd(0)-catalysed reactions to
We first prepared a-phosphono enecarbamate 8 as a model
synthesise structurally complex molecules, including natural
precursor for the generation of indole-2,3-quinodimethane
products and pharmaceuticals.1 However, the utilisation of
(Scheme 2). Thus, N-(2-iodophenyl)acetamide 5 was cross-coupled
phosphate as a leaving group in Pd(0)-catalysed reactions has
with tri-n-butylvinyltin in the presence of PdCl2(PPh3)2 to give 6.12
been limited to date.2–4 We have recently discovered that Suzuki–
After protection of the amide with Boc2O/DMAP, treatment of
Miyaura coupling using cyclic a-phosphono enol ethers is a
powerful process for convergent synthesis of marine polycyclic
ether natural products.5 In the course of our study, we noticed that
the resultant imide 7 with KHMDS and (PhO)2P(O)Cl afforded 8,
which was used without purification. The results of IHDA using 8
and a variety of dienophiles are summarised in Table 1. Treatment
there is no example of the preparation of acyclic a-phosphono
enamides and enecarbamates despite their potential utility in the
of 8 with 10 mol% of Pd(PPh3)4 in the presence of K2CO3 and
methyl acrylate in DMF at 80 uC provided an approximately 2 : 1
Pd(0)-catalysed synthesis of nitrogen heterocycles. We describe
mixture of tetrahydrocarbazoles 9a,b13 in 75% yield from 7.
herein an intramolecular Heck/Diels–Alder (IHDA) cycloaddition
Utilisation of other dienophiles such as acrylonitrile, methyl vinyl
cascade starting from acyclic a-phosphono enecarbamates; this
cascade efficiently provides a variety of nitrogen heterocycles via
ketone, dimethyl fumarate and N-methylmaleimide also gave good
yields of the corresponding tetrahydrocarbazoles. The IHDA was
indole-2,3-quinodimethanes and 2-(N-alkoxycarbonylamino)-1,3-
effectively carried out in polar solvents such as DMF, 1,4-dioxane
and CH3CN, while THF and toluene were less effective. The
regioselectivity of the cycloaddition did not depend on the solvent
or the reaction temperature. In the absence of a dienophile, the
known dimerised product 1413 was obtained in 49% yield, which
provides experimental evidence for the generation of transparent
indole-2,3-quinodimethane (Scheme 3).
dienes.
Recently, several reports have appeared6–8 on the synthesis of
heterocyclic skeletons by means of a cascade process implementing
an intramolecular Heck reaction.9 Such cascade processes are
ideal organic transformations with respect to atom economy and
overall efficiency. We envisioned that indole-2,3-quinodimethane
(i.e., 2) could be generated from acyclic a-phosphono enecarba-
mate 1 by means of an intramolecular Heck reaction, which in
turn could be trapped in situ by an appropriate dienophile 3 to
provide tetrahydrocarbazole (i.e., 4) (Scheme 1). This approach is
clearly different from the reported methods for indole-2,3-
quinodimethanes,10 which generally rely on either 1,4-elimination
of 2,3-disubstituted indole or thermal degradation of
A variety of substituted tetrahydrocarbazoles were synthesised
based on the IHDA cascade (Table 2). A diverse set of acyclic
a-phosphono enecarbamates 15–21 were prepared from the
respective 2-iodoaniline derivatives as described for 8. Exposure
Laboratory of Biostructural Chemistry, Graduate School of Life
Sciences, Tohoku University, 1-1 Tsutsumidori-amamiya, Aoba-ku,
Sendai, 981-8555, Japan. E-mail: hfuwa@bios.tohoku.ac.jp;
masasaki@bios.tohoku.ac.jp
{ Electronic supplementary information (ESI) available: Representative
experimental procedures and spectroscopic data for new compounds. See
DOI: 10.1039/b704374k
Scheme 2 Reagents and conditions: i, tri-n-butylvinyltin, PdCl2(PPh3)2,
THF, reflux, 94%; ii, Boc2O, DMAP, THF, rt, 100%; iii, KHMDS,
(PhO)2P(O)Cl, HMPA, THF, 278 uC.
2876 | Chem. Commun., 2007, 2876–2878
This journal is ß The Royal Society of Chemistry 2007

View Article Online
Table 1 Synthesis of tetrahydrocarbazole derivatives
Table 2 Synthesis of a variety of substituted tetrahydrocarbazolesa
a-Phosphono
enecarbamate
Yield
(%)
Dienophile
(eq.)
Product
Conditions
Products
Yield (%)
75
DMF,
80 uC
9a: R1 = CO2Me;
R2 = H
9b: R1 = H;
R2 = CO2Me
75
(9a : 9b =
ca. 2 : 1)
76
85
Dioxane,
80 uC
75
(9a : 9b =
ca. 2 : 1)
59
(9a : 9b =
ca. 2 : 1)
32
(9a : 9b =
ca. 2 : 1)
61
(10a : 10b =
ca. 2 : 1)
THF,
reflux
Toluene,
100 uC
93
91
76
DMF,
80 uC
10a: R1 = CN;
R2 = H
10b: R1 = H;
R2 = CN
11a: R1 = COCH3;
R2 = H
11b: R1 = H;
R2 = COCH3
DMF,
80 uC
85
(11a : 11b =
ca. 2 : 1)
CH3CN,
70 uC
83
64
CH3CN, 70 uC
33
a
All reactions were performed using 10 mol% of Pd(PPh3)4,
1.2–2.0 eq. of K2CO3 and 2–10 eq. of dienophile. Yields are overall
from imide 7.
a
10 mol% of Pd(PPh3)4, 1.2 eq. of K2CO3 and 2 eq. of dimethyl
fumarate in CH3CN at 70 uC. Yields are overall from the respective
Boc imides.
of 15–20 to Pd(PPh3)4, K2CO3 and dimethyl fumarate in CH3CN
at 70 uC afforded the desired tetrahydrocarbazoles 22–27 in good
to excellent yields. In contrast, under the same conditions, 21 gave
28 as a 1 : 1 mixture of diastereomers in only moderate yield (33%
along with 9% of recovered 21). Careful inspection of the reaction
mixture resulted in isolation of a small amount (4%) of 32 as a
byproduct, suggesting that an undesired mode of b-elimination of
the cyclopalladation intermediate (29 to 31) might account for the
low yield of 28 (Scheme 4).
Scheme 3 Intramolecular Heck reaction of
8 in the absence of
Scheme 4 Two competitive modes of b-elimination of 29.
Chem. Commun., 2007, 2876–2878 | 2877
dienophile.
This journal is ß The Royal Society of Chemistry 2007

View Article Online
Table 3 Synthesis of non-benzofused nitrogen heterocycles by IHDA
a-Phosphono
Notes and references
1 Metal-catalyzed Cross-coupling Reactions, ed. A. de Meijere and
F. Diederich, Wiley-VCH, New York, 2004.
enecarbamate
Product
Yield (%)
2 For pioneering works: K. Takai, K. Oshima and H. Nozaki,
Tetrahedron Lett., 1980, 21, 2531; M. Sato, K. Takai, K. Oshima and
H. Nozaki, Tetrahedron Lett., 1981, 22, 1609; K. Takai, M. Sato,
K. Oshima and H. Nozaki, Bull. Chem. Soc. Jpn., 1984, 57, 108;
K. Fugami, K. Oshima and K. Utimoto, Chem. Lett., 1987, 2203;
K. C. Nicolaou, G.-Q. Shi, J. L. Gunzner, P. Ga¨rtner and Z. Yang,
J. Am. Chem. Soc., 1997, 119, 5467; K. C. Nicolaou, G.-Q. Shi,
K. Namoto and F. Bernal, Chem. Commun., 1998, 1757.
73a
(34a : 34b =
1 : 1)
62a
3 C. Buon, L. Chacun-Lefevre, R. Rabot, P. Bouyssou and G. Coudert,
Tetrahedron, 2000, 56, 605; F. Lepifre, S. Clavier, P. Bouyssou and
G. Coudert, Tetrahedron, 2001, 57, 6969; F. Lo Galbo, E. G. Occhiato,
A. Guarna and C. Faggi, J. Org. Chem., 2003, 68, 6360; D. Mousset,
I. Gillaizeau, J. Hassan, F. Lepifre, P. Bouyssou and G. Coudert,
Tetrahedron Lett., 2005, 46, 3703; E. G. Occhiato, F. Lo Galbo and
A. Guarna, J. Org. Chem., 2005, 70, 7324; H. Fuwa, A. Kaneko,
Y. Sugimoto, T. Tomita, T. Iwatsubo and M. Sasaki, Heterocycles,
2006, 70, 101.
81a
4 A. L. Hansen, J.-P. Ebran, M. Ahlquist, P.-O. Norrby and
T. Skrydstrup, Angew. Chem., Int. Ed., 2006, 45, 3349.
53a
(38a : 38b =
1 : 1)
5 M. Sasaki, H. Fuwa, M. Ishikawa and K. Tachibana, Org. Lett., 1999,
1, 1075; M. Sasaki, M. Ishikawa, H. Fuwa and K. Tachibana,
Tetrahedron, 2002, 58, 1889; H. Fuwa, N. Kainuma, K. Tachibana and
M. Sasaki, J. Am. Chem. Soc., 2002, 124, 14983; M. Sasaki and
H. Fuwa, Synlett, 2004, 1851; C. Tsukano, M. Ebine and M. Sasaki,
J. Am. Chem. Soc., 2005, 127, 4326; H. Fuwa, M. Ebine and M. Sasaki,
J. Am. Chem. Soc., 2006, 128, 9648; H. Fuwa, M. Ebine,
A. J. Bourdelais, D. G. Baden and M. Sasaki, J. Am. Chem. Soc.,
2006, 128, 16989.
51b
6 For leading references: S. Kouty, B. Liegault, C. Meyer and J. Cossy,
Org. Lett., 2004, 6, 2511; J. Barluenga, M. A. Fernandez, F. Aznar and
C. Valdes, Chem.–Eur. J., 2005, 11, 2276; B. Alcaide, P. Almendros and
R. Rodriguez-Acebes, Chem.–Eur. J., 2005, 11, 5708; R. Yanada,
S. Obika, T. Inokuma, K. Yanada, M. Yamashita, S. Ohta and
Y. Takemoto, J. Org. Chem., 2005, 70, 6972.
a
10 mol% of Pd(PPh3)4, 1.2 eq. of K2CO3, DMF, 80 uC, then
add 2–5 eq. of dienophile (dimethyl fumarate, DMAD, DEAD),
b
50–80 uC. 1.2 eq. of Ag2CO3 was used as a base. Yields are overall
from the respective Boc imides.
7 Construction of polycyclic skeletons by IHDA: F. E. Meyer, K. H. Ang,
A. G. Steinig and A. de Meijere, Synlett, 1994, 191; K. H. Ang, S. Bra¨se,
A. G. Steinig, F. E. Meyer, A. Llebaria, K. Voigt and A. de Meijere,
Tetrahedron, 1996, 52, 11503; L. Bhat, A. G. Steinig, R. Appelbe and
A. de Meijere, Eur. J. Org. Chem., 2001, 1673; S. Ko¨rbe, A. de Meijere
and T. Labahn, Helv. Chim. Acta, 2002, 85, 3161; H. Nu¨ske, S. Bra¨se,
S. I. Kozhushkov, M. Noltemeyer, M. Es-Sayed and A. de Meijere,
Chem.–Eur. J., 2002, 8, 2350; M. Knoke and A. de Meijre, Synlett, 2003,
195; M. Knoke and A. de Meijre, Eur. J. Org. Chem., 2005, 2259.
8 For an example of an intermolecular Heck/Diels–Alder cascade:
S. Brown, R. Grigg, J. Hinsley, S. Korn, V. Sridharan and
M. D. Uttley, Tetrahedron, 2001, 57, 10347.
9 For reviews: S. E. Gibson and R. J. Middleton, Contemp. Org. Synth.,
1996, 3, 447; I. P. Beletskaya and A. V. Cheprakov, Chem. Rev., 2000,
100, 3009.
10 P. Magnus, T. Gallagher, P. Brown and P. Pappalardo, Acc. Chem.
Res., 1984, 17, 35; U. Pindur and H. Erfanian-Abdoust, Chem. Rev.,
1989, 89, 1681; J. L. Segura and N. Martin, Chem. Rev., 1999, 99,
3199.
11 Recently, Mukai and co-workers reported a new method for the
generation of indole-2,3-quinodimethanes: N. Kuroda, Y. Takahashi,
K. Yoshinaga and C. Mukai, Org. Lett., 2006, 8, 1843.
12 J. K. Stille, Angew. Chem., Int. Ed. Engl., 1986, 25, 508.
13 E. R. Marinelli, Tetrahedron Lett., 1982, 23, 2745.
14 Synthesis and DA cycloaddition of 2-(N-alkoxycarbonylamino)-1,3-
dienes and 2-(N-acylamino)-1,3-dienes have been less explored:
A. Terada and K. Murata, Bull. Chem. Soc. Jpn., 1967, 40, 1644;
J. D. Ha, C. H. Kang, K. A. Belmore and J. K. Cha, J. Org. Chem.,
1998, 63, 3810; F. Lo Galbo, E. G. Occhiato, A. Guarna and C. Faggi,
J. Org. Chem., 2003, 68, 6360; M. Movassaghi, D. K. Hunt and
M. Tjandra, J. Am. Chem. Soc., 2006, 128, 4592.
15 Hsung and co-workers have reported the synthesis of several a-halo
enamides, which can be considered synthetic equivalents of a-phos-
phono enamides: J. A. Mulder, K. C. M. Kurtz, R. P. Hsung,
H. Coverdale, M. O. Frederick, L. Shen and C. A. Zificsak, Org. Lett.,
2003, 5, 1547.
Finally, we exploited the IHDA of a-phosphono enecarbamates
in the synthesis of non-benzofused heterocyclic compounds
(Table 3). Treatment of 33 with Pd(PPh3)4 and K2CO3 smoothly
generated an exocyclic diene (not shown), which was reacted with
appropriate dienophiles to give 5/6-bicyclic compounds 34a,b (1 : 1
mixture of diastereomers), 35 and 36, respectively. The IHDA
cascade could also be applied to the synthesis of 6/6-bicyclic
compounds 38a,b and 39. The lack of diastereocontrol in the case
of 34a,b and 38a,b was disappointing but these data are in
accordance with the previous reports on 2-(N-acylamino)-1,3-
dienes.14 Overall, the IHDA strategy is not limited to the
generation of indole-2,3-quinodimethanes; it is generally applicable
to the generation of exocyclic 2-(N-alkoxycarbonylamino)-1,3-
dienes that readily undergo DA cycloaddition with an appropriate
dienophile to provide nitrogen heterocycles.
In conclusion, we have developed an IHDA cascade starting
from acyclic a-phosphono enecarbamates. The chemistry demon-
strated here highlights the synthetic utility of acyclic a-phosphono
enecarbamates in the Heck reaction and provides a new strategy
for the generation of indole-2,3-quinodimethanes and related
2-(N-alkoxycarbonylamino)-1,3-dienes, useful compounds for the
rapid synthesis of nitrogen heterocycles. Further exploitation of
a-phosphono enecarbamates in the context of palladium chemistry
is currently under investigation, as is the application of the IHDA
strategy to the synthesis of natural products.15
This work was supported in part by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan.
2878 | Chem. Commun., 2007, 2876–2878
This journal is ß The Royal Society of Chemistry 2007