A convenient one-pot synthesis of spirocyclic pyrido[1,2-a]indole derivatives from 3-(2-bromoethyl)indole

Article abstract of DOI:10.1055/s-2006-950252

A convenient one-pot approach for the synthesis of spirocyclic pyrido[1,2-a]indole derivatives is described. The method involves treatment of 1,3-diketones and 1,3-ketoesters with base to generate dianions, which react with 3-(2-bromoethyl)indole to const

Full text of DOI:10.1055/s-2006-950252

LETTER
3355
A Convenient One-Pot Synthesis of Spirocyclic Pyrido[1,2-a]indole
Derivatives from 3-(2-Bromoethyl)indole
Synthesis
iof Spirn
g
o[1,2-
a
]indo
l
le
D
er
i
ivative
s
ang Jiao, Yang Zhang, Robert A. Flowers II*
Department of Chemistry, Lehigh University, Bethlehem, PA 18015, USA
Fax +1(610)7586536; E-mail: rof2@lehigh.edu
Received 18 July 2006
Abstract: A convenient one-pot approach for the synthesis of spi-
rocyclic pyrido[1,2-a]indole derivatives is described. The method
involves treatment of 1,3-diketones and 1,3-ketoesters with base to
generate dianions, which react with 3-(2-bromoethyl)indole to con-
struct a spirocyclopropyl ring and an N-heterocyclic ring sequen-
tially in moderate to very good yields.
N
N
N
R1
R2
1
2
3
Key words: spirocyclic pyrido[1,2-a]indole derivatives, tandem
reactions, heterocycles.
pyrido[1,2-a]
indole skeleton
spiroindolenine
spiropyrido[1,2-a]
indole skeleton
Figure 1
The indole unit represents a key structure among natural
products and pharmaceutically important compounds.1
The synthesis of pyrido[1,2-a]indole derivatives, a class
of tricyclic compounds 1, has drawn considerable atten-
tion due to their biological activity and synthetic interest.2
Although a variety of strategies has been developed to
generate these heterocyclic derivatives,3,4 the popular
methods mainly involve the cyclization catalyzed by met-
al compounds such as Pd(II),3b,5 Sm(II),3a and Ni(II) com-
plexes.3d Solid-phase synthesis has also been used to
construct the pyrido[1,2-a]indole derivatives via radical
cyclization.6 Spiroindolenine (2) first synthesized by
Closson also contains an indole subunit.7 Compound 2
can be readily accessed from 3-(2-bromoethyl)indole8 and
was recently used as a electron-deficient adduct to synthe-
size pyrrole derivatives.9
O
O
a, R1 = Me, R2 = H;
4
b, R1 = Me, R2 = Me;
c, R1 = Ph, R2 = H;
d, R1 = OMe, R2 = H;
R1
R2
1) 2 NaH, THF, 0 °C
2) 2 n-BuLi
3)
Br
N
H
5
a, R1 = Me, R2 = H;
b, R1 = Me, R2 = Me;
c, R1 = Ph, R2 = H;
d, R1 = OH, R2 = H;
N
R1
O
While numerous approaches to 1 and 2 (Figure 1) are
available, there are no reports describing easy access to
the related spiropyrido[1,2-a]indole 3 (Figure 1), in spite
of the fact that such a protocol would provide important
approaches to a range of natural product precursors.10 In-
spired by the protocol originally described by Closson, we
reasoned that the dianions generated from 1,3-diketones
and 1,3-ketoesters11 would be good candidates to undergo
reaction with 3-(2-bromoethyl)indole to simultaneously
construct the spiro ring in 2 and the N-heterocyclic six-
membered ring in compound 1 to produce 3. A convenient
one-pot approach to spirocyclic pyrido[1,2-a]indole de-
rivatives is reported herein.
R2
Scheme 1 One-pot transformation from 3-(2-bromoethyl)indole to
spirocyclic pyrido[1,2-a]indole derivatives
lithium followed by the addition of 3-(2-
bromoethyl)indole (Scheme 1).12
The reaction worked well to afford a novel spirocyclic py-
rido[1,2-a]indole compound 5a in 85% isolated yield. The
success of this reaction encouraged us to investigate its
generality and scope. Two other 1,3-diketones (4b,c) and
a 1,3-ketoester (4d) were reacted with 3-(2-bromoeth-
yl)indole using the same procedure. The data for these re-
actions is summarized in Table 1. The data in Table 1
shows the reaction proceeds to produce spirocyclic pyri-
do[1,2-a]indole derivatives for all four 1,3-diketones and
1,3-ketoesters (4a–d). Moderate to good yields (66–85%)
were achieved and all products were purified and charac-
terized by NMR, GC–MS, and HRMS.13
To initially examine this approach, 2,4-pentadione (4a)
was treated with two equivalents of sodium hydride in tet-
rahydrofuran at 0 °C and then two equivalents of n-butyl-
SYNLETT 2006, No. 19, pp 3355–3357
0
1
.1
2
.2
0
0
6
Advanced online publication: 23.11.2006
DOI: 10.1055/s-2006-950252; Art ID: S17006ST
© Georg Thieme Verlag Stuttgart · New York

3356
J. Jiao et al.
LETTER
Table 1 Synthesis of Spirocyclic Pyrido[1,2-a]indole Derivatives
from 3-(2-Bromoethyl)indole and 1,3-Diketones or 1,3-Ketoesters
While the mechanism of the reaction was not studied in
detail, exposure of 2 to 4a in tetrahydrofuran containing
two equivalents of sodium hydride and two equivalents of
n-butyllithium produces product 5a and unreacted starting
material. As a result, it is likely that the presence of excess
base leads to deprotonation of the NH group providing the
spiroindolenine as shown by Closson.7 Reaction of 2 with
the dianion generated from the 1,3-diketones and 1,3-ke-
toesters furnishes the N-heterocyclic six-membered ring
in the product. The loss of water produces compounds 5a–
c while the loss of methanol leads to compound 5d
(Scheme 2).
Entry Substrate R1
R2
H
Product
Yield (%)a
1
2
3
4
4a
4b
4c
4d
Me
Me
Ph
5a (85%)
N
O
O
Me
Me
5b (81%)
5c (76%)
5d (66%)b
N
The convenience of the one-pot, two-component strategy
generally provides a number of advantages and this initial
contribution based on known chemistry shows that a fairly
complex product can be produced from readily available
starting materials. The extension of this reaction could po-
tentially lead to the convenient synthesis of other spiropy-
rido[1,2-a]indole compounds when the bromoethyl group
in 3-(2-bromoethyl)indole is replaced by other substitu-
ents containing a good leaving group. Such a protocol
would provide spiro compounds that can possibly serve as
platforms or intermediates for the synthesis of more com-
plex natural products. Studies on the application of this re-
action protocol are currently underway in our research
group.
Me
Me
H
N
O
Ph
OMe
H
N
O
HO
a Isolated yield.
b Keto–enol mixture.
Acknowledgment
R.A.F. is grateful to the National Institutes of Health
(1R15GM075960-01) for support of this work and to Dr. Pramod
Mohanta and Mr. James Devery for their useful comments on the
manuscript. We also thank one of the referees for insightful com-
ments on the manuscript.
Although the bridgehead methine (CHN) proton in the
products show a large coupling constant of approximately
16 Hz, this finding is consistent with other multicyclic
ring systems where a bridgehead methine is adjacent to a
methylene group (CH2CO protons).14 Nonetheless 1H–1H
1
COSY and H–13C HMQC experiments were carried out
on compound 5a to confirm the structure derived from 1H
References and Notes
1
and 13C NMR data. H–1H COSY cross peaks were ob-
(1) (a) Joule, J. A. Science of Synthesis, Vol. 10; Thomas, E. J.,
Ed.; Georg Thieme Verlag: Stuttgart, 2000, 361–652.
(b) Bosch, J.; Bonjoch, J.; Amat, M. Alkaloids 1996, 48, 75.
(c) Sundberg, R. J. Indoles; Academic Press: London, 1996.
(d) Chadwick, D. J.; Jones, R. A.; Sundberg, R. J.
Comprehensive Heterocyclic Chemistry, Vol. 4; Pergamon:
Oxford, 1984, 155–376.
(2) (a) Saxton, J. E. The Chemistry of Heterocyclic Compounds,
Vol. 25, Part IV; Academic Press: New York, 1994.
(b) Clark, R. D.; Miller, A. B.; Berger, J.; Repke, D. B.;
Weinhardt, K. K.; Kowalczyk, B. A.; Eglen, R. M.;
Bonhaus, D. W.; Lee, C. H. J. Med. Chem. 1993, 36, 2645.
served between the following signals: 2.14 ppm × 2.42
ppm, 2.14 ppm × 4.41 ppm, and 2.42 ppm × 4.41 ppm. In
a 1H–13C HMQC experiment, the proton corresponding to
a dd at d = 2.14 ppm and the proton corresponding to a
triplet at d = 2.42 ppm cross into the carbon resonance at
d = 38.4 ppm; the proton corresponding to a dd at d = 4.41
ppm crosses into the carbon resonance at d = 64.3 ppm.
The additional data are consistent with the structure of
compound 5a and further support the structure derived
from the 1H and 13C NMR data.
Br
B–
H-B
– H2O (4a–c)
– MeOH (4d)
N
N
_
N
N
R1
O
H
O
R1
O
_
2
R2
R2
O
O
O
O
1) NaH, THF, 0 °C
5
_
_
R1
R1
2) n-BuLi
R2
R2
Scheme 2 Proposed mechanism for the reaction of the dianions of 1,3-diketones and 1,3-ketoesters with 3-(2-bromoethyl)indole
Synlett 2006, No. 19, 3355–3357 © Thieme Stuttgart · New York

LETTER
Synthesis of Spirocyclic Pyrido[1,2-a]indole Derivatives
3357
(3) (a) Gross, S.; Reissig, H.-U. Org. Lett. 2003, 5, 4305.
(b) Hiroi, K.; Hiratsuka, Y.; Watanabe, K.; Abe, I.; Kato, F.;
Hiror, M. Tetrahedron: Asymmetry 2002, 13, 1351.
(c) Teuber, H. J.; Worbs, E.; Cornelius, D. Arch. Pharm.
1982, 315, 388. (d) Ozaki, S.; Mitoh, S.; Ohmori, H. Chem.
Pharm. Bull. 1996, 44, 2020.
(4) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045.
(5) Bytschkov, I.; Siebeneicher, H.; Doye, S. Eur. J. Org. Chem.
2003, 2888.
(6) Nicolaou, K. C.; Roecker, A. J.; Hughes, R.; Summeren, R.
V.; Pfefferkorn, J. A.; Winssinger, N. Bioorg. Med. Chem.
2003, 11, 465.
(7) Closson, W. D.; Roman, S. A.; Kwiatkowski, G. T.; Corwin,
D. A. Tetrahedron Lett. 1966, 21, 2271.
104.4, 64.3, 38.4, 26.6, 22.5, 15.4, 12.1. GC–MS (tR = 19.96
min): m/z = 225 (56) [M+], 197 (100), 154 (48), 115 (13).
HRMS (FAB): m/z [M + H+] calcd for C15H16ON: 226.1232;
found: 226.1216.
5b: The general procedure was followed with the use of
substrate 4b (0.68 g) and product 5b (0.97 g, 81%) was
obtained as a orange-brown solid after purification. 1H NMR
(500 MHz, CDCl3): d = 7.18 (d, J = 8.2 Hz, 1 H), 7.10 (t,
J = 7.5 Hz, 1 H), 6.88 (t, J = 7.4 Hz, 1 H), 6.69 (d, J = 7.4
Hz, 1 H), 4.30 (dd, J = 4.0, 16.4 Hz, 1 H), 2.50 (s, 3 H), 2.47
(t, J = 16.1 Hz, 1 H), 2.18 (dd, J = 3.9, 15.9 Hz, 1 H), 1.86
(s, 3 H), 1.21–1.27 (m, 2 H), 0.90–0.93 (m, 1 H), 0.73–0.76
(m, 1 H). 13C NMR (125 MHz, CDCl3): d = 191.7, 153.8,
143.8, 137.8, 127.1, 121.8, 119.3, 111.9, 111.1, 64.0, 39.2,
29.9, 18.7, 14.9, 13.4, 10.6. GC–MS (tR = 20.02 min): m/z =
239 (100) [M+], 211 (90), 196 (20), 182 (35), 168 (88), 129
(18), 115 (29). HRMS (FAB): m/z [M + H+] calcd for
C16H18ON: 240.1388; found: 240.1388.
(8) Johansen, J. E.; Christie, B. D.; Rapoport, H. J. Org. Chem.
1981, 46, 4914.
(9) Amombo, M. O.; Hausherr, A.; Reissig, H.-U. Synlett 1999,
1871.
(10) (a) Clive, D. L. J.; Wang, J.; Yu, M. Tetrahedron Lett. 2005,
46, 2853. (b) Rubiralta, M.; Diez, A.; Vila, C.; Troin, Y.;
Feliz, M. J. Org. Chem. 1991, 56, 6292.
5c: The general procedure was followed with the use of
substrate 4c (0.97 g) and product 5c (1.09 g, 76%) was
obtained as a brown-black solid after purification. 1H NMR
(500 MHz, CDCl3): d = 7.50–7.52 (m, 5 H), 6.79 (td, J = 1.0,
7.4 Hz, 1 H), 6.73 (td, J = 1.4, 7.5 Hz, 1 H), 6.65 (dd, J = 1.0,
7.3 Hz, 1 H), 5.71 (d, J = 8.2 Hz, 1 H), 5.38 (s, 1 H), 4.65
(dd, J = 4.0, 15.9 Hz, 1 H), 2.75 (t, J = 16.1 Hz, 1 H), 2.24
(dd, J = 4.0, 16.3 Hz, 1 H), 1.19–1.22 (m, 2 H), 1.08–1.12
(m, 1 H), 0.88–0.91 (m, 1 H). 13C NMR (125 MHz, CDCl3):
d = 192.4, 157.8, 145.1, 139.5, 135.7, 131.1, 128.0, 127.1,
122.6, 118.5, 116.2, 114.9, 108.8, 66.3, 39.9, 27.0, 16.0,
13.8. GC–MS (tR = 24.35 min): m/z = 287 (81) [M+], 258
(100), 230 (85), 154 (26), 129 (45). HRMS (FAB): m/z [M +
H+] calcd for C20H18ON: 288.1388; found: 288.1390.
5d: The general procedure was followed with the use of
substrate 4d (0.70 g) and product 5d (0.75 g, 66%) was
obtained as a yellow solid after purification. 1H NMR (500
MHz, CDCl3; enol–keto mixture): d = 8.15 (d, J = 8.0 Hz, 0.4
H), 7.20 (t, J = 7.5 Hz, 0.6 H), 7.06 (t, J = 7.4 Hz, 0.5 H),
6.97 (td, J = 1.0, 7.6 Hz, 0.9 H), 6.69 (d, J = 7.6 Hz, 0.6 H),
6.65 (t, J = 7.3 Hz, 0.8 H), 6.56 (t, J = 7.0 Hz, 1.6 H), 5.28
(s, 0.1 H), 4.67 (m, 0.5 H), 4.11 (m, 1 H), 3.73 (s, 3.5 H), 2.73
(m, 1 H), 2.51–2.59 (m, 2 H), 1.22–1.39 (m, 3 H), 0.79–1.03
(m, 6.5 H). 13C NMR (125 MHz, CDCl3): d = 202.5, 167.3,
150.0, 133.3, 127.5, 127.0, 125.0, 118.8, 118.5, 116.0,
108.9, 59.8, 58.8, 52.5, 49.9, 49.5, 46.7, 42.3, 30.2, 28.0,
15.9, 15.5, 14.6, 12.2. GC–MS (tR = 19.26 min): m/z = 227
(35) [M+], 199 (82), 130 (100), 115 (48). HRMS (FAB):
m/z [M + H+] calcd for C14H14O2N: 228.1025; found:
228.1013.
(11) Huckin, S. N.; Weiler, L. J. Am. Chem. Soc. 1974, 96, 1082.
(12) General Procedure for Reaction Protocol: NaH (12 mmol,
0.29 g) was weighed out with a flask in a dry box and then
THF (40 mL) was added. The flask was placed in an ice bath.
The mixture was stirred and 1,3-diketones or 1,3-ketoesters
4 (6 mmol) in THF (5 mL) was added dropwise into the
flask. The mixture was further stirred for 10 min at 0 °C and
then n-BuLi (12 mmol, 7.6 mL of 1.6 M n-BuLi solution in
hexane) was added dropwise. After 20 min, 3-(2-bromo-
ethyl) indole (5 mmol, 1.12 g) in THF (5 mL) was added
dropwise with stirring. The reaction mixture was warmed to
r.t. slowly and further stirred overnight. The reaction mixture
was hydrolyzed with 1% HCl solution (30 mL) and extracted
with Et2O. The combined organic extracts were washed with
H2O and dried over MgSO4. After filtration, the crude
product was concentrated and purified with column
chromatography. The obtained pure products 5 were
characterized with 500 MHz NMR, GC–MS, and HRMS.
(13) The NMR spectra were recorded with 500 MHz NMR
spectrometer. GC–MS method: initial temperature: 50 °C
(hold for 3 min), rate: 15 °C/min, final temperature: 280 °C
(hold for 7 min). Compound 5a: The general procedure was
followed with the use of substrate 4a (0.6 g) and product 5a
(0.95g, 85%) was obtained as a brown solid after
purification. 1H NMR (500 MHz, CDCl3): d = 7.21 (d, J =
8.2 Hz, 1 H), 7.12 (t, J = 7.3 Hz, 1 H), 6.94 (t, J = 7.4 Hz, 1
H), 6.72 (d, J = 7.2 Hz, 1 H), 5.19 (s, 1 H), 4.41 (dd, J = 4.1,
16.5 Hz, 1 H), 2.47 (s, 3 H), 2.42 (t, J = 16.2 Hz, 1 H), 2.14
(dd, J = 4.0, 15.8 Hz, 1 H), 1.22–1.29 (m, 2 H), 0.90–0.95
(m, 1 H), 0.71–0.76 (m, 1 H). 13C NMR (125 MHz, CDCl3):
d = 191.5, 156.7, 143.1, 137.8, 127.2, 122.9, 119.5, 112.3,
(14) (a) Revuelta, J.; Cicchi, S.; Brandi, A. J. Org. Chem. 2005,
70, 5636. (b) Cicchi, S.; Revuelta, J.; Zanobini, A.; Betti,
M.; Brandi, A. Synlett 2003, 2305.
Synlett 2006, No. 19, 3355–3357 © Thieme Stuttgart · New York