Regio- and stereoselective synthesis of pterocarpan derivatives on a carbazole scaffold by cascade sigmatropic rearrangements

Article abstract of DOI:10.1055/s-2006-951563

Thermal rearrangement of 1-aryloxy-4-carbazolyloxy-but-2-ynes, regio- and stereoselectively led to the formation of benzofuropyranocarbazoles in a single step in good yields. An investigation into the mechanism of the formation of these heteroannulated pt

Full text of DOI:10.1055/s-2006-951563

3358
LETTER
Regio- and Stereoselective Synthesis of Pterocarpan Derivatives on a
Carbazole Scaffold by Cascade Sigmatropic Rearrangements
R
egio- and Ste
h
r
eoselective
i
Synthe
t
sis of
P
a
terocarpan
l
D
erivatives K. Chattopadhyay,* Debalina Ghosh, Titas Biswas
Department of Chemistry, University of Kalyani, Kalyani 741235, India
Fax +91(33)25828282; E-mail: skchatto@yahoo.com
Received 22 August 2006
Cl
Abstract: Thermal rearrangement of 1-aryloxy-4-carbazolyloxy-
but-2-ynes, regio- and stereoselectively led to the formation of ben-
zofuropyranocarbazoles in a single step in good yields. An
investigation into the mechanism of the formation of these het-
eroannulated pterocarpan derivatives led to the serendipitous for-
mation of isomeric benzofurofurocarbazole ring system.
R1
Me2CO
+
OH
K2CO3, NaI
reflux, 12 h
N
H
O
R2
2a–d
1
Key words: sigmatropic rearrangements, heterocycles, regioselec-
tivity, ring contractions
O
O
H
N
H
PhNEt2
N
Me
H
Thermal rearrangement of aryl propynyl ethers to benzo-
furan and/or benzopyran derivatives is well documented.1
The operational simplicity and high efficacy of the pro-
cess has rendered it an attractive and valuable methodolo-
gy in heterocyclic synthesis over the last four decades.2
reflux, 12 h
O
O
R2
R1
R1
R2
Mechanistically, the process involves a series of consecu-
tive sigmatropic rearrangements and a great deal of atten-
tion has been paid detailing these propositions.3 In
contemporaneous studies, Thyagrajan et al. reported a
unique observation on the thermal behaviour of 1,4-di-
aryloxy-2-butynes in which pterocarpan-like structures
were formed in a single step in high yields.4 The reaction
has found applications in heterocyclic synthesis and new
observations have occasionally been made.5,6 These inter-
ested us to study the thermal behaviour of 1-aryloxy-4-
carbazolyloxy-but-2-ynes 3 (Scheme 1, Table 1) with an
additional aim to synthesise polyoxacyclic carbazole
derivatives in continuation of our interest in the synthesis
of heteroannulated carbazoles.7
3a–d
4a–d
Scheme 1
Table 1 Synthesis of 1-Aryloxy-4-carbazolyloxybut-2-ynes 3 and
benzofuropyranocarbazoles 4
Compd
R1
R2
Yield of 3a–d Yield of 4a–d
(%)
(%)
2a, 3a, 4a
2b, 3b, 4b
2c, 3c, 4c
2d, 3d, 4d
H
H
3a (65)
3b (68)
3c (61)
3d (59)
4a (73)
4b (84)
4c (81)
4d (82)
H
Me
H
Me
Cl
H
The starting materials 3a–d were easily prepared by the
reaction between commercially available 2-hydroxycar-
bazole (1) and easily obtainable 1-aryloxy-4-chlorobut-2-
ynes 2a–d.8 When compound 3a was refluxed in N,N-di-
ethylaniline, a slow conversion to a new compound was
observed. The product was characterised to be the benzo-
furopyranocarbazole derivative 4a on the basis of spectral
and analytical data. The stereochemistry of the ring junc-
tion, previously surmised from Drieding models in similar
situations to be cis,9 was established to be cis on the basis
of NOE correlation between the methyl resonance at d =
1.90 ppm and the benzylic proton at d = 3.71 ppm. Simi-
larly, compounds 3b–d provided the products 4b–d in
good yields.
The formation of 4 from 3 could be mechanistically cor-
related by invoking preferential [3,3]-sigmatropic rear-
rangement of the carbazolyloxypropyne part followed by
enolisation to provide the corresponding 2-allenyl phenol
5 (Scheme 2). The latter may undergo a [1,5]-prototropic
shift to form the dienenone derivative 6. Electrocyclic
ring-closure of the latter then would lead to the pyranocar-
bazole derivative 7. A second [3,3]-sigmatropic shift of
the allyl vinyl ether part in 7 followed by enolisation
would be expected to provide the phenol 8. Ring-closure
of the latter in a 5-exo fashion may explain the formation
of the observed products. The regioselectivity of the first
[3,3] shift to 1-position is similar to that observed during
rearrangement of 2-allyloxycarbazole.10
While the spectroscopic data fit well with the structure of
4, alternative formation of the isomeric compound 10
(Scheme 3) from the rearrangement of 3, involving the
SYNLETT 2006, No. 19, pp 3358–3360
Advanced online publication: 23.11.2006
DOI: 10.1055/s-2006-951563; Art ID: D25306ST
© Georg Thieme Verlag Stuttgart · New York
0
1
.1
2
.2
0
0
6

LETTER
Regio- and Stereoselective Synthesis of Pterocarpan Derivatives
3359
[1,5]-H
shift
[3,3]
CH2Cl
O
3
O
O
N
H
H
N
Me2CO
N
PhNEt2
,12 h
Me
H
9
H
1 +
Me
K2CO3,
,12 h
O
O
OAr
56%
OAr
ECR
5
6
74%
11
12
4
O
[3,3]
5-exo
O
N
H
OH
N
N
H
N
H
O
12
H
9
H
Me
HO
O
O
O
8
7
Scheme 2
13
10
Scheme 4
first [3,3]-sigmatropic shift in the aryloxypropynyl part,
through the structure 9 could not be ruled out. Since, the
available spectroscopic data did not allow distinction be-
tween the structures 4 and 10, we undertook an alternative
synthetic route for this distinction. We reasoned that rear-
rangement of preformed 9 under analogous conditions
should provide 10 if the mechanistic route detailed in
Scheme 2 is followed. Thus, treatment of 1 with the
known 4-chloromethyl-D3-chromene11 (11, Scheme 4) in
refluxing acetone in the presence of anhydrous potassium
carbonate led to the formation of the desired 9. However,
thermal rearrangement of 9 in refluxing N,N-diethyl-
aniline quite unexpectedly gave rise to an entirely differ-
In short, we have demonstrated the utility of cascade sig-
matropic rearrangements for the synthesis of hitherto un-
known
benzofurofurocarbazole derivatives, which are otherwise
difficult to prepare. The process is general, regio- and ste-
reoselective, atom economic, efficacious and operational-
ly simple. The compounds prepared13 may prove to be
useful in view of the known importance of naturally oc-
curring furo- and pyranocarbazoles and synthetic ana-
logues thereof.14
benzofuropyranocarbazole
and
isomeric
1
ent product. Examination of the H NMR and 13C NMR
Acknowledgment
spectra quickly revealed the presence of two methyl
groups as only signals in the entire aliphatic region. The
compound was characterised to be the benzofurofuro-
Financial assistance from DST, New Delhi, (Grant No SR/S1/OC-
51/2005) is gratefully acknowledged. D.G. and T.B. are thankful to
carbazole derivative 12 on the basis of spectroscopic and CSIR, New Delhi, for fellowships.
analytical data. The stereochemistry of the ring junction
has been tentatively assigned cis based on the belief that a
5,5-cis-fused structure will be more strain free. Mechanis-
References and Notes
(1) Iwai, I.; Ide, J. Chem. Pharm. Bull. 1962, 10, 926.
tically, compound 9 may undergo Claisen rearrangement
to 13, which then would form 10 through a 5-exo cyclisa-
tion. The latter may then undergo ring contraction to 12
via a [1,2]-H shift. This type of ring contraction has been
observed previously.12 However, its utility in hetero-
cyclic synthesis is not well documented to the best of our
knowledge.
(2) (a) Sarcevic, N.; Zsindley, J.; Schmid, H. Helv. Chim. Acta
1973, 56, 1457. (b) Rao, U.; Balasubramanian, K. K.
Tetrahedron Lett. 1983, 24, 5023. (c) Subramanian, R. S.;
Balasubramanian, K. K. Tetrahedron Lett. 1988, 29, 6797.
(d) Yang, Z.-Y.; Xia, Y.; Xia, P.; Brossi, A.; Lee, K.-H.
Tetrahedron Lett. 1999, 40, 4505.
(3) Zsindley, J.; Schmid, H. Helv. Chim. Acta 1968, 51, 1510.
(4) Thyagarajan, B. S.; Balasubramanian, K. K.; Bhima Rao, K.
Tetrahedron Lett. 1963, 1393.
(5) Majumdar, K. C.; De R, N.; Khan, A. T.; Chattopadhyay, S.
K.; Dey, K.; Patra, A. J. Chem. Soc., Chem. Commun. 1988,
777.
(6) (a) Macor, J. E.; Langer, O. D.; Gougoutas, J. Z.; Melley, M.
F.; Cornelius, L. A. M. Tetrahedron Lett. 2000, 41, 3541.
(b) Majumdar, K. C.; Das, U. J. Org. Chem. 1998, 63, 9997.
(7) Chattopadhyay, S. K.; Roy, S. P.; Ghosh, D.; Biswas, G.
Tetrahedron Lett. 2006, 47, 6895.
O
N
O
H
N
Me
H
H
3
O
O
(8) Majumdar, K. C.; Thyagarajan, B. S. Int. J. Sulfur Chem.,
Part A 1972, 2, 93.
(9) (a) Bates, D. K.; Jones, M. C. J. Org. Chem. 1978, 43, 3856.
(b) Majumdar, K. C.; Kundu, U. K.; Ghosh, S. J. Chem. Soc.,
Perkin Trans. 1 2002, 2139.
9
10
Scheme 3
Synlett 2006, No. 19, 3358–3360 © Thieme Stuttgart · New York

3360
S. K. Chattopadhyay et al.
LETTER
d = 8.65 (s, 1 H), 7.97 (d, 1 H, J = 7.8 Hz), 7.85 (d, 1 H,
(10) Ishihara, T.; Kakuta, H.; Moritani, H.; Ugawa, T.;
Yanigawa, I. Bioorg. Med. Chem. Lett. 2004, 12, 5899.
(11) Thyagarajan, B. S.; Balasubramanian, K. K.; Bhima Rao, R.
Tetrahedron 1967, 23, 1893.
(12) Thyagarajan, B. S.; Balasubramanian, K. K.; Bhima Rao, R.
Chem. Ind. (London) 1966, 2128.
(13) All new compounds reported here gave satisfactory
spectroscopic and/or analytical data. General Procedure
for the Rearrangement of 3 to 4.
J = 8.4 Hz), 7.51 (d, 1 H, J = 8.1 Hz), 7.37 (dt, 1 H, J = 7.1,
1.0 Hz), 7.22 (t, 1 H, J = 7.2 Hz), 7.09 (s, 1 H), 6.98 (d, 1 H,
J = 7.2 Hz), 6.81 (d, 1 H, J = 7.2 Hz), 6.75 (d, 1 H, J = 8.1
Hz), 4.46 (dd, 1 H, J = 11.1, 5.3 Hz), 3.82 (dd, 1 H, J = 11.0,
10.1 Hz), 3.66 (dd, 1 H, J = 10.0, 5.2 Hz), 2.30 (s, 3 H), 1.88
(s, 3 H). 13C NMR (75 MHz, CDCl3): d = 156.0 (s), 153.6
(s), 139.8 (s), 138.6 (s), 130.3 (s), 129.6 (d), 125.7 (s), 125.5
(d), 124.7 (d), 123.5 (s), 120.7 (d), 119.7 (d), 119.5 (d), 118.5
(s), 110.8 (d), 110.9 (d), 109.8 (d), 109.1 (s), 83.7 (s), 67.6
(t), 49.5 (d), 26.1 (q), 20.8 (q). Anal. Calcd for C23H19NO2:
C, 80.92; H, 5.61; N, 4.10. Found: C, 81.06; H, 5.79; N, 4.31.
MS (TOFMS ES+): m/z = 342 [M + H].
Compound 4d: mp 238–240 °C. IR (KBr): 3382, 1609,
1465, 1427, 1300, 1224 cm–1.1H NMR (300 MHz, CDCl3):
d = 8.58 (s, 1 H), 7.98 (d, 1 H, J = 7.7 Hz), 7.87 (d, 1 H,
J = 8.5 Hz), 7.52 (d, 1 H, J = 8.0 Hz), 7.38 (dt, 1 H, J = 7.2,
1.0 Hz), 7.23–7.20 (m, 2 H), 7.14 (dd, 1 H, J = 8.5, 2.1 Hz),
6.80 (t, 2 H, J = 8.4 Hz), 4.46 (dd, 1 H, J = 11.1, 5.1 Hz),
3.86 (t, 1 H, J = 9.8 Hz), 3.69 (dd, 1 H, J = 9.5, 5.3 Hz), 1.91
(s, 3 H). 13C NMR (75 MHz, CDCl3): d = 156.8 (s), 153.5
(s), 139.7 (s), 138.4 (s), 129.1 (d), 127.7 (s), 125.6 (s), 125.1
(d), 124.8 (d), 123.5 (s), 121.0 (d), 119.8 (d), 119.5 (d), 118.6
(s), 111.4 (d), 110.8 (d), 109.9 (d), 108.5 (s), 84.8 (s), 67.0
(t), 49.3 (d), 26.0 (q). Anal. Calcd for C22H16ClNO2: C,
73.03; H, 4.46; N, 3.87. Found: C, 73.27; H, 4.63; N, 4.11.
MS (TOFMS ES+): m/z = 362, 364 [M+ + H].
Compound 12: mp 288–290 °C. IR (KBr): 3348, 1639, 1460,
1226 cm–1.1H NMR (300 MHz, CDCl3): d = 8.20 (s, 1 H),
7.94–7.86 (m, 2 H), 7.48–7.43 (m, 2 H), 7.34 (t, 1 H, J = 7.4
Hz), 7.23–7.18 (m, 2 H), 6.96 (t, 1 H, J = 7.4 Hz), 6.78 (d, 1
H, J = 8.0 Hz), 6.70 (d, 1 H, J = 8.4 Hz), 2.01 (s, 3 H), 1.85
(s, 3 H). 13C NMR (75 MHz, CDCl3): d = 158.0 (s), 157.5
(s), 139.6 (s), 136.2 (s), 130.7 (d), 129.3 (s), 124.7 (d, two
signals), 123.8 (s), 122.5 (d), 121.3 (d), 120.0 (d), 119.3 (d),
118.6 (s), 110.7 (d, two signals), 110.1 (s), 103.5 (d), 96.1
(s), 96.0 (s), 20.8 (q), 20.0 (q). Anal. Calcd for C22H17NO2:
C, 80.71; H, 5.23; N, 4.28. Found: C, 80.99; H, 5.31; N, 4.45.
MS (TOFMS ES+): m/z = 328 [M+ + H].
A solution of compound 3 (0.6 mmol) in N,N-diethylaniline
(6 mL) was heated to reflux for 12 h under nitrogen
atmosphere. It was then allowed to come to r.t. and then
poured into ice-cold 2 N HCl (50 mL) while stirring with a
glass rod. The aqueous solution was extracted with EtOAc
(3 × 25 mL) and the combined organic extract was washed
sequentially with sat. aq NaHCO3 (2 × 20 mL), H2O (20
mL), brine (25 mL) and then dried (Na2SO4). It was then
filtered, and the filtrate was concentrated in vacuo to leave a
solid mass, which was chromatographed over silica gel using
mixture of EtOAc and PE as eluent.
Analytical Data.
Compound 4a: mp 184–185 °C. IR (KBr): 3392, 1595, 1493,
1211, 1177 cm–1. 1H NMR (300 MHz, CDCl3): d = 8.65 (s,
1 H), 7.98 (d, 1 H, J = 7.6 Hz), 7.86 (d, 1 H, J = 8.4 Hz), 7.52
(d, 1 H, J = 8.0 Hz), 7.38 (t, 1 H, J = 8.0 Hz), 7.30–7.17 (m,
3 H), 6.93–6.80 (m, 3 H), 4.49 (dd, 1 H, J = 10.8, 5.0 Hz),
3.83 (t, 1 H, J = 10.4 Hz), 3.71 (dd, 1 H, J = 10.0, 4.9 Hz),
1.90 (s, 3 H). 13C NMR (75 MHz, CDCl3): d = 158.1 (s),
153.7 (s), 139.8 (s), 138.5 (s), 129.2 (d), 125.8 (s), 124.9 (d),
124.7 (d), 123.5 (s), 120.9 (d), 120.7 (d), 119.7 (d), 119.5 (d),
118.5 (s), 110.8 (d), 110.4 (d), 109.9 (d), 109.0 (s), 83.8 (s),
67.6 (t), 49.5 (d), 26.2 (q). Anal. Calcd for C22H17NO2: C,
80.71; H, 5.23; N, 4.28. Found: C, 80.94; H, 5.37; N, 4.40.
MS (TOFMS ES+): m/z = 350 [M+ + Na].
Compound 4b: mp 160–161 °C. IR (KBr): 3457, 1610,
1463, 1427, 1302, 1219 cm–1.1H NMR (300 MHz, CDCl3):
d = 8.54 (s, 1 H), 7.91 (d, 1 H, J = 7.5 Hz), 7.78 (d, 1 H,
J = 8.4 Hz), 7.45 (d, 1 H, J = 8.1 Hz), 7.34 (dt, 1 H, J = 7.2,
1.0 Hz), 7.15 (d, 1 H, J = 7.2 Hz), 7.04 (d, 1 H, J = 7.5 Hz),
6.93 (d, 1 H, J = 7.5 Hz), 6.79–6.72 (m, 2 H), 4.41 (dd, 1 H,
J = 11.1, 5.1 Hz), 3.81 (t, 1 H, J = 9.6 Hz), 3.64 (dd, 1 H,
J = 9.6, 5.1 Hz), 2.17 (s, 3 H), 1.84 (s, 3 H). 13C NMR (75
MHz, CDCl3): d = 157.0 (s), 154.1 (s), 140.2 (s), 139.1 (s),
130.8 (d), 125.5 (s), 125.1 (d), 124.0 (s), 122.6 (d), 121.3 (d),
121.1 (d), 120.8 (s), 120.1 (d), 119.9 (d), 118.9 (s), 111.2 (d),
110.4 (d), 109.7 (s), 83.8 (s), 67.9 (t), 50.1 (d), 26.8 (q), 15.8
(q). Anal. Calcd for C23H19NO2: C, 80.92; H, 5.61; N, 4.10.
Found: C, 81.23; H, 5.77; N, 4.28. MS (TOFMS ES+):
m/z = 342 [M+ + H].
(14) For reviews and monographs, see: (a) Knölker, H.-J. Top.
Curr. Chem. 2005, 244, 115. (b) Knölker, H.-J.; Reddy, K.
R. Chem. Rev. 2002, 102, 4303. (c)Kirsch, G. H. Curr. Org.
Chem. 2001, 5, 507. (d) Gallagher, P. T. In Science of
Synthesis (Houben-Weyl), Vol. 10; Thomas, E. J., Ed.;
Thieme: Stuttgart, 2001, 693. (e) Moody, C. J. Synlett 1994,
681. (f) Bhattacharyya, P.; Chakraborty, D. P. In Progress in
the Chemistry of Organic Natural Products, Vol. 52; Herz,
W.; Griesebach, H.; Kirby, G. W., Eds.; Springer: Wien,
1987, 159. (g) Joule, J. A. Adv. Heterocycl. Chem. 1984, 35,
83.
Compound 4c: mp 261–262 °C. IR (KBr): 3369, 1610, 1481,
1464, 1302, 1208, 1083 cm–1.1H NMR (300 MHz, CDCl3):
Synlett 2006, No. 19, 3358–3360 © Thieme Stuttgart · New York