Synthesis of 6-oxacyclopropa[a]indene derivatives starting from Baylis-Hillman adducts via Pd-mediated C(sp3)-H activation

Article abstract of DOI:10.1016/j.tetlet.2008.04.080

We prepared novel 1-phenyl-1,6a-dihydro-6-oxacyclopropa[a]indene-1a-carboxylic acid derivatives starting from the Baylis-Hillman adducts via the palladium-mediated domino carbopalladation involving activation of C(sp³)-H bond.

Full text of DOI:10.1016/j.tetlet.2008.04.080

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3858–3861
Synthesis of 6-oxacyclopropa[a]indene derivatives starting from
Baylis–Hillman adducts via Pd-mediated C(sp3)–H activation
Hoo Sook Kim, Saravanan Gowrisankar, Sung Hwan Kim, Jae Nyoung Kim *
Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Republic of Korea
Received 21 March 2008; revised 8 April 2008; accepted 10 April 2008
Available online 16 April 2008
Abstract
We prepared novel 1-phenyl-1,6a-dihydro-6-oxacyclopropa[a]indene-1a-carboxylic acid derivatives starting from the Baylis–Hillman
adducts via the palladium-mediated domino carbopalladation involving activation of C(sp3)–H bond.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Baylis–Hillman adducts; 6-Oxacyclopropa[a]indene; Activation of C(sp3)–H bond; Palladium
Recently we reported the synthesis of novel pentacyclic
compounds from enamide derivatives of Baylis–Hillman
adducts via the consecutive carbopalladation and the final
b-elimination processes.1 In the synthesis, second carbopal-
ladation occurred successively due to the absence of
b-hydrogen atom in the intermediate formed by the first
carbopalladation.1 During the studies we imagined that
we could synthesize 6-oxacyclopropa[a]indene skeleton2,3
from the reaction of 1a by the activation of C(sp3)–H bond
of the intermediate (I),4 as depicted in Scheme 1.
From the literature survey we imagined a few possibili-
ties such as (i) formation of eight-membered ring via aryl–
aryl coupling,5 (ii) formation of polycyclic compound
(shown in Scheme 1) via 1,4-palladium migration,6 and
(iii) most probably the formation of cyclopropane ring
via C(sp3)–H activation.4 Although activation of C–H
bond of arenes has been studied extensively5 only a few
reports have been reported on C(sp3)–H bond activation
by palladium(0)-catalysis.4 However, the examples are
growing rapidly and we actually found very similar obser-
vations of Liron and Knochel during our investigation on
the activation of C(sp3)–H bond.4b
Thus, we prepared starting material 1a from the Baylis–
Hillman acetate and 2-bromophenol,7 and examined the
reaction of 1a under a few typical conditions. As summa-
rized in Table 1, we obtained compounds 2a and 3a in
moderate yields under the conditions comprising
Pd(OAc)2/TBAB/K2CO3/DMF (entries 1 and 2). In all
cases we observed variable amounts of compound 4a8
(maximum 23% in entry 7). Best results were obtained
when we subjected 1a under the conditions of entry 2 at
higher temperature (110 °C) in short time (40 min). We
obtained two diastereomers 2a and 3a in 55% and 22%
yields, respectively, under the optimized conditions.
The structures of compounds 2a and 3a were assigned
1
by their H NMR, 13C NMR, IR, and mass data and by
comparison with the spectroscopic data of reported com-
pounds having similar structure.2,3,9 In 1H NMR spectrum
of 2a, two protons at 1- and 6a-positions appeared at 2.43
and 5.54 ppm with coupling constant of 3.3 Hz. The same
protons of compound 3a appeared at 3.25 and 5.31 ppm
with coupling constant J = 6.0 Hz. The stereochemistry
of 2a and 3a was confirmed by NOE experiments (Fig.
1). The plausible reaction mechanism is depicted in Scheme
1, which involved the key intermediate (I) and the four-
membered palladacycle intermediate (II). Highly encour-
aged by the successful results and the importance of 1-phen-
yl-1,6a-dihydro-6-oxacyclopropa[a]indene-1a-carboxylic
*
Corresponding author. Tel.: +82 62 530 3381; fax: +82 62 530 3389.
E-mail address: kimjn@chonnam.ac.kr (J. N. Kim).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.080

H. S. Kim et al. / Tetrahedron Letters 49 (2008) 3858–3861
3859
OAc
Ph
COOMe
PdBr
Ph
MeOOC
MeOOC
O
2-bromophenol
K2CO3, aq THF
O
H
COOMe
H
1
Ph
2
conditions
1a
1b
+
+
COOMe
H
O
COOMe
H
O 6a
6
2a
O
5a
1a
Br
O
3a
4a
Ph
Ph
COOMe
BrPd
COOMe
- HBr
Pd
H
H
H
O
O
(I)
(II)
Scheme 1.
Table 1
Optimization of reaction conditions with compound 1a
Entry
1
Conditions
Time
8 h
2a + 3aa (%)
4aa (%)
Pd(OAc)2 (10 mol %), K2CO3 (2.0 equiv), TBAB (1.0 equiv), DMF, 80 °C
55
<5
Pd(OAc)2 (10 mol %), K2CO3 (2.0 equiv), TBAB (1.0 equiv), DMF, 110 oC
2
40 min
77
<5
3
4
5
6
7
8
a
Pd(OAc)2 (10 mol %), K2CO3 (2.0 equiv), TBAB (1.0 equiv), CH3CN, reflux
Pd(OAc)2 (10 mol %), K2CO3 (2.0 equiv), PPh3 (1.0 equiv), DMF, 110 °C
Pd(OAc)2 (10 mol %), Et3N (2.0 equiv), TBAB (1.0 equiv), DMF, 80 °C
Pd(OAc)2 (10 mol %), Cs2CO3 (2.0 equiv), TBAB (1.0 equiv), DMF, 110 °C
Pd(OAc)2 (10 mol %), Na2CO3 (2.0 equiv), TBAB (1.0 equiv), DMF, 110 °C
Pd(OAc)2 (10 mol %), KHCO3 (2.0 equiv), TBAB (1.0 equiv), DMF, 110 °C
20 h
30 min
15 h
30 min
3 h
1 h
44
28
<5
21
<5
8
13
7
11
<5
23
7
Isolated yield.
δ = 3.25 ppm
0.6%
1.2%
J
= 6.0 Hz
H
H
1.1%
H
δ = 2.43 ppm
H
J
= 3.3 Hz
1.1%
H
COOMe
COOMe
H
H
O
O
1.8%
δ = 5.31 ppm
= 6.0 Hz
δ = 5.54 ppm
J
J
= 3.3 Hz
2a (major)
3a (minor)
Fig. 1. NOE results of compound 2a and 3a.
acid derivatives,2,3 we examined the generality and the
results are summarized in Table 2.9
and the reaction with Baylis–Hillman acetate (Scheme 2).
The reaction of 6 under the same conditions produced
compounds 7 (19%) and 8 (21%). We did not observe the
formation of expected cyclopropane derivatives in appre-
ciable amounts. The formation of compound 7 must be
the result of reductive Heck type reaction caused by the sol-
vent DMF,10 and the formation of compound 8 can be
regarded similarly as the formation of compound 4a in
Scheme 1.8,11
Compounds 2a–e were isolated as the major products
(40–57%) and 3a–e as the minor (14–23%). However, the
ratio was inverted for substrate 1f with much lower com-
bined yields of 2f and 3f (entry 6). The reason is not clear
at this stage. In order to check the possibility for the syn-
thesis of the corresponding nitrogen analog, compound 6
was prepared from 2-bromoaniline by successive tosylation

3860
H. S. Kim et al. / Tetrahedron Letters 49 (2008) 3858–3861
Table 2
Synthesis of tricyclic compounds 2 and 3a
EWG
R1
H
R1
O
R1
H
R2
R2
+
O
R2
EWG
H
EWG
H
O
Br
2a-f
1a-f
3a-f
a: R1 = Ph, R2 = H, EWG = COOMe
b: R1 = Ph, R2 = H, EWG = COOEt
c: R1 = Ph, R2 = Me, EWG = COOMe
d: R1 = 4-MeC6H4, R2 = H, EWG = COOMe
e: R1 = 4-MeC6H4, R2 = Me, EWG = COOMe
f: R1 = 2-naphthyl, R2 = H, EWG = COOMe
Entry
Substrate
Products (%)
1
2
3
4
5
6
a
1a
1b
1c
1d
1e
1f
2a (55)
2b (52)
2c (57)
2d (40)
2e (40)
2f (13)
3a (22)
3b (14)b
3c (23)
3d (23)
3e (20)
3f (26)
Conditions: Pd(OAc)2 (10 mol %), K2CO3 (2.0 equiv), n-Bu4NBr (1.0 equiv), DMF, 100–110 °C, 40 min (80 min for entries 3 and 6).
Trace amounts of inseparable impurity were contaminated.
b
OAc
COOMe
COOMe
N
Ph
NH2
Br
NHTs
Br
TsCl
pyridine
K2CO3, CH3CN
50-60 oC, 4 days
Ts
Br
5 (78%)
6 (59%)
H
MeOOC
Ph
Ph
+
same conditions
90 min
COOMe
H
6
N
N
N
Ts
Ts
Ts
(not formed)
8 (21%)
7 (19%)
Scheme 2.
Lee, H. S.; Kim, S. H.; Kim, T. H.; Kim, J. N. Tetrahedron Lett. 2008,
49, 1773–1776; (c) Gowrisankar, S.; Lee, H. S.; Kim, J. M.; Kim, J. N.
Tetrahedron Lett. 2008, 49, 1670–1673.
In summary, we prepared novel 1-phenyl-1,6a-dihydro-
6-oxacyclopropa[a]indene-1a-carboxylic acid derivatives
starting from the modified Baylis–Hillman adducts via
the palladium-mediated domino carbopalladation involv-
ing activation of C(sp3)–H bond.
2. For the synthesis and synthetic applications of 6-oxacyclopropa-
[a]indene-1a-carboxylic acid derivatives, see: (a) Hedley, S. J.;
Ventura, D. L.; Dominiak, P. M.; Nygren, C. L.; Davies, H. M. L.
J. Org. Chem. 2006, 71, 5349–5356; (b) Davies, H. M. L.; Kong, N.;
Churchill, M. R. J. Org. Chem. 1998, 63, 6586–6589; (c) Fuerst, D. E.;
Stoltz, B. M.; Wood, J. L. Org. Lett. 2000, 2, 3521–3523; (d) Padwa,
A.; Wisnieff, T. J.; Walsh, E. J. J. Org. Chem. 1989, 54, 299–308; (e)
Padwa, A.; Wisnieff, T. J.; Walsh, E. J. J. Org. Chem. 1986, 51, 5036–
5038; (f) Miki, K.; Fujita, M.; Uemura, S.; Ohe, K. Org. Lett. 2006, 8,
1741–1743; (g) Kirmse, W.; Homberger, G. J. Am. Chem. Soc. 1991,
113, 3925–3934; (h) Wenkert, E.; Alonso, M. E.; Gottlieb, H. E.;
Sanchez, E. L. J. Org. Chem. 1977, 42, 3945–3949; (i) Kanchiku, S.;
Suematsu, H.; Matsumoto, K.; Uchida, T.; Katsuki, T. Angew.
Chem., Int. Ed. 2007, 46, 3889–3891.
Acknowledgments
This work was supported by the Korea Research Foun-
dation Grant funded by the Korean Government
(MOEHRD, KRF-2007-313-C00417). Spectroscopic data
were obtained from the Korea Basic Science Institute,
Gwangju branch.
References and notes
3. For the synthesis of similar cyclopropane-fused ring compounds, see:
(a) Nowak, I.; Cannon, J. F.; Robins, M. J. J. Org. Chem. 2007, 72,
532–537; (b) Welbes, L. L.; Lyons, T. W.; Cychosz, K. A.; Sanford,
M. S. J. Am. Chem. Soc. 2007, 129, 5836–5837; (c) Gnad, F.;
Poleschak, M.; Reiser, O. Tetrahedron Lett. 2004, 45, 4277–4280; (d)
1. For our recent papers on Pd-mediated reactions involving modified
Baylis–Hillman adducts, see: (a) Gowrisankar, S.; Lee, H. S.; Lee, K.
Y.; Lee, J.-E.; Kim, J. N. Tetrahedron Lett. 2007, 48, 8619–8622; (b)

H. S. Kim et al. / Tetrahedron Letters 49 (2008) 3858–3861
3861
Kim, C.; Brady, T.; Kim, S. H.; Theodorakis, E. A. Synth. Commun.
2004, 34, 1951–1965; (e) Barluenga, J.; Andina, F.; Aznar, F.; Valdes,
C. Org. Lett. 2007, 9, 4143–4146; (f) Beddoes, R. L.; Lewis, M. L.;
Quayle, P.; Johal, S.; Attwood, M.; Hurst, D. Tetrahedron Lett. 1995,
36, 471–474; (g) Sugawara, M.; Yoshida, J.-i. Tetrahedron Lett. 1999,
40, 1717–1720; (h) Witham, C. A.; Mauleon, P.; Shapiro, N. D.;
Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 5838–5839;
(i) Ye, L.-W.; Sun, X.-L.; Li, C.-Y.; Tang, Y. J. Org. Chem. 2007, 72,
1335–1340.
Compound 2a: 55%; colorless oil; IR (film) 1734, 1475, 1460, 1228,
1055 cmÀ1 1H NMR (CDCl3, 300 MHz) d 2.43 (d, J = 3.3 Hz, 1H),
;
3.50 (s, 3H), 5.54 (d, J = 3.3 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 7.00 (t,
J = 7.5 Hz, 1H), 7.20 (t, J = 8.1 Hz, 1H), 7.24–7.35 (m, 5H), 7.83 (d,
J = 7.5 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d 36.44, 41.64, 51.75,
69.35, 110.78, 121.07, 125.03, 127.39, 128.00, 128.16, 128.32, 128.80,
133.10, 159.30, 167.48; ESIMS m/z 267 (M++1). Anal. Calcd for
C17H14O3: C, 76.68; H, 5.30. Found: C, 76.44; H, 5.23.
Compound 3a: 22%; colorless oil; IR (film) 1726, 1477, 1460, 1236,
;
1085 cmÀ1 1H NMR (CDCl3, 300 MHz) d 3.25 (d, J = 6.0 Hz, 1H),
4. For the examples on C(sp3)–H bond activation, see: (a) Ren, H.; Li,
Z.; Knochel, P. Chem. Asian J. 2007, 2, 416–433; (b) Liron, F.;
Knochel, P. Tetrahedron Lett. 2007, 48, 4943–4946; (c) Ren, H.;
Knochel, P. Angew. Chem., Int. Ed. 2006, 45, 3462–3465; (d) Dyker,
G. Angew. Chem., Int. Ed. 1994, 33, 103–105; (e) Dyker, G. J. Org.
Chem. 1993, 58, 6426–6428; (f) Dyker, G. Angew. Chem., Int. Ed.
1992, 31, 1023–1025; (g) Hitce, J.; Retailleau, P.; Baudoin, O. Chem.
Eur. J. 2007, 13, 792–799; (h) Baudoin, O.; Herrbach, A.; Gueritte, F.
Angew. Chem., Int. Ed. 2003, 42, 5736–5740.
3.87 (s, 3H), 5.31 (d, J = 6.0 Hz, 1H), 6.54 (d, J = 8.1 Hz, 1H),
6.83 (t, J = 7.5 Hz, 1H), 6.94 (t, J = 7.8 Hz, 1H), 7.03–7.28 (m, 5H),
7.62 (d, J = 7.5 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d 28.95,
39.44, 52.49, 70.83, 109.68, 120.96, 126.50, 126.90, 127.78, 127.87,
128.03, 128.49, 130.61, 159.52, 170.64; ESIMS m/z 267 (M++1).
Anal. Calcd for C17H14O3: C, 76.68; H, 5.30. Found: C, 76.79; H,
5.21.
Compound 2e: 40%; yellow oil; IR (film) 1730, 1483, 1236, 1147 cmÀ1
;
5. For the examples on C(sp2)–H bond activation, see: (a) Alberico, D.;
Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174–238; (b) Jana,
R.; Samanta, S.; Ray, J. K. Tetrahedron Lett. 2008, 49, 851–854; (c)
Campeau, L.-C.; Parisien, M.; Leblanc, M.; Fagnou, K. J. Am. Chem.
Soc. 2004, 126, 9186–9187; (d) Campeau, L.-C.; Parisien, M.; Jean,
A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581–590.
1H NMR (CDCl3, 300 MHz) d 2.32 (s, 3H), 2.36 (s, 3H), 2.38 (d,
J = 3.3 Hz, 1H), 3.52 (s, 3H), 5.48 (d, J = 3.3 Hz, 1H), 6.78 (d,
J = 8.1 Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H), 7.07–7.18 (m, 4H), 7.63 (s,
1H); 13C NMR (CDCl3, 75 MHz) d 20.89, 21.12, 36.48, 41.59, 51.73,
69.54, 110.26, 125.42, 128.01, 128.49, 128.62, 129.01, 130.08, 130.45,
137.00, 157.24, 167.64; ESIMS m/z 295 (M++1). Anal. Calcd for
6. For the palladium migration and the following aryl coupling
reactions, see: (a) Huang, Q.; Fazio, A.; Dai, G.; Campo, M. A.;
Larock, R. C. J. Am. Chem. Soc. 2004, 126, 7460–7461; (b) Campo,
M. A.; Zhang, H.; Yao, T.; Ibdah, A.; McCulla, R. D.; Huang, Q.;
Zhao, J.; Jenks, W. S.; Larock, R. C. J. Am. Chem. Soc. 2007, 129,
6298–6307; (c) Zhao, J.; Yue, D.; Campo, M. A.; Larock, R. C.
J. Am. Chem. Soc. 2007, 129, 5288–5295; (d) Zhao, J.; Larock, R. C.
J. Org. Chem. 2006, 71, 5340–5348; (e) Zhao, J.; Campo, M. A.;
Larock, R. C. Angew. Chem., Int. Ed. 2005, 44, 1873–1875; (f) Ma, S.;
Gu, Z. Angew. Chem., Int. Ed. 2005, 44, 7512–7517.
C19H18O3: C, 77.53; H, 6.16. Found: C, 77.73; H, 5.98.
Compound 3e: 20%; yellow oil; IR (film) 1728, 1483, 1277, 1240,
1
1209 cmÀ1; H NMR (CDCl3, 300 MHz) d 2.17 (s, 3H), 2.25 (s, 3H),
3.17 (d, J = 6.0 Hz, 1H), 3.85 (s, 3H), 5.26 (d, J = 6.0 Hz, 1H), 6.44
(d, J = 8.4 Hz, 1H), 6.74 (d, J = 8.1 Hz, 1H), 6.85–7.10 (m, 4H), 7.42
(s, 1H); 13C NMR (CDCl3, 75 MHz) d 20.92, 21.07, 28.93, 39.49,
52.41. 71.20, 109.13, 123.36, 126.82, 127.79, 128.35, 128.53, 130.16,
130.28, 136.38, 157.76, 170.84; ESIMS m/z 295 (M++1). Anal. Calcd
for C19H18O3: C, 77.53; H, 6.16. Found: C, 77.36; H, 6.41.
Compound 7: 19%; colorless oil; IR (film) 1734, 1477, 1358, 1167,
;
1092 cmÀ1 1H NMR (CDCl3, 300 MHz) d 2.36 (s, 3H), 2.87 (d,
7. Park, D. Y.; Gowrisankar, S.; Kim, J. N. Bull. Korean Chem. Soc.
2005, 26, 1440–1442.
J = 13.5 Hz, 1H), 3.30 (d, J = 13.5 Hz, 1H), 3.62 (s, 3H), 3.98 (d, J =
11.4 Hz, 1H), 4.23 (d, J = 11.4 Hz, 1H), 6.92–6.95 (m, 2H), 7.02 (t,
J = 7.5 Hz, 1H), 7.21–7.30 (m, 6H), 7.36 (d, J= 7.8 Hz, 1H), 7.63 (d,
J = 7.8 Hz, 1H), 7.68 (d, J = 8.1 Hz, 2H); 13C NMR (CDCl3,
75 MHz) d 21.52, 44.36, 52.51, 55.54, 55.65, 114.25, 123.45, 125.41,
127.18, 127.38, 128.47, 129.40, 129.61, 129.66, 132.19, 133.96, 135.68,
141.26, 144.17, 172.29; ESIMS m/z 422 (M++1). Anal. Calcd for
C24H23NO4S: C, 68.39; H, 5.50; N, 3.32. Found: C, 68.27; H, 5.38; N,
3.26.
8. Sasaki, K.; Kondo, Y.; Maruoka, K. Angew. Chem., Int. Ed. 2001, 40,
411–414. The mechanism for the formation of compound 4a could be
a b-carbon elimination from intermediate I, followed by decarbox-
ylation. The formation of compound 8 could also be regarded
similarly. Further studies on the mechanism are currently underway.
9. Typical procedure for the synthesis of 2a and 3a: A stirred mixture of
1a (174 mg, 0.5 mmol), Pd(OAc)2 (11 mg, 10 mol %), K2CO3 (138 mg,
1.0 mmol), n-Bu4NBr (161 mg, 0.5 mmol) in DMF (2.0 mL) was
heated to 110 °C for 40 min under nitrogen atmosphere. After the
usual aqueous workup and column chromatographic purification
process (hexanes/ether, 25:1) we obtained 2a (74 mg, 55%) and 3a
(30 mg, 22%) as colorless oils. Other compounds were synthesized
similarly and the spectroscopic data of selected compounds 2a, 3a, 2e,
3e, and 7 are as follows.
10. (a) Zawisza, A. M.; Muzart, J. Tetrahedron Lett. 2007, 48, 6738–6742;
(b) Legros, J.-Y.; Primault, G.; Toffano, M.; Riviere, M.-A.; Fiaud,
J.-C. Org. Lett. 2000, 2, 433–436; (c) Brenda, M.; Knebelkamp, A.;
Greiner, A.; Heitz, W. Synlett 1991, 809–810.
11. Fuwa, H.; Sasaki, M. Org. Biomol. Chem. 2007, 5, 2214–
2218.