Synthesis of novel oxygen heterocycles: 1,10-dioxa-cyclopenta[a]fluorene and benzo[b]naphtho[2, 1-d]furans via D?tz intramolecular benzannulation

Article abstract of DOI:10.1016/j.tetlet.2009.04.123

Novel fused heterocycles 1,10-dioxa-cyclopenta[a]fluorene and benzo[b]naphtho[2, 1-d]furans were synthesized via D?tz intramolecular benzannulation of alkyne tethered aryloxy chromium Fischer carbenes.

Full text of DOI:10.1016/j.tetlet.2009.04.123

Tetrahedron Letters 50 (2009) 4128–4131
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of novel oxygen heterocycles: 1,10-dioxa-cyclopenta[a]fluorene
and benzo[b]naphtho[2, 1-d]furans via Dötz intramolecular benzannulation
b
b
b
Subhabrata Sen a, , Parag Kulkarni , Kailaskumar Borate , Nandini R. Pai
*
a BASF-India Limited, Research and Development, 12 TTC Area, Thane Belapur Road, Mumbai 700005, Maharashtra, India
b Department of Chemistry, D. G. Ruparel College, Matunga, Mumbai 400 016, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel fused heterocycles 1,10-dioxa-cyclopenta[a]fluorene and benzo[b]naphtho[2, 1-d]furans were syn-
thesized via Dötz intramolecular benzannulation of alkyne tethered aryloxy chromium Fischer carbenes.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 25 March 2009
Revised 27 April 2009
Accepted 28 April 2009
Available online 3 May 2009
Myriad fused nitrogen heterocycles have been synthesized from
tethered alkynyl amino carbenes by intramolecular Dötz benzann-
ulation.1a–e For example, a variety of vinyl and aryl-2-alkynylcarb-
enes on thermolysis generate carbazoles and benzocarbazoles.2a–c
Woodgate et al. have synthesized diterpenoid indole derivatives
via tethered chromium alkynylaminocarbenes.2d Several reactions
have also been reported for o-analogous carbenes, Wulff et al. and
Semmelhack et al. have synthesized cyclophanes, naphthoqui-
nones, and furanocoumarins from intramolecular Dötz Benzannu-
lation of alkyne tethered alkoxy carbenes.3a–d
O
O
HO
O
O
R2
R2
OH
OH
Substituted dibenzofurans
2a-e
Scheme 1. Synthetic proposal for the conversion of benzofuro [7,6-b][1] benzofu-
rans to dibenzofurans.
Recently Giese et al. have reported applications of silyl-substi-
tuted alkyne tethered aryloxy fischer carbenes for the synthesis
of rocaglamide skeleton via arrested intramolecular alkyne inser-
tion.4a Nakata et al. have utilized intramolecular Dötz reaction to
synthesize arnebinol.4b In order to further demonstrate the utility
of tethered aryloxy Fischer chromium carbenes toward novel oxy-
gen heterocycles, we herein present their intramolecular benzann-
ulation to yield heterocycles 1,10-dioxa-cyclopenta[a]fluorene
2a–e and benzo [b] naphtho [2,1-d] furans 2f–i. Compounds 2a–e
can be considered as immediate precursors of substituted dib-
enzofurans (Scheme 1).5 Importance of dibenzofurans is well
known, as it is present in a variety of natural products.6a–m This
makes our oxygen fused heterocycles a very interesting target for
synthesis.
Retrosynthetically we envisioned the formation of fused o-het-
erocycles via intramolecular benzannulation of fischer aryloxy
carbenes 1a–i, under thermal heating. The fischer carbenes 1a–i
can be synthesized by coupling of phenols 5a–e with acylated
complex 7.7 Syntheses of phenols 5a–e were accomplished by
sonogashira coupling of o-iodophenol with substituted alkynes.
The facile cyclization process common to o-hydroxy acetylenic
phenols8 thus formed was prevented by employing mild reaction
conditions.9
Hence, o-iodophenols were protected followed by sonogashira
coupling with corresponding alkynes and then deprotected to
yield the desired o-hydroxy acetylenic phenols 5a–e (Scheme
2). o-hydroxy acetylenic phenols 5a–e were then employed to
synthesize the o-alkyne tethered aryloxy Fischer carbenes 1a–i.
To synthesize the carbenes, we used Pulley’s protocol, where
the optimum procedure involves the formation of metal acyl
complex 7a–c (synthesized by addition of acetyl bromide to
ammonium ate complex 6a–c), followed immediately by the
addition of sodium salt of o-hydroxy acetylenic phenols 8a–e
at 0 °C.7 Any efforts to perform the phenolate at room tempera-
ture (according to the original protocol) resulted in an intramo-
lecular cyclization of the phenoxide 8a–e to generate
benzofurans (Scheme 2).
Complexes 1a–i are obtained as deep red oils by standard chro-
matographic techniques and are stable to storage (À4 °C) under in-
ert atmosphere for several weeks.11 The yields of the carbenes
ranged ꢀ50–60% (Table 1). Efforts are in progress toward optimiza-
tion of the yields via crystallization.
* Corresponding author. Present address: Jubilant Chemsys, C/O jubilant Organ-
isys, Lab-3, D-12, Sector 59, Noida, Gautambudhnagar 201 301, Uttar Pradesh, India.
Tel.: +91 120 436 3222; fax: +91 120 2580310.
After the synthesis of aryloxy carbenes 1a–i, our final frontier
was their intramolecular benzannulation to achieve the fused
E-mail address: subhabrata_sen@jchemsys.com (S. Sen).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.123

S. Sen et al. / Tetrahedron Letters 50 (2009) 4128–4131
4129
1) CuI, PdCl2(PPh3)2
CH3CN, rt,
2) NH4OH, rt
OH
R2
OH
OAc
1) NaH, Ac2O,
THF, rt
I
I
R2
3a-e
+
5a-e
4
R
X
R
n
-
+
ONa
R2
(CO)5Cr
X
n
NaH, AcBr
0 ºC
0 ºC to r.t.
O
+
(CO)5Cr
7a-c
R2
OCOCH3
8a-e
1a-i
AcBr
DCM
R
X
R
n
1) THF
2) Me4NBr
(CO)5Cr
Cr(CO)6
X
+
-
+
n
ONMe4
6a-c
Li
R
R2
X
n
6
7
3
5
8
a
b
c
O
H
a
b
c
d
e
a
b
c
0
1
1
a
b
c
d
e
a
n-butyl
CH
CH
p-OMe
p-Me
n-propyl
cyclohexyl
phenyl
b
c
d
e
n-pentyl
R
X
n
O
(CO)5Cr
X
Δ, 80 ºC
O
R
R2
n
R2
OH
2a-i
1a-i
1a-e / 2a-e: X = O, n = 0, R = H, R2 = n-butyl, n-propyl, cyclohexyl, phenyl
and n-pentyl respectively.
1f-i / 2f-i: X= CH, n = 1, R = p-OMe, and p-Me, R2 = n-butyl, n-propyl, n-butyl
and n-pentyl respectively
Scheme 2. Synthesis of aryloxy fischer chromium carbenes 1a–i and o-heterocycles by intramolecular Dötz benzannulation.
heterocycles. Subsequent thermolysis of 1a–i in THF generated
the desired o-fused heterocycles in 65–70% yield as light yellow
crystalline solids (Table 2).11 The reactions were also tried under
solvent-free conditions. Till date there have been no reports, to
the best of our knowledge, about conducting intramolecular
Dötz reaction under solvent free conditions. The yields under sol-
vent-free conditions are 10–15% lower (45–40%) than under sol-
vents viz. THF (65–70%). (Table 2). The advantage in this
procedure is drastic reduction of reaction time. For example, the
reaction of carbene 1f gives the o-heterocycle 2f after 18 h at
60 °C in THF while solvent-free reaction goes to completion in
15 min at 80 °C. Optimizations are in progress to improve the
yields. Also mandatory freeze-thaw degassing of the reaction mix-
ture (an integral protocol of all Dötz reaction of Fischer carbenes
to remove dissolved oxygen from the reaction mixture in order
to prevent oxidation of the carbene) is not necessary with sol-
vent-free conditions. We believe that this reaction follows a mech-
anism similar to Dötz intermolecular benzannulation.10 But we
have not conducted any mechanistic investigation toward the for-
mation of the product.
Hence a general and mild method of forming fused o-heterocy-
cle is a valuable addition to the synthetic method available to the
construction of substituted dibenzofurans.
The neutral reaction conditions are particularly attractive for
synthesis of these heterocycles featuring sensitive functionalities.
These preliminary results provide a fundamental basis to expand
this methodology and demonstrate its utility in the ultimate
synthesis of substituted dibenzofurans.

4130
S. Sen et al. / Tetrahedron Letters 50 (2009) 4128–4131
Table 1 (continued)
Table 1
Synthesis of carbenes
Entry
Carbenes
Yield (%)
Entry
Carbenes
Yield (%)
O
(CO)5Cr
9
53
(CO)5Cr
(CO)5Cr
(CO)5Cr
(CO)5Cr
(CO)5Cr
1
54
O
O
(CH2)4CH3
(CH2)3CH3
1i
1a
O
2
3
4
5
6
7
8
51
52
50
55
57
54
57
O
Table 2
(CH2)2CH3
Intramolecular Dötz benzannulation
1b
Entry Substrate Product
Yield (%) in
solution
Yield (%)
in neat
O
O
O
O
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
67
71
56
61
57
59
41
42
47
40
46
45
(CH2)3CH3
OH
O
2a
1c
O
O
O
O
(CH2)2CH3
OH
O
2b
1d
O
O
(CH2)4CH3
OH
O
1e
2c
OMe
O
O
(CO)5Cr
(CO)5Cr
O
O
OH
O
(CH2)4CH3
2d
1f
(CH2)4CH3
(CH2)2CH3
OH
2e
1g
O
(CO)5Cr
O
O
(CH2)4CH3
(CH2)3CH3
OH
2f
1h

S. Sen et al. / Tetrahedron Letters 50 (2009) 4128–4131
4131
Table 2 (continued)
4. (a) Giese, M. W.; Moser, W. H. Org. Lett. 2008, 10, 4215. and the references there
in; (b) Watanabe, M.; Tanaka, K.; Saikawa, Y.; Nakata, M. Tetrahedron Lett. 2007,
48, 203.
Entry Substrate Product
Yield (%) in
solution
Yield (%)
in neat
5. Gupta, A.; Sen, S.; Harmata, M.; Pulley, S. R. J. Org. Chem. 2005, 70, 7422.
6. (a) Tanahashi, T.; Takenaka, Y.; Nagakura, N.; Hamada, N. Phytochemistry 2001,
58, 1129; (b) Huneck, S.; Elix, J. A.; Naidu, R.; Follman, G. Aust. J. Chem 1993, 46,
407; (c) Elix, J. A.; Venables, D. A.; Lumbsch, T.; Brako, L. Aust. J. Chem. 1994, 47,
1619; (d) Elix, J. A.; Venables, D. A.; Wedin, M. Aust. J. Chem. 1994, 47, 1335; (e)
Shibata, S.; Ijtaka, Y. Chem. Pharm. Bull. 1984, 32, 366; (f) Sawada, T.; Aono, M.;
Asahawa, S.; Ito, A.; Awano, K. J. Antibiot. 2000, 53, 959; (g) Carotenuto, A.;
Fattorusso, E.; Lanzotti, V.; Magno, S. Eur. J. Org. Chem. 1998, 4, 661; (h)
Gollapudi, S. R.; Telikepalli, H.; Jampani, H. B.; Mirhom, Y. W.; Drake, S. D.;
Bhattiprolu, K. R.; Vander Velde, D.; Mitscher, L. A. J. Nat. Prod. 1994, 57, 934; (i)
Yang, S.; Chan, M.; Patel, R.; Terracciano, J.; Loebenberg, D.; Patel, M.; Chu, M. J.
Antibiot. 2004, 57, 465; (j) Morris, H. R.; Taylor, G. W.; Masento, M. S.; Jermyn,
K. A.; Kay, R. R. Nature 1987, 328, 811; (k) Abe, H.; Vchiyama, M.; Tanaka, Y.;
Saito, H. Tetrahedron Lett. 1976, 42, 3801; (l) Konjin, T. M.; Van de Meene, J. G.
C.; Bonner, J. T.; Barkely, D. S. Biochemistry 1967, 58, 1152; (m) Wang, S.; Hall, J.
E.; Tanious, F. A.; Wilson, W. D.; Patrick, D. A.; McCurdy, D. R.; Bender, B. C.;
Tidwell, R. R. Eur. J. Med. Chem. 1999, 34, 215.
O
7
8
9
1g
1h
1i
51
67
54
47
46
47
(CH2)2CH3
(CH2)3CH3
(CH2)4CH3
OH
O
2g
7. Pulley, S. R.; Sen, S.; Vorogushin, A.; Swanson, E. Org. Lett. 1999, 1, 1721.
8. (a) Fkyerat, A.; Dubin, G. M.; Tabacchi, R. Helv. Chim. Acta 1999, 82, 1418; (b)
Lütjens, H.; Scammells, P. J. Syn. Lett. 1999, 1079; (c) Defranq, E.; Zesiger, T.;
Tabacchi, R. Helv. Chim. Acta 1993, 76, 425; (d) Pinault Frangin, M. Y.; Genet,
J.-P.; Zamarlik, H. Synthesis 1990, 935.
OH
O
2h
9. Nan, Y.; Miao, H.; Yang, Z. Org. Lett. 2000, 2, 297.
10. Torrent, M.; Duran, M.; Solà, M. J. Am. Chem. Soc. 1999, 121, 1309.
11. Spectral data of few representative new compounds: Pentacarbonyl [(2-hex-1-ynyl
phenoxy) (furyl) carbene] chromium (0) (1a) 1H NMR (300 MHz, CDCl3) 7.88 (s
1H), 7.42–7.35 (m, 2H), 7.26–7.23 (m, 2H), 7.12–7.11 (m, 1H), 6.60 (s, 1H), 2.12
(t, J = 6.60 Hz 2H), 1.61–1.56 (m, 2H), 1.20–1.13 (m, 2H), 0.68 (t, J = 6.90 Hz
3H); 13C NMR (75 MHz, CDCl3) 12.5, 18.0, 20.8, 29.3, 74.5, 96.1, 111.8, 112.3,
118.2, 121.7, 125.7, 127.7, 132.3, 150.1, 158.3, 164.1, 215.2, 223.8.
Pentacarbonyl [(2-pent-1-ynyl phenoxy) (furyl) carbene] chromium (0) (1b) 1H
NMR (300 MHz, CDCl3) 7.88 (s, 1H), 7.42–7.34 (m, 2H), 7.27–7.23 (m, 2H),
7.12–7.11 (m, 1H), 6.60 (s, 1H); 2.09 (t, J = 6.99 Hz 2H), 1.30–1.18 (m, 2H), 0.73
(t, J = 7.35 Hz, 3H), 13C NMR (75 MHz, CDCl3) 11.2, 19.2, 19.6, 73.6, 94.9, 110.8,
111.2, 117.1, 120.6, 124.7, 126.7, 131.3, 149.0, 157.2, 163.1, 214.1, 222.7.
Pentacarbonyl [(2-cyclohexylethynyl phenoxy) (furyl) carbene] chromium (0) (1c)
1H NMR (300 MHz, CDCl3) 7.96 (s, 1H), 7.50–7.41 (m, 2H), 7.35–7.28 (m, 2H),
6.94 (m, 1H), 6.66 (s, 1H), 2.73–2.61 (m, 1H), 1.84–1.70 (m, 2H), 1.45–1.35 (m,
4H), 1.32–1.09 (m, 4H); 13C NMR (75 MHz, CDCl3) 24.6, 24.9, 25.8, 29. 9, 32.1,
32.7, 74.5, 96.6, 112.9, 113.3, 114.3, 120.1, 128.8, 129.6, 131.5, 133.4, 151.1,
156.8, 165.5, 216.5, 222.2.
OH
2i
Acknowledgments
We thank Dr. Amitabha Sirkar for his useful comments and sug-
gestions. We gratefully acknowledge BASF-India limited for pro-
viding financial support to K.B. and P.K.
5-Butyl-1, 10-dioxa-cyclopenta [a] fluoren-4-ol: (2a) IR (KBr) m
max cmÀ1: 3274,
Supplementary data
2955, 2855, 1664, 1466, 1346, 1040, 733; 1H NMR (300 MHz, CDCl3) 8.01 (d,
J = 8.52 Hz, 1H), 7.78 (d, J = 9.48 Hz, 2H), 7.50–7.36 (m, 2H), 6.98 (s, 1H), 4.94 (s,
1H), 3.20 (t, J = 7.74 Hz, 2H), 1.83–1.73 (m, 2H), 1.64–1.51 (m, 2H), 1.03 (t,
J = 7.26 Hz, 3H); 13C NMR (75 MHz, CDCl3) 14.3, 23.2, 26.3, 32.2, 104.5, 112.0,
116.1, 118.2, 120.5, 121.8, 122.9, 125.1, 125.9, 136.2, 138.6, 141.6, 144.4,
156.4; HRMS calcd for C18H16O3 281.1178; found: 281.1172, mp 128–130 °C.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.04.123.
5-Propyl-1,10-dioxa-cyclopenta[a]fluoren-4-ol: (2b) IR (KBr) m
max cmÀ1 : 3280,
References and notes
2960, 2840, 1634, 1458, 1374, 1035, 734; 1H NMR (300 MHz, CDCl3) 7.97–7.95
(d, J = 7.89 Hz, 1H), 7.66–7.63 (d, J = 10.06 Hz, 2H), 7.46–7.33 (m, 2H), 6.95 (s,
1H), 4.88 (s, 1H), 3.13 (t, J = 7.74 Hz, 2H), 1.86–1.72 (m, 2H), 1.12 (t, J = 7.35 Hz,
3H); 13C NMR(75 MHz, CDCl3) 14.2, 22.8, 28.2, 104.5, 112.0, 115.9, 118.2, 120.6,
121.8, 122.9, 125.1, 125.9, 136.1, 138.6, 141.7, 144.4, 156.4; HRMS calcd for
C17H14O3 267.1021; found: 267.1014, mp 136–138 °C;
1. (a) Dötz, K. H.; Harms, K.; Schäfer, T. O. Synthesis 1992, 1–2, 146; (b) Dötz, K. H.;
Harms, K.; Schäfer, T. O. Angew. Chem., Int. Ed. Engl. 1990, 29, 176; (c) Rahm, A.;
Wulff, W. D. J. Am. Chem. Soc. 1996, 118, 1807; (d) Camps, F.; Moreto, J. M.;
Ricart, S.; Vinas, J. M. Angew. Chem., Int. Ed. Engl. 1991, 30, 1470; (e) Woodgate,
P.; Sutherland, H. J. Organomet. Chem. 2001, 629, 131.
2. (a) Grotjahn, D. B.; Dotz, K. H. Syn. Lett. 1991, 5, 381; (b) Leese, T.; Dötz, K. H.
Chem. Ber. 1996, 129, 623; (c) Dötz, K. H.; Leese, T. Bull. Soc. Chim. Fr. 1997, 134,
503; (d) Woodgate, P. D.; Sutherland, H. S. J. Organomet. Chem. 2001, 629, 131.
3. (a) Semmelhack, M. F.; Bozell, J. J. Tetrahedron Lett. 1982, 23, 2931; (b)
Semmelhack, M. F.; Bozell, J. J.; Keller, L.; Sato, T.; Spiess, E. J.; Wulff, W. D.;
Zask, A. Tetrahedron 1985, 41, 5803; (c) Wulff, W. D.; McCallum, J. S.; Kunng, F.-
A. J. Am. Chem. Soc. 1988, 110, 7419; (d) Wang, H.; Wulff, W. D. J. Am. Chem. Soc.
1998, 120, 10573.
5-Cyclohexyl-1,10-dioxa-cyclopenta[a]fluoren-4-ol: (2c) IR (KBr)
m :
max cmÀ1
3413, 2929, 2853, 1664, 1450, 1339, 1020, 752; 1H NMR (300 MHz, CDCl3)
8.12 (d, J = 7.35 Hz, 1H), 7.66–7.64 (d, J = 7.62 Hz, 2H), 7.47–7.34 (m, 2H), 6.92
(s, 1H), 4.92 (s, 1H), 3.70–3.62 (m, 1H), 2.19–1.86 (m, 4H), 1.69–1.43 (m, 4H),
1.29–0.89 (m, 2H); 13C NMR (75 MHz, CDCl3) 25.9, 26.3, 26.9, 27.7, 31.4, 40.3,
104.2, 112.1, 119.3, 120.6, 121.1, 122.1, 122.7, 125.4, 125.8, 136.1, 138.4, 142.8,
144.5, 156.5; HRMS calcd for C20H18O3 306.3544; found: 306.3520, mp 151–
154 °C.