An efficient synthesis of novel estrieno[2.3-b] and [3.4-c]pyrroles

Article abstract of DOI:10.1016/S0040-4039(03)00541-0

An efficient protocol for the preparation of novel estrieno[2.3-b] and [3.4-c]pyrroles 1 and 2 using Pd(0)-catalyzed amination and Bischler indole synthesis is described.

Full text of DOI:10.1016/S0040-4039(03)00541-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3071–3073
An efficient synthesis of novel estrieno[2.3-b] and [3.4-c]pyrroles
Xuqing Zhang* and Zhihua Sui
Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 1000 Route 202, Box 300, Raritan,
NJ 08869, USA
Received 29 January 2003; revised 14 February 2003; accepted 24 February 2003
Abstract—An efficient protocol for the preparation of novel estrieno[2.3-b] and [3.4-c]pyrroles 1 and 2 using Pd(0)-catalyzed
amination and Bischler indole synthesis is described. © 2003 Elsevier Science Ltd. All rights reserved.
Steroids bearing heterocycles fused to the A-ring of the
steroid nucleus have been of pharmaceutical interest.
There are a number of reports on the preparation of the
steroids with the pyrazole, isoxazole or pyrimidine ring
fused in the 2,3-position of the nucleus.1 Many of these
steroidal heterocycles have been found to possess
potent biological activities, such as anti-microbial, anti-
inflammatory hypotensive, hypocholesterolemic and
diuretic activities.2 An ongoing program in our labora-
tory is directed at the design and synthesis of novel
estrogen receptor ligands for the treatment or preven-
tion of disorders and diseases mediated by an estrogen
receptor or as components of oral contraceptive regi-
mens. In the course of our studies, we became inter-
ested in constructing novel estrieno[2.3-b] and [3.4-c]-
pyrroles (1 and 2 in Fig. 1) as targets to investigate the
ability of the fused pyrrole group to function as a
bioisostere of the phenol group of estradiol. Herein, we
report a short and efficient synthetic pathway to regio-
isomers 1 and 2 through a Pd(0)-catalyzed amination–
Bischler indole synthesis strategy.
tion of 1 and 2, is accomplished in three steps using
either a Smiles3 or Chapman-like4 rearrangement in the
key step. Since both of these pathways suffered from
some drawbacks, such as high reaction temperature,
long reaction time, poor yield and low product purity,
it becomes desirable to develop a simple and efficient
way to overcome these drawbacks. 3-Aminoestrone (5b)
is a versatile precursor of a number of biologically
active compounds containing nitrogen moiety. These
N-containing compounds are found to exhibit a large
spectrum of activities. During the last decade, the
Pd(0)-catalyzed amination process has proven quite
valuable because of the ease with which a variety of
complicated N-containing heterocycles or carbocycles
can be rapidly constructed in good yields utilizing mild
reaction conditions.5 Recently, Poirier and co-workers
reported an efficient method for the preparation of
3-aminoestrone from estrone through a three-step
sequence with a Pd(0)-catalyzed amination as the key
6
reaction. Given the distinct advantages of the Pd(0)-
catalyzed amination reaction, we initiated our investi-
gations by carrying out the transformation of phenol to
aniline using the aryl triflate 4a as the starting material
(Scheme 1). Triflate 4a was subjected to the standard
Pd(0)-catalyzed amination condition [Pd(OAc)2,
BINAP, NaO-t-Bu in toluene 100°C, 24 h] using
BnNH2 as a NH2 equivalent. However, the reaction
resulted in very low yield of the desired aniline 5a
(ꢀ15%) with mostly recovering estrone (3), generated
by the hydrolysis of the triflate 4a under the alkaline
reaction conditions. Due to the difficulty of handling a
large scale reaction under strictly anhydrous conditions,
we then abandoned the aryl triflates route in favor of
the corresponding aryl nonaflates route.7 These non-
aflates, maintain the same chemical properties as aryl
triflates but possess stronger stability toward base
hydrolysis and are more reactive toward Pd(0)-insertion
The traditional transformation of estrone (3) into 3-
aminoestrone (5b), a key intermediate for the prepara-
Figure 1.
* Corresponding author. Fax: +1-908-526-6469; e-mail: xzhang5@
prdus.jnj.com
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00541-0

3072
X. Zhang, Z. Sui / Tetrahedron Letters 44 (2003) 3071–3073
Scheme 1.
Scheme 2.
due to their greater electron withdrawing capacity. Aryl
nonaflate 4b was readily prepared by the reaction of
estrone (3) with commercially available CF3(CF2)3SO2F
in the presence of Et3N in 88% yield. Applying this
strategy to our system, we were pleased to find that the
nonaflate 4b was smoothly transformed into the aniline
5a in 65% yield without either starting material 4b or
the estrone (3) (Scheme 1). The reaction was conducted
in toluene at 80–100°C for 2–6 h and could be readily
scaled up to ꢀ20 g without strictly anhydrous condi-
tions. 3-Aminoestrone (5b) was then obtained by
hydrogenation of the Bn protected aniline 5a in 82%
yield. In contrast to most previously described proce-
dures, the present method allows lower temperatures,
shorter reaction times and less strictly anhydrous sol-
vents to 3-aminoestrone (5b) in good yield and high
purity (>98% by HPLC).
by column chromatography and reduction of the sepa-
rated isomers by NaBH4 in MeOH at 0°C followed by
deprotection of the sulfonamide by 5% KOH in EtOH
afforded the final products estrieno[2.3-b]pyrrole 1
(80% for two steps) and estrieno[3.4-c]pyrrole 2 (85%
for two steps).10
In conclusion, we have reported a mild, efficient and
straightforward method for the synthesis of the
estrieno[2.3-b] and [3.4-c]pyrroles, 1 and 2. The Pd(0)-
catalyzed amination utilizing the aryl nonaflates as the
precursors provides a reliable way in the preparations
of some pharmaceutically useful amino steroids.
References
With a reliable method to synthesis the 3-amino
analogs of estrone secured, we turned our attention to
the preparation of estrieno[2.3-b] and [3.4-c]pyrroles 1
and 2. Bischler indole synthesis is a practical method
for the synthesis of various substituted or unsubstituted
indoles.8 Applying our palladium-catalyzed amination
of 4b with NH2CH2CH(OEt)2 as amine source afforded
5c in 57% yield.9 The aniline derivative 5c was then
protected as the sulfonamide and subjected to the acid-
catalyzed Bischler condition (PPA, toluene, reflux, 1 h)
to afford the protected estrieno[2.3-b]pyrrole 6a and its
regio-isomer [3.4-c]pyrrole 6b in ꢀ2:1 ratio (Scheme 2).
The regio-isomers 6a and 6b could be easily separated
1. (a) Clinton, R. O.; Manson, A. J.; Stonner, F. W.; Beyler,
A. L.; Potts, G. O.; Arnold, A. J. Am. Chem. Soc. 1959,
81, 1513; (b) Clinton, R. O.; Manson, A. J.; Stonner, F.
W.; Neumann, H. C.; Christiansen, R. G.; Clarke, R. L.;
Ackerman, J. H.; Page, D. F.; Dean, J. W.; Dickinson,
W. B.; Carabateas, C. J. Am. Chem. Soc. 1961, 83, 1478;
(c) Clinton, R. O.; Manson, A. J.; Stonner, F. W.;
Chrstiansen, R. G.; Beyler, A. L.; Potts, G. O.; Arnold,
A. J. Org. Chem. 1961, 26, 279; (d) Ackerman, J. H.;
Potts, G. O.; Beyler, A. L.; Clinton, R. O. J. Med. Chem.
1964, 7, 238; (e) Camoutsis, C. J. Heterocyclic Chem.
1996, 33, 539; (f) Laitonjam, W. S.; Rajkumar, T. S.;
Chingakham, B. S. Steroids 2002, 67, 203.

X. Zhang, Z. Sui / Tetrahedron Letters 44 (2003) 3071–3073
3073
2. (a) Hirschmann, R.; Buchschacher, P.; Steinberg, N. G.;
Fried, J. H.; Ellis, R.; Kent, G. J.; Tischler, M. J. Am.
Chem. Soc. 1964, 86, 1520; (b) Gupta, R.; Pathak, D.;
Jindal, D. P. Eur. J. Med. Chem. 1996, 31, 241; (c)
Manson, A. J.; Stonner, F. W.; Neumann, H. C.; Chris-
tiansen, R. G.; Clarke, R. L.; Ackerman, J. H.; Page, D.
F.; Dean, J. W.; Phillips, D. K.; Potts, G. O.; Arnold, A.;
Beyler, A. L.; Clinton, R. O. J. Med. Chem. 1963, 6, 1;
(d) Wang, S.; Xie, F.; Song, K. Chem. Abstr. 1993, 119,
203669y; (e) Hirschmann, R.; Steinberg, N. G.;
Buschacher, P.; Fried, J. H.; Kent, G. J.; Tishler, M. J.
Am. Chem. Soc. 1963, 85, 120.
3. (a) Levi, A. A.; Rains, H. C.; Smiles, S. J. Chem. Soc.
1931, 3264; (b) Evans, W. J.; Smiles, S. J. Chem. Soc.
1936, 329; (c) Weidner, J. J.; Weintraub, P. M.; Schnet-
tler, R. A.; Peet, N. P. Tetrahedron 1997, 53, 6303.
4. (a) Scherrer, R. A.; Beatty, H. R. J. Org. Chem. 1972, 37,
1681; (b) Morrow, D. F.; Butler, M. E. J. Org. Chem.
1964, 29, 1893; (c) Morrow, D. F.; Hofer, R. M. J. Med.
Chem. 1966, 9, 249; (d) Conrow, R. B.; Bernstein, S.
Steroids 1968, 11, 151.
5. (a) Wolfe, J. P.; Ahman, J.; Sadighi, J. P.; Singer, R. A.;
Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6367; (b)
Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed.
1999, 38, 2413; (c) Huang, X.; Buchwald, S. L. Org. Lett.
2001, 3, 3417; (d) Hartwig, J. F.; Richards, S.; Baranano,
D.; Paul, F. J. Am. Chem. Soc. 1996, 118, 3626.
6. Radu, I.; Poirier, D.; Provencher, L. Tetrahedron Lett.
2002, 43, 7617.
7. Knochel, P.; Rottlander, M. J. Org. Chem. 1998, 63, 203.
8. Sundberg, R. J.; Laurino, J. P. J. Org. Chem. 1984, 49,
249.
9. Typical procedure for Pd(0)-catalyzed amination of the
aryl nonaflate—the preparation of 5c. A three-necked flask
was charged with Pd(OAc)2 (0.655 mmol, 148 mg),
BINAP (0.72 mmol, 432 mg) and NaO-t-Bu (45.86
mmol, 4.39 g). The reaction mixture was stirred in tolu-
ene (400 mL) for 10 min at 80°C. A mixture of
NH2CH2CH(OEt)2 (39.31 mmol, 5.72 mL) and 4b (32.76
mmol, 18.0 g) in toluene (20 mL) was then slowly added
dropwise via syringe to the reaction mixture. After addi-
tion, the mixture was heated at 80°C with stirring for 2 h.
The reaction mixture was cooled to room temperature.
Et2O and water were added and the solution was parti-
tioned between Et2O and water. The Et2O layer was
washed with brine, dried over anhydrous Na2SO4 and
concentrate to yield 5c as a crude solid. The crude
product was purified by column chromatography using
4:1 hexanes/EtOAc to yield 5c as a colorless oil (7.16 g,
1
57%). H NMR (300 MHz, CDCl3) l 7.12 (d, J=8.8 Hz,
1H), 6.53 (d, J=8.8 Hz, 1H), 6.38 (s, 1H), 4.68 (t, J=6.0
Hz, 1H), 3.80 (br, s, 1H), 3.75 (m, 2H), 3.60 (m, 2H), 3.22
(d, J=6.0 Hz, 2H), 2.91 (m, 2H), 2.50 (dd, J=18.0, 8.8
Hz, 1H), 2.42 (m, 1H), 2.35 (m, 1H), 2.20 (m, 1H),
2.15–1.94 (m, 3H), 1.72–1.38 (m, 6H), 1.25 (t, J=7.6 Hz,
6H), 0.98 (s, 3H); MS (m/z) 408, [M+Na]+.
1
10. Spectral data for 1 and 2. 1: white solid; H NMR (300
MHz, CDCl3) l 8.01 (br, s, 1H), 7.68 (s, 1H), 7.14 (s,
1H), 7.12 (m, 1H), 6.45 (m, 1H), 3.75 (t, J=8.5 Hz, 1H),
3.05–2.95 (m, 2H), 2.52 (m, 1H), 2.43 (m, 1H), 2.15 (m,
1H), 2.05–1.88 (m, 2H), 1.80–1.58 (m, 2H), 1.55–1.28 (m,
6H), 0.85 (s, 3H); MS (m/z) 318, [M+Na]+; 296, [M+H]+.
Anal. calcd for C20H25NO. 0.2 H2O: C, 80.33; H, 8.56; N,
4.68. Found: C, 80.46; H, 8.42; N, 4.61. 2: white solid; 1H
NMR (300 MHz, CDCl3) l 8.05 (br, s, 1H), 7.15 (d,
J=6.0 Hz, 1H), 7.13 (d, J=6.0 Hz, 1H), 7.12 (m, 1H),
6.45 (m, 1H), 4.65 (t, J=9.5 Hz, 1H), 3.10–2.90 (m, 2H),
2.40–2.28 (m, 2H), 2.20–2.08 (m, 1H), 1.98 (m, 1H), 1.85
(m, 1H), 1.78 (m, 1H), 1.65 (m, 1H), 1.60–1.28 (m, 6H),
0.85 (s, 3H); MS (m/z) 318, [M+Na]+.