Synthesis of azahomosteroid ring system through intramolecular [4+2] cycloaddition of in situ generated azaisobenzofuran intermediates

Article abstract of DOI:10.1016/j.tetlet.2013.01.005

Azahomosteroid ring systems were synthesized through two-component coupling of γ,δ-unsaturated Fischer carbene complexes with o-alkynylheteroaryl carbonyl derivatives. The reaction occurs through the formation of azaisobenzofuran as transient intermediate; the latter undergoes a subsequent Diels-Alder cycloaddition reaction with in-built dienophile with high regio- and stereoselectivity. Copyright

Full text of DOI:10.1016/j.tetlet.2013.01.005

Tetrahedron Letters 54 (2013) 1440–1443
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Tetrahedron Letters
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Synthesis of azahomosteroid ring system through intramolecular [4+2]
cycloaddition of in situ generated azaisobenzofuran intermediates
Priyabrata Roy a, Partha Mitra b, Binay Krishna Ghorai a,
⇑
a Department of Chemistry, Bengal Engineering and Science University, Shibpur, Howrah 711 103, India
b Department of Inorganic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Azahomosteroid ring systems were synthesized through two-component coupling of
c,d-unsaturated
Received 30 October 2012
Revised 31 December 2012
Accepted 3 January 2013
Available online 11 January 2013
Fischer carbene complexes with o-alkynylheteroaryl carbonyl derivatives. The reaction occurs through
the formation of azaisobenzofuran as transient intermediate; the latter undergoes a subsequent Diels–
Alder cycloaddition reaction with in-built dienophile with high regio- and stereoselectivity.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Azahomosteroid
Azaisobenzofuran
Carbene complex
Diels–Alder reaction
OMe
Azahomosteroid derivatives have attracted particular attention
in the area of new drug discovery because of their interesting phar-
macological properties.1 Reported methods for the synthesis of
azahomosteroids are limited and involve multistep synthetic
transformations.1a,d Literature report shows that all the synthetic
methods depend critically on the availability of the appropriate
steroid skeletons. As part of our continuing interest in the chemis-
try of azaisobenzofurans,2 this Letter focuses on two component
coupling approach to the synthesis of azahomosteroid ring systems
using Fischer carbene chemistry. Our strategy towards azahomos-
teroids 4 is based on the pioneering work of Herndon and co-work-
ers3 as outlined in Scheme 1. This process involves the in situ
generation of azaisobenzofuran intermediates 3 through the cou-
pling of carbene complexes 2 with o-alkynylheteroaryl carbonyl
derivatives 1, and subsequent intramolecular Diels–Alder reactions
with in-built alkene.
Requisite o-alkynylheteroaryl carbonyl derivative 1a/1b was
easily prepared following the sequence of reactions depicted in
Scheme 2. Bromoalcohol 6a/6b was prepared by the ortho-lithia-
tion of bromopyridine derivative 5 with LDA at À78 °C followed
by quenching with aryldehydes. Contrary to expectations based
on the preceding literature ,4 the ortho-lithiation led to a dramatic
disruption in regioselectivity due to halogen dance.5 Carbinol 7
was prepared from 6 by the removal of the bromine atom through
the metal halogen exchange reaction. The H-6 of 7 can be differen-
tiated from the corresponding H-5 of 6 on the basis of 1H NMR
(OC)5Cr
R
R
O
HO
H
R
2
O
H
H
N
N
N
H
THF, reflux
H
O
4
OMe
3
1
Scheme 1. Synthetic strategy towards azahomosteroid ring systems.
spectral data. The appearance of a new singlet (d 8.14, 1H) in the
1H NMR spectrum of 7 suggests that halogen dance occurred.
Oxidation of alcohols 6a/6b using Collin’s reagent yielded bromo
ketones 8a/8b which on Sonogashira coupling reaction with (tri-
methylsilyl)acetylene at room temperature resulted in the alkyne
derivative 9a/9b. Treatment of 9a/9b with potassium carbonate
in methanol afforded the ketone derivative 1a/1b. Other carbonyl
derivatives 1c–1e were prepared according to the literature
procedure.3d
Initially, the coupling reaction of ketone derivative 1c with a
trans 2-alkenylcyclohexylcarbene complex (2)6 was selected to
optimize the reaction conditions (Table 1). The coupling reaction
was carried out at the refluxing temperature using a 1:1.5 ratio
of alkyne derivative 1c and carbene complex 2. The yield of the
product was considerably higher in dilute solution (entry 1 vs en-
try 2). Increase in the reaction time lowers the product yield (entry
3). THF was found to be the best solvent in our study as the use of
other solvents, for example, 1,4-dioxane or acetonitrile, decreased
the product yield (entries 4 and 5). Finally, with the use of
1.0 equiv of carbene complex 2, the product yield also decreased
⇑
Corresponding author. Tel.: +91 33 26684561; fax: +91 33 26682916.
E-mail address: bkghorai@yahoo.co.in (B.K. Ghorai).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.005

P. Roy et al. / Tetrahedron Letters 54 (2013) 1440–1443
1441
n-BuLi, THF
MeO
LDA/ RCHO
THF, -78 °C
N
-78 °C, 0.5 h
MeO
N
Br
MeO
N
H6 (δ 8.14)
N
N
R
N
R
Br
then aq.NH4Cl
OH
OH
OMe
OMe
OMe
5
7, 80%
6a, R = Ph, 88%
6b, R = p-Tol, 64%
CrO3, 2Py
CH2Cl2, rt
SiMe3
(Ph3P)2PdCl2, CuI
TMS
MeO
N
Br
MeO
N
K2CO3, MeOH
0 °C, 0.5 h
MeO
N
R
N
N
R
N
R
THF, Et3N, rt, 12h
MeO
O
MeO
O
MeO
O
8a, R = Ph, 66%
9a, R = Ph, 62%
1a, R = Ph, 83%
8b, R = p-Tol, 90%
9b, R = p-Tol, 76%
1b, R = p-Tol, 86%
Scheme 2. Synthesis of alkyne carbonyl derivatives.
Table 1
significantly (entry 6). This may be due to the decomposition of 2
under the conditions employed. On the basis of this initial study,
the optimal reactivity is obtained in refluxing THF for 5 h with a
1:1.5 ratio of alkyne derivatives 1c and carbene complex 2.
Effect of reaction conditions on the coupling of 1c and carbene complex 2a
OMe
(OC)5Cr
p-Tol
HO
H
p-Tol
O
The scope of the reaction was studied using few alkyne carbonyl
derivatives 1 and carbene complex 2 with the optimized conditions
(Table 2). Thus, exposure of 1a to a carbene complex 2 in refluxing
THF gave tetracyclic compound 4a7 as a single diastereomer in 78%
yield (entry 1). The stereochemistry of 4a was confirmed as exo iso-
mer by X-ray crystallography (Fig. 1). In all cases, the formation of
azahomosteroid skeleton 4 arising from intramolecular exo selec-
tive Diels–Alder reaction8 of azaisobenzofuran intermediate 3 with
in-built alkene was the exclusive pathway (entries 2–5). The ob-
served isomeric preferences are well-known in decalin chemistry.9
In these reactions, coupling of carbene complex 2 with alkyne 1
initially provides intermediate alkyne carbene complex 10, which
undergoes ylide formation to afford the azaisobenzofuran interme-
diate 3. The intermediate 3 undergoes intramolecular Diels–Alder
reaction with in-built alkene (Scheme 3). The initial Diels–Alder
cycloadduct 11 appears to be unstable with respect to ring opening
processes.8a The high-yielding intramolecular [4+2]-cycloaddition
2
H
N
N
1c
THF, reflux
H
O
4c
Entry
Solvent
Time (h)
Concnb (M)
Yieldc (%)
1
2
3
4
5
6
THF
THF
THF
1,4-Dioxane
Acetonitrile
THF
5
5
24
5
5
5
0.1
0.4
0.4
0.1
0.1
0.1
67
61
49
54
32
55d
a
All reactions were conducted at the reflux temperature using a 1:1.5 ratio of
alkyne derivative and carbene complex.
b
Concentration of carbene and enyne in respective solvents.
Isolated yields.
The reaction was carried out using a 1:1 ratio of alkyne derivative and carbene
c
d
complex.
Table 2
Synthesis of azahomosteroids
Entry
Alkyne carbonyl compound
Product
HO
Yield (%)
OMe O
OMe
N
Ph
N
Ph
1a
H
H
4a
4b
1
78
N
OMe
MeO
N
H
O
OMe O
N
p
-TolOMe
N
HO
N
p
-Tol
1b
H
H
2
3
72
N
OMe
MeO
H
O
p-Tol
O
p-Tol
N
HO
1c
H
H
4c
67
N
H
O
(continued on next page)

1442
P. Roy et al. / Tetrahedron Letters 54 (2013) 1440–1443
Table 2 (continued)
Entry
Alkyne carbonyl compound
Ph
Product
HO
Yield (%)
Ph
O
H
H
H
1d
4d
N
4
5
81
N
H
O
Ph
Ph
HO
N
N
N
N
O
1e
H
4e
61
H
O
OMe
(OC)5Cr
R
H
R
O
R = H
O
2
N
O
O
N
N
THF, reflux, 5h
OMe
10
1
OMe
12
R = Aryl
R
R
H
H
H
O
O
O
N
N
H
H
O
N
H
H
OMe
H
OMe
OMe
13
11
3
HO
R
O
H
O
O
O
H
N
N
N
H
H
H
+
H
O
H
H
OMe
14, 21%
Scheme 3. Proposed mechanism for the formation of azahomosteroids.
O
H
CHCl3
15, 62%
4
reaction of 3 is obviously related to entropic factors which place
the tethered double bond in close proximity to the diene system.
The isolation of 4 as a sole product suggests that no competitive
pyrone formation of 13 takes place via the intermediate 12, which
could result from the insertion of CO with the alkyne carbene
complex 10.10
In an extension of these studies, we have explored the coupling
reaction of 2-ethynyl pyridine-3-carbaldehyde11 with carbene
complex 2, which yielded a mixture of enol ether 14 and lactone
derivative 15 through domino pyrone intermediate formation fol-
lowed by intramolecular Diels–Alder reaction (Scheme 3). Forma-
tion of pyrone intermediate 13 from this reaction was not
expected initially based on previous observations using o-alkynyl-
carbonyl derivatives (Table 2), which lead to azaisobenzofuran
intermediates 3. The surprising formation of intermediate 13 in
this study might be attributed to the reduced nucleophilicity of
the carbonyl oxygen. The pyrone intermediate 13 undergoes
Diels–Alder reaction10 with in-built alkene under the reaction con-
ditions leading to the isolation of stable bridged cycloadduct 15 in
high yield. Attempt to isolate the pure enol ether 14 has failed,
since it readily converted to 1512 in chloroform at room tempera-
ture. The structure and the stereochemistry of 15 were confirmed
from X-ray single crystal structure determination (Fig. 2), which
shows that cycloaddition reaction proceeded with exclusive endo
stereoselectivity. The observed isomeric preference is well-known
in pyrone chemistry.13
In conclusion, we have developed a novel method for the
construction of azahomosteroid skeleton based on the domino

P. Roy et al. / Tetrahedron Letters 54 (2013) 1440–1443
1443
References and notes
1. (a) Covey, D. F.; Han, M.; Kumar, A. S.; de la Cruz, M. A. M.; Meadows, E. S.; Hu,
Y.; Tonnies, A.; Nathan, D.; Benz, M. C. A.; Evers, A. S.; Zorumski, C. F.;
Mennerick, S. J. Med. Chem. 2000, 43, 3201–3204; (b) Lu, L.; Weiss, R. G.
Langmuir 1995, 11, 3630–3632; (c) Trafalis, D. T. P.; Geromichalos, G. D.;
Koukoulitsa, C.; Papageorgiou, A.; Karamanakos, P.; Camoutsis, C. Breast Cancer
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Res. Treat. 2006, 97, 17–31; (d) Krstic´, N. M.; Bjelakovic´, M. S.; Zizak, Z.;
Pavlovic´, M. D.; Juranic´, Z. D.; Pavlovic´, V. D. Steroids 2007, 72, 406–414.
2. (a) Jana, G. P.; Ghorai, B. K. Tetrahedron 2007, 63, 12015–12025; (b) Mukherjee,
S.; Jana, G. P.; Ghorai, B. K. J. Organomet. Chem. 2009, 694, 4100–4106; (c) Roy,
P.; Ghorai, B. K. Beilstein J. Org. Chem. 2010, 6. http://dx.doi.org/10.3762/
bjoc.6.52; (d) Jana, G. P.; Mukherjee, S.; Ghorai, B. K. Synthesis 2010, 3179–
3187; (e) Mukherjee, S.; Roy, P.; Ghorai, B. K. Synthesis 2011, 1419–1426; (f)
Roy, P.; Ghorai, B. K. Tetrahedron Lett. 2011, 52, 251–253; (g) Roy, P.; Ghorai, B.
K. Tetrahedron Lett. 2011, 52, 5668–5671.
3. For the generation of isobenzofurans utilizing Fischer carbene chemistry
(selected papers), see (a) Jiang, D.; Herndon, J. W. Org. Lett. 2000, 2, 1267–1269;
(b) Ghorai, B. K.; Herndon, J. W. Org. Lett. 2001, 3, 3535–3538; (c) Luo, Y.;
Herndon, J. W.; Cervantes-Lee, F. J. Am. Chem. Soc. 2003, 125, 12720–12721; (d)
Li, R.; Zhang, L.; Camacho-Davila, A.; Herndon, J. W. Tetrahedron Lett. 2005, 46,
5117–5120; (e) Camacho-Davila, A.; Herndon, J. W. J. Org. Chem. 2006, 71,
6682–6685; (f) Ghorai, B. K.; Duan, S.; Jiang, D.; Herndon, J. W. Synthesis 2006,
3661–3669; (g) Patti, R. K.; Waynant, K. V.; Herndon, J. W. Org. Lett. 2011, 13,
2848–2851.
4. (a) Kress, T. J. J. Org. Chem. 1979, 44, 2081–2082; (b) Van der Plas, H. C. Acc.
Chem. Res. 1978, 11, 462–468; (c) Kauffmann, T.; Wirthwein, R. Angew. Chem.,
Int. Ed. 1971, 10, 20–33; (d) Numata, A.; Kondo, Y.; Sakamoto, T. Synthesis 1999,
306–311; (e) Turck, A.; Ple, N.; Tallon, V.; Queguiner, G. J. Heterocycl. Chem.
1993, 30, 1491–1496.
Figure 1. X-ray crystal structure of 4a.
5. Only one example of halogen dance was reported for
a reaction in the
pyrimidine series Ple, N.; Turck, A.; Couture, K.; Queguiner, G. Tetrahedron
1994, 50, 10299–10308.
6. Moser, W. H.; Hegedus, L. S. J. Am. Chem. Soc. 1996, 118, 873–7880.
7. Representative procedure. Synthesis of azahomosteroid derivative 4a: A solution of
carbene complex 2 (192 mg, 0.558 mmol) in THF (5 mL) was added dropwise
over a period of 0.5 h to a refluxing of alkynyl carbonyl derivatives 1 (100 mg,
0.372 mmol) in THF (4 mL). After the addition was complete, the mixture was
heated to reflux for a period of 5 h. The reaction mixture was allowed to cool to
room temperature and concentrated on a rotary evaporator. EtOAc (8 mL) was
added and the residue was filtered through CeliteÒ (1.0 g). After evaporation of
solvent, the crude product was purified using column chromatography (silica
gel, ethyl acetate/petroleum ether 1:1) affording azahomosteroid derivative 4a
(118 mg, 78%) as white crystalline solids. Mp 175–176 °C; IR (neat, cmÀ1) 3464,
1668; 1H NMR (300 MHz, CDCl3) d 7.35 (d, J = 1.8 Hz 1H), 7.33–7.30 (m, 3H),
7.25–7.22 (m, 2H), 4.18 (s, 1H), 4.07 (m, 2H), 4.18 (s, 1H), 3.94 (s, 3H), 2.50 (dd,
J = 12.6, 3.0 Hz, 2H), 2.29 (br d, J = 9.6 Hz, 1H), 2.08 (m, 1H), 1.98–1.89 (m, 3H),
1.79 (br s, 1H), 1.70 (br d, J = 9.6 Hz, 1H), 1.65–1.58 (m, 1H), 1.21–1.08 (m, 1H),
0.77 (m, 1H); 13C NMR (75 MHz, CDCl3) d 201.3, 169.8, 163.7, 157.7, 152.4,
144.9, 128.3 (2C), 127.8, 125.7, 125.6 (2C), 115.9, 73.8, 55.0, 54.8, 50.1, 44.0,
42.0, 37.8, 29.9, 25.4, 25.1, 25.0; HRMS (ESI) m/z [MH+] calcd for C24H27N2O4
407.1971, found 407.1964.
8. Six-membered-ring-forming
intramolecular
Diels–Alder
reaction
of
isobenzofurans proceeds with exo stereochemistry as from literature
precedent (a) Friedrichsen, W. Adv. Heterocycl. Chem. 1999, 73, 1–96; (b)
Meegalla, S. K.; Rodrigo, R. Synthesis 1989, 942–944; (c) Tobia, D.; Rickborn, B. J.
Org. Chem. 1987, 52, 2611–2615; (d) Yamaguchi, Y.; Yamada, H.; Hayakawa, K.;
Kanematsu, K. J. Org. Chem. 1987, 52, 2040–2046; (e) Menon, S.; Sinha-
Mahapatra, D.; Herndon, J. W. Tetrahedron 2007, 63, 8788–8793; (f) Luo, Y.;
Herndon, J. W. Organometallics 2005, 24, 3099–3103.
Figure 2. X-ray crystal structure of 15.
9. Thompson, H. W.; Long, D. J. J. Org. Chem. 1988, 53, 4201–4209.
10. For pyrone formation through CO insertion during the coupling reaction of o-
alkynylheteroaryl carbonyl derivatives with carbene complexes, see: (a) Zhang,
Y.; Herndon, J. W. Tetrahedron Lett. 2001, 42, 777–779; (b) Zhang, Y.; Herndon,
J. W. J. Org. Chem. 2002, 67, 4177–4185.
11. 2-Ethynyl pyridine-3-carbaldehyde was prepared by the desilylation of 2-
(trimethylsilyl)ethynylpyridine-3-carbaldehyde4d with K2CO3 in methanol at
0 °C.
azaisobenzofuran formation-intramolecular Diels–Alder reaction
followed by ring opening of the oxanorbornene ring. These
intramolecular [4+2] cycloadditions show high regio- and
stereoselectivity.
12. Compound 15: Mp 200–201 °C; IR (KBr, cmÀ1) 1752, 1714, 1581; 1H NMR
(500 MHz, CDCl3) d 8.58 (dd, J = 5.0, 1.5 Hz, 1H), 7.59 (dd, J = 7.5, 1.5 Hz, 1H),
7.26 (dd, J = 7.5, 5.0 Hz, 1H), 5.66 (dd, J = 4.5, 1.0 Hz, 1H), 3.52 (d, J = 15.0 Hz,
1H), 3.05 (dd, J = 15.0, 1.0 Hz, 1H), 2.74 (ddd, J = 13.9, 9.6, 4.2 Hz, 1H), 2.34
(ddd, J = 11.2, 9.6, 4.2 Hz, 1H), 2.11 (br d, J = 13.9 Hz, 1H), 1.95 (td, J = 11.5,
2.5 Hz, 1H), 1.78–1.70 (m, 2H), 1.67 (br d, J = 13.9 Hz, 1H), 1.51 (dd, J = 13.9,
4.0 Hz, 1H,), 1.15 (qt, J = 13.0, 3.0 Hz, 1H), 1.08–0.98 (m, 2H), 0.95 (qt, J = 13.0,
3.0 Hz, 1H), 0.56 (qd, J = 11.5, 3.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) d 207.3,
172.9, 154.8, 150.1, 131.3, 129.7, 122.7, 75.0, 53.7, 53.6, 44.8, 39.9, 39.0, 31.6,
30.8, 25.4, 25.0, 24.6; MS m/z 298 (MH+, 100); Anal. Calcd for C18H19NO3: C,
72.71; H, 6.44; N, 4.71. Found: C, 72.69; H, 6.45; N, 4.69.
Acknowledgments
Financial support from CSIR [No. 01 (2215)/08-EMR-II], Govern-
ment of India is gratefully acknowledged. The CSIR, New Delhi is
also thanked for the award of Senior Research Fellowship to P.R.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
01.005.
13. The product of the cycloaddition of pyrones is generally favoured endo
cycloadduct Afarinkia, K.; Nelson, T. D.; Vinader, M. V.; Posner, G. H.
Tetrahedron 1992, 48, 9111–9171.