Concise synthesis of 12a-methyl-11-aryl-1,2-dihydrobenzo[f]pyrrolo[1,2-a]quinolin-3(12aH)-ones as racemic 14-azaestrogen analogs

Article abstract of DOI:10.1016/j.steroids.2015.03.010

A concise method for the synthesis of 14-azasteroid analogs with angular methyl group at C-13 of the steroidal nucleus has been reported in this paper. We have developed an interesting cascade reaction of arylacetylenes and N-(naphthalen-2-yl)pent-4-ynamides under gold (III)-catalysis to produce novel tetracyclic 12a-methyl-11-aryl-1,2-dihydrobenzo[f]pyrrolo[1,2-a]quinolin-3(12aH)-ones which may be viewed as 14-azaestrogen analogs.

Full text of DOI:10.1016/j.steroids.2015.03.010

Steroids 98 (2015) 107–113
Contents lists available at ScienceDirect
Steroids
journal homepage: www.elsevier.com/locate/steroids
Concise synthesis of 12a-methyl-11-aryl-1,2-
dihydrobenzo[f]pyrrolo[1,2-a]quinolin-3(12aH)-ones as racemic
4-azaestrogen analogs
1
⇑
Ashraf M. Abdelkhalik, Nawal K. Paul, Amitabh Jha
Department of Chemistry, Acadia University, Wolfville, NS, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise method for the synthesis of 14-azasteroid analogs with angular methyl group at C-13 of the
steroidal nucleus has been reported in this paper. We have developed an interesting cascade reaction
of arylacetylenes and N-(naphthalen-2-yl)pent-4-ynamides under gold (III)-catalysis to produce novel
tetracyclic 12a-methyl-11-aryl-1,2-dihydrobenzo[f]pyrrolo[1,2-a]quinolin-3(12aH)-ones which may be
viewed as 14-azaestrogen analogs.
Received 28 October 2014
Received in revised form 4 March 2015
Accepted 12 March 2015
Available online 21 March 2015
Ó 2015 Elsevier Inc. All rights reserved.
Keywords:
1
4-Azasteroids
Estrogen analogs
2a-Methyl-11-aryl-1,2-
dihydrobenzo[f]pyrrolo[1,2-a]quinolin-
(12aH)-ones
1
3
Gold (III) catalysis
Domino reaction
1
. Introduction
Numerous hormones are known to have tetracyclic steroidal
RU-5135 (antagonist of GABA in the CNS) [13]. A large number of
N-containing heterosteroids have been studied as azaestrogens
[14,15]. Considering the fact that any minor modification in the
chemical structure of the steroid often results in a huge change
in their biological activities and applications; medicinal chemists
employ it as a tool in design and development of new drugs [5–9].
Since this investigation deals with synthesis of 14-azasteroids,
it is pertinent to briefly describe strategies adopted in past to
assemble this nucleus. There are only a handful of reports describ-
ing synthesis of 14-azasteroids [16–24]. Three related procedures
employed [4+2] hetero-Diels–Alder approach between alkenes
framework. These are classified as mineralocorticoids, glucocorti-
coids, androgens, estrogens and progestogens based on the recep-
tors to which they bind to elicit their biological response [1].
Research on steroids enjoys utmost attention in pure and applied
sciences worldwide [2]. Estrogens (Fig. 1), a category of the steroidal
hormone system having an aromatic ring, bind with and activate the
Estrogen Receptors (ER) promoting a variety of physiological
responses such as bone maturation, blood lipid profile, neuroprotec-
tive effects, reproductive functions and breast cell proliferation [3].
Heterosteroids are man-made polycyclic steroidal systems
where one or more carbons are replaced by heteroatom(s) [4].
Owing to the structural and topological similarity with natural
steroids, heterosteroids are a subject of intense research that
reports syntheses of new congeners and unveils interesting and
useful properties that they possess [5–9]. A large number of
heterosteroids have been clinically studied; some have culminated
into successful drugs [5–9]. Fig. 2 includes several notable exam-
ples viz., finasteride (antihyperplastics) [10], candocuronium
iodide (muscle relaxants) [11], danazol (antiestrogen) [12], and
and N-acyliminium ions derived from 2-naphthylamine and c-keto
acids [16,17] (or by borohydride reduction of N-2-naphthylimide
[18]). In two endeavors with somewhat similar strategy [19,20],
cross Claisen condensation between ethyl acetate and ethyl 8-
methoxybenzo[f]quinoline-3-carboxylate, prepared from 6-meth-
oxy-2-naphthalenamine in 3 steps, led to the formation of a b–keto
ester. This b–keto ester underwent intramolecular reductive
cycloamidation to produce 14-azasteroid skeleton. Falling and
Rapoport [21] reported the synthesis of a 14-azasteroid analog as
a minor product starting from 1,4-naphthoquinone and homopro-
line ester, through oxidative Michael addition, reductive O-acetyla-
tion, aryl ether formation, ester hydrolysis and intramolecular
nuclear acylation sequence. Singh and Panda [22] have reported
an asymmetric approach to the synthesis of 14-azasteroids from
⇑
Corresponding author. Tel.: +1 902 585 1515; fax: +1 902 585 1414.
E-mail address: ajha@acadiau.ca (A. Jha).
http://dx.doi.org/10.1016/j.steroids.2015.03.010
039-128X/Ó 2015 Elsevier Inc. All rights reserved.
0

1
08
A.M. Abdelkhalik et al. / Steroids 98 (2015) 107–113
OH
OH
17
OH
high pressure reaction vessel. Appropriate 2-naphthol analog (1a
1
3
or 1b) (13.9 mmol, 1 equiv.) was added, and the mixture was stir-
red for 17 h at 120 °C. The reaction mixture was filtered and the
precipitate was washed with cold 5% aq. NaOH and then dissolved
in DCM. The organic layer was again washed with 5% aq. NaOH
H
H
14
H
OH
H
H
H
H
H
H
3
HO
HO
HO
Estrone
17β-Estradiol
Estriol
(
3 ꢀ 30 mL) and dried over anh. sodium sulfate to afford 2-naph-
Fig. 1. Molecular structures of natural estrogens.
thylamines after the removal of solvent in vacuo.
2
-tetralone and L-proline derived aldehyde. 1-Bromo-3,4-diby-
2
1
.2.1.1. 2-Naphthylamine (2a). Purple solid; yield 49%; m.p. 111–
13 °C (lit. m.p. 109–111 °C [31]). The H and C NMR data of this
dronaphthalene, obtained from 2-tetralone, was lithiated and then
reacted with BOC-protected L-homoproline aldehyde. Removal of
the BOC-group resulted in intramolecular cyclization to diastere-
omeric 14-azasteroids [22]. Loven and Speckamp subjected 3-
hydroxymethyl-N-tosyl-octahydrobenzo[f]quinoline to a sequence
of side chain oxidation to aldehyde, Wittig reaction with triethyl
1
13
compound was found to be identical to those reported in the
literature [31].
2
.2.1.2. 6-Bromo-2-naphthylamine (2b). Brownish solid; yield 21%;
1
13
m.p. 124–126 °C (lit. m.p. 127–128 °C [32]). The H and C NMR
data of this compound was found to be identical to those reported
in the literature [32].
phosphonoacetate, alkene hydrogenation, LiAlH
sylation and ester reduction, and finally PBr /NaHCO
4
-induced deto-
cyclization
3
3
of the amino-alcohol to yield 14-azasteroid [24]. In another inter-
esting endeavor Sokolov et al. [23] have reported an interesting
approach to 14-aza-17-thiasteroids by stereoselectively adding
thiirane and methyl thiirane across C@N of 8-methoxy-3-methyl-
hexahydrobenzo[f]quinolone. Thus, there are mainly six distinct
approaches to synthesize 14-azasteroid nucleus.
In continuation of our efforts of developing domino methodolo-
gies to complex heterocyclic systems [18,25–30], we herein report
a concise synthesis of 14-azasteroids, namely 12a-methyl-11-aryl-
2
.2.2. General procedure for the preparation of N-(naphthalen-2-
yl)pent-4-ynamides (3)
-Pentynoic acid (1.38 g, 14.01 mmol, 1 equiv.) was dissolved in
DCM (2 mL) then added to an ice-cold solution of EDC (4.026 g,
1 mmol, 1.5 equiv.) and HOBt (2.649 g, 19.59 mmol, 1.4 equiv.)
in DCM (25 mL). A solution of appropriate 2-naphthylamine
21 mmol, 1.5 equiv.) in DCM (20 mL) was then added to the reac-
4
2
(
tion mixture and stirred. Triethylamine (2.13 g, 21 mmol, 1.5
equiv.) was added drop-wise over 10 min. then the reaction tem-
perature was allowed to increase gradually to room temperature.
The reaction mixture was stirred for 17 h. The reaction mixture
was then diluted with 20 ml DCM, washed with water, 5% aq.
HCl, saturated Aq. sodium bicarbonate solution, and brine solution.
The organic layer was dried over anh. sodium sulfate, filtered and
the solvent was evaporated under reduced pressure. The crude
was purified by column chromatography to afford the correspond-
ing N-(naphthalen-2-yl)pent-4-ynamides.
1
,2-dihydrobenzo[f]pyrrolo[1,2-a]quinolin-3(12aH)-ones, in three
simple steps.
2
. Experimental
2.1. General remarks
All the chemicals and solvents for this work were obtained from
commercial sources and were used as such. TLCs were performed
on pre-coated Merck silica gel 60F254 plates with the spots
detected under UV light. Silica gel (230–400 mesh) was used for
column chromatography. Melting points were measured with a
MEL-TEMP , an electrothermal melting point apparatus and are
uncorrected. Microwave experiments were carried out in a CEM
2
.2.2.1. N-(Naphthalen-2-yl)pent-4-ynamide (3a). Colorless solid;
1
yield 76%; m.p. 126–128 °C. H NMR (CDCl
3
, 300 MHz): d 2.18 (s,
Ò
1
H), 2.67 (brs, 4H), 7.40–7.60 (m, 4H), 7.77–7.83 (m, 3H), 8.24
Ò
13
(
brs, 1H). C NMR (CDCl
3
, 75 MHz): d 11.6, 33.2, 66.5, 79.6,
Ò
Discover microwave reactor. Q-Block-35 and Q-tube 35 ml were
1
1
13.6, 116.7, 121.8, 123.3, 124.3, 124.4, 125.5, 127.6, 130.7,
31.9, 166.0. ESI-HRMS calcd. for C15H13NO: 224.1075 [M+H] ;
1
13
used to run the high pressure reactions. H and C NMR spectra
+
were recorded using a BrukerÒ AC-300 Avance spectrometer at
found: 224.1080.
1
3
00 MHz and 75 MHz, respectively, in CDCl
3
or DMSO-d
6
.
H
NMR spectra were reported relative to residual CHCl
3
(d 7.26) or
DMSO (d 2.50). C NMR spectra were reported relative to CHCl
d 77.2) or DMSO (d 39.5). High-resolution mass spectra (HRMS)
2
.2.2.2. N-(6-Bromonaphthalen-2-yl)pent-4-ynamide (3b). Colorless
1
3
3
1
solid; yield 81%; m.p. 185–187 °C. H NMR (CDCl
2
3
, 300 MHz): d
(
.10 (s, 1H), 2.67 (brs, 4H), 7.40–7.75 (m, 5H), 7.94 (s, 1H), 8.25
were recorded in the positive ion mode using a microTOF (Bruker
Daltonics) spectrometer at Dalhousie University.
13
(
brs, 1H). C NMR (CDCl
3
, 75 MHz): d 11.6, 33.2, 66.6, 79.5,
1
1
13.5, 115.7, 117.6, 124.6, 126.0, 126.3, 126.7, 128.5, 129.2,
+
32.2, 166.2. ESI-HRMS calcd. for C15H12BrNO: 302.0181 [M+H] ;
2
2
.2. Chemical synthesis
found: 302.0183.
.2.1. Synthesis of 2-naphthylamines
2.2.3. General procedure for gold-catalyzed tandem synthesis of 15-
Ammonium hydroxide aqueous solution (841 mg, 27.8 mmol, 2
oxo-14-azasteroids (4a–l)
equiv.) was added to a freshly prepared aqueous solution of ammo-
nium sulfite monohydrate (3.2 g, 27.8 mmol, 2 equiv.) in a 35 ml
To a solution of appropriate N-naphthylpent-4-ynamide
(1 mmol) and alkyne (4 mmol) in toluene (10 mL), AuBr
3
O
H
N
OH
H
N
O
N
I
H
H
H
H
H
H
H
N
H
H
O
N
N
O
HO
H
I
H
Finastride
Candocuronium iodide
Danazole
RU-5135
Fig. 2. Examples of biologically active heterosteroids.

A.M. Abdelkhalik et al. / Steroids 98 (2015) 107–113
109
(
3 mol%) and AgSbF
6
(5 mol%) were added in a 35 mL microwave
130.4, 131.0, 132.1, 156.2, 170.0. ESI-HRMS calcd. for
C H20BrNO : 434.0756 [M+H] ; found: 434.0750.
24 2
+
vessel equipped with a magnetic stir bar. The overhead space
was flushed with argon before placing the cap. The resulting mix-
ture was placed in the microwave cavity and it was irradiated at
2.2.3.7. 11-(4-tert-Butylphenyl)-12a-methyl-1,2-dihydrobenzo[f]pyr-
rolo[1,2-a]quinolin-3(12aH)-one (4g). Yellow liquid; yield 25%; 1
NMR (CDCl , 300 MHz): d 1.28 (s, 3H), 1.35 (s, 9H), 2.20–2.35 (m,
2H), 2.51–2.85 (m, 2H), 5.98 (s, 1H), 6.95–7.35 (m, 7H), 7.80 (d,
J = 8.1 Hz, 1H), 7.88 (d, J = 8.7 Hz, 1H), 8.48 (d, J = 9.0 Hz, 1H). 13
NMR (CDCl , 75 MHz): d 19.7, 27.1, 28.1, 29.2, 31.3, 56.7, 117.5,
1
20 °C for 4 h with constant stirring. Toluene was removed under
H
reduced pressure. The residue was purified by flash column chro-
matography (hexanes/ethyl acetate 20:1) to isolate the desired
product and to recover the unreacted amide starting material.
3
C
3
2
.2.3.1. 12a-Methyl-11-phenyl-1,2-dihydrobenzo[f]pyrrolo[1,2-a]quino-
118.5, 121.0, 121.5, 122.1, 124.0, 124.1, 125.0, 126.2, 126.7,
1
lin-3(12aH)-one (4a). Light Yellow liquid; yield 21%; H NMR (CDCl
3
,
128.7, 130.0, 130.6, 132.9, 135.9, 147.3, 170.1. ESI-HRMS calcd.
+
3
2
7
00 MHz): d 1.28 (s, 3H), 2.20–2.40 (m, 2H), 2.53–2.68 (m, 1H), 2.72–
.85 (m, 1H), 5.98 (s, 1H), 7.06 (t, J = 8.1 Hz, 1H), 7.19–7.41 (m, 7H),
.80 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 8.7 Hz, 1H), 8.48 (d, J = 9.0 Hz, 1H).
for C27
H
27NO: 382.2171 [M+H] ; found: 382.2153.
2.2.3.8. 8-Bromo-11-(4-tert-butylphenyl)-12a-methyl-1,2-dihydro-
13
3
C NMR (CDCl , 75 MHz): d 22.9, 30.4, 32.4, 60.1, 120.6, 121.5,
benzo[f]pyrrolo[1,2-a]quinolin-3(12aH)-one (4h). Colorless viscous
1
1
1
3
24.5, 124.9, 127.3, 127.4, 127.6, 127.7, 128.4, 128.6, 129.7, 131.8,
liquid; yield 22%; H NMR (CDCl
3
, 300 MHz): d 1.27 (s, 3H), 1.35
33.1, 134.4, 136.0, 142.0, 173.6. ESI-HRMS calcd. for C23
26.1545 [M+H] ; found: 326.1539.
H19NO:
(s, 9H), 2.20–2.36 (m, 2H), 2.51–2.82 (m, 2H), 5.98 (s, 1H), 6.90–
+
13
7.36 (m, 6H), 7.75–7.80 (m, 2H), 8.48 (t, J = 9.0 Hz, 1H). C NMR
(
3
CDCl , 75 MHz): d 19.7, 27.0, 28.1, 29.2, 31.3, 56.7, 117.5, 118.5,
2
.2.3.2. 8-Bromo-12a-methyl-11-phenyl-1,2-dihydrobenzo[f]pyrrolo[1,2-
121.0, 121.4, 122.3, 124.0, 124.8, 125.2, 125.8, 126.2, 126.9,
1
a]quinolin-3(12aH)-one (4b). Colorless viscous liquid; yield 15%;
NMR (CDCl , 300 MHz): d 1.28 (s, 3H), 2.20–2.40 (m, 2H), 2.53–2.64
m, 1H), 2.72–2.85 (m, 1H), 6.00 (s, 1H), 6.90–7.35 (m, 7H), 7.75–
H
128.7, 130.6, 131.0, 135.5, 147.6, 170.1. ESI-HRMS calcd. for
+
3
C
27
H
26BrNO: 460.1276 [M+H] ; found: 460.1265.
(
7
1
1
.95 (m, 2H), 8.45 (t, J = 9.0 Hz, 1H). 13C NMR (CDCl
9.7, 26.4, 29.2, 56.7, 117.5, 118.5, 121.1, 121.6, 124.0, 124.5, 125.0,
25.3, 125.5, 127.0, 128.9, 130.4, 131.1, 131.4, 138.6, 139.0, 170.1.
3
, 75 MHz): d
2.2.3.9.
rolo[1,2-a]quinolin-3(12aH)-one (4i). Yellow liquid; yield 29%;
NMR (CDCl , 300 MHz): d 0.92 (t, J = 6.9 Hz, 3H), 1.27 (s, 3H),
1.29–1.48 (m, 4H), 2.20–2.37 (m, 2H), 2.51–2.81 (m, 4H), 5.98 (s,
H), 6.90–7.35 (m, 7H), 7.80 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 8.7 Hz,
11-(4-Butylphenyl)-12a-methyl-1,2-dihydrobenzo[f]pyr-
1
H
3
+
ESI-HRMS calcd. for C23
H
18BrNO: 404.0650 [M+H] ; found: 404.0645.
1
1
3
2
.2.3.3. 11-(4-Ethylphenyl)-12a-methyl-1,2-dihydrobenzo[f]pyrrolo[1,2-
3
1H), 8.48 (d, J = 9.3 Hz, 1H). C NMR (CDCl , 75 MHz): d10.5,
1
a]quinolin-3(12aH)-one (4c). Yellow liquid; yield 24%;
CDCl , 300 MHz): d 0.80–0.95 (dist. t, 3H), 1.27 (s, 3H), 2.19–2.38
m, 2H), 2.52–2.84 (m, 4H), 5.98 (s, 1H), 6.95–7.54 (m, 5H), 7.80 (d,
H
NMR
19.0, 26.4, 27.1, 29.2, 30.2, 32.0, 56.7, 117.4, 121.1, 121.5, 123.2,
124.1, 124.3, 125.0, 125.3, 126.2, 126.7, 128.7, 130.0, 130.5,
(
(
3
132.9, 136.1, 138.9, 170.0. ESI-HRMS calcd. for
382.2171 [M+H] ; found: 382.2169.
C
27
H27NO:
13
+
J = 7.5 Hz, 2H), 7.88 (d, J = 9.0 Hz, 2H), 8.48 (d, J = 8.7 Hz, 1H).
NMR (CDCl , 75 MHz): d 12.1, 19.7, 25.3, 26.4, 29.2, 56.8, 117.4,
18.5, 121.1, 121.6, 123.2, 124.3, 124.7, 125.1, 125.5, 126.3, 127.5,
28.6, 129.9, 130.7, 136.2, 140.3, 170.1. ESI-HRMS calcd. for
C
3
1
1
C
2.2.3.10. 8-Bromo-11-(4-butylphenyl)-12a-methyl-1,2-dihydroben-
zo[f]pyrrolo[1,2-a]quinolin-3(12aH)-one (4j). Colorless viscous liq-
+
1
25
H
23NO: 354.1858 [M+H] ; found: 354.1854.
uid; yield 21%. H NMR (CDCl
3
, 300 MHz): d 0.96 (t, J = 6.9 Hz,
3
H), 1.27 (s, 3H), 1.32–1.46 (m, 4H), 2.16–2.39 (m, 2H), 2.51–
2
.2.3.4. 8-Bromo-11-(4-ethylphenyl)-12a-methyl-1,2-dihydrobenzo[f]-
2.85 (m, 4H), 5.98 (s, 1H), 6.96–7.35 (m, 6H), 7.77–7.98 (m, 2H),
8.48 (t, J = 9.2 Hz, 1H). C NMR (CDCl , 75 MHz): d10.6, 19.0,
3
26.4, 27.0, 29.2, 30.2, 32.1, 56.7, 115.2, 117.4, 118.5, 121.1, 124.2,
124.8, 125.1, 125.3, 125.5, 125.8, 126.9, 129.8, 130.9, 132.5,
1
3
pyrrolo[1,2-a]quinolin-3(12aH)-one (4d). Colorless viscous liquid;
yield 27%; H NMR (CDCl
1
3
, 300 MHz): d 0.86 (t, J = 6.9 Hz, 3H), 1.27
(s, 3H), 2.20–2.35 (m, 2H), 2.51–2.83 (m, 4H), 5.98 (s, 1H), 6.90–
7
.35 (m, 6H), 7.80 (d, J = 7.8 Hz, 1H), 7.94 (s, 1H), 8.48 (d,
135.7, 139.2, 170.2. ESI-HRMS calcd. for C27
[M+H] ; found: 460.1261.
H
26BrNO: 460.1276
1
3
+
J = 9.0 Hz, 1H). C NMR (CDCl
3
, 75 MHz): d 12.0, 19.72, 25.3,
6.4, 29.2, 56.8, 115.2, 117.4, 118.5, 121.1, 121.6, 124.3, 124.8,
25.2, 125.7, 126.9, 129.8, 130.3, 130.9, 132.5, 135.8, 140.5, 170.1.
2
1
2.2.3.11.
rolo[1,2-a]quinolin-3(12aH)-one (4k). Yellow liquid; yield 13%;
NMR (CDCl , 300 MHz): d 0.92 (t, J = 6.9 Hz, 3H), 1.27 (s, 3H),
.29–1.48 (m, 4H), 1.60–1.75 (m, 2H), 2.18–2.40 (m, 2H), 2.52–
12a-Methyl-11-(4-pentylphenyl)-1,2-dihydrobenzo[f]pyr-
+
1
ESI-HRMS calcd. for
C
25
H
22BrNO: 432.0963 [M+H] ; found:
H
432.0965.
3
1
2
.2.3.5. 11-(4-Methoxyphenyl)-12a-methyl-1,2-dihydrobenzo[f]pyr-
2.83 (m, 4H), 5.98 (s, 1H), 6.96–7.35 (m, 7H), 7.80 (d, J = 7.8 Hz,
1H), 7.88 (d, J = 9.0 Hz, 1H), 8.48 (d, J = 9.0 Hz, 1H). C NMR
(CDCl , 75 MHz): d10.6, 19.2, 26.3, 27.1, 27.6, 28.1, 29.2, 32.3,
3
56.7, 117.4, 118.4, 121.0, 121.4, 124.1, 124.2, 125.0, 125.2, 126.2,
1
13
rolo[1,2-a]quinolin-3(12aH)-one (4e). Yellow liquid; yield 29%;
NMR (CDCl , 300 MHz): d 1.27 (s, 3H), 2.20–2.39 (m, 2H), 2.52–
.84 (m, 2H), 3.85 (s, 3H), 5.94 (s, 1H), 6.84–7.42 (m, 7H), 7.80
d, J = 8.1 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 8.48 (d, J = 8.7 Hz, 1H).
H
3
2
(
126.6, 128.6, 130.0, 130.5, 132.9, 136.1, 138.9, 170.0. ESI-HRMS
1
3
+
C NMR (CDCl
3
, 75 MHz): d 19.7, 27.1, 29.2, 52.0, 56.7, 110.8,
calcd. for C28
H
29NO: 396.2327 [M+H] ; found: 396.2314.
1
1
17.4, 117.7, 121.1, 121.3, 121.6, 123.3, 124.1, 125.1, 125.5,
26.3, 126.6, 130.0, 130.1, 131.4, 156.9, 170.1. ESI-HRMS calcd.
2.2.3.12. 8-Bromo-12a-methyl-11-(4-pentylphenyl)-1,2-dihydroben-
+
for C24
H21NO
2
: 356.1651 [M+H] ; found: 356.1629.
zo[f]pyrrolo[1,2-a]quinolin-3(12aH)-one (4l). Colorless viscous liq-
1
uid; yield 12%; H NMR (CDCl
3
, 300 MHz): d 0.92 (t, J = 6.9 Hz,
2.2.3.6. 8-Bromo-11-(4-methoxyphenyl)-12a-methyl-1,2-dihydroben-
3H), 1.27 (s, 3H), 1.29–1.48 (m, 4H), 1.55–1.80 (m, 2H), 2.20–2.37
zo[f]pyrrolo[1,2-a]quinolin-3(12aH)-one (4f). Colorless viscous liq-
(m, 2H), 2.51–2.82 (m, 4H), 5.98 (s, 1H), 7.00–7.35 (m, 6H), 7.75–
7.95 (m, 2H), 8.48 (t, J = 9.0 Hz, 1H). C NMR (CDCl , 75 MHz):
3
1
13
uid; yield 33%; H NMR (CDCl
3
, 300 MHz): d 1.27 (s, 3H), 2.20–
2
7
.39 (m, 2H), 2.51–2.81 (m, 2H), 3.84 (s, 3H), 5.93 (s, 1H), 6.90–
d10.7, 19.2, 26.4, 27.1, 27.7, 28.2, 29.2, 32.3, 56.7, 115.2, 117.4,
118.5, 121.1, 121.5, 124.2, 124.8, 125.2, 125.3, 125.5, 125.8,
1
3
.31 (m, 6H), 7.75–7.95 (m, 2H), 8.44–8.52 (m, 1H). C NMR
, 75 MHz): d19.7, 27.0, 29.2, 52.0, 56.7, 111.0, 117.5, 118.5,
21.1, 124.0, 124.9, 125.0, 125.2, 125.5, 125.7, 127.0, 130.1,
(
CDCl
3
127.0, 130.1, 132.5, 135.8, 139.3, 170.1. ESI-HRMS calcd. for
+
1
C
28
H
28BrNO: 474.1433 [M+H] ; found: 474.1423.

1
10
A.M. Abdelkhalik et al. / Steroids 98 (2015) 107–113
3
. Results and discussions
H
N
OH
NH
2
HO
(i)
(ii)
We envisioned a synthetic route to 14-azasteroids with general
O
O
structure A, retrosynthetic analysis of which is presented in
Scheme 1. Intramolecular 6-endo-dig hydroarylation of alkyne B
with C-1 position of naphthalene ring will generate target com-
pounds A [33]. Compounds B can be prepared from nucleophilic
addition of aryl alkynes onto the N-acyliminium ion C or the enam-
ide D [34]. The enamide D can, in turn, be formed from N-(naph-
R
R
R
3a X=H
b X=Br
1
a X=H
2a X=H
2b X=Br
3
1
b X=Br
R'
4
4
a R=H, R' = -H
b R=Br, R' = -H
(iii)
4c R=H, R' = 4-CH
2
CH
CH
3
4
4
4
d R=Br, R' = 4-CH
2
3
thalen-2-yl)pent-4-ynamides
E via 5-exo-dig hydroamidation
t
e R=H, R' = 4- Bu
f R=Br, R' = 4- Bu
reaction [35]. Amide bond formation between 2-naphthylamines
and 4-pentynoic acid will produce ynamides E. Commercially
available 2-naphthol analogs can be converted to corresponding
-naphthylamines via Bucherer reaction [31].
Several transition metal catalysts are known to catalyze hydroam-
ination and hydroarylation reactions [33,35], gold-based catalysts
have emerged as highly efficient and versatile to catalyze both of
these reactions, even in tandem when feasible [36,37]. Thus, we
selected to perform the proposed hydroamidation and hydroaryla-
t
R'
R
4g R=H, R' = 4-OCH
3
4
4
4
h R=Br, R' = 4-OCH
i R=H, R' = 4-CH CH CH CH
3
3
N
2
2
2
2
j R=Br, R' = 4-CH CH CH CH
O
2
2
2
3
2 2 2 2 3
4k R=H, R' = 4-CH CH CH CH CH
l R=Br, R' = 4-CH
CH CH CH CH
2 2 2 2 3
4
4
a-l
Scheme 2. Reagents and conditions: (i) ammonium sulfite monohydrate
NH SO O, ammonium hydroxide NH OH, H O, 120 °C, high pressure vessel,
ꢁH
7 h; (ii) EDC, HOBt, Et N, DCM, 0 °C – rt, 17 h; (iii) anh. AuBr (cat.), AgSbF (cat.),
toluene, 120 °C, microwave (MW) under argon protection, 4 h.
(
1
)
4 2
3
2
4
2
3
3
6
3 6
tion sequence using AuBr /AgSbF catalyst combination [37]. It is
well-recognized that intramolecular formation of one new carbon–
nitrogen and two new carbon–carbon bonds to make a tricyclic ring
system in a one-pot reaction is particularly challenging because the
regio- and chemoselectivity must be well-controlled to avoid forma-
tion of mixture of homo- and heterocoupled compounds.
Based on the tlc observations, a new product was formed with R
f
slightly lower than the precursor ynamide and the reaction pro-
gress virtually appeared to have stalled after 4 h of heating. The
reaction was worked-up and the new product was purified by col-
umn chromatography. To our delight, the product was identified as
the desired product where intramolecular formation of one new
carbon–nitrogen and two new carbon–carbon bonds to make 14-
azasteroid ring in a one-pot reaction was regio- and chemoselec-
tively achieved in 52% yield (based on consumed ynamide 3a). In
the interest of time, we decided to proceed with these conditions
to make analogs using variously substituted phenylacetylenes on
3a and 3b to test the generality of this reaction. The results are pre-
sented in Table 1. All 14-azasteroids reported in this manuscript
are new to chemical literature and have been completely
characterized by spectroscopic means.
Scheme 2 shows the synthetic strategy adopted to prepare
desired 14-azasteroids. Precursors 2-naphthalenamine (2a) and
6
-bromo-2-naphthalinamine (2b) were synthesized via Bucherer
reaction on corresponding naphthols (1a, 1b) [31]. The ynamides
a and 3b were synthesized from corresponding 2-naphthale-
3
namine (2a or 2b) and 4-pentynoic acid using peptide coupling
reagents EDC and HOBt in dichloromethane. These ynamides were
then subjected to tandem hydroamination and hydroarylation
3 6
reactions using AuBr (3 mol%) and AgSbF (5 mol%) catalyst sys-
tem in toluene [37] under microwave irradiation conditions.
The Bucherer reaction for converting naphthols to naphthylami-
nes and the subsequent amide bond formation with 4-pentynoic
acid to obtain compounds 3a and 3b were straightforward.
Compound 3a was then reacted with phenylacetylene using some-
what modified conditions than what was reported in the literature
3
As can be noticed in Table 1, highly electron donating –OCH at
the para position of the substituted phenylacetylene appeared to
favor the formation of the desired compound. Relatively less elec-
tron donating long alkyl groups posted comparatively lower yields.
The reaction did not work when m-flourophenylacetylene was
used. The observation appeared to suggest that the inductive
electron withdrawing effects of the fluoro-substituent was detri-
mental for the reaction. Also, the use of 1-hexyne and 1-heptyne
did not yield any product. Similar observation was made pre-
viously [37]. Use of o- and p-substituted haloacetylenes did yield
desired products in the previous report where m-substituted
haloacetylenes were not used [37]. Also, the use of electron poor
3 6
for performing a similar reaction under AuBr /AgSbF -catalysis
[
37]. The reported procedure used heating the reaction contents
in a sealed tube to perform the reaction whereas we employed
microwave irradiation as the heat source and the reaction was per-
formed under pressurized reaction vials. The progress of the reac-
tion was monitored by tlc initially at 30 min interval for up to 4 h
and then at 1 h interval for up to 9 h. Even with the use of 4 equiva-
lents phenylacetylene, the starting ynamide 3a was not completely
consumed after 9 h of heating at 120 °C in the microwave reactor.
R'
R'
+
N
Nu addition
C
O
R'
X
R
6
endo dig
N
N
N
O
O
D
O
B
A
R
R
R
5
exo dig
amide coupling
R
Bucherer reaction
R
H
N
OH
NH
2
HO
+
O
O
E
Scheme 1. Retro-synthetic analysis for the synthesis of 14-azasteroids A.

A.M. Abdelkhalik et al. / Steroids 98 (2015) 107–113
111
Table 1
1
4-Azasteroids.
0
Yielda
Entry
1
R
R
Product
H
H
52
43
59
66
67
N
O
4
a
2
3
4
5
Br
H
H
N
O
Br
4b
4-CH
4-CH
2
CH
3
N
O
4
c
Br
H
2
CH
3
N
O
Br
O
4d
4-OCH
4-OCH
3
N
O
O
4
e
6
7
Br
H
3
O
71
63
N
Br
4f
t
4- Bu
N
O
O
4
g
t
8
9
Br
4- Bu
56
N
4h
Br
H
4-CH
4-CH
2
CH
2
CH
2
CH
3
68
55
N
O
O
4
i
1
0
Br
2
CH
2
CH
2
CH
3
N
4
j
Br
1
1
1
2
H
4-CH
4-CH
2
CH
2
CH
2
CH
2
CH
3
38
36
N
O
O
4k
Br
2
CH
2
CH
2
CH
2
CH
3
N
4l
Br
(
continued on next page)

1
12
A.M. Abdelkhalik et al. / Steroids 98 (2015) 107–113
Table 1 (continued)
0
Yielda
NRb
Entry
R
R
Product
1
3
H
3-F
F
N
O
1
4
Br
3-F
F
NRb
N
O
Br
a
Yield based on consumed starting material.
NR – no reaction.
b
2
-pyridylacetylene did not yield any product in the previous
undergo a [4+2] inverse electron demand aza-Diels–Alder reaction
with arylacetylenes to produce 14-azasteroids in a concerted man-
ner [18]. However, [Au] is known to catalyze hydroarylation reac-
tion between alkynes and electron rich arenes [33] and therefore
the proposed catalytic cycle in Scheme 3 appears more probable.
report. These observations can shed light on the possible reaction
mechanism for the cyclization step.
Gold salts with complex counter anions such as –OTf or –SbF
are unstable and are generally obtained in situ by addition of
AgOTf or AgSbF as co-catalysts [38]. These bulky anions create
6
6
relatively free Au cations that can freely coordinate with alkenes
and alkynes [38]. We propose the catalytic cycle for the gold
4
. Conclusion
(
III)-catalyzed intramolecular hydroamidation transformation,
nucleophilic addition and intramolecular hydroarylation cascade
Scheme 3), which is similar to the gold-catalyzed tandem reac-
tions reported before [36,37]. The terminal alkyne moiety of 3a is
first activated by the AuBr /AgSbF catalyst system to generate
In conclusion, we have devised a concise synthesis of 14-azas-
teroids with angular methyl group at the C-13 position in three
steps from cheaply available 2-naphthol analogs. Employing
Bucherer reaction, naphthol analogs were converted to
corresponding naphthylamines, which in turn were conjugated
with 4-pentynoic acid under peptide coupling conditions. The
resulting ynamides were reacted with arylacetylenes under
(
3
6
intermediate W, which then converts to enamide intermediate X
via intramolecular hydroamination. Attack on enamide X by nucle-
ophilic arylalkynes in the presence of AuBr /AgSbF generates a
3 6
propargylamide Y. The nucleophilicity of the arylalkynes depends
on the electron donating nature of the aryl substituents. Thus, elec-
tron withdrawing substituents negatively impact the reaction out-
come. Finally, the propargylamide Y is also activated by Au/Ag-salt
catalyst to generate Z, which undergoes intramolecular hydroary-
lation to yield the final product 4.
3 6
AuBr /AgSbF catalyst system to produce the title compounds in
moderate to good yields.
Acknowledgments
The authors sincerely thank Natural Sciences and Engineering
Research Council (NSERC) of Canada (to AJ) for research funding.
AMA was supported by Scotia Scholar Award from Nova Scotia
Health Research Foundation (NSHRF) and Acadia Graduate Award
from Acadia University.
One can argue that intermediate X can resonate to generate
N-acyliminium ion (C, shown in Scheme 1), which can then
[
Au]
[Au]
Appendix A. Supplementary data
H
N
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.steroids.2015.03.
O
W
N
0
10.
H
N
O
X
R
[Au]
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