Stereoselective Synthesis of 7-(E)-Arylidene-2-chloro-6-azabicyclo[3.2.1]octanes via Aluminum Chloride-Promoted Cyclization/Chlorination of Six-Membered Ring 3-Enynamides

Article abstract of DOI:10.1002/adsc.201700271

An efficient stereoselective synthesis of 7-(E)-arylidene-2-chloro-6-azabicyclo[3.2.1]octanes is described. The aluminum chloride-promoted cyclization/chlorination of six-membered ring 3-enynamides enables a straightforward approach to the 6-azabicyclo[3.2.1]octane nucleus that is incorporated in many biologically active compounds. Acid treatment of the resultant chlorinated arylideneazabicyclooctanes furnishes 3-alkanoyl-4-chlorocyclohexanamines in excellent yields and high stereoselectivity. (Figure presented.).

Full text of DOI:10.1002/adsc.201700271

Title: Stereoselective Synthesis of 7-(E)-Arylidene-2-chloro-6-
azabicyclo[3.2.1]octanes via Aluminum Chloride Promoted
Cyclization/Chlorination of Six-Membered Ring 3-Enynamides
Authors: Ming-Chang Yeh, Yi-Mei Chang, and Hsin-Hui Lin
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the VoR from the journal website shown below when it is published
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700271
Link to VoR: http://dx.doi.org/10.1002/adsc.201700271

10.1002/adsc.201700271
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Stereoselective Synthesis of 7-(E)-Arylidene-2-chloro-6-aza-
bicyclo[3.2.1]octanes via Aluminum Chloride Promoted
Cyclization/Chlorination of Six-Membered Ring 3-Enynamides
Ming-Chang P. Yeh,a* Yi-Mei Chang,a and Hsin-Hui Lina
a
Department of Chemistry, National Taiwan Normal University, 88 Ding-Jou Road, Sec. 4, Taipei 11677, Taiwan, R.O.C.
Fax: (+886)-2-29324249; e-mail: cheyeh@ntnu.edu.tw.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
1).[16] Here, we report a straight forward approach to
Abstract: An efficient stereoselective synthesis of
7-(E)-arylidene-2-chloro-6-azabicyclo[3.2.1]octanes
is
the chlorinated 6-azabicyclo[3.2.1]octane system
from readily accessible six-membered ring
3-enynamides[17] and inexpensive AlCl3 (Scheme 1,
eq 2).
described.
cyclization/chlorination
The
aluminum
chloride
six-membered
promoted
of
ring
3-enynamides enables a straight forward approach to the
6-azabicyclo[3.2.1]octane nucleus incorporated in many
biologically active compounds. Acid treatment of the
resultant chlorinated arylideneazabicycles furnishes
3-alkanoyl-4-chlorocyclohexanamines in excellent yields
and high stereoselectivity.
Previous study: FeCl2-promoted cyclization/chlorination of
cyclic 2-enynamides[16]
Keywords:
amides;
amines;
cyclization;
(1)
diastereoselectivity; halogenation; Lewis acids
This work: AlCl3-promoted cyclization/chlorination of cyclic
3-enynamides
The 6-azabicyclo[3.2.1]octane is an important moiety
found in a variety of biologically active compounds
such as peduncularine,[1] actinobolamine,[2] and
appears as a subunit in numerous alkaloids such as
securinine,[3]
D-normorphinans,[4]
(2)
C-norbenzomorphans,[5] sarain A,[6] hetisine,[7] and
other bridged aza-derivatives.[8] Due to the
Scheme 1. Reaction of Lewis acids with cyclic
enynamides
availability
of
functionalized
6-azabicyclo[3.2.1]octane building blocks that can be
further elaborated into more complex bridged
polycyclic systems or pharmaceuticals,[9] a number of
synthetic strategies have been developed.[10] The
The requisite model substrate six-membered ring
3-enynamide 1a is synthesized starting from
commercially available 1,4-cyclohexanediol (see the
Supporting Information for details). Initially, we
focused on the screening of various Lewis acids for
the cyclization of 1a. Since FeCl2 or FeCl3 were
capable of promoting the transformation of
six-membered ring 2-enynamides into fused bicyclic
lactams (Scheme 1, eq 1), 1a was treated with 1.1
equiv of FeCl2 or FeCl3 in tetrahydrofuran (THF) at
rt. However, both reactions led to an unidentified
mixture of products (Table 1, entries 1 and 2).
Gratifyingly, when 1a was reacted with FeCl3 in
dichloromethane (DCM) at rt for 10 min, affording
the chlorinated bridged azabicyclic compound 2a as
the only stereoisomer in 38% isolated yield together
with a small amount of hydration product 3a
known
methods
included
the
semipinacol
rearrangement of cis-fused β-lactam diols,[11] the
decarbonylative radical cyclization of
α-amino
selenoester-tethered electron-deficient alkenes,[12] the
rearrangement of 2-azabicyclo[2.2.2]octanes[13a,b] and
8-azabicyclo[4.2.1]nonanes,[13c]
the
iodide-promoted intramolecular reductive coupling
reaction of the tandem
ketonitriles,[14]
samarium
Horner-Emmons olefination-conjugated addition of
3-acetamidocyclohexanone,[15] and the [3 + 2]
annulation of allylic silanes and chlorosulfonyl
isocyanate.[1c] Recently, we disclosed a simple and
mild entry into chlorinated fused bicyclic lactams via
an FeCl2-promoted cyclization/chlorination of simple
six-membered ring 2-enynamides (Scheme 1, eq
1
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10.1002/adsc.201700271
Advanced Synthesis & Catalysis
Table 1. Optimization of reaction conditionsa)
yield (%)b)
entry
MCln
solvent
[M]
T (°C)
time
2a
-
-
3a
-
1
2
3
4
5
6
7
8
FeCl2
FeCl3
FeCl3
InCl3
TiCl4
AlCl3
ZnCl2
CuCl2
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
THF
THF
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.01
0.25
0.25
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
1 d
4 min
10 min
2.5 h
2.4 h
5 h
5 h
1 d
25 min
25 min
2 d
1 h
3 h
20 min
5 h
25 min
35 min
-
DCM
DCM
DCM
DCM
DCM
DCM
ether
toluene
DCE
THF
ether
ether
ether
ether
ether
38c)
34
5c)
10
6
17
47
13
-
N.R.
N.R.
62c)
21
-
9
11c)
12
6
10
11
12
13
14
15
16
33
-
-
51c)
62
12c)
17
22c)
11c)
4
35
rt
rt
rt
60c)
72c)
55
17d)
a)
Reactions were conducted employing 0.25 mmol (1.0 equiv) of 1a with Lewis acid (1.1 equiv) in the
indicated solvent under nitrogen.
b)
c)
d)
NMR yield unless otherwise indicated.
Isolated yield from column chromatography over silica gel.
2.2 equiv of AlCl3 was employed.
(Table 1, entry 3). In this transformation, FeCl3 acts
concentration (0.25 M) in ether, the cyclization was
complete in 25 min to deliver 2a in 72% yield (Table
1, entry 16). Moreover, increasing the loading of
AlCl3 to 2.2 equiv did not improve the yield of 2a
(55%, entry 17). Therefore, we identified 1.1 equiv of
AlCl3 in ether (0.25 M) at rt under nitrogen as the
optimal reaction conditions for the formation of 2a
from 1a (Table 1, entry 16).
As shown in Table 2, the optimal conditions
allowed efficient cyclization/chlorination for
substrates bearing methyl, methoxy, or naphthyl
substituents on the phenyl ring of the alkynyl
fragment, generating the corresponding chlorinated
azabicycles in moderate to good yields (2b, 72%; 2c,
68%; 2d, 82%; 2e, 61%; 2f, 52%; 2g, 66%; 2h, 51%).
as a Lewis acid and the chloride source. The relative
stereochemistry of 2a was determined by NMR
spectroscopic measurements and was compared to
those of the azabicyclic analog 2l[18] (vide infra),
which was confirmed by single-crystal X-ray
analysis. To increase the yield of 2a, other
chloride-containing Lewis acids were examined in
DCM. Cyclization of 1a with InCl3 (34%, entry 4),
TiCl4 (17%, entry 5), and AlCl3 (47%, entry 6) gave
2a in moderate yields while only the starting material
was recovered with ZnCl2 (entry 7) and CuCl2 (entry
8). Since the best result in this series was obtained
with 1.1 equiv of AlCl3, the effect of solvent, reaction
temperature, concentration, and AlCl3 loading were
further evaluated. Performing the reaction with AlCl3
in ether (0.1 M concentration) at rt for 25 min gave a
better result (62%, entry 9) than those carried out in
toluene (21%, entry 10), dichloroethane (DCE) (33%,
entry 11), and THF (0%, entry 12). Conducting the
reaction at 0 oC for 3 h in ether decreased the yield of
2a (51%, entry 13). Running the reaction in ether at
reflux for 20 min did not improve the yield of 2a
(62%, entry 14). When 1a was reacted with AlCl3 at a
lower concentration (0.01 M) in ether at rt for 5 h, 2a
was isolated in 60% yield (entry 15). With a higher
Electron-deficient
substituents
including
trifluoromethyl-, nitro-, fluoro-, chloro-, and
bromo-substituent at the para- or ortho-position of
the phenyl ring were also reactive, affording the
desired chlorinated azabicycles 2i–n in comparable
results ranging from 49 to 68% yields. Among them,
the structure of azabicycle 2l was confirmed by X-ray
diffraction analysis.[18] In addition, substrates 1o and
1p bearing a thienyl moiety at the alkyne were also
tolerated and generated the corresponding
thienyl-containing azabicycles 2o (56%) and 2p
2
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10.1002/adsc.201700271
Advanced Synthesis & Catalysis
Table 2. Substrate scope of cyclization/chlorination of six-membered ring 3-enynamidesa), b)
a)
Reactions were performed employing AlCl3 (1.1 equiv) and 1a (0.25 mmol) in 1.0 mL of ether at
rt under nitrogen.
b)
c)
d)
A small amount of the hydration product was isolated in each case.
Compound 2s was obtained from 1a and InBr3 (1.1 equiv) in DCM (0.1 M) at rt for 10 min.
The structure was confirmed by X-ray diffraction analysis.[18]
(40%)
in moderate yields. When alkylynamides, such as
cyclopropylynamide 1q and n-hexylynamide 1r, were
subjected to the reaction conditions, the desired chlo-
rinated azabicycles 2q (37%) and 2r (24%) were
isolated in low yields. While attempting to synthesize
the brominated azabicyclic analog 2s with AlBr3
failed, the reaction of InBr3 with 1a successfully
delivered the brominated azabicycle 2s in 40%
isolated yield (DCM, rt, 10 min) (Table 2).
Scheme 2 shows a postulated reaction pathway for
Figure 1. ORTEP drawing for compound 2l.[18]
the
diastereoselective
formation
of
the
chloro-substituted
azabicycle
2a from the
six-membered ring 3-enynamide 1a. Activation of the
ynamide moiety of 1a with AlCl3 would form two
Scheme 2. Proposed mechanism for the AlCl3-promoted cyclization/chlorination of 1a
3
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10.1002/adsc.201700271
Advanced Synthesis & Catalysis
Table 3. Substrate scope for the formation of 3-alkanoyl-4-cholrocyclohexanamines 4a)
a)
All reactions were conducted by treatment of 2 with 5 molar equiv of 0.1 M HCl(aq) in EtOAc at rt.
Isolated yields.
b)
c)
The structure was confirmed by X-ray diffraction analysis.[18]
possible diastereomeric keteniminium ions I and II.
However, intermediate I should be less favored due
to a steric hindrance imposed by the bulky tetrahedral
aluminum species on the cyclohexene ring. With a
less congested planar phenyl ring at the -face of the
cyclohexene, intermediate II could undergo a highly
4a–o, alkyl-substituted azabicycles 2q and 2r
delivered low yields of the desired
3-alkanoyl-4-chlorocyclohexanamines 4p (39%) and
4q (52%).
In summary, we have disclosed an efficient
strategy
to
stereoselective
aza-Prins-type
cyclization,[19]
2-chloro-7-arylidene-6-azabicyclo[3.2.1]octane
framework by aluminum chloride promoted
cyclization/chlorination of six-membered ring
3-enynamides. The reaction proceeds smoothly at rt
providing the kinetically favored chlorinated
azabicyclo[3.2.1]octane intermediate III. Protonation
of III upon aqueous workup resulted in the formation
of 2a.
and
required
only
the
inexpensive
and
environmentally-friendly AlCl3, providing direct
access to the chlorinated bridged azabicyclic
compounds in a highly stereoselective manner. The
bridged azabicycles can be transformed quantitatively
The resultant chlorinated azabicycles could be
transformed
3-alkanoyl-4-chlorocyclohexanamines which are
found in many pharmaceutically active
stereoselectively
into
compounds.[20] Thus, treatment of 2a with 5 molar
equiv of 1.0 M HCl(aq) in EtOAc at rt for 4.5 h
afforded 3-alkanoyl-4-chlorocyclohexanamine 4a in a
quantitative yield with excellent stereoselectivity
(Table 3). While various aryl-substituted chlorinated
azabicycles 2 were converted quantitatively into the
corresponding 3-alkanoyl-4-chlorocyclohexanamines
and
stereoselectively
into
3-alkanoyl-4-chlorocyclohexanamines which may be
of interest in pharmaceutical chemistry. Further
studies on the use of Lewis acid for the synthesis of
azaspirocycles from cyclic enynamides are currently
underway.
Figure 2. ORTEP drawing for compound 4a.[18]
4
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10.1002/adsc.201700271
Advanced Synthesis & Catalysis
Experimental Section
Synthesis
(1S*,2R*,5R*)-7-((E)-Benzylidene)-2-chloro-6-tosyl-6-a
zabicyclo[3.2.1]octane (2a)
[4] T. T. Conway, T. W. Doyle, Y. G. Perron, J. Chapuis,
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21, 1105; c) H. Finch, Tetrahedron Lett. 1982, 23,
4393.
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Org. Chem. 1998, 63, 9616; b) O. Irie, K. Samizu, J. R.
Henry, S. M. Weinreb, J. Org. Chem. 1999, 64, 587; c)
R. Downham, F. W. Ng, L. E. Overman, J. Org. Chem.
1998, 63, 8096; d) M. J. Sung, H. I. Lee, Y. Chong, J.
K. Cha, Org. Lett. 1999, 1, 2017.
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123, 7429.
[8] A. P. Kozikowski, R. Schmiesing, J. Chem. Soc.,
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Tetrahedron 1983, 39, 1723.
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I. Carroll, J. Chem. Soc., Perkin Trans. 1, 1991, 1375;
b) H. M. L. Davies, G. Cao, Tetrahedron Lett. 1998,
39, 5943.
[11] R. S. Grainger, M. Betou, L. Male, M. B. Pitak, S. J.
Coles, Org. Lett. 2012, 14, 2234.
[12] J. Quirante, X. Vila, C. Escolano, J. Bonjoch, J. Org.
Chem. 2002, 67, 2323.
[13] a) A. B. Holmes, P. R. Raithby, J. Thompson, A. J. G.
Baxter, J. Dixon, J. Chem. Soc., Chem. Commun. 1983,
1490; b) G. R. Krow, D. A. Shaw, C. S. Jovais, H. G.
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F. C. Pigge, Tetrahedron Lett. 1996, 37, 2201.
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M. Weinreb, J. Org. Chem. 2000, 65, 6293.
of
To a dry and nitrogen-flushed two-neck-flask, equipped
with a magnetic stirring bar and a septum were added dry
AlCl3 (0.0367 g, 0.28 mmol, 1.1 equiv), dry ether (1.0 mL,
0.25 M), and 1a (0.0879 g, 0.25 mmol, 1.0 equiv). The
reaction mixture was allowed to stir at room temperature
until no trace of the starting material was detected on TLC.
The resulting mixture was filtered through a pad of
Celite/silica gel and concentrated under reduced pressure.
Flash column chromatography of the resulting residue over
silica gel with 1:30 ethyl acetate/hexanes gave the
chlorinated azabicycle 2a as a white solid; yield: 0.0681 g
(0.18 mmol, 72%).
Synthesis
of
N-((1R*,3S*,4R*)-4-Chloro-3-(2-phenylacetyl)cyclohex
yl)-4-methylbenzenesulfonamide (4a)
To a solution of 2a (0.0560 g, 0.14 mmol, 1.0 equiv) in
EtOAc (5.6 mL, 0.025 M) was added hydrochloric acid
(0.72 mL, 0.72 mmol, 1 M HCl). The reaction mixture was
stirred at room temperature until no trace of the starting
material was detected on TLC. The reaction mixture was
added saturated NaHCO3(aq) until the pH value of the
aqueous layer was above 10. The aqueous layer was
extracted with EtOAc (30.0 mL × 3). The organic solution
was washed with brine (30.0 mL × 3) and dried over
anhydrous MgSO4 and finally evaporated under reduced
pressure to give the crude product. The crude mixture was
purified via flash column chromatography over silica gel
(EtOAc/hexanes 1:10) to give 4a as a white solid; yield:
0.0576 g (0.14 mmol, 99%).
[15] D. J. Callis, N. F. Thomas, D. P. J. Pearson, B. V. L
Potter, J. Org. Chem. 1996, 61, 4634.
[16] M. C. P. Yeh, Y. S. Shiue, H. H. Lin, T. Y. Yu, T. C. Hu,
J. J. Hong, Org Lett. 2016, 18, 2407.
Supporting Information
Spectroscopic characterization and copies of H/13C NMR
spectra of compounds 1a–r, 2a–s, 3a, 4a–q and X-ray
crystallographic information files for compounds, 2l, 4a,
4d and 4o are available as supporting information.
1
[17] For reviews on ynamides in organic synthesis, see: a)
G. Evano, C. Theunissen, M. Lecomte, Aldrichimica
Acta. 2015, 48, 59; b) G. Evano, A. Coste, K. Jouvin,
Angew. Chem. 2010, 122, 2902; Angew. Chem. Int. Ed.
2010, 49, 2840; c) K. A. DeKorver, H. Li, A. G. Lohse,
R. Hayashi, Z. Lu, Y. Zhang, R. P. Hsung, Chem. Rev.
2010, 110, 5064; d) X. N. Wang, H. S. Yeom, L. C.
Fang, S. He, Z. X. Ma, B. L. Kedrowski, R. P. Hsung,
Acc. Chem. Res. 2014, 47, 560; e) C. A. Zificsak, J. A.
Mulder, R. P. Hsung, C. Rameshkumar, L.-L. Wei,
Tetrahedron 2001, 57, 7575.
Acknowledgements
We thank the Ministry of Science and Technology of the Republic
of China (MOST 105-2113-M-003-001) for financial support.
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Advanced Synthesis & Catalysis
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6
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10.1002/adsc.201700271
Advanced Synthesis & Catalysis
COMMUNICATION
Stereoselective Synthesis of
7-(E)-Arylidene-2-chloro-6-azabicyclo[3.2.1]
octanes via Aluminum Chloride Promoted
Cyclization/Chlorination of Six-Membered
Ring 3-Enynamides
Adv. Synth. Catal. Year, Volume, Page – Page
Ming-Chang P. Yeh,* Yi-Mei Chang, and Hsin-Hui Lin
7
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