KONaI-induced cyclization of ω-bromo α-cyano ketones: A new annulation approach for the formation of carbalkoxycyclohexane ring system

Article abstract of DOI:10.1055/s-0031-1290386

An operationally simple and highly effective annulation process, making use of ZnClcatalyzed Michael addition and KONaI-induced cyclization as key manipulations, has been developed to construct various bicyclic systems with a high level of functionalization valuable for further synthetic elaboration. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290386

LETTER
▌1653
letter
K2CO3/NaI-Induced Cyclization of ω-Bromo α-Cyano Ketones: A New Annu-
lation Approach for the Formation of Carbalkoxycyclohexane Ring System
K CO /NaI-Induced Cyclization of ω-Bromo α-Cyano Ketones
a
b
c
a
d
2
3
Che-Hao Tu, Kak-Shan Shia, Sheng-Chu Kuo, Hsing-Jang Liu,* Min-Tsang Hsieh*
a
Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan
b
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan
Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung 40402, Taiwan
c
d
Chinese Medicinal Research and Development Center, China Medical University Hospital, 2 Yude Road, Taichung 40447, Taiwan
Fax +886(4)22030760; E-mail: d917410@alumni.nthu.edu.tw
Received: 19.03.2012; Accepted after revision: 29.04.2012
equiv) at –78 °C for two hours to afford product 11 as an
inseparable diastereomeric mixture in 85% yield. The
spectral data (NMR, IR, and HRMS) of 11 was in full
agreement with the assigned structure.9 Other catalysts
such as Cu(I)10 and SnCl411 were tested, but the outcome
was inferior to ZnCl2. As such, similar reaction conditions
were then applied to other substrates with different ring
sizes to afford a series of structurally diverse ω-bromo α-
cyano ketones 10–17, existing in a mixture of keto and
enol forms (Table 1).
Abstract: An operationally simple and highly effective annulation
process, making use of ZnCl2-catalyzed Michael addition and
K2CO3/NaI-induced cyclization as key manipulations, has been de-
veloped to construct various bicyclic systems with a high level of
functionalization valuable for further synthetic elaboration.
Key words: bicyclic compounds, α-cyano ketones, Michael addi-
tion, annulation, cyclization
Methodologies intended for new carbon–carbon bond for-
mation accompanying with a high level of functionaliza-
tion are considered significant and constantly attract
attention from synthetic chemists. During the past three
decades, great effort has been dedicated to developing
various annulation processes in our laboratories,1 many of
which have been employed as a key operation in the syn-
theses of decalin-, icetexane-, lignan-, and hydridane-
based naturally occurring compounds.2 Along these lines,
we recently found that α-cyano ketones can serve as ver-
satile intermediates to facilitate a new cyclization process,
resulting in the formation of a variety of bicyclic products
containing a high level of functionality useful for further
synthetic elaboration.
Table 1 1,4-Addition of 9 to 2-Cyano-2-cycloalkenones
O
O
O
CN
EtO
Br
R
CN
9
Li
n
Br
R
ZnCl2, –78 °C to r.t., 1 h
n
CO2Et
Substrate
Producta
Yield (%)b
O
O
CN
CN
80
Br
2-Cyano-2-cycloalkenones 1–8 used for the present study
were readily prepared via a two-step sequence, involving
Thorpe–Ziegler condensation3 of the alkanedinitriles fol-
lowed by phenylselenenylation–oxidative elimination4 or
a four-step sequence, involving formylation,5 isoxazole
formation and its subsequent rearrangement,6 and phenyl-
selenenylation–oxidative elimination.4 Compounds 1–8
thus formed were found to be rather unstable in that at-
tempted purification by chromatography resulted in sub-
stantial loss of material. Therefore, crude products 1–8,
without purification, were used as Michael acceptors in
subsequent 1,4-conjugate addition under catalysis with
CO2Et
1
10
O
O
CN
CN
85
80
Br
CO2Et
2
3
11
O
O
CN
CN
Br
7
ZnCl2 to afford desired adducts 10–17 in good yields
CO2Et
(80–85%, Table 1). In a typical experiment, 2-cyano-2-
cyclohexenone (2) was treated with 1.5 equivalents of
lithium enolate 98 in THF in the presence of ZnCl2 (1.2
12
SYNLETT 2012, 23, 1653–1656
Advanced online publication: 14.06.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290386; Art ID: ST-2012-W0253-L
© Georg Thieme Verlag Stuttgart · New York

1654
C.-H. Tu et al.
LETTER
sis.15 Moreover, the stereochemistry of isomer 19a was
further deduced via a chemical correlation using base-in-
duced epimerization.16 As shown in Scheme 1, 19a was
partially transformed into 19b via keto–enol tautomeriza-
tion under basic media at ambient temperature. The stud-
ies strongly support that 19a and 19b are structurally
epimeric each other based on the C-6 center.
Table 1 1,4-Addition of 9 to 2-Cyano-2-cycloalkenones (continued)
O
O
O
CN
EtO
Br
R
CN
9
Li
n
Br
R
ZnCl2, –78 °C to r.t., 1 h
n
CO2Et
Substrate
Producta
Yield (%)b
O
O
O
CN
CN
CN
H
O
O
NaOEt, EtOH
r.t., 2 d
CN
+
CN
6
6
82
Br
H
H
CO2Et
CO2Et
CO2Et
19a
19a (45%)
19b (45%)
CO2Et
4
13
O
Scheme 1 Base-induced epimerization of 19a
O
CN
The generality of this newly developed methodology was
further demonstrated with various substrates having dif-
ferent ring sizes (Table 2). Accordingly, the annulation
appeared to take place in a completely stereocontrolled
manner. On the basis of X-ray analyses, it was found that
6/5 and 6/6 fused adducts, as exemplified by 18b17 and
25a,18 respectively, preferred to form the cis ring junction;
6/7 and 6/8 fused adducts, as indicated by 20a19 and 21a,20
respectively, potentially cyclized to the trans ring junc-
tion. These generalities are supported by the fact that
products 22b and 24b were readily reduced with NaBH4
to produce the corresponding epimeric pairs 26a, 26b, 27a
and 27b (Scheme 2); subsequent X-ray analyses of crys-
talline compounds 26a21 and 27a22 clearly revealed the cis
ring junction for these 6/6 fused adducts.
CN
85
82
80
83
Br
CO2Et
5
14
O
O
CN
CN
Br
Br
Br
CO2Et
6
15
O
O
CN
CN
CO2Et
O
OH
OH
CN
CN
CN
7
16
O
NaBH4, MeOH
r.t., 1 h
R
R
+
R
O
CN
H
H
H
CN
CO2Et
CO2Et
CO2Et
22b
24b
26a (45%)
27a (46%)
26b (46%)
27b (47%)
CO2Et
8
17
Scheme 2 Production of two hydroxy-epimeric pairs by reduction
with NaBH4
a The ratio of isomers could not be unequivocally determined due to
facile keto–enol tautomerization.
b Yields are for isolated, chromatographically pure products.
Subsequently, the stereochemistry of 18a, 20b, 21b, 22a,
24a, and 25b was fully elucidated via the base-induced
epimerization of their counterparts 18b, 20a, 21a, 22b,
24b, and 25a, structures of which have been individually
identified by a direct or indirect X-ray crystal structure
analysis as described previously.
With these compounds in hand, the newly designed
K2CO3/NaI-induced cyclization process was then ex-
plored.12 The expected annulation did occur efficiently to
give rise to bicyclic products in excellent yields (90–98%)
as illustrated in Table 2. As a typical example, upon treat-
ment with 1.1 equivalents of K2CO3 and 0.5 equivalents of
NaI in anhydrous acetone for 12 hours, α-cyano ketone 11
underwent intramolecular cyclization smoothly to furnish
bicyclic products 19a and 19b in 95% yield. The spectral
data of 19a13 and 19b14 were in full agreement with the as-
signed structures. The relative configuration of 19b was
unambiguously identified by a single-crystal X-ray analy-
Tremendous effort has been dedicated to exploring the
possibility of changing the above two-step process into a
one-pot reaction. After completion of the Michael addi-
tion, as monitored by TLC, without purification, NaI (1.2
equiv) or KI (1.2 equiv) was then added in one portion to
effect the subsequent cyclization. Although the annulation
did occur, the resulting yields are much inferior to those
of the aforementioned two-step sequence.
Synlett 2012, 23, 1653–1656
© Georg Thieme Verlag Stuttgart · New York

LETTER
K2CO3/NaI-Induced Cyclization of ω-Bromo α-Cyano Ketones
1655
Table 2 K2CO3/NaI-Induced Annulations of Various ω-Bromo
α-Cyano Ketones (continued)
In summary, under induction with K2CO3 and NaI, an ef-
ficient annulation process for ω-bromo α-cyano ketones
has been developed to prepare various bicyclic carbalkoxy-
cyclohexane systems with a high level of functionaliza-
tion. The newly developed process was expected to be of
great utility in light of its operational simplicity, and easy
access to readily available 2-cyano-2-cycloalkenone sub-
strates.
O
O
CN
NaI, K2CO3
CN
R
R
acetone, r.t., 12 h
n
n
CO2Et
EtO2C
Br
Substrate Products
Yield
(%)a
dr
Table 2 K2CO3/NaI-Induced Annulations of Various ω-Bromo
α-Cyano Ketones
O
O
O
O
CN
CN
CN
NaI, K2CO3
CN
R
+
R
acetone, r.t., 12 h
n
16
97
98
1:1
n
H
H
CO2Et
CO2Et
CO2Et
EtO2C
Br
24a
24bc
Substrate Products
Yield
(%)a
dr
–
O
O
CN
H
CN
H
+
O
O
CN
CN
17
1:1
CO2Et
CO2Et
+
10
95b
25ac
25b
H
H
CO2Et
CO2Et
a Yields are calculated by a combination of two isolated, chroma-
tographically pure diastereomers.
18bc
18a
b A mixture of two inseparable diastereomers was produced.
c The stereochemistry was assigned based on a single-crystal X-ray
analysis.
O
O
CN
H
CN
+
d The cis ring junction was tentatively assigned.
11
12
95
1:4
1:1
H
CO2Et
CO2Et
19bc
19a
Acknowledgment
O
O
This work was supported by grants from the National Science
Council of Taiwan and China Medical University Hospital (DMR-
101-104).
CN
CN
+
90
H
H
O
CO2Et
CO2Et
References and Notes
20ac
20b
21b
(1) (a) Liu, H. J.; Sun, D.; Shia, K. S. Tetrahedron Lett. 1996,
37, 8073. (b) Kung, L. R.; Tu, C. H.; Shia, K. S.; Liu, H. J.
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M. T.; Chou, H. H.; Liu, H. J.; Wu, H. M.; Ly, T. W.; Wu,
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2010, 7, 78. (h) Chin, C. L.; Liao, C. F.; Liu, H. J.; Wong, Y.
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O
CN
CN
+
13
14
15
98
95
94
1:1.7
H
H
CO2Et
CO2Et
21ac
O
O
CN
CN
H
+
1:3
H
CO2Et
CO2Et
22a
22bc
O
O
CN
H
CN
H
(2) (a) Liu, H. J.; Sun, D. Tetrahedron Lett. 1997, 38, 6159.
(b) Liu, H. J.; Ho, Y. L.; Wu, J. D.; Shia, K. S. Synlett 2001,
1805. (c) Liu, H. J.; Zhu, J. L.; Chen, I. C.; Jankowska, R.;
Han, Y.; Shia, K. S. Angew. Chem. Int. Ed. 2003, 42, 1851.
(d) Liu, H. J.; Ly, T. W.; Tai, C. L.; Wu, J. D.; Liang, J. K.;
Guo, J. C.; Tseng, N. W.; Shia, K. S. Tetrahedron 2003, 59,
+
1:1
CO2Et
CO2Et
23ad
23bd
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1653–1656

1656
C.-H. Tu et al.
LETTER
1209. (e) Chin, C. L.; Tran, D. P. P.; Shia, K. S.; Liu, H. J.
Synlett 2005, 417. (f) Chang, W. S.; Shia, K. S.; Liu, H. J.;
Ly, T. W. Org. Biomol. Chem. 2006, 4, 3751. (g) Hsieh,
M. T.; Liu, H. J.; Ly, T. W.; Shia, K. S. Org. Biomol. Chem.
2009, 7, 3285. (h) Amancha, P. K.; Liu, H. J.; Ly, T. W.;
Shia, K. S. Eur. J. Org. Chem. 2010, 3473. (i) Jan, N. W.;
Liu, H. J.; Hsieh, M. T.; Shia, K. S. Eur. J. Org. Chem. 2010,
4271. (j) For a review on hydrindanes, see: Jankowski, P.;
Marczak, S.; Wicha, J. Tetrahedron 1998, 54, 12071.
IR (CH2Cl2 cast): νmax = 2950, 2233, 1731, 1715 cm–1. 1H
NMR (600 MHz, CDCl3): δ = 4.10 (q, J = 7.1 Hz, 2 H), 2.78
(ddd, J = 13.4, 13.0, 7.1 Hz, 1 H), 2.61 (dt, J = 8.6, 3.1 Hz,
1 H), 2.48–2.41 (m, 2 H), 2.30–2.19 (m, 2 H), 1.98–1.83 (m,
3 H), 1.73–1.64 (m, 2 H), 1.59–1.46 (m, 3 H), 1.20 (t, J = 7.2
Hz, 3 H). 13C NMR (150 MHz, CDCl3): δ = 201.8 (C), 173.3
(C), 120.1 (C), 61.7 (CH2), 48.9 (C), 44.8 (CH), 42.6 (CH),
38.9 (CH2), 30.0 (CH2), 28.4 (CH2), 25.5 (CH2), 21.7 (CH2),
20.3 (CH2), 14.1 (CH3). HRMS (EI): m/z calcd for
(3) Marshall, J. A.; Peterson, J. C.; Lebioda, L. J. Am. Chem.
Soc. 1984, 106, 6006.
(4) Liotta, D.; Barnum, R. P.; Zima, G.; Bayer, C.; Kezar,
H. S. III. J. Org. Chem. 1981, 46, 2920.
C14H19NO3: 249.1365; found: 249.1383.
(14) (1R*,4aS*,8aR*)-4a-Cyano-5-oxodecahydro-
naphthalene-1-carboxylic Acid Ethyl Ester (19b)
IR (CH2Cl2 cast): νmax = 2947, 2240, 1737, 1722 cm–1.
1H NMR (600 MHz, CDCl3): δ = 4.08 (m, 2 H), 2.81 (dt,
J = 8.5, 4.1 Hz, 1 H), 2.65 (dt, J = 8.7, 4.0 Hz, 1 H), 2.49–
2.38 (m, 2 H), 2.07–2.03 (m, 1 H), 1.95–1.89 (m, 2 H), 1.85–
1.82 (m, 1 H), 1.80–1.75 (m, 1 H), 1.73–1.65 (m, 3 H), 1.64–
1.59 (m, 1 H), 1.52–1.48 (m, 1 H), 1.19 (t, J = 7.1 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 202.8 (C), 172.6 (C),
118.7 (C), 60.6 (CH2), 55.1 (C), 42.9 (CH), 42.1 (CH), 36.6
(CH2), 27.5 (CH2), 23.9 (CH2), 21.7 (CH2), 20.9 (CH2), 20.5
(CH2), 14.0 (CH3). HRMS (EI): m/z calcd for C14H19NO3:
249.1365; found: 249.1380. Anal. Calcd for C14H19NO3: C,
67.45; H, 7.68; N, 5.62. Found: C, 67.49; H, 7.67; N, 5.30.
(15) Crystallographic data have been deposited with Cambridge
Crystallographic Data Centre (CCDC 845718).
(5) Jones, R. A.; Stokes, M. J. Tetrahedron 1984, 40, 1051.
(6) (a) Zhu, J. L.; Shia, K. S.; Liu, H. J. Chem. Commun. 2000,
1599. (b) Fleming, F. F.; Iyer, P. S. Synthesis 2006, 893.
(7) Demailly, G.; Solladie, G. J. Org. Chem. 1981, 46, 3102.
(8) Procedure for the Preparation of Lithium Enolate 9
To a stirred solution of ethyl 5-bromovalerate (0.58 mL, 3.64
mmol) in THF (4.5 mL) at –78 °C was added LDA (2 M in
THF, 2.5 mL, 5.04 mmol) dropwise under nitrogen. The
reaction mixture was stirred at the same temperature for 30
min, and the resulting stock solution (7 mL, 0.52 M) was
used directly for subsequent 1,4-addition.
(9) 5-Bromo-2-(2-cyano-3-oxocyclohexyl)pentanoic Acid
Ethyl Ester (11)
IR (CH2Cl2 cast): νmax = 3431, 2946, 2249, 1731 cm–1. 1H
NMR (600 MHz, CDCl3): δ = 4.23–4.14 (m, 2 H), 3.69 (d,
J = 12.3 Hz, 0.4 H), 3.52 (d, J = 12.0 Hz, 0.6 H), 3.50–3.46
(m, 1 H), 3.43–3.34 (m, 2 H), 2.77–2.73 (m, 0.6 H), 2.67 (dt,
J = 7.6, 3.3 Hz, 0.4 H), 2.61–2.56 (m, 1 H), 2.47–2.25 (m, 2
H), 2.21–2.01 (m, 2 H), 1.97–1.86 (m, 2 H), 1.85–1.76 (m, 2
H), 1.75–1.58 (m, 1 H), 1.29–1.20 (m, 3 H). 13C NMR (100
MHz, CDCl3): δ = 200.4 (C), 199.8 (C), 172.9 (C), 172.1
(C), 116.5 (C), 115.5 (C), 61.1 (CH2), 61.0 (CH2), 48.2 (CH),
47.7 (CH), 47.4 (CH), 45.1 (CH), 44.2 (CH), 43.3 (CH), 40.4
(CH2), 40.2 (CH2), 33.1 (CH2), 32.0 (CH2), 30.7 (CH2), 29.5
(CH2), 28.7 (CH2), 26.7 (CH2), 26.0 (CH2), 25.1 (CH2), 24.5
(CH2), 23.6 (CH2), 14.3 (CH3), 14.1 (CH3). HRMS (EI): m/z
calcd for C14H20NO3Br: 329.0627; found: 329.0625.
(10) Gilman, H.; Jones, R. G.; Woods, L. A. J. Org. Chem. 1952,
17, 1630.
(16) To a stirred solution of 19a (10 mg, 0.04 mmol) in EtOH (5
mL) was added NaOEt (8.8 mg, 0.13 mmol) in one portion.
The reaction mixture was stirred at r.t. for 2 d and quenched
with H2O (5 mL). The aqueous layer was separated and
extracted with CH2Cl2 (3 × 5 mL). The combined organic
extracts were washed with brine, dried over MgSO4, filtered,
and concentrated to give the crude residue, which was
purified by flash chromatography on silica gel with EtOAc–
n-hexane (1:4) to afford 19a (4.5 mg) and 19b (4.5 mg) in a
combination of 90% yield.
(17) Crystallographic data has been deposited with Cambridge
Crystallographic Data Centre (CCDC 845716).
(18) Crystallographic data has been deposited with Cambridge
Crystallographic Data Centre (CCDC 845720).
(19) Crystallographic data has been deposited with Cambridge
Crystallographic Data Centre (CCDC 845714).
(11) Takai, K.; Heathcock, C. H. J. Org. Chem. 1985, 50, 3247.
(12) Wojtasiewicz, A.; Barbasiewicz, M.; Makosza, M. Eur. J.
Org. Chem. 2010, 1885.
(20) Crystallographic data has been deposited with Cambridge
Crystallographic Data Centre (CCDC 845715).
(21) Crystallographic data has been deposited with Cambridge
Crystallographic Data Centre (CCDC 845717).
(13) (1S*,4aS*,8aR*)-4a-Cyano-5-
oxodecahydronaphthalene-1-carboxylic Acid Ethyl
Ester (19a)
(22) Crystallographic data has been deposited with Cambridge
Crystallographic Data Centre (CCDC 845719).
Synlett 2012, 23, 1653–1656
© Georg Thieme Verlag Stuttgart · New York

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