Conia-ene annulation of the α-cyano β-TMS-capped alkynyl cycloalkanone system and its synthetic application

Article abstract of DOI:10.1039/c1ob05591g

Under catalysis with ZnI₂, an effective annulation process of ω-silylacetylenic α-cyano ketones, leading to the formation of various bicyclic frameworks characterized with a TMS-containing methylenecyclopentane ring, has been developed. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1ob05591g

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COMMUNICATION
Conia-ene annulation of the a-cyano b-TMS-capped alkynyl cycloalkanone
system and its synthetic application†
Chih-Lung Chin,a Cheng-Feng Liao,a Hsing-Jang Liu,a Ying-Chieh Wong,b Ming-Tsang Hsieh,b
Prashanth K. Amancha,b Chun-Ping Changb and Kak-Shan Shia*b
Received 13th April 2011, Accepted 11th May 2011
DOI: 10.1039/c1ob05591g
Under catalysis with ZnI2, an effective annulation process of
x-silylacetylenic a-cyano ketones, leading to the formation
of various bicyclic frameworks characterized with a TMS-
containing methylenecyclopentane ring, has been developed.
The broad synthetic utility of the a-cyano ketone/ester system
With these substrates in hand,‡ Conia-ene reaction was at-
has been well documented, mainly depending on the fact that not
tempted by the use of cyano ketone 11 as an initial model.
only can the cyano group activate the a carbon to the ketone/ester
Its cyclization was examined using a panel of Lewis acids and
carbonyl for condensation (e.g., Knoevenagel condensation), but
various reaction conditions. The particular Lewis acids (stannic
also it can serve as an effective directing group for consecutive
chloride and zinc iodide) were chosen because they had been noted
alkylation to construct trisubstituted ketones/esters with com-
previously as appropriate catalysts for the related cyclization.21,22
plete regiocontrol.1–6 Our long-lasting interest in the a-activated
The results are summarized in Table 2. As indicated, the reaction
cross-conjugated cycloalkenone system in organic synthesis7 has
system presented in Entry 5 (Table 2) appears superior to others
developed many synthetically useful a-cyano ketones/esters, part
in terms of the reaction rate and a high isolated yield of the
of which have been employed as key intermediates for the synthesis
desired product. As a typical experiment, upon treatment with
of naturally occurring products.8–11 Along these lines, Conia-ene
1 equiv. of ZnI2 in refluxing toluene, compound 11 was found
cyclization12 for the titled system to generate a variety of bicyclic
to undergo cyclization with complete regio- and stereocontrol
a-cyano ketones was then explored. Results and discussion are
to give product 21 in high yield (88%). The spectral data of 21
delineated as follows.
are in full agreement with the assigned structure, and the relative
For the present studies, a series of structurally diverse w-alkynyl
configuration is unambiguously identified by a single crystal X-ray
a-cyano ketones 10–18† (Table 1) were readily prepared via 1,4-
analysis.23
conjugate addition of 1-(trimethylsilyl)-1-butyn-4-yl magnesium
The above synthetic protocol was tentatively considered to be
chloride to the corresponding 2-cyano-2-cycloalkenones 1–9 ac-
the method of choice and then applied to other substrates with
cording to the synthetic procedures reported in the literature.13–17
various ring sizes.24 The results are compiled in Table 3. The pref-
Most of 1,4-adducts thus obtained are quite stable and can be
erential formation of a TMS-appended methylenecyclopentane
handled as usual with the exception of 10 and 11. It was discovered
ring was observed for all substrates examined irrespective of the
that compounds 10 and 11 were quite sensitive to oxygen; upon
parent ring size. Moreover, a single stereoisomer was generated
exposure to air, the autoxidative annulation occurred rapidly to
in all cases regarding the newly formed ring junction, with the
afford the corresponding cyclic acylsilanes 19 and 20, respectively,
unambiguous confirmation of the cis-arrangement for cyclization
in ca. 30 ~ 35% yield.18,19 Thus, it is suggested that they be
products 21 and 25,23,25 implying strongly that all 5/5 and other
stored under inert gas atmosphere or used immediately after
5/6 fused products 23, 24, 26 and 27 are very likely to possess a
chromatographic purification.
cis-ring junction as well. The desired 5/7 and 5/12 fused products
28 and 30 were tentatively assigned to have a cis-and trans-ring
junction, respectively, on the basis of the previous observation,
wherein a similar cyclization process occurred starting with the
same substrates.18 The stereochemistry of the 5/8 fused product
aDepartment of Chemistry, National Tsing Hua University, Hsinchu, Taiwan,
30013, ROC
bInstitute of Biotechnology and Pharmaceutical Research, National Health
29 was unambiguously determined based on the X-ray analysis of
its corresponding alcohol 29a,26 readily produced by reduction of
29 with NaBH4 at 0 ◦C in methanol as shown in Scheme 1.
The proposed mechanism for the formation of 5/5, 5/6 and 5/7
fused products is illustrated in Scheme 2 using substrate 11 as a
specific example. Accordingly, the aforementioned ZnI2-mediated
Research Institutes, Miaoli County, 35053, Taiwan, ROC. E-mail:
ksshia@nhri.org.tw; Fax: +886-37-586-456; Tel: +886-37-246-166
† Electronic supplementary information (ESI) available: Experimental
details and analytical data (1H, 13C and HRMS/ESMS) for all new
compounds; the X-ray crystallographic pictures for 21, 25 and 29a. CCDC
reference numbers 765388–765390. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c1ob05591g
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Table 1 1,4-Addition of (4-buty-1-nyl)trimethylsilane magnesium chlo-
ride to 2-cyano-2-cycloalkenones
Table 2 Optimization of Conia-ene cyclization with an initial model 11
Entry
Conditions
Product (s)
(Yield%)a
Substrate
Product
Yield (%)a
1
2
3
4
5
TiCl4 (1.8 eq.)
CH2Cl2, rt, 23 h
SnCl4 (1.0 eq.)
CH2Cl2, rt, 16 h
ZnCl2 (1.0 eq.)
Toluene, reflux, 48h
ZnI2 (1.0 eq.)
Toluene, reflux, 48h
ZnI2 (1.0 eq.)
21 (13%)
68b (cis:trans = 1 : 3)
22 (34%)
22 (7%)
22 (6%)
21 (61%)
21 (80%)
21 (88%)
77b (cis:trans = 1 : 2)
40b (cis:trans = 3 : 2)
75b (cis:trans = 1 : 1)
72b (cis:trans = 2 : 5)
74c,d
Toluene, reflux, 3h
a Yields are for isolated, chromatogrphically pure products.
Scheme 1
72b (cis:trans = 3 : 1)
Scheme 2
leading to the observed bicyclic products after protonation with
hydriodic acid. As for the medium- and large-membered ring
systems, the most favourable transition state might fit into a trans
conformation due to a lower activation energy, thus resulting in
trans-fused products instead (e.g. 29).
71d
To clarify the role of the TMS group, representative substrates
10, 11 and 16 were further subjected to deprotection under
standard conditions27 to afford the corresponding acetylene
compounds 31–33. Under similar reaction conditions (Scheme
3), these TMS-removed compounds were found to undergo the
desired cyclization as efficiently as or even slightly more efficient
than their TMS-containing analogues, suggesting that the TMS
functionality appears not to be essential for the title system to
effect Conia-ene reaction.
For comparison, a-ester counterparts 37 and 38 were also
prepared,28 and treated with the same reaction conditions. As
illustrated in Scheme 4,12,21 the expected cyclization did occur to
afford products 39 (77%) and 40 (71%), but yields were inferior
to the corresponding a-cyano products 21 (88%) and 35 (90%),
respectively, by 11% and 19% (vide supra).
69d
a Yields are for isolated, chromatographically pure products. b The ratio of
the keto:keto diastereomeric forms. c The stereochemistry was confirmed
by NOE experiments. d A single set of 1H and 13C NMR spectrum,
respectively, was obtained.
Conia-ene cyclization should proceed through intramolecular
addition of the metal enolate to the acetylenic moiety with the
trimethylsilyl group pointing outward to relieve 1,3-allylic strain,
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Table 3 ZnI2 mediated Conia-ene reaction of various w-silylalkynyl-a-
cyano ketones
Substrate
Product
Yield (%)a
85
Scheme 3
10
12
77
Scheme 4
13
14
15
16
86
83
85
80
Scheme 5
corresponding alkylated products in much higher yields than their
TMS-free counterparts (i.e., 41 (87%) vs. 42 (58%) and 43 (64%)
vs. 44 (38%)). Nevertheless, whether the TMS group accounts for
such a distinct difference in yields in LN-induced alkylation still
needs to be further studied before any conclusions can be derived.
The stereochemistry of products 41 and 42 possessing a cis ring
junction was determined by NOE experiments (Fig. 1), as well as a
chemical correlation30,31 via removal of the TMS moiety; however,
the cis configuration of products 43 and 44 are tentatively assigned
based on previously structurally closely related compounds,13 and
remains to be determined.
17
18
81
78
Fig. 1 NOE data of compound 41.
As demonstrated above, though the title system just replaced a
conventional a-ester with an a-cyano group to promote a known
cyclization process under Lewis acid catalysis, it may complement
inadequate functions of its ester counterpart, such as reductive
alkylation, for more advanced synthetic elaboration and undergo a
unique autoxidative cyclization, which is hitherto unknown,18 and
thus will be a valuable addition to the current synthetic chemistry.
In summary, under induction with ZnI2, the Conia-ene annula-
tion process for w-silylalkynyl a-cyano ketones has been developed
to effectively construct various bicyclic skeletons in moderate to
good yields with complete stereo- and regioselectivity. It is con-
ceivable that this newly developed methodology can be extended
to the synthesis of other frequently encountered ring systems by
suitable modifications of the starting material. As well, the angular
cyano group thus formed in the cyclization products may allow for
a Yields are for isolated, chromatographically pure products.
Cyclization products thus obtained, as exemplified by com-
pounds 21, 28, 35 and 36 in Scheme 5, were subsequently applied
to reductive alkylation, a two-step sequence involving decyanation
with lithium naphthalenide (LN)29 followed by alkylation in one
pot. The reaction took place smoothly in a stereoselective manner
at -45 ◦C in THF, leading to a single stereoisomer in all cases
examined.
It was somewhat unexpected that the TMS functionality could
survive the LN-induced reductive conditions. Also intriguing is
the finding that TMS-containing reactants appear to give the
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facile access to the corresponding angularly substituted derivatives
via a simple operation of LN-induced alkylation, which is difficult
to achieve by the presence of any other functionalities.
16 F. F. Fleming, Y. Pu and F. Tercek, J. Org. Chem., 1997, 62, 4883.
17 F. F. Fleming, V. A. Vu, B. C. Shook, M. Rahman and O. W. Steward,
J. Org. Chem., 2007, 72, 1431.
18 Y. C. Wong, M. T. Hsieh, P. K. Amancha, C. L. Chin, C. F. Liao, C. W.
Kuo and K. S. Shia, Org. Lett., 2011, 13, 896.
19 As demonstrated in ref. 18, the a-ester counterparts could not undergo
autoxidative cyclization under the same reaction conditions.
20 C. L. Deng, T. Zou, Z. Q. Wang, R. J. Song and J. H. Li, J. Org. Chem.,
2009, 74, 412.
Acknowledgements
We are grateful to the National Science Council and the National
Health Research Institutes of the Republic of China for financial
support.
21 W. P. Jackson and S. V. Ley, J. Chem. Soc., Perkin Trans. 1, 1981,
1516.
22 W. Li, X. Z. Liu, X. F. Zhou and C. S. Lee, Org. Lett., 2010, 12, 548.
23 Crystal data for 21: C14H21NOSi, M = 247.41; monoclinic, space group
◦
Notes and references
˚
P21/c; a = 17.6183(11), b = 6.9260(4), c = 25.7319(16) A, b = 109.769(1) ,
3
-1
˚
V = 2912.2(3) A , T = 296(2)K; Z = 8; m = 0.147 mm ; reflections: total =
18658, unique = 6904 (Rint = 0.0567); R indices (all data): R1 = 0.1407,
wR2 = 0.1664. CCDC 765390.
‡ An isolated case of the b-alkynyl a-cyano ketone using copper/silver as
co-catalyst to effect Conia-ene reaction was recently reported by Li and
co-workers.20
24 Transition metal catalysts, including Pd(OAc)2, CpCo(CO)2,
(PPh3)AuCl, W(CO)6 and Mo(CO)6 were also screened to facilitate
Conia-ene cyclization. However, they are all inferior to ZnI2, pre-
sumably due to the presence of the bulky TMS group disfavoring the
formation of a metal-alkyne complex.
1 K. S. Shia, N. Y. Chang, J. Yip and H. J. Liu, Tetrahedron Lett., 1997,
38, 7713.
2 H. J. Liu and J. L. Zhu, Tetrahedron Lett., 1998, 39, 4183.
3 J. L. Zhu, K. S. Shia and H. J. Liu, Tetrahedron Lett., 1999, 40, 7055.
4 H. J. Liu and J. Yip, Synlett, 2000, 1119.
5 J. L. Zhu, Y. C. Ko, C. W. Kuo and K. S. Shia, Synlett, 2007, 1274.
6 P. K. Amancha, Y. C. Lai, I. C. Chen, H. J. Liu and J. L. Zhu,
Tetrahedron, 2010, 66, 871.
7 For a review, see: Y. K. Wu, T. W. Ly and K. S. Shia, Curr. Org. Synth.,
2010, 7, 78.
25 Crystal data for 25: C16H25NOSi, M = 275.46; monoclinic, space group
◦
˚
P21/c; a = 11.914(4), b = 11.740(4), c = 12.726(4) A, b = 106.442(5) ,
3
-1
˚
V = 1707.1(9) A , T = 273(2)K; Z = 4; m = 0.132 mm ; reflections:
total = 19759, unique = 4247 (Rint = 0.0866); R indices (all data): R1 =
0.1543, wR2 = 0.1603. CCDC 765388.
26 Crystal data for 29a: C16H27NOSi, M = 277.48; monoclinic, space group
˚
P21/c; a = 10.5629(9), b = 12.6906(10), c = 12.5122(9) A, V = 1648.4(2)
8 J. D. Wu, K. S. Shia and H. J. Liu, Tetrahedron Lett., 2001, 42, 4207.
9 H. J. Liu, T. W. Ly, C. L. Tai, J. D. Wu, J. K. Liang, J. C. Guo, N. W.
Tseng and K. S. Shia, Tetrahedron, 2003, 59, 1209.
10 W. S. Chang, K. S. Shia, H. J. Liu and T. W. Ly, Org. Biomol. Chem.,
2006, 4, 3751.
3
-1
˚
A , T = 100(1)K; Z = 4; m = 0.137 mm ; reflections: total = 12156,
unique = 2914 (Rint = 0.0690); R indices (all data): R1 = 0.0836, wR2 =
0.0668. CCDC 765389.
27 P. Cruciani, R. Stammler, C. Aubert and M. Malacria, J. Org. Chem.,
1996, 61, 2699.
11 P. K. Amancha, H. J. Liu, T. W. Ly and K. S. Shia, Eur. J. Org. Chem.,
28 J. L. Renaud, M. Petit, C. Aubert and M. Malacria, Synlett, 1997,
931.
2010, 3473.
12 For a review, see: M. L. Clarke and M. B. France, Tetrahedron, 2008,
64, 9003.
13 J. L. Zhu, K. S. Shia and H. J. Liu, Chem. Commun., 2000, 1599.
14 F. F. Fleming and B. C. Shook, Org. Synth., 2002, 78, 254.
15 L. R. Kung, C. H. Tu, K. S. Shia and H. J. Liu, Chem. Commun., 2003,
2490.
29 For preparation of LN as a stock solution, see: H. J. Liu, J. Yip and K.
S. Shia, Tetrahedron Lett., 1997, 38, 2253.
30 Y. L. Kuo, M. Dhanasekaran and C. K. Sha, J. Org. Chem., 2009, 74,
2033.
31 C. H. Chen, Y. K. Chen and C. K. Sha, Org. Lett., 2010, 12, 1377.
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The Royal Society of Chemistry 2011
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