Lewis acid catalyzed [2+2] cycloaddition of ynamides and propargyl silyl ethers: Synthesis of alkylidenecyclobutenones and their reactivity in ring-opening and ring expansion

Article abstract of DOI:10.1039/c6cc04648g

A family of four-membered enones, polysubstituted alkylidenecyclobutenones, were easily prepared by a Lewis acid catalyzed [2+2] cycloaddition of ynamides and propargyl silyl ethers. This challenging regioselective [2+2] cycloaddition enables the efficient construction and conversion of four-membered enones, which provides high-value and structurally diverse products through the unexpected ring-opening and ring expansion of alkylidenecyclobutenone with Grignard reagents, organolithium, primary amines, and water.

Full text of DOI:10.1039/c6cc04648g

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Lewis acid catalyzed [2+2] cycloaddition of
ynamides and propargyl silyl ethers: synthesis of
alkylidenecyclobutenones and their reactivity in
ring-opening and ring expansion†
Cite this:DOI: 10.1039/c6cc04648g
Received 3rd June 2016,
Accepted 3rd July 2016
Ling Chen,a Jian Cao,*a Zheng Xu,a Zhan-Jiang Zheng,a Yu-Ming Cuia and
DOI: 10.1039/c6cc04648g
Li-Wen Xu*ab
www.rsc.org/chemcomm
A family of four-membered enones, polysubstituted alkylidenecyclo-
Ynamides have emerged as important synthons in modern
butenones, were easily prepared by a Lewis acid catalyzed [2+2] organic synthesis and a variety of important cyclic systems have
cycloaddition of ynamides and propargyl silyl ethers. This challenging been successfully constructed from ynamides via [4+2], [3+2] and
regioselective [2+2] cycloaddition enables the efficient construction [2+2] cycloaddition reactions.8 Specifically, [2+2] cycloaddition
and conversion of four-membered enones, which provides high- reactions of ynamides with alkenes have been established to con-
value and structurally diverse products through the unexpected struct cyclobutenes and cyclobutenones derivatives. For example,
ring-opening and ring expansion of alkylidenecyclobutenone with Hsung pioneered the Ficini reaction of ynamides to afford amido-
Grignard reagents, organolithium, primary amines, and water.
cyclobutene (Scheme 1a)9 and Tam reported the Ru-catalyzed
ynamide-[2+2] cycloaddition of norbornene (Scheme 1b).10 In
Cyclobutenones, bearing a carbon–carbon double bond and addition, Danheiser established thermal cycloaddition of ketenes
carbonyl group in a strained four-membered ring, are important and ynamides (Scheme 1c),11 while Lam developed the Rh-catalyzed
building blocks.1 Because of the inherent ring strain, cyclo- cycloaddition of ynamides with nitroalkenes (Scheme 1d).12 Intra-
butenones can easily undergo carbon–carbon bond breakage via molecular [2+2] processes through enyne cyclo-isomerizations
thermal 4p-electron electrocyclic cleavage,2 oxidative addition by using platinum or gold catalysts were also realized by Malacria13
transition metal catalyst,3 and recently reported organocatalytic and Cossy (Scheme 1e).14 However, to the best of our knowledge,
carbon–carbon bond activation.4 However, the synthetic routes
to access the more strained alkylidenecyclobutenones, with an
additional carbon–carbon double bond on the four-membered
enones, are still limited. Therefore, little is known about the
reactivity of alkylidenecyclobutenones except that they are the
precursors for allenylketenes.5 Despite previously reported
methods established to prepare alkylidenecyclobutenones, such
as a methylenation reaction of cyclobutene-1,2-diones with low
regioselectivity,6 and [3,3]-rearrangement of alkynyl propargyl
sulfides and subsequent ring closure followed by oxidative hydro-
lytic process,7 the facile and efficient synthesis of alkylidene-
cyclobutenones remains a formidable challenge.
a Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of
Education, Hangzhou Normal University, No 1378, Wenyi West Road,
Science Park of HZNU, Hangzhou 311121, P. R. China.
E-mail: caojian@hznu.edu.cn, liwenxu@hznu.edu.cn
b State Key Laboratory for Oxo Synthesis and Selective Oxidation Lanzhou Institute
of Chemical Physics (LICP), Chinese Academy of Sciences (CAS), P. R. China
† Electronic supplementary information (ESI) available: Experimental procedures,
characterization data, crystallographic data in CIF and NMR spectra. CCDC
Scheme 1 Construction of cyclobutene derivatives via [2+2] cycloaddition
1446541 (3a), 1446542 (7a) and 1446543 (8). For ESI and crystallographic data in
of ynamides.
CIF or other electronic format see DOI: 10.1039/c6cc04648g
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the [2+2] cycloaddition reaction for the construction of alkylidene- acids such as FeCl3, Sc(OTf)3, and Yb(OTf)3 were less effective
cyclobutenones has never been accomplished. Recently, we (entries 5–14). The reaction was sensitive to solvents; the other
reported carbocation-induced cyclization and addition reactions common solvents such as toluene, Et2O, and CH3CN were not
of ynamides.15 Considering that propargylic alcohol derivatives suitable (entries 15–21). Further optimization of the reaction
can serve as propargylic/allenyl cation equivalents which could temperature failed to improve the yield (entries 22 and 23).
initiate electrophilic addition or cyclization reactions with Thus, the following reaction conditions were chosen as optimum
alkynes to afford complex cyclic compounds,16 we anticipate for all subsequent reactions: 1.0 equiv. of 1, 1.0 equiv. of 2, and
that alkylidenecyclobutenones might be constructed via a [2+2] 0.2 equiv. of BF3ꢀOEt2 in CH2Cl2 were stirred at rt under N2. The
cycloaddition reaction of ynamides and propargyl silyl ethers structure of 3a was established by X-ray diffraction analysis
(Scheme 1f). Herein, we report the realization of this novel (CCDC 1446541).
strategy for the synthesis of multisubstituted alkylidenecyclo-
Under the optimal conditions, the scope and limitations of
butenones and their reactivity in ring-opening and ring expansion. this [2+2] cycloaddition reaction were then investigated using
At the outset of our investigation, the reaction conditions were various ynamides 2. As demonstrated in Table 2, aryl substituted
optimized by using propargyl silyl ether 1a and ynamide 2a. ynamides with various functional groups at the 4-position including
Initially, 1.0 equivalent of ZnBr2 was first chosen as the Lewis F, Cl, Br, Me, and OMe groups were well tolerated in this
acid to generate the allenyl cation with 1a in CH2Cl2. To our transformation (entries 1–6). Aromatic ynamide with an ortho-
delight, the expected alkylidenecyclobutenone 3a was afforded substituent gave a good result too (entry 7). Besides, styryl sub-
in 37% yield (Table 1, entry 1). Replacing propargyl silyl ether 1a stituted ynamide 2h also afforded the corresponding product 3h,
with propargyl alcohol 1a0 resulted in a diminished yield (entry 2), albeit in a lower yield (entry 8). We next focused our attention
and ynsulfonamide 2a0 did not improve the yield either (entry 3). on the scope of propargyl silyl ether. The scope of R2 was broad:
Fortunately, a breakthrough was achieved when we replaced substituted aryl, 2-thiophenyl, styryl, and alkyl groups were all
ZnBr2 with BF3ꢀOEt2 (entry 4). Reducing the amount of BF3ꢀOEt2 tolerated (entries 9–14). R1 in propargyl silyl ether can be an
to 0.2 equivalent did not affect the yield significantly (entry 5). aryl group substituted with either an electron-donating or
Subsequent screening of various Lewis acids showed that -withdrawing group (entries 15–17). Unfortunately, the reaction
BF3ꢀOEt2 was the best choice, and the other common Lewis failed to produce the expected product when R1 was Me or H.
A possible mechanism is proposed in Scheme 2. Initially,
allenyl cation A would be formed from propargyl silyl ether 1
Table 1 Optimization of the reaction conditionsa
with BF3ꢀOEt2. Electrophilic addition of the in situ generated
carbocation with ynamide 2 gives the keteniminium ion B and
the subsequent 4p-electron electrocyclization provides an unstable
iminium ion C (path a). Alternatively, a concerted [2+2] process
Table 2 Synthesis of alkylidenecyclobutenonesa
Entry
Lewis acid
Solvent
Temp.
Yield of 3a (%)
1
ZnBr2
ZnBr2
ZnBr2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
Et2O
CH3CN
(CH2Cl)2
CHCl3
Hexane
THF
CH2Cl2
CH2Cl2
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
40 1C
0 1C
37
20
27
68
65
52
50
37
40
43
34
Trace
Trace
61
Trace
NR
Trace
49
2b
3c
4
BF3ꢀOEt2
BF3ꢀOEt2
FeCl3
In(OTf)3
Bi(OTf)3
AgOTf
Sc(OTf)3
Yb(OTf)3
BCl3
5
6
7
8
Entry
1 (R1/R2)
2 (R3)
Yield of 3 (%)
9
1
2
3
4
5
6
7
8
1a (Ph/Ph)
1a
1a
1a
1b (Ph/4-MeOC6H4)
1b
1b
1b
2a (Ph)
2b (4-FC6H4)
2c (4-ClC6H4)
2d (4-BrC6H4)
2e (4-MeC6H4)
2f (4-MeOC6H4)
2g (2-MeC6H4)
2h ((E)-styryl)
2a
2a
2a
2a
2a
2a
2a
2a
2a
65 (3a)
71 (3b)
73 (3c)
67 (3d)
59 (3e)
60 (3f)
76 (3g)
35 (3h)
63 (3i)
65 (3j)
55 (3k)
48 (3l)
48 (3m)
37 (3n)
62 (3o)
68 (3p)
52 (3q)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
BBr3
B(C6F5)3
BF3ꢀOEt2
BF3ꢀOEt2
BF3ꢀOEt2
BF3ꢀOEt2
BF3ꢀOEt2
BF3ꢀOEt2
BF3ꢀOEt2
BF3ꢀOEt2
BF3ꢀOEt2
9
1b
10
11
12
13
14
15
16
17
1c (Ph/4-MeC6H4)
1d (Ph/4-ClC6H4)
1e (Ph/2-thiophenyl)
1f (Ph/(E)-styryl)
1g (Ph/n-Bu)
1h (4-MeC6H4/Ph)
1i (4-MeOC6H4/Ph)
1j (4-ClC6H4/Ph)
37
Trace
NR
58
55
a
Unless otherwise specified, the reaction was carried out using 1a
(0.3 mmol)/2a/Lewis acid (1:1: 1 for entries 1–4; 1:1 :0.2 for entries 5–16)
b
a
in solvent (3 mL) under N2 for 2–12 h. Alcohol 1a0 was used instead of 1a.
Unless otherwise specified, the reaction was carried out using 1/2/BF3ꢀOEt2
c
Ynsulfonamide 2a0 was used instead of 2a.
(1:1:0.2) in CH2Cl2 under N2 for 6–12 h.
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Scheme 2 Proposed reaction mechanism.
leads directly to C (path b), which undergoes an addition process
with the [TMSO–BF3]ꢁ complex to form the intermediate D and
regenerate the catalyst BF3. Final loss of the N-trimethylsilyl
oxazolin-2-one affords the product alkylidenecyclobutenone 3.
Scheme 3 The reactions of 3a with Grignard reagents.
To confirm the plausible mechanism and the source of the oxygen of 3a with alkyl magnesium bromide, could also be converted to
in the product, we performed the reaction with the 18O-labelled 1a. 4,5-dien-2-one 5c in the presence of LDA through electrocyclic
The result clearly showed the oxygen in the propargyl silyl ether 1a cleavage.
served as the source of the oxygen.
The ring-opening and ring expansion reactions of alkylidene-
The ring-opening reaction as well as ring expansion of cyclo- cyclobutenone 3a with amines and water were also investigated
butenones offers a number of potentially divergent compounds. (Scheme 4). Although the nucleophilic addition of secondary
Thus, upon the successful development of an efficient [2+2] amine to alkylidenecyclobutenone 3a led to many unidentified
cycloaddition strategy for the synthesis of alkylidenecyclobute- mixtures, the ring-opening reaction of 3a with the aid of primary
nones, we investigated possible ring-opening transformations amines turned out to be a synthetically useful procedure. The
of the alkylidenecyclobutenones with various nucleophiles. First, corresponding imines 7a–c containing highly substituted enones
we tried the Grignard addition reaction of alkylidenecyclo- backbones could be obtained in good isolated yields (68–83%).
butenone 3a with alkyl magnesium chloride or bromide. To our The structure of 7a was established by X-ray diffraction analysis
delight, the reaction smoothly produced the corresponding alkyl- (CCDC 1446542). In addition, to explore the stability of alkyl-
idenecyclobutenols 4a–c in good yields (Scheme 3). Notably, such idenecyclobutenone 3a under photoreaction conditions, the
types of cyclobutenols are of great interest due to the broad utility hydrolysis was examined in the presence of DABCO in wet THF
of these compounds in organic synthesis.17 Interestingly, the at room temperature. As shown in Scheme 4, the light-driven
reaction with aryl magnesium bromide afforded 4,5-dien-2- procedure resulted in the formation of a new product, poly-
ones 5a–b while vinyl magnesium chloride produced the substituted furanone 8, and the structure of 8 was established
cyclohex-2-enone 6.18 These three types of different reactions using X-ray diffraction analysis (CCDC 1446543). Besides, the
or approaches may proceed through the highly regioselective reaction with the D2O clearly showed that water was involved in
1,2-addition of a Grignard reagent to carbonyl CQO on alkyl- this reaction.
idenecyclobutenone 3a (the formation of intermediate I), and
In summary, we have developed a novel approach for the
subsequent electrocyclic cleavage (the formation of intermediate synthesis of four-membered enones via a [2+2] cycloaddition
II or III). Interestingly, the domino cyclization on the intermedi- reaction of ynamides with propargyl silyl ethers. This strategy
ate III leading to highly substituted cyclohexenone 6 unexpectedly features readily available starting material and mild reaction
occurred in this reaction, which gave an important aspect of the conditions, providing an efficient entrance to a variety of alkyl-
synthetic application of small-ring compounds in the construc- idenecyclobutenone derivatives, which are not readily available
tion of new molecules. Furthermore, it should be noted that the from traditional methods. Additionally, various structurally
alkylidenecyclobutenol 4a derived from the Grignard addition diverse products are easily provided via unexpected ring-opening
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4 (a) B.-S. Li, Y. Wang, Z. Jin, P. Zheng, R. Ganguly and Y. R. Chi, Nat.
Commun., 2015, 6, 6207; (b) B.-S. Li, Y. Wang, Z. Jin and Y. R. Chi,
Chem. Sci., 2015, 6, 6008.
5 (a) W. Huang, D. Fang, K. Temple and T. T. Tidwell, J. Am. Chem.
Soc., 1997, 119, 2832; (b) W.-W. Huang, H. Henry-Riyad and T. T.
Tidwell, J. Am. Chem. Soc., 1999, 121, 3939; (c) W. Huang and T. T.
Tidwell, Synthesis, 2000, 457.
6 A. A. Ardakani, N. Maleki and M. R. Saadein, J. Org. Chem., 1978,
43, 4128.
7 S. Aoyagi, K. Kikuchi, K. Shimada and Y. Takikawa, Synlett, 2007,
2553.
8 For recent reviews on the chemistry of ynamides, see: (a) K. A.
DeKorver, H. Li, A. G. Lohse, R. Hayashi, Z. Lu, Y. Zhang and R. P.
Hsung, Chem. Rev., 2010, 110, 5064; (b) G. Evano, A. Coste and
K. Jouvin, Angew. Chem., Int. Ed., 2010, 49, 2840; (c) G. Evano,
K. Jouvin and A. Coste, Synthesis, 2013, 17; (d) X. Wang, H. Yeom,
L. Fang, S. He, Z. Ma, B. L. Kedrowski and R. P. Hsung, Acc. Chem.
Res., 2014, 47, 560.
9 (a) H. Li, R. P. Hsung, K. A. DeKorver and Y. Wei, Org. Lett., 2010,
12, 3780. Also see: (b) C. Schotes and A. Mezzetti, Angew. Chem., Int.
Ed., 2011, 50, 3072; (c) C. Schotes and A. Mezzetti, J. Org. Chem.,
2011, 76, 5862; (d) Y. Yuan, L. Bai, J. Nan, J. Liu and X. Luan, Org.
Lett., 2014, 16, 4316.
10 (a) N. Riddell, K. Villeneuve and W. Tam, Org. Lett., 2005, 7, 3681;
(b) K. Villeneuve, N. Riddell and W. Tam, Tetrahedron, 2006, 62, 3823.
11 (a) A. L. Kohnen, X. Y. Mak, T. Y. Lam, J. R. Dunetz and R. L.
Danheiser, Tetrahedron, 2006, 62, 3815; (b) Y.-P. Wang and R. L.
Danheiser, Tetrahedron Lett., 2011, 52, 2111. Also see: (c) X. Zhou,
I. Zafar and G. Dong, Tetrahedron, 2015, 71, 4478; (d) Y. Bai, J. Yin,
Z. Liu and G. Zhu, J. Org. Chem., 2015, 80, 10226.
12 D. L. Smith, S. R. Chidipudi, W. R. Goundry and H. W. Lam, Org.
Lett., 2012, 14, 4934.
13 (a) F. Marion, J. Coulomb, C. Courillon, L. Fensterbank and
M. Malacria, Org. Lett., 2004, 6, 1509; (b) F. Marion, J. Coulomb,
A. Servais, C. Courillon, L. Fensterbank and M. Malacria, Tetrahedron,
2006, 62, 3856. Also see: (c) E. Soriano and J. Marco-Contelles, J. Org.
Chem., 2005, 70, 9345.
Scheme 4 The nucleophilic addition of 3a with primary amine and water,
respectively.
and ring expansion of alkylidenecyclobutenone with Grignard
reagents, organolithium, primary amines, and water.
Financial support from the National Natural Science Foundation
of China (No. 21102029, 21173064, and 21472031) and the Zhejiang
Provincial Natural Science Foundation of China (No. LY14B020013
and LR14B030001) is gratefully acknowledged.
14 (a) S. Couty, C. Meyer and J. Cossy, Angew. Chem., Int. Ed., 2006, 45, 6726;
(b) S. Couty, C. Meyer and J. Cossy, Tetrahedron, 2009, 65, 1809.
15 (a) Y. Kong, K. Jiang, J. Cao, L. Fu, L. Yu, G. Lai, Y. Cui, Z. Hu and
G. Wang, Org. Lett., 2013, 15, 422; (b) L. Chen, L. Yu, Y. Deng, Y. Cui,
G. Bian and J. Cao, Org. Biomol. Chem., 2016, 14, 564; (c) L. Chen,
L. Yu, Y. Deng, Z.-J. Zheng, Z. Xu, J. Cao and L.-W. Xu, Adv. Synth.
Catal., 2016, 358, 480. For an annulation of ynamides with 2-
methoxyaroyl chlorides, see: (d) H. Liu, Y. Yang, S. Wang, J. Wu,
X.-N. Wang and J. Chang, Org. Lett., 2015, 17, 4472.
Notes and references
1 (a) L. Souillart and N. Cramer, Chem. Rev., 2015, 115, 9410; (b) T. Xu,
A. Dermenci and G. Dong, Top. Curr. Chem., 2014, 346, 233;
(c) A. Flores and R. Martin, Synthesis, 2013, 563; (d) J. C. Namyslo
and D. E. Kaufmann, Chem. Rev., 2003, 103, 1485.
2 (a) R. L. Danheiser and S. K. Gee, J. Org. Chem., 1984, 49, 1672;
(b) S. T. Perri, L. D. Foland, O. H. W. Decker and H. W. Moore, J. Org. 16 (a) Y. Zhu, L. Sun, P. Lu and Y. Wang, ACS Catal., 2014, 4, 1911; (b) L.-N.
Chem., 1986, 51, 3067; (c) X. Y. Mak, A. L. Crombie and R. L. Danheiser,
J. Org. Chem., 2011, 76, 1852.
3 (a) P.-H. Chen, T. Xu and G. Dong, Angew. Chem., Int. Ed., 2014,
53, 1674; (b) P.-H. Chen, J. Sieber, C. H. Senanayake and G. Dong,
Guo, X.-H. Duan and Y.-M. Liang, Acc. Chem. Res., 2011, 44, 111.
17 (a) T. Matsuda and N. Miura, Org. Biomol. Chem., 2013, 11, 3424;
(b) G. Chai, S. Wu, C. Fu and S. Ma, J. Am. Chem. Soc., 2011, 133, 3740;
(c) M. Murakami, Y. Miyamoto and Y. Ito, J. Am. Chem. Soc., 2001,
123, 6441.
´
´
Chem. Sci., 2015, 6, 5440; (c) F. Julia-Hernandez, A. Ziadi, A. Nishimura
and R. Martin, Angew. Chem., Int. Ed., 2015, 54, 9537; (d) M. A. 18 J. E. Ezcurra, C. Pham and H. W. Moore, J. Org. Chem., 1992,
Huffman and L. S. Liebeskind, J. Am. Chem. Soc., 1993, 115, 4895.
57, 4787.
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