Alkoxide-induced ring opening of bicyclic 2-vinylcyclobutanones: A convenient synthesis of 2-vinyl-substituted 3-cycloalkene-1-carboxylic acid esters

Article abstract of DOI:10.3762/bjoc.8.72

The fused 2-vinyl or 2-phenyl substituted cyclobutanones 4 undergo stereoselective ring openings by the action of alkoxide ions (t-BuO- or MeO-) to produce novel vicinally disubstituted cycloalkene derivatives 5 and 6 in moderate to high yields. The ring cleavage usually occurs with complete regioselectivity. The accessibility of γ,δ-unsaturated ester or acid derivatives makes this transformation a good supplementary method for the well-established Johnson-Claisen rearrangement.

Full text of DOI:10.3762/bjoc.8.72

Alkoxide-induced ring opening of bicyclic
2-vinylcyclobutanones: A convenient synthesis
of 2-vinyl-substituted 3-cycloalkene-
1-carboxylic acid esters
Xiufang Ji1, Zhiming Li1, Quanrui Wang*1 and Andreas Goeke*2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 650–657.
1Department of Chemistry, Fudan University, 220 Handan Road,
200433 Shanghai, P. R. China and 2Shanghai Givaudan Ltd.,
Fragrances, 298 Li Shi Zhen Road, 201203 Shanghai, P. R. China
doi:10.3762/bjoc.8.72
Received: 28 January 2012
Accepted: 30 March 2012
Published: 26 April 2012
Email:
Quanrui Wang* - qrwang@fudan.edu.cn; Andreas Goeke* -
andreas.goeke@givaudan.com
Associate Editor: J. Murphy
* Corresponding author
© 2012 Ji et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
alkoxide; cyclobutanones; esters; fused ring systems; ring opening
Abstract
The fused 2-vinyl or 2-phenyl substituted cyclobutanones 4 undergo stereoselective ring openings by the action of alkoxide ions
(t-BuO− or MeO−) to produce novel vicinally disubstituted cycloalkene derivatives 5 and 6 in moderate to high yields. The ring
cleavage usually occurs with complete regioselectivity. The accessibility of γ,δ-unsaturated ester or acid derivatives makes this
transformation a good supplementary method for the well-established Johnson–Claisen rearrangement.
Introduction
A great variety of methods are available for the synthesis of of the cyclobutane caused by the substitution at C-2 and C-4,
cyclobutane derivatives. Frequently employed ones include the also offer both interesting preparative and mechanistic aspects
thermal [2 + 2] cycloaddition of ketenes to alkenes and the [11]. The ease of ring opening of cyclobutanones is influenced
polar addition of cyclopropyl ylides to carbonyls [1,2]. These by the strain of the four-membered rings, the substitution
methods generally allow regioselective as well as stereoselec- pattern on the ring, and the properties of the reagents as well as
tive syntheses of extensively substituted four-membered ring the reaction conditions. In particular, the ring opening of certain
carbocycles. In particular, due to their facile accessibility [3-8] fused-ring cyclobutanones, which are easily prepared by the
and expeditious ring transformations, the use of cyclobu- well-established [2 + 2] cycloadditions of ketenes with various
tanones as extremely versatile and useful starting materials or cycloalkenes, has been extensively investigated [3-8,12-14]. To
intermediates in the construction of carbon skeletons has flour- achieve the ring opening, many reaction conditions have been
ished over the past three decades [9,10]. In addition, the high investigated, such as acidic conditions, basic conditions, nucleo-
electrophilicity of the carbonyl carbon atom, and the puckering philic attack, thermolysis, and oxidizing as well as reducing
650

Beilstein J. Org. Chem. 2012, 8, 650–657.
conditions [4,11]. Cohen and Matz described the [1,2]- and triethylamine-promoted 1,4- or 1,2-dehydrochlorination of acyl
[1,3]-acyl migration of 2-vinylcyclobutanones, leading to chlorides 2 [1]. The in situ generated vinylketenes or phenyl-
cyclopentenones or cyclohexenones, respectively [15]. ketenes 3 were trapped by reaction with excessive amount of
Danheiser and co-workers reported an oxyanion-accelerated alkenes 1 in methylene chloride. The reaction of ketenes
[1,3]-rearrangement of in situ reduced 2-vinylcyclobutanones, (R2C=C=O) with alkenes under thermal conditions to give
by applying mixtures of LiBu3BH-MeLi and HMPT to give cyclobutanone products is generally described as an [π2s + π2a]
bicyclic cyclohexenols [16], which were also subsequently process from orbital symmetry considerations. However, there
described by Cohen who elaborated the method into a synthesis is strong evidence that formation of the Staudinger-type
of (−)-β-selinene [17]. The core structures of ophiobolins A and cycloadducts by using cyclic (s-cis) 1,3-dienes proceeds by a
other natural products can be synthesized by an alkenylation/ two-step process, involving an initial hetero Diels–Alder cyclo-
oxy-Cope/methylation sequence of vinylcyclobutones in one addition of the diene and the ketene carbonyl group, followed
pot [18-23]. Ring-opening reactions of cyclobutanones are by a [3,3]-sigmatropic (Claisen) rearrangement [25,26].
expected to be a valuable methodology for vicinal difunctional-
ization of double bonds. A prerequisite for this reaction to take The most effective conditions were achieved by the employ-
place is the presence at C-2 of substituents capable of stabi- ment of a slightly excessive amount of olefins 1. The cycloaddi-
lizing the developing vicinal carbanion [6-8]. In this context, tions proceeded with complete regio- and stereoselectivity with
α,α-dihalosubstituents, thioketal, sulfoxide, ester or aryl respect to the olefin 1, but less so with respect to the ketene 3
substituents have been reported to facilitate the ring cleavage (Table 1), such that endo-4 and exo-4 isomers were formed in
[6-8].
variable amounts, depending on the nature of the substrates. In
general, the conversions of cyclopenta-1,3-diene 1a and the
We recently reported a novel metathetic cycloreversion of spiroheptadiene (1c) gave high yields of product 4 at 0 °C.
7-vinyl and aryl bicyclo[3.2.0]hept-2-en-6-ones giving rise to However, the yields were moderate to low with cyclic mono
linear polyene ketones. The reaction was triggered by an in situ olefin 1f or styrene (1g), even under reflux conditions. Mixtures
alkylation with alkyl or aryllithium reagents in the presence of of endo- and exo-isomers of compounds 4 were used in the
catalytic amounts of Li-chelating agents (e.g., Scheme 1) [24]. subsequent ring-opening step without prior separation.
The configuration of the newly formed double bond in position
6 was diastereoselectively determined by the configuration of The configurations were determined from their 1H NMR spectra
the bicyclic precursor.
and mechanistic considerations [27]. For example, the C-7
methyl signal in the endo-bicyclo[3.2.0]heptenone systems was
found in 1H NMR at a lower field (δ = 1.40 for endo-4a), while
that for the exo-counterpart appeared at a higher field (δ = 1.10
for exo-4a). The configuration of compound 4g was discernible
from 1H NMR spectra and confirmed by 2D NMR spec-
troscopy. Thus, the NOESY spectrum of trans-4g indicated a
correlation between the signal at 6.05 ppm from the α-vinyl
proton of the vinyl group and the triplet at 3.74 ppm from the
C-3 proton (Figure 1).
Scheme 1: Metathetic ring opening of 7-methyl-7-
vinylbicyclo[3.2.0]hept-2-en-6-one to a linear polyene ketone.
Our ongoing interest in constructing odorants from easily acces- Taking the high degree of ring strain in substrates 4 into
sible starting materials prompted us to search further for novel account, an alkoxide-promoted ring opening to vicinally
transformations of cyclobutanones. We were pleased to find functionalized products 5 or 6 was expected. To validate
that selective ring cleavage of bicyclic cyclobutanones 4 this proposal, the 7-methyl-7-vinyl substituted
bearing a vinyl or phenyl group in the alpha position can be bicyclo[3.2.0]heptenone 4a was employed as a model substrate
achieved by the action of sodium methoxide or potassium tert- with sodium methoxide or potassium tert-butoxide as the base.
butoxide. This approach constitutes an efficient path to vici- Various reaction conditions, including the amount of metal
nally disubstituted ester products 5 or 6.
alkoxide, solvents and reaction temperature were examined.
Representative results are listed in Table 2.
Results and Discussion
We began our investigation with the preparation of cyclobu- It was found that both MeONa and t-BuOK can promote the
tanones as shown in Scheme 2. The reaction involves genera- ring opening to furnish the alkyl 2-substituted cyclopent-3-
tion of the intermediate vinylketenes or phenylketenes by the enecarboxylate 5a or 6a. Using 1.2 equiv of MeONa with
651

Beilstein J. Org. Chem. 2012, 8, 650–657.
Scheme 2: Synthesis of vinyl or phenyl substituted cyclobutanones 4a–i.
methanol as solvent gave 5a in moderate isolated yield, after 2 h (Table 2, entry 2). The more bulky tert-BuOK was also a suit-
at room temperature, in form of an E/Z isomeric mixture about able base to trigger the ring opening, giving acceptable yields of
the 2-vinyl double bond, in a ratio of 6:4 (Table 2, entry 1). product 6a. Not surprisingly, the use of tert-BuOK as base
Reducing the amount of the base significantly decreased the provided 6a with a higher diastereoselectivity of 9:1 in favour
yield. Using 0.01 equiv of MeONa afforded no more than 10% of the E-isomer. It seems that 1.2 equiv of the base had to be
yield, even though the reaction time was prolonged to 16 h applied, and THF as solvent was superior to tert-butanol in
Table 1: Formal [2 + 2] cycloaddition of vinylketenes 2 with olefins.a
entry
alkene 1
acid chloride 2
timeb (h)
product 4
endo:exoc
yieldd (%)
1
1a
1b
1c
1d
1e
1f
2a
2a
2a
2a
2a
2a
2a
2b
2b
3
4a
4b
4c
4d
4e
4f
30:70
50:50
25:75
50:50
35:65
25:75
33:67f
95:5
76
80
40
34
40
60
16
85
21
2
3
3
4
4
8
5
8
6e
7e
8
10
12
3
1g
1a
1e
4g
4h
4i
9
7
>95:5
aReagents and conditions (cf. Scheme 2): alkene 1 (1.5 equiv), Et3N (1.2 equiv), acid chloride 2 (1.0 equiv), 0 °C. bTime required for the olefin to
achieve maximal conversion. cthe exo/endo ratio was determined by 1H NMR spectroscopy. dIsolated yields after purification by column chromatog-
raphy on silica gel. eUsing chloroform as solvent under reflux. fcis/trans ratio. Structures are shown in Scheme 2.
652

Beilstein J. Org. Chem. 2012, 8, 650–657.
terms of yield and reaction rate (Table 2, entry 3 versus 4, entry
3 versus 6). A detrimental effect of enhancing the temperature
was observed. Thus, an attempt to accelerate the reaction led to
the decomposition of the cyclobutanone 4a under reflux condi-
tions, without the detection of any desired product 6a (Table 2,
entry 5). In addition, the use of a K-chelating agent, i.e.,
dibenzo-18-crown-6, did not show any improvement of the
yield of compound 6a (Table 2, entry 8).
In light of the above promising results, the substrate scope of
this base-promoted ring-opening reaction was assessed by using
a variety of cyclobutanones 4b–i (Scheme 3, Table 3). Diverse
Figure 1: Determination of the structure of 3-phenyl-2-vinyl substi-
tuted cyclobutanone 4g.
Table 2: Cleavage reaction of 4a with metal alkoxide.a
entry
alkoxide (equiv) solvent
time (h)
product
E:Zb
yieldc (%)
1
2
3
4
5d
6
7
8
NaOMe (1.2)
MeOH
2
5a
5a
6a
6a
6a
6a
6a
6a
60:40
55:45
9:1
40
NaOMe (0.010) MeOH
16
2
<10
46
t-BuOK (1.2)
t-BuOK (0.010)
t-BuOK (1.2)
t-BuOK (1.2)
t-BuOK (0.010)
t-BuOK (1.2)e
THF
THF
16
0.5
24
24
2
75:25
—
<10
decomp.
30
THF
t-BuOH
t-BuOH
THF
>99:1
95:5
90:10
<10
47
aAddition of 4a to the alkoxide was performed at 0 °C, then continued at rt. bE/Z ratio was determined by GC–MS prior to chromatography. cIsolated
yield after column chromatography on silica gel. dUnder reflux. eUsing 0.05 equiv dibenzo-18-C-6 as a K-chelating agent.
Scheme 3: Ring opening of cyclobutanones 4 to afford products 5 or 6.
653

Beilstein J. Org. Chem. 2012, 8, 650–657.
Table 3: Reaction of 4 with MeONa or t-BuOK.a
entry
ketone 4
ROM
time (h)
product
product label
E:Zb
yieldc (%)
1
2
4a
4a
MeONa
t-BuOK
2
2
5a
6a
60:40
9:1
40
46
3
4
4b
4b
MeONa
t-BuOK
4
6
5b
6b
50:50
95:5
41
50
5
6
4c
4c
MeONa
t-BuOK
4
16
5c
6c
67:33
80:20
18
43
7
8
4d
4d
MeONa
t-BuOK
24
24
5d
6d
60:40
>99:1
37
29
9
4e
4e
4f
MeONa
t-BuOK
MeONa
t-BuOK
14
5e
6e
5f
55:45
>99:1
60:40
-
41
72
51
60
10
11
12
3
3
4f
5
6f
13
14
4g
4g
MeONa
2
5
5g
6g
60:40
>99:1
45
65
t-BuOK
654

Beilstein J. Org. Chem. 2012, 8, 650–657.
Table 3: Reaction of 4 with MeONa or t-BuOK.a (continued)
15
16
4h
4h
MeONa
t-BuOK
12
2
5h
6h
-
-
63
74
17
18
4i
4i
MeONa
t-BuOK
6
3
5i
6i
-
-
57
70
a1.2 equiv of base was employed. For MeONa methanol was the solvent, and for t-BuOK THF was the solvent. The progression was monitored by
GC. bThe E/Z ratio was determined by GC-MS before chromatography. cIsolated yield after silica-gel column chromatography.
substitution patterns at both the ketene and the olefin moiety
were compatible with this ring-opened method. Thus, cyclobu-
tanones carrying both vinyl (Table 3, entries 1–14) and phenyl
(Table 3, entries 15–18) substituents underwent the cleavage
reaction. The monocyclic butanone 4g was also tolerated to give
moderate yields (Table 3, entries 13 and 14). Another notice-
able observation is that the use of t-BuOK furnished generally
better yields than MeONa, except for compound 4d, which was
Scheme 4: Reaction of 4a with LDA.
obtained in a slightly higher yield in the presence of MeONa as
the base (Table 3, entries 7 and 8).
ring strain of the cyclobutanones, the ring is very sensitive to
Surprisingly, the reaction of 4f with t-BuOK led to ester 6f the influence of nucleophiles. As exemplified by 4a, the reac-
(Table 3, entry 12) carrying an allylic instead of a vinylic side tion begins with the nucleophilic exo-facial attack on the car-
chain. In the case of the 2-phenyl substituted cyclobutanone 4g bonyl group by an alkoxide ion to trigger the cleavage of the
the reaction afforded a 65% yield of γ,δ-unsaturated acid prod- four-membered ring. The presence of a vinyl group facilitates
uct (E)-6g (Table 3, entry 14). Finally, an attempt using the ster- the ring fission since the resultant carbanion can be stabilized
ically hindered base LDA only led to the formation of aldol by resonance. Protonation leads to the formation of the isolated
adduct 7 (Scheme 4).
products 5a or 6a. When the hindered base t-BuOK is
employed, the reaction occurs with a high preference for
Although the mechanism is not fully understood, a tentative E-product formation. This may be a result of thermodynamic
mechanistic rationale is depicted in Scheme 5. Due to the high control.
Scheme 5: Plausible mechanism for ring opening of 4a.
655

Beilstein J. Org. Chem. 2012, 8, 650–657.
11.Belluš, D.; Ernst, B. Angew. Chem. 1988, 100, 820–850.
Conclusion
doi:10.1002/ange.19881000607
In conclusion, our intention to synthesize potential olfactorily
useful compounds led us to disclose the facial ring opening of a
series of cyclobutanones to produce 1,2-disubstituted cyclopen-
tene derivatives with high selectivity. The economic cycloaddi-
tion/ring-opening sequence is significant in that it allows a
useful functional group to be easily introduced under mild
conditions. Furthermore, the products have a general γ,δ-unsat-
urated carbonyl skeleton, and hence the protocol should be a
good surrogate for the well-established Johnson orthoester
Claisen rearrangement [28,29].
Angew. Chem., Int. Ed. Engl. 1988, 27, 797–827.
doi:10.1002/anie.198807971
12.Baldwin, J. E.; Leber, P. A. Org. Biomol. Chem. 2008, 6, 36–47.
doi:10.1039/B711494J
13.Leber, P. A.; Baldwin, J. E. Acc. Chem. Res. 2002, 35, 279–287.
doi:10.1021/ar010100p
14.Bronson, J. J.; Danheiser, R. L. In Comprehensive Organic Synthesis,
1st ed.; Trost, B. M.; Flemming, I.; Paquette, L. A., Eds.; Pergamon
Press: Oxford, 1991; pp 1016 ff.
15.Matz, J. R.; Cohen, T. Tetrahedron Lett. 1981, 22, 2459–2462.
doi:10.1016/S0040-4039(01)92932-6
16.Danheiser, R. L.; Martinez-Davila, C.; Sard, H. Tetrahedron 1981, 37,
3943–3950. doi:10.1016/S0040-4020(01)93268-5
17.Cohen, T.; Bhupathy, M.; Matz, J. R. J. Am. Chem. Soc. 1983, 105,
520–525. doi:10.1021/ja00341a035
Supporting Information
Supporting Information File 1
Detailed experimental procedures.
18.Huston, R.; Rey, M.; Dreiding, A. S. Helv. Chim. Acta 1984, 67,
1506–1514. doi:10.1002/hlca.19840670614
19.Huston, R.; Rey, M.; Dreiding, A. S. Helv. Chim. Acta 1982, 65,
451–461. doi:10.1002/hlca.19820650203
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-72-S1.pdf]
20.Huston, R.; Rey, M.; Dreiding, A. S. Helv. Chim. Acta 1982, 65,
1563–1575. doi:10.1002/hlca.19820650530
Supporting Information File 2
21.Danheiser, R. L.; Gee, S. K.; Sard, H. J. Am. Chem. Soc. 1982, 104,
7670–7672. doi:10.1021/ja00390a054
NMR spectral data for unknown compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-72-S2.pdf]
22.Paquette, L. A.; Colapret, J. A.; Andrews, D. R. J. Org. Chem. 1985,
50, 201–205. doi:10.1021/jo00202a012
23.Paquette, L. A.; Andrews, D. R.; Springer, J. P. J. Org. Chem. 1983,
48, 1147–1149. doi:10.1021/jo00155a059
24.Ji, X.; Wang, Q.; Goeke, A. Chem. Commun. 2010, 46, 8845–8847.
doi:10.1039/c0cc02694h
References
1. Lee-Ruff, E.; Mladenova, G. Chem. Rev. 2003, 103, 1449–1484.
25.Machiguchi, T.; Hasegawa, T.; Ishiwata, A.; Terashima, S.;
Yamabe, S.; Minato, T. J. Am. Chem. Soc. 1999, 121, 4771–4786.
doi:10.1021/ja990072u
doi:10.1021/cr010013a
2. Lee-Ruff, E. Synthesis of Cyclobutanes. In The Chemistry of
Cyclobutanes; Rappoport, Z.; Liebman, J. F., Eds.; John Wiley & Sons,
Ltd.: West Sussex, UK, 2005; pp 281–356.
26.Ussing, B. R.; Hang, C.; Singleton, D. A. J. Am. Chem. Soc. 2006, 128,
7594–7607. doi:10.1021/ja0606024
doi:10.1002/0470864028.ch8
27.Rey, M.; Roberts, S.; Dieffenbacher, A.; Dreiding, A. S.
Helv. Chim. Acta 1970, 53, 417–432. doi:10.1002/hlca.19700530223
28.Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T. J.;
Li, T.-T.; Faulkner, D. J.; Petersen, M. R. J. Am. Chem. Soc. 1970, 92,
741–743. doi:10.1021/ja00706a074
3. Brady, W. T. Synthesis 1971, 415–422. doi:10.1055/s-1971-21750
4. Ali, S. M.; Lee, T. V.; Roberts, S. M. Synthesis 1977, 155–166.
doi:10.1055/s-1977-24302
5. Moore, H. W.; Gheorghiu, M. D. Chem. Soc. Rev. 1981, 10, 289–328.
doi:10.1039/CS9811000289
29.Daub, G. W.; Edwards, J. P.; Okada, C. R.; Allen, J. W.; Maxey, C. T.;
Wells, M. S.; Goldstein, A. S.; Dibley, M. J.; Wang, C. J.;
Ostercamp, D. P.; Chung, S.; Cunningham, P. S.; Berliner, M. A.
J. Org. Chem. 1997, 62, 1976–1985. doi:10.1021/jo9614250
6. Trost, B. M. Sulfuranes in organic reactions and synthesis. In New
Concepts I; Davison, A.; Dewar, M. J. S., Eds.; Topics in Current
Chemistry, Vol. 41; Springer: Berlin, Heidelberg, 1973; pp 1–29.
doi:10.1007/3-540-06333-1_17
7. Conia, J. M.; Robson, M. J. Angew. Chem. 1975, 87, 505–516.
doi:10.1002/ange.19750871404
Angew. Chem., Int. Ed. Engl. 1975, 14, 473–485.
doi:10.1002/anie.197504731
8. Trost, B. M. Acc. Chem. Res. 1974, 7, 85–92.
doi:10.1021/ar50075a004
9. Wong, H. N. C.; Lau, K.-L.; Tam, K.-F. The application of cyclobutane
derivatives in organic synthesis. In Small Ring Compounds in Organic
Synthesis I; de Meijere, A., Ed.; Topics in Current Chemistry, Vol. 133;
Springer: Berlin, Heidelberg, 1986; pp 83–157.
doi:10.1007/3-540-16307-7_2
10.Moore, H. W.; Decker, O. H. W. Chem. Rev. 1986, 86, 821–830.
doi:10.1021/cr00075a006
656

Beilstein J. Org. Chem. 2012, 8, 650–657.
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.8.72
657