Synthesis of functionalized cyclobutene derivatives via selective sN2' reaction of dichlorocyclobutenes

Article abstract of DOI:10.1246/cl.2002.748

Dichlorocyclobutenone acetals, available via the cycloaddition of dichloroketene and alkynes followed by acetalization, undergo selective S_N2' attack by various nucleophiles to give a variety of functionalized cyclobutene derivatives in high yi

Full text of DOI:10.1246/cl.2002.748

748
Chemistry Letters 2002
Synthesis of Functionalized Cyclobutene Derivatives via Selective
SN2’ Reaction of Dichlorocyclobutenes
Toshiyuki Hamura, Michiko Kakinuma, Shinsuke Tsuji, Takashi Matsumoto, and Keisuke Suzukiꢀ
Department of Chemistry, Tokyo Institute of Technology and
CREST, Japan Science and Technology Corporation (JST), O-okayama, Meguro-ku, Tokyo 152-8551
(Received April 26, 2002; CL-020365)
Dichlorocyclobutenone acetals, available via the cyclo-
and stirred for 1 h. After quenching with water, purification by
addition of dichloroketene and alkynes followed by acetalization,
undergo selective SN2’ attack by various nucleophiles to give a
variety of functionalized cyclobutene derivatives in high yields.
silica-gel flash column chromatography gave the SN2’ product
5a8 in quantitative yield (eq 3). None of the SN2 product, if any,
was detected. The corresponding reaction of 4b also gave the
SN2’ product 5b in high yield.
Cyclobutene derivatives display various useful reactivities in
organic synthesis.1 In this regard, squarate esters 1 have been
extensively used, due to the ability to assemble one or two
nucleophilic components followed by reorganization.1 However,
less known is the fact that squarates often cause severe contact
dermatitis,2 as experienced in our laboratories.
Interestingly, although the substitution cleanly occurred also
for the silyl congener 4c, the product 5d was without the silyl
group (eq 3). Since tlc assay showed that 5d was already present in
the reaction mixture prior to workup, the formation of 5d could be
rationalized by the protonation by p-CH3OC6H4CH2OH of the
initially formed SN2’ product 5c, via the corresponding silicate
III (Scheme 1).9
We became interested in dichlorocyclobutenone 2 as an
alternative starting point, which is readily available by [2 þ 2]
cycloaddition of alkynes and dichloroketene.3 Although the
oxidation level of 2 is lower than 1, our hope was that two
chlorides in 2 could be used for assemblage of molecules via
nucleophilic displacement, while they are usually just reductively
removed en route to cyclobutene 3.4 Experiments along these
lines revealed a clean and reliable SN2’ reactivity inherent to
protected dichlorocyclobutenones I, reacting with various
nucleophiles uniformly in a site-selective manner,5;6 to give
functonalized cyclobutene derivatives II (eq 1).
Scheme 1.
Three known dichlorocyclobutenones 2a–c7 were converted
to the corresponding ethylene acetals 4a–c (ethylene glycol, cat.
TsOH, benzene, Dean–Stark apparatus).
Products 5a and 5b (eq 3) are particularly attractive, in that
they are convertible to 8a and 8b, which could be viewed as
mono-protected cyclobutenedione derivatives with high syn-
thetic versatility (eq 4). Deprotection of the MPM ether (DDQ,
wet CH2Cl2) in 5a and 5b followed by Swern oxidation gave
mono-acetals 8a and 8b in high yields, respectively.
Acetals 4a–c undergo clean reaction with a variety of
nucleophiles. The reaction of 4a with sodium p-methoxy-
phenylmethoxide is representative: To
a solution of p-
CH3OC6H4CH2OÀNaþ (1.5 equiv NaH, 2.0equiv p-CH3O-
C6H4CH2OH) in DMF was added cyclobutene 4a in DMF at 0 ꢁC,
Other substrate/nucleophile combinations were tested under
similar conditions. Three hetero-nucleophiles (CH3OC6H4OÀ,
Copyright Ó 2002 The Chemical Society of Japan

Chemistry Letters 2002
749
NÀ3 , C6H5SÀ) were reacted with dichlorocyclobutenes 4a–c, and
the results are summarized in Table 1. In general, the reactions
proceeded cleanly to give the corresponding SN2’ products in
excellent yields. Two exceptions were observed for substrate 4b
(R =n-Bu), which failed to react with phenoxide or NaN3 at all.
Repeated attempts under various conditions resulted only in the
recovery of 4b, although the reasons remain unclear.
propynyllithium reacted cleanly with 4a, in the case of the
substrates 4b (R = Bu) and 4c (R = TMS), the expected products
were not obtained at all. Examination under various conditions
were unfruitful.
In summary, we have described a new route to highly
functionalized cyclobutenes by the selective SN2’ reaction of the
dichlorocyclobutene acetals. Further studies are currently under-
way in our laboratories.
Table 1. Reaction of 4a–c with hetero-nucleophiles
References and Notes
1
For selected recent examples, see: a) F. Geng, J. Liu, and L. A.
Paquette, Org. Lett., 4, 71 (2002). b) A. R. Hergueta and H. W.
Moore, J. Org. Chem., 67, 1388 (2002). c) S. T. Perri and H. W.
Moore, J. Am. Chem. Soc., 112, 1897 (1990). d) F. Liu and L. S.
Liebeskind, J. Org. Chem., 63, 2835 (1998). e) R. L. Danheiser, S.
K. Gee, and J. J. Perez, J. Am. Chem. Soc., 108, 806 (1986).
`
2
a) R. Prohens, M. C. Rotger, M. N. Pin˜a, P. M. Deya, J. Morey, P.
Ballester, and A. Costa, Tetrahedron Lett., 42, 4933 (2001). b) A.
Frattasio, M. Germino, S. Cargnello, and P. Patrone, Contact
Dermatitis, 36, 118 (1997).
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4
5
For a review, see: W. T. Brady, Tetrahedron, 37, 2949 (1981).
R. L. Danheiser and S. Savariar, Tetrahedron Lett., 28, 3299 (1987).
For related reactions, see: a) M. C. Caserio, H. E. Simmons, Jr., A.
E. Johnson, and J. D. Roberts, J. Am. Chem. Soc., 82, 3102 (1960).
b) Y. Kitahara, M. C. Caserio, F. Scardiglia, and J. D. Roberts, J.
Am. Chem. Soc., 82, 3106 (1960). c) E. F. Jenny and J. Druey, J. Am.
Chem. Soc., 82, 3111 (1960).
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The SN2’ reactivity of dichlorocyclobutenone 2a in its ‘‘non-
protected’’ form was reported [J. L. Dillon and Q. Gao, J. Org.
Chem., 59, 6868 (1994)]. Our preliminary attempts on the same
reaction with harder nucleophiles such as n-BuLi led to the
competing SN2’ and the carbonyl addition. As described in this
paper, use of the acetal allows the reaction with various
nucleophiles including carbon nucleophiles, thereby significantly
expanding the scope of this class of compounds. We thank one of
the referees for bringing this point to our attention.
a) R. L. Danheiser and H. Sard, Tetrahedron Lett., 24, 23 (1983). b)
R. L. Danheiser, S. Savariar, and D. D. Cha, ‘‘Organic Synthesis,’’
Wiley, New York (1993), Collect. Vol. VIII, pp 82–86. c) A.
Hassner and J. L. Dillon, Jr., J. Org. Chem., 48, 3382 (1983).
A typical procedure: To a suspension of NaH (60% dispersion in
mineral oil, 23.6 mg, 0.59 mmol) in DMF (0.6 mL) was added p-
CH3OC6H4CH2OH (109 mg, 0.789 mmol) in DMF (1.5 mL) at
0 ꢁC, to which was added cyclobutene 4a (101 mg, 0.393 mmol) in
DMF (1.5 mL), and stirred for 1 h. After quenching with water,
products were extracted with Et2O (X3), dried (Na2SO4), and
concentrated in vacuo. The residue was purified by silica-gel flash
column chromatography (hexane/EtOAc ¼ 92=8) to give the SN2’
product 5a (151 mg, quant.). Recrystallization from hexane/Et2O
gave colorless prisms: mp 93.6–94.2 ꢁC. 1H NMR (CDCl3) ꢀ 3.80
(s, 3H), 3.95–4.12 (m, 2H), 4.16–4.24 (m, 2H), 4.62 (s, 2H), 4.91 (s,
1H), 6.89 (d, 2H, J ¼ 8:5 Hz), 7.32 (d, 2H, J ¼ 8:5 Hz), 7.35–7.41
(m, 3H), 7.67–7.71 (m, 2H); 13C NMR (CDCl3) ꢀ 55.3, 65.6, 65.9,
70.9, 83.9, 111.3, 113.8, 125.2, 127.7, 128.5, 129.7, 130.0, 130.2,
144.6, 159.3; IR (neat) 2884, 1611, 1514, 1322, 1043, 948,
700 cmÀ1; Anal. Calcd for C20H19ClO4: C, 66.95; H, 5.34. Found:
C, 66.69; H, 5.41.
The SN2’ reactivity of 4a–c was also observed with carbon
nucleophiles (Table 2). When 4a was treated with n-BuLi (1.2
equiv.) in THF at À78 ꢁC, the SN2’ reaction occurred to give 12a
in quantitative yield. In a similar manner, treatment of 4c with n-
BuLi also gave 12c in 96% yield. However, in the case of the
substrate 4b (R = Bu), yield of the desired SN2’ product 12b was
low, giving an intractable mixture of products, presumably due to
the acidity of the allylic proton, where n-BuLi acted as a base to
induce side reactions.
Other carbon nucleophiles, i.e., vinyl-, and aryllithiums
reacted cleanly with acetals 4a–c (Table 2). In these cases, 4b also
behaved as a good substrate for the SN2’ reaction to give the
corresponding substitution products 13b and 15b in high yields,
respectively. Again with no obvious reason, peculiar lack of
reactivity was seen for the reaction of alkynyllithium. Although
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Table 2. Reaction of 4a–c with carbon nucleophiles
9
The proposed mechanism is supported by the following reaction:
treatment of 12c with NaOMe and MeOD (0.1 equiv NaH, 3.0 equiv
MeOD) in DMF gave the deuterated product 6 (96% D) in 86%
yield.