Asymmetric synthesis of functionalized, monocyclic chlorocyclobutenes

Article abstract of DOI:10.1021/ol101559b

Figure presented. The selective synthesis of a variety of stereopure monocyclic chlorocyclobutenes is described. These derivatives could be coupled with Grignard reagents; two dienes from coupling with vinylmagnesium bromide reacted smoothly with maleic anhydride to yield illudol-related [4 + 2] cycloadducts.

Full text of DOI:10.1021/ol101559b

ORGANIC
LETTERS
2010
Vol. 12, No. 18
3994-3997
Asymmetric Synthesis of Functionalized,
Monocyclic Chlorocyclobutenes
Benjamin Darses, Andrew E. Greene, and Jean-Franc¸ois Poisson*
De´partement de Chimie Mole´culaire (SERCO) UMR-5250, ICMG FR-2607, CNRS
UniVersite´ Joseph Fourier, BP 53, 38041 Grenoble Cedex 9, France
jean-francois.poisson@ujf-grenoble.fr
Received July 7, 2010
ABSTRACT
The selective synthesis of a variety of stereopure monocyclic chlorocyclobutenes is described. These derivatives could be coupled with
Grignard reagents; two dienes from coupling with vinylmagnesium bromide reacted smoothly with maleic anhydride to yield illudol-related
[4 + 2] cycloadducts.
The synthesis of functionalized monocyclic cyclobutenes has
received relatively little attention over the years1 despite their
potential as building blocks in organic synthesis.2 As far as
halocyclobutenes (vinylic) derivatives are concerned, the situ-
ation is particularly striking: there are few reports1a-e,h,3 on
the preparation of functionalized monocyclic halocy-
clobutenes; moreover, such compounds have invariably been
prepared in racemic form (as have been the vast majority of
cyclobutenes synthesized to date4). Monocyclic halocy-
clobutene derivatives should be readily susceptible to further
elaboration, especially through coupling reactions, and thus
a general enantioselective approach to these compounds
would be of particular interest.
We wondered whether it might be possible to transform the
dichlorocyclobutanones stemming from the diastereoselective
cycloaddition of dichloroketene (DCK) to chiral enol ethers5
into chlorocyclobutenes and under conditions mild enough to
avoid electrocyclic ring opening of the products once obtained.
Our plan, drawing on an earlier isolated report,3a was to convert
cyclobutanones II into the dichlorocyclobutanol derivatives III
(R2 ) electron-withdrawing group); a mild and selective
reductive elimination might then furnish the chlorocyclobutenes
IV (Figure 1).
(1) Other than enol and squaric acid derivatives. For some methods of
preparation, see: (a) Caserio, M. C.; Simmons, H. E., Jr.; Johnson, A. E.;
Roberts, J. D. J. Am. Chem. Soc. 1960, 82, 3103–3106. (b) Sullivan, R.;
Lacher, J. R.; Park, J. D. J. Org. Chem. 1964, 29, 3664–3668. (c) Steinmetz,
R.; Hartmann, W.; Schenck, G. O. Chem. Ber 1965, 98, 3854–3873. (d)
Snider, B. B.; Roush, D. M.; Rodini, D. J.; Gonzalez, D.; Spinell, D. J.
Org. Chem. 1980, 45, 2773–2785. (e) Goodman, M. M.; Shoup, T. PCT
Int. Appl. WO 9717092 A1 19970515, 1997. (f) Gourdel-Martin, M.-E.;
Huet, F. J. Org. Chem. 1997, 62, 2166–2172. (g) Takahashi, T.; Shen, B.;
Nakajima, K.; Xi, Z. J. Org. Chem. 1999, 64, 8706–8708. (h) Hamura, T.;
Kakinuma, M.; Tsuji, S.; Matsumoto, T.; Suzuki, K. Chem. Lett. 2002, 748–
749. (i) Liu, Y.; Liu, M.; Song, Z. J. Am. Chem. Soc. 2005, 127, 3662–
3663. (j) Fu¨rstner, A.; A¨ıssa, C. J. Am. Chem. Soc. 2006, 128, 6306–6307.
(k) Shi, M.; Liu, L.-P.; Tang, J. J. Am. Chem. Soc. 2006, 128, 7430–7431.
(l) Debleds, O.; Campagne, J.-M. J. Am. Chem. Soc. 2008, 130, 1562–
1563. (m) Tian, G.-Q.; Yuan, Z.-L.; Zhu, Z.-B.; Shi, M. Chem. Commun.
2008, 2668–2670. (n) Xu, H.; Zhang, W.; Shu, D.; Werness, J. B.; Tang,
W. Angew. Chem., Int. Ed. 2008, 47, 8933–8936. (o) Masarwa, A.; Fu¨rstner,
A.; Marek, I. Chem. Commun. 2009, 5760–5762. (p) Barluenga, J.; Riesgo,
L.; Lopez, L. A.; Rubio, E.; Tomas, M. Angew. Chem., Int. Ed. 2009, 48,
7569–7572. (q) Lopez-Carillo, V.; Echavarren, A. J. Am. Chem. Soc. 2010,
132, 9292–9294.
(3) For the synthesis of some polycyclic halocyclobutenes, see: (a)
Hassner, A.; Fletcher, V. R. Tetrahedron Lett. 1970, 58, 5053–5056. (b)
Ohkita, M.; Ando, K.; Tsuji, T. Chem. Commun. 2001, 2570–2571. (c)
Fu¨rstner, A.; Schlecker, A.; Lehmann, C. Chem. Commun. 2007, 4277–
4279. (d) Allen, A.; Villeneuve, K.; Cockburn, N.; Fatila, E.; Riddell, N.;
Tam, W. Eur. J. Org. Chem. 2008, 4178–4192.
(4) For some routes to enantioenriched cyclobutenes, see: (a) Villeneuve,
K.; Tam, W. Angew. Chem., Int. Ed. 2004, 43, 610–613. (b) Shibata, T.;
Takami, K.; Kawachi, A. Org. Lett. 2006, 8, 1343–1345. (c) Ishihara, K.;
Fushimi, M. J. Am. Chem. Soc. 2008, 130, 7532–7533, and refs 1o, 2b,
and 3a.
(2) For reviews on cyclobutane derivatives, see: (a) The Chemistry of
Cyclobutanes; Rappoport, Z., Liebman, J. F., Eds.; John Wiley & Sons,
Ltd.: West Sussex, England, 2005; Vols. 1 and 2. (b) Lee-Ruff, E.;
Mladenova, G. Chem. ReV. 2003, 103, 1449–1483.
(5) Darses, B.; Greene, A. E.; Coote, S. C.; Poisson, J.-F. Org. Lett.
2008, 10, 821–824.
10.1021/ol101559b  2010 American Chemical Society
Published on Web 08/19/2010

rather unstable corresponding dichlorocyclobutanone (dr ca.
95:5). The crude cycloadduct, on treatment with sodium
borohydride, afforded a complex mixture of products, from
which cyclobutanol 2a could be isolated in low yield (22%
for 2 steps). The use of Dibal-H did not improve the results.
Fortunately, however, lithium aluminum hydride at 0 °C was
more rewarding, affording the cyclobutanol 2a in 73% yield;
better yet, direct addition of the supernatant from the
cycloaddition reaction mixture to an ethereal solution of
LiAlH4 at 0 °C led to cyclobutanol 2a in 88% yield for the
2 steps (entry 1). Alcohol 2a was obtained as a single isomer,
all cis, resulting from hydride attack on the less hindered
face of the molecule.7
Figure 1. Chlorocyclobutenes IV from enol ethers I.
We began our study with chiral enol ether 1a (Table 1).6
Reaction of this ether with dichloroketene, generated from
trichloroacetyl chloride with zinc-copper couple, led to the
This optimized procedure was next applied to a variety
of Stericol-derived enol ethers (1b-g, Table 1). It proved
efficient with the benzyl-, allyl-, and benzyloxymethyl-
substituted enol ethers 1b-d (entries 2-4), affording the
corresponding cyclobutanols in 66-85% yields for the 2
steps. Unexpectedly, the same procedure when applied to
the triisopropylsilyloxymethyl enol ether 1e led to cleavage
of the silyl ether to give the corresponding diol in low yield
(36%). Fortunately, with this substrate sodium borohydride
gave a satisfactory result, producing cyclobutanol 2e in 71%
yield (2 steps). Enol ether 1f underwent surprisingly clean
conversion into cyclobutanol 2f under the general conditions,
without detectable reduction of the benzoyloxy group (entry
6). Finally, the “naked” enol ether 1g produced cyclobutanol
2g, albeit in slightly lower yield (62%), also under the general
conditions. In every case, the cyclobutanol 2 was isolated
as a single diastereoisomer.
Table 1. Cyclobutanols Synthesisa
With this effective procedure in hand, selective reductive
elimination in the dichlorocyclobutanols 2 was next ad-
dressed beginning with 2a. This alcohol was first transformed
into the corresponding mesylate 3a and triflate 3a′ (95% and
88% yields, respectively).8 These substrates were then
subjected to a number of reductive elimination procedures,
which indicated zinc metal to be the most promising reducing
agent (Table 2). Addition of an ethereal solution of mesylate
3a to a suspension of zinc-copper couple in acidic methanol,
followed by heating at 55 °C under microwave irradiation,
led to chlorocyclobutene 4a in 80% yield (entry 1). Also
formed, however, was a small amount of diene (ring-opened
product). By conducting the same reaction in refluxing
ether-methanol without microwave irradiation, though, the
problem of electrocyclic ring opening could be suppressed
and 4a obtained in somewhat better yield (Table 2, entry 2).
Finally, the cleanest and most efficient conversion was
produced with a suspension of zinc-copper couple in
(6) All enol ethers used in this work were obtained from Stericol
[1-(2,4,6-triisopropylphenyl)ethanol] through the dichloroenol and ynol
ethers, following a procedure similar to that described in. (a) Kann, N.;
Bernardes, V.; Greene, A. E. Org. Synth 1997, 74, 13–22. For the mechanism
of the formation of ynol ethers from dichloroenol ethers, see: (b) Darses,
B.; Milet, A.; Philouze, C.; Greene, A. E.; Poisson, J.-F. Org. Lett. 2008,
10, 4445–4447.
(7) The relative stereochemistry in 2a has been assigned from consider-
able antecedent for the face of the cycloaddition and by NOE experiments
for the face of the reduction.
(8) Reductive elimination was also attempted directly on 2a with
chromium perchlorate; however, a mixture of products containing only a
minor amount of cyclobutene 4a was produced.
a
SStOH ) (S)-(-)-1-(2,4,6-triisopropylphenyl)ethanol. RStOH )
(R)-(+)-1-(2,4,6-triisopropylphenyl)ethanol. b Cl3CCOCl, Zn/Cu, Et2O, 20
°C, then LiAlH4, Et2O, 0 °C. c After flash chromatography (in all cases, dr
>98:2). d Cl3CCOCl, Zn/Cu, Et2O, 20 °C, then NaBH4, EtOH, 0 °C.
Org. Lett., Vol. 12, No. 18, 2010
3995

Table 2. Chlorocyclobutene 4a from Alcohol 2a
Table 3. Chlorocyclobutenes 4a-g from Alcohols 2a-g
entry substrate dechlorination conditions yield of 4a (%)a
1
2
3
3a
3a
3a
Zn/Cu, MeOH/NH4Clsat,
Et2O, µ-wave, 55 °C
Zn/Cu, MeOH/NH4Clsat,
80
84
93
Et2O, reflux
Zn/Cu, MeOH/NH4Clsat,
Et2O, ultrasound, 35 °C
t-BuLi, THF, -78 °C
Zn/Cu, MeOH/NH4Clsat,
Et2O, ultrasound, 35 °C
t-BuLi, THF, -78 °C
4
5
3a
3a′
86
89
6
3a′
94
a Yield from 3a or 3a′ after chromatography.
ether-methanol in the presence of ammonium chloride at
35 °C under sonication, which afforded chlorocyclobutene
4a in an excellent 93% yield (88% for the 2 steps, entry 3).
Alternative conditions for avoiding the formation of the
ring-opened diene were also examined. Since R-deprotona-
tion appeared unlikely, chlorine-lithium exchange with tert-
butyllithium at low temperature seemed possible. The
addition of 2 equiv of tert-butyllithium to mesylate 3a in
THF at -78 °C indeed led to the desired product in high
yield (entry 4).
With the triflate derivative 3a′, both methods (Zn/Cu and
t-BuLi) afforded 4a in yields similar to those above (entries
5 and 6); however, since formation of the mesylate was more
efficient than that of the triflate and the derivative was more
stable, mesylates were subsequently used.
Thus, two complementary reductive elimination methods
for the formation of chlorocyclobutenes have been developed,
one using zinc metal that requires near ambient temperature
and the other employing tert-butyllithium at -78 °C.
These optimized methods were next applied to alcohols
2b-g (Table 3). The benzyl-substituted chlorocyclobutene
4b could be obtained from alcohol 2b in 78% overall yield
(2 steps, entry 2; 65% from the enol ether). Similarly, the
allyl- and benzyloxymethyl-substituted cyclobutanols 2c and
2d afforded the corresponding cyclobutenes 4c and 4d in
high yields (entries 3 and 4). The mesylate from cyclobutanol
2e, however, under the Zn-Cu reductive elimination condi-
tions successful in the above examples, led to a 3.3:1 mixture
of chlorocyclobutene 4e and ring-opened diene. As expected,
though, the chlorine-lithium exchange procedure generated
4e in excellent yield, without a trace of ring-opened product
(entry 5). The mesylate from cyclobutanol 2f could be
transformed uniquely into chlorocyclobutene 4f, again by
using Zn-Cu (90%, entry 6), but that derived from the less-
substituted cyclobutanol 2g was better converted into the
thermally sensitive chlorocyclobutene 4g with tert-butyl-
lithium at -78 °C (82%, entry 7).
a Yield of isolated product after flash chromatography. b Zn-Cu, Et2O,
MeOH/NH4Clsat, ultrasound, 35 °C. c t-BuLi (2 equiv), THF, -78 °C.
Importantly, the chiral control group can be readily and
selectively cleaved in these chlorocyclobutenes, leaving a
synthetically useful hydroxyl, as illustrated in Scheme 1.
Scheme 1. Stericol Cleavage
Significant also is that these vinylic choride derivatives
are good Kumada-Corriu coupling9 partners: reaction of
ent-4a with phenylmagnesium bromide in the presence of
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Org. Lett., Vol. 12, No. 18, 2010

PdCl2(PPh3)2 gave the phenyl-substituted cyclobutene 6 in
excellent yield (89%) and those of ent-4a and 4c with
vinylmagnesium bromide yielded the vinyl-substituted cy-
clobutenes 7a and 7c (Scheme 2). These dienes were prone
cycloadducts 8a and 8c, respectively, in 52% overall yield
in each case. It should be noted that this sequence of reactions
constitutes a potential approach to the illudol family of
natural products.
In conclusion, we have described the first general, asym-
metric entry to (poly)functionalized monocyclic chlorocy-
clobutenes. The cyclobutenes are formed in good overall
yields and are sufficiently stable toward ring opening to allow
Kumada-Corriu coupling with aryl and vinyl Grignard
reagents. We expect that there will be other applications of
this chemistry.
Scheme 2. Elaboration of Chlorocyclobutenes 4a,c
Acknowledgment. We thank Dr. J. Einhorn (UJF) for his
interest in our work, the CNRS and the French Ministry of
Research for financial support (UMR 5250), and the French
Ministry of Research for a fellowship (to B.D.).
Supporting Information Available: Complete charac-
1
terization data and H and 13C NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL101559B
(9) For examples of vinylic chloride coupling reactions, see: (a)
Ramiandrasoa, P.; Bre´hon, B.; Thivet, A.; Alami, M.; Cahiez, G. Tetra-
hedron Lett. 1997, 14, 2447–2450. (b) Tan, Z.; Negishi, E. Angew. Chem.,
Int. Ed. 2006, 45, 762–765. (c) Lemay, A. B.; Vulic, K. S.; Ogilvie, W. W.
J. Org. Chem. 2006, 71, 3615–3618.
to ring opening, however, and thus immediately subjected
to reaction with maleic anhydride to afford the [4 + 2] endo
Org. Lett., Vol. 12, No. 18, 2010
3997