Functionalized cyclobutenes via multicomponent thermal [2 + 2] cycloaddition reactions

Article abstract of DOI:10.1021/ol051675f

(Chemical Equation Presented) Enamine [2 + 2] cycloadditions can be achieved in useful yields simply by stirring a mixture of an aldehyde, diethylamine, a dialkyl fumarate, and potassium carbonate in acetonitrile at 25°C, conditions that are compatible with the presence of a potential leaving group on the β-position of the intermediate enamine. Methylation and elimination of the product cyclobutanes completes a mild nonphotochemical route to functionalized cyclobutenes.

Full text of DOI:10.1021/ol051675f

ORGANIC
LETTERS
2
005
Vol. 7, No. 19
233-4236
Functionalized Cyclobutenes via
4
Multicomponent Thermal [2
Cycloaddition Reactions
+ 2]
Helen M. Sheldrake, Timothy W. Wallace,* and Craig P. Wilson
School of Chemistry, The UniVersity of Manchester, Oxford Road,
Manchester M13 9PL, UK
tim.wallace@manchester.ac.uk
Received July 15, 2005
ABSTRACT
Enamine [2
and potassium carbonate in acetonitrile at 25
+
2] cycloadditions can be achieved in useful yields simply by stirring a mixture of an aldehyde, diethylamine, a dialkyl fumarate,
C, conditions that are compatible with the presence of a potential leaving group on the -position
°
â
of the intermediate enamine. Methylation and elimination of the product cyclobutanes completes a mild nonphotochemical route to functionalized
cyclobutenes.
The unique features of the cyclobutene ring have provided
a focus for the development of some fundamental structural
principles over the years, notably those that underpin the
by the substitution patterns that emerge from the [2 + 2]
thermal cycloadditions of enamines to electron-deficient
alkenes, a process studied in depth by Brannock et al. some
1
8
electrocyclization reactions. This has in turn ensured a
40 years ago and occasionally exploited for cyclobutene
2
,3
9
sustained interest in the preparation of cyclobutenes and
synthesis. We chose to reevaluate this process and herein
4
10
their exploitation in synthesis, e.g., as diene precursors.
report that it can be run as a multicomponent reaction under
5
Our interest in this area led us to seek an alternative to
the [2 + 2] photoaddition methods that have traditionally
(
2) (a) Carbocyclic Four-Membered Ring Compounds, Houben-Weyl
Methods of Organic Chemistry; de Meijere, A., Ed.; Thieme: Stuttgart,
997; Vol. 17f, E17e-f. (b) Negishi, E.-i.; Liu, F.; Choueiry, D.; Mohamud,
M. M.; Silveira, A., Jr.; Reeves, M. J. Org. Chem. 1996, 61, 8325-8328.
c) Liu, F.; Negishi, E.-i Tetrahedron Lett. 1997, 38, 1149-1152. (d)
Maughon, B. R.; Grubbs, R. H. Macromolecules 1997, 30, 3459-3469.
e) Kowalczyk, B. A.; Smith, T. C.; Dauben, W. G. J. Org. Chem. 1998,
6
1
provided access to key intermediates such as 1-3, from
5
which various targets (e.g., geometrically pure polyenes,
(
7
nucleoside analogues ) can be prepared. We were attracted
(
6
3, 1379-1389. (f) Kn o¨ lker, H.-J.; Baum, G.; Schmitt, O. Tetrahedron Lett.
(
1) (a) Woodward, R. B.; Hoffmann, R. Angew. Chem., Int. Ed. Engl.
1998, 39, 7705-7708. (g) Limanto, J.; Snapper, M. L. J. Org. Chem. 1998,
63, 6440-6441. (h) Barbero, A.; Cuadrado, P.; Garcia, C.; Rincon, J. A.;
Pulido, F. J. J. Org. Chem. 1998, 63, 7531-7533.
(3) For recent developments in [2 + 2] photoaddition methodology,
see: (a) Bradford, C. L.; Fleming, S. A.; Ward, S. C. Tetrahedron Lett.
1995, 36, 4189-4192. (b) Booker-Milburn, K. I.; Cowell, J. K.; Delgado
Jim e´ nez, F.; Sharpe, A.; White, A. J. Tetrahedron 1999, 55, 5875-5888.
(c) White, J. D.; Kim, J.; Drapela, N. E. J. Am. Chem. Soc. 2000, 122,
8665-8671.
1
969, 8, 781-853. (b) Marvell, E. N. Thermal Electrocyclic Reactions;
Academic Press: New York, 1980; Chapter 5, pp 124-213. (c) Rondan,
N. G.; Houk, K. N. J. Am. Chem. Soc. 1985, 107, 2099-2111. (d) Dolbier,
W. R.; Koroniak, H.; Houk, K. N.; Sheu, C. Acc. Chem. Res. 1996, 29,
4
2
71-477. (e) Gourdel-Martin, M.-E.; Huet, F. J. Org. Chem. 1997, 62,
166-2172. (f) Murakami, M.; Miyamoto, Y.; Ito, Y. Angew. Chem., Int.
Ed. 2001, 40, 189-190. (g) Lee, P. S.; Zhang, X.; Houk, K. N. J. Am.
Chem. Soc. 2003, 125, 5072-5079.
1
0.1021/ol051675f CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/25/2005

and 7 are stirred with the diester 8 and potassium carbonate
in acetonitrile at room temperature. The results using this
mild and straightforward procedure are shown in Table 1.
Table 1. One-Pot Access to Cyclobutane-1,2-dicarboxylatesa
Figure 1. Synthetically useful cyclobutene derivatives.
mild conditions that are compatible with the presence of a
potential leaving group, viz., a protected hydroxyl, in the
enamine component, making it a simple and convenient
source of 2-cyclobutene-1,2-dicarboxylates of the form 4.
8
In initial experiments we used the conventional method,
reacting enamines 5a-c, prepared by condensation of the
respective aldehydes 6a-c and diethylamine 7a, with the
fumarate 8a (Scheme 1). Although quantities of the desired
Scheme 1. Reactions of Enamines 5 with Dimethyl Fumaratea
aldehyde amine
isolated products
(yield %)b
entry
(mmol)
(equiv) ester
method
1
2
3
4
5
6
7
8
9
6a (2.2) 7a (2)
8a
8a
8a
8b
8c
8a
8a
8a
8a
8a
9 (65), 16 (15)
10 (64), 17 (9)
10 (62), 17 (16)
12 (63), 18 (10)
A
A
B
A
A
A
A
A
B
A
6b (18)
7a (2)
6b (0.6) 7a (1)
6b (0.7) 7a (2)
6b (0.6) 7a (2)
c
10 (65)
a
2 3
Enamines prepared with K CO using the method in ref 8. All
6c (0.9)
6d (15)
7a (2)
7a (2)
11 (39)
13 (58)
b
yields based on starting aldehyde 6. The enamine was distilled.
c
d
d
c,e
6d (0.9) 7b (1)
6d (0.9) 7b (1)
6e (1.4) 7a (2)
14 (36), 19b (36)
c
14 (61)
products 9, 10, and 11 were obtained, in our hands the
sequence suffered from irreproducibility associated with
manipulating the enamines, especially 5b and 5c.
To address the problems associated with the isolation of
enamines, we developed a one-pot, multicomponent variant
of these cycloadditions in which the enamine precursors 6
10
15 (26)
a
Method A: a mixture of 6, 7, K2CO3 (1 mol per mol of 7), and 8 (1.2
mol per mol of 6) in MeCN (1 mL per mmol of 6) was stirred at room
temperature for 2-3 d. Method B: as method A, but with 8 added after 1
h. Yield based on 6. c No other products were investigated. The amine
b
d
e
was added as a 2 M solution in THF. Yield based on 8a.
(
4) For examples, see: (a) Namyslo, J. C.; Kaufmann, D. E. Chem. ReV.
The initial targets 9-11 were obtained in improved and
consistent yields working on various scales (entries 1-6).
The products with fumarate 8a and maleate 8c (entry 5) were
2
4
7
003, 103, 1485-1537. (b) Paquette, L. A.; Geng, F. Org. Lett. 2002, 4,
547-4549. (c) Geng, F.; Liu, J.; Paquette, L. A. Org. Lett. 2002, 4, 71-
3. (d) Nicolaou, K. C.; Vega, J. A.; Vassilikogiannakis, G. Angew. Chem.,
Int. Ed. 2001, 40, 4441-4445.
8
,11
(5) (a) Binns, F.; Hayes, R.; Ingham, S.; Saengchantara, S. T.; Turner,
the same, a feature of this type of reaction
that can be
R. W.; Wallace, T. W. Tetrahedron 1992, 48, 515-530. (b) Binns, F.;
Hayes, R.; Hodgetts, K. J.; Saengchantara, S. T.; Wallace, T. W.; Wallis,
C. J. Tetrahedron 1996, 52, 3631-3658.
attributed to the rapid isomerization of maleate into fumarate
12
on contact with the enamine or a related species. The minor
(6) (a) Bloomfield, J. J.; Owsley, D. C. Org. Photochem. Synth. 1976,
stereoisomers formed in the cycloadditions with 6a and 6b
2
, 36-40 and references therein. (b) Gauvry, N.; Comoy, C.; Lescop, C.;
Huet, F. Synthesis 1999, 574-576.
7) (a) Jung, M. E.; Sledeski, A. W. J. Chem. Soc., Chem. Commun.
(
1
993, 589-591. (b) Gourdel-Martin, M.-E.; Comoy, C.; Huet, F. Tetra-
hedron: Asymmetry 1999, 10, 403-410. (c) Pichon, C.; Hubert, C.;
Alexandre, C.; Huet, F. Tetrahedron: Asymmetry 2000, 11, 2429-2434.
(d) Hubert, C.; Alexandre, C.; Aubertin, A.-M.; Huet, F. Tetrahedron 2002,
5
8, 3775-3778. (e) Gharbaoui, T.; Legraverend, M.; Bisagni, E. Tetrahe-
dron Lett. 1992, 33, 7141-7144.
8) Brannock, K. C.; Bell, A.; Burpitt, R. D.; Kelly, C. A. J. Org. Chem.
964, 29, 801-812.
9) (a) Ichihara, A.; Kimura, R.; Yamada, S.; Sakamura, S. J. Am. Chem.
(
1
(
Soc. 1980, 102, 6353-6355. (b) Johnson, C. R.; De Jong, R. L. J. Org.
Chem. 1992, 57, 594-599. (c) Kitayama, T.; Kawauchi, T.; Ueda, N.; Kniep,
C. S.; Shin, W. S.; Padias, A. B.; Hall, H. K., Jr. Macromolecules 2002,
3
5, 1591-1598.
10) Bienaym e´ , H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem. Eur. J.
000, 6, 3321-3329.
(
Figure 2. Structures relating to Table 1 and other experiments.
2
4234
Org. Lett., Vol. 7, No. 19, 2005

Scheme 2. Elimination Sequences with 9, 10, 16, and 17a
a
4 2 3 6
CAN ) Ce(NH ) (NO )
. b Not isolated pure.
(
and probably 6d) were not observed when using preformed
6d, the use of the hindered amine 7c led mainly to the
elimination product 20a (63%), whereas the use of piperidine
7d gave 19c and 20a as the only identifiable products.
For the dual purpose of determining the structures of the
cycloadducts listed in Table 1 and establishing access to
cyclobutenes of the desired type, the cycloadducts derived
from aldehydes 6a and 6b were taken through Hofmann
elimination sequences using mild modifications of known
enamines (Scheme 1). Further experiments revealed that the
efficiency of the multicomponent method is finely balanced.
Imine formation with diethylamine 7a is evidently rapid,
allowing enamine formation and [2 + 2] cycloaddition to
compete successfully with the conjugate addition of the
amine to the fumarate to produce 19a. On changing to
dimethylamine 7b, conjugate addition to give 19b and
elimination to give 20a become more significant (entry 8).
These side reactions are inhibited and the yield of 14
improved if the introduction of the fumarate 8a is delayed
for 1 h (entry 9). However, such a delay provided no obvious
benefit with 7a as the amine (entry 3).
In other experiments with the aldehyde 6b, the use of an
additional equivalent of the amine 7a merely promoted the
formation of 19a, while attempts to use less solvent caused
a considerable rise in the yields of the usual byproducts 20b
and 21. These compounds are presumed to arise via the
elimination of 20b from the zwitterion 22 formed in the first
step of the [2 + 2] addition process. In experiments with
8
,9b
procedures (Scheme 2). Thus, the methylation of 9 gave
a crystalline salt 23a whose stereochemistry was confirmed
1
3
by X-ray crystallography. The corresponding salt 23b
obtained from 10 was not crystalline but is presumed to be
analogous to 9 on the basis of the following observations.
Treating either of the salts 23 with potassium carbonate
in acetonitrile gave the respective cyclobutene 24 in good
yield, and heating 24a or 24b to 100-110 °C brought about
thermal electrocyclic ring opening, which yielded a single
diene 25 in quantitative yield. The (Z,E)-geometry of 25a
1
and 25b, evident from their H NMR spectra (H-1′ at δ 6.1-
6.4 ppm), is consistent with the 1,4-trans relationship in 24a14
(
11) (a) Risaliti, A.; Valentin, E.; Forchiassin, M. Chem. Commun. 1969,
(13) Crystallographic data (excluding structure factors) for compound
22a have been deposited with the Cambridge Crystallographic Data Centre
as supplementary publication number CCDC 276887. Copies of the data
can be obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge,CB21EZ,U.K.(fax: +44-1223-336033ore-mail: deposit@ccdc.cam.ac.uk).
2
4
33-234. (b) Lewis, F. D.; Ho, T.-I.; DeVoe, R. J. J. Org. Chem. 1980,
5, 5283-5286.
(12) Cook, A. G.; Voges, A. B.; Kammrath, A. E. Tetrahedron Lett.
2
001, 42, 7349-7552.
Org. Lett., Vol. 7, No. 19, 2005
4235

and 24b. When the cycloadducts 16 and 17 were taken
through the same elimination sequence, the resulting cy-
clobutenes 27 were different from their analogues 24 and
also more prone to electrocyclic ring opening. This lability
of 27 compared to 24 and the exclusive (E,E)-geometry of
the derived dienes 28 (H-1′ at δ 7.3-7.5 ppm) is consistent
with a 1,4-cis relationship in 27 and illustrates the ability of
cyclobutenes bearing substituents with complementary con-
rotatory preferences to undergo thermal electrocyclic ring-
5
opening with enhanced rates and stereoselectivity. The 1,4-
cis relationship in 27b was confirmed by its ready conversion
into the lactone 29.
Although the above sequences confirm the 1,4-cis nature
of 16 and 17, the other stereochemical relationships in this
pair are open to question. The structures are tentatively
assigned as depicted on the basis of computer modeling of
the four possible 1,4-cis diastereoisomers for each (Figure
3). The structures A and E are predicted to possess the lowest
minimum steric energies in their respective series and would
be expected to predominate if formed reversibly or under
product development (i.e., kinetic) control.
Although there is evidence in some cases that both steps
1
1
of the enamine [2 + 2] cycloaddition are reversible, we
speculate that the 1,4-cis structures 16 and 17 formed in these
reactions are a consequence of the presence of (Z)-enamines
in the reaction mixtures, since they were not observed in
reactions with isolated enamines. We saw no decomposition
or equilibration of 9 and 16 or 10 and 17 when they were
subjected to the conditions of the one-pot procedure, indicat-
ing that the first step of the cycloaddition process, i.e., the
formation of 22, is not significantly reversible under these
conditions. However, reversibility in the second (ring closure)
step is a distinct possibility.
Figure 3. Calculated minimum steric energies (kJ mol-1) of the
1,4-cis diastereoisomers of 16 and 17 (Macromodel 8.0, MM3).
access to cyclobutenes with the functionality normally
generated using alkyne [2 + 2] photoadditions. Various
mechanistic aspects and the synthetic potential of this
methodology are under investigation in our laboratory.
In summary, thermal [2 + 2] cycloadditions of aldehyde-
derived enamines to fumarates can be carried out in multi-
component fashion by stirring the aldehyde, secondary amine,
and fumarate components with potassium carbonate in
acetonitrile. The procedure is a convenient source of
Acknowledgment. We thank the EPSRC for financial
support, and are also grateful to Stacy Lloyd for carrying
out preliminary experiments and to Robin Pritchard for the
X-ray analysis.
4-substituted 3-dialkylaminocyclobutane-1,2-dicarboxylates
that can be converted into functionalized cyclobutenes via
methylation and elimination. The mildness of the overall
sequence is compatible with the use of protected forms of
Supporting Information Available: Experimental pro-
cedures and characterization of compounds, including X-ray
data for compound 23a and molecular modeling parameters
3-hydroxypropanal as the starting aldehyde and thus provides
(CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
(
14) The diethyl ester analogous to 24a was reported by Ichihara et al.,9a
8
who wrongly attributed its preparation to Brannock et al.
OL051675F
4236
Org. Lett., Vol. 7, No. 19, 2005