Synthesis of 3,4-bis(benzylidene)cyclobutenes

Article abstract of DOI:10.1055/s-0030-1260777

The syntheses of several derivatives of 3,4-bis(benzylidene)cyclobutene are reported. Previously unknown 1,2-dibromo-3,4-bis(benzylidene)cyclobutene was obtained through in situ generation of 1,6-diphenyl-3,4-dibromo-1,2,4,5-tetraene followed by electrocy

Full text of DOI:10.1055/s-0030-1260777

LETTER
1519
Synthesis of 3,4-Bis(benzylidene)cyclobutenes
S
ynthesis of 3,4-
e
is(benzyli
b
dene)cyclobu
e
tene
s
cca R. Parkhurst, Timothy M. Swager*
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, MA 02139, USA
Fax +1(617)2537929; E-mail: tswager@mit.edu
Received 25 February 2011
Although 1 is highly reactive, it is possible to synthesize
air-stable analogues by installing electron-withdrawing
groups, thereby reducing antiaromatic character.4 The
most prominent example of this is 1,2-dibromo-3,4-
Abstract: The syntheses of several derivatives of 3,4-bis(ben-
zylidene)cyclobutene are reported. Previously unknown 1,2-dibro-
mo-3,4-bis(benzylidene)cyclobutene was obtained through in situ
generation of 1,6-diphenyl-3,4-dibromo-1,2,4,5-tetraene followed
by electrocyclic ring closure. Ensuing reduction and metal-cata- bis(diphenylmethylene)cyclobutene (2),5 originally syn-
thesized by Toda et al.6 The debrominated derivative 3 is
lyzed cross-coupling provided additional derivatives. The effects of
ring strain on the geometry and electronics of these derivatives were
readily available via reduction with zinc metal in acetic
examined by X-ray crystallography and 1H NMR spectroscopy, re-
acid and is moderately air-stable as compared to 1
spectively.
(Scheme 2).7 This synthetic scheme is limited in scope
Key words: electrocyclic reactions, ring closure, allenes, highly
strained ring systems, metal-catalyzed cross-coupling
and functional-group tolerance, due to its dependence on
the use of tertiary propargyl alcohols and harsh, acidic
conditions. A new scheme is required to access less sub-
stituted derivatives and a wider range of functional
groups.
3,4-Bis(methylene)cyclobutene (1) is a highly strained
and air-sensitive isomer of benzene that was first detected
in 1961 from the Hofmann elimination of 3,4-bis[(trime-
thylammonio)methyl]cyclobutene dihydroxide.1 The rel-
ative thermal stability of derivatives of 1 initially came as
a surprise due to the significant ring strain. As a result,
there has been much fascination with the synthesis and re-
activity of compounds bearing this core structure. Unsub-
stituted 1 can be generated quantitatively through the
thermal rearrangement of 1,5-hexadiyne: an initial [3,3]-
sigmatropic rearrangement affords hexa-1,2,4,5-tetraene,
which undergoes conrotatory [2+2]-electrocyclic ring clo-
sure to yield 1 (Scheme 1).2
Br
Ph
Ph
HO
OH
HBr
Ph
Ph
C
C
Ph
Ph
Ph
Ph
AcOH
Br
Δ
Ph
Ph
Ph
Br
Br
Ph
Ph
Ph
Zn, AcOH
Δ
Ph
Ph
3
2
Scheme 2 Synthesis of 2 and 3 reported by Toda et al.
CH2
5
C
4
The rearrangement of propargyl alcohols to allenyl ha-
lides is a well-studied transformation.8 Glaser coupling of
the corresponding terminal alkyne produces 1,6-diphenyl-
2,4-diyn-1,6-diol (4) on a large scale in good yield (100 g,
90%).9 Treatment of 4 with substoichiometric amounts of
copper(I) bromide (CuBr) and concentrated hydrobromic
acid (HBr) in acetic acid provides the desired 1,6-diphe-
nyl-3,4-dibromo-1,2,4,5-tetraene (5, Scheme 3).10 Unfor-
375 °C
1
2
3
C
6
CH2
1
Scheme 1 Rearrangement of 1,5-hexadiyne to 1
Compound 1 has a significant dipole (m = 0.616 0.002
D) for a simple hydrocarbon, as increased electron density
at C5 and C6 reduces the antiaromatic character of the
ring.2c Theoretical and experimental studies have shown
that 1 is more similar to a cross-conjugated diene than to
a triene. Additionally, the exo-methylene groups in 1 do
not react as a Diels–Alder diene, as the resulting product
would contain antiaromatic cyclobutadiene. The primary
factor influencing the unique structure and reactivity of 1
is the energetic cost of antiaromaticity.3
tunately, isolation of
5 is difficult, leading to
decomposition and low yields (13–26%). Therefore, a
HO
Ph
HO
Ph
OH
Ph
CuCl, TMEDA
2
air, acetone, r.t.
4, 90%
CuBr, HBr
AcOH, r.t.
Br
Ph
C
C
Ph
Br
5, 13–26%
SYNLETT 2011, No. 11, pp 1519–1522
x
x
.x
x
.2
0
1
1
Advanced online publication: 10.06.2011
DOI: 10.1055/s-0030-1260777; Art ID: S01811ST
Scheme 3 Synthesis of intermediates 4 and 5
© Georg Thieme Verlag Stuttgart · New York

1520
R. R. Parkhurst, T. M. Swager
LETTER
synthesis that circumvents the direct isolation of 5 was racemic 1-phenyl-2-propyn-1-ol, compounds 4 and 6 are
pursued.
a 1:1 mixture of the rac and meso stereoisomers, which re-
arrange to the corresponding isomers of 5. The meso iso-
mer then undergoes conrotatory cyclization to form
exclusively 7 (in,out) while the rac isomers cyclize to ei-
ther 7 (in,in) or 7 (out,out). Therefore, a 2:1:1 ratio of
(in,out)/(in,in)/(out,out) isomers is expected. The distribu-
tion of products at different loadings of CuBr is listed in
Table 1.15 The (in,out) isomer consistently accounts for
approximately 50% of the product. When a pure sample of
each isomer was irradiated with UV light,16 each isomer-
ized to a mixture of approximately 67% (in,out), 23%
(in,in), and 10% (out,out) isomers.15 This observation is
consistent with calculations that predict the (out,out) iso-
mer to be the highest in energy, although the differences
are small.17
Copper(I) salts catalyze the reversible rearrangement of
propargyl halides to allenyl halides.11 Jacobs et al. report-
ed a maximum conversion of alkyne to allene of 65% in
the case of 3-bromopropyne. Interestingly, copper(I) salts
have also been shown to catalyze the electrocyclic ring
closure of diallenes to 3,4-bis(methylene)cyclobutenes.12
The present system exploits the dual ability of copper(I)
salts to achieve tandem rearrangement and irreversible
electrocyclic ring closure (Scheme 4). Upon treatment
with phosphorus tribromide (PBr3), diol 4 is converted in
high yield to dibromide 6.13 As expected, upon heating to
40 °C in THF in the presence of 5 mol% CuBr, the crude
product 6 was converted to a mixture of three isomers of
1,2-dibromo-3,4-bis(benzylidene)cyclobutene (7).
Table 1 Thermal Distribution of Isomers of 7
Br
Br
HO
Ph
OH
Ph
PBr3, Et2O
CuBr (%)
Ratio of (in,out):(in,in):(out,out)
4.9: 3.1: 2.0
–10 °C to r.t.
Ph
Ph
4
6, 93%
5
50
cat. CuBr
40 °C, THF
4.6: 2.5: 2.9
Ph
Ph
100
250
4.8: 2.1: 3.1
Br
Br
Br
irreversible
cyclization
Ph
C
5.0: 1.9: 3.1
C
Ph
Br
The increased energy of 7 (out,out) indicates the energetic
cost of the phenyl groups twisting out of plane to reduce
steric repulsion with the bromine atoms. The ability of the
phenyl groups to p-stack is able to counterbalance the ef-
fect of steric repulsion and twisting in 7 (in,in). As shown
in Table 1, the ratio of 7 (out,out) to 7 (in,in) increases
with increased levels of the copper(I) source. Similarly,
Pasto et al. found greater yields of sterically congested
products with copper(I)-catalyzed ring closure of dial-
lenes to 3,4-bisalkylidenecyclobutenes as compared to the
strictly thermal process.12,18 It is proposed that the cop-
per(I)-catalyzed cyclization occurs through a radical-an-
ion process (Scheme 5). Theoretical investigation of the
transformation of 1,2,4,5-hexatriene to 1 performed by
Pasto et al. indicates that ring closure of the radical anion
is more exothermic than that of the neutral compound,
creating an earlier transition state in which steric conges-
tion [in the case of 7 (out,out)] or p-stacking [as in 7
(in,in)] in the product are less important.
7, 64%
5
Scheme 4 Rearrangement and irreversible cyclization to form 7
The three isomers arise from the E/Z stereochemistry
about the exocyclic double bonds and have been labeled
as 7 (in,out), (in,in), and (out,out) referring to the position
of the phenyl groups using nomenclature analogous to that
used by Toda et al.14 The isomers of 7 are separable by
column chromatography, and the structure of each has
been confirmed by X-ray crystallography (Figure 1).
The formation of three isomers is consistent with the
mechanism of the overall transformation. Starting from
Ph
Ph
Br
Br
Br
C
C
Cu(I)
Br
Ph
5
5
7
7
Ph
Figure 1 Space-filling (a–c) and front and side ellipsoid views (d–
f) of X-ray crystal structures of isomers of 7 (a, d) (in,out) (b, e) (in,in)
(c, f) (out,out). Aromatic hydrogens omitted for clarity
Scheme 5 Copper(I)-catalyzed cyclization of 5 to 7 via radical an-
ion intermediates
Synlett 2011, No. 11, 1519–1522 © Thieme Stuttgart · New York

LETTER
Synthesis of 3,4-Bis(benzylidene)cyclobutenes
1521
Table 2 Structural Information of 1 (B3LYP/6-31G**) and Crystal Structures of 7. Redundant Bond and Torsion Angles for Symmetrical
Compounds Have Been Omitted
1
7 (in,out)
1.357
1.472
1.495
1.522
3.508
130
7 (out,out)
7 (in,in)
Bond length (Å) C1–C2
1.336
1.484
1.484
1.509
3.409
134
–
1.345
1.375
C1–C4
C2–C3
C3–C4
1.479
1.482
1.531
3.679
134
–
1.494
1.477
1.507
3.340
131
–
Distance (Å)
Angle (°)
C5–C6
C1–C2–H(Br)
C2–C1–H(Br)
C2–C3–C6
133
137
–
131
130
–
139
–
C1–C4–C5
140
Torsion (°)
C2–C3–C6–Ph
C1–C4–C5–Ph
0
29
43
42
–
30
–
–
The structural differences between the isomers of 7 and zylidene group in 7 (in,out) is a likely explanation for its
the calculated structure of parent compound 1 (B3LYP/6- favored formation in the photochemical isomerization.
31G**) are summarized in Table 2. There is a notable de-
viation in internuclear distance between C5 and C6. This
value is related to the bonding angle of C2–C3–C6 (and
C1–C4–C5) and is determined by the steric interaction be-
tween either a phenyl ring and a bromine atom or between
two phenyl rings. In the case of compound 1, which lacks
this steric interaction, the C5–C6 distance is 3.409 Å with
a corresponding angle of 137°. The corresponding values
Single isomers of 7 can be reduced to 3,4-bis(ben-
zylidene)cyclobutene (8) with retention of the E/Z config-
uration by heating with zinc powder in acetic acid
(Scheme 6). Compound 8 is moderately stable, but de-
1
composes slowly under air.19 A comparison of the H
NMR spectra of 7 and 8 is available in the Supporting In-
formation (Figure S1). In the case of 8 (in,in) and 8
(out,out), growth of the new Hb peak is evident. As ex-
of compound 7 (out,out) deviate the least from those of 1,
pected from the dipole moment of parent compound 1, the
0.069 Å and 2°, respectively. Compound 7 (in,in), where
the phenyl rings must twist in order to stack face-to-face
and reduce steric repulsion, deviates the most from 1 with
an increase in C5–C6 distance of 0.270 Å and a 7° de-
crease in the C2–C3–C6 angle.
vinyl peaks for Hb are significantly deshielded and posi-
tioned downfield of the aromatic region. Previously, the
synthesis of a single symmetrical isomer of 7 from the
iron tricarbonyl complex of substituted cyclobutadiene
was reported.20 Based on our findings, however, it seems
The effects of steric bulk are also evident in variations of likely the authors had actually generated a mixture of
the angle defined by C1–C2–H(Br) [or C2–C1–H(Br)]. In symmetrical isomers [8 (in,in) and 8 (out, out)].
this regard, 7 (in,in) is the most similar to 1. The angle is
decreased by 3° in 7 (out,out) as the bromine atoms are
forced closer together to accommodate the outward-point-
ing phenyl rings and minimize their twisting. As expected
unsymmetrical 7 (in,out) exhibits both types of bond an-
Compound 7 can also be used as a coupling partner for
metal-catalyzed cross-coupling reactions (Scheme 7).
Ph
Ph
Hb
Hb
Ha
Ha
Br
Br
Ha
Ha
Zn
gles dependent on the position of the phenyl group.
AcOH, Δ
Finally, and perhaps most significantly, is the difference
in torsion angle caused by the twisting of the phenyl
groups. In 7 (in,out) the phenyl groups only twist 29° and
30° out of plane whereas in 7 (in,in) and 7 (out,out) the
corresponding values are 43° and 42°, respectively. In-
creased planarity (and therefore conjugation) of the ben-
Ph
Ph
8, 95%
7
Scheme 6 Reduction of single isomers of 7 to single isomers of 8
with retention of E/Z configuration
Synlett 2011, No. 11, 1519–1522 © Thieme Stuttgart · New York

1522
R. R. Parkhurst, T. M. Swager
LETTER
Coupling reactions were generally carried out using a sin- Supporting Information for this article is available online at
gle isomer of 7, however, no difference in efficiency of http://www.thieme-connect.com/ejournals/toc/synlett.
the reaction between isomers was observed. Two-fold
Suzuki cross-coupling reaction between 3-thiophene bo-
ronic acid and 7 gave compound 9 in 89% yield. Attempts
Acknowledgment
The authors thank Dr. Peter Müller for collecting and solving X-
Ray crystal structure data. This work was supported by the National
Science Foundation and the Army Research Office through the In-
stitute for Soldier Nanotechnologies.
at oxidative cyclization between the thiophene rings of 9
to form benzodithiophene21 were unsuccessful due to the
increased bond angles around the four-membered ring.
Compound 7 also successfully participated in two-fold
Sonogashira cross-coupling with phenylacetylene to pro-
duce 10 in 59% yield (Scheme 7). The absorption and References and Notes
emission spectra of 10 (out,out) are shown in Figure 2; a
difference in the optical characteristics between different
isomers of 10 was not observed.
(1) Blomquist, A. T.; Maitlis, P. M. Proc. Chem. Soc. (London)
1961, 332.
(2) (a) Huntsman, W. D.; Wristers, H. J. J. Am. Chem. Soc.
1963, 85, 3308. (b) Huntsman, W. D.; Wristers, H. J. J. Am.
Chem. Soc. 1965, 89, 342. (c) Coller, B. A. W.; Heffernan,
M. L.; Jones, A. J. Aust. J. Chem. 1968, 21, 1807. (d) Hopf,
H. Angew. Chem., Int. Ed. Engl. 1970, 9, 732.
S
Ph
S
B(OH)2
Pd(PPh3)4, Na2CO3
(3) Toda, F.; Garratt, P. Chem. Rev. 1992, 92, 1685.
(4) Braverman, S.; Suresh Kumar, E. V. K.; Cherkinsky, M.;
Sprecher, M.; Goldberg, I. Tetrahedron 2005, 61, 3547.
(5) For examples of the use of 2, see: (a) Toda, F.; Akagi, K.
J. Chem. Soc., Chem. Commun. 1970, 764. (b) Toda, F.;
Akagi, K. Tetrahedron 1971, 27, 2801. (c) Iyoda, M.;
Kuwatami, Y.; Oda, M. J. Am. Chem. Soc. 1989, 111, 3761.
(d) Toda, F.; Tanaka, K.; Sano, I.; Isozaki, T. Angew. Chem.
1994, 106, 1856. (e) Kuwatani, Y.; Yamamato, G.; Iyoda,
M. Org. Lett. 2003, 5, 3371. (f) Kuwatani, Y.; Yamamoto,
G.; Oda, M.; Iyoda, M. Bull. Chem. Soc. Jpn. 2003, 5, 2188.
(6) Toda, F.; Kumada, K.; Ishiguro, N.; Akagi, K. Bull. Chem.
Soc. Jpn. 1970, 43, 3535.
PhMe, EtOH, H2O
reflux
S
Ph
Ph
Ph
9, 89%
Br
Br
Ph
Ph
Ph
7
(PPh3)2PdCl2, CuI
Et3N, r.t.
(7) Toda, F. J. Chem. Soc., Chem. Commun. 1969, 1219.
(8) Brandsma, L. Synthesis of Acetylenes, Allenes and
Cumulenes; Elsevier: Oxford, 2004, 235–265.
Ph
Ph
10, 59%
(9) (a) Ulman, A.; Manassen, J. J. Am. Chem. Soc. 1975, 97,
6540. (b) Smith, C. D.; Tchabanenko, K.; Adlington, R. M.;
Baldwin, J. E. Tetrahedron Lett. 2006, 47, 3209.
(10) Landor, S. R.; Demetriou, B.; Evans, R. J.; Grzeskowiak, R.;
Devey, P. J. Chem. Soc., Perkin Trans. 2 1972, 1995.
(11) Jacobs, T. L.; Brill, W. F. J. Am. Chem. Soc. 1953, 75, 1314.
(12) (a) Kleveland, K.; Skattebøl, L. J. Chem. Soc., Chem.
Commun. 1973, 432. (b) Pasto, D. J.; Yang, S.-H. J. Org.
Chem. 1989, 54, 3544.
Scheme 7 Examples of metal-catalyzed cross-coupling of 7
(13) Dibromide 6 was found to rearrange to 5 (ca. 50%) and
hydrolyze to 4 (ca. 50%) upon chromatography on silica gel
and decomposed partially during recrystallization attempts.
(14) Toda, F.; Tanaka, K.; Tamashima, T.; Kato, M. Angew.
Chem. Int. Ed. 1998, 37, 2724.
(15) The distribution of isomers was determined by 1H NMR.
(16) Photolysis experiments were conducted in hexane using a
Hg pen-lamp, without the use of optical filters.
(17) Spartan B3LYP/6-31+g*, relative E (kcal/mol): 7
(in,out) = –0.4487, 7 (in,in) = 0, 7 (out,out) = 0.0056.
(18) Pasto, D. J.; Kong, W. J. Org. Chem. 1989, 54, 4028.
(19) Attempts to purify compound 8 via column chromatography
or recrystallization were unsuccessful due to its limited
stability. Any impurities visible in Figure S1 are believed to
be primarily high-molecular-weight decomposition
products.
(20) Roberts, B. W.; Wissner, A. J. Am. Chem Soc. 1972, 94,
7168.
(21) For examples of this methodology in the synthesis of
polycyclic aromatic compounds, see: (a) Tovar, J. D.;
Swager, T. M. Adv. Mater. 2001, 13, 1775. (b) Tovar, J. D.;
Rose, A.; Swager, T. M. J. Am. Chem. Soc. 2002, 124, 7762.
Figure 2 Absorption and emission curves of 10 (out,out) in chloro-
form (Fem = 0.63, t = 5.77 ns)
In conclusion, we have developed a method for the syn-
thesis of previously unknown 1,2-dibromo-3,4-bis(ben-
zylidene)cyclobutene (7). Each of the three possible
isomers of 7 were isolated and characterized by X-ray
crystallography. The utility of 7 as a starting material in
the synthesis of additional highly strained molecules via
reduction and metal-catalyzed cross-coupling has also
been demonstrated.
Synlett 2011, No. 11, 1519–1522 © Thieme Stuttgart · New York