Regioselective formation of alkylidenecyclopropanes from 2-substituted cyclobutylidenes generated from geminal dibromocyclobutanes and methyllithium

Article abstract of DOI:10.1021/ol036348r

Four different 2-substituted geminal dibromocyclobutanes were reacted with methyllithium at -78°C. In contrast to previous studies using diazocyclobutanes as carbene precursors at temperatures above 200°C via reaction of the corresponding tosylhydrazone s

Full text of DOI:10.1021/ol036348r

ORGANIC
LETTERS
2
004
Vol. 6, No. 5
15-718
Regioselective Formation of
Alkylidenecyclopropanes from
7
2-Substituted Cyclobutylidenes
Generated from Geminal
Dibromocyclobutanes and Methyllithium
†
Tore Nordvik, Jean-Luc Mieusset, and Udo H. Brinker*
Institut f u¨ r Organische Chemie, UniVersit a¨ t Wien, W a¨ hringer Strasse 38,
A-1090 Wien, Austria
udo.brinker@uniVie.ac.at
Received December 2, 2003
ABSTRACT
Four different 2-substituted geminal dibromocyclobutanes were reacted with methyllithium at −78 °C. In contrast to previous studies using
diazocyclobutanes as carbene precursors at temperatures above 200 °C via reaction of the corresponding tosylhydrazone sodium salts, the
organometallic route in each case produces only an alkylidenecyclopropane that could be isolated in good yields. B3LYP calculations were
employed to rationalize the observed regioselective ring contraction of the generated cyclobutyliden(oid)s.
1
a,b
Small-ring carbenes, e.g., cyclopropylidenes and cyclobutyl-
idenes,1 have been used successfully as building blocks
in organic synthesis. When compared with cyclopropyl-
idenes, however, much less attention has been paid to
cyclobutylidenes. This is clearly due to the more laborious
tion with readily available gem-dibromocyclopropanes is the
most frequently used route to cyclopropyliden(oid)s, the
Bamford-Stevens reaction, where a lithium or sodium salt
of the cyclobutanone tosylhydrazone is either flash-pyrolyzed
or photolyzed, has been the method of choice for the
c-e
1
c-e,2
routes involved in the generation of the divalent carbon in
generation of cyclobutylidenes.
A second approach to
four-membered rings.1
c-e,2a
While the alkyllithium reac-
liberate cyclobutylidenes from the corresponding diazo
2a,b
compounds has been introduced by Warkentin. Photolysis
of oxadiazolines afforded dialkyldiazo compounds. Impor-
tantly, the Bamford-Stevens and the alkyllithium reaction
differ considerably in their operational temperatures. Thus,
while the organometallic route to cyclopropylidenes is
usually applied at temperatures below 0 °C, the thermal
Bamford-Stevens reaction generally requires temperatures
*
Corresponding author. Phone: +43-1-4277-52121. Fax: +43-1-4277-
5
2140.
†
Carbene Rearrangements. 59. For Part 58, see: Knoll, W.; Bobek, M.
M.; Kalchhauser, H.; Rosenberg, M. G.; Brinker, U. H. Org. Lett. 2003, 5,
943.
1) Cyclopropylidenes: (a) Backes, J.; Brinker, U. H. In Houben-Weyl
Methoden der Organischen Chemie); Regitz, M., Ed.; Thieme: Stuttgart,
989; Vol. E 19b, pp 391-510. (b) Jones, W. M.; Brinker, U. H. In
2
(
(
1
Pericyclic Reactions; Marchand, A. P., Lehr, R. E., Eds.; Academic: New
York, 1977; Vol. 1, pp 169-191. Cyclobutylidenes: (c) Backes, J.; Brinker,
U. H. In Houben-Weyl (Methoden der Organischen Chemie); Regitz, M.,
Ed.; Thieme: Stuttgart, 1989; Vol. E 19b, pp 511-541. (d) Baron, W. J.;
DeCamp, M. R.; Hendrick, M. E.; Jones, M., Jr.; Levin, R. H.; Sohn, M.
B. In Carbenes; Jones, M., Jr., Moss, R. A., Eds.; Wiley: New York, 1973;
Vol. 1, pp 42-44. (e) Kirmse, W. In Carbene Chemistry, 2nd ed.;
Academic: New York, 1971; pp 473-475.
(2) (a) Pezacki, J. P.; Pole, D. L.; Warkentin, J.; Chen, T.; Ford, F.;
Toscano, J. P.; Fell, J.; Platz, M. S. J. Am. Chem. Soc. 1997, 119, 3191. (b)
Majchrzak, M. W.; B e´ zhazi, M.; Tse-Sheepy, I.; Warkentin, J. J. Org. Chem.
1989, 54, 1842. (c) Brinker, U. H.; Boxberger, M. Angew. Chem., Int. Ed.
Engl. 1984, 23, 974. (d) Brinker, U. H.; Weber, J. Tetrahedron Lett. 1986,
27, 5371.
1
0.1021/ol036348r CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/31/2004

9
above 200 °C. Only a few examples are known for the
generation of cyclobutylidene(oid)s 2 from gem-dibromo-
cyclobutanes 1 (Scheme 1) with alkyllithium.2
gem-dibromocyclopropane with methyllithium. Besides the
typical rearrangement to an allene, a 1,5 C-H insertion led
to the formation of an entropically favored five-membered
ring. Surprisingly, for all systems described here, only
compounds 3 could be isolated in good yields (Table 1). No
c,d,4,5
Scheme 1. Generation and Reaction of 2-Substituted
Cyclobutylidenes from Geminal Dibromocyclobutanes
Table 1. Isolated Yields of Alkylidenecyclopropanes 3a-d
entry
R
yield (%)
3
3
3
3
a
b
c
d
n-hexyl
79
75
93
81
cyclobutylmethyl
cyclohexylmethyl
benzyl
cyclobutenes or products resulting from C-H insertions were
1
0
found. In sharp contrast, the pyrolysis of the sodium salt
of 2-hexylcyclobutanone tosylhydrazone at 240 °C/0.01 Torr
afforded a mixture of C10H
18 products, 3a (91.9%), 5a11
1
2
(
5.8%), 4a (1.8%), and a compound found in trace amounts,
Intramolecular reactions of the parent system 1 (R ) H)
have been reported to give methylenecyclopropane (3) (R
1
which according to the H NMR and mass spectrum probably
is 6a (0.4%).
)
H) and cyclobutene (5) (R ) H), with the ratio depending
According to early MINDO/3 semiempirical calculations
4
5
on the reaction conditions. Except for a tetracyclic example,
1
3
by Schoeller, singlet 2 (R ) H) undergoes a ring contraction
to 3 (R ) H) in a two-step process via a nonclassical bicyclic
carbene 7 (R ) H) (Scheme 2). Later this rearrangement
intramolecular reactions of 2-substituted gem-dibromo-
cyclobutanes are hitherto unknown. Recently, we have
developed a more general method for the synthesis of gem-
dibromocyclobutanes that allows the introduction of substit-
6
uents at C2. Moreover, nucleoside analogues comprising a
Scheme 2. Mechanism of Ring Contraction of 2-Substituted
(Z)- or an (E)-alkylidenecyclopropane moiety have been
Cyclobutylidenes
shown recently to be active against human immunodeficiency
7
virus 1 (HIV-1) in vitro. Therefore, a simple low-temper-
ature route to regioselective formation of alkylidenecyclo-
propanes 3 may be warranted.
Herein we report on the reactions of four 2-substituted
gem-dibromocyclobutanes 1a-d with methyllithium that
regioselectively afford alkylidenecyclopropanes 3a-d as the
sole product in good yields. For cyclobutylidene 2a (R )
n-hexyl), we wanted to compare the products from the
8
Bamford-Stevens reaction with those obtained via the
1
4
was reinvestigated at a higher level of theory. Hadad, Platz,
and Schaefer III, et al. using Møller-Plesset perturbation
as well as hybrid Hartree-Fock/density functional theory
methods again predicted singlet cyclobutylidene to possess
organometallic route from the corresponding gem-dibromo-
cyclobutane 1a. We anticipated from both reactions a similar
spectrum of primary products. Furthermore, to a small extent,
an insertion into the C-H bonds of the side chain could also
be expected, since this type of reaction had been observed
for the corresponding cyclopropylidenoid generated from the
1
5
a nonclassical bicyclic structure. Finally, McMahon and
Karney et al. using ab initio (MP2, CCSDCT) and density
functional theory (BLYP, B3LYP) calculations confirmed
some transannular bonding between the divalent carbon and
(
(
3) Friedman, L.; Shechter, H. J. Am. Chem. Soc. 1960, 62, 1002.
4) Brinker, U. H.; Schenker, G. J. Chem. Soc., Chem. Commun. 1982,
the opposing CH
2
group in a bicyclobutane-like structure.16
6
79.
5) Jefford, C. W.; Rossier, J.-C.; Zuber, J. A.; Kennard, O.; Cruse, W.
B. T. Tetrahedron Lett. 1983, 24, 181.
6) (a) Nordvik, T.; Brinker, U. H. J. Org. Chem. 2003, 68, 9394. (b)
Nordvik, T.; Brinker, U. H. J. Org. Chem. 2003, 68, 7092.
7) (a) Yoshimura, K.; Feldman, R.; Kodama, E.; Kavlick, M. F.; Qiu,
Y.-L.; Zemlicka, J.; Mitsuya, H. Antimicrob. Agents Chemother. 1999, 43,
(
(9) Brinker, U. H.; Miebach, T. J. Org. Chem. 1999, 64, 8000.
(10) Brinker, U. H.; K o¨ nig, L. Chem. Ber. 1983, 116, 882.
(11) Kasai, K.; Liu, Y.; Hara, R.; Takahashi, T. Chem. Commun. 1998,
(
(
1989.
(12) Hsiao, C.-N.; Shechter, H. J. Org. Chem. 1988, 53, 2688.
(13) Schoeller, W. W. J. Am. Chem. Soc. 1979, 101, 4811.
(14) Wang, B.-Z.; Deng, C.-H. Chin. J. Chem. 1990, 8, 102.
(15) Sulzbach, H. M.; Platz, M. S.; Schaefer, H. F., III; Hadad, C. M. J.
Am. Chem. Soc. 1997, 119, 5862.
2
5
479. (b) Cheng, C.; Shimo, T.; Somekawa, K.; Baba, M. Tetrahedron 1998,
4, 2031.
(8) For a 2-substituted cyclobutylidene comprising a double bond at C-3
of the side chain generated from the corresponding tosylhydrazone sodium
salt, see: Brinker, U. H.; Schrievers, T.; Xu, L. J. Am. Chem. Soc. 1990,
(16) Stracener, L. L.; Halter, R. J.; McMahon R. J.; Castro, C.; Karney,
W. L. J. Org. Chem. 2000, 65, 199.
1
12, 8609.
716
Org. Lett., Vol. 6, No. 5, 2004

The extraordinary structure of cyclobutylidene seems to
play an important role for the uncommon preference for the
For 2-hexylcyclobutylidene (2a) with 3.8 kcal/mol (6-
31G*), a similar value was calculated. In contrast, for the
rearrangement of the parent system 2 (R ) H) f 3 (R )
H), 9.1 kcal/mol (cc-pVTZ) is necessary to reach the TS.
Therefore, an alkyl substituent accelerates this rearrangement.
For the cyclopropylcarbene-cyclobutene rearrangement, a
1,2-C over the competing 1,2-H migration. Moreover, for
cyclobutylidene, the triplet-singlet energy gap was calcu-
lated to be 5.9 kcal/mol, with the singlet being the ground
1
4
state.
17
23
Computational Methods. The Spartan 02 program was
used for density functional theory calculations, employing
Becke’s18 three-parameter hybrid method and the exchange
methyl group was observed to have a similar effect. Since
some charge is developed in the TS of the rearrangement,
an alkyl group weakens the breaking bond and stabilizes the
19
23
functional of Lee, Yang, and Parr (B3LYP). The geometry
optimizations of the structures were achieved at the HF/3-
developing charges. The 1,2-H shift of the tertiary hydrogen
atom in 2-methyl-2 (R ) CH
(2a) to give cyclobutene 5 (R ) CH
3
) and 2-hexylcyclobutylidene
) and 5a, respectively,
2
6
1G(*) level.20 Energies were evaluated by using B3LYP/
-31G* single-point calculations. The transition state (TS)
3
at the 6-31G* level requires comparable activation energies
of 2.7 and 3.5 kcal/mol. At the higher level of theory,
however, for 2-methylcyclobutylidene 2 (R ) CH ) an
3
geometries obtained with all methods were verified by
calculation of their harmonic vibrational frequencies. In the
case of the C10
H
18-compounds, the lowest energy conformers
increase to 8.4 kcal/mol was calculated. This is in agreement
with the experimental results from the organometallic reac-
tion of 1a in which no 1-hexylcyclobutene (5a) was formed.
The alternative ring contraction to the alkylmethylenecyclo-
were first determined by a conformational search using the
21
semiempirical AM1 model prior to the geometry optimiza-
tion. Since neither the HF/3-21G(*) nor the B3LYP/6-31G*
geometry calculations gave the nonclassical structure 7
propanes 4 (R ) CH
7.3 and 7.5 kcal/mol (6-31G*), respectively, while for the
rearrangement 2 f 4 (R ) CH ), 10.0 kcal/mol (cc-pVTZ)
3
) and 4a needs an activation energy of
1
5,16
(
Scheme 2) obtained by higher level calculations,
calculations were also performed on 2-methylcyclobutylidene
2) (R ) CH ) as a model system at the 6-311+G** level
and with Dunning’s triple-ú correlation-consistent basis set,
the
3
(
3
are required. These substantially higher energies, when
compared with the activation energies for the rearrangement
2 f 3, explain why 4a was not observed in the organo-
metallic generation of carbene 2a. Moreover, intramolecular
insertion reactions to give bicyclo[2.1.0]pentanes and bicyclo-
[3.2.0]heptanes require activation energies in the range of
about 5 to 6 kcal/mol.
2
2
cc-pVTZ. From Table 2 it is obvious that the energy
Table 2. Energy Values (kcal/mol) Relative to the Carbene
Singlet Ground State for the Transition States
Finally, at the B3LYP/cc-pVTZ level of theory, the triplet
state of methylcyclobutylidene (2a) lies 7.6 kcal/mol above
the singlet ground state. For the ring contraction 3 f 4,
respectively, at first a bond between C1 and C3 has to be
formed leading to the bicyclobutane-like structure 7 (Scheme
2). Next, either the bond between C2 and C3 or C3 and C4
has to break to give 3 and 4, respectively. In our study, the
higher substituted C2-C3 bond is exclusively broken, and
concomitantly the C1-C3 bond is established. No methyl-
enecyclopropane 4 could be observed, where the R group is
attached to the cyclopropane ring. This experimental result
is corroborated by the calculations. Thus, the structure of 2
R )
methyl
R )
methyl
R )
a
b
hexylb
exo-bicyclo[2.1.0]pentane
-R-cyclobutene 6
alkylmethylenecyclopropane 4
endo-bicyclo[2.1.0]pentane
exo-bicyclo[3.2.0]heptane
endo-bicyclo[3.2.0]heptane
14.2
12.2
10
6.3
7.0
7.3
4.3
7.3
7.5
5.9
5.5
4.7
3.5
3.8
0
3
1
-R-cyclobutene 5
8.4
3.2
0
2.7
3.5
0
alkylidenecyclopropane 3
carbene 2
a
B3LYP/cc-pVTZ energies and geometries. b B3LYP/6-31G* single-
point energy calculations at HF/3-21G(*) geometries.
3
(R ) CH ) (Figure 1) at the cc-pVTZ level of theory shows
already a longer C2-C3 bond (1.66 Å) when compared with
the C3-C4 bond (1.59 Å) (Table 3). Moreover, the C1-C2
required for 2 (R ) CH
of the ring contraction reaction to 3 (R ) CH
cc-pVTZ) and 3.5 kcal/mol (6-31G*), respectively, is the
lowest of all competing pathways.
3
) to reach the transition state (TS)
3
) with 3.2
(
(17) Kong, J.; White, C. A.; Krylov, A. I.; Sherrill, C. D.; Adamson, R.
D.; Furlani, T. R.; Lee, M. S.; Lee, A. M.; Gwaltney, S. R.; Adams, T. R.;
Ochsenfeld, C.; Gilbert, A. T. B.; Kedziora, G. S.; Rassolov, V. A.; Maurice,
D. R.; Nair, N.; Shao, Y.; Besley, N. A.; Maslen, P. E.; Dombroski, J. P.;
Daschel, H.; Zhang, W.; Korambath, P. P.; Baker, J.; Byrd, E. F. C.; Van
Voorhis, T.; Oumi, M.; Hirata, S.; Hsu, C.-P.; Ishikawa, N.; Florian, J.;
Warshel, A.; Johnson, B. G.; Gill, P. M. W.; Head-Gordon, M.; Pople, J.
A. J. Comput. Chem. 2000, 21, 1532.
(
(
(
18) Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
19) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785.
20) Binkley, J. S.; Pople, J. A.; Hehre, W. J. J. Am. Chem. Soc. 1980,
Figure 1. Structure of 2-methylcyclobutylidene 2 (R ) CH
the transition state 8 that leads to alkylidenecyclopropane 3 (R )
CH ).
3
) and
1
02, 939.
21) Dewar, M. J. S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J. J. P. J.
Am. Chem. Soc. 1985, 107, 3902.
22) Dunning, T. H., Jr. J. Chem. Phys. 1989, 90, 1007.
(
3
(
Org. Lett., Vol. 6, No. 5, 2004
717

Table 3. Bond Lengths and Dihedral Angles for 2-Hexyl- and 2-Methylcyclobutylidene 2a and 2 (R ) CH
Structure 8, and Alkylidenecyclopropane 3 (R ) CH
3
), the Transition State
3
)
hexyl
methyl
methyl
methyl
8
3 (R ) CH3)
cc-pVTZa
1.437
1.651
1.593
1.453
1.737
38.2
cc-pVTZa
1.435
1.658
1.590
1.454
1.734
38.4
6-311+G**a
1.445
1.646
1.599
1.458
6-31G*a
1.535
1.556
1.550
1.519
2.214
14.6
cc-pVTZa
1.380
2.011
1.522
1.473
1.633
46.1
cc-pVTZa
1.318
2.675
1.539
1.462
C1-C2
C2-C3
C3-C4
C1-C4
C1-C3
dihedral angle
1.752
38.1
1.465
C1-C2-C3-C4
a
B3LYP calculations.
bond is slightly shorter than the C1-C4 bond. Since in 2 (R
CH ) the C2-C3 bond eventually has to be broken and
the C1-C2 bond has to become the double bond in 3 (R )
CH ), this is even more pronounced in the TS structure 8.
With 1.38 Å, the C1-C2 bond now has almost reached the
final length of the double bond of the product, ethylidene-
cyclopropane (3) (R ) CH ), while the distance between
3
C2 and C3 is further elongated to 2.01 Å.
As expected, with a distance of 1.63 Å, the central C1-
C3 bond of the nonclassical bicyclic carbene 2 (R ) CH ),
3
In conclusion, we have shown that the methyllithium
reaction of 2-substituted gem-dibromocyclobutanes 1 in all
cases gives only one product, i.e., alkylidenecyclopropanes
3. This is in stark contrast to systems previously studied,
where under Bamford-Stevens reaction conditions both
possible ring contraction products were always observed.
Moreover, in the organometallic approach presented here,
no cyclobutenes or the corresponding ring-opened products,
i.e., 1,3-butadienes, were found. This is markedly different
from the reaction of the parent 1,1-dibromocyclobutane (1)
(R ) H), where also cyclobutene (5) (R ) H) could be
)
3
3
when compared with that of the TS structure 8, has been
further shortened during its transformation to a lateral
4
isolated in yields up to 17%.
3
cyclopropane bond of 3 (R ) CH ).
Acknowledgment. Dedicated to Professor Manfred T.
Reetz on the occasion of his 60th birthday. We thank Ms.
S. Felsinger and Ms. C. Tyl for the recording of 400 MHz
H and 100 MHz C NMR spectra and Ms. M. Pacar for
technical assistance.
It has been shown that alkylidenenecyclopropanes 3 are
the secondary thermal products of 4.24 In this study, this
would require, however, that the rearrangement 4 f 3 had
taken place already at temperatures as low as -78 °C during
the reaction, at workup at about 0 °C, or at distillation
temperatures (20-50 °C). As has been observed (vide supra),
the reactions of 1 with methyllithium afforded exclusively
1
13
Supporting Information Available: Energy values for
1
13
3
the products of 2a and 2 (R ) CH ) and H and C NMR
spectra of compounds 3a-d and of 2-hexylcyclobutanone
tosylhydrazone. This material is available free of charge via
the Internet at http://pubs.acs.org.
3
. Since the rearrangement 4 f 3 demands temperatures of
2
4
about 150 °C, the firsthand formation of methylenecyclo-
propanes 4 from 2, under the reaction conditions applied in
our study, is highly unlikely.
OL036348R
(
23) Thamattoor, D. M.; Snoonian, J. R.; Sulzbach, H. M.; Hadad, C.
(24) Gajewski, J. J. Hydrocarbon Thermal Isomerizations; Academic:
New York, 1981; pp 51-61.
M. J. Org. Chem. 1999, 64, 5886.
718
Org. Lett., Vol. 6, No. 5, 2004