Fate of diradicals in the caldera: Stereochemistry of thermal stereomutation and ring enlargement in cis- and trans-1-cyano-2(E)- propenylcyclopropanes

Article abstract of DOI:10.1021/ja0305961

This study of thermally induced stereomutation and ring enlargement in both (-)-trans-1-cyano-2(E)-propenylcyclopropane [(-)-trans-1] and (+)-cis-1-cyano-2(E)-propenylcyclopropane [(+)-cis-1] to cyclopentenes definitively contraindicates the usefulness of Woodward-Hoffmann rules of orbital symmetry as a theoretical basis for predicting the stereochemistry of the products. From both diastereomers, the same (+)-trans-4-cyano-3- methylcyclopentene [(+)-trans-2] is the major product among the four diastereomeric products, "allowed" and formally the result of a single internal rotation of the cyano-bearing carbon atom from (-)-trans-1, "forbidden" and the result of zero internal rotations from (+)-cis-1. Stereomutation and ring enlargement are discussed in detail in terms of rotational propensity, thermodynamic preference, and the possible role of diradicals in transit and diradicals as intermediates in a caldera.

Full text of DOI:10.1021/ja0305961

Published on Web 09/11/2004
Fate of Diradicals in the Caldera: Stereochemistry of Thermal
Stereomutation and Ring Enlargement in cis- and
trans-1-Cyano-2(E)-propenylcyclopropanes
William von E. Doering* and Edward Albert Barsa
Contribution from the Department of Chemistry and Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts 02138-2902
Received October 24, 2003; E-mail: doering@chemistry.harvard.edu
Abstract: This study of thermally induced stereomutation and ring enlargement in both (-)-trans-1-cyano-
2(E)-propenylcyclopropane [(-)-trans-1] and (+)-cis-1-cyano-2(E)-propenylcyclopropane [(+)-cis-1] to
cyclopentenes definitively contraindicates the usefulness of Woodward-Hoffmann rules of orbital symmetry
as a theoretical basis for predicting the stereochemistry of the products. From both diastereomers, the
same (+)-trans-4-cyano-3-methylcyclopentene [(+)-trans-2] is the major product among the four dia-
stereomeric products, “allowed” and formally the result of a single internal rotation of the cyano-bearing
carbon atom from (-)-trans-1, “forbidden” and the result of zero internal rotations from (+)-cis-1.
Stereomutation and ring enlargement are discussed in detail in terms of rotational propensity, thermodynamic
preference, and the possible role of diradicals in transit and diradicals as intermediates in a caldera.
Introduction
Vinylcyclopropanes undergo thermally induced ring enlarge-
ments to cyclopentenes, and stereomutations to configurational
isomers (see Figure 1).1 Although the products of ring enlarge-
ment are formed kinetically much more slowly than the products
of stereomutation, they are thermodynamically “massively
favored at equilibrium”.1c As a consequence ring enlargement
has seen significant application in synthetic organic chemistry,
while stereomutation has been the object only of mechanistic
experimentation and speculation. Investigation into the stereo-
chemistry of the ring enlargement begins with Mazzochi and
Tamburin,2 continues with Doering and Sachdev3 and Andrews
and Baldwin,4 and extends to this work by Barsa.5 Both ring
enlargement and stereomutation are illuminated more brightly
when cis and trans educts can be compared side by side as here
and in Sachdev.6
The early 1970s were characterized by widespread hope that
the theory of orbital symmetry of Woodward and Hoffmann
would provide the basis for a useful prediction of the stereo-
chemical outcome of not obviously concerted, possibly diradical
intermediated reactions. In that pursuit, the thermal rearrange-
ment of vinylcyclopropanes played a prominent role.1c Con-
temporary experimentation was limited to trans-1,2-disubstituted
cyclopropanes,7 and led to agreement that the major paths of
Figure 1. Interconversions of racemic trans- and cis-1-cyano-2(E)-
propenylcyclopropane (trans-1 and cis-1; ktc and kct) and their ring
enlargements to cis- and trans-4-cyano-3-methylcyclopentene (trans-2 and
cis-2; kts and kta , and kcs and kca). Specific rate constants at 207.1 °C in the
gas phase are given in units of 10-7 s-1
.
ring enlargement to cyclopentenes from vinylcyclopropanes
were Woodward-Hoffmann allowed processes, suprafacial in
the cisoid allyl group (s) and “with inversion” at the secondary
radical (i). Coincidentally it was also a period strongly under
the spell of Benson’s dubious ∼9 kcal mol-1 as the energy of
activation for reclosure of 1,3- and 1,4-diradicals,8,9 widespread,
(1) Reviews: (a) Gajewski, J. J. Hydrocarbon Thermal Isomerizations;
Academic Press: New York, 1981; pp 81-87 among others. (b) Baldwin,
J. E. J. Comput. Chem. 1998, 19, 222-231. (c) (Especially advised)
Baldwin, J. E. Chem. ReV. 2003, 103, 1197-1212.
(2) Mazzochi, P. H.; Tamburin, H. J. Am. Chem. Soc. 1970, 92, 7220-7221;
1975, 97, 555-561.
(7) In many of the early examples, a methyl group, used as the second
substituent, precluded observation of stereomutation and ring enlargement
of the cis isomers by preemption by a faster homoretroene reaction.
(8) Doering, W. v. E. Proc. Natl. Acad. Sci. U.S.A. 1981, 78, 5279-5283.
(9) Isborn, C.; Hrovat, D. A.; Borden, W. T. J. Phys. Chem. 2004, 108, 3024-
3029.
(3) Doering, W. v. E.; Sachdev, K. J. Am. Chem. Soc. 1975, 97, 5512-5520.
(4) Andrews, G. D.; Baldwin, J. E. J. Am. Chem. Soc. 1976, 98, 6705-6706.
(5) Barsa, E. A. Ph.D. Dissertation, Harvard University, 1976; Diss. Abstr.
Int. B 1977, 37, 5077 (order no. 77-9303).
(6) Doering, W. v. E.; Sachdev, K. J. Am. Chem. Soc. 1974, 96, 1168-1187.
9
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J. AM. CHEM. SOC. 2004, 126, 12353-12362
12353

A R T I C L E S
Scheme 1
Doering and Barsa
Scheme 2
uncritical acceptance of which encouraged a classical conceptual
scheme for the transition region.
Publication of this portion of Barsa’s extensive mechanistic
work so long after that of Andrews and Baldwin4 on trans-1-
methyl-2(E)-propenylcyclopropane not only complements the
recent appearance of two studies of a similarly substituted pair
of cyclobutanes,10,11 but provides the only direct comparison
of both the cis and trans isomers of a cyclopropane. Barsa’s
goal was the full set of 14 specific rate constants that describe
thermal interconversion among the pairs of enantiomers of cis-
and trans-1-cyano-2(E)-propenylcyclopropanes (cis-1 and trans-
1), and their irreversible ring enlargements to the enantiomers
of the diastereomeric 4-cyano-3-methylcyclopentenes (trans-2
and cis-2; Figure 1 shows the racemic pair). Whereas a methyl
group cis to the propenyl group, as in the analogous example
of Andrews and Baldwin, undergoes a more rapid homoretroene
cleavage effectively to the exclusion of ring enlargement, the
cyano-substituted analogue is free of that frustrating complica-
tion, and possessed of other often extolled advantages.
sarkomycin, [R]25 ) +66.7°, was taken as that of optically
pure material on the assumption that sarkomycin, its precursor,
having been of natural origin, was likely optically pure.16
D
Interrelation of Configurations
Interrelating the relative chiralities of the cyclopropanes and
the cyclopentenes has been accomplished through the device
of absolute configurations in the absence of direct chemical
interrelations. The absolute configuration of the cyclopropanes
is based on the relation of active (S)-(-)-amyl alcohol to (2S,3S)-
L-(+)-isoleucine as the key reference compounds,17 and to
Kirmse’s establishment thereby of the (1R,2R) configuration for
(+)-trans-dimethylcyclopropane.18 By chemical connection to
this compound, Walborsky et al. have assigned an absolute
configuration to dimethyl (1R,2R)-(-)-trans-cyclopropane-1,2-
dicarboxylate. In the present work, (-)-trans-1 has in turn been
related to Walborsky’s (1R,2R)-(+)-trans-dimethylcyclopropane
(for depiction and details, see Scheme 2).
The absolute configuration of the cyclopentenes depends first
on the relation of (R,S)-(+)-dihydrosarkomycin (5s; Scheme 3)
to (R)-(+)-3-methylcyclohexanone (6) of known absolute con-
figuration as established by Hill et al.19 and on the relation of
(S,R)-(-)-dihydrosarkomycin (5r) to (+)-trans-2 by way of
methyl 3-methylcyclopentene-4-carboxylate (7r), and of 7s to
methyl 1-methylcyclopentane-2-carboxylate (8s) as the connect-
ing compounds. Establishing the relation to (+)-cis-2 is trivial.
Preparation of Materials
Preparation of (-)-trans-1 and (+)-cis-1 began with trans-
1-hydroxymethyl-2(E)-propenylcyclopropane (3; Scheme 1).12
Optical activity was introduced by resolution of the quinine salt
of trans-2(E)-propenylcyclopropane-1-carboxylic acid (4). The
question of optical purity and absolute configuration was
addressed by transformation to dimethyl cyclopropane-1,2-
dicarboxylate, the optical purity of which had occupied the
attention of Walborsky et al.13 and Sachdev.6 In the kinetic
calculations, (-)-trans-1 of [R]25 ) -916.5° was assumed
to be 100% optically pure and was confidently g97%.
365
The products of ring enlargement, trans-2 and cis-2, were
prepared from dihydrosarkomycin, itself prepared following a
sequence owed to Newman and McPherson.14 Dihydrosarko-
mycin was resolved by fractional crystallization of its brucine
salt from ethyl acetate following the procedure of Shemyakin
et al.15 The specific rotation reported by Hooper for dihydro-
(10) Baldwin, J. E.; Burrell, R. C. J. Org. Chem. 2002, 67, 3249-3256.
(11) Doering, W. v. E.; Cheng, X.-h.; Lee, K.-w.; Lin, Z.-s. J. Am. Chem. Soc.
2002, 124, 11642-11652.
(12) Baldwin, J. E.; Ullenius, C. J. Am. Chem. Soc. 1974, 96, 1542-1547.
(13) Inouye, Y.; Sugita, T.; Walborsky, H. M. Tetrahedron 1964, 20, 1695-
1699.
(14) Newman, M. S.; McPherson, J. L. J. Org. Chem. 1954, 19, 1717-1723.
(15) Shemyakin, M. M.; Shchukina, L. A.; Vinogradova, E. I.; Kolosov, M.
N.; Vdovina, R. G.; Karapetyan, M. G.; Rodionov, V. Ya.; Ravdel, G. A.;
Shvetsov, Y. B.; Bamdas, E. M.; Chaman, E. S.; Ermolaev, K. M.; Semkin,
E. P. J. Gen. Chem. USSR 1957, 27, 817-822; Zh. Obshch. Khim. 1957,
27, 742-747.
(16) Hooper, I. R.; Cheney, L. C.; Cron, M. J.; Fardig, O. B.; Johnson, D. A.;
Johnson, D. L.; Palermiti, F. M.; Schmitz, H.; Wheatley, W. B. Antibiot.
Chemother. 1955, 5, 585-595.
(17) Trommel, J.; Bijvoet, J. M. Acta Crystallogr., B 1954, 7, 703-709.
(18) Doering, W. v. E.; Kirmse, W. Tetrahedron 1960, 11, 272-275.
(19) Hill, R. K.; Foley, P. J., Jr.; Gardella, L. A. J. Org. Chem. 1967, 32, 2330-
2335.
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Fate of Diradicals in the Caldera
A R T I C L E S
Scheme 3
Figure 2. Six specific rate constants in units of 10-7 s-1 for stereomutations
among enantiomeric and diastereomeric cis- and trans-1-cyano-2(E)-
propenylcyclopropanes at 207.1 °C in the gas phase. The enantiomers of
the educts actually used are depicted for the sake of consistency with other
similar schemes.
Table 1. First-Order Specific Rate Constants at 207.1 °C for the
Thermally Induced Stereomutations and Ring Enlargements of cis-
and trans-Cyano-2(E)-propenylcyclopropanes (cis-1 and trans-1,
Respectively)
1
reaction
k ×
10-7, s-
trans-1 f cis-1 (ktc)a
cis-1 f trans-1 (kct)a
trans-1 f cis-2 (kts)a
trans-1 f trans-2 (kta)a
190 ( 3
277 ( 6
1.44 ( 0.03
2.86 ( 0.08
4.70 ( 0.13
8.35 ( 0.25
194.9 ( 6.5
134.1 ( 3.3
82.8 ( 2.5
57.0 ( 1.5
106.6 ( 6.0
97.7 ( 2.0
0.56
2.31
0.97
0.48
5.72
2.66
1.82
2.89
Kinetics
cis-1 f cis-2 (kcs)a
With the configurational relation of (-)-trans-1 to (+)-cis-
1, and of (+)-trans-2 to (+)-cis-2, and the relation of each set
to the other firmly in hand, elucidation of the kinetics of the
complete system could be undertaken. The study began with
the kinetics of the racemic system in Figure 1, the data bearing
on which are found in the Supporting Information, Table SI-1.
Its six specific rate constants fell into two distinct sets differing
considerably in magnitude. The two constants describing the
interconversion of trans- and cis-1, ktc and kct, were easily
determined with acceptably high precision, while the four
describing the ring enlargements to trans-2 (kta and kca) and
cis-2 (kts and kcs) (Figure 1), being smaller by almost 2 orders
of magnitude, could still be measured simultaneously with the
faster two interconversions, but at low conversion and cor-
respondingly at a substantially lower level of precision. Opti-
mization of the six specific rate constants was accomplished in
the usual fashion by application of the Runge-Kutta method
to the set of four partial differential equations involving the six
rate constants. While our earlier program produced the same
values as a later program created by Roth and Fink,20 only the
latter incorporated the method of Marquardt21 for the evaluation
of the individual uncertainties (recorded at 3σ, the 95%
confidence level). A more accurate determination of the sums
of the rate constants k3 + k4 and k5 + k6 (Figure 2) could have
been obtained by starting from equilibrium concentrations of
trans- and cis-1 and operating at higher temperatures to higher
degrees of conversion, but without adding any improvement in
the ratios within the pairs.
a
cis-1 f trans-2 (kca.
)
(+)-cis-1 f (-)-trans-1 (k1)b
(-)-trans-1 f (+)-cis-1 (k2)b
(+)-cis-1 f (+)-trans-1 (k3)b
(-)-trans-1 f (-)-cis-1 (k4)b
(+)-cis-1 f (-)-cis-1 (k5)b
(-)-trans-1 f (+)-trans-1 (k6)b
(-)-trans-1 f (-)-trans-2 (k7)c
(-)-trans-1 f (+)-trans-2 (k8)c
(-)-trans-1 f (-)-cis-2 (k9)c
(-)-trans-1 f (+)-cis-2 (k10)c
(+)-cis-1 f (+)-trans-2 (k11)c
(+)-cis-1 f (-)-trans-2 (k12)c
(+)-cis-1 f (-)-cis-2 (k14)c
(+)-cis-1 f (+)-cis-2 (k13)c
a Values for the same rate constants calculated by the program of Roth
and Fink (see the text) are recorded in Figure 1. b Also reported in Figure
2. c Also reported in Scheme 6 (as the enantiomeric set for consistency
with other schemes).
Dissection of the specific rate constants of the racemic
compounds is accomplished in our usual manner from estimation
of the ratio of enantiomers at zero time. The specific rate
constants derived from the kinetic data are collected in Table
1, Figure 2, and Scheme 6.
Mechanistic Models
The conceptual scheme propounded for thermal rearrange-
ments in small ring compounds consists of three, long obvious,
superficially simple elements of bond-breaking, internal rota-
tions, and bond-making, the reverse of bond-breaking. The
ultimate goal is the identification of factors that will allow the
effect of constitutional and configurational perturbations to be
predictedsat least qualitatively.
(20) Roth, W. R.; Fink, R. Unpublished results.
(21) Marquardt, D. W. J. Soc. Ind. Appl. Math. 1963, 11, 431-441.
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A R T I C L E S
Doering and Barsa
conformational minima at a rate substantially faster than that
of exit to products.
Stereomutations
Interconversions among the stereoisomeric cyclopropanes are
markedly favored kinetically if not thermodynamically over ring
enlargements: 98.6% faster from (-)-trans-1, 96.7% from (+)-
cis-1. Stereomutation and ring enlargement are formally ac-
complished by homolysis of the weakest carbon-carbon bond
(here the C1-C2 bond) to a diradical, rotation about the C1-
C3 bond (hereafter referred to as “cyano rotation”) or about
the C2-C3 bond (“(E)-propenyl rotation”) by single rotation
(or both, by double rotation), and reclosure to stereoisomers of
cyclopropanes or cyclopentenes (Figure 2 and Scheme 6,
respectively). Hidden from view are the “identity” reactions of
reclosure to educt of unchanged stereochemistry! Taking the
sum of the three rate constants for stereomutation for each
isomer to be 100%, the two processes of single rotation account
for 72.2% from (-)-cis-1, and 66.1% from (+)-trans-1. Even
more strikingly, single rotation by cyano is favored over (E)-
propenyl rotation: 50.7% as (+)-trans-1 versus 21.5% as (-)-
trans-1 from (-)-cis-1, and 46.4% as (-)-cis-1 versus 19.7%
as (+)-cis-1 from (+)-trans-1. This observation is yet another
example of rotational propensity favoring the slender cyano
group.
In a circle of reversible reactions of this type,22 the ratio of
the specific rate constants for formation of the products of single
rotation about one carbon atom vis-a`-vis that of another is a
constant, whether starting from (+)-trans-1 or (-)-cis-1. This
constant, dubbed rotational propensity (RA),3 here defines the
ratio of rotation of the cyano-bearing carbon atom to that of
the (E)-propenyl-bearing carbon atom (notation cyano/(E)-
propenyl). This ratio, 2.36, may be compared to values reported
for other cyclopropanes: 2.20 for cyano/isopropenyl,3 2.4723
and 2.3024 for cyano/phenyl, 1.76 for cyano/phenylacetylenyl,23
and 0.90 for cyano/methyl.25 Parenthetically, the similarity of
rotational propensities in related cyclobutanes is noteworthy:
most appositely, 2.41 for cyano/(E)-propenyl (Figure 4), but
also 1.93 for cyano/(Z)-propenyl11 and 1.48 for cyano/vinyl.26
As a relevant diversion, we note that substitution at the
formally uninvolved, third carbon atom of the cyclopropane ring
(C3) is a factor in determining the magnitude of RA, and is not
to be ignored. As an illustration, the influence of the methyl
group at C3 in 1-cyano-2(Z)-propenyl-3-methylcyclopropane is
strongly reflected in four values for RA, which range from 1.04
to 4.86.27 (The effect of disubstitution at C3, e.g., in an
appropriate derivative of chrysanthemic acid, has not appeared
in the literature.) Rotational propensities are perhaps better
notated with a subscript indicating the nature of the substitution
at C3, e.g., as (RA)CHH in the present example, (RA)CHMe in those
cited immediately above, and [(RA)CMeMe] in a hypothetical 3,3-
dimethyl example.
Figure 3. Stereomutation modeled by dynamically controlled diradicals
in transit proceeding from (-)-cis-1 by a continuous, disrotatory (both
outward; three other modes not shown), double rotation to (+)-cis-1, and
each by single-rotational processes to (-)-trans-1 (propenyl rotation) and
(+)-trans-1 (cyano rotation).
In the first, bond-breaking phaseswhich may be designated
as a collection of entry channels into the calderasan excitation
energy, equivalent to that which would be required to break
the covalent bond in an analogously substituted acyclic example
less any ring strain released, is acquired in the usual manner by
collisions, and then concentrated into the apposite stretching
mode by the reverse of intramolecular vibrational relaxation
(ivr). In contrast to the acyclic instance where two radicals can
then be generated by bond dissociation, in the cyclic instance
vibrational excitation can be carried to ever higher vibrational
levels without accomplishing bond-breaking. Coupling with a
torsional mode and its conversion to an internal rotation are
required to effect bond-breaking and generation of an (unex-
cited) diradical.
At this point a bifurcation is visualized. By conservation of
the torsional momentum involved in the bond-breaking, the
diradical may continue on to its predestined product. In this
process the diradical is not an intermediate, but is perhaps more
informatively described as a “diradical in transit”. It does not
pause in the caldera to explore its own internal torsional modes,
but rather proceeds on without further intervention to bond-
making. There being several appropriate torsional modes in
cyclic organic molecules of any realistic size and substitu-
tion, several stereochemically distinct paths to bond-breaking
may comprise a collection of entrance channels and their
corresponding exit channels. In the three examples discussed
in this paper, these modes may include two single-rotational
processes, and four double-rotational processes leading to (0°,
0°) transoid conformations (only one of two disrotational
processes is shown in Figure 3), each corresponding to a distinct
diradical in transit.
Alternatively, the diradical may be diverted to the status of
an intermediate by ivr, that is, to another of the several shallow
conformational minima accessible to the diradical. The diradical
may now be described as a “diradical as intermediate” able to
explore its various conformations by conversions of apposite
torsional modes into internal rotations. Among these will be
the conformation from which return to the activated state of
the cyclic educt without stereochemical change is a viable if
not observable process. The extreme expression of this alterna-
tive is the establishment of an equilibrium among available
That most of the available experimental evaluations of RA
have cyano in common is not meant to imply that this group
(22) Onsager, L. Phys. ReV. 1931, 37, 405-426.
(23) Doering, W. v. E.; Barsa, E. A. Tetrahedron Lett. 1978, 2495-2498.
(24) Baldwin, J. E.; Carter, C. G. J. Am. Chem. Soc. 1978, 100, 3942-3944.
(25) Baldwin, J. E.; Carter, C. G. J. Am. Chem. Soc. 1982, 104, 1362-1368.
(26) Doering, W. v. E.; Mastrocola, A. R. J. Am. Chem. Soc. 1974, 96, 1168-
1187.
(27) Doering, W. v. E.; Barsa, E. A. Proc. Natl. Acad. Sci. U.S.A. 1980, 79,
2355-2357.
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Fate of Diradicals in the Caldera
A R T I C L E S
Figure 4. Six specific rate constants in units of 10-7 s-1 for stereomutations
among enantiomeric and diastereomeric cis- and trans-1-cyano-2(E)-
propenyl-cis-3,4-dideuteriocyclobutanes at 198.0 °C in the gas phase, along
with values of the rotational propensity (RA) and equilibrium constant.
Figure 5. Entry into a hypothetical caldera with an equilibrated intermediate
in common, followed by exit by two single-rotational processes, a double-
rotational process, and a zero-rotational (the “identity” reaction) process
for educts (+)-trans-1 (blue arrows) and (-)-cis-1 (mauve arrows).
constitutes or should constitute a reference standard. Note for
instance methyl/ethyl (RA ) 1.17)28 (but see Baldwin and Seldon
for a newer value of RA ≈ 1.0)29 and isopropyl/phenyl (RA )
1.27).23 Indeed, it is problematic whether it makes sense to seek
an intrinsic factor for each individual group since interactions
among the substituents at all three carbon atoms appear to
determine the observed rotational propensities.
Disubstitution at one of the rotating carbon atoms is exempli-
fied by methyl 1,2-diphenylcyclopropane-2-carboxylate as
uncovered by Chmurny and Cram30 and examined in more detail
by Doering, Robertson, and Ewing.31 These compounds show
a very high value of RA ) 18 ( 3 (phenyl,hydrogen/
carbomethoxy,phenyl). Replacement of the carbomethoxy group
by cyano returns RA to an unexceptional value, 2.21 (phenyl,
hydrogen/cyano,phenyl). Note also the unexceptional values of
RA ) 1.69 shown by methyl 1-phenylcyclopropane-2-carbox-
ylate (carbomethoxy,hydrogen/phenyl,hydrogen), 2.30 shown by
cyano,hydrogen/phenyl,hydrogen, and 1.37 for cyano,hydrogen/
cyano,methyl.32
Between the two extremes of hypothetical mechanistic
schemes for stereomutation, a continuum of the ratio of reclosure
to internal rotation from very largesdiradical in transit (dint)s
to very smallsdiradical as intermediate (dasi)scan be discerned.
Distinction between the two extremes becomes possible only
when data from both cis and trans educts are available. Under
the operation of dasi, the same distribution of products would
be expected regardless of the stereochemistry of the educts; that
is, the ratios of the two products in common, (-)-trans-1 and
(+)-cis-1 from either (+)-trans-1 or (-)-cis-1, should be
identical (Figure 5). The experimental ratios being 1.72 and 0.78,
respectively, this criterion seems not to be satisfied. The
possibility that these ratios might in reality be identical can be
assessed by estimating the changes in relative rates of formation
that would be required to bring about identity. Calculation (for
example, to a common value of 0.94, which slightly favors the
trans educt over the cis educt) reveals that these changes would
have to amount to 18-32% of their experimental values, values
that do not appear credibly to fall within our estimate of
experimental uncertainties.33 In a superficially more forgiving
examination, the average of the two values from (+)-trans-1
and (-)-cis-1 for the stereoisomers resulting from cyano
rotation, (E)-propenyl rotation, and double rotation are, respec-
tively, 48.6 ( 2.1%, 20.6 ( 1.1%, and 30.8 ( 3.0% (from
Figure 5). The apparent uncertainties in these values are perhaps
small enough to be more supportive of equilibration within the
caldera. What is missing is a set of three or more repetitions of
the kinetics that would have provided a better grip on experi-
mental uncertainties. The hypothesis of product distribution
coming from equilibration within the caldera gains in credibility
from a consistency with the other two examples in the literature.
Relative contributions from the same three rotational compo-
nents from the cis- and trans-1-methyl-2(E)-propenylcyclo-
butanes are 45.8 ( 1.3%, 32.9 ( 1.0%, and 22.0 ( 2.1%,
respectively (Figure 6),10 while from cis- and trans-1-methyl-
2(E)-propenyl-cis-3,4-dideuteriocyclobutane these contributions
are 50.4 ( 0.7%, 21.0 ( 0.8%, and 28.6 ( 1.5%, respectively
(Figure 4).11 Within possibly acceptable limits of uncertainties,
a credible case can be made for the distribution of the
stereomutational products being independent of the stereochem-
istry of the educt, or nearly so. The rub is in “nearly so”. The
conclusion would be stronger were experiments of higher
(28) Carter, W. L.; Bergman, R. G. J. Am. Chem. Soc. 1969, 91, 7411-7425.
(29) Baldwin, J. E.; Seldon, C. B. J. Am. Chem. Soc. 1993, 115, 2239-2248.
(30) Chmurny, A. B.; Cram, D. J. J. Am. Chem. Soc. 1973, 95, 4237-4244.
(31) Doering, W. v. E.; Robertson, L. R.; Ewing, E. E. J. Org. Chem. 1983, 48,
4280-4286.
(32) Doering, W. v. E.; Horowitz, G.; Sachdev, K. Tetrahedron 1977, 33, 273-
283.
(33) Arithmetically expressed, (19.7 + ct)/(33.8 - ct) ) 0.94 when ct ) 6.2
while (27.7 - cc)/(21.5 + cc) ) 0.94 when cc ) 3.9 is the result.
9
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A R T I C L E S
Doering and Barsa
Scheme 4
Ring Enlargements
Before beginning discussion of the minor, products of ring
enlargement, we note that a single caldera is not an acceptable
conceptual scheme where two or more noninterconverting
calderas may be involved.34,35 In the three examples cited, entry
can lead to transoid and cisoid configurations of the caldera,
neither being likely to interconvert within the short lifetime of
the individual calderas (see Scheme 4). Exit from the presumably
major transoid caldera may lead only to products of stereo-
mutation, while exit from the minor cisoid set can lead in
addition to ring enlargement (in an unknown ratio). This latter
process amounts to no more than ∼2.5% stereomutation. The
relative distribution among the three cyclopropanes from the
cisoid calderasor from the transoid for that mattersis not
known. Neither are the ratios of the two configurations starting
from (-)-cis-1 or (+)-trans-1. If it be assumed that the ratios
are quite similar in magnitude, the hypothesis of two calderas
common to both remains acceptable, otherwise not.
Although ring enlargements are the least prominent kinetically
among the thermal rearrangements of vinyl-substituted cyclo-
propanes, they have attracted a disproportionate amount of
attention because their stereochemistry can be analyzed in terms
of the rules of Woodward-Hoffmann orbital symmetry.36
Several studies on trans-2-methylcyclopropanes variously sub-
stituted by 1-substituted vinyl groups were quite uniformly
distinguished by strong favoring of the two Woodward-
Hoffmann allowed processes. During this period, observation
of the role of the corresponding cis isomers was completely
thwarted by their predilection for a homoretroene reaction so
much faster than stereomutation or ring enlargement that no
relevant signals could be detected (see, for example, the reaction
investigated by Andrews and Baldwin in Scheme 5).4 Once the
offending methyl group had been replaced by a group such as
cyano, the retroene reaction was, of course, completely elimi-
nated, and the role of the cis isomers could then be observed
(Scheme 6).5,6
Figure 6. Six specific rate constants (in units of 10-6 s-1 and numbered
as in Figure 3) are given for stereomutations among enantiomeric and
diastereomeric cis- and trans-1-methyl-2(E)-propenylcyclobutanes at 275
°C in the gas phase, along with values of the rotational propensity (RA)
and equilibrium constant.
precision and accuracy to confirm the complete independence
of product distribution of the stereochemistry of the educt.
Under the operation of dint, the ratios among the various
bond-breaking modes determine the distribution of stereoisomers
in stereomutation; that is, product distributions are dependent
on the stereochemistry of the educt. Only by coincidence could
the product distribution coincide with that expected of dasi and
thus appear to be independent. A believable model is essential
for comparison with experiment, but such a model eludes us.
Even about a possible difference between disrotatory double
rotation from (-)-cis-1 (Figure 3) and conrotatory double
rotation from (+)-trans-1 (Figure SI-1) we know nothing,
although it is hard to believe the two processes should be as
nearly identical in magnitude as would appear.
Validation of the dint extreme may be forthcoming only
through theoretical calculations of the dynamic trajectory type.
Analysis of the paths or trajectories followed from entry into,
and through exit from, the multidimensional potential energy
“surface” of a large number of molecules excited to the total
energy level of a diradical can in principle, and increasingly in
practice, lead to the correct prediction of the ratios among
products emerging from the caldera. This purely calculational
approach promises to generate highly reliable quantitative
predictions of rate constants on an ad hoc basis, but probably
at the cost of not bringing to light qualitative factors influencing
the distribution among entrance channels and therefore among
products. A timely, detailed, and sympathetic overview with
references is given in sections 6 and 7 of Baldwin’s review.1c
Some hope may be attached to an experimental comparison
of sterically more disparate pairs, such as cis- and trans-1-tert-
butyl-2(E)-propenylcyclopropane (cyclobutane) or cis- and
trans-1-phenyl-2(E)-propenylcyclopropane (cyclobutane), among
others imaginable. But in this endeavor the point may have been
reached where the multiplicity of variables is too great to expect
qualitatively useful factors or correlations to emerge.
(34) Thermal interconversion within a caldera between the two sets requires
cis-trans isomerization of allylic radicals, and is rendered highly improb-
able within the lifetime of a caldera by an enthalpy of activation estimated
to be ∼16 kcal mol-1
.
(35) Korth, H.-G.; Trill, H.; Sustmann, R. J. Am. Chem. Soc. 1981, 103, 4483-
4489.
(36) Woodward, R. B.; Hoffmann, R. The ConserVation of Orbital Symmetry;
Verlag Chemie: Weinheim, Germany, 1970; p 121.
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Fate of Diradicals in the Caldera
A R T I C L E S
Scheme 5
Scheme 7
Scheme 8
Scheme 6
Ring enlargements of the type for (+)-trans-1 and (-)-cis-1
to cis- and trans-4-cyano-3-methylcyclopentenes (cis- and trans-
2) look superficially more amenable to a mechanistic under-
standing in that they may occur only through the family of cisoid
configurations of the continuous or intermediary diradicals
(Scheme 4). However, they amount kinetically to no more than
1.4% and 3.3% of the kinetic fates of (+)-trans-1 and (-)-cis-
1, respectively (inevitably in neglect of the unknowable identity
reactions). As a consequence the stereochemistry of the cyclo-
pentenes obtained as final products in good yield (owing to the
highly favorable thermodynamics) has been so highly compro-
mised that it is of little theoretical interest or synthetic value.
No matter. The specific rate constants of their formation remain
mechanistically interesting.
That ring enlargements of cyclopropanes should be so much
slower than stereomutation is uncontroversially explained by
the adverse steric interactions inherent in generating the apposite
diradical in the obligatorily cisoid configuration (Scheme 4).
In the cyclobutanes, ring enlargement competes comfortably
with stereomutation. The contrast finds no facile explanation
(cf. Figure 4 and Scheme 8, or Figure 6 and Scheme 7).
That trans isomers should be favored is consistent with the
difference in steric energy of 0.6 kcal mol-1 estimated by MM2
calculations of isomeric cis- and trans-2, but correct analysis
must be in terms of kinetic control. At the much higher
temperature of 387.4 °C, the rates of formation of trans-2 are
compressed somewhat to 60% and 59%, respectively, but are
certainly not notably temperature-dependent. The close similarity
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A R T I C L E S
Doering and Barsa
to the trans-1-methyl-2(E)-propenylcyclopropane investigated
by Andrews and Baldwin is shown in Scheme 5.4 A similar
preponderance is observed in several other studies of trans-
1,2-disubstituted cyclopropanes (64-79%; see Table 1 in
Baldwin’s review).1c
of the two cyclobutanes (Figures 4 and 6). The fastest reaction
is interconversion of the two educts by internal rotation of the
cyano group, an outcome consistent with the RA value. Beyond
that, double rotation is somewhat favored over a single rotation
of the (E)-propenyl group in the present example, but not in
that of Baldwin and Burrell (Figure 6).
In striking contrast to the trans isomers, the favored processes
in the ring enlargement of the cis isomers formally follow
Woodward-Hoffmann forbidden pathways. Thus, the two
enantiomers of trans-2 from (+)-trans-1 are produced by
formally allowed processes to the extent of 67%, and from (-)-
cis-1 by forbidden processes to the extent of 64% (Scheme 6).
Similar behavior is seen in the two cyclobutanes. Thus, Baldwin
and Burrell have made the same observation in their heroic study
of the 1-methyl-2(E)-propenylcyclobutanes: (S,S)-trans-10 leads
to 63% trans-13 in allowed processes, while (R,S)-cis-10 leads
to 71% trans-13 in forbidden processes (Scheme 7).10,37 In the
parallel study of 1-cyano-2(E)-propenyl-cis-3,4-dideuterio-
cyclobutanes (Scheme 8),11 (S,S)-trans-9 favors ring enlargement
to trans-14 seemingly by Woodward-Hoffmann allowed pro-
cesses (67%), while (R,S)-cis-9 favors the same trans-14 by
Woodward-Hoffmann forbidden processes (82%). These ob-
servations, acquired by extensive, painstaking, and critical
experimental work, have laid to rest any predictive value in the
application of the Woodward-Hoffmann rules to ring enlarge-
ments in these vinyl-substituted cyclopropanes and cyclobutanes.
Closer inspection of the distribution of enantiomers in the
favored trans isomers reveals a striking excess of the same
enantiomeric cyclopentene, (-)-trans-2, from either (+)-trans-1
as the educt (54%) or (-)-cis-1 (44%). The other trans
component, (+)-trans-2, is a minor product (13% and 20%,
respectively) even though equally favored thermodynamically.
Its contributions, incidentally, represent the maximum that a
necessarily achiral (0°, 0°) diradical as intermediate could play
in the caldera.
The relative ease of the rotational element associated with
the production of each of the four cyclopentenes may be a factor.
The major stereoisomer, (-)-trans-2, from (+)-trans-1 (54%)
is formally the result of a single, cyano rotation, and the result
of a zero rotational process from (-)-cis-1 (44%). The minor
trans component, (+)-trans-2, requires a single internal rotation
of the (E)-propenyl group starting from (+)-trans-1, or a double
rotation, that of the cyano group and the (E)-propenyl group,
from (-)-cis-1. In stereomutation, it may be recalled that the
rotational propensity (RA) is the ratio of rotation of the cyano-
bearing carbon atom vis-a`-vis that of (E)-propenyl, and has the
value 2.36. In the ring enlargement of (+)-trans-1 to (-)- and
(+)-trans-2, cyano rotation is favored over rotation of the (E)-
propenyl group by a factor of 4.1. In the ring enlargement of
(-)-cis-1, the same rotations are in a ratio of 1.6, but lead to
the thermodynamically less favored cis isomers (-)-cis-2 and
(+)-cis-2. Much the same picture can be seen in the rearrange-
ments of cyclobutanes, Schemes 7 and 8.
In ring enlargement, very much the minor reaction kinetically,
the same product, (-)-trans-2, predominates regardless of the
eductsby cyano rotation from (+)-trans-1, by zero internal
rotation from (-)-cis-1. From each educt, the minor product,
(+)-trans-2, requires an internal rotation of the (E)-propenyl
group, the slower rotating group in stereomutation, by single
and double rotation, respectively.
As long as attention is focused only on trans educts, a
favoring of Woodward-Hoffmann “allowed” paths (is and ra)
has been sustained. But any imputed, more general predictive
value evaporates when it is recognized that the cis isomers favor
the “forbidden”, rs and ia paths! This behavior has been
confirmed not only in the comparable cyclobutane, but also in
the more recent examples of cis-1-phenyl-2(E)-propenylcyclo-
propanes38 and cis-1-phenyl-2(E)-styrylcyclopropanes.39 It is not
amiss to restate the usefulness of application of the Woodward-
Hoffmann rules: reactions that follow allowed paths may be
concerted in mechanism, while reactions that follow forbidden
paths are not concerted.
The favoring of trans isomers in ring enlargement is
consistent with a thermochemical advantage, but the substantial
favoring of one enantiomer over its mirror image appears to
originate in the dynamics of internal rotations. The model of a
diradical as intermediate, fully equilibrated in the caldera, is
not supported in ring enlargement, although the similarity in
distribution of products from both educts suggests a partial
approach to equilibrium within the caldera prior to exit.
Each of the three related examples of the behavior of both
cis and trans educts has required a notable amount of exacting
work, and has been more than justified by having provided a
definitive answer to the long-standing issue of the role of the
Woodward-Hoffmann rules in not obviously concerted thermal
rearrangements. A better understanding of the centrally impor-
tant internal rotational component may involve examination of
more disparately substituted examples, but other still arcane
aspects may well demand new experimental and theoretical
tactics beyond those utilized here.
Experimental Section
General Procedures. NMR spectra were recorded on Varian T-20
and A-60 spectrometers in CDCl3 unless otherwise stated. Chemical
shifts and coupling constants (J) are reported in parts per million (δ)
from tetramethylsilane and hertz (Hz), respectively. Infrared (IR) spectra
were recorded on a Perkin-Elmer model 337 grating spectrophotometer,
and are reported in reciprocal centimeters (cm-1). Optical rotations were
determined on a Perkin-Elmer 141 digital-readout polarimeter in a 1
dm quartz cell at the reported temperatures ( 0.5 °C, and recorded in
grams per 100 mL of solution. Uncertainties in specific rotations are
estimated to be no more than (2%. Preparative separations by HPLC
were effected on a Waters Associates ALC instrument with an M-6000
pump. Quantitative analyses were made on a Perkin-Elmer model 990
instrument, relative areas being measured by a Digital Integrator Autolab
model 6300-01. Purification and separation of larger samples was
Conclusions
In stereomutation the equivalent of a diradical as intermediate
common to (+)-trans-1 and (-)-cis-1 as educts appears to be
closely approached. It is also strongly indicated in the behavior
(37) Relatively, the retroene reaction has been slowed enough in this cyclobutane
system to allow observation of the stereochemistry of ring enlargement
from the cis isomer despite the presence of the methyl group at C2.
(38) Baldwin, J. E.; Boncorsi, S. J. J. Org. Chem. 1994, 59, 7401-7409.
(39) Ascuncion, L. A.; Baldwin, J. E. J. Am. Chem. Soc. 1995, 117, 10672-
10677.
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Fate of Diradicals in the Caldera
A R T I C L E S
accomplished by means of an Aerograph model A90-P3 instrument
employing the following columns: column A, 13 ft × 0.25 in., 10%
Carbowax 20M on Anakrom ABS 70/80; column B, 10 ft × 0.25 in.,
5% OV 22 on Anakrom ABS 50/60. Exact masses were determined
with an AEI model MS-9 double-focusing mass spectrometer. Melting
points were determined without correction in a Hershberg apparatus.
N, 13.07. Found: C, 78.44; H, 8.54; N, 13.12 The ratio of (-)-trans-1
to (+)-cis-1 after equilibration was 50.3:49.7.
Dimethyl (-)-trans-1,2-Cyclopropanedicarboxylate. A mixture of
0.4 g of a sample of (-)-trans-1 ([R]23 -199.9° (c 0.729, EtOH;
365
e21.8% (199.9/916.5) optical purity), 10 mL of 10 M sodium
hydroxide, and 10 mL of ethanol was boiled under reflux for 8 h. The
solution was extracted with ether, acidified with concentrated aqueous
HCl at 0 °C, and extracted with two 50 mL portions of ether. Washed
with 10 mL of water, dried over MgSO4, and concentrated, the ethereal
extract gave an oil which was treated with an excess of ethereal
diazomethane at 0 °C. The usual workup was followed by isolation by
GC on column A at 125 °C to give 0.3 g of methyl (-)-trans-2(E)-
propenylcyclopropane-1-carboxylate: [R]23 -55.0°, -54.9°; [R]23
(-)-trans-2(E)-Propenylcyclopropane-1-carboxylic Acid. To a 4.8
g sample of trans-1-hydroxymethyl-2(E)-propenylcyclopropane (3),12
in 100 mL of acetone, was added 30 mL of 2.67 M Jones reagent (from
26.7 g of CrO3, 23 mL of concentrated H2SO4, and water to bring the
volume to 100 mL) over a period of 1 h at 10-15 °C with stirring.
After an additional 1 h of being stirred, the mixture was poured onto
ice-water, and extracted twice with methylene chloride. This extract
was washed with water, dried over MgSO4, and concentrated to a
residue. Distillation in vacuo gave 2.6 g of a slightly yellow liquid:
1H NMR spectrum identical with that reported.40
D
365
1
-193.4° (c 0.863, 0.815, respectively, CH3OH); H NMR (CCl4) 5.6
(qd, J ) 6 and 16 Hz, 1H), 5.0 (dd, J ) 7 and 16 Hz, 1H), 3.6 (s, 3H),
1.65 (d, J ) 6 Hz, 3H), 2.1-0.6 (m, 4H).
To a solution of this sample in 40 mL of 80% aqueous tert-butyl
alcohol was added a solution of 20 mg of potassium permanganate
and 2 g of sodium periodate (NaIO4) in 50 mL of water. The pH of the
solution was kept between 8 and 9 by the addition of portions of
potassium carbonate. After 0.5 h of standing, tert-butyl alcohol was
removed in vacuo. The resulting aqueous suspension was acidified with
concentrated HCl at 0 °C and extracted three times with 50 mL portions
of ether. Dried over MgSO4 and concentrated, the resulting solution
was treated with excess ethereal diazomethane at 0 °C. The product of
the usual workup was separated into major components by GC on
column B at 120 °C. The second component had the same retention
time and IR spectrum as an authentic sample of dimethyl (-)-trans-
1,2-cyclopropanedicarboxylate and specific rotations of [R]27D -51.2°
A solution of 21 g of this acid and 54.4 g of anhydrous quinine in
140 mL of acetone was allowed to crystallize at 25 °C for 6 h and
then at -5 °C for an additional 12 h. Filtered and washed with 100
mL of 1:2 acetone/petroleum ether, this material (21 g) was recrystal-
lized from 50 mL of acetone (6 h at 25 °C; 12 h at -5 °C). After three
more recrystallizations, 8.5 g of quinine salt was obtained. Recovered
in the usual way, 2.1 g of crude acid was obtained: [R]25578 -190° (c
0.60, EtOH).
(-)-trans-1-Cyano-2(E)-propenylcyclopropane [(-)-trans-1]. A
solution of 4.0 g of crude optically active acid as prepared above and
4.44 mL of triethylamine in 40 mL of methylene chloride was added
dropwise at -25 °C under nitrogen over 20 min to a solution of 3.1
mL of ethyl chloroformate in 30 mL of methylene chloride. After an
additional period of stirring for 1.5 h at -20 to -5 °C, ammonia was
bubbled through the mixture for 20 min. After being stirred further at
25 °C for 1.5 h, the mixture was filtered to remove salts. Concentration
left a solid residue, which was crystallized from water to give 2.6 g of
and -50.8° and [R]27 -52.9° and -52.6° (c 0.635 and 0.724,
568
respectively, CH3OH) (corresponds to [R]27 g -234° for optically
D
pure material).
Resolution of Dihydrosarkomycin. Racemic dihydrosarkomycin
(trans-2-methyl-3-oxocyclopentanecarboxylic acid) was prepared fol-
lowing the procedure of Newman and McPherson and purified by
crystallization from ether: mp 90 °C (lit.14 mp 94 °C); 1H NMR (CDCl3)
12.0 (s, 1H), 2.8-2.1 (m, 6H), 1.2 (d, J ) 6 Hz, 3H). Contrary to the
published results, the brucine salt of the (+)-acid was first to crystallize
at 37 °C, while the salt of the (-)-acid crystallized from the mother
liquor at -20 °C. The (-)-acid from this salt was recrystallized from
ether: mp 93.0-94.5 °C after drying in vacuo (lit.15 mp 98.0-99.5);
[R]20 -36.0°, -36.4°; [R]20 -300.9°, -303.9° (c 1.124, 1.188,
(-)-trans-2(E)-propenylcyclopropane-1-carboxamide: mp 121-122 °C;
1
[R]25 -232° (c 0.60, EtOH); H NMR (acetone-d6) 7.5-6.0 (s, 2H),
D
5.65 (qd, J ) 5 and 16 Hz, 1H), 5.1 (dd, J ) 7 and 16 Hz, 1H), 2.2-
0.6 (m, 4H), 1.6 (d, J ) 5 Hz, 3H).
A solution of 1.8 g of p-toluenesulfonyl chloride (TsCl) in 2 mL of
pyridine was added at 5 °C over a 15 min period to a solution of 1.2
g of the (-)-amide above in 1.5 mL of dry pyridine. After being stirred
for 8 h at 10-22 °C, the mixture was diluted with 50 mL of ether. The
salts were separated by filtration and washed three times each with 20
mL of ether. The combined ether solutions were washed with cold 0.5
M HCl and water, then dried over MgSO4, and concentrated by
distillation to an oil. Separation of the major product by GC (column
A, 140 °C; retention time 30 min) from a minor product (2%; retention
time 40 min) afforded 0.8 g of (-)-trans-1: bp 175 °C; 1H NMR (CCl4)
5.7 (qd, J ) 6 and 16 Hz, 1H), 5.0 (dd, J ) 7 and 16 Hz, 1H), 2.2-1.7
D
365
respectively, distilled water) (lit.15 [R]26 -68.0°).
D
A sample of this (-)-acid was converted in the usual manner to its
methyl ester by diazomethane. Purification of methyl (-)-trans-2-
methylcyclopentan-3-one-1- carboxylate was effected on column B at
120 °C: [R]22 -39.4°, -39.4°; [R]22 -354.6°, -358.0° (c 1.037,
D
365
1.752, respectively, EtOH); 1H NMR (CCl4) 3.7 (s, 3H), 2.8-1.95 (m,
6H), 1.1 (d, J ) 6 Hz, 3H).
(m, 1H), 1.7 (d, J ) 6 Hz, 3H), 1.5-0.9 (m, 3H); [R]23 -270.2°;
D
Methyl (+)-trans-3-Methylcyclopentene-4-carboxylate. A solution
of 3.0 g of the ester above in 20 mL of tetrahydrofuran (THF) was
added at 0 °C over a 5 min period to a solution of 10.0 g of LiAlH-
(OC(CH3)3)3 in 25 mL of anhydrous THF. After resting at 0 °C for 1
h, the mixture was poured into 100 mL of cold, 5% aqueous acetic
acid and extracted twice each with 75 mL of ether. The ethereal solution
was washed with 20 mL of saturated aqueous potassium bicarbonate,
dried over MgSO4, and concentrated to an oil, which was not explored
further but was carried directly to the next step.
A 1 M excess of TsCl was added to a solution of 1.2 g of these
alcohols in 25 mL of pyridine. After 34 h at 5 °C, this mixture was
poured onto 40 mL of ice-water and extracted twice with 50 mL
portions of ether. The ether extract was washed successively with cold
6 M HCl and 10 mL of water until acidic, dried over MgSO4, and
concentrated to a crude, solid tosylate.
[R]23578 -280.9°, [R]23365 -916.5° (c 1.062, EtOH); MS m/z calcd for
C7H9N 107.0771, found 107.0732.
(+)-cis-1-Cyano-2(E)-propenylcyclopropane [(+)-cis-1]. A 0.9 g
sample of the (-)-trans-1 prepared immediately above was epimerized
in 10 mL of dimethyl sulfoxide (DMSO) containing 1 g of sodium
methoxide for 20 min at 25 °C. Workup in the usual way (water, ether
extraction, washing, drying, concentration by distillation) afforded an
oil, which was separated by GC on column A at 140 °C into a fraction
(retention time 30 min) of (-)-trans-1 of unchanged specific rotation
([R]23365 -916.5°) and one of (+)-cis-1 (retention time 40 min): [R]23
D
+108.9°; [R]23 +434.9° (c 0.699, EtOH); H NMR (CCl4) 5.8 (qd,
1
365
J ) 6 and 15 Hz, 1H), 5.2 (dd, J ) 7 and 15 Hz, 1H), 1.8 (d, J ) 6
Hz, 3H), 2.2-0.8 (m, 4H). Anal. Calcd for C7H9N: C, 78.46; H, 8.47;
(40) Lishanskii, I. S.; Pomerantsev, V. I.; Illarionova, N. G.; Khachaturov, A.
S.; Vakorina, T. I. J. Org. Chem. USSR 1971, 7, 1870-1875; Zh. Org.
Khim. 1971, 7, 1803-1810.
An 8.0 g sample of the tosylate in 10 mL of THF containing 12 g
of diazabicycloundecane (DBU) was heated at 85-90 °C for 8 h under
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A R T I C L E S
Doering and Barsa
nitrogen. Poured onto 20 mL of ice-water, the mixture was extracted
twice with 50 mL portions of ether. The combined ether extracts were
washed successively with 15 mL of dilute HCl, 15 mL of saturated
aqueous sodium bicarbonate, and water, then dried over MgSO4, and
concentrated to a solution, which was separated by GC on column A
at 120 °C into four components. The first (45%) was identified as
methyl (+)-trans-3-methylcyclopentene-4-carboxylate: 1H NMR (CCl4)
-40.1°, [R]23 -134.5° (c 0.927, cyclohexane)}, followed by 100
365
mg of glacial acetic acid in 2.0 mL of dioxane in 0.2 mL portions at
intervals of 1.5 h until the yellow salt had been consumed. Extraction
with ether, filtration, washing with 5 mL of dilute sodium bicarbonate,
washing twice with 10 mL of water, drying over MgSO4, and
concentration afforded a crude product from which 100 mg of methyl
(-)-trans-2-methylcyclopentane-1-carboxylate was isolated by GC on
1
5.6 (s, 2H), 3.7 (s, 3H), 3.2-2.4 (m, 4H), 1.2 (d, J ) 6 Hz, 2H); [R]23
column A at 115 °C: H NMR (CCl4) 3.8 (s, 3H), 2.5-1.0 (m, 8H),
D
+72.9°; [R]23 +244.3° (c 0.752, CH3OH).
1.1 (br d, J ) 7 Hz, 3H); [R]25 -16.6°, -16.9°, -16.8°; [R]25
365
D
365
(+)-trans-4-Cyano-3-methylcyclopentene [(+)-trans-2]. The fol-
lowing four steps were effected without isolation of intermediate
products. The unseparated mixture of methyl esters immediately above
was saponified with 10% aqueous NaOH overnight at 40 °C. The usual
workup afforded ∼1 g of carboxylic acids, which were converted to a
mixture of acid chlorides by the ethyl chloroformate procedure described
above, thence to the amides (without isolation to avoid altering the
optical purity), and finally by treatment with TsCl to a mixture of cyano
compounds. Separation by GC on column A at 130 °C gave as the
-51.2°, -51.1°, -51.3° (c 1.036, 0.865, 0.542, respectively, CCl4).
A solution of 100 mg of methyl (()-trans-3-methylcyclopentene-
4-carboxylate in 1 mL of ethyl acetate containing 30 mg of 10% Pd
on carbon was shaken under hydrogen for 5 h at 25 °C. The filtered
solution was subjected to GC on column A at 115 °C to yield methyl
(()-trans-2-methylcyclopentane-1-carboxylate as its major component
(80%). The minor product is likely the cis isomer: 1H NMR (CCl4)
3.8 (s, 3H), 3.1-2.6 (m, 1H), 2.5-1.2 (m, 7H), 0.95 (d, J ) 7 Hz,
3H).
General Method for Kinetics. Thermal rearrangements in the gas
phase or in solution were effected in sealed Pyrex ampules (100 × 4
mm i.d.) suspended in the vapors of boiling tetralin at 207.1 °C in a 1
L Pyrex flask fitted with a 46 × 5 cm neck. These ampules had been
prepared beforehand by first soaking in aqueous ammonia (20%)
overnight, rinsing with water and acetone, drying, then treating with
dichlorodimethylsilane (20% in benzene), rinsing with benzene and
acetone, and drying. The lower 36 cm of the bath was insulated with
several layers of asbestos and a final wrapping of Fiberglas. The
uncovered upper portion of the neck served as an air-cooled condenser.
The temperature of the vapors was measured with an iron-constantan
thermocouple and a Leeds and Northrop no. 8686 millivolt potenti-
ometer. In no runs did temperature fluctuation exceed 0.3 °C. Samples
were purified before use by GC, and transferred by microsyringe to
the ampules, which were then sealed under reduced pressure (∼10-4
mmHg), and suspended in the boiling vapors by means of a wire hook.
The time lag to thermal equilibrium was ∼1 min.
first major peak ∼0.2 g [7% overall from dihydrosarkomycin, [R]20
D
-36.2° (c 1.124, distilled water)] of (+)-trans-2: 1H NMR (CCl4) 5.63
(s, 2H), 3.2-2.3 (m, 4H), 1.22 (d, J ) 7 Hz, 3H); [R]23 +101.9°,
D
+101.6°; [R]23365 +337.8°, +338.5° (c 0.576, 0.615, cyclohexane); MS
m/z calcd 107.0771, found 107.0730.
A 150 mg sample of (+)-trans-2, [R]23
+337.0° (c 1.013,
365
cyclohexane), was boiled under reflux for 10 h in a solution of 5 mL
of 10 M NaOH and 5 mL of ethanol. The cooled, two-phase mixture
was treated with 6 mL of water, extracted with ether, acidified at 0 °C
with concentrated HCl, and extracted three times with 15 mL each of
ether. The dried (MgSO4) ethereal extract was concentrated and treated
with ethereal diazomethane as described above. Collected by GC, the
methyl (+)-trans-3-methylcyclopentene-4-carboxylate had [R]23
365
+244.0° (c 0.990, CH3OH).
(+)-cis-4-Cyano-3-methylcyclopentene [(+)-cis-2]. To a solution
of a 150 mg sample of the (+)-trans-2 above in 1 mL of DMSO was
added 100 mg of sodium methoxide at 25 °C under nitrogen. After
standing for 20 min, the mixture was treated with 8 mL of water, and
worked up in the usual manner. Separation by GC on column A gave
recovered (+)-trans-2 [62.3%; [R]23365 +337.0° (c 0.656, cyclohexane)]
and (+)-cis-2 (37.7%): 1H NMR (CCl4) 5.76 (s, 2H), 3.4-2.6 (m, 4H),
1.2 (d, J ) 8 Hz, 3H); [R]23D +64.4°, +64.9°, +64.2°; [R]23365 +224.6°,
+225.0°, +223.4° (c 0.817, 0.663, 0.457, respectively, cyclohexane);
MS m/z calcd 107.0771, found 107.0717.
Acknowledgment. We are grateful to the National Science
Foundation (Grants CHE 73 08689 and 76 24300) for its support
of this work. Our warmest thanks go to Professor John E.
Baldwin for his constructive criticisms and many helpful
suggestions.
Supporting Information Available: A figure comple-
menting Figure 6 and three tables of kinetic data (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
Reduction of Methyl (-)-trans-3-Methylcyclopentene-4-carbox-
ylate to Methyl (-)-trans-2-Methylcyclopentane-1-carboxylate. To
0.8 g of yellow potassium azodicarboxylate in 5 mL of dioxane (distilled
from sodium; stored over molecular sieves) under nitrogen was added
200 mg of methyl (-)-trans-3-methylcyclopentene-4-carboxylate {[R]23
JA0305961
D
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12362 J. AM. CHEM. SOC. VOL. 126, NO. 39, 2004