Stereochemistry of Cyclopropane Formation Involving Group IV Organometallic Complexes

Article abstract of DOI:10.1021/ja030436p

The reaction of (Z)-HDC=CHCH(OCH₃)C₆H₅ (1) with Cp₂Zr(D)Cl followed by BF₃·OEt₂ gave phenylcyclopropanes 3a and 3b, both having cis deuterium. This stereochemical outcome requires inversion

Full text of DOI:10.1021/ja030436p

Published on Web 01/27/2004
Stereochemistry of Cyclopropane Formation Involving
Group IV Organometallic Complexes
Charles P. Casey* and Neil A. Strotman
Contribution from the Department of Chemistry, UniVersity of Wisconsin,
Madison, Wisconsin 53706
Received July 18, 2003; E-mail: casey@chem.wisc.edu
Abstract: The reaction of (Z)-HDCdCHCH(OCH3)C6H5 (1) with Cp2Zr(D)Cl followed by BF3‚OEt2 gave
phenylcyclopropanes 3a and 3b, both having cis deuterium. This stereochemical outcome requires inversion
of configuration at the carbon bound to zirconium and is consistent with a “W-shaped” transition state
structure for cyclopropane formation. In a Kulinkovich hydroxycyclopropanation, trans-3-deutero-1-methyl-
cis-2-phenyl-1-cyclopropanol (5) was formed stereospecifically from Ti(O-i-Pr)4, ethyl acetate, EtMgBr, and
trans-â-deuterostyrene. This stereochemistry requires retention of configuration at the carbon bound to
titanium and is consistent with frontside attack of the carbon-titanium bond on a carbonyl group coordinated
to titanium. In a de Meijere cyclopropylamine synthesis, a 3:1 mixture of N,N-dimethyl-N-(trans-3-deutero-
trans-2-phenylcyclopropyl)amine (6a) and N,N-dimethyl-N-(cis-3-deutero-cis-2-phenylcyclopropyl)amine (6b)
was formed from Ti(O-i-Pr)4, DMF, Grignard reagents, and trans-â-deuterostyrene. This stereochemistry
requires inversion of configuration at the carbon bound to titanium and is consistent with a W-shaped
transition structure for ring closure.
Scheme 1
Introduction
Chemists’ continuing fascination with cyclopropanes and their
stereoselective synthesis was highlighted in a recent thematic
issue of Chemical ReViews.1 The cyclopropane unit plays an
important role in pharmaceuticals, agrochemicals, theoretically
interesting molecules, and intermediates in synthesis.2 Group
IV transition metal species are becoming widely used in the
synthesis of diverse arrays of polysubstituted cyclopropanes.3
For example, the Kulinkovich hydroxycyclopropanation of
alkenes, discovered in 1989,4 produces high yields of cyclo-
propanols from esters, Grignard reagents, and Ti(O-i-Pr)4
(Scheme 1). Catalytic amounts of Ti can be employed.5 The
Kulinkovich reaction has been applied both diastereo- and
enantioselectively.6,7 The reaction is proposed to involve Ti-
(II)-alkene complexes generated from the Grignard reagent.
The exchange of alkenes with the initial Ti(II)-alkene complex
has broadened the scope of the procedure.
nard reagents, and Ti(O-i-Pr)4 (Scheme 1).8 Exchange of alkenes
with a Ti(II)-alkene intermediate has broadened the scope of
this cyclopropylamine synthesis.9 The reaction requires stoi-
chiometric Ti(IV) but provides an efficient route to polysub-
stituted cyclopropylamines not readily obtained by other routes.
Primary cyclopropylamines have also been synthesized recently
from Ti(O-i-Pr)4, Grignard reagents, and nitriles.10
Recently, an efficient new synthesis of cyclopropanes, via
hydrozirconation of allylic ethers followed by addition of a
Lewis acid, was reported by Gandon and Szymoniak (Scheme
1).11 This procedure produced high yields of cyclopropanes
under mild conditions and was compatible with a variety of
alkyl, aryl, and alkenyl substituents.
A similar methodology was developed by de Meijere for the
synthesis of cyclopropylamines from N,N-dialkylamides, Grig-
(1) de Meijere, A. Chem. ReV. 2003, 103, 931.
(2) (a) Pietruszka, J. Chem. ReV. 2003, 103, 1051. (b) Gnad, F.; Reiser, O.
Chem. ReV. 2003, 103, 1603. (c) Wessjohann, L. A.; Brandt, W.; Thiemann,
T. Chem. ReV. 2003, 103, 1625. (d) Dolbier, W. R.; Battiste, M. A. Chem.
ReV. 2003, 103, 1071.
(3) For recent reviews of cyclopropane formation using early transition metal
reagents, see: (a) Kulinkovich, O. G.; de Meijere, A. Chem. ReV. 2000,
100, 2789. (b) Sato, F.; Urabe, H.; Okamoto, S. Chem. ReV. 2000, 100,
2835. (c) Titanium and Zirconium in Organic Synthesis; Marek, I., Ed.;
Wiley-VCH: Weinheim, 2002; pp 390-434.
(8) (a) Chaplinski, V.; de Meijere, A. Angew. Chem., Int. Ed. Engl. 1996, 35,
413. (b) Chaplinski, V.; Winsel, H.; Kordes, M.; de Meijere, A. Synlett
1997, 111. (c) Williams, C. M.; de Meijere, A. J. Chem. Soc., Perkin Trans.
1 1998, 3699. (d) de Meijere, A.; Chaplinski, V.; Gerson, F.; Merstetter,
P.; Haselbach, E. J. Org. Chem. 1999, 64, 6951.
(9) de Meijere, A.; Williams, C. M.; Kourdioukov, A.; Sviridov, S. V.;
Chaplinski, V.; Kordes, M.; Savchenko, A. I.; Stratmann, C.; Noltemeyer,
M. Chem.-Eur. J. 2002, 8, 3789.
(4) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevskii, D. A.; Pritytskaya, T. S.
Zh. Org. Khim. 1989, 25, 2244.
(5) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevski, D. A. Synthesis 1991, 234.
(6) (a) Kulinkovich, O. G.; Savchenko, A. I.; Sviridov, S. V.; Vasilevski, D.
A. MendeleeV Commun. 1993, 230. (b) Kasatkin, A.; Sato, F. Tetrahedron
Lett. 1995, 36, 6079. (c) Lee, J.; Kang, C. H.; Kim, H.; Cha, J. K. J. Am.
Chem. Soc. 1996, 118, 291. (d) Epstein, O. L.; Savchenko, A. I.;
Kulinkovich, O. G. Tetrahedron Lett. 1999, 40, 5935.
(10) (a) Bertus, P.; Szymoniak, J. Chem. Commun. 2001, 1792. (b) Bertus, P.;
Szymoniak, J. J. Org. Chem. 2002, 67, 3965. (c) Bertus, P.; Szymoniak, J.
Synlett 2003, 265. (d) Laroche, C.; Bertus, P.; Szymoniak, J. Tetrahedron
Lett. 2003, 44, 2485.
(7) Corey, E. J.; Rao, S. A.; Noe, M. C. J. Am. Chem. Soc. 1994, 116, 9345.
(11) Gandon, V.; Szymoniak, J. Chem. Commun. 2002, 1308.
9
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J. AM. CHEM. SOC. 2004, 126, 1699-1704
1699

A R T I C L E S
Casey and Strotman
Scheme 2
Scheme 3
Grignard reagent, and Ti(O-i-Pr)4 is shown to proceed with
retention of configuration at the titanium-carbon bond.
Results
Stereochemistry of Cyclopropane Formation from Allylic
Ethers, Cp2Zr(H)Cl, and Lewis Acids. The reaction of Cp2-
Zr(H)Cl with an allylic ether produces a γ-alkoxy-alkylzirco-
nium species, which upon treatment with a Lewis acid undergoes
nucleophilic substitution of the alkoxy group by the carbon
adjacent to zirconium.11 Three different transition structures for
cyclopropane ring closure and their stereochemical consequences
are shown in Scheme 2: (1) transition structure A depicted by
Gandon and Szymoniak which leads to retention of configura-
tion at both the carbon bound to zirconium and the carbon bound
to the ether oxygen,11 (2) transition structure B in which the
frontside of the carbon-zirconium bond attacks the backside
of the carbon oxygen bond of the Lewis acid coordinated ether
and results in retention of configuration at the carbon bound to
zirconium and inversion at the carbon bound to the ether oxygen,
and (3) our proposed W-shaped transition structure C which
leads to inversion of configuration at both carbon centers.
To distinguish between these stereochemical implications, we
investigated the cyclopropane formation using deuterium label-
ing. Cis addition15 of Cp2Zr(D)Cl to the allylic ether (Z)-HDCd
CHCH(OCH3)C6H5 (1) gave a mixture of diastereomeric alkyl
zirconium compounds 2a and 2b (Scheme 3).16 The stereo-
chemistry of labeled phenylcyclopropanes obtained from reac-
tion of this diastereomeric mixture of 2a and 2b with Lewis
acids is determined by the mechanism of ring closure. Transition
structures A and B predict formation of phenylcyclopropane
bearing trans deuterium labels. In contrast, the W-shaped
transition structure predicts formation of two isomers of
phenylcyclopropane, both bearing cis deuterium labels.
Gandon and Szymoniak envisioned that cyclopropane forma-
tion might result from coordination of the ether oxygen to both
zirconium and the added Lewis acid, followed by a frontside
displacement of the alkoxy group by the carbon-zirconium
bond (structure A, Scheme 2). This mechanism retains the
configuration of the carbon bound to zirconium and of the
carbon bound to oxygen. However, this ring closure mechanism
seemed questionable because an ether oxygen already coordi-
nated to a Lewis acid would not be expected to coordinate to
zirconium. Moreover, frontside displacement at an sp3 hybrid-
ized ether center is very unfavorable.
We hypothesized that this cyclopropane formation might oc-
cur via a “W-shaped” transition state structure in which the back-
side of the carbon-zirconium bond attacks the backside of the
carbon-oxygen bond of the Lewis acid coordinated ether (struc-
ture C, Scheme 2). The W-shaped transition structure results
in inversion of configuration at both the carbon bound to zir-
conium and the carbon bound to the ether oxygen. Our group12
and Brookhart’s13 have shown that W-shaped transition struc-
tures are involved in cyclopropane formation in organoiron
chemistry. W-shaped transition structures were first established
for cyclopropanations involving organotin compounds.14 Be-
cause organometallic species most often react with retention of
configuration at the carbon-metal bond, we decided to test our
prediction that Gandon and Szymoniak’s cyclopropane synthesis
occurred with inversion of configuration at the carbon-
zirconium bond.
Following a procedure similar to that of Gandon and Szymo-
niak,11 deuterium labeled allyl ether 1 was added to a solution
of Cp2Zr(D)Cl in CH2Cl2 at room temperature. After 30 min,
the solution was cooled to 0 °C, the Lewis acid BF3‚OEt2 was
added, and the solution was warmed to room temperature over
1 h. Labeled phenylcyclopropanes were isolated in 53% yield
after flash column chromatography on silica gel (Scheme 4).17
Here, we report that cyclopropane formation from an allylic
ether, Cp2Zr(H)Cl, and a Lewis acid occurs with inversion of
configuration at the zirconium-carbon bond consistent with a
W-shaped transition structure. In addition, formation of cyclo-
propylamines from an amide, a Grignard reagent, and Ti(O-i-
Pr)4 is shown to proceed with inversion of configuration at the
titanium-carbon bond and occurs via a W-shaped transition
structure. In contrast, cyclopropanol formation from an ester, a
1
1D and 2D H NMR spectroscopy showed that the phenyl-
cyclopropane was a 5:1 mixture of 3a:3b, both of which have
cis deuterium, and that less than 3% of 4, which has trans
(12) (a) Casey, C. P.; Smith, L. J. Organometallics 1989, 8, 2288. (b) Casey,
C. P.; Vosejpka, L. J. S. Organometallics 1992, 11, 738.
(15) Hydrozirconation of olefins has been shown to proceed by cis addition.
(a) Labinger, J. A.; Hart, D. W.; Seibert, W. E., III; Schwartz, J. J. Am.
Chem. Soc. 1975, 97, 3851. (b) Schwartz, J.; Labinger, J. A. Angew. Chem.,
Int. Ed. Engl. 1976, 15, 333.
(13) (a) Brookhart, M.; Liu, Y. Organometallics 1989, 8, 1569. (b) Brookhart,
M.; Liu, Y. J. Am. Chem. Soc. 1991, 113, 939.
(14) (a) Davis, D. D.; Chambers, R. L.; Johnson, H. T. J. Organomet. Chem.
1970, 25, C13. (b) Davis, D. D.; Black, R. H. J. Organomet. Chem. 1974,
82, C30. (c) Davis, D. D.; Johnson, H. T. J. Am. Chem. Soc. 1974, 96,
7576. (d) Fleming, I.; Urch, C. J. Tetrahedron Lett. 1983, 24, 4591. (e)
Fleming, I.; Urch, C. J. J. Organomet. Chem. 1985, 285, 173.
(16) In the 1H NMR spectrum of the alkylzirconium species 2a and 2b, only
resonances for the major isomer were readily discernible. The configuration
of the major isomer could not be assigned.
(17) The reaction of the mixture of 2a and 2b with TMSOTf as the Lewis acid
gave a 29% yield of a 5:1 mixture of labeled phenylcyclopropanes 3a:3b.
9
1700 J. AM. CHEM. SOC. VOL. 126, NO. 6, 2004

Stereochemistry of Cyclopropane Formation
A R T I C L E S
Scheme 4
Scheme 5
deuterium, was present (Scheme 4). In the 1H NMR spectrum,
the major isomer, 3a, gave rise to a doublet (J ) 8.4 Hz) at δ
0.927 corresponding to the two cis hydrogens each trans to
phenyl, and to a triplet (J ) 8.4 Hz) at δ 1.874 for the proton
geminal to phenyl.18,19 The minor isomer, 3b, exhibited a doublet
(J ) 5.1 Hz) at δ 0.673 for the two protons cis to phenyl and
a triplet (J ) 5.1 Hz) at δ 1.872 for the proton geminal to phenyl,
which was completely obscured by the resonance of 3a at δ
1.874. Compound 4 would have produced a doublet of doublets
(J ) 8.4, 5.1 Hz) at δ 0.927 with the outermost peaks ∼2.5 Hz
outside of the doublet resulting from 3a. Integration of this
region put an upper limit of 5% on the amount of 4 produced.20
In a 1D TOCSY experiment in which the hydrogens trans to
phenyl (δ 0.927) were pulsed, a major signal at δ 1.874 (t, J )
8.4 Hz) was observed due to magnetization transfer to the proton
geminal to phenyl in 3a, and a very minor signal (<3%) was
seen at δ 0.67 due to hydrogens cis to phenyl either in mono-
deuterated phenyl cyclopropane or in 4. In a second 1D TOCSY
experiment in which the hydrogens cis to phenyl (δ 0.673) were
pulsed, a major signal at δ 1.872 (J ) 5.1 Hz) was observed
due to magnetization transfer to the proton geminal to phenyl
in 3b, and a minor signal (<15%) was seen at δ 0.93 due to
hydrogens trans to phenyl either in monodeuterated phenyl cy-
clopropane or in 4. Observation of COSY cross-peaks demon-
strated coupling between the protons of 3a at δ 0.927 and δ
1.874 and between the protons of 3b at δ 0.673 and δ 1.872.
The failure to see a cross-peak between the resonances at δ
0.673 and δ 0.927 establishes that only negligible amounts of
4 were present.
The exclusive formation of 3a and 3b, both of which have
cis deuterium, requires inversion of configuration at the carbon
bound to zirconium and is consistent with a W-shaped transition
state structure for this cyclopropanation. This stereochemistry
excludes all ring closure mechanisms involving retention of
stereochemistry at the carbon bound to zirconium including
those involving transition structures A and B. In addition, the
5:1 ratio of 3a:3b observed indicates a preference for addition
of Cp2Zr(D)Cl to one face of the allylic ether and excludes a
step in which the stereochemical information is lost.
Stereochemistry of Cyclopropanol Formation. In the
Kulinkovich hydroxycyclopropanation, ring closure has been
suggested to occur by intramolecular addition of a titanium alkyl
to an electrophilic carbon γ to titanium (Scheme 5). This is an
arrangement similar to that seen in cyclopropane formation via
hydrozirconation of allylic ethers followed by addition of a
Lewis acid. As shown above, this ring closure occurs with in-
version of configuration at the carbon-zirconium bond via a
W-shaped transition structure. We wondered whether the
Kulinkovich hydroxycyclopropanation might also proceed with
inversion of configuration at the carbon-titanium bond via a
W-shaped transition structure.
The well-studied variation of the Kulinkovich hydroxycy-
clopropanation in which 1-methyl-cis-2-phenyl-1-cyclopropanol
is formed by reaction of Ti(O-i-Pr)4, ethyl acetate, RMgBr, and
styrene6a,d,7 provides a convenient platform for studying the
stereochemistry of ring closure if deuterium labeling is em-
ployed. In the proposed catalytic cycle (Scheme 5), reaction of
2 equiv of EtMgBr with Ti(O-i-Pr)4 generates an unstable di-
alkyltitanium species (D) which eliminates ethane to form a
Ti(II) ethylene complex (E). A sequence involving styrene
displacement of ethylene, coordination of ethyl acetate, and re-
ductive coupling of styrene and ethyl acetate leads to formation
of a five-membered titanacycle (F).21 F is shown with phenyl
R to Ti by analogy with quenching studies of the reaction of
ketones or imides with alkenes.22 This regiochemistry is also
suggested by DFT calculations.23 Transfer of the ethoxy group
to titanium and breaking of the Ti-O bond of titanacycle F
produces an alkyltitanium species with a γ-ketone group (G).
Intramolecular addition of the alkyltitanium to the ketone pro-
duces a titanium cyclopropoxide. Subsequent reaction with
EtMgBr produces the magnesium cyclopropoxide and regener-
ates the catalyst.
Three pathways for ring closure and their stereochemical
consequences are shown in Scheme 6. In the first, the backside
of the carbon-titanium bond of G attacks the ketone carbonyl
via a W-shaped transition structure that involves inversion of
configuration at the carbon bound to titanium. In the second,
chelation of the ketone carbonyl to titanium via either σ- or
π-complexation is followed by frontside attack of the carbon-
titanium bond on the coordinated carbonyl to effect ring closure
with retention of configuration at the carbon bound to titanium.
The third is similar to the second but involves the alkoxy bridged
dititanium species H with one titanium acting as a Lewis acid
to activate the carbonyl and the other acting as a nucleophilic
alkyl. This third pathway also involves the frontside of the
(21) The regiochemistry of insertion of styrene is shown as having the Ph R to
Ti. If the titanacycle had formed with the alternative regiochemistry with
Ph â to titanium, the observed stereochemistry of the cyclopropane would
also have required retention of configuration at the carbon bonded to
titanium.
(22) (a) Morlender-Vais, N.; Solodovnikova, N.; Marek, I. Chem. Commun. 2000,
1849. (b) Lee, J.; Ha, J. D.; Cha, J. K. J. Am. Chem. Soc. 1997, 119, 8127.
(23) Wu, Y.-D.; Yu, Z.-X. J. Am. Chem. Soc. 2001, 123, 5777.
(18) These NMR data are similar to those reported by Brookhart.13
(19) In cyclopropanes, cis couplings are larger than trans couplings. Pretsch,
E.; Bu¨hlmann, P.; Affolter, C. Structure Determination of Organic
Compounds; Springer: New York, 2000.
(20) Because of deuterium coupling, it was not possible to use line shape
simulations to estimate the amount of 4.
9
J. AM. CHEM. SOC. VOL. 126, NO. 6, 2004 1701

A R T I C L E S
Casey and Strotman
Scheme 6
Figure 1. nOe enhancements upon irradiation of methyl resonance of 5.
Scheme 8
Scheme 7
alkyltitanium species and leads to ring closure with retention
of configuration at the carbon bound to titanium.
trans-â-Deuterostyrene was prepared by addition of [(CH3)2-
CHCH2]2AlH (DIBAL-H) to phenylacetylene, followed by
quenching with EtOD (Scheme 7). Residual phenylacetylene
was removed by treatment with AgNO3 in tributylamine, and
pure trans-â-deuterostyrene was obtained by subsequent distil-
lation.24 Using a modification of Kulinkovich’s procedure,6d we
synthesized monodeuterated 1-methyl-cis-2-phenyl-1-cyclopro-
panol by slow addition of ethylmagnesium bromide (2.5 equiv)
to ethyl acetate, Ti(O-i-Pr)4 (0.2 equiv), and trans-â-deuterosty-
rene (2 equiv) in refluxing ether, followed by quenching with
cold 10% sulfuric acid. Recrystallization from pentane/ether
gave monodeuterated 1-methyl-cis-2-phenyl-1-cyclopropanol as
a white crystalline solid. None of the related trans isomer was
observed.4,6,7
The exclusive formation of 5 indicates retention of config-
uration at the carbon bound to titanium. This result precludes a
W-shaped transition state structure and requires a closure
pathway involving frontside attack by the carbon-titanium
bond. This is most likely facilitated by σ- or π-carbonyl
coordination to the same titanium or to a second titanium.
Stereochemistry of Cyclopropylamine Formation. The pro-
posed mechanism of cyclopropylamine formation from Ti(O-
i-Pr)4, Grignard reagents, an alkene, and a formamide is similar
to that proposed for the Kulinkovich cyclopropanol synthesis
up to the formation of a titanacycle intermediate.3a,8a,b,9 In the
case of cyclopropylamine formation, metallacycle I is suggested
to ring open to give an iminium unit tethered to titanium in J.
Ring closure is unlikely to proceed by the unfavorable coordina-
tion of a cationic iminium unit to an electropositive titanium.
Two distinguishable processes for ring closure are shown in
Scheme 8. The first involves frontside attack of the carbon-
titanium bond on the iminium carbon, resulting in retention of
configuration at the carbon bound to titanium. The second
involves the W-shaped transition structure K in which the back
lobe of the carbon-titanium bond attacks the iminium center,
resulting in inversion of configuration at the carbon bound to
titanium. These pathways are distinguishable when trans-â-
deuterostyrene is employed: retention of configuration leads
to cyclopropylamines with deuterium and phenyl trans to one
another, while inversion of configuration leads to cyclopropyl-
amines with deuterium and phenyl cis to one another.
1H NMR spectroscopy established that the only cyclopropane
isomer formed was trans-3-deutero-1-methyl-cis-2-phenyl-1-
cyclopropanol (5) (Figure 1). In unlabeled 1-methyl-cis-2-
phenyl-1-cyclopropanol, the hydrogen on C3 cis to the OH
group appears at δ 1.25 and has a large cis coupling (J ) 10.2
Hz) to the benzylic hydrogen, while the hydrogen on C3 trans
to the OH group appears at δ 0.99 and has a small trans coupling
1
(J ) 6.0 Hz) to the benzylic hydrogen on C2. The H NMR
spectrum of 5 showed chemical shifts consistent with those
observed for the unlabeled species, but lacked a resonance at δ
1.25 corresponding to a proton at C3 cis to the hydroxyl. Based
on the integration of the δ 1.25 region, an upper limit of 2%
can be placed on the amount of cis-3-deutero-1-methyl-cis-2-
phenyl-1-cyclopropanol and nondeuterated 1-methyl-cis-2-phen-
yl-1-cyclopropanol formed.
NOESY 1D spectroscopy confirmed the labeling assignment
(Figure 1). When the methyl resonance of 5 at δ 1.20 was
pulsed, magnetization transfer resulted in a 5.0% nOe enhance-
ment of the δ 0.97 resonance of the proton on C3 cis to the
methyl group and in a 2.1% nOe enhancement of the δ 7.14
resonance of the ortho phenyl protons, but only a 1.0% nOe
enhancement of the δ 2.35 resonance of the benzylic proton
(trans to methyl). These nOe observations support both the
stereochemical assignment of 1-methyl-cis-2-phenyl-1-cyclo-
propanol and the labeling pattern of 5.
trans-â-Deuterostyrene was converted to cis and trans isomers
of N,N-dimethyl-N-(2-phenylcyclopropyl)amine using a modi-
fication of de Meijere’s procedure.9 CH3Ti(O-i-Pr)3 was gener-
ated from Ti(O-i-Pr)4 and MeMgCl. DMF and trans-â-
deuterostyrene were added, and then cyclohexylmagnesium
chloride was added dropwise at 0 °C. Flash column chroma-
tography gave a mixture of monodeuterated N,N-dimethyl-N-
(trans-2-phenylcyclopropyl)amine (6a) and N,N-dimethyl-N-
(24) Fagan, M. A. Ph.D. Thesis, University of Wisconsin-Madison, 1999; p 166.
9
1702 J. AM. CHEM. SOC. VOL. 126, NO. 6, 2004

Stereochemistry of Cyclopropane Formation
A R T I C L E S
Scheme 9
Scheme 10
interaction within a transition state having an agostic interaction
between an R carbon-hydrogen bond and titanium.23
Inversion of configuration at the carbon bound to the metal
center was observed in the de Meijere cyclopropylamine
synthesis of 6a and 6b (Scheme 9). Reaction at the frontside of
the carbon metal bond is disfavored by steric effects, and
reaction at the backside of the carbon metal bond with a
γ-electrophile is sterically more accessible. Ouhamou and Six
observed a similar inversion of stereochemistry at a titanium
carbon bond in an intramolecular cyclopropylamine synthesis
(Scheme 10).27
Inversion of configuration at the carbon bound to the metal
center was also observed in the formation of phenylcyclopropane
from Cp2Zr(D)Cl, an allylic ether, and BF3‚OEt2 (Scheme 4).
The W-shaped transition structure C suggested for phenylcy-
clopropane formation is well precedented in both iron and tin
chemistry (Scheme 2). The 5:1 ratio of 3a:3b is mechanistically
significant. It requires that the zirconium hydride add selectively
to one diastereoface of the alkene and that the stereochemical
information not be lost in a subsequent step. Thus, a mechanism
in which Lewis acid assisted ionization of the carbon-oxygen
bond occurred to give a carbocation intermediate can be ex-
cluded,28 because rotation about the carbon-carbon bond of
such a carbocation intermediate would have given a 1:1 ratio
of 3a:3b.
The switch from retention of configuration at the carbon
bound to titanium in the Kulinkovich hydroxycyclopropanation
to inversion of configuration in the de Meijere cyclopropylamine
synthesis can be readily explained. In the Kulinkovich hydroxy-
cyclopropanation, frontside attack of the carbon-titanium bond
on a carbonyl group is strongly favored by its coordination to
titanium. In contrast, the positively charged iminium group in
the de Meijere cyclopropylamine synthesis cannot coordinate
to the electrophilic titanium. Ring closure therefore occurs via
the less sterically demanding W-shaped transition state structure
K in which the backside of the carbon-titanium bond attacks
the electrophilic γ-iminium group to produce a cyclopropylam-
ine with inversion at the carbon bound to titanium (Scheme 8).
(cis-2-phenylcyclopropyl)amine (6b) in 36% and 12% yields,
respectively (Scheme 9).
The minor isomer was shown to be N,N-dimethyl-N-(cis-3-
deutero-cis-2-phenylcyclopropyl)amine (6b) by proton NMR
spectroscopy (Scheme 9). The proton geminal to deuterium (δ
1.04) showed two large couplings of 9.0 and 6.9 Hz to cis pro-
tons. The other two cyclopropyl protons (δ 1.98, δ 1.84) each
showed two large coupling constants, supporting the cis dis-
position of all three protons.19 This requires that the deuterium,
phenyl, and N,N-dimethylamino groups all be on the same face
of the cyclopropane and establishes the structure of 6b.
In the 1H NMR spectrum of the major isomer, N,N-dimethyl-
N-(trans-3-deutero-trans-2-phenylcyclopropyl)amine (6a), a dou-
blet of doublets at δ 1.08 was seen for the proton geminal to
deuterium with one large coupling constant (J ) 9.6 Hz) to a
cis proton and one smaller coupling constant (J ) 4.5 Hz) to a
trans proton. Although this established the trans relationship of
the phenyl and N,N-dimethylamino groups, the orientation of
the deuterium could not be definitively assigned because the
protons adjacent to the phenyl and amino groups had very
similar frequencies.
1D NOESY spectroscopy definitively established the con-
figuration at the carbon bearing deuterium in 6a. When the CHD
resonance at δ 1.08 was pulsed, magnetization transfer resulted
in a 0.5% nOe enhancement of the δ 2.38 resonance of the NMe2
group and a 4.6% nOe enhancement of the δ 1.96 resonance of
the benzylic proton, but no enhancement of any of the phenyl
resonances (Scheme 9). This requires that the proton geminal
to deuterium (δ 1.08) be cis to NMe2 and trans to phenyl.
In the major product 6a, the two large substituents are trans
to one another, while in the minor isomer 6b they are cis. More
significantly, in both 6a and 6b, deuterium and phenyl are cis
to one another. This stereochemical outcome requires inversion
of configuration at the carbon bearing titanium and is consistent
with a W-shaped transition state structure for ring closure
(Scheme 8).
Experimental Section
(Z)-CHDdCHCH(OH)C6H5.29 1-Phenyl-2-propyn-1-ol (1.32 g,
10.0 mmol) was added to a solution of LiAlH4 (380 mg, 10.0 mmol)
in THF (30 mL) at 0 °C and was stirred for 24 h at room temperature.
D2O (1 mL) was added dropwise over 15 min followed by an additional
6 mL of D2O. The reaction mixture was poured into Et2O (600 mL).
The ether solution was washed with H2O (3 × 150 mL) and dried
(MgSO4). Evaporation of solvent gave (Z)-3-deutero-1-phenyl-2-propen-
Discussion
The Kulinkovich hydroxycyclopropanation occurs with reten-
tion of configuration at the carbon bound to titanium. This is
the usual stereochemical result for reactions of organolithium
and magnesium reagents with electrophiles.25 Coordination of
the carbonyl group to titanium in either a mononuclear (G) or
a bridged dititanium (H) transition structure for ring closure
would favor attack by the frontside of the carbon titanium bond
and result in retention of configuration (Scheme 6). A rationale
for production of only the thermodynamically less stable cis
isomer 526 has been proposed. On the basis of DFT calculations,
Wu suggested that the cis preference derives from steric
(25) (a) Jensen, F. R.; Nakamaye, K. L. J. Am. Chem. Soc. 1966, 88, 3437. (b)
Hoffmann, R. W.; Ho¨lzer, B. Chem. Commun. 2001, 491.
(26) The configuration of 5 had been confirmed by X-ray diffraction.7
(27) Ouhamou, N.; Six, Y. Org. Biomol. Chem. 2003, 1, 3007.
(28) Brookhart found evidence for intermediate carbocations γ to iron in
cyclopropane formation from the reaction of a cationic iron carbene complex
with (Z)-HDCdCHC6H4-p-OMe. Brookhart, M.; Kegley, S. E.; Husk, G.
R. Organometallics 1984, 3, 650. He also suggested involvement of
γ-carbocation intermediates in cyclopropane formation in the reaction of
(γ-methoxy)alkyliron compounds with Lewis acids.13
(29) (a) Grant, B.; Djerassi, C. J. Org. Chem. 1974, 39, 968. (b) Kang, M. J.;
Jang, J.-S.; Lee, S.-G. Tetrahedron Lett. 1995, 36, 8829.
9
J. AM. CHEM. SOC. VOL. 126, NO. 6, 2004 1703

A R T I C L E S
Casey and Strotman
1
1-ol as a yellow oil (1.36 g, 109%). H NMR (300 MHz, CDCl3): δ
7.40-7.25 (m, aromatic), 6.04 (ddt, JHH ) 10.2, 6.0 Hz, JHD ) 3.3 Hz,
HDCdCH), 5.18 (dd, J ) 10.2, 1.2 Hz, HDCdC), 5.20 (broad dd, J
) 5.9, 2.8 Hz, HCO), 2.06 (broad s, OH). 13C NMR {1H} (75 MHz,
CDCl3): δ 142.78, 140.33, 128.76 (2C), 127.95, 126.52 (2C), 115.04
(t, JCD ) 23.8 Hz), 75.51. HRMS (ESI) calcd for C9H9DO (M+)
135.0794, found 135.0795.
mL) was added dropwise to a solution of EtOAc (0.98 mL, 10 mmol),
trans-â-deuterostyrene (2.10 g, 20 mmol), and Ti(O-i-Pr)4 (0.59 mL,
2.0 mmol) in ether (15 mL) heated at reflux. After an additional 30
min at reflux, the reaction mixture was poured into ice-cold 10% sulfuric
acid (50 mL), and the organic layer was separated. The aqueous layer
was extracted with ether (2 × 20 mL), and the combined organic layers
were washed with saturated aqueous sodium bicarbonate (40 mL) and
then H2O (40 mL). Evaporation of solvent and subsequent recrystal-
lization from pentane/ether gave 5 (0.43 g, 29%) as a white crystalline
solid, mp 78-80 °C (lit30 80-81 °C). 1H NMR (300 MHz, CDCl3): δ
7.28 (t, J ) 7.2 Hz, meta), 7.22-7.12 (m, ortho/para), 2.35 (d, J ) 6.9
Hz, HCPh), 2.11 (br s, OH), 1.20 (s, CH3), 0.97 (d, J ) 6.9 Hz, HDC).
NOESY 1D (500 MHz, CDCl3): the methyl resonance at δ 1.20 was
pulsed and integrated for -3.000 H, the resonance at δ 0.97 for the
proton on C3 cis to the methyl group integrated for 0.050 H (5.0%),
the resonance at δ 2.35 for the benzylic hydrogen integrated for 0.010
H (1.0%), and the resonance at δ 7.14 for the ortho phenyl protons
integrated for 0.042 H (2.1%). 13C NMR {1H} (75 MHZ, CDCl3): δ
138.75, 128.60 (2C), 128.36 (2C), 126.18, 57.68, 30.80, 20.88, 18.77
(t, JCD ) 24.8 Hz). HRMS (EI) calcd for C10H11OD (M+) 149.0951,
found 149.0950.
(Z)-HDCdCHCH(OCH3)C6H5 (1). (Z)-3-Deutero-1-phenyl-2-pro-
pen-1-ol (1.00 g, 7.41 mmol) in THF (7.4 mL) was added dropwise to
a suspension of NaH (800 mg, 60% dispersion in mineral oil, 20 mmol)
in a THF (12 mL) solution of CH3I (1.21 mL, 19.4 mmol) at 45 °C.
After 45 min, H2O was added dropwise at room temperature until
hydrogen evolution ceased. An additional 30 mL of H2O was added,
and the mixture was extracted with Et2O (2 × 200 mL). The combined
Et2O layers were washed with H2O (4 × 100 mL), dried (MgSO4),
and concentrated on a rotary evaporator. Flash column chromatography
(silica gel, 20:1 pentane:ether) gave 1 as a colorless oil (0.76 g, 69%).
1H NMR (300 MHz, CDCl3): δ 7.4-7.2 (m), 5.92 (ddt, JHH ) 10.2,
6.9, JHD ) 2.5 Hz, HDCdCH), 5.19 (dd, J ) 10.2, 0.9 Hz, HDCdC),
4.62 (dd, J ) 6.6, 0.9 Hz, CHO), 3.32 (s, OCH3). 13C NMR {1H} (75
MHz, CDCl3): δ 141.1, 138.9, 128.7 (2C), 127.9, 127.0 (2C), 116.2
(t, JCD ) 23.8 Hz), 84.9, 56.6. HRMS (ESI) calcd for C10H11DONa
(M + Na+) 172.0848, found 172.0844.
2-cis-3-cis-Dideuterophenylcyclopropane (3a) and 2-trans-3-trans-
Dideuterophenylcyclopropane (3b).11 A solution of 1 (298 mg, 2.0
mmol) in 1 mL of CH2Cl2 was added to a suspension of Cp2Zr(D)Cl
(518 mg, 2.00 mmol) in 6 mL of CH2Cl2. After 30 min, the solution
was cooled to 0 °C, and BF3‚OEt2 (279 mL, 2.2 mmol) was added by
syringe. After 5 min at 0 °C and 1 h at room temperature, saturated
aqueous NaHCO3 (10 mL) was added, and the mixture was extracted
with CH2Cl2 (3 × 20 mL). The combined extracts were washed with
H2O (2 × 10 mL), dried (MgSO4), and concentrated on a rotary
evaporator. Flash column chromatography (silica gel, 20:1 pentane:
ether) gave a 5:1 mixture of 3a:3b as a colorless oil (127 mg, 53%).
HRMS (EI) calcd for C9H8D2 (M+) 120.0908, found 120.0904. 13C
NMR {1H} (75 MHz; CDCl3): δ 144.160, 128.468 (2C), 125.86 (2C),
125.547, 15.40, 8.94 (t, JCD ) 24.6 Hz). 1H NMR (300 MHz, CDCl3)
assigned to 3a: δ 7.25 (t, J ) 7.2 Hz, meta), 7.13 (tt, J ) 7.4, 1.4 Hz,
para), 7.07 (d, J ) 7.6 Hz, ortho), 1.874 (t, J ) 8.4 Hz, HCPh), 0.927
(d, J ) 8.4 Hz, CHDCHD); assigned to 3b: δ 0.673 (d, J ) 5.1 Hz,
CHDCHD), CHPh of 3b obscured. 1D TOCSY (500 MHz, CDCl3)
pulsed at δ 0.673 w δ 1.872 [t, J ) 5.1 Hz, HCPh (3b)], pulsed at δ
0.927 w δ 1.874 [t, J ) 8.4 Hz, HCPh (3a)].
trans-â-Deuterostyrene.24 [(CH3)2CHCH2]2AlH (DIBAL-H) (182
mL, 1 M solution in hexane, 0.182 mol) was added to a solution of
phenylacetylene (20.0 mL, 0.182 mol) and hexane (160 mL) and stirred
at 60 °C for 5 h. Evaporation of hexane and unreacted phenylacetylene
under vacuum (4 × 10-2 Torr) overnight gave a red oil. The red oil
was dissolved in 40 mL of ether, and EtOD (2 mL) was added slowly
at -78 °C. After the vigorous reaction had subsided, additional EtOD
(25 mL) was added, and the solution warmed to room temperature.
The resulting solution was poured into a 2 M solution of sodium
potassium tartrate (500 mL) and was extracted with ether (2 × 200
mL). The combined organic layer was washed with H2O (200 mL)
and was concentrated on a rotary evaporator. The resulting mixture of
styrene and phenylacetylene was added to a suspension of AgNO3 (10.2
g, 0.060 mol) in tributylamine (17.2 mL, 0.070 mol) and tetraglyme
(20 mL). A gray precipitate (silver acetylides) formed over 1.5 h. The
volatiles were vacuum transferred (4 × 10-2 Torr) from the reaction
mixture into a flask cooled with liquid nitrogen. This material was
distilled (37 °C, 10-20 Torr) through a Vigreux column to give trans-
â-deuterostyrene as a colorless oil (9.5 g, 50%). This material was
shown by 1H NMR spectroscopy to contain less than 1% phenylacety-
lene and less than 2% undeuterated styrene.
N,N-Dimethyl-N-(trans-3-deutero-trans-2-phenylcyclopropyl)-
amine (6a) and N,N-Dimethyl-N-(cis-3-deutero-cis-2-phenylcyclo-
propyl)amine (6b).9 A solution of CH3Ti(O-i-Pr)3 was prepared by
adding MeMgCl (1.79 mL, 3.0 M solution in THF, 5.37 mmol)
dropwise over 10 min to Ti(O-i-Pr)4 (1.43 mL, 4.88 mmol) in THF
(15 mL) at 0 °C. After the mixture was stirred for an additional 5 min,
N,N-dimethylformamide (0.344 mL, 4.44 mmol) in THF (6 mL) and
then trans-â-deuterostyrene (0.560 mL, 4.88 mmol) were added. While
the solution was maintained at 0 °C, cyclohexylmagnesium chloride
(2.69 mL, 2.0 M solution in Et2O, 5.38 mmol) was added dropwise
over 50 min. The mixture was stirred at room temperature for 20 h
and then quenched with H2O (2.5 mL) to give a gray precipitate. The
solution was vacuum filtered, and the solid was washed with Et2O (20
mL). The combined yellow filtrate was concentrated by rotary evapora-
tion and was purified by flash column chromatography (silica gel, 100:
2-100:6 pentane:ether). Compound 6b (84 mg, 12%) eluted first as a
colorless oil, followed by 6a (257 mg, 36%) as a pale yellow oil.
For 6a, 1H NMR (300 MHz, CDCl3): δ 7.25 (t, J ) 7.2 Hz, meta),
7.15 (tt, J ) 7.2, 1.5 Hz, para), 7.06 (d, J ) 7.7 Hz, 2H, ortho), 2.38
(s, NMe2), 1.96 (dd, J ) 9.6, 3.0 Hz, HCPh), 1.78 (dd, J ) 3.9, 3.3
Hz, HCN), 1.08 (dd, J ) 9.6, 4.5 Hz, HCD). NOESY 1D (500 MHz,
CDCl3): the proton geminal to deuterium at δ 1.08 was pulsed and
integrated for -1.000 H, the resonance at δ 1.96 for the benzylic
hydrogen integrated for 0.046 H (4.6%), and the resonance at δ 2.38
for the dimethylamino group integrated for 0.033 H (0.5%). 13C NMR
{1H} (125 MHz, CDCl3): δ 142.33, 128.42 (2C), 126.25 (2C), 125.76,
50.30, 45.20 (2C), 25.39, 17.11 (t, JCD ) 25.0 Hz). 1D NOESY (500
MHz, CDCl3): δ 1.08 w δ 2.38 (0.5%), δ 1.96 (4.6%). HRMS (EI)
calcd for C11H14DN (M+) 162.1266, found 162.1258.
For 6b, 1H NMR (300 MHz, CDCl3): δ 7.28 (d, J ) 7.6 Hz, ortho),
7.24 (t, J ) 7.9 Hz, meta), 7.15 (tt, J ) 6.9, 1.8 Hz, para), 2.13 (s,
NMe2), 1.98 (t, J ) 8.0 Hz, HCPh), 1.84 (t, J ) 7.1 Hz, HCN), 1.04
(dd, J ) 9.0, 6.9 Hz, HCD). 13C NMR {1H} (75 MHz, CDCl3): δ
139.10, 128.44 (2C), 127.72 (2C), 125.48, 47.46, 45.37 (2C), 24.13,
13.36 (t, JCD ) 24.2 Hz). HRMS (EI) calcd for C11H14DN (M+)
162.1266, found 162.1266.
Acknowledgment. Financial support from the National Sci-
ence Foundation is gratefully acknowledged.
JA030436P
trans-3-Deutero-1-methyl-cis-2-phenyl-1-cyclopropanol (5).6d Over
1 h, EtMgBr (8.33 mL, 3 M solution in ether, 25 mmol) in ether (7
(30) DePuy, C. H.; Breitbeil, F. W.; DeBruin, K. R. J. Am. Chem. Soc. 1966,
88, 3347.
9
1704 J. AM. CHEM. SOC. VOL. 126, NO. 6, 2004