Dimethylzinc-mediated additions of alkenylzirconocenes to aldimines. New methodologies for allylic amine and C-cyclopropylalkylamine syntheses

Article abstract of DOI:10.1021/ja028092a

Hydrozirconation of alkynes with zirconocene hydrochloride followed by in situ transmetalation to dimethylzinc provides access to reactive alkenyl organometallic reagents from readily available precursors. Upon addition of imines, 1,2-attack leads to synthetically useful allylic amine building blocks. In the presence of CH₂I₂ or CH₂Cl₂, the N-metalated allylic amide intermediate is cyclopropanated and C-cyclopropylalkylamines are formed in high yield and excellent diastereoselectivities favoring the anti products. The use of enynes as starting materials for this domino reaction provides conjugated biscyclopropanes and thus allows the stereoselective formation of five new carbon-carbon bonds. A transition state that explains the need for both zirconocene complex and alkyl zinc in the cyclopropanation reaction is proposed.

Full text of DOI:10.1021/ja028092a

Published on Web 12/20/2002
Dimethylzinc-Mediated Additions of Alkenylzirconocenes to
Aldimines. New Methodologies for Allylic Amine and
C-Cyclopropylalkylamine Syntheses
Peter Wipf,* Christopher Kendall, and Corey R. J. Stephenson
Contribution from the Department of Chemistry, UniVersity of Pittsburgh,
Pittsburgh, PennsylVania 15260
Received August 9, 2002 ; E-mail: pwipf@pitt.edu
Abstract: Hydrozirconation of alkynes with zirconocene hydrochloride followed by in situ transmetalation
to dimethylzinc provides access to reactive alkenyl organometallic reagents from readily available precursors.
Upon addition of imines, 1,2-attack leads to synthetically useful allylic amine building blocks. In the presence
of CH2I2 or CH2Cl2, the N-metalated allylic amide intermediate is cyclopropanated and C-cyclopropylalkyl-
amines are formed in high yield and excellent diastereoselectivities favoring the anti products. The use of
enynes as starting materials for this domino reaction provides conjugated biscyclopropanes and thus allows
the stereoselective formation of five new carbon-carbon bonds. A transition state that explains the need
for both zirconocene complex and alkyl zinc in the cyclopropanation reaction is proposed.
with zinc alkyne complexes.10 As an extension of our studies
on the use of zirconocenes for the preparation of allylic alco-
Introduction
The formation of chiral secondary alcohols through the
enantioselective addition of organozinc reagents to aldehydes
in the presence of amino alcohols is one of the most widely
studied reactions in organic synthesis and asymmetric catalysis.1
The corresponding nucleophilic addition to aldimines is not
nearly as developed, partly due to the diminished electrophilicity
and the softer Lewis base character of imines compared to
carbonyl groups.2 Soai et al. showed that the diphenylphosphi-
noyl group could be used to activate aldimines toward enantio-
selective alkylation with dialkylzinc reagents in the presence
of stoichiometric quantities of N,N-dialkylnorephedrines.3 Sev-
eral alternative chiral amino alcohols have subsequently been
developed that can be used as ligands for this reaction.4 Other
activated imines such as N-(amidobenzyl)benzotriazoles,5 ni-
trones,6 N-arylimines,7 and N-tosylimines8 can also be alkylated
with dialkylzincs under the appropriate reaction conditions, and
alkylation of selected N-alkyl aldimines with triorganozincates
has been reported,9 as has alkynylation of N-benzyl nitrones
hols,11,12 we became interested in the synthesis of allylic amines
4 by addition of vinylzinc reagents 2, prepared in situ by the
hydrozirconation13 of alkynes followed by transmetalation with
dimethylzinc,14 to aldimines 3 (Scheme 1).15
Interestingly, when CH2Cl2 was used as the solvent for this
reaction in place of tetrahydrofuran (THF) or toluene, C-cyclo-
propylalkylamines 5 were obtained instead (Scheme 2, path a).
The latter products were obtained as well if CH2Cl2 or CH2I2
were added to a solution of 2 and 3 in toluene. Furthermore,
switching the order of addition of reaction components and
adding imine 3 last led to a new reaction dichotomy in the
formation of homoallylic amine products 6 (Scheme 2, path b).16
We now report a study of the scope and limitations of using
the hydrozirconation-transmetalation-imine addition sequence
for the preparation of allylic amines and C-cyclopropylalkyl-
amines.17
Results and Discussion
Preparation of Allylic Amides. Our initial goal was to
prepare allylic amides 4 in one pot in a single solvent system.
(1) (a) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 49.
(b) Soai, K.; Niwa, S. Chem. ReV. 1992, 92, 833. (c) Pu, L.; Yu, H.-B.
Chem. ReV. 2001, 101, 757. (d) Knochel, P.; Millot, N.; Rodriguez, A. L.;
Tucker, C. E. Org. React. 2001, 58, 417.
(2) (a) Bloch, R. Chem. ReV. 1998, 98, 1407. (b) Enders, D.; Reinhold: U.
Tetrahedron: Asymmetry 1997, 8, 1895. (c) Denmark, S. E.; Nicaise, O.
J.-C. J. Chem. Soc., Chem. Commun. 1996, 999.
(3) Soai, K.; Hatanaka, T.; Miyazawa, T. J. Chem. Soc., Chem. Commun. 1992,
1097.
(8) Fujihara, H.; Nagai, K.; Tomioka, K. J. Am. Chem. Soc. 2000, 122, 12055.
(9) Alvaro, G.; Pacioni, P.; Savoia, D. Chem. Eur. J. 1997, 3, 726.
(10) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc. 1999, 121,
11245.
(11) (a) Wipf, P.; Xu, W. Tetrahedron Lett. 1994, 35, 5197. (b) Wipf, P.; Xu,
W. Org. Synth. 1996, 74, 205.
(4) (a) Suzuki, T.; Shibata, T.; Soai, K. J. Chem. Soc., Perkin Trans. 1 1997,
2757. (b) Sato, I.; Kodaka, R.; Shibata, T.; Hirokawa, Y.; Shirai, N.; Ohtake,
K.; Soai, K. Tetrahedron: Asymmetry 2000, 11, 2271. (c) Andersson, P.
G.; Guijarro, D.; Tanner, D. J. Org. Chem. 1997, 62, 7364. (d) Pinho, P.;
Andersson, P. Tetrahedron 2001, 57, 1615. (e) Jimeno, C.; Reddy, K. S.;
Sola`, L.; Moyano, A.; Perica`s, M. A.; Riera, A. Org. Lett. 2000, 2, 3157
(5) Katritzky, A. R.; Harris, P. Tetrahedron: Asymmetry 1992, 3, 437.
(6) Ukaji, Y.; Kenmoku, Y.; Inomata, K. Tetrahedron: Asymmetry 1996, 7,
53.
(12) Wipf, P.; Ribe, S. J. Org. Chem. 1998, 63, 6454.
(13) (a) Carr, D. B.; Schwartz, J. J. Am. Chem. Soc. 1979, 101, 3521. (b) Wipf,
P.; Jahn, H. Tetrahedron 1996, 52, 12853.
(14) Wipf, P.; Kendall, C. Chem. Eur. J. 2002, 8, 1778.
(15) For related preparations of allylic amines, see: (a) Buchwald, S. L.; Watson,
B. T.; Wannamaker, M. W.; Dewan, J. C. J. Am. Chem. Soc. 1989, 111,
4486. (b) Grossman, R. B.; Davis, W. M.; Buchwald, S. L. J. Am. Chem.
Soc. 1991, 113, 2321. (c) Hauske, J. R.; Dorff, P.; Julin, S.; Martinelli, G.;
Bussolari, J. Tetrahedron Lett. 1992, 33, 3715. (d) Pandya, S. U.; Garc¸on,
C.; Chavant, P. Y.; Py, S.; Valle´e, Y. J. Chem. Soc., Chem. Commun. 2001,
1806.
(7) (a) Hou, X. L.; Zheng, X. L.; Dai, L. X. Tetrahedron Lett. 1998, 39, 6949.
(b) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J. Am.
Chem. Soc. 2001, 123, 984.
(16) Wipf, P.; Kendall, C. Org. Lett. 2001, 3, 2773.
9
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J. AM. CHEM. SOC. 2003, 125, 761-768
761

A R T I C L E S
Wipf et al.
Scheme 1
Alternatively, hydrozirconation in toluene avoided the need for
a solvent switch by maintaining a single solvent for the entire
one-pot reaction (entry 7), but led to a significant increase in
the hydrozirconation time (>60 min at 40 °C). The use of
diethylzinc in place of dimethylzinc resulted in a much lower
isolated yield of 4a (entry 8). No addition to the imine was
observed in any solvent in the absence of the dialkylzinc additive
(entry 9); however, as was found for the allylic alcohol
synthesis,20 substoichiometric quantities of dimethylzinc could
be used to affect the same transformation, though the reaction
time was increased (entry 10).
Scheme 2
Using the optimal reaction conditions reported in Table 1,
entry 6, the reaction scope was further investigated (Table 2).
The isolated yields of all but one of the allylic amides were in
the range of 60-90%. Only the electron-rich p-methoxy sub-
stituted imine 3c led to a lower yield (entry 7). The symmetrical
internal alkyne 1b was used to form trisubstituted double bonds
(entry 2). Functional groups such as silyl ethers (entry 3), silyl
esters (entry 4), and sulfonamides and carbamates (entry 5) were
tolerated on the alkyne segment. However, sterically very
hindered alkynes such as trimethylsilylacetylene were hydrozir-
conated but not further converted to allylic amides under these
conditions. In remarkable contrast to diethylzinc additions to
N-diphenylphosphinoylimines,4d electron-withdrawing groups
on the benzaldimine did not affect the reaction yield (entry
6), whereas the presence of electron-donating groups signifi-
cantly reduced the amount of isolated compound, possibly due
to the instability of the desired product (entry 7). Addition to
R,â-unsaturated aldimine 3d and alkynylimine 3e afforded
allylic amides 4h,i (entries 8 and 9); however, we have been
unable to synthesize N-diphenylphosphinoyl aldimine substrates
derived from enolizable aldehydes.21 In contrast, N-tosylalkyl-
imines 3g,h were readily available22 and proved to be excellent
substrates for this reaction (entries 11 and 12). Similarly,
N-tosylbenzaldimine 3f was converted to the allylic sulfonamide
4j in high yield (entry 10).
Table 1. Reaction Optimization for Allylic Amide Formation
entry solvent 1a/Cp2ZrHCl(equiv) Me2Zn(equiv)
temp (°C)
time (h) yielda (%)
1
2
3
4
5
6
7
8
9
CH2Cl2
CH2Cl2
CH2Cl2
THF
1.5
1.5
3.0
1.5
2.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
3.0
1.5
2.0
1.5
1.5
1.5c
0
room temp
reflux
reflux
room temp
40
room temp
room temp
room temp
room temp
room temp
18
1
16
35
1
2
4
6
4
16
41
54
11
54
65
76
59
26
0
THF
tolueneb
toluene
toluene
tolueneb
10 tolueneb
0.2
72
a Yields of isolated products based on 3a. b Hydrozirconation was
performed in CH2Cl2, which was subsequently removed in vacuo and
replaced with toluene. c Et2Zn was used in place of Me2Zn.
Synthesis of C-Cyclopropylalkylamides. While optimizing
the alkyne hydrozirconation-transmetalation-aldimine addition
reaction sequence, we discovered a novel three-component
cyclopropane synthesis. When the imine addition step was
performed in CH2Cl2 at reflux in the presence of 3 equiv of
both the vinylzirconocene and dimethylzinc (Table 1, entry 3),
the C-cyclopropylmethylamide anti-5a was formed in 58%
yield, in addition to 11% of the expected allylic amide 4a
(Scheme 3). A single diastereomer, later found to have the anti
stereochemistry by X-ray analysis of benzamide anti-8a, was
Even though toluene is the solvent of choice for the asymmetric
synthesis of allylic alcohols12 and for diethylzinc additions to
N-diphenylphosphinoylimines,18 we first used CH2Cl2 and THF
since hydrozirconation is much faster in these two solvents than
in toluene.19 While the reaction was successful, yields of the
desired allylic amide 4a did not exceed 54 and 65% in CH2Cl2
and THF, respectively (Table 1, entries 1-5). In CH2Cl2, the
maximum yield was obtained when the reaction was performed
at reflux with 1.5 equiv of alkyne, zirconocene hydrochloride,
and dimethylzinc (entry 2). Doubling the amount of these three
reagents had a detrimental effect on the yield of 4a (entry 3),
due to formation of the C-cyclopropylalkylamide (vide infra).
In THF, the highest yield was obtained when the reaction was
performed at 40 °C (entry 5). A higher and more reproducible
yield was achieved at room temperature in toluene. For small-
scale reactions, the alkyne was hydrozirconated in CH2Cl2 (<10
min reaction time at 25 °C), and the solvent was then switched
to toluene prior to transmetalation with dimethylzinc (entry 6).
1
observed by H NMR analysis of the crude reaction mixture.
When the reaction was performed in CD2Cl2 at reflux, the
geminal bis-deuterated cyclopropane anti-5b was formed, thus
confirming that the chlorinated solvent served as the origin of
the extra carbon in the product. To the best of our knowledge,
this is the first example of a preparative cyclopropanation in
which CH2Cl2 serves as the carbene precursor.23 Moreover, we
found that it was not necessary to use CH2Cl2 as the solvent;
performing this reaction in toluene at room temperature in the
presence of 10 equiv of CH2Cl2 as an additive resulted in a
(20) Wipf, P.; Xu, W.; Takahashi, H.; Jahn, H.; Coish, P. D. G. Pure Appl.
Chem. 1997, 69, 639.
(17) For a preliminary communication of this work, see: Wipf, P.; Kendall,
C.; Stephenson, C. R. J. J. Am. Chem. Soc. 2001, 123, 5122.
(18) Soai, K.; Suzuki, T.; Shono, T. J. Chem. Soc., Chem. Commun. 1994, 317.
(19) Wipf, P.; Takahashi, H.; Zhuang, N. Pure Appl. Chem. 1998, 70, 1077.
(21) See also Yamada, K.; Harwood, S. J.; Groger, H.; Shibasaki, M. Angew.
Chem., Int. Ed. 1999, 38, 3504.
(22) Chemla, F.; Hebbe, V.; Normant, J.-F. Synthesis 2000, 75.
9
762 J. AM. CHEM. SOC. VOL. 125, NO. 3, 2003

Additions of Alkenylzirconocenes to Aldimines
A R T I C L E S
Table 2. Addition of in Situ Prepared Alkenylorganometallics to Aldimines. Reaction Scope of Allylic Amide Formations
a Reaction conditions: (i) 1.5 equiv of Cp2ZrHCl, 1.5 equiv of alkyne 1, CH2Cl2, room temp, 10 min; (ii) 1.5 equiv of Me2Zn, toluene, -78 °C, 5 min;
(iii) 1.0 equiv of aldimine 3, toluene, room temp, 2-5 h. b Yields of isolated products are based on aldimines 3.
Scheme 3
43% yield of anti-5a (in addition to 26% of isolated 4a) after
36 h reaction time.
To increase the yield and the relative rate of cyclopropanation,
we added CH2I2 to the reaction mixture. The isolated yield of
anti-5a increased to 74%. Using these optimized conditions, a
broad range of functionalized C-cyclopropylalkylamides were
obtained in 45-85% yield (Table 3). Furthermore, we found
that addition of 1 equiv of benzyl alcohol had a significant
(23) While both CH2I2 and CH2Br2 are routinely utilized in the Simmons-
Smith reaction, CH2Cl2 is generally considered unreactive in a wide range
of modifications of this method: (a) Simmons, H. E.; Smith, R. D. J. Am.
Chem. Soc. 1959, 81, 4256. (b) LeGoff, E. J. Org. Chem. 1964, 29, 2048.
(c) Maeda, T.; Tada, H.; Yasuda, K.; Okawara, R. J. Organomet. Chem.
1971, 27, 13. (d) Miyano, S.; Hashimoto, H. Bull. Chem. Soc. Jpn. 1973.
46, 892. (e) Charette, A. B.; Beauchemin, A. Org. React. 2001, 58, 1. It
positive effect on the isolated yield of anti-5a (entry 2), possibly
due to the replacement of the potentially reactive methyl ligand
on zirconium with an alkoxide group (vide infra).15a,b The
trisubstituted cyclopropane anti-5c was formed in 46% yield
has, however, been reported that a mixture of alkene and methylene chloride
reacts with heated zinc film at low pressure to give traces of cyclopropane
products: (f) Fauveau, C.; Gault, Y.; Gault, F. G. Tetrahedron Lett. 1967,
3149.
9
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A R T I C L E S
Wipf et al.
Table 3. Three-Component C-Cyclopropylalkylamide Synthesis
a Only the major stereoisomer is shown. b Reaction conditions: (i) 3 equiv of Cp2ZrHCl, 3 equiv of alkyne 1, CH2Cl2, room temp, 10 min; (ii) 3 equiv
of Me2Zn, CH2Cl2, -78 °C, 5 min; (iii) 1 equiv of aldimine 3, CH2Cl2, reflux, 1-2 h; (iv) 5 equiv of CH2I2, CH2Cl2, reflux, 2-12 h. c Yields of isolated
products are based on aldimine 3. d Determined by HPLC analysis of the crude reaction mixture. e 1 equiv of PhCH2OH was added to the reaction mixture.
1
f Determined by H NMR analysis of the crude reaction mixture. g Additional Me2Zn (3 equiv) and CH2I2 (10 equiv) were added to the reaction mixture.
h Et2Zn (6 equiv) and CH3CHI2 (12 equiv) were added to the reaction mixture. i Hydrozirconation was performed in THF, and the solvent was exchanged
with ClCH2CH2Cl for the remainder of the reaction.
using internal alkyne 1b (entry 3). Functional groups tolerated
on the alkyne segment included silyl ethers (entry 4), silyl esters
(entry 5), sulfonamides, and carbamates (entry 6). Both electron-
rich and electron-deficient benzaldimines were effective sub-
strates (entries 7-9). Alkynylimine 3e afforded anti-5j in 60%
yield (entry 10), and, as with all benzaldimine substrates, only
under the general reaction conditions. As observed for the
formation of allylic amides, N-tosylaldimine 3f was nearly as
effective as N-phosphinoylimine 3a (entry 11). A diminished
anti:syn diastereomeric ratio (dr) of 87:13 was observed when
alkylimine 3g was used (entry 12), and the more bulky aldimine
3h further eroded the dr to 40:60 (entry 13). This reaction was
the most sluggish and required addition of further equivalents
of dimethylzinc to the reaction mixture in order to achieve high
conversion. Also, unlike Scheme 3, no trace of 5m was formed
if the reaction was performed in CH2Cl2 at reflux in the absence
1
one diastereomer was observed by H NMR analysis of the
crude reaction mixture. The R,â-unsaturated aldimine 3d was
not an effective substrate, since a complex mixture of bis-
cyclopropane and mono-cyclopropane products was formed
9
764 J. AM. CHEM. SOC. VOL. 125, NO. 3, 2003

Additions of Alkenylzirconocenes to Aldimines
A R T I C L E S
Scheme 4
Scheme 6
Scheme 5
Scheme 7
of added CH2I2. Finally, this methodology could also be
extended to the synthesis of trisubstituted cyclopropanes by
replacing CH2I2 with CH3CHI2 (entry 14); however, the use of
24
(CH3)2CI2 afforded only trace amounts of the desired tetra-
substituted cyclopropane. With diiodoalkanes as carbenoid
precursors, the hydrozirconation had to be performed in a solvent
other than CH2Cl2 in order to avoid formation of anti-5a as the
major product.
diastereomeric azides.29 Reduction of the mixtures of epimeric
azides 11 with H2 and Pd on carbon followed by N-tosylation
and epimer separation by chromatography on SiO2 afforded anti-
5l in 66% overall yield. Finally, the relative configuration of
anti-5j was similarly determined chemically by reduction,
deprotection, and tosylation to give anti-5l (Scheme 6).
An important extension of this new methodology was
achieved by the conversion of enynes 1g and 1i to the cor-
responding biscyclopropanes 5o and 5q (Schemes 7 and 8).
While the second cyclopropanation required more forcing con-
ditions and addition of an excess of CH2I2,30 a single diaster-
eomeric product with a total of five new C,C-bonds was found
in both reaction mixtures. Starting enyne 1g was obtained by
carboalumination31 of alkyne 1f followed by iodination of the
intermediate vinyl alane, O-silylation, and Sonogashira coup-
ling32 with trimethylsilane (TMS)-acetylene followed by
C-desilylation in basic methanol.33 Enyne 1i was obtained
The anti configuration was observed for the major diastere-
omer of all C-cyclopropylalkylamides but 5m. The stereochem-
istry of anti-5b, anti-5c, anti-5d, anti-5e, anti-5f, anti-5g, anti-
5h, and anti-5i was assigned by analogy to anti-5a. Deprotection25
and N-tosylation of anti-5a afforded anti-5k, confirming an
identical relative configuration for the major diastereomers of
both N-phosphinoyl and N-sulfonyl amides (Scheme 4). The
relative configuration of C-cyclopropylalkylamide anti-5l was
determined chemically (Scheme 5). Allylic alcohol 9 was pre-
pared using our Zr-Zn transmetalation, aldehyde addition meth-
odology.11 An alcohol-directed Simmons-Smith cyclopropa-
26
nation of 9 with Zn(CH2I)2 afforded 10 as an 86:14 mixture
of easily separable diastereomers.27 Mitsunobu substitution of
the secondary alcohol in syn-10 with DPPA28 in the presence
of DEAD and triphenylphosphine gave an 78:22 mixture of
(24) Charette, A. B.; Wilb, N. Synlett 2002, 176.
(25) Ramage, R.; Hopton, D.; Parrott, M. J.; Kenner, G. W.; Moore, G. A. J.
Chem. Soc., Perkin Trans. 1 1984, 1357.
(26) (a) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron 1968, 24, 53.
(b) Denmark, S. E.; Edwards, J. P.; Wilson, S. R. J. Am. Chem. Soc. 1992,
114, 2592.
(27) Compound syn-10 was expected to be the major diastereomer based upon
extensive precedence by, among others: (a) Charette, A. B.; Lebel, H. J.
Org. Chem. 1995, 60, 2966. (b) Harada, S.; Kowase, N.; Tabuchi, N.;
Taguchi, T.; Dobashi, Y.; Dobashi, A.; Hanzawa, Y. Tetrahedron 1998,
54, 753.
(28) Lal, B.; Pramanik, B. N.; Manhas, M. S.; Bose, A. K. Tetrahedron Lett.
1977, 18, 1977.
(29) The structural assignment of the major epimer of the azide displacement
as the SN2 product, anti-11, was confirmed by subjecting anti-10 to
analogous Mitsunobu reaction conditions. A 15:85 mixture of diastereomers
favoring the epimer, syn-11, was isolated in the latter conversion.
(30) The reduced cyclopropanation rate for the distal double bond can readily
be explained by the greater distance between the N-ligated zinc carbenoid
specied and the alkene in the transition-state structures (cf. Scheme 9).
Due to the long N-Zn and Zn-C bonds (ca. 2 Å), intramolecular delivery
is still feasible, however.
(31) Negishi, E.; Takahashi, T. Synthesis 1988, 1.
9
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A R T I C L E S
Wipf et al.
tions,38 we were, at first, surprised at the exceptionally high
anti selectivity in the formation of C-cyclopropylalkylamides
5. In addition, the activation of CH2Cl2 as a zinc carbenoid
source was quite unprecedented, and, moreover, the presence
of zirconocene proved to be crucial for an efficient cyclopro-
panation. Under otherwise analogous conditions but using vinyl
alanes or vinyl boranes as substrates and subjecting them to
one-pot AlfZn39 or BfZn40 transmetalation processes, only
allylic amides 4 were isolated after addition of aldimine 3a to
the reaction mixture in CH2Cl2 at reflux. Even in the presence
of 5 equiv of CH2I2, no cyclopropanated product was detected
in the boron-based reaction, whereas a low yield of cyclopropyl
amide 5 was generated from the vinyl zinc species obtained by
transmetalation of the corresponding vinyl alane. Furthermore,
if an organozirconocene complex was not present in the reaction
mixture, excess dimethylzinc in CH2Cl2 at reflux temperatures
did not convert allylic amide 4a into cyclopropane 5a. Even
after addition of Cp2ZrCl2, allylic amide 4a was recovered quan-
titatively. Interestingly, subjecting 4a to standard Simmons-
Smith cyclopropanation conditions afforded 5a in good yield,
but in a lower anti:syn ratio of 71:29, thus clearly confirming
that the zirconocene complex was involved both in the genera-
tion of the active cyclopropanating agent and in the stereose-
lectivity-determining step of the zinc carbenoid addition. Fur-
thermore, if 4a was added to the reaction mixture used for prepa-
ration of anti-5k (Table 2, entry 10), anti-5a was isolated in
>20:1 dr. If the same transformation was attempted in the ab-
sence of added CH2I2, the conversion of 4a to anti-5a was found
to be significantly higher than the ratio of anti-5k to 4j.
Accordingly, cyclopropanation of phosphinoylamides was ac-
celerated vs sulfonylamide substrates.41 The importance of an
intramolecular activating group was also supported by the ob-
servation that addition of an unactivated alkene (CH2dCH-
(CH2)2OBDPS) or even alcohol 9 to the reaction mixture did
not yield cyclopropanated derivatives of these alkenes. It is
therefore unlikely that this cyclopropanation is an intermolecular
process mediated by a mixed phosphinoylamide methylzinc
reagent.42 The lack of reactivity of allylic alcohol 9 toward
further conversion to cyclopropane also explained why we had
not observed this process previously in our addition reactions
to aldehydes.11,12
Scheme 8
analogously by water-accelerated carboalumination34 of 1h via
vinyl iodide 12b.35 Since neither biscyclopropane 5o nor 5q
was sufficiently crystalline for X-ray structure determination,
the silyl protective group of 5o was cleaved with tetrabutylam-
monium fluoride (TBAF) and the anti-anti configuration of
biscyclopropane 5p was elucidated by X-ray analysis. The one-
pot conversion of enynes to these C-biscyclopropylalkylamides
represents a highly stereoselective and efficient approach for
the synthesis of conjugated oligocyclopropanes. Traditionally,
multistep pathways have been required for the assembly of
these structurally intriguing natural and unnatural building
blocks.36
Mechanistic Proposal. In all cases, allylic amide formation
clearly preceded the appearance of cyclopropanated product,
therefore indicating that a metalated derivative of 4 was the
reactive substrate for carbene transfer onto the alkene moiety.
When the reaction mixture was quenched prematurely (with no
added CH2I2), a low conversion to 5 was observed. After 1 h at
reflux, for example, the isolated yield of anti-5a dropped to
29%, along with a corresponding increase in the yield of 4a to
43%. In contrast, after 16 h at reflux, a 58% yield of anti-5a
and a 11% yield of 4a was observed. An alternative mechanism
for this transformation, i.e., the generation of a cyclopropylzinc
species,37 followed by nucleophilic addition to imine, was
rendered unlikely by these observations. Furthermore, the
cyclopropylzinc reagent derived from 1-hexyne via hydrozir-
conation, transmetalation to zinc, and cyclopropanation was
found to be completely unreactive toward aldimine 3f.
While there is ample precedence for the formation of syn-
diasteromers by directed Simmons-Smith-type cyclopropana-
While mechanistic details of the multicomponent zirconocene/
zinc aldimine addition-cyclopropanation process remain some-
what obscure, we propose a stepwise process that is in agreement
with all experimental observations (Scheme 9). After trans-
metalation of alkenylzirconocene to dimethylzinc, addition to
aldimine 3 affords N-metalated allylic amide intermediate 14.
Insertion of zinc into dihalomethane forms the halomethylzinc
species 15.27,43 This carbon-halogen bond insertion might be
facilitated by the presence of the nitrogen ligand on zinc, the
zirconocene complex, or both.27b,44 The zirconocene formed in
the transmetalation reaction serves the role of a Lewis acid
activator for zinc carbenoid formation by complexing the
(32) Sonogashira, K. In Metal-Catalyzed Cross-Coupling Reactions; Diederich,
F., Stang, P. J., Eds.; Wiley-VCH: New York, 1998; pp 203-229.
(33) Bick, S.; Zimmermann, S.; Meuer, H.; Sheldrick, W. S.; Welzel, P.
Tetrahedron 1993, 49, 2457.
(38) See Scheme 5 and refs 23e and 27, as well as: Molander, G. A.; Harring,
L. S. J. Org. Chem. 1989, 54, 3525.
(34) (a) Wipf, P.; Lim, S. Angew. Chem., Int. Ed. Engl. 1993, 32, 1068. (b)
Ribe, S.; Wipf, P. J. Chem. Soc., Chem. Commun. 2001, 299.
(35) Iwasawa, N.; Maeyama, K. J. Org. Chem. 1997, 62, 1918.
(36) (a) Faust, R. Angew. Chem., Int. Ed. 2001, 40, 2251. (b) Donaldson, W.
A. Tetrahedron 2001, 57, 8589. (c) Barrett, A. G. M.; Tuestin, G. J. J.
Chem. Soc., Chem. Commun. 1995, 355.
(39) Zeng, F.; Negishi, E. Org. Lett. 2001, 3, 719.
(40) Srebnick, M. Tetrahedron Lett. 1991, 32, 2449.
(41) (a) Russ, P.; Ezzitouni, A.; Marquez, V. E. Tetrahedron Lett. 1997, 38,
723. (b) Momose, T.; Nishio, T.; Kirihara, M. Tetrahedron Lett. 2002, 37,
4987.
(42) See, for example: Charette, A. B.; Beauchemin, A.; Francoeur, S. J. Am.
Chem. Soc. 2001, 123, 8139.
(37) Yachi, K.; Shinokubo, H.; Oshima, K. Angew. Chem., Int. Ed. 1998, 37,
2515.
(43) Denmark, S. E.; Edwards, J. P. J. Org. Chem. 1991, 56, 6974.
9
766 J. AM. CHEM. SOC. VOL. 125, NO. 3, 2003

Additions of Alkenylzirconocenes to Aldimines
A R T I C L E S
Scheme 9
amide is cyclopropanated in situ, and high yields of C-
cyclopropylalkylamines are isolated in excellent diastereose-
lectivities. If CH2Cl2 is used as a reaction solvent, this process
can be considered a domino reaction48 that provides a total of
three new carbon-carbon bonds and a synthetically valuable
structural motif in a single step.49 The use of enynes as starting
materials expands this chemistry further and results in the
stereoselective formation of five new C,C-bonds. In addition
to dimethylzinc, the presence of zirconocene is crucial for
realizing these transformations,14 and a mechanistic hypothesis
that takes advantage of the dual Lewis acidic and halide bridging
properties of the zirconocene complex is consistent with all
experimental observations and the high anti selectivity observed
for the cyclopropane products. Further studies of the novel
reactivity patterns of zirconocene/zinc complexes as well as the
development of an enantioselective version of this reaction are
continuing in our laboratories.
Experimental Section.
N-(1-Phenylhept-2-enyl)-P,P-diphenylphosphinamide (4a). Gen-
eral Protocol A. A suspension of 208 mg (0.807 mmol) of Cp2ZrHCl
in 2 mL of CH2Cl2 was treated at room temperature with 105 µL (0.914
mmol) of 1-hexyne, stirred for 5 min, and concentrated in vacuo. A
solution of the resulting yellow solid in 2 mL of toluene was cooled to
-78 °C, treated with 380 µL (0.760 mmol) of Me2Zn (2.0 M solution
in toluene), warmed to room temperature over a period of 5 min, and
cannulated into a suspension of 155 mg (0.508 mmol) of imine 3a in
2 mL of toluene. The reaction mixture was stirred at room temperature
for 2 h, quenched with saturated NaHCO3, diluted with EtOAc, filtered
through Celite, washed with H2O and brine, dried (MgSO4), filtered
through a pad of Florisil, and concentrated in vacuo. The residue was
chromatographed on deactivated SiO2 (1:9, hexanes/EtOAc containing
1% Et3N) to yield 151 mg (76%) of 4a as a colorless solid: mp 139-
140 °C (EtOAc/hexane); IR (KBr) 3127, 2952, 2922, 2859, 1456, 1437,
1194, 1182, 1121, 1109 cm-1; 1H NMR δ 8.00-7.93 (m, 2 H), 7.89-
7.82 (m, 2 H), 7.55-7.23 (m, 11 H), 5.69 (ddt, 1 H, J ) 15.3, 6.2, 1.2
Hz), 5.53 (dtd, 1 H, J ) 15.3, 6.6, 1.1 Hz), 4.83 (td, 1 H, J ) 9.4, 6.4
Hz), 3.34 (dd, 1 H, J ) 9.4, 6.2 Hz), 2.01 (q, 2 H, J ) 6.4 Hz), 1.34-
1.26 (m, 4 H), 0.90 (t, 3 H, J ) 7.0 Hz); 13C NMR δ 143.03, 142.96,
133.73, 133.39, 132.45, 132.29, 132.17, 132.06, 132.01, 131.67, 128.44,
128.37, 128.21, 127.10, 126.92, 56.87, 31.77, 31.12, 22.19, 13.88; EIMS
m/z 389 (M+, 15), 332 (19), 306 (25), 216 (98), 201 (92), 188 (100),
172 (35), 143 (55), 129 (87), 115 (35), 91 (33); HRMS (EI) m/z calcd
for C25H28NOP 389.1909, found 389.1906.
halogen atom of the halomethyl zinc species 16 and increasing
electron density on zinc by providing a bridging chloride
ligand.45 Of the two feasible transition states 17 and 18,45a,46
the former suffers from large steric interactions between the
diphenylphosphinoyl substituent and the alkene moiety. In
contrast, 18 is subjected to the 1,3-allylic strain interaction that
is usually responsible for high syn selectivity,27 but the steric
strain around the bulky diphenylphosphinoyl group is now
relieved. Transition-state 18 provides the major isomer, anti-
19. The high level of anti selectivity is also consistent with
diastereoselectivities observed in the Simmons-Smith cyclo-
propanation of allylic ethers.47
Preparation of anti-5a in the Presence of CH2I2. General Protocol
B. A suspension of 390 mg (1.51 mmol) of Cp2ZrHCl in 2 mL of
CH2Cl2 was treated at room temperature with 190 µL (1.65 mmol) of
1-hexyne. After 5 min, the yellow solution was cooled to -78 °C,
treated with 750 µL (1.50 mmol) of Me2Zn (2.0 M solution in toluene),
warmed to room temperature over a period of 5 min, treated with a
solution of 153 mg (0.501 mmol) of imine 3a in 2 mL of CH2Cl2, and
heated to reflux for 1 h. The reaction mixture was cooled to room
temperature, treated with 200 µL (2.48 mmol) of CH2I2, heated to reflux
for a further 2 h, quenched with saturated NH4Cl, diluted with EtOAc
and saturated NaHCO3, filtered through Celite, washed with H2O and
brine, dried (MgSO4), filtered through a pad of Florisil, and concentrated
in vacuo. The residue was chromatographed on deactivated SiO2 (1:9,
Conclusions
The sequential hydrozirconation-transmetalation-imine ad-
dition of alkynes establishes an efficient new route for the
preparation of synthetically useful allylic amine building blocks.
In the presence of CH2I2 or CH2Cl2, the N-metalated allylic
(44) (a) Charette, A. B.; Beauchemin, A.; Francoeur, S.; Be´langer-Garie´py, F.;
Enright, G. D. Chem. Commun. 2002, 466. (b) Charette, A. B.; Francoeur,
S.; Martel, J.; Wilb, N. Angew. Chem., Int. Ed. 2000, 39, 4539. (c) Yang,
Z. Q.; Lorenz, J. C.; Shi, Y. Tetrahedron Lett. 1998, 39, 8621.
(45) (a) Nakamura, M.; Hirai, A.; Nakamura, E. J. Am. Chem. Soc. 1998, 120,
5844. (b) Takahashi, H.; Yoshioka, M.; Shibasaki, M.; Ohno, M.; Imai,
N.; Kobayashi, S. Tetrahedron 1995, 51, 12013. (c) Charette, A. B.; Brochu,
C. J. Am. Chem. Soc. 1995, 117, 11367. (d) Charette, A. B.; Molinaro, C.;
Brochu, C. J. Am. Chem. Soc. 2001, 123, 12160.
(48) Tietze, L. F. Chem. ReV. 1996, 96, 115.
(49) For typical multistep approaches to C-cyclopropylalkylamines, see, for
example: (a) Shuto, S.; Ono, S.; Imoto, H.; Yoshii, K.; Matsuda, A. J.
Med. Chem. 1998, 41, 3507. (b) Ma, D.; Ma, Z. Tetrahedron Lett. 1997,
38, 7599. (c) Shimamoto, K.; Ishida, M.; Shinozaki, H.; Ohfune, Y. J. Org.
Chem. 1991, 56, 4167. For a 3-component synthesis of aliphatic amines,
see: (d) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J.
Am. Chem. Soc. 2001, 123, 10409.
(46) For discussions of the transition-state geometry of Simmons-Smith
cyclopropanations, see: (a) Bernardi, F.; Bottoni, A.; Miscione, G. P. J.
Am. Chem. Soc. 1997, 119, 12300. (b) Hoveyda, A. H.; Evans, D. A.; Fu,
G. C. Chem. ReV. 1993, 93, 1307.
(47) Charette, A. B.; Lebel, H.; Gagnon, A. Tetrahedron 1999, 55, 8845.
9
J. AM. CHEM. SOC. VOL. 125, NO. 3, 2003 767

A R T I C L E S
Wipf et al.
hexanes/EtOAc containing 1% Et3N) to yield 149 mg (74%) of anti-
5a [dr ) 97:3 (HPLC)] as a colorless solid.
Supporting Information Available: Comprehensive experi-
1
mental protocols and spectroscopic data, H and 13C NMR
spectra for 4b-l, anti-5b, anti-5e, anti-5j, anti-5k, anti-5l, and
5m-q (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by the National
Science Foundation (Grant CHE-0078944). We thank Dr. Steven
Geib (University of Pittsburgh) for X-ray analyses of cyclo-
propane products. C.K. thanks Aventis Pharmaceuticals for a
graduate fellowship.
JA028092A
9
768 J. AM. CHEM. SOC. VOL. 125, NO. 3, 2003