Three-component aldimine addition-cyclopropanation. An efficient new methodology for amino cyclopropane synthesis

Full text of DOI:10.1021/ja0157494

5122
J. Am. Chem. Soc. 2001, 123, 5122-5123
Three-Component Aldimine
Scheme 1
Addition-Cyclopropanation. An Efficient New
Methodology for Amino Cyclopropane Synthesis
Peter Wipf,* Christopher Kendall, and Corey R. J. Stephenson
Department of Chemistry, UniVersity of Pittsburgh
Pittsburgh, PennsylVania 15260
ReceiVed March 2, 2001
ReVised Manuscript ReceiVed April 12, 2001
and at shorter reaction times confirmed that 1,2-addition preceded
The hydrozirconation of alkenes and alkynes is one of the most
versatile and direct pathways for the formation of organometallic
intermediates for organic synthesis. Due to the steric shielding
10
the cyclopropanation and that no cyclopropyl zinc species were
11
1
formed prior to imine addition. In analogy to recent results by
Charette and co-workers,12 we therefore propose the mechanism
shown in Figure 1. Hydrozirconation of the alkyne followed by
transmetalation to dimethyl zinc leads to an alkenyl zinc species
that readily adds to the phosphinoylimine to give allylic amide
5. While the facile formation of the zinc carbenoid species 6 from
of the C-Zr bond by the cyclopentadienyl ligands, however, many
applications of organozirconocenes have been limited to oxidative
cleavage with halogens. In addition to chloride abstractions with
silver(I) salts and subsequent cascade processes initiated by
2
formally cationic zirconocenes, transmetalation of the C-Zr bond
5
and dichloromethane is unprecedented,13 the intrinsically high
to other metal salts is an effective way to utilize the potential of
1
4
reactivity of (chloromethyl)zinc derivatives is well-known, and
an amide nitrogen has been shown to be a powerful directing
group15 for Wittig-Furukawa reagents.
the organozirconocene intermediate for carbon-carbon bond
1
formation. We have previously developed a protocol for Zr f
16
Zn transmetalation that allows in situ addition to aldehydes and,
in the presence of a chiral ligand, the enantioselective preparation
To improve on the yield and the rate of the transformation of
3
1 to 3, we added 5 equiv of CH
were able to obtain the desired amino cyclopropane in 74% yield
after 2 h in refluxing CH Cl . Under these optimized conditions,
2 2
I to the reaction mixture and
of allylic alcohols. We now report an extension of this trans-
metalation strategy toward the three-component condensation of
organozirconocenes, aldimines, and dihalomethanes and the
stereoselective formation of amino cyclopropanes.
2
2
functionalized terminal and internal alkynes were converted to
amino cyclopropanes in moderate to high yields and with excellent
diastereoselectivity (Table 1).
Traces of unreacted allylic amine intermediates were the only
identifiable side products, but no stereoisomeric cyclopropanes
could be identified in 1H NMR analyses of crude reaction
mixtures. The transformation enjoys a significant functional group
tolerance, since silyl ethers (entries 3 and 7), silyl esters (entry
Hydrozirconation of 1-hexyne (1) in CH
2
Cl
2
with Schwartz
2
Zn and addition
reagent followed by in situ transmetalation to Me
of N-diphenylphosphinoylimine 24 provided the trans-amino
cyclopropane 3 in 58% yield and the allylic amide 4 in 11% yield
after heating the reaction mixture at reflux for 16 h (Scheme 1).5
In contrast, when the reaction was performed in THF, a 65% yield
6
of 4 was obtained as the sole product. We rationalized this novel
4), and carbamate or sulfonamide functions (entry 5) in the alkyne
solvent-dependent reaction dichotomy by the formation of a
transient zinc-carbenoid species from CH Cl , which subjected
2 2
segment do not interfere. Significantly, internal alkyne 8 provided
trisubstituted cyclopropane 9 (entry 2). Both electron-donating
(entry 9) and electron-withdrawing substitutents (entries 6, 7, and
the intermediate allylic amine derivative to an efficient Simmons-
7
Smith type cyclopropanation. N-Metalation of the phosphinoyl-
8
) in the benzaldimine portion are tolerated. The yields based on
imine range from 45% for the highly functionalized alkyne 14 to
4% in the addition to ester-substituted 16, which is remarkable
amine moiety from the 1,2-addition step was clearly crucial for
the ensuing Simmons-Smith process, since control experiments
showed that only a protocol involving deprotonation of 4 with
8
considering that three C,C-bonds and one C,H-bond are formed
stereoselectively during the three-component condensation pro-
cess. The alkynyl imine 23 led to cyclopropane adduct 24 in 44%
yield, thus illustrating that the presence of an aromatic substituent
at the imine carbon is not essential for the process. N-Phosphi-
BuLi followed by treatment with Me
conocene in CH Cl led to further conversion to 3. In the absence
of BuLi, neutral 4 remained unchanged.
Interestingly, the presence of dimethyl zinc alone in the absence
of zirconocene is also not sufficient for effecting cyclopropanation,
2
Zn and addition to vinylzir-
2
2
since the hexenyl zinc derivative obtained from 1 via hydro-
(
8) Srebnik, M. Tetrahedron Lett. 1991, 32, 2449.
9) Instead, allylic amide 4 was isolated in 49% yield.
8
did not convert 2 to 3.9
boration-transmetalation in CH
2
Cl
2
(
Control experiments in different solvents, at lower temperatures,
(10) Yachi, K.; Shinokubo, H.; Oshima, K. Angew. Chem., Int. Ed. 1998,
7, 2515.
(11) Use of CD Cl as a solvent led to geminal bisdeuterated cyclopropane,
2 2
thus confirming that the solvent served as carbene precursor.
(12) Charette, A. B.; Francoeur, S.; Martel, J.; Wilb, N. Angew. Chem.,
Int. Ed. 2000, 39, 4539.
(13) Both CH and CH
reaction, but CH Cl is generally considered unreactive in a wide range of
modifications of this method: 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. It 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: Faveau, C.; Gault, Y.; Gault, F. G. Tetrahedron Lett. 1967, 3149.
(14) Denmark, S. E.; Edwards, J. P. J. Org. Chem. 1991, 56, 6974. It is
possible that the zirconocene derivative obtained from transmetalation to Me
Zn facilitates carbenoid formation from CH Cl
(15) Russ, P.; Ezzitouni, A.; Marquez, V. E. Tetrahedron Lett. 1997, 38,
723.
(16) The observed anti-selectivity of cyclopropane formation is surprising,
given the generally strong preference for syn-selective cyclopropanation of
allylic alcohols: Molander, G. A.; Etter, J. B. J. Org. Chem. 1987, 52, 3944.
3
(
1) Wipf, P.; Jahn, H. Tetrahedron 1996, 52, 12853.
(
2) (a) Wipf, P.; Aslan, D. C. J. Org. Chem. 2001, 66, 337. (b) Wipf, P.;
Tsuchimoto, T.; Takahashi, H. Pure Appl. Chem. 1999, 71, 415. (c) Suzuki,
K. Pure Appl. Chem. 1994, 66, 1557.
(3) (a) Wipf, P.; Ribe, S. J. Org. Chem. 1998, 63, 6454. (b) Wipf, P.; Xu,
2
I
2
2 2
Br have been utilized in the Simmons-Smith
W.; Takahashi, H.; Jahn, H.; Coish, P. D. G. Pure Appl. Chem. 1997, 69,
39. (c) Wipf, P.; Xu, W. Tetrahedron Lett. 1994, 35, 5197.
4) For precedence for the addition of organozinc species to N-di-
2 2
6
(
phenylphosphinoylimines, see: (a) Soai, K.; Hatanaka, T.; Miyazawa, T. J.
Chem. Soc., Chem. Commun. 1992, 1097. (b) Suzuki, T.; Shibata, T.; Soai,
K. J. Chem. Soc., Perkin Trans. 1 1997, 2757. (c) Guijarro, D.; Pinho, P.;
Andersson, P. G. J. Org. Chem. 1998, 63, 2530. (d) Jimeno, C.; Reddy, K.
S.; Sola, L.; Moyano, A.; Pericas, M. A.; Riera, A. Org. Lett. 2000, 2, 3157.
For relevant imine reviews, see: (e) Bloch, R. Chem. ReV. 1998, 98, 1407.
(
f) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895. (g) Fache,
F.; Schulz, E.; Tommasino, M. L.; Lemaire, M. Chem. ReV. 2000, 100, 2159.
5) The relative stereochemistry of 3 was determined by X-ray analysis of
2
-
2
2
.
(
a p-nitrobenzoyl derivative of 25.
(
6) In the absence of Me
2
Zn, no reaction took place in either solvent.
(
7) (a) Simmons, H. E.; Cairns, T. L.; Vladuchick, S. A.; Hoiness, C. M.
Org. React. 1973, 20, 1.
1
0.1021/ja0157494 CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/03/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 21, 2001 5123
2 2
Table 1. Three-Component Condensation of Alkynes, Benzaldimines, and CH I
a
Yields of isolated products are based on imines.
effective agent for cyclopropanation in the Simmons-Smith
reaction. While CH Cl currently needs to be used as a solvent
and does not quite match the reactivity of CH , it is nonetheless
intriguing that in a reaction medium containing Me Zn, a
2
2
2 2
I
2
metalated allyl phosphinoylamine, and zirconocene complex, a
reactive zinc carbenoid species is readily obtained by zinc
insertion into the C,Cl-bond of CH Cl . The present work also
2 2
reveals the strong directing and possibly activating effects of
N-diphenylphosphinoylamines in the cyclopropanation reaction.
Figure 1. Proposed mechanism.
20
Finally, a novel application of in situ prepared alkenyl zir-
conocenes was demonstrated that provides new methodology and
significant functional group tolerance for the synthesis of amino
Scheme 2
cyclopropanes. A simple switch in reaction solvents from CH
Cl to THF allows the isolation of intermediate allylic amines,
which are by themselves important organic building blocks.
2
-
2
2
1,22
Studies toward enantioselective variants of zirconocene-mediated
allylic amine and amino cyclopropane syntheses are currently
underway in our laboratories and will be reported in due course.
noylimines derived from R,â-unsaturated aldehydes such as
cinnamaldehyde and R-methylcinnamaldehyde, however, provided
complex mixtures of mono- and biscyclopropanated products.
Attempts to prepare N-phosphinoylimines derived from enolizable
aldehydes, such as hydrocinnamaldehyde, failed.17
Acknowledgment. This work was supported by the National Science
Foundation (CHE-0078944).
The N-phosphinoylamino cyclopropane products are readily
deprotected to give free amino cyclopropanes by acid hydrolysis
(
1
Supporting Information Available: Experimental procedures, H and
Scheme 2).18 Prior alternative protocols for the preparation of
13
C NMR spectra for all new compounds, and X-ray structure of the
p-nitrobenzoyl derivative of 25 (PDF). This material is available free of
these versatile building blocks for organic synthesis have been
quite limited in scope.19
charge via the Internet at http://pubs.acs.org.
In conclusion, the three-component condensation of in situ
JA0157494
prepared alkenyl zirconocenes, aldimines, and CH
many fundamentally new aspects of organo-zirconocene and zinc
chemistry. For the first time, CH Cl has been proven to be an
2 2
X highlights
(
20) While aldehydes provide allylic alocohols under these reaction
3
conditions, no cyclopropyl alcohols are formed. However, N-tosyl imines
undergo an analogous addition-cyclopropanation process: Kendall, C.; Wipf,
P. Unpublished results.
2
2
(
17) See also: Yamada, K.-i.; Harwood, S. J.; Gr o¨ ger, H.; Shibasaki, M.
Angew. Chem., Int. Ed. 1999, 38, 3504.
18) Ramage, R.; Hapton, D.; Parrott, M. J.; Kenner, G. W.; Moore, G. A.
J. Chem. Soc., Perkin Trans. 1 1984, 1357.
19) (a) Tomilov, Y. V.; Kostitsyn, A. B.; Shulishov, E. V.; Nefedov, O.
M. Synthesis 1990, 247. (b) Parham, W. E.; Potoski, J. R. J. Org. Chem.
967, 32, 275.
(21) See, for example: (a) Agami, C.; Couty, F.; Evano, G. Org. Lett.
2000, 2, 2085. (b) Hollis, T. K.; Overman, L. E. J. Organomet. Chem. 1999,
576, 290. (c) Johannsen, M.; Jørgensen, K. A. Chem. ReV. 1998, 98, 1689.
(d) Otsuka, S. Acta Chem. Scand. 1996, 50, 353.
(
(
(22) For the preparation of allylic amines from primary amines and alkynes
2
with Cp Zr(Me)Cl, see: Buchwald, S. L.; Watson, B. T.; Wannamaker, M.
1
W.; Dewan, J. C. J. Am. Chem. Soc. 1989, 111, 4486.