Synthesis of frans-2-(1-aryl-1-methylethyl)cyclohexylamines

Article abstract of DOI:10.1021/ol005568r

(equation presented) As a first example of opening a secondary aziridine with a tertiary carbanion, the title amines (3a-c, aryl = phenyl, 4-tert-butylphenyl, 2-naphthyl) were synthesized by opening N-(diphenylphosphinoyl)-7-azabicyclo[4.1.0]heptane, aziridine 1, with the corresponding α-potassium isopropylarenes, followed by hydrolysis of the resulting phosphinamides 2a-c.

Full text of DOI:10.1021/ol005568r

ORGANIC
LETTERS
2000
Vol. 2, No. 7
931-932
Synthesis of trans-2-
(1-Aryl-1-methylethyl)cyclohexylamines
Wen-yee Lee, James M. Salvador,* and Kalavathi Bodige
Department of Chemistry, UniVersity of Texas at El Paso, El Paso, Texas 79968
james@salVador.chemistry.utep.edu
Received January 19, 2000
ABSTRACT
As a first example of opening a secondary aziridine with a tertiary carbanion, the title amines (3a−c, aryl ) phenyl, 4-tert-butylphenyl, 2-naphthyl)
were synthesized by opening N-(diphenylphosphinoyl)-7-azabicyclo[4.1.0]heptane, aziridine 1, with the corresponding r-potassium isopropylarenes,
followed by hydrolysis of the resulting phosphinamides 2a−c.
Toward making chiral-stationary phases for high-perfor-
mance liquid chromatography (HPLC)1 based on highly
enantioselective 8-phenylmenthyl derivatives,2,3 we report a
one-pot synthesis of trans-2-(1-aryl-1-methylethyl)cyclo-
hexylamines (3a-c).4 In analogy to the short synthesis of
trans-2-(1-aryl-1-methylethyl)cyclohexanols from cyclohex-
ene oxide,5 the title compounds were made by opening
strained N-(diphenylphosphinoyl)-7-azabicyclo[4.1.0]heptane,
aziridine 1, with R-potassium isopropylarenes and hydrolysis
of the resulting phosphinamides (2a-c) as follows.
Three isopropylarenes were metalated with potassium tert-
pentoxide and n-butyllithium5 and reacted with aziridine 1
(Scheme 2).4 Unlike the rapid opening of cyclohexene oxide
Scheme 2. Ring Opening of Aziridine 14
Aziridine 1 was synthesized6 by diphosphinylation and
base-promoted ring closing of trans-2-aminocyclohexanol7
(Scheme 1). Recrystallization from hexanes and ethyl acetate
with 1 equiv of R-potassium isopropylarenes, opening
aziridine 1 required up to 5 days and 5 equiv of nucleophile.
Quenching the reactions with saturated ammonium chloride
and purification, by radial chromatography or recrystalliza-
tion, gave moderate yields of trans-2-(1-aryl-1-methylethyl)-
N-(diphenylphosphinoyl)cyclohexylamines (phosphinamides
2a-c) (Table 1). Increasing the reaction time to 9 days
Scheme 1. Preparation of Aziridine 16
(3) Whitesell, J. K. Chem. ReV. 1992, 92, 953.
(4) Bodige, K. Masters Thesis, The University of Texas at El Paso, El
Paso, TX, 1996.
(5) Comins, D. L.; Salvador, J. M. J. Org. Chem. 1993, 58, 4656.
(6) Osborn, H. M. I.; Cantrill, A. A.; Sweeney, J. B.; Howson, W.
Tetrahedron Lett. 1994, 35, 3159.
gave 1 as a white solid (mp 161-162 °C) in 75% yield.
This one-pot synthesis of an activated aziridine also circum-
vented working with toxic 7-azabicyclo[4.1.0]-heptane.8
(1) Lee, W. Masters Thesis, The University of Texas at El Paso, El Paso,
TX, 1995.
(2) Corey, E. J.; Ensley, H. E. J. Am. Chem. Soc. 1975, 97, 6908.
(7) Melting point (mp): 65-66 °C, 65 °C: Wilson, N. A. B.; Read, J.
J. Chem. Soc. Part VII, 1935, 1269.
(8) Paris, O. E.; Fanta, P. E. J. Am. Chem. Soc. 1952, 74, 3007
10.1021/ol005568r CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/08/2000

previously used to kinetically resolve analogous cyclohex-
anols5 and other chiral amines.12,13 Methyl methoxyacetate14
was selected as the acyl source since methyl laurate only
produced ammonium laurate salts with (()-3a.4 Though
methyl methoxyacetate reacted in less than 3 h with amines
(()-3a-c to make amides 4a-c, Scheme 4, subsequent 1H
Table 1. Percent Yield and Melting Point of (()-2a-c4
N-phosphinamide
yield (%)
mp (°C)
2a
2b
2c
70
70
35
171-172
232-233
98-100
Scheme 4. Attempted Resolution of Title Amines (()-3a4
decreased the yield of 2a to 48%.1 Attempted activation of
1 with BF3‚Et2O9 in the presence of an R-cumyl potassium
suspension led only to the disappearance of the dark purple
color5 of the latter.1 Nevertheless, to our knowledge, this is
the first report of a secondary aziridine being opened by a
tertiary carbanion.10 Phosphinamides 2a-c were subse-
quently hydrolyzed to the title amines 3a-c in greater than
90% yield as shown in Scheme 3.11
NMR analysis15 of diastereomer salts of remaining 3a and
(+)-mandelic acid showed little enantioselectivity. Further
work on the synthesis of enantiomerically pure title amines
is in progress.
Scheme 3. Hydrolysis of Phosphinamides (()-2a-c11
Acknowledgment. We acknowledge the financial support
of the Welch Foundation (Grant AH-1305), the NIH/MBRS
(SO6GMO80120020) program, the UTEP University Re-
search Institute (1992-1993), and the Department of Chem-
istry, UTEP.
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds 1, 2a and 3a. This
material is available free of charge via the Internet at
http://pubs.acs.org.
We attempted to enantioselectively acylate amines (()-
3a-c in hexanes using the same commercially available
lipase from Candida rugosa and lauroyl function that were
OL005568R
(12) Takahashi, M.; Ogasawara, K. Tetrahedron: Asymmetry 1995, 6,
1617.
(13) Reetz, M. T.; Dreisbach, C. Chimia 1994, 48, 570.
(14) Balkenhohl, F.; Ditrich, K.; Nuebling, C. PCT Int. Appl. WO
9623,894.
(9) Eis, M. J.; Wrobel, J. E.; Ganem, B. J. Am. Chem. Soc. 1984, 106,
3693.
(10) Osborn, H. M. I.; Sweeney, J. B.; Howson, W. Tetrehedron Lett.
1994, 35, 2739.
(11) Ramage, R.; Hopton, D.; Parrott, M. J.; Kenner, G. W.; Moore, G.
A. J. Chem. Soc., Perkin Trans. 1 1984, 1357.
(15) Benson, S. C.; Cai, P.; Colon, M.; Haiza, M. A.; Tokles, M.; Snyder,
J. K. F. Org. Chem. 1988, 53, 5335.
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Org. Lett., Vol. 2, No. 7, 2000