A highly enantioselective allylic amination reaction using a commercially available chiral rhodium catalyst: Resolution of racemic allylic carbonates

Article abstract of DOI:10.1021/ol901031b

A novel method for the kinetic resolution of unsymmetrical acyclic allylic carbonates and the concurrent synthesis of enantioenriched secondary amines using a commercially available chiral catalyst is disclosed.

Full text of DOI:10.1021/ol901031b

ORGANIC
LETTERS
2009
Vol. 11, No. 14
3140-3142
A Highly Enantioselective Allylic
Amination Reaction Using a Commercially
Available Chiral Rhodium Catalyst:
Resolution of Racemic Allylic Carbonates
Derek C. Vrieze,* Garrett S. Hoge, Perrine Z. Hoerter, Jared T. Van Haitsma, and
Brian M. Samas
Pfizer Global Research and DeVelopment, 2800 Plymouth Road, Ann Arbor, Michigan 48105
derek.Vrieze@pfizer.com
Received May 11, 2009
ABSTRACT
A novel method for the kinetic resolution of unsymmetrical acyclic allylic carbonates and the concurrent synthesis of enantioenriched secondary
amines using a commercially available chiral catalyst is disclosed.
The stereochemical resolution of allylic carbonates and their
analogous alcohols and the preparation of enantioenriched
allylic amines are important because of the synthetic utility
they provide in the construction of biologically important
natural and unnatural products.1,2 For the kinetic resolution
of chiral racemic carbonates, the palladium-catalyzed allylic
substitution has been the primary reaction.3 Recently, other
transition metals such as iridium and ruthenium have proven
useful for this reaction.4,5 Of the resolutions described, most
are of cyclic or acyclic symmetric derivatives of allylic
alcohols; there are few examples of the resolution of
unsymmetrical acyclic allylic carbonates. Evans and co-
workers have described the rhodium-catalyzed enantiospe-
cific and regioselective allylic amination of enantiomerically
enriched unsymmetrical allylic carbonates.6 However, the
rhodium-catalyzed enantioselective amination of allylic
carbonates as well as the rhodium-catalyzed resolution of
asymmetric acyclic allylic carbonates has not been described.
Herein we describe a new method for the kinetic resolution
of unsymmetrical acyclic allylic carbonates and the tandem
regioselective synthesis of chiral secondary amines in high
yield and enantioselectivity using a commercially available
chiral rhodium catalyst.
(1) For a recent review on allylic amination, see: Johannsen, M.;
Jorgensen, K. A. Chem. ReV. 1998, 98, 1689
.
(2) For the importance of resolved allyic carbonates and alcohols, see:
(a) Evans, P. A.; Leahy, D. K. J. Am. Chem. Soc. 2003, 125, 8974. (b)
Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135. (c) Corey, E. J.;
Helal, C. J. Angew. Chem., Int Ed. 1998, 37, 1986. (d) Charette, A. B.;
Beauchemin, A. Org. React. 2001, 58, 1. (e) Hanson, R. M. Org. React.
2002, 60, 1
.
(3) For representative references of kinetic resolution in allylic substitu-
tions using Pd catalysts, see: (a) Hayashi, T.; Yamamoto, A.; Ito, Y. J. Chem.
Soc., Chem. Commun. 1986, 1090. (b) Gais, H.-J.; Eichelman, H.; Spalthoff,
N.; Gerhards, F.; Frank, M.; Raabe, G. Tetrahedron: Asymmetry. 1998, 9,
235. (c) Ramdeehul, S.; Dierkes, P.; Aguado, R.; Kamer, P. C. J.; Van
Leeuwen, P. W. N. M.; Osborn, J. A. Angew. Chem., Int. Ed. 1998, 37,
3118. (d) Reetz, M. T.; Sostmann, S. J. Organomet. Chem. 2000, 603, 105.
(e) Longmire, J. M.; Wang, B.; Zhang, X. Tetrahedron Lett. 2000, 41, 5435.
(f) Gais, H.-J.; Spalthoff, N.; Jagusch, T.; Frank, M.; Raabe, G. Tetrahedron
Lett. 2000, 41, 3809. (g) Gilbertson, S. R.; Lan, P. Org. Lett. 2001, 3, 2237.
(h) Lu¨ssem, B. J.; Gais, H.-J. J. Am. Chem. Soc. 2003, 125, 6066. (i) Gais,
H.-J.; Jagusch, T.; Spalthoff, N.; Gerhards, F.; Frank, M.; Raabe, G.
Chem.sEur. J. 2003, 9, 4202. (j) Jansat, S.; Go´mez, M.; Philippot, K.;
Muller, G.; Guiu, E.; Claver, C.; Castillo´n, S.; Chaudret, B. J. Am. Chem.
Soc. 2004, 126, 1592. (k) Faller, J. W.; Wilt, J. C.; Parr, J. Org. Lett. 2004,
6, 1301. (l) Lu¨ssem, B. J.; Gais, H.-J. J. Org. Chem. 2004, 69, 4041. (m)
During the course of our work, toward the synthesis of
drug intermediates, we envisioned the rhodium-catalyzed
(4) Iridium as catalyst: Fischer, C.; Defieber, C.; Suzuki, T.; Carreira,
E. M. J. Am. Chem. Soc. 2004, 126, 1628
(5) Ruthenium as catalyst: Onitsuka, K.; Matsushima, Y.; Takahashi,
S. Organometallics 2005, 24, 6472
(6) Evans, P. A.; Robinson, J. E.; Nelson, J. D. J. Am. Chem. Soc. 1999,
121, 6761.
.
.
Gais, H.-J.; Bondarev, O.; Hetzer, R. Tetrahedron Lett. 2005, 46, 6279
.
10.1021/ol901031b CCC: $40.75
Published on Web 06/15/2009
 2009 American Chemical Society

resolution of unsymmetrical acyclic allylic carbonates as an
intermediate process for the preparation of asymmetric allylic
amines. To explore this hypothesis, we set up a screen in
which racemic carbonate 1a was reacted with 0.5 equiv of
benzylamine in either methanol or tetrahydrofuran in the
presence of nine different commercially available chiral
rhodium catalysts frequently used for asymmetric hydrogena-
tion.7 Tetrahydrofuran was chosen for its wide use in the
allylic substitution reaction, and methanol was chosen for
its broad use in hydrogenations. A number of catalysts
showed excellent activity (see the Supporting Information
for a full list of catalysts and results). The three best catalysts
for conversion and selectivity were (S)-Binapine-Rh (4),
(R,R)-Ph-BPE-Rh (5), and (S,S,R,R)-Tangphos-Rh (6) (see
Figure 1). All three catalysts are unprecedented for use in
Table 1. Catalyst Screen for Resolution of 1a
yield of ee 2ac ee 3ac
solvent 3ab (%)
(%) (%)
entry
ligand
1
2
3
4
5
6
(S)-binapine
(S)-binapine
(R,R)-Ph-BPE
(R,R)-Ph-BPE
(S,S,R,R)-Tangphos MeOH
(S,S,R,R)-Tangphos THF
MeOH
THF
MeOH
THF
50
>99.9 >99.9
9.5 >99.9
10.2
39.0
13.5
35.2
50
66.3
97.6
96.6
89.0
97.3
13.1
45.7
>99.9
a All reactions were carried out on a 1 mmol (1a) scale using 1 mol %
of catalyst and 0.525 equiv of benzylamine at 0.5 M for 16 h. b Assay yield,
theoretical yield is 50%, determined by the ratio of 3a to benzylamine, no
other UV-active products were formed in the reaction. c Limits of detection
are e0.1%; see the Supporting Information for methods.
Carbonates 2a-d were confirmed by optical rotation to
have the R absolute configuration, while the amines 3a-d
Scheme 1. Resolution of 1a-e Using (S,S,R,R)-Tangphos-Rh
were confirmed by X-ray analysis to have the S absolute
configuration (see the Supporting Information). Since 2a-d
and 3a-d have opposite absolute stereochemistry, a double-
inversion mechanism is implicated.8 Presumably 6 is able
to form matched/mismatched pairs with 1a-d resulting in a
rate difference between the conversion of (S)-2a-d and (R)-
2a-d to (S)-3a-d and (R)-3a-d, respectively (Scheme 2).
Figure 1. Ligand structures.
the allylic substitution reaction. These six reactions were
repeated on a 1.0 mmol scale with a 1 mol % catalyst loading
(Table 1). Our results show that (S)-Binapine-Rh and
(S,S,R,R)-Tangphos-Rh are both excellent catalysts for the
resolution of 1a. In addition, the % ee’s for the obtained
secondary amine (3a) ranged from 89.0 to >99.9.
To demonstrate the generality of the reaction, carbonates
1a-e were subjected to the resolution conditions using 6 as
the catalyst on a 10.0 mmol scale to facilitate isolation and
characterization of the products (Scheme 1, Table 2). The
resolved carbonates 2a-d were each a single enantiomer,
and the amines 3a-d were >91% ee.
Table 2. Preparation of 2a-d and 3a-e with
(S,S,R,R)-Tangphos-Rha
yieldb of
2 (%)
yieldb
3 (%)
ee of
2c (%)
ee of
3c (%)
entry
1
regio-3d
1
2
3
1a
1b
1c
1d
1e
1e
44
42
47
36
34
46
49
50
>99.9
>99.9
>99.9
>99.9
16.1
97.5
95.2
91.5
>99.9
89.0
89.1
ND
ND
ND
ND
ND
ND
4
5e
6f
(7) (a) Patent Pending, PCT/US02/35788 . (b) US Patent 5,021,131. (c)
US Patent 5,171,892.
88
(8) (a) Hayashi, T.; Hagihara, T.; Konishi, M.; Kumada, M. J. Am. Chem.
Soc. 1983, 105, 7767. (b) Trost, B. M. Acc. Chem. Res. 1980, 13, 385. (c)
Evans, P. A., Leahy, D. K., In Modern Rhodium-Catalyzed Organic
Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim, 2005; Chapter 10, p
202.
a All reactions were carried out on a 10 mmol (1) scale using 0.005
equiv of (S,S,R,R)-Tangphos-Rh and 0.5 equiv of benzylamine in THF (0.5
M) for 3 h. b Isolated yield 50% is theoretical yield. c Limits of detection
are e0.1%; see the Supporting Information for methods. d ND ) not
detected, determined by NMR, no resonances consistent with that expected
for the regioisomers were observed. e Products were not isolated; the assay
yield of 3 was 50%. f One equivalent of benzylamine used.
(9) The reaction was run for 6 days to ensure completeness. HPLC assay
of the crude reaction mixture showed no benzylamine present and 3a
integrated for 90%. The ratio of 3a to its linear regioisomer was determined
1
by H NMR. The chiral assay of 3a was 96.28% ee.
Org. Lett., Vol. 11, No. 14, 2009
3141

and the concurrent synthesis of enantioenriched secondary
amines using a chiral rhodium catalyst. To the best of our
knowledge, we are unaware of other examples of a rhodium-
catalyzed enantioselective allylic amination or the resolution
of acyclic asymmetric allylic carbonates. This resolution
offers significant advantages over the current methodology:
both the catalyst and nucleophile are commercially available
and the product and unreacted starting material are easily
separated by simple aqueous acidic extraction. The carbon-
ates are isolated in >99.9% ee, and the amines are isolated
in 91f 99.9% ee free of linear regioisomers. The method is
general for the aliphatic carbonates examined except benzylic
carbonate 3e which could be completely converted to its
secondary amine in an enantio- and regioselective fashion.
Scheme 2. Proposed Mechanism for the Kinetic Resolution of
1a-d and the Asymmetric Transformation of 1e to 3e
The amines 3a-e did not contain detectable amounts of the
corresponding terminal regioisomers.
Acknowledgment. We thank Kevin Henegar and Derek
Pflum of Pfizer Global Research and Development for their
helpful suggestions. Pfizer Inc. is acknowledged for its
continuous support of this research.
Interestingly, recovered carbonate 1e showed very little
resolution under the conditions, even though amine 3e was
89.0% ee. Apparently, although 6 is able to form matched/
mismatched pairs with 1a-d its ability to do so with 1e is
greatly diminished. To capitalize on this phenomenon, we
reacted 1e with a full equivalent of benzylamine in the
presence of 6. As anticipated, 1e was converted to 3e in 88%
isolated yield and 89.1% ee (entry 6). In order to determine
if this outcome was unique to the benzylic carbonate, 1a
was reacted with a full equivalent of benzylamine to give
complete conversion to a 55:45 mixture of 3a to its linear
regioisomer, respectively.9
Supporting Information Available: General procedures
for the catalyst screen, resolution of carbonates, and synthesis
of amines; physical characterization data for resolved
carbonates and amines, proof of absolute configuration of
carbonates and amines including X-ray crystal structures for
all amines, as well as analytical methods for determining
the enantiomeric excess of all carbonates and amines. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, we have discovered a novel method for the
kinetic resolution of unsymmetrical acyclic allylic carbonates
OL901031B
3142
Org. Lett., Vol. 11, No. 14, 2009