Catalytic enantioselective synthesis of 4-vinyl-2-trichloromethyloxazoline: An access to enantioenriched vinylglycinol surrogate

Article abstract of DOI:10.1021/jo101781y

Cationic Pd(II) catalysts generated from chiral biphenyl diphosphine complexes or from COP-Cl promote enantioselective cyclization of E- and Z-configured allylic bis-trichloroacetimidates to highly enantioenriched 2-trichloromethyl-4-vinyloxazoline. This

Full text of DOI:10.1021/jo101781y

pubs.acs.org/joc
and natural products.3 Protected vinylglycinol 1 has been
Catalytic Enantioselective Synthesis of 4-Vinyl-2-
trichloromethyloxazoline: An Access to
Enantioenriched Vinylglycinol Surrogate
obtained in enantiomerically pure form by separation of
racemic mixture4 or starting from enantiopure serine,2a,5
methionine,1b,c,2a,6 and buten-1,2-diol.7 Chiral auxiliary-
controlled diastereoselective addition of vinyl-organometallic
reagents to oxime ethers8 or sulfinylimines9 has also been
used to obtain vinylglycinol 1 derivatives in high enantio-
meric purity. In addition, several synthetically useful
enantioselective catalytic methods have been developed.
Asymmetric Pd(0)-catalyzed allylic alkylation of phthalimide
with butadiene monoxide provided N-Phth protected
vinylglycinol 2.3a-c,10 Enantioselective Ir catalysis has been
used for the amination of allylic carbonates leading to a
range of N,O- or N-protected vinylglycinols 3.11 Asymmetric
Ni(0)- and Pd(II)-catalyzed cyclization of allylic carbamates
to N-protected vinyloxazolidinones 4 has been reported.12,13
Rearrangement of O-allylic acetimidates catalyzed by planary
chiral Pd(II) complexes has provided N-trichloroacetyl- and
N-trifluoroacetylvinylglycinol derivatives 5 in high enantio-
meric excess (Figure 1).14
Ansis Maleckis, Kristine Klimovica, and Aigars Jirgensons*
Latvian Institute of Organic Synthesis, Riga, LV-1006, Latvia
aigars@osi.lv
Received September 10, 2010
Cationic Pd(II) catalysts generated from chiral biphenyl
diphosphine complexes or from COP-Cl promote enantio-
selective cyclization of E- and Z-configured allylic bis-
trichloroacetimidates to highly enantioenriched 2-tri-
chloromethyl-4-vinyloxazoline. This represents an
exclusive example for olefin amination in high yield
and enantioselectivity with trichloroacetimidate as the
N-nucleophile by using a cationic palladium(II) complex
as a catalyst providing an easy-to-deprotect enantio-
enriched vinylglycinol derivative.
FIGURE 1. Vinylglycinol 1 and its derivatives 2-5 obtained by
enantioselective catalysis.
2-Trichloromethyl-4-vinyloxazoline (8) (Scheme 1) is a use-
ful vinylglycinol surrogate for the synthesis of complex prod-
ucts.4,15 Unfortunately, it has been obtained only in racemic
form by a Pd(II)-catalyzed cyclization of bis-trichloroacetimidate
Z-7. The high synthetic utility of vinyloxazoline 8 prompted
Vinylglycinol 1 and its protected analogues (Figure 1) have
been widely used as building blocks for the synthesis of un-
natural amino acids,1 pharmaceutically relevant compounds,2
(4) Sabat, M.; Johnson, C. R. Org. Lett. 2000, 2, 1089.
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847. (b) Yamanoi, K.; Ohfune, Y.; Watanabe, K.; Li, P. N.; Takeuchi,
H. Tetrahedron Lett. 1988, 29, 1181. (c) Hashimoto, K.; Horikawa, M.;
Shirahama, H. Tetrahedron Lett. 1990, 31, 7047. (d) Horikawa, M.; Hashimoto,
K.; Shirahama, H. Tetrahedron Lett. 1993, 34, 331. (e) Yoo, S.-E.; Sang-Hee,
L.; Nakcheol, J.; Inho, C. Tetrahedron Lett. 1993, 34, 3435. (f) Shimamoto,
K.; Ishida, M.; Shinozaki, H.; Ohfune, Y. J. Org. Chem. 1991, 56, 4167.
(g) Del Valle, J. R.; Goodman, M. J. Org. Chem. 2004, 69, 8946.
(3) (a) Trost, B. M.; Horne, D. B.; Woltering, M. J. Angew. Chem., Int.
Ed. 2003, 42, 5987. (b) Trost, B. M.; Horne, D. B.; Woltering, M. J. Chem.;
(8) Cooper, T. S.; Laringo, A. S.; Laurent, P.; Moody, C. J.; Takle, A. K.
Org. Biomol. Chem. 2005, 3, 1252.
(9) Rech, J. C.; Yato, M.; Duckett, D.; Ember, B.; LoGrasso, P. V.;
Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2007, 129, 490.
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B. M.; Bunt, R. C.; Lemoine, R. C.; Calkins, T. L. J. Am. Chem. Soc. 2000,
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12. (b) Kirsch, S. F.; Overman, L. E. J. Org. Chem. 2005, 70, 2859.
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DOI: 10.1021/jo101781y
r
Published on Web 10/25/2010
J. Org. Chem. 2010, 75, 7897–7900 7897
2010 American Chemical Society

Maleckis et al.
JOCNote
SCHEME 1. Synthesis of 4-Vinyloxazolines R-8 and S-8
us to achieve the enantioselective cyclization of imidate 7 to
enantiomers R-8 and S-8 (Scheme 1).
Previously it has been reported that only neutral Pd(II)
catalysts14,16 are compatible with allylic trichloroacetimidates.
In turn, cationic Pd(II) complexes promote elimination
of trichloroacetamide by generation of an allyl cation17
that prohibits the use of commercially available chiral
polydentate ligands. Nevertheless, we speculated that bis-
trichloroacetimidate 7 could serve as a substrate for cationic
Pd(II)-catalyzed reactions because the tendency to form allylic
cation might be reduced due to the field effect of the second
imidate functional group. Indeed, brief screening of Pd(II)
catalysts derived from commercially available ligands revealed
that in situ generated cationic diphosphine Pd(II) complexes
afford the desired product 8 in high chemical yield from both
bis-imidate isomers E-7 and Z-7 in a short time under mild
reaction conditions (Tables 1 and 2; see Figure 2 for diphos-
phine ligands).
FIGURE 2. Diphosphine ligands and COP-Cl complex used to gener-
ate the Pd(II) catalyst system for the synthesis of vinyloxazolines
R-8 and R-8.
entry 1). An efficient catalytic system could also be prepared
in situ from PdCl2(MeCN)2 by mixing it with (R)- or
(S)-BINAP followed by addition of AgBF4 (Table 1, entries 2
and 3). Other axially chiral diphosphines such as (R)-T-
BINAP, (S)-Xyl-BINAP, (S)-MeO-BIPHEP, and (S)-DTB-
MeO-BIPHEP were also found to be efficient for the enantio-
selective cyclization of imidate E-7 (Table 1, entries 4-7)
while (S)-SEGPHOS induced moderate enantioselectivity
(Table 1, entries 8). Control experiments with imidate E-7
were performed to confirm that (R)-BINAPPdCl2 complex
in its coordinatively saturated form has no catalytic activity
and that AgBF4 alone cannot promote the reaction (Table 1,
entries 9 and 10).
Isomeric bis-imidates E-7 and Z-7 required different
catalytic systems to achieve high enantioselectivity of
vinyloxazoline 8 formation as shown in Tables 1 and 2. We were
pleased to find that bis-trichloroacetimidate E-7 was trans-
formed to vinyloxazoline R-8 in high enantiomeric excess by
using a (R)-BINAPPdCl2/AgBF4 catalytic system (Table 1,
TABLE 1. Diphosphine-Pd(II) Complex Catalyzed Cyclization of Bis-imidate E-7 to Enantioenriched Vinyloxazoline 8
entry
catalyst systema
time
ee,b (S or R)c
yield, %
1
2
3
4
5
6
7
8
9
10
(R)-BINAPPdCl2/ AgBF4
1 h
1 h
1 h
1 h
2.5 h
2.5 h
2.5 h
2.5 h
>1 d
>1 d
94%,d (R)
90%, (R)
93%, (S)
89%, (R)
87%, (S)
93%, (S)
94%, (S)
66%, (S)
93
(R)-BINAP/PdCl2(CH3CN)2 /AgBF4
(S)-BINAP/PdCl2(CH3CN)2/ AgBF4
(R)-T-BINAP/PdCl2(CH3CN)2 /AgBF4
(S)-Xyl-BINAP PdCl2(CH3CN)2 /AgBF4
(S)-MeO-BIPHEP PdCl2(CH3CN)2 /AgBF4
(S)-DTB-MeO-BIPHEP PdCl2(CH3CN)2 /AgBF4
(S)-SEGPHOS PdCl2(CH3CN)2 /AgBF4
(R)-BINAPPdCl2
88e
94e
91e
84
89
93
87
n.r.
n.r.
AgBF4
aSubstrate/ligand/PdCl 2(CH3CN) 2/AgBF4 ratio 100/3/2.5/8 or 100/4/3/10. bDetermination of ee by GC on 6-TBDMS-2,3-Me-β-CD column unless
otherwise indicated. cConfiguration of the major enantiomer. dDetermination of ee by reverse phase HPLC after hydrolysis and subsequent
derivatization with chiral reagents.18 eAverage yield of two runs. Please see the Supporting Information for details
TABLE 2. Diphosphine-Pd(II) Complex Catalyzed Cyclization of Bis-imidate Z-7 to Enantioenriched Vinyloxazoline 8
entry
catalyst systema
time, h
ee,b (S or R)c
yield, %
1
2
3
4
5
6
7
8
(R)-BINAPPdCl2/ AgBF4
1
2
30%,d (R)
50%, (S)
44%, (S)
80%, (S)
84%, (S)
83%, (S)
80%, (S)
6%, (R)
85
76
86
79
78
88
83
97
(S)-MeO-BIPHEP/PdCl2(CH3CN)2 /AgBF4
(S)-SEGPHOS/PdCl2(CH3CN)2 /AgBF4
(S)-Xyl-BINAP/PdCl2(CH3CN)2 /AgBF4
(S)-DM-SEGPHOS/PdCl2(CH3CN)2 /AgBF4
(S)-3,5-DM-MeO-BIPHEP/PdCl2(CH3CN)2 /AgBF4
(S)-TMO-MeO-BIPHEP/PdCl2(CH3CN)2 /AgBF4
(S)-DTB-MeO-BIPHEP/PdCl2(CH3CN)2 /AgBF4
2 h
2 h
2 h
2 h
2 h
2 h
aSubstrate/ligand/PdCl2(CH3CN)2/AgBF4 ratio 100/3/2.5/8 or 100/4/3/10. bDetermination of ee by GC on 6-TBDMS-2,3-Me-β-CD column unless
otherwise indicated. cConfiguration of the major enantiomer. dDetermination of ee by reverse phase HPLC after hydrolysis and subsequent
derivatization with chiral reagents. Please see the Supporting Information for details.
7898 J. Org. Chem. Vol. 75, No. 22, 2010

Maleckis et al.
JOCNote
TABLE 3. COP-Cl-Catalyzed Synthesis of Enantioenriched Vinyl-
oxazoline 8
SCHEME 2. Possible Pathways for Vinyloxazoline 7 Formation
entry imidate
catalyst systema
time ee,b (S or R)c yield, %
1
2
3
E-7
E-7
Z-7
(S)-COP-Cl
(S)-COP-Cl/AgBF4
(S)-COP-Cl/ /AgBF4 1 h
6 d
1 h
6%, (R)
94%, (R)
88e
89e
97
14%,d (R)
aSubstrate/COP-Cl//AgBF4 ratio 100/1/2. bDetermination of ee by
GC on 6-TBDMS-2,3-Me-β-CD column unless otherwise indicated.
cConfiguration of the major enantiomer. dDetermination of ee by
reverse phase HPLC after hydrolysis and subsequent derivatization
with chiral reagents.18 eAverage yield of two runs. Please see the
Supporting Information for details.
Isomeric bis-imidate Z-7 was a more challenging sub-
strate. Diphosphines (R)-BINAP, (S)-MeO-BIPHEP, and
(S)-SEGPHOS as Pd(II) ligands induced low to moderate
enantioselectivity (Table 2, entries 1-3). Gratifyingly, ligands
bearing m-Me- or m-MeO-substituted phenyl groups such as
(S)-Xyl-BINAP, (S)-DM-SEGPHOS, (S)-3,5-DM-MeO-
BIPHEP, and (S)-TMO-MeO-BIPHEP allowed synthetically
useful enantiomeric excess of enantioenriched vinyloxazo-
line 8 to be achieved (Table 2, entries 4-7). Increasing the
bulk of substituents at the phenyl groups of the ligand, e.g.,
using (S)-DTB-MeO-BIPHEP, resulted in loss of enantios-
electivity (Table 2, entry 8).
SCHEME 3. Synthesis of Vinylglycinol Hydrochloride S-1 HCl
and Its N-Cbz Derivative 10
3
Overman’s catalyst (COP-Cl, Figure 2) used for the enantio-
selective rearrangement of allylic imidates13 was also explored
for the cyclization of bis-trichloroacetimidates E-7 and Z-7.
Surprisingly, when COP-Cl catalyst was used in its neutral
form, bis-imidate E-7gave nearly racemic vinyloxazoline 8, and
the rearrangement product was not observed (Table 3, entry 1).
The cationic catalyst derived from COP-Cl exhibited
markedly increased activity, leading to vinyloxazoline 8 for-
mation in very high yield from both isomeric bis-imidates
E-7 and Z-7 (Table 3, entries 2 and 3). However, high enantio-
selectivity was observed only when bis-imidate E-7 was used as
a substrate (Table 3, entry 2). Unfortunately, the enantioselec-
tivity was low in the case of isomeric bis-imidate Z-7 (Table 3,
entry 3). It should be noted that it was difficult to purify the
product 8 from the colored minor impurities by chromatogra-
phy when using COP-Cl as a catalyst precursor in contrast to
the Pd(II) catalysts derived from diphosphine ligands.
Two possible mechanistic pathways were considered to
explain vinyloxazoline 8 formation (Scheme 2). Pathway A
involves metal-catalyzed Overman rearrangement of bis-
imidate 7 proceeding by well-established 6-endo aminopal-
ladation-deoxypalladation sequence via an intermediate
A.19 The rearrangement product 9 theoretically can undergo
cyclization to vinyloxazoline 8 promoted by Lewis acidic
Pd2þ catalyst. To establish if Pathway A is operational,
amide 9 was prepared by thermal Overman rearrangement
from Z-720 and was subjected to 20 mol % of the catalytic
system;(S)-BINAP/PdCl2(CH3CN)2/AgBF4 (4/3/10). No
reaction of compound 9 was observed under these conditions
in 3 h time. On the basis of this observation we propose that
the product 8 formation may proceed by Pathway B that
involves 5-exo aminopalladation to form an intermediate B
followed by the deoxypalladation step in analogy to the
mechanism proposed for similar reactions.13a,21
It was an interesting finding that both bis-imidates E-7 and
Z-7 were transformed to the same vinyloxazoline 8 enantio-
mer if the catalyst of the same configuration was used.
Although the isomerization of imidate Z-7 to E-7 was not
observed in the course of the reaction, it cannot be ruled out
if proceeding faster than the cyclization.
Finally, we demonstrated that vinyloxazoline 8 can be
transformed to vinylglycinol hydrochloride S-1 HCl under
3
milder conditions than reported previously4 and it was
further transformed to the known N-Cbz-protected (S)-
vinylglycinol 10 (Scheme 3). The value and the sign of optical
rotation of compound 10 was in agreement to that reported
in the literature.10a
In summary we have demonstrated that cationic Pd(II)
catalysts generated from axially chiral biphenyl diphospine
complexes or from COP-Cl promote enantioselective cycli-
zation of bis-trichloroacetimidates E-7 and Z-7 to highly
enantioenriched 2-trichloromethyl-4-vinyloxazoline (8). A
short and high-yielding synthetic route as well as commer-
cially available catalyst precursors in both enantiomeric
forms renders this a practical method for the synthesis of
enantioenriched vinylglycinol surrogate 8 possessing high
derivatization potential.
Experimental Section
(16) Kirsch, S. F.; Overman, L. E.; Watson, M. P. J. Org. Chem. 2004, 69,
8101.
˚
E-7. Molecular sieves 4 A and DBU (76 mg; 75 μL; 0.5 mmol)
(17) (a) Overman, L. E.; Hollis, T. K. J. Org. Chem. 1999, 576, 290.
(b) Donde, Y.; Overman, L. E. J. Am. Chem. Soc. 1999, 121, 2933. (b) Jiang,
Y.; Longmire, J. M.; Zhan, X. Tetrahedron Lett. 1999, 40, 1449.
(18) Harada, K.-I.; Shimizu, Y.; Fuji, K. Tetrahedron Lett. 1998, 39,
6245.
were added to a solution of E-but-2-en-1,4-diol22 (6) (0.95 g;
10.8 mmol) in THF (15 mL) at room temperature. The solution
(19) (a) Overman, L. E.; Carpenter, N. E. In Organic Reactions; Overman,
L. E., Ed.; Wiley: Hoboken, NJ, 2005; Vol. 66, p 653. (b) Watson, M. P.;
Overman, L. E.; Bergman, R. G. J. Am. Chem. Soc. 2007, 129, 5031.
(20) Vyas, D. M.; Chiang, Y.; Doyle, T. W. J. Org. Chem. 1984, 49, 2037.
(21) Maleckis, A.; Jaunzeme, I.; Jirgensons, A. Eur. J. Org. Chem. 2009,
6407.
(22) Bellamy, F. D.; Bondoux, M.; Boubia, B.; Dodey, P.; Mioskowski,
C. Tetrahedron: Asymmetry 1992, 3, 355.
J. Org. Chem. Vol. 75, No. 22, 2010 7899

Maleckis et al.
JOCNote
was cooled to -5°C and to this trichloroacetonitrile (3.75 g; 2.61 mL,
26.0 mmol) was added. The mixture was stirred for 1 h until complete
consumption of the starting material (TLC control, eluent hexane/
EtOAc=8/1). The reaction mixture was diluted with light petroleum
ether (150 mL) and filtered trough the pad of Celite. The solvent was
removed in vacuo and the residue applied to short silica gel column
eluting with a mixture of hexane/EtOAc=8/1 to give E-7 (3.70 g,
91%) as a viscous oil that solidified in the freezer. Mp 40-41 °C;
1H NMR (400 MHz, CDCl3) δ8.35 (2H, s), 6.07-6.09 (2H, m), and
4.85-4.86 (4H, m); 13C NMR (100 MHz, CDCl3) δ 162.4, 127.4,
91.2, and 68.4; HRMS (EI) [M - Cl3 (CdO)NH]þ calcd for C6H8-
NOCl3 213.9593, found 213.9535. Elemental Anal. Calcd (%) for
C8H8Cl6N2O2 (376.88): C 25.50, H 2.14, N 7.43. Found: C 25.89,
H 2.00, N 7.29.
obtained was added 6 N aqueous HCl (4 mL). After the con-
sumption of starting material was complete (TLC control, ca. 12 h),
the reaction mixture was evaporated in vacuo. The residue was
suspended in toluene and evaporated, this was repeated several
times until crystalline material was obtained. The residue was
treated with EtOAc and the precipitate was collected on a filter
and dried in vacuo over P2O5 to give S-1 HCl (80.6 mg, 70%) as
3
a crystalline, very hygroscopic compound. The spectroscopic
characterization of compound S-1 HCl was identical with that
3
described in the literature.23 [R]D þ10.1 (MeOH, c 0.42) [lit.9 for
S-10 [R]D þ10.0 (MeOH, c 0.53)]. Elemental Anal. Calcd (%) for
C4H10ClNO 0.5H2O (M = 132.6): C 36.23, H 8.36, N 10.56.
Found: C 35.84, H 8.39, N 11.00.
S-10. Vinylglycinol (S-1 HCl) (63 mg, 0.53 mmol) was dis-
3
3
R-8: Representative Procedure. The catalyst system was pre-
pared by mixing PdCl2(CH3CN)2 (65 mg; 0.25 mmol), (R)-BINAP
(187 mg; 0.30 mmol), AgBF4 (156 mg; 0.80 mmol), and molecular
solved in the biphasic mixture of saturated aqueous NaHCO3
(7 mL) and EtOAc (13 mL). The mixture was cooled to 0 °C and
to this was added CbzCl (182 μL, 1.2 mmol) in one portion. The
stirring was continued at 0 °C for 2 h and then at room tem-
perature for 6 h and the organic phase was separated. The aque-
ous phase was extracted with EtOAc (1 ꢀ 10 mL) and the com-
bined organic phase was washed with water (2 ꢀ 10 mL) then
with brine (2 ꢀ 10 mL) and dried over Na2SO4. The solvent was
removed in vacuo and the residue was purified by flash chro-
matography on silica gel, eluting with a mixture of light petro-
leum ether/EtOAc=1/1 to give product S-10 (91 mg, 80%). The
spectroscopic characterization of compound S-10 was identical
with that described in the literature.4 [R]D -29.2 (CHCl3, c 1.54)
[lit.10a for S-10 [R]D -32.2 (CHCl3, c 1.47)].
˚
sieves 4 A in CH2Cl2 (50 mL) under Ar atmosphere at room
temperature. The suspension was stirred intensively for 20 min and
to this was added (E)-bis-trihloracetimidate E-7 (3.90 g; 10.3 mmol)
in one portion. The suspension was stirred at room temperature for
ca. 1 h, until complete consumption of the starting material (TLC
control, eluent hexane/EtOAc = 8/1). The reaction mixture was
diluted with light petroleum ether (150 mL) and filtered through the
pad of Celite. The solvent was removed in vacuo and the residue
applied to silica gel column eluting with a mixture of hexane/
EtOAc = 8/1 to give R-8 (2.02 g, 92%) as a colorless oil.
[R]20D þ102.8 (c 4.0, CH2Cl2). The spectroscopic characteriza-
tion was identical with the literature data of the racemic compound.4
Enantiomeric excess: (a) ee 94% (by derivatization with chiral
shift reagent, see the Supporting Information) and (b) ee 90%
(GC on a chiral stationary phase). For the determination of
absolute configuration see the Supporting Information.
S-8. The synthetic procedure to obtain (S)-2-trichloromethyl-
4-vinyloxazoline (S-8) was analogues to the synthesis of enan-
tiomer R-8. To the catalyst system prepared by mixing PdCl2-
(CH3CN)2 (31 mg; 0.12 mmol), (S)-BINAP (99 mg; 0.16 mmol),
and AgBF4 (79 mg; 0.41 mmol) in CH2Cl2 (8 mL) was added a
solution of E-7 (1.50 g; 4.0 mmol) in CH2Cl2 (7 mL) to give S-8
(838 mg, 98%), [R]20D -108.1 (c 4.0, CH2Cl2), ee 92.6% (GC on
a chiral stationary phase)
Acknowledgment. Funding from Latvian Council of
Science is acknowledged. We thank Prof. E. Liepins for
assistance in structure determination by NMR spectroscopy.
Supporting Information Available: Determination of the
absolute configuration of R-8 and S-8 by derivatization with
chiral shift reagents and 1H NMR, 13C NMR, and NOESY
NMR spectra of derivatization products; copies of NMR
spectra of E-7; and chromatograms for ee determination by
GC on the chiral stationary phase. This material is available free
of charge via the Internet at http://pubs.acs.org.
S-1 HCl. 2-Trichloromethyl-4-vinyloxazoline (S-8) (200 mg,
0.93 mmol) was dissolved in EtOH (4 mL) and to the solution
3
(23) Cardillo, G.; Orena, M.; Sandri., S. J. Org. Chem. 1986, 51, 713.
7900 J. Org. Chem. Vol. 75, No. 22, 2010