Enantiomerically enriched vic-amino alcohols from 2-iminobornanes

Article abstract of DOI:10.1016/S0957-4166(02)00486-X

Enantiomerically enriched vic-amino alcohols derived from D-camphor have been synthesized by condensation of the highly electrophilic N-nitroimine of D-camphor with ethanolamine, (R)-phenylglycinol and (1R,2S)-norephedrine to afford imines 8a-c. The imino

Full text of DOI:10.1016/S0957-4166(02)00486-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1849–1854
Enantiomerically enriched vic-amino alcohols from
2-iminobornanes†
Michael D. Squire,a Amanda Burwell,b Gregory M. Ferrenceb and Shawn R. Hitchcocka,*
aDepartment of Chemistry, Illinois State University, Normal, IL 61790-4160, USA
bDepartment of Chemistry, Structure Determination Laboratory, Illinois State University, Normal, IL 61790-4160, USA
Received 3 June 2002; accepted 21 August 2002
Abstract—Enantiomerically enriched vic-amino alcohols derived from
D-camphor have been synthesized by condensation of the
highly electrophilic N-nitroimine of -camphor with ethanolamine, (R)-phenylglycinol and (1R,2S)-norephedrine to afford imines
D
8a–c. The iminobornanes were reduced with lithium aluminum hydride to afford the corresponding amines in good yield
(78–88%). The stereochemistry of the reduction was confirmed by X-ray crystallographic studies of the N-nitrosated
norephedrine–camphor derivative 12. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
report on the synthesis of chiral, non-racemic vic-amino
alcohols derived from -camphor.
D
The need for enantiomerically pure materials has
steadily increased over the past several decades, espe-
cially in the pharmaceutical market because of regula-
tions concerning the efficacy of chiral drugs.1 In answer
to the escalating demand for chiral, non-racemic mate-
rials, a variety of catalytic, asymmetric methods have
been developed that are capable of producing enan-
tiomerically enriched compounds. Among these meth-
ods are catalytic asymmetric reductions of prochiral
ketones2 and asymmetric 1,2-addition of organozinc
reagents to aldehydes.3a–c,e A central theme to these
synthetic transformations is the use of amino alcohols
that are most often derived from the chiral pool (a-
amino acids, terpenes, alkaloids, etc.).4 In particular,
2. Results and discussion
The vic-amino alcohols that we envisioned preparing
involved a synthetic pathway that would require the
formation of an iminobornane from
subsequent reduction. In our initial experimentation we
attempted to condense -camphor 7 with (1R,2S)-
D-camphor and
D
norephedrine under reflux conditions in dichloroethane
(Scheme 1). After 100 h, we obtained the desired imine
8 in 12% yield after column chromatography. At this
many research groups have pursued the use of
D-cam-
phor as a template for creating diverse vic-amino alco-
hols for the purpose of application in asymmetric
synthesis (Chart 1).3
In conjunction with our program focused on the study
of 1,3,4-oxadiazinan-2-ones,5 we became interested in
developing syntheses of vic-amino alcohols. Herein, we
* Corresponding author. Tel.: +309-438-7854; fax: +309-438-5538;
e-mail: hitchcock@xenon.che.ilstu.edu
† Part of this work was presented at the 222nd National Meeting of
the American Chemical Society, Chicago, IL, August 2001, Abstract
No. 243-CHED.
Chart 1.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00486-X

1850
M. D. Squire et al. / Tetrahedron: Asymmetry 13 (2002) 1849–1854
Danks and co-workers10 were able to successfully
reduce camphor imines derived from a-substituted ben-
zylamines using sodium borohydride in ethanol. In a
similar fashion, imines 8a–c were subjected to sodium
borohydride reduction in an attempt to acquire amines
11a–c. This process failed to generate the desired vic-
amino alcohols in acceptable yield and purity. We then
opted to use lithium aluminum hydride in THF at
reflux to perform the transformation. The LAH reduc-
tion proceeded cleanly to afford the corresponding
amines in high yield and purity after column chro-
matography (78–88%). The addition of hydride to the
endo-face of the iminobornane system was expected to
be the dominant reaction pathway although there have
been observations of the exo-addition of hydride to
camphor imines.10a,11 To confirm this stereochemical
assignment, the norephedrine based vic-amino alcohol
11c was converted to its corresponding N-nitrosamine12
which was subjected to X-ray crystallographic studies
(Scheme 3, Table 1). The X-ray crystal structure (Fig.
1)13 confirmed that hydride added to the endo-face to
give the 2-exo-amino product.
Scheme 1.
point, we decided to pursue a more effective route to
the iminobornane. Several research groups have devel-
oped methods for circumventing the relatively low elec-
trophilicity of camphor via modification of carbonyl by
introduction of the N-nitroimine functionality.6 N-
Nitroimines are considerably more reactive than their
ketone counterparts and probably react as Michael
acceptors with the concomitant evolution of nitrous
oxide.6c
The N-nitroimine of
D-camphor was thus prepared as
described in the literature (Scheme 2).6c This process
was straightforward and could be conducted on multi-
gram scales (25–100 g). With the N-nitroimine in hand,
we pursued the condensation reaction with a variety of
vic-amino alcohols including ethanolamine, (1R,2S)-
norephedrine and (R)-phenylglycinol.7,8 The formation
of the camphor based imines 8a–c proceeded in high
yield (78–88%).9 Numerous attempts were made to
condense the N-nitroimine with 2-amino-2-methyl-1-
propanol. Unfortunately, the imine product was not
observed; only an unidentified by-product was pro-
duced in low yield. The failure to achieve complete
condensation to afford the desired imine is most likely
due to the steric environment near the nitrogen.10 The
stereochemistry of the isolated imines 8a–c was not
3. Conclusion
Diastereomerically pure vic-amino alcohols have been
prepared by reaction of the N-nitroimine of D-camphor
with ethanolamine, (1R,2S)-norephedrine and (R)-
phenylglycinol to yield iminobornanes 8a–c which were
reduced by lithium aluminum hydride to afford the
1
determined although H and 13C NMR spectroscopy
Scheme 3.
suggested that there was a single isomer in each case.
Scheme 2.

M. D. Squire et al. / Tetrahedron: Asymmetry 13 (2002) 1849–1854
1851
Table 1. Summary of data collection, solution and refine-
ment parameters
data were corrected for absorption through the use of
empirical psi-scans.17
Molecular formula
Fw (g/mol)
Crystal dimensions (mm)
Color, shape
Crystal system
Space group
C19H28N2O2
315.4
0.39×0.18×0.29
beige plate
Orthorhombic
P212121
Solution and data analysis was performed using the
WinGX software package.18 The structure of 1 was
solved using the direct method program SIR-92 and the
refinement was completed using the program SHELXL-
97.19 Hydrogen atoms were assigned positions based on
the geometries of their attached carbon atoms, and
were given thermal parameters of 20% greater than
those of the attached atoms. Full-matrix least-squares
refinement on F2 led to convergence with R1=0.032
Unit cell parameters
,
a (A)
8.7419(15)
10.119(2)
20.887(3)
1847.66(6)
4
1.13
,
b (A)
,
c (A)
3
2
2
,
V (A )
Z
and wR2=0.084 for 2404 data with Fo >2|(Fo ). A final
difference Fourier synthesis showed features in the
Dcalcd (g cm−3
)
−3
,
range of +0.100 to −0.178 e A .
v (cm−1
)
0.73
Diffractometer
Bru¨ker-Nonius
CAD4/MACH3/Scintillation
0.71073
298
2.0–25.9
4.2. General remarks
,
Wavelength (u, A)
Temperature (K)
q Range
Tetrahydrofuran (THF) was distilled from a potassium/
sodium alloy containing benzophenone ketyl. Methyl-
ene chloride (CH2Cl2) was distilled from calcium
hydride. Flash chromatography was conducted with
F(000)
Reflections collected
683.9
4021 (05h510, 05k512,
−255l525)
3579
2722 (I\25(I))
0.037 (0.064)
0.092 (0.102)
209 (0)
None
1.043
0.000 (0.000)
0.110 and −0.156
1
silica gel (32–63 mesh). All H and 13C NMR spectra
Independent reflections
Reflections observed
R indices observed (all data)
wR2 observed (all data)
Parameters (restraints)
Extinction coefficient
Goodness-of-fit
Shift/e.s.d. max (mean)
Largest difference peak and
hole (e A
were recorded at 25°C on a Varian spectrometer in
CDCl3 operating at 400 and 100 MHz, respectively.
Chemical shifts are reported in parts per million (l
scale), and coupling constants (J values) are listed in
hertz (Hz). Infrared spectra are reported in reciprocal
centimeters (cm−1). Melting points were recorded on a
Mel-Temp apparatus and are uncorrected. Elemental
analyses were conducted by the Microanalytical Labo-
ratory, School of Chemical Sciences, University of Illi-
nois, Urbana-Champaign.
−3
,
)
corresponding amines 11a–c in good overall yield (60–
77%). The stereochemistry of the reduction was con-
firmed to have given the 2-exo-amine product by X-ray
crystallographic studies of the N-nitrosated nore-
phedrine–camphor derivative 12. Research is underway
for the preparation of novel [1,3,4]oxadiazinan-2-ones
from the vic-amino alcohols 11a–c.
4.3. General procedures for the formation of imines 8
In a round-bottomed flask containing a minimal
,
4 A molecular sieves, N-
amount of pre-dried
nitroimino- -bornane (3.30 g, 16.8 mmol) was dis-
D
solved in 1,2-dichloroethane (15 mL). To the resulting
solution was added primary amine (15.3 mmol) and the
reaction was heated under reflux for 24 h under a
nitrogen atmosphere. The reaction was then gravity
filtered and the filtrate was washed with chloroform (30
mL). The resulting solution was extracted with a satu-
rated aqueous solution of NaHCO3 (3×50 mL). The
organic layer was washed with a saturated aqueous
solution of brine (50 mL) and dried over MgSO4. The
solvents were removed by rotary evaporation and crude
product was purified by column chromatography
(EtOAc/hexanes, 1:4). The reported yields reflect chro-
matographically pure material.
4. Experimental
4.1. Crystal structure determination
A beige plate of approximate dimensions 0.39×0.18×
0.29 mm was mounted on a glass fiber with Superglue
and transferred to a Bru¨ker-Nonius CAD4/Mach3 dif-
fractometer. The X-ray diffraction data were collected
at room temperature using Mo Ka radiation. Data
collection and cell refinement was performed using
CAD4 Express.14 Data reduction was carried out using
XCAD4.15 The unit cell parameters were obtained from
a least-squares refinement of 25 centered reflections.
The systematic absences indicated the space group
P212121 (no. 19).16 The N-nitrosamine derivative 12 was
found to crystallize in the orthorhombic crystal system
4.3.1. (1R,2R)-2-(1,7,7-Trimethylbicyclo[2.2.1]hept-2-yli-
deneamino)ethanol, 8a. Note: This reaction preparation
is initially exothermic with the release of nitrous oxide
gas. 78% yield as colorless crystals; mp 65–66°C (hex-
1
anes); [h]D=−27.1 (c 1, MeOH); H NMR: l 0.75 (s,
with the following unit cell parameters: a=8.7419(15),
3H), 0.93 (s, 3H), 0.97 (s, 3H), 1.21 (ddd, J=17.6, 9.6,
4.0 Hz, 1H), 1.35 (ddd, J=18.0, 9.6, 4.4 Hz, 1H), 1.68
(td, J=12.4, 4.4 Hz, 1H), 1.81–1.89 (m, 2H), 2.35 (dt,
J=17.2, 3.2 Hz, 1H), 2.89 (s, 1H), 3.3 (m, 2H), 3.80 (m,
3
,
,
b=10.119(2), c=20.887(3) A, V=1847.66(6) A , Z=4.
A total of 4021 reflections were collected, of which 3579
2
2
were unique, and 2722 were observed Fo >2|(Fo ). The

1852
M. D. Squire et al. / Tetrahedron: Asymmetry 13 (2002) 1849–1854
Figure 1. ORTEP of N-nitrosamine 12 with 20% probability ellipsoids.
2H); 13C NMR (CDCl3): l 11.3, 18.9, 19.5, 27.4, 32.1,
l 11.5, 15.0, 18.9, 19.3, 27.3, 31.8, 35.3, 43.6, 46.8, 53.4,
36.1, 43.8, 47.2, 53.5, 53.9, 62.3, 184.6; IR (Nujol):
3147, 2926, 1681, 1076 cm−1. Anal. calcd for
C12H21NO: C, 73.80; H, 10.84; N, 7.17. Found: C,
73.50; H, 10.97; N, 7.28%.
62.1, 76.7, 126.4, 126.9, 127.8, 142.1, 180.7; IR (KBr):
3200, 2868, 1668, 1043 cm−1. Anal. calcd for
C19H27NO: C, 79.95; H, 9.54; N, 4.91. Found: C, 79.88;
H, 9.69; N, 5.12%.
4.3.2.
(1R,1%R,4%R)-2-Phenyl-2-(1,7,7-trimethylbicy-
4.4. General procedures for the formation of secondary
amines 11
clo[2.2.1]hept-2-ylideneamino)ethanol, 8b. 83% yield as
colorless crystals; mp 72–73°C (hexanes); [h]D=−94.1 (c
1
1, MeOH); H NMR (CDCl3): l 0.79 (s, 3H), 0.92 (s,
In a flame dried three-necked, round-bottomed flask,
lithium aluminum hydride 0.946 g (24.9 mmol) was
suspended in THF (50 mL) and heated to reflux. A
solution of the imine (1.622 g, 8.305 mmol) in THF (17
mL) was added to the reaction flask via a pressure
equilibrating addition funnel and was allowed to reflux
for 24 h under a nitrogen atmosphere. The solution was
then cooled to 0°C and quenched by dropwise addition
of water (100 mL). The organic layer was washed with
NaOH (6 M, 3×100 mL), then treated with saturated
aqueous solution of NaCl (100 mL), and dried over
MgSO4. The solvents were removed by rotary evapora-
tion and the crude product was purified by column
chromatography (EtOAc/hexanes, 1:4). The reported
yields reflect chromatographically pure material.
3H), 0.93–0.99 (m, 1H), 1.043 (s, 3H), 1.27 (ddd, J=
18.0, 9.6, 4.4 Hz, 1H), 1.64 (td, J=12.0, 4.4 Hz, 1H),
1.71–1.79 (m, 1H), 1.87 (t, J=4.2 Hz, 1H), 2.45 (dt,
J=17.2, 3.2 Hz, 1H), 2.78 (s, 1H), 3.73–3.84 (m, 2H),
4.38 (dd, J=8.0, 4.8 Hz, 1H), 7.19–7.28 (m, 5H); 13C
NMR (CDCl3): l 11.4, 18.8, 19.6, 27.1, 31.8, 36.1, 43.8,
46.7, 54.2, 65.7, 68.3, 126.8, 127.1, 128.2, 141.2, 185.6;
IR (Nujol): 3254; 3022; 1601; 1053 cm−1. Anal. calcd
for C18H25NO: C, 79.66; H, 9.28; N, 5.16. Found: C,
79.80; H, 9.29; N, 5.45%.
4.3.3. (1R,1%R,2S,4%R)-1-Phenyl-2-(1,7,7-trimethylbicy-
clo[2.2.1]hept-2-ylideneamino)propan-1-ol, 8c. 88% yield
as colorless crystals; mp 84–85°C (hexanes); [h]D=−2.9
(c 1, MeOH); 1H NMR (CDCl3): l 0.70 (s, 3H), 0.87 (s,
3H), 0.91 (s, 3H), 0.96 (d, J=6.4 Hz, 3H), 0.98–1.08
(m, 2H), 1.53 (td, J=12.8, 3.6 Hz, 1H), 1.67–1.78 (m,
1H), 1.83 (t, J=4.4 Hz, 1H), 2.2 (dt, J=16.4, 4.0 Hz,
1H), 3.51 (quintet, J=6.4 Hz, 1H), 3.63 (s, 1H), 4.64 (d,
J=5.2 Hz, 1H), 7.20–7.37 (m, 5H); 13C NMR (CDCl3):
4.4.1. (1R,2%S,4R)-2-(1,7,7-Trimethylbicyclo[2.2.1]hept-
2-ylamino)ethanol, 11a. 78% yield as colorless crystals;
1
mp 48–49°C (hexanes); [h]D=−80.1 (c 1, MeOH); H
NMR: l 0.82 (s, 3H), 0.89 (s, 3H), 1.00 (s, 3H),
1.06–1.08 (m, 2H), 1.50–1.71 (m, 5H), 1.90 (bs, 1H),

M. D. Squire et al. / Tetrahedron: Asymmetry 13 (2002) 1849–1854
1853
2.54 (dd, J=7.6, 5.2 Hz, 1H), 2.67–2.76 (m, 2H), 3.57
(t, J=4.8 Hz, 2H); 13C NMR: l 12.1, 20.5, 20.5, 27.2,
36.9, 39.1, 45.0, 46.6, 48.4, 49.8, 61.0, 66.4; IR (Nujol):
3320, 3176, 1067 cm−1. Anal. calcd for C12H23NO: C,
73.04; H, 11.75; N, 7.10. Found: C, 72.80; H, 11.89; N,
7.25%.
3066, 1420, 1361, 1081, 757, 704 cm−1. Anal. calcd for
C19H28N2O2: C, 72.12; H, 8.92; N, 8.85. Found: C,
72.15; H, 9.13; N, 8.94%.
Acknowledgements
4.4.2. (1R,1%R,2%S,4%R)-2-Phenyl-2-(1,7,7-trimethylbicy-
clo[2.2.1]hept-2-ylamino)ethanol, 11b. 82% yield as col-
orless crystals; mp 76–77°C (hexanes); [h]D=−26.0 (c 1,
We gratefully acknowledge support from the depart-
ment of chemistry of Illinois State University, Merck &
Co, Inc. We also thank the donors of the Petroleum
Research Fund administered by the American Chemical
Society for partial support of this research.
1
MeOH); H NMR: l 0.56 (dd, J=12.8, 4.4 Hz, 1H),
0.78 (s, 3H), 0.83 (s, 3H), 0.89 (s, 3H), 1.09 (ddd, J=9.2
Hz, 4.4 Hz, 4.4 Hz, 1H), 1.27–1.35 (m, 1H), 1.51 (t,
J=4.4 Hz, 1H), 1.63–1.72 (m, 1H), 1.76–1.82 (m, 1H),
1.97–2.05 (m, 1H), 2.83 (ddd, J=10.0, 4.4, 1.6 Hz, 1H),
3.47 (dd, J=10.4, 8.4 Hz, 1H), 3.67 (dd, J=10.4, 4.4
Hz, 1H), 3.75 (dd, J=8.0, 4.4 Hz, 1H), 7.25–7.36 (m,
5H); 13C NMR: l 14.3, 18.5, 19.8, 27.3, 28.4, 39.5, 45.1,
17.9, 49.3, 61.7, 64.7, 65.9, 127.0, 127.4, 128.5, 142.3;
IR (Nujol): 3285, 3155, 3060, 3025, 1042 cm−1. Anal.
calcd for C18H27NO: C, 79.07; H, 9.95; N, 5.12. Found:
C, 79.11; H, 10.04; N, 5.31%.
References
1. ‘Chiral Pharmaceuticals’: Stinson, S. C. Chem. Eng. News
2001, 79, 79–97.
2. (a) Delogu, G.; Fabbri, D.; de Candia, C.; Patti, A.;
Pedotti, S. Tetrahedron: Asymmetry 2002, 13, 891; (b)
Zhou, H.; Lu, S.; Xie, R.; Chan, A. S. C.; Yang, T.-K.
Tetrahedron Lett. 2001, 42, 1107; (c) Santhi, V.; Rao, J.
M. Synth. Commun. 2000, 30, 4329; (d) Altava, B.;
Burguete, M. I.; Garc´ıa Verdugo, E.; Luis, S. V.; Pozo,
O.; Salvador, R. V. Eur. J. Org. Chem. 1999, 2263; (e)
Reiners, I.; Wilken, J.; Martens, J. Tetrahedron: Asymme-
try 1995, 6, 3063; (f) Kim, H. Y.; Park, D. H.; B., I. S.;
Yoon, I. K.; Park, C. S. J. Org. Chem. 1993, 58, 4511.
3. (a) Garc´ıa Martinez, A.; Teso Vilar, E.; Garc´ıa Fraile, A.;
de la Moya Cerero, S.; Mart´ınez-Ruiz, P.; Chicharro
Villas, P. Tetrahedron: Asymmetry 2002, 13, 1; (b) Dim-
itrov, V.; Dobrikov, G.; Genov, M. Tetrahedron: Asym-
metry 2001, 12, 1323; (c) Orsini, F.; Sello, G.; Bestetti, G.
Tetrahedron: Asymmetry 2001, 12, 2961; (d) Garc´ıa Mar-
tinez, A.; Teso Vilar, E.; Garc´ıa Fraile, A.; de la Moya
Cerero, S.; Mart´ınez-Ruiz, P. Tetrahedron: Asymmetry
1998, 9, 1737; (e) Przeslawski, R. M.; Newman, S.;
Thornton, E. R.; Joullie, M. M. Synth. Commun. 1995,
25, 2975; (f) Noyori, R.; Kitamura, M. Angew. Chem.,
Int. Ed. Engl. 1991, 30, 49; (g) Kouklovsky, C.; Pouihes,
A.; Langlois, Y. J. Am. Chem. Soc. 1990, 112, 6672.
4. (a) Seyden-Penne, J. Chiral Auxiliaries and Ligands in
Asymmetric Synthesis; John Wiley & Sons: New York,
1995; (b) Koskinen, A. Asymmetric Synthesis of Natural
Products; John Wiley & Sons: New York, 1993.
5. (a) Hitchcock, S. R.; Nora, G. P.; Casper, D. M.; Squire,
M. D.; Maroules, C. D.; Ferrence, G. M.; Szczepura, L.
F.; Standard, J. M. Tetrahedron 2001, 57, 9789; (b)
Hitchcock, S. R.; Casper, D. M.; Nora, G. P.; Blackburn,
J. R.; Bentley, J. T.; Taylor, D. C. J. Heterocycl. Chem.
2002, 39, 823.
6. (a) Page, P. C. B.; Murrell, V. L.; Limousin, C.; Laffan,
D. D. P.; Bethell, D.; Slawin, A. M. Z.; Smith, T. A. D.
J. Org. Chem. 2000, 65, 4204; (b) Morris, D. G.; Ryder,
K. S. Synthesis 1997, 620; (c) Guziec, F. S., Jr.; Russo, J.
M. Synthesis 1984, 479; (d) Bondavalli, F.; Schenone, P.;
Ranise, A. Synthesis 1979, 830.
4.4.3. (1R,1%R,2S,2%S,4%R)-1-Phenyl-2-(1,7,7-trimethylbi-
cyclo[2.2.1]hept-2-ylamino)propan-1-ol, 11c. 88% yield as
colorless crystals; mp 47–48°C (hexanes); [h]D=−31.3 (c
1, MeOH); 1H NMR: l 0.77 (d, J=6.8 Hz, 3H), 0.84 (s,
3H), 0.93 (s, 3H), 0.94 (s, 3H), 1.09 (AB spin system,
J=18.8, 8.4 Hz, 2H), 1.50–1.59 (m, 2H), 1.68–1.73 (m,
2H), 1.81 (dd, J=12.8, 8.8 Hz, 1H), 2.63 (dd, J=8.4,
4.4 Hz, 1H), 2.94 (dq, J=6.8, 4.0 Hz, 1H), 4.017 (bs,
1H), 4.68 (d, J=4.4 Hz, 1H), 7.21–7.45 (m, 5H); 13C
NMR: l 12.7, 16.1, 20.5, 20.6, 27.2, 37.0, 41.1, 45.1,
16.7, 48.4, 57.5, 64.0, 72.5, 126.0, 126.8, 127.9, 141.4;
IR (KBr): 3416; 3062, 3028 cm−1. Anal. calcd for
C19H29NO: C, 79.39; H, 10.17; N, 4.87. Found: C,
79.40; H, 10.07; N, 5.08%.
4.4.4.
(1R,1%R,2S,2%S,4%R)-2-(1,7,7-trimethylbicy-
clo[2.2.1]hept-2-yl-N-nitrosoamino)-1-phenylpropan-1-ol,
12. Amine 11c (11.8 g, 41.1 mmol) was dissolved in
THF (18 mL) and to this solution was added sodium
nitrite (3.12 g, 45.2 mmol) followed by the cautious
addition of an aqueous solution of HCl (2.74 M, 17.3
mL, 47.3 mmol). The reaction was stirred overnight
and was quenched by the addition of a saturated
aqueous solution of sodium bicarbonate (100 mL). The
N-nitrosamine product was extracted from this mixture
by the use of ethyl acetate (2×100 mL). The combined
organic layers were treated with a saturated aqueous
solution of brine (100 mL), dried (MgSO4) and the
solvent was removed by rotary evaporation to afford
the title compound as yellow crystals in nearly quanti-
tative yield. A small sample was recrystallized from
pure hexanes for characterization: mp 118.5–120°C
1
(hexanes); [h]D=+180 (c 5, MeOH); H NMR: l 0.54–
0.59 (m, 1H), 0.55 (s, 3H), 0.73 (s, 3H), 0.76 (s, 3H),
0.99–1.05 (m, 1H), 1.45–1.50 (m, 1H), 1.56–1.68 (m,
2H), 1.70 (d, J=6.8 Hz, 3H), 2.59 (d, J=2.4 Hz, 1H),
4.25–4.37 (m, 3H), 5.05 (dd, J=6.0, 2.0 Hz, 1H),
7.24–7.36 (m, 5H); 13C NMR: l 10.2, 11.5, 13.0, 17.9,
20.2, 20.3, 26.3, 31.8, 35.9, 38.5, 44.4, 46.3, 52.5, 59.9,
63.1, 78.1, 126.3, 127.8, 128.2, 141.3; IR (KBr): 3356,
7. (R)-(−)-Phenylglycinol was obtained by reduction of
commercially available (R)-phenylglycine. See: (a)
McKennon, M. J.; Meyers, A. I.; Drauz, K.; Schwarm,
M. J. Org. Chem. 1993, 58, 3568; (b) Kanth, J. V. B.;
Periasamy, M. J. Org. Chem. 1991, 56, 5964; (c) The

1854
M. D. Squire et al. / Tetrahedron: Asymmetry 13 (2002) 1849–1854
12. Caution: Many N-nitrosamines are known to have car-
enantiomeric purity of the synthesized (R)-(−)-phenylgly-
cinol was determined to be at least 95% ee based on a
comparison of the optical activity of the sample {[h]D=
−31.3 (c 0.71, 1N HCl)} and the literature value of
[h]D=−31.7 (c 0.76, 1N HCl) from Aldrich Chemical Co.
cinogenic activity. See: (a) Nitrosamines and Related N-
Nitroso Compounds: Chemistry and Biochemistry;
Loeppky, R. N.; Michejda, C. J., Eds.; ACS Symposium
Series 553, 1994; (b) Linjinsky, W.; Reuber, M. D.;
Saavedra, J. E.; Singer, G. M. J. Natl. Cancer Inst. 1983,
70, 959.
8. For examples of (R)-(−)-phenylglycinol as a chiral auxil-
iary, see: (a) Meyers, A. I.; Downing, S. V.; Weiser, M. J.
J. Org. Chem. 2001, 66, 1413; (b) Santes, V.; Go´mez, E.;
Za´rate, V.; Santillan, R.; Farfa´n, N.; Rojas-Lima, S.
Tetrahedron: Asymmetry 2001, 12, 241; (c) Roussi, F.;
Bonin, M.; Chiaroni, A.; Micouin, L.; Riche, C.; Husson,
H.-P. Tetrahedron Lett. 1998, 39, 8081.
13. Crystallographic data (excluding structure factors) for
structure 12 reported in this paper have been deposited
with the Cambridge Crystallographic Data Centre. The
atomic coordinates and equivalent isotropic displacement
coefficients are included in the deposited material (CCDC
190337) as are a complete list of bond distances and
angles. Copies of available material can be obtained, free
of charge, on application to the CCDC, 12 Union Road,
Cambridge CB2, 1EZ, UK (Fax:+44-1223-336033 or e-
mail: deposit@ccdc.am.ac.uk).
14. Enraf-Nonius, CAD4 Express Software, Delft, The
Netherlands, 1994.
15. Harms, K.; Wocadlo, S. XCAD-4: Program for Process-
ing CAD-4 Diffractometer Data, University of Marburg,
Germany, 1995.
9. 13C NMR and IR spectroscopy established that the iso-
lated material was indeed the imine; 13C NMR spectrum:
lavg(imine)=183.6 ppm; IR spectrum: wavg(imine)=1650
cm−1). There was no direct evidence for the presence of
the oxazolidine, the product of cyclization of the imine
with the appendant alcohol moiety. In addition there was
no observable equilibration between the imine or the
putative oxazolidine based on the detection limits of the
1H NMR spectra.
10. (a) Bolton, R.; Danks, T. N.; Paul, J. M. Tetrahedron
Lett. 1994, 35, 3411; (b) Danks and co-workers noted
that sterically hindered amines either require long reac-
tion times to react with camphor in the presence of
anhydrous ZnCl2 or fail to yield any product in signifi-
cant amounts.
11. (a) Love, B. E.; Ren, J. J. Org. Chem. 1993, 58, 5556; (b)
Cerreta, F.; Leriverend, C.; Metzner, P. Tetrahedron Lett.
1993, 34, 6741.
16. McArdle, P. J. Appl. Crystallogr. 1996, 29, 306.
17. North, A. C. T.; Phillips, D. C.; Mathews, F. S. Acta
Crystallogr. 1968, A24, 351.
18. Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837.
19. (a) Altomare, A.; Cascarano, G.; Giacovazzo, C.;
Guagliardi, A. J. Appl. Crystallogr. 1993, 26, 343; (b)
Sheldrick, G. M. SHELX-97: Programs for Crystal Struc-
ture Analysis (Release 97-2), University of Go¨ttingen,
Germany, 1997.