X-ray crystallographic and proton nuclear magnetic resonance studies of β-hydroxy-N-nitrosamines derived from α-amino acids and ephedrine

Article abstract of DOI:10.1016/S0040-4020(00)00837-1

β-Hydroxy-N-nitrosamines derived from L-leucine, L-valine, L-phenylalanine, D-phenylglycine and (1R,2S)-ephedrine have been synthesized and analyzed. These compounds all exhibit rotameric populations of (E)- and (Z)-stereoisomers that are a result of the

Full text of DOI:10.1016/S0040-4020(00)00837-1

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 8799±8807
X-Ray Crystallographic and Proton Nuclear Magnetic Resonance
Studies of b-Hydroxy-N-nitrosamines derived from a-Amino
Acids and Ephedrine
a,*
a
Shawn R. Hitchcock, George P. Nora, Christine Hedberg, David M. Casper,
a
a
a
Laura S. Buchanan, Michael D. Squire and Douglas X. West
a
b
a
Department of Chemistry, Illinois State University, Normal, IL 61790-4160, USA
Department of Chemistry, Box 351700, University of Washington, Seattle, WA 98195-1700, USA
b
Received 24 July 2000; revised 12 September 2000; accepted 13 September 2000
AbstractÐb-Hydroxy-N-nitrosamines derived from l-leucine, l-valine, l-phenylalanine, d-phenylglycine and (1R,2S)-ephedrine have
been synthesized and analyzed. These compounds all exhibit rotameric populations of (E)- and (Z)-stereoisomers that are a result of the
barrier to rotation about the N-nitroso (N±NvO) group. A correlation is made between the X-ray crystallographic data of the N-nitroso-
1
ephedrine derivative 6 and the H NMR of the N-nitrosamines 4a±4d. From this comparison, the identities and ratios of (E)- and (Z)-rotamers
were unambiguously assigned. Finally, the H NMR also provides some insight into the conformational changes that occur when the
nitrosamine rotamers interconvert. q 2000 Elsevier Science Ltd. All rights reserved.
1
Introduction
Results and Discussion
In connection with an ongoing research project that focuses
on the chemistry of chiral, non-racemic tetrahydro-1,3,4-
oxadiazin-2-ones, several b-hydroxy-N-nitrosamines were
prepared. The N-nitrosamines represent a large class of
compounds that are of interest because they are known to
The a-amino acids 2a±2d [2a: Rˆ(CH
3
)
2
CH± (l-Val); 2b:
RˆPhCH
± (l-Phe); 2c: Rˆ(CH
)
3
CHCH ± (l-Leu);
2
2
2
2dˆPh± (d-Phg)] were acylated with benzoyl chloride in
basic media to afford the corresponding N-benzoylated
a-amino acids (Scheme 1). These compounds were then
cleanly reduced to the N-benzyl-vic-aminoalcohols 3a±3d
1
have carcinogenic properties. Nonsymmetrical N-nitros-
amines such as b-hydroxy-nitrosamines exists as (E)- and
4
a
by using the protocol originated by Kanth and Periasamy
H /tetrahydrofuran gener-
2 6
4
and developed by Meyers (B
b
(
N±NvO moiety. As with amides and carbamates,
Z)-rotamers due to the stereochemical nature of the
2
a
2b
ated in situ from NaBH and I , Scheme 1). The N-benzyl-
4
2
5
vic-aminoalcohols were treated with tert-butyl nitrite in
contributing resonance structures are invoked as giving
rise to the barrier of rotation (Fig. 1).
In the course of our synthesis efforts we were faced with the
interesting problem of assigning the identity and ratios of
the rotamers. Karabatsos and Taller had conducted earlier
studies on the assignment of (E)- and (Z)-stereochemistry of
1
3
N-nitrosamines based on comparative H NMR studies.
Herein we report on the H NMR and X-ray crystallographic
1
data of a representative N-nitrosamine derived from
(
1
1R,2S)-ephedrine. These data are compared to the H
NMR data of b-hydroxy-N-nitrosamines derived from
a-amino acids.
Keywords: nitrosamines; X-ray crystallography; conformation.
* Corresponding author. Tel.: 1309-438-7854; fax: 1309-438-5538;
e-mail: hitchcock@xenon.che.ilstu.edu
Figure 1. The (E)- and (Z)-rotamers of the b-hydroxy-N-nitrosamines.
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00837-1

8
800
S. R. Hitchcock et al. / Tetrahedron 56 (2000) 8799±8807
Scheme 1. Synthesis of the N-nitrosamines 4a±4d and 6.
anhydrous diethyl ether to afford b-hydroxy-N-nitrosamines
about N1 (i.e. C2±N1±C1, 121.7(6)8; C2±N1±N2,
114.2(6)8 and C1±N1±N2, 124.1(6)8 are closer to that
expected for a sp hybridized nitrogen rather than an sp
4
3
. These conditions were satisfactory in the case of 3a and
c. However, the remaining aminoalcohols were not soluble
2
3
in the reaction medium. Consequently, the aminoalcohols
b and 3d were treated with sodium nitrite (NaNO ) in the
presence of an aqueous HCl/THF mixture to afford the
hybridized nitrogen suggesting that the pair of electrons
formally located on N1 are delocalized as would be
expected for N-nitrosamines. In terms of the overall confor-
3
2
7
corresponding b-hydroxy-N-nitrosamines 4b and 4d in
good yield. In like fashion, (1R,2S)-ephedrine (5) was
cleanly nitrosated (HCl/NaNO ) to afford the N-nitroso-
2
mation of the N-nitrosoephedrine, the C2±N1±C1±N2±O1
Ê
Ê
farthest from the plane, 0.0125(0.0062) A. The angle
6
group has a mean plane deviation of 0.0013 A with C2 the
ephedrine derivative 6.
between the mean planes of the aromatic residue C5±C6±
C7±C8±C9±C10 and the nitroso moiety C2±N1±C1±N2±
O1 is 53.8(3.4)8. Intermolecular hydrogen bonding (O2±
Attempts to grow crystals of b-hydroxy-N-nitrosamines
4a±d suitable for X-ray crystallography studies were not
0
H2¼O1 ) is evidenced by the following bond distances
Ê
and bond angle: O2±H2, 1.088(5) A; H2¼O1,
successful. Fortunately, a suitable crystal of N-nitroso-
ephedrine (6) was grown by slow diffusion of hexanes
into a CH Cl solution of 6 at room temperature. The
Ê
1.942(6) A; O2¼O1, 3.023(8) A and a bond angle of O2±
Ê
H2¼O1, 172.1(3)8. There is also a weaker interaction
Ê
between H2 and N2: H2¼N2, 2.122(6) A; O2±H2¼N2,
2
2
molecular structure of 6 is represented in Fig. 2.
Ê
.082(8) A and an O2±H2¼N2 angle of 145.6(4)8. This
3
The N-nitroso group, N2±O1, has a bond distance of
Ê
.23(1) A, which is consistent with its formal double
latter interaction also helps to draw electron density away
from N1 as discussed above.
1
bond, but the N1±N2 distance of 1.302(8) is closer to a
double bond than a single bond. An average distance of the
1
Correlation of the X-ray crystal structure with the H NMR
7
N±N bond in N-nitrosamines is 1.31 A. The bond angles
Ê
unambiguously establishes the identities of the rotamers.
The X-ray crystallographic data describe a molecular
geometry that corresponds to the E-rotamer (Fig. 1) for
the N-nitrosoephedrine (6). Based on X-ray crystallographic
analysis, the identities of the individual rotamers can then be
1
easily assigned in the 400 MHz H NMR spectrum. The
major isomer that was analyzed by X-ray crystallographic
1
analysis is the major isomer in the H NMR spectrum.
1
Speci®cally, there are two diagnostic peaks in the
H
NMR that are employed in determining the identity and
ratio of rotamers (Fig. 3). The diagnostic signals for Z-6
and E-6 are based on the methyl group bonded to the
N±NvO moiety. The resonance signal that represents the
major rotamer for E-6 occurs at 3.02 ppm and the signal that
represents the minor rotamer occurs at 3.78 ppm (Z-6-
isomer). In the case of the E-rotamer, the methyl group is
in the shielding region of the N-nitroso group, whereas the
methyl group is not in the shielding region of the nitroso
group in the Z-rotamer. This system where the E-rotamer
alkyl group is shielded and Z-rotamer alkyl group is not
shielded provides the basis for the determination of the
identities and ratios of isomers for the nitrosamines (Table
Figure 2. ORTEP diagram of 6 (50% probability ellipsoids).

S. R. Hitchcock et al. / Tetrahedron 56 (2000) 8799±8807
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8
802
S. R. Hitchcock et al. / Tetrahedron 56 (2000) 8799±8807
1
Table 1. 400 MHz H NMR data for 4a±d and 6
mational changes that these molecules would undergo
would be similar (Fig. 6).
Compound
d (center)
Description
Dn (Hz)
J (Hz)
E-4a (major isomer)
Z-4a (minor isomer)
E-4b (major isomer)
Z-4b (minor isomer)
E-4c (major isomer)
Z-4c (minor isomer)
E-4d (major isomer)
Z-4d (minor isomer)
E-6 (major isomer)
Z-6 (minor isomer)
4.82
5.23
4.72
5.14
4.74
5.3
4.7
5.2
3.02
3.78
AB quartet
singlet
AX
AB
AB
AB
AX
AX
singlet
singlet
48
±
170
112
96.7
62
647
208
±
14
±
14.8
15.2
14.6
16
14.7
16
±
The d-phenylglycine nitrosamine derivative has the most
striking H NMR of this set of compounds. The H NMR
1
1
of the major rotamer E-4d shows a resonance signal at
4
.74 ppm with a coupling constant of 14.7 Hz and
1
Dnˆ647 Hz. The H NMR spectrum of the corresponding
minor rotamer Z-4d is centered at 5.20 ppm with a coupling
constant of 16.0 Hz and a Dnˆ207.3 Hz. The AX spin
system for the minor isomer Z-4d is positioned in between
the doublets of the E-4d rotamer. The broad Dn may be an
indication that the aromatic ring is rotated away from plane
of the nitroso group to alleviate any steric strain. This
rotation away from the plane most likely extends the diag-
nostic benzyl group (±CH H Ph) resonance signals further
±
±
1). It was determined that in all cases the major isomer is the
E-rotamer. This observation agrees with the general trend
that steric forces control the orientation of the N-nitroso
group.
A
B
3
into the shielding (H : dˆ3.83 ppm) and deshielding (H :
A
B
dˆ5.49 ppm) region of the proton NMR. The phenylglycine
derivative is more closely related to the valine derivative in
that there is a signi®cant change in conformation based on
the reporter group.
1
The H NMR resonance signal of interest in the case of the
N-nitrosamines derived from the a-aminoacids is that of
the methylene unit of the benzyl group (±CH Ph) attached
2
to the N±NvO moiety. This resonance signal offers con-
siderably more intrinsic information on structural features
as compared to that of the resonance signal of the methyl
group that is present in the ephedrine-nitrosamine 6. Under
both (E)- and (Z)-conformational circumstances, the diag-
nostic methyl group of 6 appears as a singlet. In contrast, the
benzyl group is a better reporter of its immediate surround-
ings because of the diastereotopic relationship of the hydro-
gens.
Fig. 6 represents potential conformations that the N-nitros-
amines may adopt in the E-rotamer and Z-rotamer. These
conformations have been constructed based on the earlier
3
8
independent works of Karabatsos and Nauman. Karabat-
sos demonstrated that the methylene protons that are syn to
the oxygen of the N±NvO group resonate at higher ®elds
and the methylene protons that are anti resonate at lower
®elds. Consequently, the preferred conformation of the
methylene group of N-nitrosamines 4a±4d must be in or
near the plane of the nitroso group. Nauman showed that
the conformation of N-nitrosamines is also dependent on the
steric interactions of the two alkyl substituents, R and R ,
In the case of the l-valine derived nitrosamine the major
rotamer, E-4a, shows a diagnostic ABquartet centered at
4
.82 ppm with a coupling constant of Jˆ14.0 Hz and
1
2
1
Dnˆ48 Hz in the 400 MHz H NMR spectrum (Fig. 4).
The corresponding minor rotamer Z-4a has a diagnostic
resonance signal that is a singlet centered at 5.23 ppm.
This apparent change in the nature of the signal may repre-
sent a major conformational change to alleviate torsional
strain induced by the presence of the sterically demanding
isopropyl group. In contrast to the valine based 4a system,
that span the N-nitroso group (R R N±NvO). The N-nitros-
1 2
amines in Fig. 6 have been arranged so that there are no
major steric interactions across the span of the nitroso
group. This arrangement leaves the appended alcohol in
an anti-conformation relative to the nitroso group.
The conformations of Fig. 6 also re¯ect information
gathered from the X-ray crystallographic data of
N-nitrosamine 6.
1
the 400 MHz H NMR spectrum of the major rotamer of the
phenylalanine derived b-hydroxy-N-nitrosamine E-4b (Fig.
5
) shows an AX spin system centered at 4.72 ppm with a
In regard to the factors that contribute to the conformational
analysis of the N-nitrosamines of this work, the argument is
made that the optimal conformation of the N-nitrosamines
depends on the orientation of the N±NvO group, steric
interactions across the span of the N-nitroso group and to
a lesser degree hydrogen bonding. There is clearly inter-
molecular hydrogen bonding (O±H¼OvN) in the solid
state but there is no apparent indication of such extensive
hydrogen bonding in the solution state of the NMR samples.
The hydrogen bonding observed in the solid state may be
a consequence of the conformation that is adopted by
N-nitrosamine rather than a result of hydrogen bonding
forces dictating the overall conformation. Another con-
sideration that must be taken into account is that of
intramolecular hydrogen bonding in the solution state. Intra-
molecular hydrogen bonding (O±H¼NvO) signi®cantly
increases the non-bonding steric interactions across the
N±NvO span and so is considered to play a very minor
role if any. These statements do not entirely rule out differ-
ent modes of hydrogen bonding. There is still a possibility
1
coupling constant of 14.8 Hz and a Dnˆ170 Hz. The H
NMR spectrum of the minor isomer Z-4b shows an AB
spin system centered at 5.14 ppm with a coupling constant
of 15.2 Hz and a Dnˆ112 Hz. This similarity of the signals
would seem to indicate that there is no major conforma-
tional change (Fig. 5). This is not surprising considering
that the phenylalanine derivative does not have the bulky
isopropyl group present.
1
The H NMR of the major rotamer of the l-leucine derived
N-nitrosamine E-4c shows an AB spin system centered at
4.74 ppm with a coupling constant of 14.6 Hz and
1
Dnˆ96.7 Hz. The H NMR of the minor isomer Z-4c is
centered at 5.30 ppm with a coupling constant of 16.0 Hz
and a Dnˆ62 Hz. This system is a re¯ection of the phenyl-
alanine system. The steric environments of the leucine
derivative [Rˆ±CH CH(CH ) ] and phenylalanine deriva-
2
3 2
tive [Rˆ±CH Ph] are similar and it is expected that the
2
proton NMR would represent this. Furthermore, the confor-

S. R. Hitchcock et al. / Tetrahedron 56 (2000) 8799±8807
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8
804
S. R. Hitchcock et al. / Tetrahedron 56 (2000) 8799±8807

S. R. Hitchcock et al. / Tetrahedron 56 (2000) 8799±8807
8805
Experimental
General remarks
Tetrahydrofuran (THF) and diethyl ether (Et O) were
2
distilled from a potassium/sodium amalgam containing
benzophenone ketyl. Methylene chloride (CH Cl ) was
2
2
distilled from calcium hydride. Lithium aluminum hydride
was purchased from Aldrich Chemicals. Flash chroma-
tography was conducted with silica gel purchased from
1
13
Selecto Scienti®c (32±63 mesh). All H and C NMR
spectra were recorded at 258C on a Varian spectrometer in
CDCl3 operating at 400 and 100 MHz, respectively.
Chemical shifts are reported in parts per million (d scale),
and coupling constants (J values) are listed in hertz (Hz).
Infrared spectra are reported in reciprocal centimeters
2
1
(
cm ) and are measured either in chloroform or as a KBr
window. Melting points were recorded on a Mel-Temp
apparatus and are uncorrected. Low resolution gas chroma-
tography was performed on a Hewlett±Packard Instrument
(
G1800A/GCD) with an ionization voltage of 70 eV; peaks
are reported as m/z (% intensity relative to the base peak).
Elemental analyses were conducted by Galbraith Labora-
tories Inc., Knoxville, TN.
9
Crystal structure determination
A prismatic crystal of N-nitrosoephedrine (6) was grown by
slow diffusion of hexanes into a CH Cl solution of 6 at
2
2
room temperature. This crystal was mounted on a glass
ber and used for data collection at 293 K on a Nonius
MACH3 automatic diffractometer
(MoKa, lˆ
.71073 A). Cell constants and an orientation matrix for
®
Ê
0
data collection were obtained by least squares re®nement
of the diffraction data from 25 re¯ections. The structure was
solved with direct methods and missing atoms were found
by difference-Fourier synthesis. All non-hydrogen atoms
were re®ned with anisotropic temperature factors and the
hydrogen attached to oxygen was found on the difference
Fourier map. The H atoms attached to carbons were ®xed at
Figure. 6. Potential conformational changes in the b-hydroxy-N-nitros-
amines.
Ê
dˆ0.96 A, allowed to ride on the C atoms and assigned
2
Ê
that some hydrogen bonding does occur but it is not the
major factor that controls the overall conformation.
®xed isotropic temperature factor, Uˆ0.05 A . The coordi-
nates of the H atom attached to O were re®ned isotropically.
Re®nement of the structures was made by full-matrix least-
squares on F. Scattering factors are from Wassmaire and
1
0
11
Conclusion
Kirfel, calculations were done by maXus, version 2.0,
and graphics are Platon for Windows.
1
2
In summary, we have synthesized several examples of b-hy-
droxy-N-nitrosamines derived from commercially available
a-amino acids and ephedrine. X-Ray crystallographic
analysis of the ephedrine derived N-nitrosamine con®rmed
that the major rotamer was the E-rotamer and that there is
intermolecular hydrogen bonding in the solid state. Corre-
General procedure for the reduction of the N-benzoy-
lated a-amino acids 3a±3d
In a dry 1L 3-neck ¯ask ®tted with a re¯ux condenser and
addition funnel was added NaBH (4.05 g, 107 mmol) and
4
1
lation of the X-ray crystallographic data to H NMR data
freshly distilled THF (200 mL) under a nitrogen atmos-
phere. The a-amino acid (44.6 mmol) was then added in
one portion. The addition funnel was charged with a
solution of iodine (11.3 g, 44.6 mmol) in THF (100 mL).
The iodine was then added dropwise and upon complete
addition the mixture was heated to re¯ux for 12 h. The
reaction was cooled to room temperature and then quenched
by the addition of methanol (50 mL) to destroy any remain-
ing diborane. The solvent was then removed by rotary
evaporation to yield a white paste. The paste was dissolved
provides a reliable means of determining the rotameric
identity and ratio of b-hydroxy-N-nitrosamines derived
from the a-amino acids. The (E)- and (Z)-conformations
illustrated in Fig. 6 attempt to take into account the collected
1
H NMR evidence, the X-crystallographic data and litera-
ture precedents. Speci®cally, the N-benzyl group provides
some insight into the conformational changes that occur in
the b-hydroxy-N-nitrosamines especially in the cases of the
l-valine and d-phenylglycine.

8
806
S. R. Hitchcock et al. / Tetrahedron 56 (2000) 8799±8807
in an aqueous solution of KOH (2 M, 100 mL) and stirred
for 45 min. The mixture was then diluted with EtOAc
freshly distilled diethyl ether (5 mL). tert-Butyl nitrite
(16.8 mL, 136 mmol) was then added by syringe. The
mixture was then heated to re¯ux for 12 h followed by cool-
ing to room temperature and removal of the solvent by
rotary evaporation to yield a viscous oil. The oil was deter-
mined to be a mixture of E and Z isomers (,8.5:1 ratio, ca.
(
100 mL) and the layers were separated. The organic layer
was then washed with an aqueous saturated solution of brine
50 mL), dried (MgSO ) and the solvent was removed by
(
4
rotary evaporation to produce the desired b-amino alcohol.
8
9% E-rotamer). The material was crystallized by cooling
(2S)-N-Benzyl-2-amino-3-methyl-1-butanol (3a). Com-
pound 3a was obtained as a colorless oil in 89% yield
to 48C in a solution of hexanes and CH Cl to yield white
2
2
1
crystals in 67% yield (8.04 g). Mp: 56±588C; H NMR
1
7.60 g, 39.6 mmol): H NMR (CDCl ) d 0.93 (d, 3H,
(
(CDCl ) d 0.95 (d, 3H, Jˆ7.0 Hz), 1.04 (d, 3H, Jˆ
3
3
Jˆ6.6 Hz), 0.99 (d, 3H, Jˆ6.6 Hz), 1.89 (m, 1H), 2.23 (s,
7.0 Hz), 1.60 (br s, 1H), 2.30 (m, 1H, Jˆ6.8 Hz), 3.99 (m,
1H), 4.04 (d, 2H, Jˆ7.2 Hz), 4.82 (ABq, 2H,
Dnˆ48.0 Hz, Jˆ14.0 Hz), 7.17±7.20 (m, 2H), 7.27±
1
3
H), 2.50 (`t', 1H, Jˆ6.6 Hz), 3.39 (dd, 1H, Jˆ7.0, 3.7 Hz),
.66 (dd, 1H, Jˆ10.6, 4.0 Hz) 3.81 (AB spin system, 2H,
1
3
Jˆ12.8, 7.3 Hz), 7.25±7.30 (m, 3H), 7.35 (d, 2H,
7.34 (m, 3H); C NMR (CDCl ) d 20.9, 21.2, 29.8,
3
1
3
Jˆ4.4 Hz); C NMR (CDCl ) d 18.2, 19.3, 28.6, 51.1,
49.9, 63.5, 72.2, 129.0, 129.5, 129.9, 135.8; IR (KBr)
3
2
1
6
2
1
0.1, 63.5, 126.6, 127.7, 128.0, 139.8; IR (neat): 3415,
3209, 2980, 1438, 1018 cm . Anal. Calcd for C H N O :
12 18 2 2
2
965 cm ; GC-MS (EI): m/z (% rel. abundance) 192 (1),
1
C, 64.84; H, 8.16; N, 12.60. Found: C, 64.53; H, 8.29; N,
12.49.
62 (33), 91 (100).
(
2S)-N-Benzyl-2-amino-3-phenyl-1-propanol (3b). Com-
(2S)-N-Benzyl-N-nitroso-2-amino-3-phenyl-1-propanol
(4b). (S)-N-Benzylphenylalanol (2b) (2.07 g, 8.59 mmol)
was dissolved in THF (15 mL) and an aqueous solution of
HCl (7.20 mL, 19.7 mmol). To this reaction mixture was
added sodium nitrite (0.651 g, 9.45 mmol) in small portions.
The reaction stirred for 12 h before dilution with EtOAc
(50 mL) and an aqueous solution of HCl (3 M, 50 mL).
The layers were separated and the organic layer was
extracted with an aqueous saturated solution of brine
pound 3b was obtained as a waxy solid that was recrystal-
lized by the addition of hexanes and by slow cooling down
to 48C. In this way, N-benzoylphenylalanine (14.2 g,
5
(
1
7
3
1
1
3
2.8 mmol) afforded the title product as a crystalline wax
1
10.1 g, 84%). Mp: 67±688C; H NMR (CDCl ) d 2.08 (br s,
3
H), 2.80 (dd, 1H, Jˆ10.0, 7.0 Hz), 2.76 (dd, 1H, Jˆ39,
.0 Hz), 2.94±3.00 (m, 1H), 3.34 (dd, 1H, Jˆ9.0, 5.0 Hz),
.65 (dd, 1H, Jˆ10, 4 Hz), 3.78 (s, 2H), 7.15±7.32 (m,
1
3
0H); C NMR (CDCl ) d 38.5, 51.2, 59.5, 62.6, 126.4,
(50 mL). The organic layer was dried (MgSO ) and the
4
3
27.1, 128.0, 128.5, 128.6, 129.2, 138.4, 140.0; IR (KBr):
279, 3022, 2995 cm ; GC-MS (EI): m/z (% rel. abun-
solvent was removed via rotary evaporation. The crude
residue was dissolved in the minimum amount of CH Cl2
2
1
2
dance) 240 (1), 91 (100).
followed by the addition of hexane. This solution was
allowed to stand at room temperature and crystal formation
occurred after several hours. This process afforded the title
compound as a mixture of E and Z isomers (,5.7:1 ratio, ca.
(
2S)-N-Benzyl-2-amino-4-methyl-1-pentanol (3c). l-N-
Benzoylleucine (8.00 g, 34.0 mmol) afforded compound
c as a white crystalline solid after recrystallization from
CH Cl /hexanes in 72% yield (5.23 g, 25.2 mmol. Mp: 58±
1
3
85% E-rotamer) in 73% yield (1.70 g). Mp: 81±828C; H
NMR (CDCl ) d 1.79 (br s, 1H), 2.83 (d, 1H, Jˆ7.3 Hz),
2
2
1
3
5
98C; H NMR (CDCl ) d 0.90 (`t', 6H, Jˆ6.8 Hz, dia-
3.20 (AB of ABX, 2H, Dn ˆ22.4 Hz, Dn ˆ14.0 Hz,
3
AX
BX
stereomeric methyl groups), 1.22±1.29 (m, 1H), 1.39±
JABˆ14.1 Hz), 3.96 (d, 2H, Jˆ6.0 Hz), 4.72 (AX spin
1
1
1
.46 (m, 1H), 1.60±1.67 (m, 1H), 2.07 (s, 1H), 2.76 (dq,
H, Jˆ7.0, 2.9 Hz), 3.28 (dd, 1H, Jˆ10.6, 6.2 Hz), 3.67 (dd,
H, Jˆ10.4, 3.6 Hz), 3.80 (ABq, 1H, Jˆ12.8, 7.6 Hz), 4.70
system, 4H, Dn ˆ170 Hz, Jˆ14.8 Hz,), 7.00 (s, 2H),
AX
1
3
7.01 (d, 2H, Jˆ7.3 Hz), 7.25±7.38 (m, 6H); C NMR
(CDCl ) d 38.7, 49.7, 65.3, 67.4, 128.0, 129.0, 129.3,
3
1
3
(
s, 1H), 7.33±7.34 (m, 5H); C NMR (CDCl ) d 22.7, 23.1,
129.8, 129.9, 130.0, 130.2, 135.0, 138.0; IR (KBr) 3343,
3
2
1
2
5.0, 40.9, 50.8, 56.2, 63.0, 127.0, 128.0, 128.3, 139.5; IR
3087, 2924 cm . Anal. Calcd for C H N O : C, 70.93;
16 18 2 2
2
1
KBr) 3287, 3060, 2958 cm ; GC-MS (EI): m/z (% rel.
(
abundance)190 (1), 176 (47), 91 (100).
H, 6.70; N, 10.34. Found: C, 70.71; H, 6.70; N, 10.26.
(
S)-N-Benzyl-N-nitroso-2-amino-4-methyl-1-pentanol
(
2R)-N-Benzyl-2-amino-2-phenyl-1-ethanol (3d). d-N-
(4c). In a ¯ame-dried, nitrogen purged round bottom ¯ask
containing a stir bar was placed (S)-N-benzylleucinol (3c)
(4.10 g, 19.8 mmol) and CH Cl (15 mL). To this reaction
mixture was added tert-butylnitrite (5.3 mL, 44 mmol) via
syringe. This reaction mixture was allowed to stir for 12 h at
re¯ux and the solvent removed under reduced pressure to
afford the title compound as an oil. The crude reaction
material is a mixture of E and Z rotamers (,8.5:1 ratio,
ca. 90% E-rotamer). The residue was chromatographed
Benzoylphenylglycine (2d) (10.0 g, 39.2 mmol) yielded
the corresponding b-aminoalcohol as an oil that was recrys-
tallized using EtOAc/hexanes (6.85 g, 77% yield). Mp: 70±
2
2
1
7
18C; H NMR (CDCl ) d 2.33 (broad s, 1H), 3.56 (X of
3
ABX, 1H, DnABˆ6.0 Hz, Jˆ10.6 Hz), 3.70 (AB spin system,
DnABˆ63.0 Hz, Jˆ13.0 Hz), 3.72 (dd, 2H, Jˆ10.6, 4.4 Hz),
1
3
3
.78 (dd, Jˆ8.8, 4.4 Hz), 7.29±7.41 (m, 10H); C NMR
(
CDCl ) d 51.0, 63.6, 66.6, 126.8, 127.0, 127.4, 127.9,
3
1
9
28.1, 128.4, 139.6, 140.1; IR (neat) 3247, 1097,
78 cm ; GC-MS (EI): m/z (rel. abundance) 196 (52), 91
(SiO , 3:2 hexanes/EtOAc; column dimensions 11£5 cm;
2
2
1
28 fractions at 3 mL each) to afford the product in 76%
1
(
100).
yield (3.54 g): H NMR (CDCl ) d 0.84 (dd, 6H, Jˆ8.0,
3
5
.9 Hz), 1.78 (br s, 1H), 3.85 (d, 2H, Jˆ6.2 Hz), 4.47±
(
2S)-N-Benzyl-N-nitroso-2-amino-3-methyl-1-butanol
4a). In a ¯ame-dried, nitrogen purged round bottom ¯ask
4.50 (m, 1H), 4.84 (AX spin system, 2H, Dn ˆ96.7 Hz,
AB
1
3
(
was placed N-benzylvalinol 3a (10.5 g, 54.4 mmol) and
Jˆ14.6 Hz), 7.16±7.18 (m, 1H), 7.28±7.38 (m, 4H);
NMR (CDCl ) d IR (KBr): 3404, 3031, 2957, 1452 cm .
3
C
2
1

S. R. Hitchcock et al. / Tetrahedron 56 (2000) 8799±8807
8807
Anal. Calcd for C H N O : C, 66.07; H, 8.53; N, 11.85.
1
Acknowledgements
3
20
2
2
Found: C, 65.53; H, 8.74; N, 11.72.
We thank Susan Pasquale for her technical assistance.
S. R. H. wishes to thank Drs R. C. Freeman and J. F. Hansen
for helpful discussions on N-nitrosamines. We acknowledge
also the helpful comments provided by the reviewers. We
gratefully acknowledge ®nancial support from Illinois State
University (University Research Grant) and the UNCF-
Merck Science Initiative.
(
(
S)-N-Benzyl-N-nitroso-2-amino-2-phenyl-1-ethanol (4d).
S)-N-benzylphenylglycinol (3d) (2.0 g, 8.8 mmol) was
dissolved in THF (10 mL) and an aqueous solution of HCl
6.40 mL, 17.6 mmol). To this reaction mixture was added
(
sodium nitrite (0.638 g, 9.25 mmol) in portions. The reac-
tion stirred for 12 h before dilution with EtOAc (50 mL) and
an aqueous solution of HCl (3 M, 50 mL). The layers were
separated and the organic layer was extracted with an
aqueous saturated solution of brine (50 mL). The organic
layer was dried (MgSO ) and the solvent was removed via
4
References
rotary evaporation. The crude residue was dissolved in the
minimum amount of CH Cl followed by the addition of
hexanes. This solution was allowed to stand at room
temperature and crystal formation occurred after several
hours. This process afforded the title compound as a mixture
1. (a) Loeppky, R. N., Michejda, C. J., Eds. Nitrosamines and
Related N-Nitroso Compounds: Chemistry and Biochemistry;
ACS Symposium Series 553; 1994. (b) Linjinsky, W.; Reuber,
M. D.; Saavedra, J. E.; Singer, G. M. J. Natl. Cancer Inst. 1983,
70, 959. (c) Lunn, G.; Sansone, E. B.; Keefer, L. K. Carcinogenesis
1983, 4, 315. (d) Linjinsky, W.; Saavedra, J. E.; Reuber, M. D.;
Blackwell, B. N. Cancer Lett. 1980, 10, 325.
2
2
of E and Z isomers (,12.5:1 ratio, ca. 92% E-rotamer) in 53
1
yield (1.20 g). Mp: 55±568C; H NMR (CDCl ) d 2.18 (s,
%
3
1
8
4
7
H), 4.12 (dd, 1H, Jˆ11.7, 4.8 Hz), 4.49 (dd, 1H, Jˆ12.4,
.4 Hz), 5.1 (dd, 1H, Jˆ8.4, 4.4 Hz), 4.70 (AX spin system,
2. (a) Perrin, C. L.; Thoburn, J. D.; Kresge, A. J. J. Am. Chem. Soc.
1992, 114, 8800. (b) Stewart, W. E.; Sidall, III T. H. Chem. Rev.
1970, 70, 517.
H, Dn ˆ647 Hz, Jˆ14.7 Hz), 7.03±7.05 (m, 2H), 7.21±
AB
1
.23 (m, 2H), 7.28±7.3 (m, 3H), 7.38±7.40 (m, 3H); H
NMR (CD OD) d 4.05 (dd, 3H, Jˆ10.0, 5.7 Hz), 4.41
3. Karabatsos, G. J.; Taller, R. A. J. Am. Chem. Soc. 1964, 86,
4373. For an earlier reference on the con®gurations of N-nitros-
amines compounds that is incorrect, see: Looney, C. E.; Phillips,
W. D.; Reilly, E. L. J. Am. Chem. Soc. 1957, 79, 6136.
4. (a) Kanth, J. V. B.; Periasamy, M. J. Org. Chem. 1991, 56,
5964. (b) McKennon, M. J.; Meyers, A. I.; Drauz, K.; Schwarm,
M. J. Org. Chem. 1993, 58, 3568.
3
(
`t,' 3H, Jˆ8.8 Hz), 4.71 (AX spin system, 4H, Dn
ˆ
AB
3
7
7
1
03 Hz, Jˆ14.8 Hz), 5.24 (dd, 3H, Jˆ6.5, 5.5 Hz), 6.99±
.02 (m, 3H), 7.18±7.20 (m, 2H), 7.24±7.27 (m, 2H), 7.30±
.33 (m, 3H); C NMR (CDCl ) d 48.2, 65.7, 69.7, 128.5,
29.0, 129.3, 129.9, 130.0, 130.2, 134.8, 136.8. Anal. Calcd
1
3
3
for C H N O : C, 70.29; H, 6.29; N, 10.93. Found: C,
1
5
16
2
2
7
0.99; H, 6.34; N, 10.92.
5. Enders, D.; Eichnlauer, H. Angew. Chem., Int. Ed. Engl. 1976,
1
5, 549.
6. Corey, E. J.; McCaully, R. J.; Sachdev, H. S. J. Am. Chem. Soc.
1970, 92, 2476.
(
1R,2S)-N-Methyl-N-nitroso-2-amino-1-phenyl-1-propa-
nol (6). In a 100 mL round bottom ¯ask equipped with a
stir bar was placed (1R,2S)-(1)-ephedrine (5) (20.00 g,
7. Rademacher, P.; Stolevik, R. Angew. Chem., Int. Ed. Engl.
1968, 7, 806.
1
21.0 mmol) and THF (40 mL). After the mixture became
homogeneous an aqueous solution of HCl (100 mL, 1 M,
00 mmol) was added, followed by the addition of sodium
8. Battiste, D. R.; Davis, L. P.; Nauman, R. V. J. Am. Chem. Soc.
1975, 97, 5072.
1
nitrite (9.186 g, 133.1 mmol) in small portions over 10 min.
and stirred for 24 h. The mixture was then diluted with a
saturated aqueous solution of NaHCO3 (60 mL). The
reaction mixture was then extracted with EtOAc
9. Crystallographic data (excluding structure factors) for the
structures reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre. The atomic coordinates
and equivalent isotropic displacement coef®cients are included in
the deposited material (CCDC 141801) 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: 144-1223-336033 or
e-mail: deposit@ccdc.am.ac.uk).
(
3£60 mL) and the extract was washed with saturated
aqueous NaCl (50 mL). The resulting solution was dried
Na SO ) and the solvent was removed by rotary evapo-
(
2
4
ration. This yielded a yellow solid which was recrystallized
with using a mixture of CH Cl and hexanes to yield a
2
2
1
yellow crystalline solid (20.99 g, 89%): Mpˆ92±948C. H
10. Wassmaier, D.; Kirfel, A. Acta Cryst. 1995, A51, 416.
11. Mackay, S.; Edwards, C.; Henderson, A.; Gilmore, C.;
Stewart, N.; Shankland, K.; Donald, A. University of Glasgow,
Scotland, 1997.
NMR (CDCl ): 1.47 (d, 3H, Jˆ6.96 Hz), 2.40 (bs, 1H), 2.96
3
(
(
s, 3H), 4.69 (m, 1H), 5.07 (d, 1H, Jˆ5.1 Hz), 7.35±7.37
m, 5H); C NMR (CDCl ): 13.4, 31.4, 65.3, 74.6, 126.4,
3
1
3
1
28.4, 128.8, 141.0; IR (KBr): 3374, 2983, 1452; GCMS
12. Spek, A. L. PLATON, A Multipurpose Crystallographic Tool;
Utrecht University, Utrecht, The Netherlands, 1999.
(
EI): m/z (% rel. abundance) 159 (1), 105 (95), 77 (100).