Diamine synthesis: Exploring the regioselectivity of ring opening of aziridinium ions

Full text of DOI:10.1021/jo010824e

304
J . Org. Chem. 2002, 67, 304-307
Dia m in e Syn th esis: Exp lor in g th e
Regioselectivity of Rin g Op en in g of
Azir id in iu m Ion s
Peter O’Brien* and Timothy D. Towers
Department of Chemistry, University of York,
Heslington, York YO10 5DD, UK
paob1@york.ac.uk
Received August 13, 2001
F igu r e 1. Aziridinium Ions
Sch em e 1
Chiral 1,2-diamines continue to attract synthetic inter-
est as they are prevalent in pharmaceuticals and in
nature, and they are also utilized as chiral ligands in
asymmetric synthesis.1 Because of their abundance and
usefulness, there is a need to develop regio- and stero-
controlled syntheses of 1,2-diamines. One general ap-
proach that has attracted recent attention is the reaction
of an amine with an aziridinium ion,2-7 a reaction that
we have been interested in for some time now.8
Some trends are emerging from previous studies on the
ring opening of aziridinium ions. For example, terminal
aziridinium ions 1-4 are preferentially attacked by
amines at the least hindered position with good to
excellent levels of regiocontrol (Figure 1).3-5 These reac-
tions are mainly controlled by steric effects, although the
strongly electron-withdrawing CF3 group also has an
important role in the opening of aziridinium ion 3. In
contrast, when the aziridinium ion has a benzylic position
as in 5-7 (R ) Ph), virtually exclusive ring opening by
amines at this position is the norm.6-8 As Gmeiner and
co-workers have recently demonstrated,9 the regioselec-
tivity of aziridinium ion ring opening is also nucleophile
dependent: opening of aziridinium ion 7 (R ) Bn) occurs
at the least hindered position with cyanide9 (in an
analogous fashion to aziridinium ions 1-4) but at the
more hindered position with chloride or bromide.9,10
Set against this background, we have systematically
varied R (Me, Bn, iPr, Ph) in aziridinium ions 7 and have
uncovered the effect on the regioselectivity of ring open-
ing of 7 with methylamine. Furthermore, using a novel
deuterium substitution approach, we have confirmed that
aziridinium ions are intermediates in the conversion of
N,N-dialkylamino alcohols into 1,2-diamines.
We were especially interested in studying the regio-
selectivity in the conversion of N,N-dialkylamino alcohols
into 1,2-diamines using our previously reported diamine-
forming reaction conditions.8 Thus, four dibenzylamino
i
alcohols (S)-8a -d (R ) Me, Bn, Pr, Ph, respectively)
were prepared by standard dibenzylation8a of the parent
amino alcohols and subjected to mesylation in diethyl
ether followed by reaction with aqueous methylamine.
We expected these reactions to generate mixtures of
regioisomeric diamines (S)-9a -d and (R)-10a -d via
formation of aziridinium ions 7 (Scheme 1). Before we
could determine the regioselective outcome of these
diamine-forming reactions, we needed to synthesize each
regioisomer independently for subsequent comparison of
1H and 13C NMR spectroscopic data. As described in the
Experimental Section, diamines (S)-9 were prepared by
Swern oxidation of amino alcohol (S)-8 followed by
reductive amination with methylamine; diamines (S)-10
were prepared via a known11 two-step route from N-Cbz-
protected amino acids [(i) isobutyl chloroformate-medi-
ated coupling of dibenzylamine with N-Cbz-protected
phenylalanine and then (ii) LiAlH4 reduction (NHCbz f
NHMe with concomitant amide reduction)].
The results of the diamine-forming reactions (Scheme
1) are presented in Table 1. High crude yields (78-96%)
of mixtures of diamines (S)-9 and (R)-10 were obtained
and for R ) alkyl (entries 1-3) preferential attack at the
least hindered end of the proposed aziridinium ion
intermediate occurred. Under identical conditions, es-
sentially exclusive attack at the benzylic position was
observed starting from 8d (R ) Ph; entry 4). The
sterically less demanding methyl group in 8a (R ) Me)
resulted in a lowering of the regioselectivity, and a 70:
30 ratio of (S)-9a and (R)-10a was obtained in this case
(entry 1). The results we obtained with amino alcohol 8b
and methylamine show essentially the same level of
regioselectivity as that in Gmeiner’s work with the same
amino alcohol and cyanide as the nucleophile.9
* To whom correspondence should be addressed. Phone: +44 (0)-
1904 432535. Fax: +44 (0)1904 432516.
(1) For a review, see: Lucet, D.; Legall, T.; Mioskowski, C. Angew.
Chem., Int. Ed. 1998, 37, 2580.
(2) Gmeiner, P.; J unge, D.; Ka¨rtner, A. J . Org. Chem. 1994, 59, 6766.
(3) Richardson, P. F.; Nelson, L. T. J .; Sharpless, K. B. Tetrahedron
Lett. 1995, 36, 9241.
(4) Katagiri, T.; Takahashi, M.; Fujiwara, Y.; Ihara, H.; Uneyama,
K. J . Org. Chem. 1999, 64, 7323.
(5) Liu, Q.; Marchington, A. P.; Boden, N.; Rayner, C. M. J . Chem.
Soc., Perkin Trans. 1 1997, 511.
(6) Chuang, T.-H.; Sharpless, K. B. Org Lett. 1999, 1, 1435.
(7) (a) Anderson, S. R.; Ayers, J . T.; DeVries, K. M.; Ito, F.;
Mendenhall, D.; Vanderplas, B. C. Tetrahedron: Asymmetry 1999, 10,
2655. (b) Saravanan, P.; Singh, V. K. Tetrahedron Lett. 1998, 39, 167.
(c) Miao, G.; Rossiter, B. E. J . Org. Chem. 1995, 60, 6424. (d) Dieter,
R. K.; Deo, N.; Lagu, B.; Dieter, J . W. J . Org. Chem. 1992, 57, 1663.
(8) (a) de Sousa, S. E.; O’Brien, P.; Poumellec, P. J . Chem. Soc.,
Perkin Trans. 1 1998, 1483. (b) Colman, B.; de Sousa, S. E.; O’Brien,
P.; Towers, T. D.; Watson, W. Tetrahedron: Asymmetry 1999, 10, 4175.
(9) Weber, K.; Kuklinski, S.; Gmeiner, P. Org. Lett. 2000, 2, 647.
(10) Nagle, A. S.; Salvatore, R. N.; Chong, B.-D.; J ung, K. W.
Tetrahedron Lett. 2000, 41, 3011.
(11) Rossiter, B. E.; Eguchi, M.; Miao, G.; Swingle, N. M.; Hernan-
dez, A. E.; Vickers, D.; Fluckiger, E.; Patterson, R. G.; Reddy, K. V.
Tetrahedron 1993, 49, 965.
10.1021/jo010824e CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/14/2001

Notes
J . Org. Chem., Vol. 67, No. 1, 2002 305
Ta ble 1. Stu d y of Regioselectivity of Dia m in e Syn th esis
Sch em e 3
starting
material
entrya
R
% yieldb
(S)-9:(R)-10c
1
2
3
4
8a
8b
8c
8d
Me
Bn
iPr
Ph
96 (78)
94 (70)
81 (62)
78 (-)
70:30
94:6
93:7
2:98
a
b
Reaction conditions described in Scheme 1. Yield of crude
product mixture (yield in brackets refers to the yield after
purification by flash chromatography). c Ratio of regioisomeric
diamines (S)-9 and (R)-10 in the crude product mixtures deter-
mined by 1H NMR spectroscopy. These ratios of diamines were
virtually identical after purification by flash chromatography.
spectroscopy) of deuterated amino alcohol 11 was ob-
tained from this reduction, and we assigned it as syn
assuming Felkin-Anh attack and on the basis of prece-
dent.12,13 The stereocontrolled synthesis of each of the
diamines syn- and anti-12 is shown in Scheme 3.
Aldehyde (S)-13 was converted into an imine by
reaction with methylamine, and then reduction with
sodium borodeuteride (MeOH, -20 °C) under Felkin-
Anh control gave diamine syn-12 in 66% yield after
chromatography. Stereocontrolled additions of sodium
borohydride and other nucleophiles to similar imines
have previously been described by Reetz and co-work-
ers.14 Reversing the order of incorporation of hydrogen
and deuterium gave diamine anti-12. Thus, reductive
amination of deuterated aldehyde rac-14 (obtained by
lithium aluminum deuteride reduction of the correspond-
ing methyl ester followed by Swern oxidation) using
methylamine and sodium borohydride gave a 67% yield
of diamine anti-12, which had different 1H NMR spec-
troscopic data than syn-12.
Finally, reaction of amino alcohol syn-11 under the
diamine-forming conditions generated a 96% crude yield
of a 94:6 regioisomeric diamine mixture. Examination of
the 1H NMR spectrum of the crude product indicated that
the major regioisomer was composed of an 85:15 mixture
of diamine syn-12 and diamine anti-12. This result
indicates that, under these reaction conditions, 15% of
the substitution reaction proceeds via direct SN2 dis-
placement and 85% proceeds via the aziridinium ion
intermediate (Scheme 2). Thus, it appears that some
direct SN2 substitution should be factored into the
observed regioselectivites reported in entries 1-3 of Table
1 as only about 85% of the reaction proceeds via an
aziridinium ion.
Sch em e 2
The results in Scheme 1 and Table 1 indicate that
amino alcohols 8a -c are converted preferentially into
diamines (S)-9a -c upon mesylation and reaction with
methylamine. Such a regioselectivity could, in principle,
have been obtained by direct SN2 substitution of the
mesylate from the hydroxyl group in the starting amino
alcohols 8a -c without the need of invoking an aziri-
dinium ion 7. Obviously, the preparation of (R)-10d from
amino alcohol (S)-8d must have proceeded via an aziri-
dinium ion to account for the dibenzylamino group
migration. To investigate whether the preparation of
diamines (S)-9a -c also proceeds via an aziridinium ion,
we have investigated the chemistry outlined in Scheme
2.
The dibenzylamino group, originally introduced and
further exploited by Reetz, is a well-known and widely
used stereocontrolling element in synthesis.12 We pro-
posed to use the dibenzylamino group to control the
stereochemistry of deuterium incorporation and then to
use stereochemical information to follow the mechanism
of our diamine synthesis. If we could prepare amino
alcohol syn-11, then we could investigate whether sub-
sequent diamine formation occurred with retention or
inversion of stereochemistry at C* (see Scheme 2):
conversion of syn-11 into diamine syn-12 would indicate
stereochemical retention via an aziridinium ion, whereas
transformation of syn-11 into diamine anti-12 would
occur via direct SN2 substitution. A mixture of the two
mechanisms would lead to the formation of both diamines
syn- and anti-12. Crucial to the success of our proposed
approach was the stereocontrolled synthesis of each of
syn-11, syn-12, and anti-12.
In summary, from a mechanistic viewpoint, we have
established the intermediacy of aziridinium ions in the
conversion of N,N-dialkylamino alcohols into 1,2-di-
amines and we have further investigated the regioselec-
tivity of ring opening of aziridinium ions. However, our
results indicate that only around 85% of the reaction
proceeds via the aziridinium ion. Furthermore, syntheti-
cally, we have reported regioselective syntheses of chiral
1,2-diamines (S)-9b, (S)-9c, and (R)-10d and two routes
(see Schemes 2 and 3) for the stereocontrolled synthesis
of deuterated diamines syn- and anti-12.
Exp er im en ta l Section
Gen er a l Meth od s. Distilled water was used. THF and Et2O
were dried over sodium-benzophenone and distilled before use.
CH2Cl2 was dried over calcium hydride and distilled before use.
Amino alcohol syn-11 was prepared in 76% yield by
Swern oxidation of amino alcohol (S)-8b and subsequent
reduction with sodium borodeuteride at -20 °C (Scheme
2).13 A single diastereoisomer (by 1H and 13C NMR
(13) Reetz, M. T.; Drewes, M. W.; Lennick, K.; Schmitz, A.; Hold-
gru¨n, X. Tetrahedron: Asymmetry 1990, 1, 375.
(14) (a) Reetz, M. T.; Schmitz, A. Tetrahedron Lett. 1999, 40, 2741.
(b) Reetz, M. T.; J aeger, R.; Drewlies, R.; Hu¨bel, M. Angew. Chem.,
Int. Ed. Engl. 1991, 30, 103.
(12) Reetz, M. T. Chem. Rev. 1999, 99, 1121.

306 J . Org. Chem., Vol. 67, No. 1, 2002
Notes
Petrol refers to the fraction of petroleum ether boiling in the
range of 40-60 °C and was redistilled before use. All nonaqueous
reactions were carried out under oxygen-free nitrogen using
oven-dried glassware. Flash column chromatography was carried
out using ICN Biomedicals GmbH 33-63 silica (60 Å) or Fisher
Matrex silica 60. Thin-layer chromatography was carried out
on commercially available Merck 5554 aluminum-backed silica
plates.
Proton (270 MHz) and carbon (67.9 MHz) NMR spectra were
recorded on a 270 MHz spectrometer using an internal deute-
rium lock. All samples were recorded as solutions in deuterated
chloroform, and chemical shifts are quoted in parts per million
downfield of tetramethylsilane. Coupling constant (J ) values are
given in Hertz. Carbon NMR spectra were recorded with broad
band proton decoupling.
HRMS (CI, NH3) m/z calcd for C31H31N2O3 (M + H)+ 479.2335,
found 479.2337.
A solution of the dibenzylamide (200 mg, 0.4 mmol) in THF
(1 mL) was added dropwise to a stirred suspension of LiAlH4
(71 mg, 1.7 mmol) in THF (2 mL) at room temperature under
N2. The mixture was heated at reflux for 16 h and then coooled
to room temperature, and EtOAc was added until effervescence
ceased. Water (0.5 mL) and then 4 M NaOH(aq) (0.5 mL) were
added. After 5 min, water (1 mL) was added, and after an
additional 15 min, the precipitate was removed by filtration. The
filtrate was evaporated under reduced pressure to give the crude
product. Purification by flash column chromatography on silica
with CHCl3-MeOH-NH3 (10:1:0.1) as the eluent gave diamine
(S)-10b (141 mg, 68%) as a colorless oil: Rf (10:1:0.1 CHCl3-
MeOH-NH3) 0.5; [R]D +44.8 (c 1.05, CHCl3); 1H NMR (270 MHz,
CDCl3) δ 7.31-7.06 (m, 15H), 3.59 (d, 2H, J ) 13.5), 3.41 (d,
2H, J ) 13.5), 2.71-2.60 (m, 2H), 2.50-2.30 (m, 3H), 2.27 (s,
3H); 13C NMR (67.9 MHz, CDCl3) δ 139.3, 139.0, 129.2, 128.9,
128.6, 128.2, 127.1, 126.0, 59.4, 58.9, 57.5, 38.8, 34.1.
Gen er a l P r oced u r e for Dia m in e F or m a tion fr om Am in o
Alcoh ols. MsCl (2.1 mmol) was added dropwise to a stirred
solution of amino alcohol (1.8 mmol) and Et3N (2.8 mmol) in Et2O
(10 mL) at 0 °C under N2. A white precipitate formed. After 30
min, Et3N (3.5 mmol) was added and the mixture was allowed
to warm to room temperature. Then, MeNH2(aq) (40%; 30.0 mmol)
was added and the two-phase mixture was stirred vigorously
for 16 h at room temperature. The layers were separated, and
the aqueous layer was extracted with Et2O (2 × 20 mL). The
combined organic extracts were washed with 5% NaHCO3(aq) (30
mL) and water (30 mL), dried (Na2SO4), and evaporated under
reduced pressure to give the crude product. The ratio of
regioisomers (see Table 1) was determined from the 1H NMR
spectrum of the crude product.
Melting points were measured on a digital melting point
apparatus. Infrared spectra were recorded on an FT IR spec-
trometer as solutions in chloroform. Chemical ionization and
high-resolution mass spectra were recorded on an Autospec
spectrometer. Optical rotations were recorded on a polarimeter
(using the sodium D line; 589 nm) at 20 °C, and [R]D values are
given in units of 10-1 deg cm2 g-1
.
Rep r esen ta tive P r oced u r es for Syn th esis of Regioiso-
m er ic Dia m in es 9 a n d 10 (2S)-N2,N2-Diben zyl-N1-m eth yl-
3-p h en yl-1,2-p r op a n ed ia m in e (9b). DMSO (0.16 mL, 2.4
mmol) was added dropwise to a stirred solution of oxalyl chloride
(0.12 mL, 1.4 mmol) in CH2Cl2 (4 mL) at -78 °C under N2. After
5 min, a solution of amino alcohol (S)-8b (400 mg, 1.2 mmol) in
CH2Cl2 (2 mL) was added dropwise. After an additional 10 min,
Et3N (0.72 mL, 4.8 mmol) was added dropwise and the reaction
mixture was allowed to warm to room temperature over 1 h
before water (2 mL) was added. The layers were separated, and
the aqueous layer was extracted with Et2O (1 × 15 mL). The
combined organic extracts were washed with 5% NaHCO3(aq) (30
mL), water (30 mL), and brine (30 mL), dried (Na2SO4), and
evaporated under reduced pressure to give the crude aldehyde
(S)-13 as a viscous yellow-green oil. To the aldehyde (S)-13 in
MeOH (5 mL) was added MeNH2 (2 M in MeOH, 0.48 mL, 2.4
mmol) at room temperature under N2. The mixture was heated
at reflux for 4 h and then cooled to -20 °C, and NaBH4 (46 mg,
1.2 mmol) was added. After 4 h at -20 °C, 2 M HCl(aq) was added
dropwise until effervescence ceased. Then, water (5 mL) and
KOH pellets were added until pH > 9 and Et2O (20 mL) was
added. The layers were separated, and the aqueous layer was
extracted with Et2O (3 × 20 mL). The combined organic extracts
were washed with water (20 mL), dried (Na2SO4), and evapo-
rated under reduced pressure to give the crude product. Puri-
fication by flash column chromatography on silica with CHCl3-
MeOH (10:1) as the eluent gave diamine (S)-9b (211 mg, 53%)
as a colorless oil: Rf (10:1 CHCl3-MeOH) 0.2; [R]D +27.0 (c 0.95,
(2S)-N2,N2-Diben zyl-N1-m eth yl-1,2-p r op a n ed ia m in e (9a )
a n d (2R)-N1,N1-Dib en zyl-N2-m et h yl-1,2-p r op a n ed ia m in e
(10a ). Using the general procedure for diamine synthesis, we
obtained the crude product (201 mg, 96%), which contained a
70:30 mixture of diamines (S)-9a and (R)-10a (by 1H NMR
spectroscopy), from amino alcohol (S)-8a (200 mg, 0.8 mmol).
Purification by flash column chromatography on silica with
CHCl3-MeOH-NH3 (200:10:1) as the eluent gave an 80:20
mixture of diamines (S)-9a and (R)-10a (163 mg, 78%) as an
orange oil: Rf (200:10:1 CHCl3-MeOH-NH3) 0.2. Diagnostic
signals for (S)-9a : 1H NMR (270 MHz, CDCl3) δ 3.74 (d, 2H, J
) 13.5), 3.35 (d, 2H, J ) 13.5), 2.19 (s, 3H), 0.99 (d, 3H, J )
6.5); 13C NMR (67.9 MHz, CDCl3) δ 139.7, 58.1, 52.4, 50.8, 34.8,
9.6. Diagnostic signals for (R)-10a : 1H NMR (270 MHz, CDCl3)
δ 3.67 (d, 2H, J ) 13.5), 3.43 (d, 2H, J ) 13.5), 2.25 (s, 3H), 0.91
(d, 3H, J ) 6.5); 13C NMR (67.9 MHz, CDCl3) δ 138.2, 59.6, 53.8,
51.4, 32.6, 16.5.
1
EtOH); H NMR (270 MHz, CDCl3) δ 7.34-7.07 (m, 15H), 3.86
(2S)-N2,N2-Diben zyl-N1-m eth yl-3-p h en yl-1,2-p r op a n ed i-
a m in e (9b) a n d (2R)-N1,N1-Diben zyl-N2-m eth yl-3-p h en yl-
1,2-p r op a n ed ia m in e (10b). Using the general procedure for
diamine synthesis, we obtained the crude product (981 mg, 94%),
which contained a 94:6 mixture of diamines (S)-9b and (R)-10b
(by 1H NMR spectroscopy), from amino alcohol (S)-8b (1.0 g, 3.0
mmol). Purification by flash column chromatography on silica
with CHCl3-MeOH (10:1) as the eluent gave a 95:5 mixture of
diamines (S)-9b and (R)-10b (127 mg, 70%) as a colorless oil:
Rf (10:1 CHCl3-MeOH) 0.2; IR (CDCl3) 3319, 1602 cm-1; MS
(CI, NH3) m/z 345 (M + H)+, 100; HRMS (CI, NH3) m/z calcd for
(d, 2H, J ) 13.5), 3.52 (d, 2H, J ) 13.5), 3.16-3.01 (m, 2H),
2.68 (dd, 1H, J ) 10, 12), 2.49-2.34 (m, 2H), 2.08 (s, 3H); 13C
NMR (67.9 MHz, CDCl3) δ 139.9, 129.1, 128.8, 128.4, 127.1,
126.0, 58.9, 53.7, 51.7, 35.9, 33.1.
(2S)-N1,N1-Diben zyl-N2-m eth yl-3-p h en yl-1,2-p r op a n ed i-
a m in e (10b). 4-Methylmorpholine (0.11 mL, 1.0 mmol) was
added dropwise to a stirred solution of N-Cbz-protected pheny-
lalanine (300 mg, 1.0 mmol) and isobutyl chloroformate (0.13
mL, 1.0 mmol) in THF (2 mL) at -15 °C under N2. After 5 min,
a solution of Bn2NH (0.19 mL, 1.0 mmol) in THF (1 mL) was
added. After 1 h at -15 °C, the solvent was evaporated under
reduced pressure and the residue was dissolved in EtOAc (20
mL) and water (30 mL). The layers were separated, and the
organic layer was washed with 1 M HCl(aq) (2 × 30 mL), water
(20 mL), 5% NaHCO3(aq) (2 × 30 mL), water (20 mL), and brine
(20 mL), dried (Na2SO4), and evaporated under reduced pressure
to give the crude product. Purification by flash column chroma-
tography on silica with petrol-EtOAc (2:1) as the eluent gave
the dibenzylamide (1.63 g, 91%) as a gummy colorless oil: Rf
(2:1 petrol-EtOAc) 0.6; [R]D -9.4 (c 1.0, CHCl3); IR (CDCl3) 3427,
C
24H29N2 (M + H)+ 345.2331, found 345.2330.
(2S)-N2,N2-Diben zyl-N1-3-dim eth yl-1,2-bu tan ediam in e (9c)
a n d (2R)-N1,N1-Diben zyl-N2-3-d im eth yl-1,2-bu ta n ed ia m in e
(10c). Using the general procedure for diamine synthesis, we
obtained the crude product (422 mg, 81%), which contained a
93:7 mixture of diamines (S)-9c and (R)-10c (by 1H NMR
spectroscopy), from amino alcohol (S)-8c (500 mg, 1.8 mmol).
Purification by flash column chromatography on silica with
CHCl3-MeOH (10:1) as the eluent gave a 94:6 mixture of
diamines (S)-9c and (R)-10c (327 mg, 62%) as an orange oil: Rf
(10:1 CHCl3-MeOH) 0.2; IR (CDCl3) 3317, 1602, 1494, 1454,
1716, 1641 cm-1 1H NMR (270 MHz, CDCl3) δ 7.35-7.33 (m,
;
20H), 5.74 (d, 1H, J ) 8.5), 5.06 (s, 2H), 5.00-4.92 (m, 1H), 4.76
(d, 1H, J ) 14.5), 4.30 (d, 1H, J ) 16.5), 4.22 (d, 1H, J ) 14.5),
4.17 (d, 1H, J ) 16.5), 3.10-2.95 (m, 2H); 13C NMR (67.9 MHz,
CDCl3) δ 172.0, 155.5, 136.4, 136.3, 127.8, 127.7, 127.5, 126.8,
66.7, 52.2, 49.6, 48.3, 39.9; MS (CI, NH3) m/z 479 (M + H)+, 100;
1196 cm-1 1H NMR (270 MHz, CDCl3) δ 7.44-7.19 (m, 10H),
;
3.80 (d, 2H, J ) 13.5), 3.78 (d, 2H, J ) 13.5), 2.68-2.52 (m, 3H),
2.25 (s, 3H), 2.07 (dsept (appearing as an octet), 1H, J ) 6.5,
6.5), 1.78 (br s, 1H), 1.04 (d, 3H, J ) 6.5), 0.93 (d, 3H, J ) 6.5);
13C NMR (67.9 MHz, CDCl3) δ 140.4, 128.8, 128.2, 126.8, 62.5,

Notes
J . Org. Chem., Vol. 67, No. 1, 2002 307
54.5, 49.8, 36.1, 27.7, 22.3, 20.1; MS (CI, NH3) m/z 297 (M +
H)+, 100; HRMS (CI, NH3) m/z calcd for C20H29N2 (M + H)+
297.2331, found 297.2328. Diagnostic signals for (R)-10c: 1H
NMR (270 MHz, CDCl3) δ 3.44 (d, 2H, J ) 13.5), 2.28 (s, 3H),
0.0.82 (d, 3H, J ) 6.5).
Syn th esis of Dia m in e syn -12. To the aldehyde (S)-13 (50
mg, 0.15 mmol) in MeOH (5 mL) was added MeNH2 (2 M in
MeOH, 0.08 mL, 0.02 mmol) at room temperature under N2. The
mixture was heated at reflux for 4 h and then cooled to -20 °C,
and NaBD4 (7 mg, 0.2 mmol) was added. After 4 h at -20 °C, 2
M HCl(aq) was added dropwise until effervescence ceased. Then,
water (5 mL) and KOH pellets were added until pH > 9 and
Et2O (20 mL) was added. The layers were separated, and the
aqueous layer was extracted with Et2O (3 × 20 mL). The
combined organic extracts were washed with water (20 mL),
dried (Na2SO4), and evaporated under reduced pressure to give
the crude product. Purification by flash column chromatography
on silica with CH2Cl2-MeOH-NH3 (10:1:0.1) as the eluent gave
diamine syn-12 (33 mg, 66%) as an orange oil: Rf (10:1:0.1 CH2-
Cl2-MeOH-NH3) 0.2; [R]D +31.0 (c 1.0, CHCl3); IR (CDCl3) 3320
Syn th esis of Am in o Alcoh ol syn -11. DMSO (0.21 mL, 3.0
mmol) was added dropwise to a stirred solution of oxalyl chloride
(0.16 mL, 1.8 mmol) in CH2Cl2 (10 mL) at -78 °C under N2.
After 5 min, a solution of amino alcohol (S)-8b (500 mg, 1.5
mmol) in CH2Cl2 (2 mL) was added dropwise. After an additional
10 min, Et3N (0.84 mL, 6.0 mmol) was added dropwise and the
reaction mixture was allowed to warm to room temperature over
1 h before water (2 mL) was added. The layers were separated,
and the aqueous layer was extracted with Et2O (1 × 15 mL).
The combined organic extracts were washed with 5% NaHCO3(aq)
(30 mL), water (30 mL), and brine (30 mL), dried (Na2SO4), and
evaporated under reduced pressure to give the crude aldehyde
(S)-13 (500 mg, 100%) as a viscous yellow-green oil. To the
aldehyde (S)-13 (50 mg, 0.15 mmol) in MeOH (5 mL) at -20 °C
under N2 was added NaBD4 (7 mg, 0.2 mmol). After 1 h at -20
°C and 3 h at room temperature, water was added dropwise until
effervescence ceased and Et2O (20 mL) was added. The layers
were separated, and the aqueous layer was extracted with Et2O
(20 mL). The combined organic extracts were washed with brine
(20 mL), dried (Na2SO4), and evaporated under reduced pressure
to give the crude product. Purification by flash column chroma-
tography on silica with petrol-Et2O (1:1) as the eluent gave
amino alcohol syn-11 (38 mg, 76%) as a white solid: mp 62-63
°C; Rf (1:1 petrol-Et2O) 0.4; [R]D +39.6 (c 1.0, CHCl3); IR (CDCl3)
cm-1 1H NMR (270 MHz, CDCl3) δ 7.35-7.08 (m, 15H), 3.86
;
(d, 2H, J ) 13.5), 3.52 (d, 2H, J ) 13.5), 3.16-3.05 (m, 2H),
2.49-2.35 (m, 3H), 2.08 (s, 3H); 13C NMR (67.9 MHz, CDCl3) δ
139.9, 139.8, 129.1, 128.8, 128.1, 128.0, 127.0, 126.0, 58.75, 53.65,
51.05 (1:1:1 triplet, J ) 21), 35.66, 33.02; MS (CI, NH3) m/z 346
(M + H)+, 100; HRMS (CI, NH3) m/z calcd for C24H28DN2 (M +
H)+ 346.2394, found 346.2393.
Syn th esis of Dia m in e a n ti-12. To the aldehyde rac-14 (50
mg, 0.15 mmol) in MeOH (5 mL) was added MeNH2 (2 M in
MeOH, 0.08 mL, 0.02 mmol) at room temperature under N2. The
mixture was heated at reflux for 4 h and then cooled to -20 °C,
and NaBH4 (7 mg, 0.2 mmol) was added. After 4 h at -20 °C, 2
M HCl(aq) was added dropwise until effervescence ceased. Then,
water (5 mL) and KOH pellets were added until pH > 9 and
Et2O (20 mL) was added. The layers were separated, and the
aqueous layer was extracted with Et2O (3 × 20 mL). The
combined organic extracts were washed with water (20 mL),
dried (Na2SO4), and evaporated under reduced pressure to give
the crude product. Purification by flash column chromatography
on silica with CH2Cl2-MeOH-NH3 (10:1:0.1) as the eluent gave
diamine anti-12 (35 mg, 67%) as an orange oil: Rf (10:1:0.1 CH2-
3440 cm-1 1H NMR (270 MHz, CDCl3) δ 7.35-7.08 (m, 15H),
;
3.92 (d, 2H, J ) 13.0), 3.48 (d, 2H, J ) 13.0), 3.31 (d, 1H, J )
4.0), 3.15-3.01 (m, 3H), 2.47-2.39 (m, 1H); 13C NMR (67.9 MHz,
CDCl3) δ 139.2, 139.1, 129.0, 128.5, 127.3, 126.2, 60.8, 59.9
(1:1:1 triplet, J ) 21), 53.2, 31.7; MS (CI, NH3) m/z 333 (M +
H)+, 100; HRMS (CI, NH3) m/z calcd for C23H25DNO (M + H)+
333.2077, found 333.2068.
Syn th esis of Aldeh yde r a c-14. A solution of methyl 2-(diben-
zylamino)-3-phenylpropanoate (580 mg, 1.6 mmol) in THF (2
mL) was added dropwise to a stirred suspension of LiAlD4 (136
mg, 3.2 mmol) in THF (3 mL) at 0 °C under N2. After 40 min,
water was added dropwise until effervescence ceased. Then, Et2O
(20 mL) was added and the layers were separated. The aqueous
layer was washed with water (20 mL), dried (Na2SO4), and
evaporated under reduced pressure to give the crude product.
Purification by flash column chromatography on silica with
petrol-Et2O (1:1) as the eluent gave bis deuterated amino
alcohol (438 mg, 81%) as a white solid: mp 92-94 °C; Rf (1:1
Cl2-MeOH-NH3) 0.2; IR (CDCl3) 3322 cm-1 1H NMR (270
;
MHz, CDCl3) δ 7.35-7.08 (m, 15H), 3.86 (d, 2H, J ) 13.5), 3.52
(d, 2H, J ) 13.5), 3.16-3.02 (m, 2H), 2.69-2.63 (m, 1H), 2.48-
2.39 (m, 2H), 2.08 (s, 3H); 13C NMR (67.9 MHz, CDCl3) δ 140.0,
139.9, 129.1, 128.8, 128.4, 128.3, 127.0, 125.9, 58.75, 53.65, 51.11
(1:1:1 triplet, J ) 20), 35.74, 33.04.
Syn th esis of Dia m in e syn -12 fr om Am in o Alcoh ol syn -
11. MsCl (0.07 mL, 0.9 mmol) was added dropwise to a stirred
solution of amino alcohol syn-11 (248 mg, 0.75 mmol) and Et3N
(0.17 mL, 1.2 mmol) in Et2O (15 mL) at 0 °C under N2. A white
precipitate formed. After 30 min, Et3N (0.21 mL, 1.5 mmol) was
added and the mixture was allowed to warm to room tempera-
ture. Then, MeNH2(aq) (40%; 1.09 mL, 12.7 mmol) was added and
the two-phase mixture was stirred vigorously for 16 h at room
temperature. The layers were separated, and the aqueous layer
was extracted with Et2O (2 × 20 mL). The combined organic
extracts were washed with 5% NaHCO3(aq) (30 mL) and water
(30 mL), dried (Na2SO4), and evaporated under reduced pressure
to give the crude product (247 mg, 96%), which contained a 94:6
mixture of regioisomeric diamines (by 1H NMR spectroscopy).
The major regioisomer contained an 85:15 mixture of diamine
syn-11 and diamine anti-12 (by 1H NMR spectroscopy).
1
petrol-Et2O) 0.3; H NMR (270 MHz, CDCl3) δ 7.36-7.09 (m,
15H), 3.92 (d, 2H, J ) 13.0), 3.48 (d, 2H, J ) 13.0), 3.31 (d, 1H,
J ) 4.0), 3.15-3.03 (m, 2H), 2.98 (s, 1H), 2.48-2.37 (m, 1H);
13C NMR (67.9 MHz, CDCl3) δ 139.2, 139.1, 129.0, 128.8, 128.5,
127.3, 126.2, 60.7, 59.9 (quintet, J ) 20.5, appearing as a triplet),
53.2, 31.7; MS (CI, NH3) m/z 334 (M + H)+, 100; HRMS (CI,
NH3) m/z calcd for C23H24D2NO (M + H)+ 334.2140, found
334.2145.
DMSO (0.08 mL, 1.05 mmol) was added dropwise to a stirred
solution of oxalyl chloride (0.06 mL, 0.6 mmol) in CH2Cl2 (5 mL)
at -78 °C under N2. After 5 min, a solution of the amino alcohol
(175 mg, 0.5 mmol) in CH2Cl2 (2 mL) was added dropwise. After
an additional 10 min, Et3N (0.03 mL, 2.1 mmol) was added
dropwise and the reaction mixture was allowed to warm to room
temperature over 1 h before water (2 mL) was added. The layers
were separated, and the aqueous layer was extracted with Et2O
(1 × 15 mL). The combined organic extracts were washed with
5% NaHCO3(aq) (30 mL), water (30 mL), and brine (30 mL), dried
(Na2SO4), and evaporated under reduced pressure to give the
crude product aldehyde (S)-13 (500 mg, 100%) as a viscous
yellow-green oil. Purification by flash column chromatography
on silica with petrol-Et2O (1:1) as the eluent gave deuterated
aldehyde rac-14 (54 mg, 31%) as a yellow oil: Rf (1:1 petrol-
Et2O) 0.5; 1H NMR (270 MHz, CDCl3) δ 7.29-7.12 (m, 15H),
3.80 (d, 2H, J ) 13.5), 3.60 (d, 2H, J ) 13.5), 3.55 (d, 1H, J )
6.0, 7.5), 3.13 (dd, 1H, J ) 7.5, 14.0), 2.92 (dd, 1H, J ) 6.0, 14.0);
13C NMR (67.9 MHz, CDCl3) δ 201.8 (1:1:1 triplet, J ) 26), 139.1,
138.8, 129.4, 128.7, 128.6, 128.4, 127.3, 126.2, 68.3, 54.8, 30.0;
MS (CI, NH3) m/z 331 (M + H)+, 100; HRMS (CI, NH3) m/z calcd
for C23H23DNO (M + H)+ 331.1921, found 331.1919.
Ack n ow led gm en t. We thank the EPSRC and Lan-
caster Synthesis for a CASE award (to T.D.T.) and Drs.
E. Cuthbertson, B. Colman, and W. Watson for their
interest in this work.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds (S)-9b, (S)-10b, syn-11, rac-14, syn-12, and anti-
12 as well as the crude mixtures of compounds (S)-9a and (R)-
10a , (S)-9b and (R)-10b, and (S)-9c and (R)-10c. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O010824E