Catalytic asymmetric addition of diethylzinc to aldehydes via chiral, non-racemic β-hydroxy and β-methoxy salicylhydrazone catalysts

Article abstract of DOI:10.1016/j.tetasy.2010.04.021

(1S,2S)-Pseudoephedrine and (1S,2S)-pseudonorephedrine have been converted to their corresponding hydrazines and condensed with either o-salicylaldehyde or 2-hydroxy-1-naphthaldehyde to afford a series of β- hydroxysalicylhydrazones that have been employed in the asymmetric addition of diethylzinc to 2-naphthaldehyde in up to 56% ee. In addition to this, the Ephedra hydrazines were also condensed with the o-hydroxyacetophenone derivative to form related hydrazones. The use of these corresponding hydrazones in the asymmetric addition reaction with the diethylzinc did not yield improved enantioselectivities. Finally, Enders' hydrazine was used as a chiral scaffold for the synthesis of β-methoxysalicylhydrazones. These compounds were employed in the asymmetric addition of diethylzinc to a variety of aromatic aldehydes with enantiomeric excesses as high as 68% ee.

Full text of DOI:10.1016/j.tetasy.2010.04.021

Tetrahedron: Asymmetry 21 (2010) 837–845
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Catalytic asymmetric addition of diethylzinc to aldehydes via chiral,
non-racemic b-hydroxy and b-methoxy salicylhydrazone catalysts
*
Sucharita Banerjee, Gregory M. Ferrence, Shawn R. Hitchcock
Department of Chemistry, Illinois State University, Normal, IL 61790-4160, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 March 2010
Accepted 19 April 2010
(1S,2S)-Pseudoephedrine and (1S,2S)-pseudonorephedrine have been converted to their corresponding
hydrazines and condensed with either o-salicylaldehyde or 2-hydroxy-1-naphthaldehyde to afford a ser-
ies of b-hydroxysalicylhydrazones that have been employed in the asymmetric addition of diethylzinc to
2-naphthaldehyde in up to 56% ee. In addition to this, the Ephedra hydrazines were also condensed with
the o-hydroxyacetophenone derivative to form related hydrazones. The use of these corresponding
hydrazones in the asymmetric addition reaction with the diethylzinc did not yield improved enantiose-
lectivities. Finally, Enders’ hydrazine was used as a chiral scaffold for the synthesis of b-meth-
oxysalicylhydrazones. These compounds were employed in the asymmetric addition of diethylzinc to a
variety of aromatic aldehydes with enantiomeric excesses as high as 68% ee.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Chiral, non-racemic hydrazones have recently been reported as
useful catalytic ligands in the addition of diethylzinc to
aldehydes.1–3 Mino et al. were the first to develop chiral hydrazone
ligands for this purpose.1 Arai et al. developed related salicylhydraz-
one derivatives using a binaphthyl template (Fig. 1).2 When em-
ployed in the asymmetric 1,2-addition of diethylzinc, these ligands
afforded enantiomeric excesses as high as 80% ee. In related work,
Hayashi and co-workers3 disclosed that a b-hydroxyimine derived
from tert-leucinol was also an effective catalyst for the asymmetric
addition of diethylzinc to aldehydes.3 Previously, we prepared a ser-
ies of tridentate b-hydroxysalicylhydrzone ligands from (1R,2S)-
ephedrine and (1R,2S)-norephedrine and tested these compounds
in the catalytic asymmetric addition of diethylzinc to aldehydes.
These reactions exhibited enantiomeric ratios ranging from 89:11
to 96:4.4
Based on the earlier work with b-hydroxysalicylhydrazones by
Arai, Hayashi, and based on our own efforts, we developed an
interest in the synthesis and application of other derivatives of
the b-hydroxysalicylhydrazone families of compounds having sig-
nificant structural differences that could be exploited for enhanced
enantioselectivities. In particular we became interested in prepar-
ing a series of hydrazones using the Ephedra alkaloids (1S,2S)-
pseudoephdrine and (1S,2S)-pseudonorephedrine as scaffolds.
Herein, we describe the synthesis of variety of salicylhydrazone li-
gands and their structural modifications and their application in
the catalytic asymmetric addition of diethylzinc to aldehydes.
The synthesis of the b-hydroxysalicylhydrazones was initiated
by reaction of (1S,2S)-pseudonorephedrine5 with acetone or benz-
aldehyde followed by treatment with sodium borohydride to gen-
erate the N-alkylated derivatives 7b and 7c (Scheme 1).
Pseudoephedrine 7a and derivatives 7b–c were then N-nitrosated
to produce N-nitrosamines 8a–c,6 and subsequently reduced to
the corresponding b-hydroxyhydrazine by 9a–c. These hydrazines
were then condensed with either salicylaldehyde 10a or 2-hydro-
xy-1-naphthaldehyde 10b to form hydrazones 11–15 which were
purified by chromatography (Scheme 1). These hydrazones pre-
sumably formed with trans-configured geometry about the C@N
bond.7 This geometry was observed in the solid state for ligand
14 as evidenced by single crystal X-ray crystallography (Fig. 2).8
There was also an interest in synthesizing a ligand similar to Ephe-
dra-based salicylhydrazones but with restricted rotation of the hy-
droxyl and amine moieties.
Attention was focused on the use of the commercially available,
conformationally rigid cis-1-amino-2-indanol. The synthesis of the
indanol-based salicylhydrazone was initiated by the acylation of
(1R,2S)-cis-1-amino-2-indanol 16 (Scheme 2). The product of the
acylation was reduced with LiAlH4 to generate the N-methyl deriv-
ative 18. This secondary amine was then N-nitrosated with sodium
nitrite and HCl to afford 19 in 76% yields. The N-nitrosamine was
reduced with lithium aluminum hydride to produce hydrazine 20
and the resultant hydrazine was then condensed with 2-hydro-
xy-1-naphthaldehyde to form the salicylhydrazone ligand 21. The
yield of the condensation was very low (9%). It was assumed that
the low stability of the hydrazine and steric environment of the
ligand were responsible for the low yield of 21.
* Corresponding author.
E-mail address: hitchcock@ilstu.edu (S.R. Hitchcock).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.021

838
S. Banerjee et al. / Tetrahedron: Asymmetry 21 (2010) 837–845
H
N
Ph
H
N
t-Bu
CH2OCH3
N
N
N
OH
OH
HO
OH
1, Mino et al.1
2, Arai et al.2
3, Hayashi et al. 3
R1
R2
OH HO
Ph
OH HO
Structural Modification
R5
N
N
N
H3C
N
R3
R4
CH3
H
4, Hitchcock et al.4
5,derived from chiral, non-racemic
β-aminoalcohols
Figure 1. b-Hydroxysalicylhydrazone examples.
OH
OH
OH
NO
N
NaNO2, HCl
THF
LiAlH4, THF
RR’CO,MgSO4;
NHR
NH2
Ph
R
Ph
Ph
NaBH4
CH3
6 (pseudonorephedrine)
CH3
CH3
8a (89%)
8b (58%)
8c (59%)
7a: R = -CH3 (pseudoephedrine)
7b: R = -CH2Ph (65%)
7c: R = -CH (CH3)2 (99%)
CHO
OH
10
toluene, MgSO4
OH
NH2
N
R
Ph
OH HO
Ph
OH HO
N
N
Ph
R
N
N
H3C
H3C
CH3
9a-c
R
H
R
H
11: R = -CH3 (45%)
13: R = -CH3 (44%)
14: R = -CH2Ph (27%)
15: R = -CH(CH3)2 (77%)
12: R = -CH(CH3)2 (81%)
Scheme 1. Synthesis of b-hydroxysalicylhydrazones 11–15.
The synthesis of salicylhydrazones using the (1S,2S)-pseudoe-
At this stage, it was determined that (1R,2S)-ephedrine-based
salicylhydrazones were more effective at carrying out 1,2-asym-
metric addition reactions compared to (1S,2S)-pseudoephedrine-
based salicylhydrazones. So, attention was focused on the
structural modification of the ephedrine-based salicylhydrazone
with the goal of improving the observed enantiomeric excesses
from the addition process. In this context, the impact of removal
of the hydroxy group from the naphtholic ring and the removal
of the imine bond were explored. This effort was initiated by con-
densation of the ephedrine hydrazine 22 with either 2-hydroxy-1-
napthaldehyde or 1-naphthaldehyde to form hydrazones 28 and 29
(Scheme 5). The resultant hydrazones were reduced with lithium
aluminum hydride to form hydrazines 30 and 31. Hydrazone 28
was employed as a ligand in our previous work.4 Hydrazone 29
and hydrazines 30 and 31 were tested as ligands in the asymmetric
addition process (Table 2). The results from this work suggested
that hydrazine that did not have the naphtholic hydroxyl group
was the superior catalyst over the systems that were prepared.
The improved enantioselectivity was a positive sign, but the ligand
itself proved to have low stability (observable degradation by 1H
NMR spectroscopy when the material was stored at 0 °C). Nonethe-
less, this work suggested that the coordinating hydroxyl group
could be contributing to compromised selectivities.
phedrine 9a and (1R,2S)-ephedrine-based hydrazines 22 and the
methyl ketone analog of salicylaldehyde was also pursued. Based
on this idea, 1-(2-hydroxy-5-methylphenyl)ethanone 23 was con-
densed with the Ephedra-derived hydrazines to form hydrazones
24 and 25 (Scheme 3). With compounds 11–15, 21, 24, and 25 in
hand, we pursued the hydrazone ligand-catalyzed asymmetric
addition of diethylzinc to 2-naphthaldehyde. The results of these
reactions are collected in Table 1.
The asymmetric 1,2-addition process yielded enantioselectivi-
ties that ranged from 4% to 56% ee. Of the salicylaldehyde and 2-
hydroxy-1-naphthaldehyde-derived hydrazones, the maximum
enantiomeric excess was generated by the use of the N-isopro-
pylsalicylhydrazone ligand 12. The hydrazone ligands 24 and 25
also afforded the desired product in low enantiomeric excess in
addition to the 2-naphthylmethanol, the product of reduction as
evidenced by 1H NMR spectroscopy. Ultimately, none of the
(1S,2S)-pseudoephedrine-based hydrazone ligands or the related
ligands in this work proved to be superior to the diastereomeric
(1R,2S)-ephedrine that was previously prepared. The lower enan-
tiomeric excess was attributed to multiple intermediates that
may be accessible with the pseudoephedrine configuration versus
that of the ephedrine configuration (Scheme 4).

S. Banerjee et al. / Tetrahedron: Asymmetry 21 (2010) 837–845
839
HO
R1
R2
H3C
CH3
NH2
N
OH
R2
OH HO
O
23
R1
CH3
toluene, MgSO4
reflux
N
N
CH3
H3C
CH3
CH3
CH3
9a: R1 = -H; R2 = -Ph
22: R1 = -Ph; R2 = -H
24: R1 = -H; R2 = -Ph (58%)
25: R1 = -Ph; R2 = -H (73%)
Scheme 3. Synthesis of ketone-based salicylhydrazones 24 and 25.
hydes (Table 3). The hydrazone derived from the condensation of
Enders’ hydrazine with 3,5-di-tert-butyl-2-hydroxybenzaldehyde
(35) afforded an enantiomeric excess of 58% ee in the asymmetric
addition of diethylzinc with 2-naphthaldehyde.
Salicylhydrazone 35 was also employed with other aldehydes,
although the enantioselectivities were not as high. An interesting
observation from this work was that the absolute configuration
of the alcohol product was determined to be the (R)-configuration
when ligands 33 and 34 were employed; the alcohol product was
determined to be the (S)-configuration when ligand 35 was used.
It is proposed that the ligands 33 and 34 involve the formation of
intermediates where diethylzinc coordination occurs at the pheno-
lic oxygen (Scheme 7). In contrast, ligand 35 inhibits coordination
at the phenolic oxygen due to the presence of the tert-butyl group
at the ortho-position.
3. Conclusions
A series of b-hydroxysalicylhydrazones based on the Ephedra
alkaloids (1S,2S)-pseudoephedrine and (1S,2S)-pseudonorephe-
drine have been synthesized and applied in the asymmetric addition
of diethylzinc. The observed enantioselectivities for the alcohol
products were not as high as those observed for diastereomeric
(1R,2S)-ephedrine. Modification of the b-hydroxy salicylhydrazones
either by the introduction of ketone as starting materials or by the
reduction of the hydrazone functional group, in some cases, im-
proved the enantioselectivity of product formation. Unfortunately,
some of the modified compounds proved to have low stability. En-
ders’ hydrazine was used in the synthesis of b-methoxysalicylhyd-
razones that proved to have better stability, although the
enantioselectivities of the product were only moderate.
Figure 2. ORTEP-III diagram of 14 with the atomic numbering scheme and
intramolecular H-bonding. Displacement ellipsoids are drawn at the 50% probabil-
ity level.
To circumvent the problem of the free alcohol, a commercially
available, enantiomerically pure, stable hydrazine was sought as
a scaffold for the synthesis of hydrazones that would not have a
free hydroxyl group. Inspired by Mino’s earlier work,1 Enders’
hydrazine9 was selected and employed as a template for the for-
mation of a series of ligands for the asymmetric addition process.
The synthesis of the hydrazones was carried out by condensation
of 32 with salicylaldehyde and other related aldehyde derivatives
to give hydrazones 33–35 in yields of 90–93% (Scheme 6).
4. Experimentals
4.1. General remarks
Once these ligands were synthesized, a series of reactions were
carried out in which the ligands were employed as catalysts in the
asymmetric addition of diethylzinc to a variety of aromatic alde-
Toluene was purchased as an anhydrous reagent and used with-
out further purification. Diethylzinc was directly purchased from
NHCH3
NH2
NHCOOMe
ClCO2CH3 , TEA
CH2Cl2
LiAlH4 ,THF
NaNO2, HCl
OH
OH
OH
THF
76%
52%
58%
18
16
H3C
17
H3C
N
NO
CHO
OH
N
NH2
OH HO
LiAlH4, THF
N
N
OH
OH
toluene, MgSO4
97%
CH3
H
9%
19
20
21
Scheme 2. An indanol derivative of salicylhydrazone.

840
S. Banerjee et al. / Tetrahedron: Asymmetry 21 (2010) 837–845
Table 1
Catalytic asymmetric addition of diethylzinc to 2-naphthaldehyde
OH
O
ligands, Et2Zn
Et
H
toluene, 18 hrs, RT
26
Yielda (%)
27
Entry
Ligand
Enantiomeric ratio S:Rb (%ee)
Absolute configurationc
1
2
3
4
5
6
7
8
11
12
13
14
15
21
24
25
56
94
90
52.0:48.0 (4)
78.1:21.9 (56)
63.0:37.0 (26)
63.4:37.6 (26)
69.0:31.1 (38)
63.4:36.6 (27)
65.6:34.4 (31)
43.6:56.4 (13)
S
S
S
S
S
S
S
R
47
46
90
58d
66d
a
b
c
All reactions went to completion as determined by 1H NMR spectroscopy and HPLC.
The enantiomeric ratio (er) values were determined via CSP HPLC using a Chiralcel-OD column.
The configuration was determined by comparison of the literature values (see Ref. 4).
Combined yield of addition and reduction product.
d
R
R
Et
O
Et
Et
Et
Zn
O
Zn
O
H
H
O
Et2Zn
Ph
O
H
Ph
O
N
12
Zn
N
Zn
N
toluene
H3C
N
H3C
H
TS-12-Et2Zn-RCHO
TS-12'-Et2Zn-RCHO
R
R
(S)-enantiomer
(R)-enantiomer
Et
HO
Et
H
H
OH
Scheme 4. Proposed transition states for the reaction of 12 with diethylzinc.
CHO
R
Ph
OH
N
R
Ph
OH
N
R
OH
NH2
N
10b: R= -OH
26: R = -H
LiAlH4, THF
reflux
H
N
N
toluene, MgSO4
reflux
CH3
Ph
H3C
H3C
CH3
CH3
H
CH3
22
28: R = -OH (64%)
29: R = -H (64%)
30: R = -OH (97%)
31: R = -H (23%)
Scheme 5. Synthesis of ligand 30 and 31.
Aldrich. All reactions were run under a nitrogen atmosphere. Un-
less otherwise noted, all 1H and 13C NMR spectra were recorded
in CDCl3 using an NMR spectrometer operating in 500 MHz or
400 MHz, 125 MHz or 100 MHz, respectively. Chemical shifts were
reported in parts per million (d scale), and coupling constant (J val-
ues) were listed in hertz (Hz). Tetramethylsilane (TMS) was used as
internal standard (d = 0 ppm). Infrared spectra are reported in reci-
procal centimeters (cmꢀ1) and are measured either as Nujol mull
or as a neat liquid. Melting points were recorded on a Mel-Temp
apparatus and are uncorrected. Optical activities were measured
at 589 nm using a digital polarimeter. Enantiomeric ratio of the
catalysis was determined using chiral phase HPLC using AD, AS,
or OD column. High resolution mass spectra were obtained from
the mass Spectrometry laboratory, School of Chemical Science,
University of Illinois, Urbana-Champaign. Anhydrous toluene was
used for the catalysis reaction.
4.2. General procedure for reductive alkylation to form 7b and
7c
In a 250 mL round-bottomed flask were added (1S,2S)-pseudo-
ephedrine (5.00 g, 33.1 mmol), ethanol (100 mL), and the selected

S. Banerjee et al. / Tetrahedron: Asymmetry 21 (2010) 837–845
841
Table 2
(2.50 g, 66.1 mmol) was added and the reaction mixture was stir-
red overnight. The reaction mixture was diluted with a 20% aque-
ous solution of sodium hydroxide (50 mL) and extracted with ethyl
acetate (2 ꢁ 50 mL). The organic layer was then treated with brine
(100 mL) and dried over magnesium sulfate (MgSO4).
Catalytic asymmetric addition of diethylzinc to 2-naphthaldehyde
ligands, Et2Zn
26
27
toluene, 18 hrs, RT
Entry
Ligand
Yielda (%)
Enantiomeric ratio
Absolute configurationc
S:Rb (%ee)
4.2.1. (1S,2S)-2-(Benzylamino)-1-phenyl-1-propanol, 7b
1
1
2
29
30
31
38
92
96
33.3:66.7 (33)
42.7:57.3 (15)
16.0:84.0 (68)
R
R
R
Benzaldehyde was employed as the selected carbonyl com-
pound. The solvent was evaporated via rotary evaporation. The
white residue was purified by flash chromatography using (7:3)
hexanes/ethyl acetate. The title compound was obtained as a
All reaction went to completion as determined by 1H NMR spectroscopy and
HPLC.
The enantiomeric ratio (er) values were determined via CSP HPLC using a
Chiralcel-OD column.
a
white solid (65%).
½
a 2D5
ꢂ
¼ þ135:9 (c 1.0, CHCl3). Mp = 143–
b
146 °C. 1H (500 MHz, CDCl3), (d ppm): 0.88 (d, J = 6.4 Hz, 3H),
2.69–2.75 (m, 1H), 3.60 (d, J = 13.0 Hz, 1H), 3.81 (d, J = 13.0 Hz,
1H), 4.13 (d, J = 8.2 Hz, 1H), 7.19–7.26 (m, 10H). 13C (125 MHz,
CDCl3), (d ppm): 16.1, 50.9, 58.9, 77.4, 126.7, 126.8, 127.3,
127.9, 128.0, 128.2, 139.8, 142.2. IR (nujol): 3292, 1382, 1042,
c
The configuration was determined by comparison of the literature values.
carbonyl compound (9.00 mL, 82.7 mmol). The reaction mixture
was stirred overnight at room temperature. Sodium borohydride
759 cmꢀ1 ESI-HRMS calcd for C16H20NO (M+H)+: 242.1545.
.
Found: 242.1542.
HO
H
H3CO
HO
O
N
toluene, MgSO4, reflux
N
90%
33
HO
H
H3CO
HO
O
OCH3
N
N
toluene, MgSO4, reflux
93%
N
NH2
34
Ender's hydrazine
32
C(CH3)3
HO
C(CH3)3
H
H3CO
HO
C(CH3)3
O
N
N
C(CH3)3
toluene, MgSO4, reflux
92%
35
Scheme 6. Synthesis of hydrazones 33–35.
Table 3
1,2-Asymmetric addition of diethylzinc to aldehydes
H3CO
HO
R
N
N
O
H
OH
Et
33-35
Et2Zn
toluene, 18h ,25 oC
R
H
R
27
26
Entry
Ligand
RCHO
2-C10H7–
t-PhCH@CH–
2-C10H7–
t-PhCH@CH–
2-C10H7–
t-PhCH@CH–
1-C10H7–
Yielda (%)
Enantiomeric ratiob (%ee)
Absolute configurationc
1
2
3
4
5
6
7
8
9
33
33
34
34
35
35
35
35
35
71
44
66
81
61
63
65
76
71
45.8:54.2 (8)
45.8:54.2 (8)
48.8:51.2 (2)
52.3:47.7 (5)
78.7:21.2 (58)
46.2:53.8 (8)
64.6:35.4 (29)c
32.7:67.3 (35)b
29.8:70.2 (40)b
R
R
R
R
S
S
S
S
S
C6H5–
4-MeO-C6H5–
a
b
c
Yield was reported after purification via flash chromatography.
Enantiomeric excess was determined by CSP HPLC using OD column.
Absolute configuration was determined from the literature.

842
S. Banerjee et al. / Tetrahedron: Asymmetry 21 (2010) 837–845
R
dominant peaks were only reported as there are two stereoiso-
H
O
Et
Zn
H3C
H
O
R
Et
Et
mer’s present), (d ppm): 0.92 (d, J = 6.8 Hz, 3H), 1.12 (d,
J = 6.8 Hz, 3H), 1.21 (d, J = 6.9 Hz, 3H), 4.14–4.19 (m, 1H), 4.26–
4.31 (m, 1H), 4.85 (s, 1H), 5.04–5.10 (m, 1H), 7.26–7.36 (m, 5H).
13C NMR (125 MHz, CDCl3), (d ppm): 13.8, 18.3, 20.3, 45.2, 60.1,
75.3, 126.2, 128.1, 128.5, 141.5. IR (nujol) cmꢀ1: 3258, 1353,
1055, 754. ESI-HRMS calcd for C12H19N2O2 (M+H)+: 223.1447.
Found: 223.1438.
CH3
CH3
H3C
Zn
Et
H
C
H3C
H
O
O
O
O
Zn
N
Zn
N
CH3
CH3
H
N
N
H
H
TS-33-Et2Zn-RCHO
TS-35-Et2Zn-RCHO
4.4. General procedure for N-nitrosamine reduction to form
hydrazines 9a–c
H
R
H
R
In a 1 L round-bottomed flask were added lithium aluminum
hydride (200 mmol) and THF (500 mL). The reaction mixture was
then heated to 50 °C. To the reaction mixture a solution of N-nitro-
samine 8a, 8b, or 8c (100 mmol) in THF (100 mL) was added drop-
wise in about 20 min. The reaction mixture was heated for 2 h and
then cooled to 0 °C. An aqueous solution of NaOH (1 M, 150 mL)
was added dropwise to the reaction mixture (caution: this process
is highly exothermic). The solvents were removed by rotary evap-
oration and the residue was extracted with ethyl acetate
(2 ꢁ 300 mL) and NaOH solution (1 M, 150 mL). The organic layer
was washed with brine and dried over magnesium sulfate. The sol-
vent was evaporated via rotary evaporation. This process afforded
hydrazines 9a–c. The hydrazines were not characterized due to
their low stability and were used immediately to create the hydra-
zones 11–15.
HO
Et
Et
(S)-enantiomer
OH
(R)-enantiomer
Scheme 7. Proposed mechanisms for the addition reactions of 33 and 35.
4.2.2. (1S,2S)-2-(Isopropylamino)-1-phenyl-1-propanol, 7c
Acetone was employed as the selected carbonyl compound. The
solvent was evaporated via rotary evaporation. A colorless liquid
was obtained in quantitative yield. ½a D25
ꢂ
¼ þ53:6 (c 0.5, CHCl3). 1H
NMR (500 MHz, CDCl3), (d ppm): 0.85 (d, J = 6.3 Hz, 3H), 1.01 (d,
J = 6.2 Hz, 3H), 1.05 (d, J = 6.2 Hz, 3H), 2.64–2.69 (m, 1H), 2.83–2.87
(m, 1H), 3.15 (s, 1H), 4.04 (d, J = 8.3 Hz, 1H), 7.21–7.31 (m, 5H). 13C
NMR (125 MHz, CDCl3), (d ppm): 16.5, 22.2, 23.8, 45.66, 56.8,
126.7, 127.0, 127.7, 142.1. IR (neat): 3389, 2924, 1650, 759 cmꢀ1
.
ESI-HRMS calcd for C12H20NO (M+H+): 194.1545. Found: 194.1541.
4.5. General procedure for the formation of salicylhydrazones
11 and 12
4.3. General procedure for N-nitrosation for the formation of
8a–c
In 250 mL round-bottomed flask were added toluene (120 mL),
hydrazine 9a or 9c (2.00 g, 11.0 mmol), salicylaldehyde (11.0
mmol), and magnesium sulfate (2 g). The reaction mixture was
heated up to reflux and stirred 18 h at reflux. It was then allowed
to cool to room temperature. The reaction mixture was extracted
with ethyl acetate (150 mL) and brine (100 mL). The organic layer
was then dried over magnesium sulfate and filtered. The solvent
was removed via rotary evaporation.
In a 250 mL round-bottomed flask were placed 8a,b or c (4.60 g,
19.1 mmol), THF (10 mL), NaNO2 (1.51 g, 22.0 mmol), and HCl
(3 M, 8.8 mL). The reactionmixture was stirred 18 h at roomtemper-
ature and the reaction was quenched with KOH solution (20%,
50 mL), and the reaction mixture was extracted with ethyl acetate
(100 mL). The organic layer was washed with brine (100 mL) and
dried over MgSO4. The solvent was removed via rotary evaporation
to yield the crude nitrosamine.
4.5.1. 2-((E)-(2-((1S,2S)-1-Hydroxy-1-phenyl-2-propyl)-2-methy-
lhydrazono)methyl) phenol, 11
4.3.1. (1S,2S)-2-(N-Methyl-N-nitrosamino)-1-phenyl-1-propanol, 8a
Using pseudoephedrine (7a) as the starting material, the title
compound was obtained as viscous yellow residue (89%). The 1H
and 13C NMR spectroscopic data matched the literature values
for this compound.6
Hydrazine 9a was employed in the condensation reaction. The
crude product was purified with flash chromatography using 9:1
hexanes and ethyl acetate. The chromatographed product was then
recrystallized from hexanes and ethyl acetate. The title compound
was obtained as a white solid (45%). ½a D20
¼ ꢀ13:9 (c 1.0, CHCl3).
ꢂ
Mp = 95–98 °C. 1H NMR (500 MHz, CDCl3), d (ppm): 0.89 (d,
J = 6.7 Hz, 3H), 2.96 (s, 3H), 3.07 (s, 1H), 3.43–3.48 (m, 1H), 4.71
(d, J = 9.3 Hz, 1H), 6.86–6.96 (m, 5H), 7.15–7.41 (m, 4H), 7.52 (s,
1H), 11.46 (s, 1H). 13C (125 MHz, CDCl3) d (ppm): 12.6, 36.5, 69.3,
76.5, 116.4, 119.2, 119.7, 127.2, 128.2, 128.5, 129.0, 129.1, 138.7,
140.9, 156.9. IR (nujol): 3491, 1595, 1276, 1060, 761 cmꢀ1. ESI-
HRMS calcd for C17H21N2O2 (M+H)+: 285.1603. Found: 285.1591.
4.3.2. (1S,2S)-2-(N-Benzyl-N-nitrosamino)-1-phenyl-1-propanol,
8b
Using 7b, the title compound was obtained as white solid (58%)
after recrystallization from ethyl acetate and hexanes. ½a D25
¼
ꢂ
þ204:7 (c 1.0, CHCl3). Mp: 90–92 °C. 1H (500 MHz, CDCl3, extra
peaks were present due to the presence of two stereoisomers), (d
ppm): 1.26 (d, J = 7.1 Hz, 3H), 2.69 (d, J = 4.5 Hz, 1H), 4.40–4.46
(m, 1H), 4.45 (d, J = 14.8 Hz, 1H), 5.20 (d, J = 14.8 Hz, 1H), 5.33 (d,
J = 15.1 Hz, 1H), 7.25–7.37 (m, 10H). 13C (125 MHz, CDCl3, extra
peaks were due to the presence of two stereoisomers), (d ppm):
17.6, 48.3, 64.3, 77.7, 126.5, 127.7, 128.1, 128.4, 128.7, 128.9,
134.6, 140.9. IR (nujol) cmꢀ1: 3496, 1374, 766. ESI-HRMS calcd
for C16H19N2O2 (M+H)+: 271.1447. Found: 271.1447.
4.5.2. 2-((E)-(2-((1S,2S)-1-Hydroxy-1-phenyl-2-propyl)-2-isopropyl-
hydrazono)methyl) phenol, 12
Hydrazine 9c was employed in the condensation reaction. The
crude product was purified with flash chromatography using 9:1
hexanesand ethylacetate. The titlecompoundwas obtainedas a yel-
low liquid (81%). ½a D23
ꢂ
¼ þ17:1 (c 1.0, CHCl3). 1H NMR (500 MHz,
4.3.3. (1S,2S)-2-(N-Isopropyl-N-nitrosamino)-1-phenyl-1-
propanol, 8c
CDCl3), (d ppm): 0.95 (d, J = 6.7 Hz, 3H), 1.11 (d, J = 6.6 Hz, 3H),
1.33 (d, J = 6.6 Hz, 3H), 3.54–3.60 (m, 1H), 3.95–4.00 (m, 1H), 4.60
(d, J = 8.9 Hz, 1H), 6.85 (t, J = 7.6 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H),
7.10 (d, 7.6 Hz, 1H), 7.15 (m, 1H), 7.26–7.39 (m, 5H), 7.56 (s, 1H).
13C (125 MHz, CDCl3), (d ppm): 14.9, 18.2, 21.1, 48.2, 59.4, 76.1,
Using 7c, the title compound was obtained as white solid (59%)
after recrystallization from ethyl acetate and hexanes. ½a D25
¼
ꢂ
þ188:0 (c 0.2, CHCl3). Mp = 92–95 °C. 1H NMR (500 MHz, CDCl3,

S. Banerjee et al. / Tetrahedron: Asymmetry 21 (2010) 837–845
843
116.3, 119.1, 119.7, 127.3, 128.0, 128.4, 128.9, 129.0, 138.5, 141.0,
157.0. IR (nujol): 3468, 1622, 1377, 761 cmꢀ1. ESI-HRMS calcd for
C19H25N2O2 (M+H)+: 312.1827. Found: 312.1830.
at ambient temperature and then the reaction was quenched with
1 M HCl (100 mL). The reaction mixture was extracted with dichlo-
romethane (100 mL). The organic layer was washed with brine
(100 mL) and dried over magnesium sulfate. The solvents were re-
moved via rotary evaporation. The residue was recrystallized with
ethyl acetate and hexanes. The product was obtained in 58% yield.
4.6. General procedure for the formation of hydrazones 13–15
In 250 mL round-bottomed flask were added toluene (120 mL),
hydrazine 9a,b or c (11.0 mmol), 2-hydroxy-1-naphthaldehyde
(1.90 g. 11.0 mmol), and magnesium sulfate (2 g). The reaction
mixture was heated up to reflux and stirred 18 h at reflux. It was
then allowed to cool to room temperature. The reaction mixture
was extracted with ethyl acetate (150 mL) and brine (100 mL).
The organic later was then dried over magnesium sulfate and fil-
tered. The solvent was evaporated via rotary evaporation.
½
a 2D3
ꢂ
¼ þ19:1 (c 1.0, CHCl3). Mp: 95–98 °C. The 500 MHz NMR
spectrum indicated the presence of a mixture of diastereomers in
ratio of 55:45 that complicated interpretation. 1H NMR
a
(500 MHz, CDCl3), d (ppm): 2.87–3.09 (m, 2H), 3.27–3.39 (m, 1H),
3.70 (s, 3H), 5.09 (d, J = 7.2 Hz, 1H), 5.61 (s, 1H), 7.00 (s, 1H),
7.20–7.29 (m, 4H). 13C NMR (125 MHz, CDCl3), (d ppm): 8.4, 38.7,
39.4, 45.7, 52.2, 59.1, 61.1, 73.2, 80.4, 124.3, 124.8, 125.12, 125.4,
126.9, 127.7, 127.9, 129.2, 139.6, 139.8, 140.2, 140.7. IR (nujol):
3440, 3327, 1751, 752 cmꢀ1. ESI-HRMS calcd for C11H13NO3Na
(M+H)+: 230.0793. Found: 230.0792.
4.6.1. 1-((E)-(2-((1S,2S)-1-Hydroxy-1-phenyl-2-propyl)-2-methyl-
hydrazono)methyl)-2-naphthol, 13
The residue was purified by flash chromatography using (9:1)
hexanes/ethyl acetate followed by recrystallization using hexanes
4.6.5. (1R,2S)-1-(Methylamino)-2,3-dihydro-1H-inden-2-ol, 18
In a 500 mL round-bottomed flask were added LiAlH4 (1.45 g,
38.2 mmol) and THF (450 mL). The reaction mixture was heated
to reflux. A solution of 17 (3.50 g, 19.1 mmol) in THF (50 mL) was
added dropwise to the reaction mixture. The reaction mixture
was then heated to reflux for 18 h. The reaction mixture was then
cooled to 0 °C. Water (300 mL) was added dropwise to quench the
reaction. The reaction solvent was removed by rotary evaporation
and the reaction mixture was extracted with 1 M NaOH (150 mL)
and ethyl acetate (100 mL). The aqueous layer was extracted with
ethyl acetate (50 mL). The combined organic layers were washed
with brine (150 mL) and dried over magnesium sulfate. The solvent
was removed by rotary evaporation. The brown residue was
recrystallized with ethyl acetate and hexanes. The titled compound
and ethyl acetate (44%). ½a D20
¼ ꢀ29:5 (c 1.0, CHCl3). Mp = 143–
ꢂ
146 °C. 1H NMR (500 MHz, CDCl3), (d ppm): 0.94 (d, J = 6.7 Hz,
3H), 3.07 (s, 3H), 3.50–3.54 (m, 1H), 4.77 (d, J = 9.3 Hz, 1H), 7.19–
7.24 (m, 3H), 7.29–7.38 (m, 3H), 7.42–7.49 (m, 3H), 7.69 (d,
J = 8.7, 1H), 7.6 Hz (d, J = 8.0 Hz, 1H), 8.02 (d, J = 8.7 Hz, 1H), 8.35
(s, 1H), 12.70 (s, 1H). 13C NMR (125 MHz, CDCl3), (d ppm): 12.6,
36.7, 69.5, 109.9, 119.0, 120.1, 123.1, 126.8, 127.3, 128.2, 128.4,
128.9, 129.0, 130.4, 131.5, 135.0, 135.2, 140.8, 156.3. IR (nujol):
3475, 1621, 1454, 1039, 742 cmꢀ1
.
ESI-HRMS calcd for
C21H23N2O2 (M+H)+: 335.1760. Found: 335.1753.
4.6.2. 1-((E)-(2-((1S,2S)-1-Hydroxy-1-phenyl-2-propyl)-2-isopropyl-
hydrazono)methyl)-2-naphthol, 15
was obtained as an off-white solid (52%). ½a D24
¼ ꢀ10:2 (c 1.0,
ꢂ
The residue was purified by flash chromatography using (9:1)
hexanes/ethyl acetate. The title compound was obtained as a yellow
CHCl3). Mp: 108–110 °C. 1H NMR (500 MHz, CDCl3), d (ppm):
2.61 (s, 3H), 2.97 (dd, J = 16.4 Hz, J = 4.0 Hz, 1H), 3.06 (dd,
J = 16.4 Hz, 4.0 Hz, 1H), 3.96 (d, J = 5.2 Hz, 1H), 4.44–4.47 (m, 1H),
7.23–7.26 (m, 4H). 13C NMR (125 MHz, CDCl3), (d ppm): 35.3,
39.7, 67.7, 70.3, 123.6, 125.6, 126.6, 128.0, 141.1, 142.1. IR (nujol):
3309, 1457, 737 cmꢀ1. ESI-HRMS calcd for C10H14NO (M+H)+:
164.1075. Found: 164.1077.
liquid (77%). ½a D25
ꢂ
¼ þ43:4 (c 1.0, CHCl3). 1H NMR (500 MHz, CDCl3),
(d ppm): 1.01 (d, J = 6.6 Hz, 3H), 1.21 (d, J = 6.6 Hz, 3H), 1.38 (d,
J = 6.6 Hz, 3H), 3.43 (s, 1H), 3.58–3.64 (m, 1H), 4.04–4.11 (m, 1H),
4.63 (d, J = 9.0 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.28–7.456 (m, 7H),
7.67 (d, J = 8.7 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 8.7 Hz,
1H), 8.56 (s, 1H), 13.05 (s, 1H). 13C (100 MHz, CDCl3), (d ppm):
14.5, 18.6, 21.3, 49.3, 60.2, 76.2, 109.7, 119.1, 119.9, 123.1, 126.9,
127.4, 128.1, 128.5, 129.1, 130.7, 131.6, 138.1, 141.1, 157.3, 170.2.
4.6.6. N-((1R,2S)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)-N-
methylnitrous amide, 19
IR (nujol): 3468, 1622, 1377, 761 cmꢀ1
.
ESI-HRMS calcd for
In a 250 mL round-bottomed flask were added (1R,2S)-1-(meth-
ylamino)-2,3-dihydro-1H-inden-2-ol (2.25 g, 13.97 mmol), THF
(20 mL), HCl (10 mL, 3 M), and sodium nitrite (1.15 g, 18.80 mmol).
The reaction mixture was stirred for 18 h at ambient temperature
and the reaction was quenched with HCl (1 M, 25 mL) and ethyl
acetate (50 mL). The organic layer was washed with brine and
dried over magnesium sulfate. The solvent was evaporated via ro-
tary evaporation. The residue was recrystallized with ethyl acetate
and hexanes. The title compound was obtained as a yellow solid
C23H27N2O2 (M+H+): 363.2073. Found: 363.2065.
4.6.3. 1-((E)-(2-Benzyl-2-((1S,2S)-1-hydroxy-1-phenyl-2-propyl)-
hydrazono)methyl)-2-naphthol, 14
The residue was purified by flash chromatography using (9:1)
hexanes/ethyl acetate followed by recrystallization using hexanes
and ethyl acetate. The title compound was obtained as a white so-
lid (27%).
½
a 2D5
ꢂ
¼ þ11:5 (c 1.0, CHCl3). Mp = 128–131 °C. 1H
(500 MHz, CDCl3), (d ppm): 1.12 (d, J = 6.7 Hz, 3H), 2.92 (s, 1H),
4.40–4.46 (m, 1H), 3.59–3.64 (m, 1H), 4.55 (d, J = 15.0 Hz, 1H),
4.60 (d, J = 15.0 Hz, 1H), 4.85 (d, J = 8.9 Hz, 1H), 7.16–7.71 (m,
11H), 8.17 (s, 1H), 12.67 (s, 1H). 13C (125 MHz, CDCl3), (d ppm):
14.2, 56.6, 68.4, 78.2, 110.1, 119.0, 120.0, 122.9, 126.6, 126.8,
127.1, 127.6, 128.0, 128.2, 128.5, 128.8, 129.1, 130.2, 131.3,
136.1, 137.0, 141.3, 156.3. IR (nujol): 3400, 1459, 769 cmꢀ1. ESI-
HRMS calcd for C27H19N2O2 (M+H)+: 411.2073. Found: 411.2080.
(76%).
½
a 2D4
ꢂ
¼ þ60:4 (c 1.1, CHCl3). Mp = 91–93 °C. 1H NMR
(500 MHz, CDCl3), d (ppm): 2.92 (s, 3H), 3.07 (dd, J = 16.8 Hz, J =
5.9 Hz, 1H), 3.37 (dd, J = 16.8 Hz, J = 5.9 Hz, 1H), 4.98–5.02 (m,
1H), 6.18 (d, J = 6.6 Hz, 1H), 7.19–7.37 (m, 4H). 13C NMR
(125 MHz, CDCl3), (d ppm): 31.8, 39.9, 70.2, 73.6, 125.5, 125.6,
127.6, 129.4, 136.5 and 140.9. IR (nujol): 3331, 1460, 751 cmꢀ1
.
ESI-HRMS calcd for C10H13N2O2 (M+H)+: 193.0977. Found: 193.080.
4.6.7. (1R,2S)-1-(1-Methylhydrazinyl)-2,3-dihydro-1H-inden-2-
ol, 20
4.6.4. Methyl (1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-ylcar-
bamate, 17
In a 250 mL round-bottomed flask were added (1R,2S)-cis-1-
amino-2-indanol (5.02 g, 33.5 mmol), dichloromethane (100 mL),
methyl chloroformate (2.72 mL, 35.2 mmol), and triethylamine
(9.30 mL, 67.0 mmol). The reaction mixture was stirred for 18 h
In a 250 mL round-bottomed flask were added LiAlH4 (0.52 g,
10.4 mmol) and THF (30 mL). A solution of 19 (1.0 g, 5.2 mmol)
in THF (15 mL) was added dropwise to the reaction mixture in
20 min. The reaction was stirred for 2 h. The reaction was cooled
to 0 °C and water (50 mL) was added dropwise to quench the reac-

844
S. Banerjee et al. / Tetrahedron: Asymmetry 21 (2010) 837–845
tion. The solvent was removed via rotary evaporation. The reaction
was extracted with NaOH (1 M, 25 mL) and Ethyl acetate (25 mL).
The aqueous layer was extracted with ethyl acetate (25 mL). The
combined organic layer was washed with brine (50 mL) and dried
over magnesium sulfate. The solvent was evaporated via rotary
evaporation. The title compound was obtained as a yellow liquid
(97%). This material was used without further purification due to
stability concerns.
1H), 6.89 (d, J = 8.3 Hz, 1H), 7.10–7.12 (m, 1H), 7.24 (s, 1H), 7.34–
7.36 (m, 5H), 13.4 (s, 1H). 13C (125 MHz, CDCl3), (d ppm): 8.9,
14.7, 20.6, 41.5, 68.3, 76.3, 117.4, 118.8, 127.4, 127.9, 128.2,
128.3, 132.6, 140.8, 157.9, 169.7. IR (nujol): 3447, 1600,
754 cmꢀ1. ESI-HRMS calcd for C19H25N2O2 (M+H)+: 313.1916.
Found: 313.1919.
4.7.3. ((1R,2S)-2-((E)-1-Methyl-2-(1-naphthylmethylene)-
hydrazinyl)-1-phenyl-1-propanol, 29
4.6.8. (1-((E)-(2-((1R,2S)-2-Hydroxy-2,3-dihydro-1H-inden-1-
yl)-2-methylhydrazono) methyl)-2-naphthol, 21
Hydrazine 22 (1.50 g, 8.30 mmol), 2-naphthaldehyde (1.30 g,
8.30 mmol), toluene (85 mL), and magnesium sulfate (2 g) were
combined in a 250 mL round-bottomed flask. The reaction mixture
was heated to reflux and then stirred overnight at reflux tempera-
ture. The reaction mixture was then cooled to room temperature.
The reaction was quenched with brine (100 mL) and ethyl acetate
(100 mL). The organic layer was dried over magnesium sulfate. The
solvent was evaporated via rotary evaporation. The residue was
purified by recrystallization from hexanes and ethyl acetate. The ti-
Toluene(46 mL), hydrazine20 (0.93 g, 5.20 mmol), 2-hydroxy-1-
naphthaldehyde (0.90 g, 5.20 mmol), and magnesium sulfate (1 g)
were combined in a 250 mL round-bottomed flask and the reaction
mixture was heated to reflux and stirred 18 h. It was then allowed
to cool to room temperature. The reaction mixture was extracted
with ethyl acetate (50 mL) and brine (50 mL). The organic later
was then dried over magnesium sulfate and filtered. The solvent
was removed via rotary evaporation. The residue was purified by
flash chromatography using (9:1) hexanes/ethyl acetate followed
by recrystallization using hexanes and ethyl acetate. The title com-
tle compound was obtained as a white solid (64%). ½a D24
¼ þ169:5 (c
ꢂ
1.0, CHCl3). Mp = 128–130 °C. 1H NMR (500 MHz, CDCl3), d (ppm):
1.09 (d, J = 6.7 Hz, 3H), 2.95 (s, 3H), 3.41–3.45 (m, 1H), 4.92 (s, 1H),
5.36 (d, J = 2.2 Hz, 1H), 7.21–7.80 (m, 12H). 13C NMR (125 MHz,
CDCl3), d (ppm): 9.4, 37.8, 67.5, 76.7, 122.5, 125.6, 125.7, 125.8,
126.1, 126.3, 127.0, 127.8, 127.9, 128.1, 128.4, 132.9, 133.1, 133.6,
134.0, 141.9. IR (nujol): 3423, 1461, 874 cmꢀ1. ESI-HRMS calcd for
C21H23N2O (M+H)+: 319.1810. Found: 319.1809.
pound was obtained as a light brown solid (9%). ½a D23
¼ þ122:7 (c
ꢂ
0.2, CHCl3). Mp = 145–148 °C. 1H NMR (400 MHz, CDCl3), d (ppm):
3.02 (dd, J = 16.6 Hz, J = 4.7 Hz, 1H), 3.16 (s, 3H), 3.28 (dd, J = 16.6,
4.7 Hz, 1H), 4.83–4.88 (m, 1H), 5.02 (d, J = 6.4 Hz, 1H), 7.12 (d, J =
8.8 Hz, 1H), 7.29–7.36 (m, 4H), 7.44–7.48 (m, 1H), 7.63 (d,
J = 8.8 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 8.31
(s, 1H), 12.00 (s, 1H). 13C NMR (100 MHz, CDCl3), d (ppm): 36.8,
40.6, 73.6, 74.7, 110.1, 119.1, 120.2, 122.9, 125.7, 125.9, 126.6,
127.3, 128.3, 128.9, 129.0, 129.8, 131.4, 132.5, 138.5, 140.6, 155.9.
4.7.4. 1-((2-((1R,2S)-1-Hydroxy-1-phenyl-2-propyl)-2-methyl-
hydrazinyl)methyl)-2-naphthol, 30
In a 250 mL round-bottomed flask were added LiAlH4 (0.12 g,
3.00 mmol) and THF (8 mL). The reaction mixture was heated up
to 50 °C. A solution of (1R,2S)-salicylhydrazone (0.50 g, 1.50 mmol)
in THF (5 mL) was added to the reaction mixture dropwise in about
20 min. The reaction mixture was heated up to reflux after addition
and allowed to run at reflux for 18 h. The reaction mixture was
cooled to room temperature and then to 0 °C. Water (20 mL) was
added dropwise to the reaction mixture (highly exothermic). THF
was completely evaporated via rotary evaporation. The residue
was treated with 1 M NaOH (50 mL) and ethyl acetate (50 mL).
The aqueous layer was again extracted with ethyl acetate
(10 mL). The combined organic layer was washed with brine
(150 mL) and dried over magnesium sulfate. The solvent was com-
pletely evaporated via rotary evaporation. The residue was recrys-
tallized using hexanes and ethyl acetate (8:2). The titled compound
IR (nujol): 3490, 1620, 1377, 741 cmꢀ1
. ESI-HRMS calcd for
C21H21N2O2 (M+H)+: 333.1603. Found: 333.1605.
4.7. General procedure for the formation of hydrazones 24 and
25
In 250 mL round-bottomed flask were added toluene (110 mL),
hydrazine 9a or 22 (2.00 g, 11.1 mmol), 1-(2-hydroxy-5-methyl-
phenyl)ethanone (1.67 g, 11.1 mmol), and magnesium sulfate
(2 g). The reaction mixture was heated up to reflux and stirred
18 h at reflux. It was then allowed to cool to room temperature.
The reaction mixture was extracted with ethyl acetate (100 mL)
and brine (100 mL). The organic later was then dried over magne-
sium sulfate and filtered. The solvent was evaporated via rotary
evaporation.
was obtained as an off-white solid (97%). ½a D24
¼ þ123:4 (c 0.3,
ꢂ
CHCl3). Mp = 129–132 °C. 1H NMR (500 MHz, CDCl3), d (ppm):
0.94 (d, J = 6.7 Hz, 3H), 3.07 (s, 3H), 3.50–3.54 (m, 1H), 4.77 (d,
J = 9.3 Hz, 1H), 7.19–7.24 (m, 3H), 7.29–7.38 (m, 3H), 7.42–7.49
(m, 3H), 7.69 (d, J = 8.7 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 8.02 (d,
J = 8.7 Hz, 1H), 8.35 (s, 1H), 12.70 (s, 1H). 13C NMR (125 MHz,
CDCl3), d (ppm): 12.6, 36.7, 69.5, 109.9, 119.0, 120.1, 123.1,
126.8, 127.3, 128.2, 128.4, 128.9, 129.0, 130.4, 131.5, 135.0,
135.2, 140.8, 156.3. IR (nujol): 3230, 1620, 1376, 767 cmꢀ1. ESI-
HRMS calcd for C21H25N2O2 (M+H)+: 337.1916. Found: 337.1903.
4.7.1. 2-((E)-1-(2-((1R,2S)-1-Hydroxy-1-phenylpropan-2-yl)-2-
methylhydrazono)ethyl)-4-methylphenol, 25
The residue was purified by flash chromatography using (9:1)
hexanes/ethyl acetate. The title compound was obtained as a yellow
solid (29%). ½a 2D5
ꢂ
¼ þ59:6 (c 1.0, CHCl3). Mp = 143–146 °C. 1H NMR
(500 MHz, CDCl3), (d ppm): 1.11 (d, J = 6.7 Hz, 3H), 2.30 (s, 3H),
2.36 (s, 3H), 2.54 (s, 3H), 3.14–3.18 (m, 1H), 4.88 (d, J = 7.4 Hz, 1H),
6.88 (d, J = 8.3 Hz, 1H), 7.09 (d, J = 8.3 Hz, 1H), 7.25–7.32 (m, 6H).
13C NMR (125 MHz, CDCl3), (d ppm): 9.7, 14.4, 20.6, 42.5, 67.8,
74.5, 117.4, 118.8, 126.1, 127.1, 127.5, 128.1, 128.4, 132.4, 141.9,
158.1, 169.9. IR (nujol):3463, 1602, 1363, 761 cmꢀ1. ESI-HRMS calcd
for C19H25N2O2 (M+H)+: 313.1916. Found: 313.1908.
4.7.5. (1R,2S)-2-(1-Methyl-2-(naphthylmethyl)hydrazinyl)-1-
phenyl-1-propanol, 31
In a 500 mL round-bottomed flask were added LiAlH4 (0.22 g,
5.97 mmol) and THF (200 mL). The reaction mixture was heated
up to 50 °C. A solution of 29 (1.00 g, 2.98 mmol) in THF (50 mL)
was added to the reaction mixture dropwise in about 20 min.
The reaction mixture was heated up to reflux after addition and al-
lowed to run at reflux for 18 h. The reaction mixture was cooled to
room temperature and then to 0 °C. Water (50 mL) was added
dropwise to the reaction mixture (highly exothermic). The solvent
was removed via rotary evaporation. The residue was treated with
4.7.2. 2-((E)-1-(2-((1S,2S)-1-Hydroxy-1-phenyl-2-propyl)-2-methyl-
hydrazono)ethyl)-4-methylphenol, 24
The residue was purified by flash chromatography using (9:1)
hexanes/ethyl acetate. The title compound was obtained as a yel-
low liquid (58%). ½a D25
ꢂ
¼ ꢀ371:9 (c 1.1, CHCl3). 1H (500 MHz,
CDCl3), d (ppm): 1.01 (d, J = 6.6 Hz, 3H), 2.31 (s, 3H), 2.54 (s, 3H),
2.64 (s, 3H), 2.98–3.05 (m, 1H), 4.04 (s, 1H), 4.29 (d, J = 9.7 Hz,

S. Banerjee et al. / Tetrahedron: Asymmetry 21 (2010) 837–845
845
1 M NaOH (100 mL) and ethyl acetate (100 mL). The aqueous layer
was again extracted with ethyl acetate (50 mL). The combined or-
ganic layer was washed with brine (150 mL) and dried over mag-
nesium sulfate. The solvent was removed via rotary evaporation
and the residue was recrystallized using ethyl acetate and hexanes.
The title compound was obtained as white solid (54%).
(s, 1H). 13C NMR (125 MHz, CDCl3) (d ppm): 22.2, 26.7, 49.5, 59.3,
63.7, 74.8, 110.4, 119.1, 120.3, 122.8, 126.5, 128.3, 129.0, 129.5,
131.4, 133.8 and 156.1. IR (nujol) cmꢀ1: 3463, 1602, 1252, 765.
ESI-HRMS calcd for C17H21N2O2 (M+H)+: 285.1603. Found:
285.1600.
½
a 2D5
ꢂ
¼ þ43:4 (c 1.0, CHCl3). Mp = 95–98 °C. 1H NMR (500 MHz,
4.8.3. (S,E)-2,4-Di-tert-butyl-6-((2-(methoxymethyl)pyrrolidin-
1-ylimino)methyl)phenol, 35
Using 2-hydroxy-3,5-di-tert-butylbenzaldehyde, the residue
was purified by flash chromatography using 9:1 (hexanes/ethyl
acetate). The product was obtained as yellow solid (93%).
CDCl3), d (ppm): 0.81 (d, J = 6.7 Hz, 3H), 2.61 (s, 3H), 2.76–2.81
(m, 1H), 4.13 (s, 2H), 5.25 (s, 1H), 6.01 (s, 1H), 7.18–7.50 (m, 7H),
7.76–7.82 (m, 5H). 13C NMR (125 MHz, CDCl3), (d ppm): 3.5, 42.0,
54.1, 65.0, 77.4, 125.9, 126.1, 126.6, 127.0, 127.6, 127.7, 127.8,
127.9, 128.3, 132.8, 133.3, 134.8, 142.5. IR (nujol): 3314, 1601,
1372, 763, 701 cmꢀ1. ESI-HRMS calcd for C21H25N2O (M+H)+:
321.1967. Found: 321.1968.
½
a 2D3
ꢂ
¼ ꢀ126:5 (c 1.0, CHCl3). Mp = 95–97 °C. 1H NMR (500 MHz,
CDCl3), d (ppm): 1.30 (s, 9H), 1.45 (s, 9H), 1.84–1.87 (m, 1H),
1.96–2.07 (m, 3H), 3.41 (s, 3H), 3.49–3.54 (m, 1H), 3.58–3.61 (m,
3H), 6.96 (d, J = 2.4 Hz, 1H), 7.21 (m, J = 2.4 Hz, 1H), 7.45 (s, 1H),
7.45 (s, 1H), 11.68 (s, 1H). 13C NMR (125 MHz, CDCl3), d (ppm):
22.1, 26.6, 29.5, 31.6, 34.1, 35.0, 49.5, 59.3, 63.5, 74.5, 119.0,
4.8. General procedure for the synthesis of the hydrazones 33–
35
123.3, 123.9, 135.9, 139.3, 140.3 and 153.7. IR (nujol) cmꢀ1
:
In a 250 mL round-bottomed flask were added Enders’ hydra-
zine (1.00 g, 7.68 mmol), salicylaldehyde (1.32 g, 7.68 mmol), tolu-
ene (77 mL), and MgSO4 (2 g). The reaction mixture was heated to
reflux for 18 h and then cooled to 25 °C. A brine solution was added
and the mixture was extracted with ethyl acetate. The organic
layer was dried over MgSO4, filtered, and the solvent was removed
by rotary evaporation.
3463, 1602, 1248, 761. ESI-HRMS calcd for C21H35N2O2 (M+H+):
347.2699. Found: 347.2693.
Acknowledgments
The authors acknowledge support for this work by the donors of
the Petroleum Research Fund as administered by the American
Chemical Society (PRF 48367-B1). The NMR data collected in this
work are based, in part, upon work supported by the National Sci-
ence Foundation under major research instrumentation grant CHE-
0722385.
4.8.1. (S,E)-2-((2-(Methoxymethyl)pyrrolidinyl-1-imino)methyl)-
phenol, 33
The solvent was evaporated via rotary evaporation and the res-
idue was purified by flash chromatography using 95:05 (hexanes/
ethyl acetate). The product was obtained as yellow liquid (57%).
References
½
a 2D3
ꢂ
¼ ꢀ202:9 (c 1.1, CHCl3). 1H NMR (400 MHz, CDCl3) d (ppm):
1. (a) Mino, T.; Suzuki, A.; Yamashita, M.; Narita, S.; Shirae, Y.; Sakamoto, M.;
Fujita, T. J. Organomet. Chem. 2006, 691, 4297–4303; (b) Mino, T.; Shiotsuki, M.;
Yamamoto, N.; Suenaga, T.; Sakamoto, M.; Fujita, T.; Yamashita, M. J. Org. Chem.
2001, 66, 1795.
2. Arai, T.; Endo, Y.; Yanagisawa, A. Tetrahedron: Asymmetry 2007, 18, 165–169.
3. Tanaka, T.; Yasuda, Y.; Hayashi, M. J. Org. Chem. 2006, 71, 7091–7093.
4. Parrott, R. W.; Dore, D. D.; Chandrashekar, S. P.; Bentley, J. T.; Morgan, B. S.;
Hitchcock, S. R. Tetrahedron: Asymmetry 2008, 19, 607–611.
1.76–1.83 (m, 1H), 1.90–2.04 (m, 3H), 2.93–2.99 (m, 1H), 3.37 (s,
3H), 3.45–3.60 (m, 4H), 6.81 (td, J = 7.8 Hz, 1.0 Hz, 1H), 6.90 (dd,
J = 7.8 Hz, J = 1.0 Hz, 1H), 7.05–7.12 (m, 2H), 7.33 (s, 1H), 11.44 (s,
1H). 13C NMR (100 MHz, CDCl3) (d ppm): 21.8, 26.4, 48.7, 59.0,
63.1, 74.4, 116.2, 118.9, 119.9, 136.6 and 156.5. IR (neat) cmꢀ1
:
3463, 3002, 2998, 1602, 1252, 761. ESI-HRMS calcd for
C13H19N2O2 (M+H+): 235.1447. Found: 235.1449.
5. Groeper, J. A.; Hitchcock, S. R.; Ferrence, G. M. Tetrahedron: Asymmetry 2006, 17,
2884–2889.
6. Hitchcock, S. R.; Nora, G. P.; Casper, D. M.; Squire, M. D.; Maroules, C. D.;
Ferrerence, G. M.; Szczepura, L. F.; Standard, G. M. Tetrahedron 2001, 57, 9789–
9798.
4.8.2. (S,E)-1-((2-(Methoxymethyl)pyrrolidin-1-ylimino)methyl)-
naphthalen-2-ol, 34
7. Takahashi and co-workers studied Ephedra based hydrazones in an unrelated
study and determined by 1H NMR spectroscopy that these compounds have a
strong preference for the formation of the trans-configured product. Please see:
(a) Takahayashi, H.; Tomita, K.; Noguchi, H. Chem. Pharm. Bull. 1981, 29, 3387;
(b) Takahayashi, H.; Inagaki, H. Chem. Pharm. Bull. 1982, 30, 922.
8. X-ray quality crystals were grown by evaporation of an ethyl acetate/hexanes
solution of the compound. Crystallographic data (excluding structure factors)
for 14 has been deposited with the Cambridge Crystallographic Data Center as
supplementary publication number CCDC 770158.
Using 2-hydroxy-1-naphthaldehyde the solvent was evaporated
via rotary evaporation and the residue was purified by flash chro-
matography using 99:1 (hexanes/ethyl acetate). The product was
obtained as yellow solid (92%).
½
a 2D3
ꢂ
¼ ꢀ225:6 (c 1, CHCl3).
Mp = 78–80 °C. 1H NMR (500 MHz, CDCl3), d (ppm): 1.80–1.90
(m, 1H), 1.97–2.09 (m, 3H), 3.11 (q, J = 7.3 Hz, 1H), 3.42 (s, 3H),
3.55–3.62 (m, 3H), 3.68 (p, J = 5.4 Hz, 1H), 7.18 (d, J = 8.9 Hz, 1H),
7.29 (t, J = 7.5 Hz, 1H), 7.43–7.46 (m, 1H), 7.64 (d, J = 8.9 Hz, 1H),
7.74 (d, J = 7.8 Hz, 1H), 7.98 (d, J = 8.6 Hz, 1H), 8.21 (s, 1H), 12.60
9. (a) Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D. Tetrahedron 2002, 58,
2253; (b) Vicario, J. L.; Job, A.; Wolberg, M.; Muller, M.; Enders, D. Org. Lett. 2002,
4, 1023.