Reductive alkylation of hydrazine derivatives with α-picoline-borane and its applications to the syntheses of useful compounds related to active pharmaceutical ingredients

Article abstract of DOI:10.1055/s-0033-1340484

An efficient method for the direct reductive alkylation of hydrazine derivatives with α-picoline-borane has been developed to synthesize a variety of N-alkylhydrazine derivatives. This method provided N,N-dialkylhydrazine derivatives and N-monoalkylhydrazine derivatives upon fine-tuning of the substrates and the reagent equivalency in a one-pot manner. The method was applied to the synthesis of active pharmaceutical ingredients of therapeutic drugs such as isocarboxazid.

Full text of DOI:10.1055/s-0033-1340484

PAPER
▌455
paper
Reductive Alkylation of Hydrazine Derivatives with α-Picoline-Borane and
Its Applications to the Syntheses of Useful Compounds Related to Active
Pharmaceutical Ingredients
α-PicBH -Mediated Reductive Alkylation of Hydrazines
a
a
a
a
b
c
3
Yasushi Kawase, Takehiro Yamagishi, Jun-ya Kato, Teruo Kutsuma, Tadashi Kataoka, Takeo Iwakuma,
Tsutomu Yokomatsu*a
a
School of Pharmacy, Tokyo University of Pharmacy & Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Fax +81(42)6763239; E-mail: yokomatu@toyaku.ac.jp
b
Yokohama College of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama, Kanagawa 245-0066, Japan
c
Fine Chemical Department, Chemicrea Incorporation, Quattro Muromachi Bldg. 9F., 4-1-6, Nihonbashi Muromachi, Chuo-ku, Tokyo
103-0022, Japan
Received: 12.09.2013; Accepted after revision: 03.12.2013
Abstract: An efficient method for the direct reductive alkylation of
hydrazine derivatives with α-picoline-borane has been developed to
synthesize a variety of N-alkylhydrazine derivatives. This method
N
provided N,N-dialkylhydrazine derivatives and N-monoalkylhydra-
zine derivatives upon fine-tuning of the substrates and the reagent
equivalency in a one-pot manner. The method was applied to the
synthesis of active pharmaceutical ingredients of therapeutic drugs
such as isocarboxazid.
O
t-Bu
OH
Ph
O
H
H
N
N
N
OMe
HO
MeO
N
N
H
H
O
t-Bu
O
OH
Key words: alkylation, hydrazones, reduction, hydrazines, α-pico-
line-borane
OH
1
O
H
N
HO
N
H
NH2
O
Hydrazine derivatives are widely used in the pharmaceu-
tical, agricultural, photographic, and dyestuff industries as
well as precursors for heterocyclic compounds such as
pyrazoles, pyrazines, and indoles.1 In particular, they are
important compounds in the pharmaceutical field, be-
cause many compounds possessing a hydrazine moiety
show various pharmacological activities and some of
them are clinically used as active pharmaceutical ingredi-
ents (APIs) of therapeutic drugs (Figure 1). Atazanavir
(1), which has a hydrazine-based peptidomimetic struc-
ture and shows potent inhibitive activity against HIV pro-
tease, is applied as a therapeutic agent against AIDS.2
Benserazide (2), an acylhydrazide compound, inhibits
DOPA decarboxylase to potentiate the anti-Parkinsonian
effect of levodopa, and has been used as a therapeutic
agent for Parkinsonism in combination with levodopa.3
Isocarboxazid (3) is used as an antidepressant drug due to
its monoamine oxidase inhibition.4 N-Aminoazacycles,
which possess an amino functionality on the nitrogen
atom of cyclic amines, may also be new drug candidates.5
For example, N-aminomorpholine derivative 4 has been
studied as an oral-administrative antifungal agent.5c
2
H
N
Ph
N
H
Ph
N
O
3
O
N N
4
Figure 1 Hydrazine-based active pharmaceutical ingredients
ly applied for the N-alkylation of the hydrazine moieties.
The isolated hydrazones are generally reduced by metal
hydride reagents or by catalytic hydrogenation under the
appropriate conditions.7,8 Although these stepwise meth-
ods steadily provided the target N-alkylhydrazines, the
methods require isolation of the hydrazones and, in some
cases, highly toxic or explosive metal hydride reagents
such as sodium cyanoborohydride and pyridine-borane
for the reduction of the isolated hydrazones.9 Therefore,
there is still room in improvement for N-alkylation of hy-
drazines from a process chemistry point of view.
To discover the method for selective N-alkylation of hy-
drazines applicable to the industrial processes, we consid-
ered reductive alkylation of hydrazines with carbonyl
compounds using a stable and nontoxic metal hydride re-
agent.9 The reductive alkylation can be conducted in a
one-pot manner without isolation of hydrazones and
should have some merits for the industrial preparation of
N-alkylhydrazines on a large scale. We have recently re-
ported on a safe and scalable procedure for the preparation
For the syntheses of these APIs, highly selective and pre-
parative methods for the N-alkylation of simple hydra-
zines are required.6 Strategies for the sequent preparation
and reduction of hydrazones, prepared from the corre-
sponding hydrazines and carbonyl compounds, are usual-
SYNTHESIS 2014, 46, 0455–0464
Advanced online publication: 02.01.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-13408484; Art ID: SS-2013-F0602-OP
© Georg Thieme Verlag Stuttgart · New York

456
Y. Kawase et al.
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of α-picoline-borane (α-PicBH3)10 and its applications to
the synthesis of alkoxyamine derivatives11 and N-benzyl-
amino acid derivatives through reductive alkylation se-
quences.12 In this paper, we wish to describe the α-
PicBH3-mediated reductive alkylation of hydrazine deriv-
atives (Scheme 1) as an extension of the previous re-
ports.13,14 Furthermore, in regard to the application of our
method, we will also report on the efficient syntheses of 3
and an important synthetic intermediate of 1.
R1
R2
O
O
O
H
NH2
N
R1
Ph
N
H
α-PicBH3
3 M HCl (0–4 equiv)
Ph
O
N
H
R2
MeOH–AcOH (10:1)
r.t.
5
6
R1
R2
N
O
R2
Ph
N
N
R2
H
R1
Ph
N
H
R1
R1
R1
R2
R3
R4
7
8
aldehydes or ketones
N
NH2
N
N
R2
Scheme 2 Reductive alkylation of benzohydrazide 5
(α-PicBH3)
N
When the reductive alkylation of 5 with benzaldehyde
was carried out under the same conditions, the desired N′-
benzylbenzohydrazide (6e) was obtained in a 35% yield
(entry 5). A large amount of unreduced hydrazone 8e was
recovered in a 43% yield from this reaction. Even though
the reaction was carried out by prolongation of the reac-
tion time from 2 to 7 hours, the yield of 6e was not im-
proved (entry 5 vs 6).
BH3
Scheme 1 Reductive alkylation of hydrazines with α-PicBH3
Reductive Alkylation of Acylhydrazines
We first tried to establish α-PicBH3-mediated reductive
alkylation of benzohydrazide (5) with aliphatic and aro-
matic carbonyl compounds (Scheme 2 and Table 1). The
reductive alkylation was carried out under the conditions
reported previously.10,13 Thus, a mixture of 5 and one
equivalent of cyclohexanecarbaldehyde was treated with
α-PicBH3 (1.5 equiv) in a mixture of methanol–acetic acid
(10:1) at room temperature for 2 hours to give the corre-
sponding N′-cyclohexylmethylbenzohydrazide (6a) in a
64% yield, along with 5% of N′,N′-dialkylbenzohydrazide
7a (Table 1, entry 1). Similar results were observed for the
reaction with n-hexanal under the same conditions (entry
2). On the other hand, the reactions of the aliphatic ke-
tones gave the corresponding N′-monoalkylbenzohydra-
zides 6c and 6d in excellent yields under these conditions,
respectively (entries 3 and 4). It is noteworthy that neither
dialkylated compounds nor 5 were detected in these cases.
We have previously reported that reduction of oxime
ethers with α-PicBH3 to alkoxyamines was promoted by
the addition of hydrochloric acid.11 On the basis of these
findings, we examined the reductive alkylation of 5 with
benzaldehyde in the presence of 4 equivalents of 3 M
aqueous HCl (entry 7). As expected, this reaction pro-
ceeded rapidly to give 6e in a 78% yield, along with 7%
of dialkylation product 7e. For the reaction with acetophe-
none, addition of 3 M aqueous HCl was also required for
promotion of the reaction to give N-alkylated product 6f
in a good yield similar to the reaction with benzaldehyde
(entry 8 vs 9).
The reasons why hydrochloric acid accelerates the reduc-
tive alkylation with aromatic compounds are speculated
as follows: 1) Complete protonation on the nitrogen of hy-
Table 1 Product Distribution of the α-PicBH3-Mediated Reductive Alkylation of 5 with Various Carbonyl Compounds
Entry
R1
R2
HCl (equiv)
Time (h)
6 (Yield %)
7 (Yield %)
8 (Yield %)
1
2
3
4
5
6
7
8
9
c-C6H11
n-C5H11
c-C6H11
n-Pr
Ph
H
0
0
0
0
0
0
4
0
4
2
2
2
2
2
7
2
2
2
6a (64)a
6b (49)b
6c (94)
6d (99)
6e (35)
6e (14)
6e (78)c
6f (57)
6f (70)
7a (5)
7b (5)
7c (0)
7d (0)
7e (0)
7e (0)
7e (7)
7f (0)
7f (0)
8a (0)
8b (0)
8c (0)
8d (0)
8e (43)
8e (64)
8e (0)
8f (21)
8f (0)
H
Me
n-Pr
H
Ph
H
Ph
H
Ph
Me
Me
Ph
a Unreacted 5 was recovered in a 5% yield.
b Unreacted 5 was recovered in a 26% yield.
c Unreacted 5 was recovered in a 7% yield.
Synthesis 2014, 46, 455–464
© Georg Thieme Verlag Stuttgart · New York

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α-PicBH3-Mediated Reductive Alkylation of Hydrazines
457
drazones with a strong acid is necessary for the smooth re-
duction of hydrazones derived from aromatic compounds,
because the C=N bond of hydrazones derived from aro-
matic carbonyl compounds is less reactive than that of hy-
drazones derived from aliphatic carbonyl compounds
against reduction with α-PicBH3 due to their electronic
nature. 2) Hydrochloric acid enhances the solubility of hy-
drazones in the solvent to accelerate the reactions. In the
reaction of benzaldehyde and acetophenone, the heteroge-
neous reaction mixture turns to a clear solution upon ad-
dition of hydrochloric acid. Although a detailed
investigation is still needed, we believe that the latter issue
should be a main factor in promotion of the reactions, be-
cause the reaction of some aromatic aldehyde-derived hy-
drazone soluble in methanol–acetic acid proceeded
smoothly without addition of hydrochloric acid as will be
described later.
Table 2 Conditions and Yields of Reductive Alkylation of Morpho-
lin-4-amine (9) with α-PicBH3
Entry
R
Conditionsa,b,c Productd Yield (%)
1
2
Ph
A
B
C
A
B
C
A
B
C
B
C
B
10a
10a
10a
10b
10b
10b
10c
10c
10c
10d
10d
10e
79
85
82
87
72
86
89
85
78
76
91
74
Ph
3
Ph
4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
(E)-PhCH=CH
(E)-PhCH=CH
c-C6H11
5
6
7
8
9
10
11
12
Reductive Alkylation of N-Aminoazacycles
Next, this method was extended to the N′-alkylation of
N,N-dialkylhydrazines to prepare N-(dialkylamino)azacy-
cles, which show various biological activities as described
in the introduction.5 These compounds are usually pre-
pared by reduction of the isolated hydrazones with a re-
ducing reagent such as NaBH(OCOMe)3.8 To develop a
more facile method, the reductive alkylation of morpho-
lin-4-amine (9) with various aldehydes was examined us-
ing α-PicBH3 as a model study (Scheme 3 and Table 2).
13
14
15
A
B
C
10f
10f
10f
90
56
66
O
O
a Conditions A: MeOH–AcOH (10:1) for solvent and 6 M aq HCl (1.5
equiv) as an additive.
b Conditions B: MeOH for solvent and 6 M aq HCl (1.75 equiv) as an
additive.
c Conditions C: MeOH for solvent and (COOH)2 (3.0 equiv) as an ad-
ditive.
d All products were isolated as the oxalate.
RCHO, α-PicBH3
O
N NH2
O
N
N
R
H
an 85% yield.15 It is noteworthy that 6 M aqueous HCl
could be replaced by readily handling oxalic acid to pro-
mote the reductive alkylation giving 10a in an 82% yield
(entry 3). These procedures can be applicable to the reduc-
tive alkylation with aromatic aldehydes bearing electron-
withdrawing or electron-donating groups as well as ali-
phatic aldehydes (entries 4–15). Since all products are
prone to be oxidized to the corresponding hydrazones
upon standing in an atmosphere of air, they were isolated
as the stable oxalates.
9
10
Scheme 3 Reductive alkylation of morpholin-4-amine 9 with α-
PicBH3
Initially, a mixture of 9 and benzaldehyde was treated
with 1.5 equivalents of α-PicBH3 in methanol–acetic acid
(10:1) at room temperature for 2 hours. However, the re-
ductive alkylation did not take place, while the formation
of the corresponding hydrazone proceeded. On the other
hand, the desired product 10a was obtained in a 79%
yield, when 9 was treated with benzaldehyde and α-
PicBH3 in methanol–acetic acid (10:1) for 2 hours at room
temperature and subsequently the resulting mixture was
treated with 1.5 equivalents of 6 M aqueous HCl for 1
hour (Table 2, entry 1). This reaction also proceeded in
methanol containing 6 M aqueous HCl without acetic acid
as a co-solvent (entry 2). Thus, a mixture of 9 and benzal-
dehyde in methanol was stirred in the presence of 0.3
equivalent of 6 M aqueous HCl at room temperature for 2
hours, followed by treatment of α-PicBH3 (1.5 equiv) and
6 M aqueous HCl (1.5 equiv) for 1.5 hours to give 10a in
In an effort to survey the generality of the reductive alkyl-
ation of N-aminoazacycles, the respective reactions of 9
with acetophenone and pentan-3-one were examined
(Scheme 4). However no desired products were observed
upon conducting the reactions under the conditions C us-
ing oxalic acid and methanol as an additive and the sol-
vent, respectively. On the other hand, we found that the
desired reaction proceeded to give 10g and 10h in 68%
and 63% yield, respectively, when the reaction was con-
ducted in methanol–acetic acid in the presence of 6 M
aqueous HCl (conditions A).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 455–464

458
Y. Kawase et al.
PAPER
1) R1CHO, (COOH)2 (0.3 equiv)
MeOH, r.t., 1 h
2) α-PicBH3, (COOH)2 (0.7 equiv)
r.t., 1 h
R1
O
R1
R2
R2
H
R2
R1
O
N N
O
N NH2
α-PicBH3
X
N
NH2
X
N N
10g R1 = Ph, R2 = Me
3) R2CHO (1.5 equiv)
r.t., 2 h
9
10h R1 = R2 = Et
9 X = O
13 X = CH2
11 and 14
Scheme 4 α-PicBH3-mediated reductive alkylation of morpholin-4-
amine (9) with ketones
Scheme 6 Reductive double alkylation of 9 and 13 in a one-pot syn-
thesis
Synthesis of Symmetrical and Unsymmetrical
Table 3 Yields for the Double Reductive Alkylation of 9 and 13
N-(N′,N′-Dialkylamino)azacycles
Entrya R1
R2
X
Product Yield
(%)
As described in the introduction, some unsymmetrical
N-(N′,N′-dialkylamino)azacycles show interesting biolog-
ical activities and are used as APIs. Double reductive al-
kylation of the primary amine of N-aminoazacycles
should be a useful method to introduce appropriate func-
tional groups to the nitrogen atom. Therefore, we tried the
double reductive alkylation of 9 and N-aminopiperidine
(13) using α-PicBH3.
1
2
3
4
4-MeC6H4
4-MeC6H4
4-MeC6H4
Ph
O
O
O
O
11b
11b
11c
11d
72
39b
69
69
4-MeC6H4
Ph
4-ClC6H4
4-ClC6H4
O
O
O
O
O
O
O
O
First, the reductive alkylation of the 10c-oxalate, prepared
in the previous section, was examined to verify the effica-
cy of the reductive alkylation at the secondary amine de-
rived from 9 through our method (Scheme 3). Thus, a
mixture of 10c-oxalate and piperonal was treated with 1.5
equivalents of α-PicBH3 for 2 hours in methanol in the
presence of 1 equivalent of triethylamine to give 11a in an
84% yield. Compound 11a could be also prepared in a
69% yield, when the isolated hydrazone 12 was reduced
with α-PicBH3 in the presence of oxalic acid in methanol
and subsequently the resulting mixture was treated with
piperonal in the same flask (Scheme 5).
5
6
7
O
O
11e
11f
66
66
43
Et
O
O
CH2 14
8
9
naphthalen-1-yl (E)-PhCH=CH
(E)-PhCH=CH Et
O
O
11g
11h
44
44
a All reactions were carried out in MeOH in the presence of oxalic
acid (1.0 equiv) and α-PicBH3 (1.5 equiv), unless otherwise stated.
b The yield refers to the reaction using 6 M aqueous HCl as an acid
promoter.
piperonal
10c-oxalate
O
N
N
Et3N, α-PicBH3
MeOH, r.t., 2 h
O
O
84%
11a
The results showed that this method gave not only sym-
metrical N-(N′,N′-dialkylamino)azacycles 11b–e and 14
but also unsymmetric N-(N′,N′-dialkylamino)azacycles
11f–h in good to moderate yields by fine-tuning the com-
bination and equivalency of aromatic and aliphatic alde-
hydes in the individual reductive alkylation step.16
1) α-PicBH3 (1.5 equiv)
(COOH)2 (1.5 equiv)
MeOH, r.t., 1 h
69%
2) piperonal (2 equiv)
r.t. 3 h
4-MeC6H4CHO
9
O
N N
MeOH–AcOH
r.t., 2 h
Application to the Synthesis of APIs
12
89%
As for the application of the method to the synthesis of
API-related compounds, we tried to synthesize isocarbox-
azid (3) and the important segment 17 of atazanavir (1)
(Scheme 7). Isocarboxazid (3) is usually synthesized by
aminolysis of 5-methyl-3-isoxazole carboxylic acid esters
with benzylhydrazine or reduction of the benzhydrazone
derived from 5-methyl-3-isoxazole carboxazide with
LiAlH4.4 We have synthesized 3 in a 83% yield through
reductive alkylation method using α-PicBH3 in methanol–
acetic acid in the presence of 6 M aqueous HCl.
Scheme 5 Synthesis of 11a from 10c-oxalate and amine 9
The above results suggest that oxalic acid is a reliable acid
to promote our double reductive N-alkylation of hydra-
zines. As such, this method was expanded to the one-pot
synthesis of N-(N′,N′-dialkylamino)azacycles 11 and 14
through sequential double reductive alkylation of N-ami-
noazacycles 9 and 13 (Scheme 6 and Table 3).15
Synthesis 2014, 46, 455–464
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α-PicBH3-Mediated Reductive Alkylation of Hydrazines
459
O
H
O
N
Ph
NH2
α-Pic-BH3 (1 equiv)
N
N
H
H
+
PhCHO
N
N
6 M HCl (4 equiv)
O
O
MeOH–AcOH (10:1), r.t., 2 h
83%
3
15
N
α-Pic-BH3 (1 equiv)
H
N
BocNHNH2
+
Boc
N
MeOH–AcOH, r.t., 2 h
76%
N
H
OHC
18
17
16
Scheme 7 Synthesis of API-related compounds
1H NMR (400 MHz, CDCl3): δ = 0.98 (2 H, m), 1.25 (3 H, m), 1.56
(1 H, m), 1.72 (3 H, m), 1.82 (2 H, m), 2.79 (2 H, d, J = 6.7 Hz),
7.43 (2 H, m), 7.50 (1 H, m), 7.74 (2 H, m).
13C NMR (100 MHz, CDCl3): δ = 26.0, 26.6, 31.3, 36.7, 59.0,
126.8, 128.7, 131.8, 133.0, 167.1.
MS (ESI, MeOH): m/z = 233 ([M + H]+).
HRMS-ESI: m/z [M + H]+ calcd for C14H21N2O: 233.1654; found:
Compound 17 has usually been synthesized through the
catalytic hydrogenation of the hydrazone derived from al-
dehyde 16 and tert-butoxycarbonylhydrazide (18).2 To
synthesize 17 more efficiently, reductive alkylation of 18
with the benzaldehyde derivative 16 was carried out in
methanol–acetic acid for 2 hours using α-PicBH3 as a re-
ducing reagent. This reaction proceeded homogeneously
and was completed without addition of hydrochloric acid
to give 17 in a 76% yield.
233.1653.
7a
Yield: 30 mg (5%); colorless oil.
In conclusion, an efficient synthesis of N-alkylhydrazine
derivatives by reductive alkylation with α-PicBH3 and its
application to the syntheses of two API-related com-
pounds have been achieved. We believe that this study
will be of value for the development of new processes for
the synthesis of hydrazine derivatives as well as for the
discovery of new hydrazine-based compounds showing
interesting biological activity.
1H NMR (400 MHz, CDCl3): δ = 0.91 (4 H, m), 1.23 (6 H, m), 1.46
(2 H, m), 1.66 (6 H, m), 1.88 (4 H, m), 2.71 (3 H, d, J = 7.1 Hz),
6.81 (1 H, br d), 7.26–7.49 (3 H, m), 7.70 (1 H, m).
13C NMR (100 MHz, CDCl3): δ = 26.1, 26.8, 36.3, 64.8, 126.9,
128.6, 128.7, 131.4, 134.4, 166.2.
MS (ESI, MeOH): m/z = 329 ([M + H]+).
HRMS-ESI: m/z [M + H]+ calcd for C21H33N2O: 329.2593; found:
329.2581.
All melting points are uncorrected. IR spectra were measured di-
rectly between a NaCl plate or as KBr disks. 1H NMR spectra (400
or 500 MHz) and 13C NMR spectra (100 or 125 MHz) were mea-
sured for a solution in CDCl3, CD3OD, or D2O. The chemical shift
N′-(1-Hexyl)benzohydrazide (6b) and N′,N′-Bis(1-hexyl)benzo-
hydrazide (7b)
Prepared from hexanal (188 mg, 1.88 mmol) and 5 (256 mg, 1.88
mmol) in an analogous manner for the preparation of 6a and 7a.
1
data for each signal on H NMR are given in units of δ relative to
CHCl3 (δ = 7.26), CH3OH (δ = 3.30), or H2O (δ = 4.79). For 13C
NMR spectra, the chemical shifts are recorded relative to CDCl3
(δ = 77.0), CD3OD (δ = 49.0), or (COOH)2 (δ = 162.3). Mass spec-
tra were measured by electrospray ionization or direct insertion at
70 eV.
6b
Yield: 203 mg (49%); colorless crystals; mp 163–165 °C.
IR (KBr): 3272, 1627 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.88 (3 H, t, J = 6.7 Hz), 1.28 (6
H, m), 1.53 (2 H, m), 2.93 (2 H, t, J = 7.2 Hz), 7.43 (2 H, m), 7.51
(1 H, m), 7.75 (2 H, m).
13C NMR (100 MHz, CDCl3): δ = 14.0, 22.5, 26.8, 28.0, 31.7, 52.4,
126.8, 128.6, 131.7, 132.9, 167.2.
MS (ESI, MeOH): m/z = 221 ([M + H]+).
HRMS-ESI: m/z [M + H]+ calcd for C13H21N2O: 221.1654; found:
N′-(Cyclohexylmethyl)benzohydrazide (6a) and N′,N′-Bis(cy-
clohexylmethyl)benzohydrazide (7a); Typical Procedure
To a solution of cyclohexanecarbaldehyde (211 mg, 1.88 mmol)
and 5 (256 mg, 1.88 mmol) in MeOH (5 mL) were added AcOH (0.5
mL) and α-PicBH3 (201 mg, 1.88 mmol) at 0 °C. The mixture was
stirred for 2 h at r.t. and concentrated in vacuo. The residue was
treated with 10% aq HCl (10 mL) at 0 °C and stirred at r.t. for 30
min. The mixture was basified with 25% aq Na2CO3 (10 mL) and
extracted with EtOAc (3 × 10 mL). The combined extracts were
washed with brine (3 × 10 mL), dried (MgSO4), filtered, and the fil-
trate was concentrated in vacuo. The residue was purified by silica
gel column chromatography (n-hexane–EtOAc, 20:1 → 10:1 → 3:1
and EtOAc–MeOH, 20:1) to give 6a and 7a, along with 16% of un-
reacted 5.
221.1637.
7b
Yield: 29 mg (5%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 0.87 (6 H, t, J = 6.8 Hz), 1.11–
1.31 (12 H, m), 1.53 (4 H, br quint, J = 7.2 Hz), 2.87 (4 H, t, J = 7.3
Hz), 7.40–7.45 (2 H, m), 7.48–7.49 (1 H, m), 7.73–7.77 (2 H, m).
13C NMR (100 MHz, CDCl3): δ = 14.0 (2 C), 22.6 (2 C), 26.9 (2 C),
27.0 (2 C), 31.7 (2 C), 58.2 (2 C), 126.9 (2 C), 128.6 (2 C), 131.5,
134.1, 166.6.
6a
Yield: 277 mg (64%); colorless crystals; mp 93–94 °C.
MS (ESI, MeOH): m/z = 305 ([M + H]+).
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HRMS-ESI: m/z [M + H]+ calcd for C19H33N2O: 305.2593; found:
305.2614.
13C NMR (100 MHz, CDCl3): δ = 59.3, 126.7 (2 C),127.5 (2 C),
128.4 (2 C), 128.5 (2 C), 129.3 (2 C), 134.0, 137.4, 167.3.
MS (ESI, MeOH): m/z = 317 ([M + H]+).
N′-(1-Cyclohexylethyl)benzohydrazide (6c)
Prepared from 1-cyclohexylethanone (237 mg, 1.88 mmol) and 5
(256 mg, 1.88 mmol) in an analogous manner for the preparation of
6a; yield: 434 mg (94%); colorless oil.
IR (neat): 3320, 1632 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.06 (3 H, d, J = 6.5 Hz), 1.08–
1.28 (4 H, m), 1.41–1.46 (1 H, m), 1.67–1.70 (1 H, m), 1.76–1.80 (5
H, m), 2.91 (1 H, quint, J = 6.5 Hz), 7.42–7.46 (2 H, m), 7.49–7.52
(1 H, m), 7.73–7.76 (2 H, m).
13C NMR (100 MHz, CDCl3): δ = 15.2, 26.4, 26.5, 26.6, 27.9, 29.8,
41.5, 60.5, 126.8 (2 C), 128.6 (2 C), 131.7, 133.0, 167.3.
MS (ESI, MeOH): m/z = 247 ([M + H]+).
HRMS-ESI: m/z [M + H]+ calcd for C15H23N2O: 247.1810; found:
HRMS-ESI: m/z [M + H] calcd for C21H21N2O: 317.1654; found:
317.1642.
N′-(1-Phenylethyl)benzohydrazide (6f)
Prepared from acetophenone (226 mg, 1.88 mmol) and 5 (256 mg,
1.88 mmol) in an analogous manner for the preparation of 6e; yield:
316 mg (70%); colorless oil.
IR (neat): 3308, 1632 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.44 (3 H, d, J = 6.6 Hz), 4.26 (1
H, q, J = 6.6 Hz), 7.26–7.36 (1 H, m), 7.37–7.40 (6 H, m), 7.41–
7.43 (1 H, m), 7.60–7.63 (2 H, m).
13C NMR (100 MHz, CDCl3): δ = 21.2, 60.0, 126.8 (2 C), 127.2 (2
C), 127.6 (2 C), 128.57 128.60 (2 C), 137.7, 132.9, 143.1, 167.3.
247.1828.
MS (ESI, MeOH): m/z = 241 ([M + H]+).
N′-(Heptan-4-yl)benzohydrazide (6d)
HRMS-ESI: m/z [M + H]+ calcd for C15H17N2O: 241.1341; found:
241.1343.
Prepared from heptan-4-one (215 mg, 1.88 mmol) and 5 (256 mg,
1.88 mmol) in an analogous manner for the preparation of 6a; yield:
439 mg (99%); colorless oil.
N-Benzylmorpholin-4-amine Oxalate (10a);18 Typical Proce-
dures
IR (neat): 3289, 1632 cm–1.
Conditions A: A mixture of benzaldehyde (106 mg, 1 mmol) and 9
(102 mg, 1 mmol) in MeOH–AcOH (10:1, 3 mL) was stirred for 2
h at r.t. To the mixture was added α-PicBH3 (160 mg, 1.5 mmol) and
6 M aqueous HCl (0.25 mL, 1.5 mmol). After stirring for 1.5 h at
r.t., the mixture was treated with 6 M aq HCl (0.25 mL, 1.5 mmol)
for 15 min at r.t. After removal of the solvents by evaporation in
vacuo, the residue was diluted with CHCl3 (10 mL) and the organic
layer was washed with 10% aq NaHCO3 (10 mL). The aqueous lay-
er was extracted with CHCl3 (2 × 5 mL), the combined organic lay-
ers were dried (MgSO4), filtered, and the filtrate was concentrated
in vacuo. The residual oil was diluted with xylene (5 mL). The vol-
atile components of the mixture were evaporated in vacuo to re-
move α-picoline. The residue was dissolved in Et2O (2 mL) and the
solution was treated with a solution of oxalic acid (135 mg, 1.5
mmol) in Et2O (6 mL). The resulting precipitate was collected by
filtration to give the oxalate of 10a; yield: 222 mg (79%); colorless
plates; mp 156–157 °C.
1H NMR (400 MHz, CDCl3): δ = 0.90–0.94 (6 H, m), 1.37–1.46 (8
H, m), 2.92 (1 H, m), 7.39–7.43 (2 H, m), 7.48–7.49 (1 H, m), 7.75–
7.78 (2 H, m).
13C NMR (100 MHz, CDCl3): δ = 14.3, 18.9, 34.9, 59.9, 126.9 (2
C), 128.5 (2 C), 131.6, 133.0, 167.3.
MS (ESI, MeOH): m/z = 235 ([M + H]+).
HRMS-ESI: m/z [M + H]+ calcd for C14H23N2O: 235.1810; found:
235.1793.
N′-Benzylbenzohydrazide (6e)17 and N′,N′-Dibenzylbenzohy-
drazide (7e)
To a solution of benzaldehyde (200 mg, 1.88 mmol) and 5 (256 mg,
1.88 mmol) in MeOH (5 mL) was added AcOH (0.5 mL) at 0 °C.
The mixture was stirred for 1 h at r.t. The resulting mixture was
treated with α-PicBH3 (201 mg, 1.88 mmol) and stirred for 5 min at
the same temperature. To the mixture was added 3 M aq HCl (2.51
mL, 7.52 mmol) at 0 °C and the mixture was stirred for 30 min at
r.t. The reaction was quenched with 25% aq Na2CO3 (10 mL) and
extracted with EtOAc (3 × 20 mL). The combined extracts were
washed with brine (10 mL), dried (MgSO4), filtered, and the filtrate
was concentrated in vacuo. The residue was purified by silica gel
column chromatography (n-hexane–EtOAc, 10:1–1:20) to give 6e
and 7e along with 7% of 5.
1H NMR (500 MHz, D2O): δ = 2.76 (4 H, br s), 3.41 (4 H, br s), 3.92
(2 H, s), 7.01 (5 H, s).
13C NMR (125 MHz, D2O): δ = 56.5, 59.7, 72.3, 136.3, 136.7,
137.2, 162.3.
MS (free base, EI): m/z = 192 (M+), 101 (base peak).
Anal. Calcd for C13H18N2O5: C, 55.31; H, 6.43; N, 9.92. Found: C,
55.22; H, 6.49; N, 9.94.
6e
Conditions B: To a mixture of benzaldehyde (106 mg, 1 mmol) and
9 (102 mg, 1 mmol) in MeOH (3 mL) was added 6 M aq HCl (0.05
mL, 0.3 mmol) and the mixture was stirred for 2 h at r.t. To the re-
sulting mixture was successively added α-PicBH3 (160 mg, 1.5
mmol) and 6 M aq HCl (0.25 mL, 1.5 mmol). After stirring for 1.5
h at r.t., the mixture was treated with 6 M aq HCl (0.25 mL, 1.5
mmol) and stirred for 15 min at r.t. After removal of MeOH by
evaporation in vacuo, the residue was diluted with CHCl3 (10 mL)
and the organic layer was washed with 10% aq NaHCO3 (5 mL).
The aqueous layer was extracted with CHCl3 (2 × 5 mL), the com-
bined organic layers were dried (MgSO4), filtered, and the filtrate
was concentrated in vacuo. The residual oil was diluted with xylene
(5 mL) and the volatile components of the mixture were evaporated
in vacuo to remove α-picoline. The residue was dissolved in Et2O (2
mL) and the solution was treated with a solution of oxalic acid (135
mg, 1.5 mmol) in Et2O (6 mL). The resulting precipitate was col-
lected by filtration to give the oxalate of 10a (240 mg, 85%) as col-
orless plates.
Yield: 333 mg (78%); colorless crystalline powder; mp 114–
116 °C.
IR (KBr): 3281, 1637 cm–1.
1H NMR (400 MHz, CDCl3): δ = 4.09 (2 H, s), 7.25–7.45 (7 H, m),
7.49 (1 H, m), 7.68–7.69 (2 H, m).
13C NMR (100 MHz, CDCl3): δ = 56.0, 128.6 (2 C), 127.7, 128.6 (2
C), 128.7 (2 C), 129.1 (2 C), 131.9, 132.9, 137.5, 167.4.
MS (ESI, MeOH): m/z = 227 ([M + H]+).
HRMS-ESI: m/z [M + H]+ calcd for C14H15N2O: 227.1184; found:
227.1173.
7e
Yield: 42 mg (7%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 4.31 (4 H, m), 6.93 (1 H, br s),
7.26–7.32 (10 H, m), 7.40 (5 H, m).
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α-PicBH3-Mediated Reductive Alkylation of Hydrazines
461
Conditions C: To a mixture of benzaldehyde (106 mg, 1 mmol) and
9 (102 mg, 1 mmol) in MeOH (3 mL) was added oxalic acid (135
mg, 1.5 mmol). The mixture was stirred for 2 h at r.t. To this mixture
was added α-PicBH3 (160 mg, 1.5 mmol) and oxalic acid (135 mg,
1.5 mmol). After stirring for 1.5 h at r.t., MeOH was removed by
evaporation in vacuo. The residue was diluted with CHCl3 (10 mL)
and the organic layer was washed with 10% aq NaHCO3. The aque-
ous layer was extracted with CHCl3 (2 × 5 mL), the combined or-
ganic layers were dried (MgSO4), filtered, and the filtrate was
concentrated in vacuo. The residual oil was diluted with xylene (5
mL) and the volatile component of the mixture was evaporated in
vacuo to remove α-picoline. The residue was dissolved in Et2O (2
mL) and the solution was treated with a solution of oxalic acid (135
mg, 1.5 mmol) in Et2O (6 mL). The resulting precipitate was col-
lected by filtration to give the oxalate of 10a (232 mg, 82%) as col-
orless plates.
Yield: 213 mg (74%); colorless needles; mp 160–162 °C (MeOH–
EtOAc).
1H NMR (500 MHz, D2O): δ = 0.80–0.9 (2 H, m), 0.94–1.14 (4 H,
m), 1.46–1.51 (1 H, m), 1.51–1.64 (4 H, m), 2.92 (2 H, d, J = 6.9
Hz), 2.95 (4 H, br s), 3.69 (4 H, br s).
13C NMR (125 MHz, D2O): δ = 34.5, 35.0, 39.6, 43.2, 60.8, 61.7,
75.1, 162.3.
MS (free base, EI): m/z = 198 (M+), 115 (base peak).
Anal. Calcd for C13H24N2O5: C, 54.15; H, 8.39; N, 9.72. Found: C,
53.87; H, 8.33; N, 9.70.
N-(1-Phenylethyl)morpholin-4-amine Oxalate (10g)
Prepared from acetophenone (120 mg, 1 mmol) and 9 (102 mg, 1
mmol) in an analogous manner for the synthesis of 10a by condi-
tions A.
Yield: 201 mg (68%); colorless crystalline powder; mp 177–178
°C.
1H NMR (400 MHz, D2O): δ = 1.68 (3 H, d, J = 6.8 Hz), 3.12 (2 H,
m), 3.20 (2 H, m), 3.82 (4 H, br t, J = 4.4 Hz), 4.76 (1 H, q, J = 6.8
Hz), 7.51–7.57 (5 H, m).
13C NMR (100 MHz, D2O): δ = 14.0, 49.9 (2 C), 53.7, 62.0 (2 C),
124.7 (2 C), 126.2 (2 C), 126.5, 132.8, 162.3.
N-(4-Chlorobenzyl)morpholin-4-amine Oxalate (10b)
Prepared from 4-chlorobenzaldehyde (141 mg, 1 mmol) and 9 (102
mg, 1 mmol) in an analogous manner for the synthesis of 10a by
conditions A–C.
Yield: conditions A, 276 mg (87%); conditions B, 228 mg (72%);
conditions C, 272 mg (86%); colorless prisms; mp 180–181 °C.
1H NMR (500 MHz, D2O): δ = 2.93 (4 H, br s), 3.67 (4 H, br s), 4.04
(2 H, s), 7.13 (2 H, d, J = 8.5 Hz), 7.16 (2 H, d, J = 8.5 Hz).
13C NMR (125 MHz, D2O): δ = 45.4, 49.3, 61.7, 125.7, 125.9,
128.2, 131.5, 162.3.
MS (free base, ESI): m/z = 207 ([M + H]+).
HRMS-ESI: m/z [M + H]+ calcd for C12H19N2O: 207.1497; found:
207.1503.
MS (free base, EI): m/z = 226 (M+), 101 (base peak).
N-(Pentan-3-yl)morpholin-4-amine Oxalate (10h)
Prepared from 3-pentanone (86 mg, 1 mmol) and 9 (102 mg, 1
mmol) in an analogous manner for the synthesis of 10a by condi-
tions A.
Anal. Calcd for C13H17ClN2O5: C, 49.30; H, 5.41; N, 8.84. Found:
C, 49.21; H, 5.31; N, 8.87.
N-(4-Methylbenzyl)morpholin-4-amine Oxalate (10c)
Prepared from p-tolualdehyde (120 mg, 1 mmol) and 9 (102 mg, 1
mmol) in an analogous manner for the synthesis of 10a by condi-
tions A–C.
Yield: 164 mg (63%); colorless crystalline powder; mp 135–137
°C.
1H NMR (400 MHz, D2O): δ = 0.99 (6 H, t, J = 7.5 Hz), 1.77 (4 H,
br quint, J = 7.1 Hz), 3.11 (4 H, m), 3.45 (1 H, br quint, J = 5.9 Hz),
3.88 (4 H, m).
13C NMR (100 MHz, D2O): δ = 6.3 (2 C), 19.0 (2 C), 50.4 (2 C),
57.3, 63.6 (2 C), 162.3.
Yield: conditions A, 264 mg (89%); conditions B, 252 mg (85%);
conditions C, 231 mg (78%); colorless prisms; mp 190–192 °C
(MeOH–EtOAc).
1H NMR (500 MHz, D2O): δ = 2.06 (3 H, s), 2.92 (4 H, br s), 3.58
(4 H, br s), 4.07 (2 H, s), 7.02 (2 H, d, J = 8.0 Hz), 7.09 (2 H, d,
J = 8.0 Hz).
MS (free base, ESI): m/z = 173 ([M + H]+).
HRMS-ESI: m/z [M + H]+ calcd for C9H21N2O: 173.1654; found:
13C NMR (125 MHz, D2O): δ = 42.4, 71.4, 74.7, 87.4, 149.1, 151.9,
152.3, 162.3.
173.1655.
MS (free base, EI): m/z = 206 (M+), 101 (base peak).
N-(Benzo[d][1,3]dioxol-5-ylmethyl)morpholin-4-amineOxalate
(10f)
Prepared from piperonal (150 mg, 1mmol) and 9 (102 mg, 1 mmol)
in an analogous manner for the synthesis of 10a by conditions A–C.
N-[(E)-Cinnamyl]morpholin-4-amine Oxalate (10d)
Prepared from cinnamaldehyde (132 mg, 1 mmol) and 9 (102 mg, 1
mmol) in an analogous manner for the synthesis of 10a by condi-
tions B and C.
Yield: conditions A, 294 mg (90%); conditions B, 183 mg (56%);
conditions C, 215 mg (66%); colorless needles; mp 162–163 °C
(MeOH–EtOAc).
1H NMR (500 MHz, D2O): δ = 3.10 (4 H, br s), 3.77 (4 H, br s), 4.20
(2 H, s), 5.89 (2 H, s), 6.80 (1 H, d, J = 7.4 Hz), 6.87 (1 H, d, J = 7.4
Hz), 6.88 (1 H, s).
13C NMR (125 MHz, D2O): δ = 46.5, 49.7, 62.4, 98.7, 106.0, 107.4,
120.7, 121.6, 144.8, 145.3, 162.3.
MS (free base, EI): m/z = 236 (M+), 101 (base peak).
Yield: conditions B, 234 mg (76%); conditions C, 281 mg (91%);
colorless plates; mp 182–183 °C (MeOH–EtOAc).
1H NMR (500 MHz, D2O): δ = 3.01 (4 H, br s), 3.70 (4 H, br s), 3.84
(2 H, d, J = 7.4 Hz), 6.12 (1 H, dt, J = 16.0, 7.4 Hz), 6.71 (1 H, d,
J = 16.0 Hz), 7.18–7.27 (3 H, m), 7.35 (2 H, d, J = 6.8 Hz).
13C NMR (125 MHz, D2O): δ = 44.2, 49.1, 62.0, 113.9, 162.3.
MS (free base, EI): m/z = 218 (M+), 101 (base peak).
Anal. Calcd for C14H18N2O7: C, 51.53; H, 5.56; N, 8.59. Found: C,
51.28; H, 5.43; N, 8.57.
Anal. Calcd for C15H20N2O5: C, 58.43; H, 6.54; N, 9.09. Found: C,
58.24; H, 6.68; N, 9.10.
N-(Benzo[d][1,3]dioxol-5-ylmethyl)-N-(4-methylbenzyl)mor-
pholin-4-amine (11a) from 10c-oxalate
To a mixture of 10c-oxalate (148 mg, 0.5 mmol), piperonal (150
mg, 1 mmol), and α-PicBH3 (80 mg, 0.75 mmol) in MeOH (2 mL)
was added Et3N (51 mg, 0.5 mmol) with stirring and the reaction
mixture was stirred for 3 h at r.t. The mixture was concentrated in
N-(Cyclohexylmethyl)morpholin-4-amine Oxalate (10e)
Prepared from cyclohexanecarbaldehyde (112 mg, 1 mmol) and 9
(102 mg, 1 mmol) in an analogous manner for the synthesis of 10a
by conditions B.
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462
Y. Kawase et al.
PAPER
vacuo and the residue diluted with CHCl3 (10 mL). The organic lay-
er was washed with 10% aq Na2CO3 (10 mL) and the aqueous layer
was extracted with CHCl3 (2 × 5 mL). The combined organic layers
were dried (MgSO4), filtered, and the filtrate was concentrated in
vacuo. The residue was diluted with xylenes (5 mL) and the volatile
components were evaporated in vacuo to remove α-picoline. The re-
sidual oil was purified by silica gel column chromatography
(CHCl3–n-hexane, 2:1) to give 11a; yield: 143 mg (84%); colorless
needles; mp 65–67 °C.
1H NMR (500 MHz, CDCl3): δ = 0.82 (3 H, t, J = 7.4 Hz), 1.49 (2
H, sext, J = 6.9 Hz), 2.40 (2 H, t, J = 6.9 Hz), 2.74 (4 H, t, J = 4.6
Hz), 3.59 (2 H, s), 3.70 (4 H, t, J = 4.6 Hz), 5.94 (2 H, s), 6.72 (1 H,
d, J = 7.4 Hz), 6.74 (1 H, dd, J = 7.4, 1.0 Hz), 6.88 (1 H, d, J = 1.0
Hz).
13C NMR (125 MHz, CDCl3): δ = 11.8, 21.1, 48.7, 51.7, 53.0, 67.5,
100.8, 107.7, 109.0, 121.4, 134.3, 146.2, 147.4.
MS (EI): m/z = 278 (M+), 143 (base peak).
1H NMR (500 MHz, CDCl3): δ = 2.32 (3 H, s), 2.78 (4 H, t, J = 4.6
Hz), 3.60 (2 H, s), 3.62 (4 H, t, J = 4.6 Hz), 3.67 (2 H, s), 5.92 (2 H,
s), 6.70 (1 H, d, J = 7.4 Hz), 6.73 (1 H, br d, J = 7.4 Hz), 6.87 (1 H,
br s), 7.09 (2 H, d, J = 8.0 Hz), 7.21 (2 H, d, J = 8.0 Hz).
13C NMR (125 MHz, D2O): δ = 21.1, 49.0, 53.0, 53.2, 67.3, 100.7,
107.6, 109.1, 121.6, 128.6, 128.7, 134.0, 136.2, 136.7, 147.3.
Anal. Calcd for C15H22N2O3: C, 64.73; H, 7.97; N, 10.06. Found: C,
64.58; H, 8.05; N, 10.00.
N,N-Dibenzylmorpholin-4-amine (11c)
Prepared from benzaldehyde (265 mg, 2.5 mmol) and morpholin-4-
amine (9; 102 mg, 1 mmol) in an analogous manner for preparation
of 11f; yield: 195 mg (69%); colorless prisms; mp 75 °C.
MS (free base, EI): m/z = 340 (M+), 205 (base peak).
1H NMR (500 MHz, CDCl3): δ = 2.81 (4 H, t, J = 4.6 Hz), 3.61 (4
H, t, J = 4.6 Hz), 3.72 (4 H, s), 7.21 (2 H, t, J = 7.4 Hz), 7.25–7.31
(6 H, m), 7.33 (2 H, d, J = 7.4 Hz).
Anal. Calcd for C20H24N2O3: C, 70.56; H, 7.11; N, 8.22. Found: C,
70.53; H, 7.25; N, 8.25.
13C NMR (125 MHz, CDCl3): δ = 49.0, 53.5, 67.3, 126.6, 128.0,
N-(Benzo[d][1,3]dioxol-5-ylmethyl)-N-(4-methylbenzyl)mor-
pholin-4-amine (11a) from Morpholin-4-amine (9) via 1-(4-
Methylphenyl)-N-(morpholin-4-yl)methanimine (12)
A solution of 9 (102 mg, 1 mmol) and 4-methylbenzaldehyde (120
mg, 1 mmol) in MeOH–AcOH (10:1, 3 mL) was stirred at r.t. for 2
h. The resulting precipitate was collected by filtration to give 12.
Compound 12 was used without further purification for the next re-
action.
128.7, 140.0.
MS (free base, EI): m/z = 282 (M+), 191 (base peak).
Anal. Calcd for C18H22N2O: C, 76.56; H, 7.85; N, 9.92. Found: C,
76.46; H, 7.68; N,9.81.
N,N-Bis(4-chlorobenzyl)morpholin-4-amine (11d)
Prepared from 4-chlorobenzaldehyde (351 mg, 2.5 mmol) and mor-
pholin-4-amine (9; 102 mg, 1 mmol) in an analogous manner for the
preparation of 11f; yield: 242 mg (69%); colorless prisms; mp 80
°C.
1H NMR (500 MHz, CDCl3): δ = 2.77 (4 H, t, J = 4.6 Hz), 3.61 (4
H, t, J = 4.6 Hz), 3.65 (4 H, s), 7.21–7.27 (8 H, m).
12
Yield: 182 mg (89%); colorless crystals; mp 91–92 °C.
1H NMR (500 MHz, CDCl3): δ = 2.35 (3 H, s), 3.15 (4 H, t, J = 4.1
Hz), 3.88 (4 H, t, J = 4.1 Hz), 7.15 (2 H, d, J = 10.0 Hz), 7.49 (2 H,
d, J = 10.0 Hz), 7.59 (1 H, s).
13C NMR (125 MHz, CDCl3): δ = 48.9, 52.8, 67.2, 128.2, 129.9,
To a solution of 12 (102 mg, 0.5 mmol) in MeOH (2 mL) were add-
ed α-PicBH3 (80 mg, 0.75 mmol) and oxalic acid (68 mg, 0.75
mmol), and the mixture was stirred for 1 h at r.t. To the reaction
mixture was added piperonal (150 mg, 1 mmol) and the mixture was
stirred for 3 h at r.t. and concentrated in vacuo. The residue was di-
luted with CHCl3 (10 mL). The organic layer was washed with 10%
aq Na2CO3 (10 mL), and the aqueous layer was extracted with
CHCl3 (2 × 5 mL). The combined organic layers were dried
(MgSO4), filtered, and the filtrate was concentrated in vacuo. The
residue was diluted with xylenes (5 mL) and the volatile compo-
nents were evaporated in vacuo to remove α-picoline. The residual
oil was purified by silica gel column chromatography (EtOAc–
n-hexane, 1:3) to give 11a. The spectral data were identical to those
of 11a prepared from 10c-oxalate.
132.4, 138.1.
MS(EI): m/z = 350 (M+), 225 (base peak).
Anal. Calcd for C18H20Cl2N2O: C, 61.55; H, 5.74; N,7.97. Found: C,
61.37 H, 5.72; N, 8.03.
N,N-Bis(benzo[d][1,3]dioxol-5-ylmethyl)morpholin-4-amine
(11e)
Prepared from piperonal (450 mg, 2.5 mmol) and morpholin-4-
amine (9; 102 mg, 1mmol) in an analogous manner for the prepara-
tion of 11f; yield: 244 mg (66%); colorless prisms; mp 129–130 °C.
1H NMR (500 MHz, CDCl3): δ = 2.77 (4 H, t, J = 4.6 Hz), 3.60 (4
H, s), 3.62 (4 H, t, J = 4.6 Hz), 5.93 (4 H, s), 6.72 (4 H, m), 6.86 (4
H, br s).
13C NMR (125 MHz, CDCl3): δ = 49.0, 53.1, 67.3, 100.7, 107.7,
109.1, 121.6, 133.8, 146.2, 147.4.
MS (EI): m/z = 370 (M+), 135 (base peak).
N-(Benzo[d][1,3]dioxol-5-ylmethyl)-N-propylmorpholin-4-
amine (11f) from Molpholin-4-amine (9); Typical Procedure
To a mixture of piperonal (150 mg, 1 mmol) and morpholin-4-
amine (9; 102 mg, 1 mmol) in MeOH (2 mL) was added oxalic acid
(27 mg, 0.3 mmol) and the mixture was stirred for 1 h at r.t. To this
mixture was successively added α-PicBH3 (160 mg, 1.5 mmol) and
oxalic acid (63 mg, 0.7 mmol) with stirring. After stirring for 1 h at
r.t., the mixture was treated with propionaldehyde (87 mg, 1.5
mmol) for an additional 2 h at r.t. The reaction mixture was concen-
trated in vacuo and the residue was diluted with CHCl3 (10 mL).
The organic layer was washed with 10% aq Na2CO3 (10 mL) and
the aqueous layer was extracted with CHCl3 (2 × 5 mL). The com-
bined organic layers were dried (MgSO4), filtered, and the filtrate
was concentrated in vacuo. The residue was diluted with xylene (5
mL) and the volatile components of the mixture were evaporated in
vacuo to remove α-picoline. The residual oil was purified by silica
gel column chromatography (EtOAc–n-hexane, 1:3) to give 11f;
yield: 184 mg (66%); colorless prisms; mp 80–81 °C.
Anal. Calcd for C20H22N2O5: C, 64.85; H, 5.99; N, 7.56. Found: C,
64.61; H, 6.03; N, 7.56.
N,N-Bis(benzo[d][1,3]dioxol-5-ylmethyl)piperidin-1-amine (14)
Prepared from piperonal (450 mg, 2.5 mmol) and N-aminopiperi-
dine (13; 100 mg, 1 mmol) in an analogous manner for the prepara-
tion of 11f; yield: 158 mg (43%); colorless prisms; mp 86–87 °C.
1H NMR (500 MHz, CDCl3): δ = 1.30 (2 H, m), 1.50 (4 H, m), 2.92
(4 H, m), 3.58 (4 H, s), 5.92, 5.917, and 5.915 (each 2 H, s), 6.69 (2
H, d, J = 8.0 Hz), 6.72 (2 H, d, J = 8.0 Hz), 6.87 (2 H, s).
13C NMR (125 MHz, CDCl3): δ = 24.7, 26.4, 49.7, 53.0, 100.7,
107.6, 109.2, 121.5, 134.5, 146.1, 147.4, 162.3.
MS (EI): m/z = 368 (M+), 233 (base peak).
Anal. Calcd for C21H24N2O4: C, 68.46; H, 6.57; N, 7.60. Found: C,
68.31; H, 6.56; N, 7.61.
Synthesis 2014, 46, 455–464
© Georg Thieme Verlag Stuttgart · New York

PAPER
α-PicBH3-Mediated Reductive Alkylation of Hydrazines
463
N-[(E)-Cinnamyl]-N-(naphthalen-1-ylmethyl)morpholin-4-
amine (11g)
Prepared from 1-naphthaldehyde (156 mg, 1 mmol), cinnamalde-
hyde (198 mg, 1.5 mmol) and morpholin-4-amine (9; 102 mg, 1
mmol) in an analogous manner for the preparation of 11f; yield: 158
mg (44%); colorless needles; mp 92 °C.
1H NMR (500 MHz, CDCl3): δ = 2.88 (4 H, t, J = 4.6 Hz), 3.47 (2
H, dd, J = 6.3, 1.1 Hz), 3.65 (4 H, t, J = 4.6 Hz), 4.23 (2 H, s), 6.27
(1 H, dt, J = 16.0, 6.3 Hz), 6.47 (1 H, d, J = 16.0 Hz,), 7.25–7.32 (5
H, m), 7.39 (1 H, dd, J = 6.9, 8.0 Hz), 7.44–7.51 (3 H, m), 7.74 (1
H, d, J = 8.0 Hz), 7.84 (1 H, dd, J = 7.4, 1.7 Hz), 8.32 (1 H, d,
J = 7.4 Hz).
13C NMR (125 MHz, CDCl3): δ = 49.1, 52.5, 52.8, 67.4, 124.5,
125.1, 125.4, 125.5, 126.2, 127.2, 127.4, 127.6, 128.4, 128.5, 128.6,
131.3, 132.4, 133.8, 135.0.
concentrated in vacuo and to the residue was added 10% aq HCl (10
mL) at 0 °C. The mixture was warmed to r.t. and stirred for 30 min
at the same temperature. After cooling to 0 °C, 25% aq Na2CO3 (20
mL) was added to the mixture and extracted with EtOAc (3 × 20
mL). The combined extracts were washed with brine (10 mL), dried
(MgSO4), filtered, and the filtrate was concentrated in vacuo. The
residue was purified by silica gel column chromatography (n-hex-
ane–EtOAc, 5:1–1:1) to give 17; yield: 437 mg (78%); colorless oil.
IR (neat): 3410, 1683 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.47 (9 H, s), 4.11 (2 H, s), 7.23
(1 H, m), 7.45 (2 H, d, J = 7.7 Hz), 7.73 (2 H, m), 7.96 (2 H, d,
J = 7.9 Hz), 8.69 (1 H, br s).
13C NMR (100 MHz, CDCl3): δ = 14.1, 28.3 (3 C), 55.4, 120.4,
122.0, 127.0 (2 C), 129.3 (2 C), 136.7, 138.6, 149.7, 156.6, 157.2.
ESI-MS: m/z = 300 ([M + H]+).
ESI-HRMS: m/z [M + H]+ calcd for C17H22N3O2: 300.1712; found:
MS (EI): m/z = 358 (M+), 241 (base peak).
Anal. Calcd for C24H26N2O: C, 80.41; H, 7.31; N, 7.81. Found: C,
80.23; H, 7.47; N, 7.77.
300.1721.
N-[(E)-Cinnamyl]-N-propylmorpholin-4-amine (11h)
Prepared from cinnamaldehyde (132 mg, 1 mmol), propionalde-
hyde (87 mg, 1.5 mmol) and molpholin-4-amine (9; 102 mg, 1
mmol) in an analogous manner for the preparation of 11f; yield: 115
mg (44%); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 0.89 (3 H, t, J = 7.4 Hz), 1.55 (2
H, sext, J = 7.4 Hz), 2.49 (2 H, t, J = 7.4 Hz), 2.74 (4 H, t, J = 4.6
Hz), 3.35 (2 H, dd, J = 6.6, 1.7 Hz), 3.70 (4 H, t, J = 4.6 Hz), 6.26
(1 H, dt, J = 16.0, 6.3 Hz), 6.49 (1 H, d, J = 16.0 Hz), 7.20–7.24 (2
H, m), 7.29–7.34 (2 H, m), 7.37 (1 H, dd, J = 7.4, 1.1 Hz).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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References
(1) Hydrazine and its Derivatives, In Kirk-Othmer Encylopedia
Chemical Technology, 4th ed., Vol. 13; Kirk, R. E.; Othmer,
D. F., Eds.; Wiley: New York, 1995.
(2) Bold, G.; Fassler, A.; Capraro, H-G.; Cozens, R.; Klimkait,
T.; Lazdins, J.; Mestan, J.; Poncioni, B.; Rosel, J.; Stover,
D.; Tintelnot-Blomley, M.; Acemoglu, F.; Ucci-Stoll, K.;
Wyss, D.; Lang, M. J. Med. Chem. 1988, 41, 3387.
(3) The Japanese Pharmacopeia, 16th edition:
13C NMR (125 MHz, CDCl3): δ = 11.9, 21.3, 48.7, 52.0, 52.2, 67.5,
126.2, 127.2, 128.5, 128.8, 131.2, 137.3.
MS (EI): m/z = 260 (M+), 143 (base peak).
http://www.pmda.go.jp/english/pharmacopoeia/online.html.
(4) Gardner, T. S.; Rutherford Lee, J.; Fells, E.; Wenis, E. US
Patent US2908688, 1959; Chem. Abstr. 1962, 56, 25114.
(5) (a) Tsubouchi, H.; Sasaki, H.; Itotani, M.; Haraguchi, Y.;
Miyamura, S.; Matsumoto, M.; Hashizume, H.; Tomishige,
T.; Kawasaki, M.; Ohguro, K.; Shimada, T.; Hasegawa, T.;
Tanaka, K.; Takemura, I. Patent WO2005-042542, 2005;
Chem. Abstr. 2005, 142, 463728. (b) Kobayashi, K.;
Nishiyama, T.; Nakade, M. JP11302280, 1999; Chem. Abstr.
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(d) Kametani, T.; Kigasawa, K.; Hiragi, M.; Wagatsuma, N.;
Uryu, T.; Araki, K. J. Med. Chem. 1973, 16, 301.
(e) Kametani, T.; Kigasawa, K.; Hiragi, M.; Wagatsuma, N.;
Kuama, O.; Uryu, T. Chem. Pharm. Bull. 1976, 24, 2563.
(6) Selective double N-alkylation of hydrazine derivatives
through their dianions has been reported: Bredihin, A.;
Maeorg, U. Tetrahedron 2008, 64, 6788.
(7) (a) Perdichia, D.; Licandro, E.; Maiorana, S.; Baldoli, C.;
Giannini, C. Tetrahedron 2003, 59, 7733. (b) Ragnarsson,
U. Chem. Soc. Rev. 2001, 30, 205. (c) Arterburn, J. B.; Rao,
K. V.; Ramdas, R.; Dible, B. R. Org. Lett. 2001, 3, 1351.
(d) Brosse, N.; Pinto, M. F.; Bodiguel, J.; Jamart-Gregoire,
B. J. Org. Chem. 2001, 66, 2869. (e) Brosse, N.; Pinto, M.;
Jamart-Gregoire, B. J. Org. Chem. 2000, 65, 4370.
(f) Baruah, B.; Dutta, M. P.; Boruah, A.; Prajapati, D.;
Sandhu, J. S. Synlett 1999, 409. (g) Katritzky, A. R.; Qiu, G.;
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Grehn, L.; Ragnarsson, U. Angew. Chem., Int. Ed.. Engl.
1996, 35, 2626.
N′-Benzyl-5-methylisoxazole-3-carbohydrazide (3, Isocarboxa-
zid)4
To a stirred solution of 5-methylisoxazole-3-carbohydrazide (15;
265 mg, 1.88 mmol) in MeOH (3 mL) was added a solution of benz-
aldehyde (200 mg, 1.88 mmol) in MeOH (2 mL) under an atmo-
sphere of N2 and the mixture was stirred for 10 min at r.t. After
cooling to 0 °C, AcOH (0.5 mL) and α-PicBH3 (201 mg, 1.88
mmol) were added and the mixture was stirred for 5 min at the same
temperature. To the mixture was added 3 M aq HCl (2.51 mL, 7.52
mmol) at 0 °C, and was allowed to warm to r.t. After stirring for 30
min, the mixture was poured into 25% aq Na2CO3 (10 mL) and ex-
tracted with EtOAc (3 × 20 mL). The combined organic layers were
washed with brine, dried (MgSO4), filtered, and the filtrate was con-
centrated in vacuo. The residue was purified by silica gel column
chromatography (n-hexane–EtOAc, 9:1) to give 3; yield: 339 mg
(83%); colorless crystals: mp 105–106 °C.
IR (KBr): 3227, 1674 cm–1.
1H NMR (400 MHz, CD3OD): δ = 2.46 (3 H, s), 4.03 (2 H, s), 6.41
(1 H, s), 7.26–7.28 (1 H, m), 7.30–7.34 (2 H, m), 7.39 (2 H, d,
J = 7.7 Hz).
13C NMR (100 MHz, CD3OD): δ = 11.9, 56.4, 101.9, 128.6, 129.4
(2 C), 130.1 (2 C), 138.6, 159.1, 160.4, 172.8.
ESI-MS: m/z = 232 ([M + H]+).
ESI-HRMS: m/z [M + H]+ calcd for C12H14N3O2: 232.1086;
found:232.1077.
tert-Butyl 2-[4-(Pyridin-2-yl)benzyl]hydrazinecarboxylate
(17);2 Intermediate for the Synthesis of Atazanavir (1)
To a mixture of N-tert-butoxycarbonylhydrazine (18; 249 mg, 1.88
mmol) and 4-(pyridin-2-yl)benzaldehyde (16; 344 mg, 1.88 mmol)
in MeOH (5 mL) was added AcOH (0.5 mL) and α-PicBH3 (201
mg, 1.88 mmol) at 0 °C. The reaction mixture was allowed to warm
to r.t. and stirred for 2 h at the same temperature. The mixture was
(8) Mizufune, H.; Yamamoto, H.; Nakamura, M.; Miki, S.
Tetrahedron 2008, 64, 6275.
(9) (a) Terada, T.; Fujimoto, K.; Nomura, M.; Yamashita, J.;
Wierzba, K.; Yamazaki, R.; Shibata, J.; Sugimoto, Y.;
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 455–464

464
Y. Kawase et al.
PAPER
Yamada, Y.; Kobunai, T.; Takeda, S.; Minami, Y.; Yoshida,
K. J. Med. Chem. 1993, 36, 1689. (b) Nelson, S. F.;
Weisman, G. R. Tetrahedron Lett. 1973, 26, 2321.
(14) For a report on α-PicBH3-mediated reductive alkylation of
2,4-dinitrophenylhydrazine supported on silica gel with
aldehydes, see: Uchiyama, S.; Inaba, Y.; Matsumoto, M.;
Suzuki, G. Anal. Chem. 2009, 81, 485.
(15) Although acid catalysts are effective to accelerate the
formation of hydrazone, excess amount of acids may inhibit
the formation of hydrazone due to protonation of hydrazine
moiety. Therefore, we added hydrochloric acid or oxalic
acid in the steps for the formation of hydrazone and for the
reduction separately.
(10) Kawase, Y.; Yamagishi, T.; Kutsuma, T.; Zhibao, H.;
Yamamoto, Y.; Kimura, T.; Nakata, T.; Kataoka, T.;
Yokomatsu, T. Org. Process Res. Dev. 2012, 16, 495.
(11) Kawase, Y.; Yamagishi, T.; Kutsuma, T.; Ueda, K.;
Iwakuma, T.; Nakata, T.; Yokomatsu, T. Heterocycles 2009,
78, 463.
(12) Kawase, Y.; Yamagishi, T.; Kutsuma, T.; Kataoka, T.; Ueda,
K.; Iwakuma, T.; Nakata, T.; Yokomatsu, T. Synthesis 2010,
1673.
(13) For a previous report on general reductive amination of
carbonyl compounds with amines using α-PicBH3, see: Sato,
S.; Sakamoto, T.; Miyazawa, E.; Kikugawa, Y. Tetrahedron
2004, 60, 7899.
(16) The sequential double alkylation with cyclohexane-
carbaldehyde and n-hexanal failed under the conditions.
(17) Okawa, T.; Kanazawa, Y.; Yamasaki, T.; Furukawa, M.
Synthesis 1987, 183.
(18) For the synthesis of the hydrochloride salt, see ref. 7a.
Synthesis 2014, 46, 455–464
© Georg Thieme Verlag Stuttgart · New York