Regiospecific rearrangement of hydroxylamines to secondary amines using diisobutylaluminum hydride

Article abstract of DOI:10.3987/COM-10-S(E)126

A systematic investigation of a reductive ring-expansion reaction of N-monosubstituted hydroxylamines with diisobutylaluminum hydride (DIBALH) was carried out. The reaction regiospecifically provided a variety of bicyclic or tricyclic heterocycles or linear secondary amines containing nitrogen attached to an aromatic ring. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-10-S(E)126

HETEROCYCLES, Vol. 82, No. 2, 2011
1633
HETEROCYCLES, Vol. 82, No. 2, 2011, pp. 1633 - 1644. © The Japan Institute of Heterocyclic Chemistry
Received, 17th September, 2010, Accepted, 26th October, 2010, Published online, 11th November, 2010
DOI: 10.3987/COM-10-S(E)126
REGIOSPECIFIC REARRANGEMENT OF HYDROXYLAMINES TO
†
SECONDARY AMINES USING DIISOBUTYLALUMINUM HYDRIDE
a,b
b
b
b
Hidetsura Cho,* Kenji Sugimoto, Yusuke Iwama, Nakako Mitsuhashi,
b
b
Kentaro Okano, and Hidetoshi Tokuyama*
a
b
Graduate School of Sciences and Graduate School of Pharmaceutical Science,
Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, 980-8578, Japan
E-mail: hcho@mail.pharm.tohoku.ac.jp, tokuyama@mail.pharm.tohoku.ac.jp
Abstract – A systematic investigation of a reductive ring-expansion reaction of
N-monosubstituted hydroxylamines with diisobutylaluminum hydride (DIBALH)
was carried out. The reaction regiospecifically provided a variety of bicyclic or
tricyclic heterocycles or linear secondary amines containing nitrogen attached to
an aromatic ring.
INTRODUCTION
The development of synthetic methods for unsubstituted basic skeletons of heterocycles is important from
the viewpoint of both synthetic chemistry and medicinal chemistry. In particular, the synthesis of bicyclic
or tricyclic fused heterocycles containing nitrogen attached to an aromatic ring such as benzazepine,
benzoxazine, benzoxazepine, benzthiazine, and benzthiazepine, is essential, because these skeletons often
form the core structures of pharmaceuticals or clinical candidates. However, only a few straightforward
1
and versatile synthetic procedures are available to construct the heterocyclic systems.
X
X
DIBALH
n
n
N
H
NOH
n = 0~3
X = CH , O, S
n = 0~3
X = CH , O, S
2
2
Scheme 1. Previous Reductive Ring-Expansion Reaction of Cyclic Ketoximes using DIBALH
†
This paper is dedicated to Professor Albert Eschenmoser on the occasion of his 85th birthday.

1634
HETEROCYCLES, Vol. 82, No. 2, 2011
Recently, we have reported an investigation of the reductive ring expansion reaction of cyclic ketoximes
2
a,2b
fused to aromatic rings using diisobutylaluminum hydride (DIBALH) (Scheme 1).
The treatment of
an E/Z mixture of ketoximes with 5 equiv of DIBALH furnished the corresponding ring expansion
product with nitrogen attached to the aromatic ring as the sole isomer. According to preliminary results
(
Table 1, entry 2) showing that the treatment of the hydroxylamine with DIBALH gave the reductive ring
expansion product and theoretical calculations based on the density functional theory (DFT), we proposed
a reaction mechanism involving the 1,2-reduction of an oxime to hydroxylamine and a regiospecific
2
b
rearrangement via a partial phenonium cation intermediate (Scheme 2).
+
2
R AlH
2
R
+
R
N
N
R
Al
Al
R
R
Al
O
R
R
N
Al
O
OH
R
1
2
3
R AlH
aq NaF
2
N
N
N
H
R Al O
Al
Al
R
R
R
R
4
5
6
R
Scheme 2. Reaction Mechanism based on DFT Calculations
It is known that hydroxylamines activated by an electron-withdrawing group on the oxygen and O-alkyl
hydroxylamines activated by aluminum agents undergo rearrangement reactions. Hoffman described the
3
a,b
rearrangement of O-arylsulfonyl hydroxylamines (Scheme 3, eq 1). Yamamoto and Maruoka reported
3
c
a rearrangement-alkylation sequence of hydroxylamine carbonate effected by trialkylaluminum (eq 2).
3
d
The reductive migration of O-methyl hydroxylamine with LAH was reported by Booth (eq 3), and the
3
e-h
reaction of hydroxylamine with Red-Al was described by Naito and Miyata (eq 4). In contrast to these
examples, no report has appeared on the reductive rearrangement of unfunctionalized hydroxylamines to
the best of our knowledge.
Therefore, we carried out a systematic investigation of the rearrangement reaction of hydroxylamine.
Herein, we report its scope and generality of the reaction.

HETEROCYCLES, Vol. 82, No. 2, 2011
1635
AcOEt
C4H9 NHONs
C H
N
4
9
25 °C
(eq 1)
Ph
OCO2Et
Ph
N
AlMe3
N
Me
(eq 2)
Me
H
NHOMe
N
Me
OH
LiAlH4
(eq 3)
NHOMe
OH
H
N
Red-Al
(eq 4)
MeO
MeO
Scheme 3. Rearrangement of Hydroxylamine Derivatives
RESULTS AND DISCUSSION
First, bicyclic hydroxylamines were synthesized from readily accessible fused bicyclic ketoximes by
4
1
,2-reduction with sodium cyanoborohydride under acidic conditions; they were then subjected to
reductive conditions with DIBALH (Table 1). Thus, hydroxylamines were treated with 6 equiv of
1
,2
DIBALH at 0 °C to room temperature. The reaction was quenched by adding NaF. Although the
theoretical amount of DIBALH was 3 equiv, we used an excess amount of the reagent to achieve
complete consumption of the substrate.
The reductive rearrangement of hydroxylamines was found to be applicable to a variety of bicyclic
substrates (Table 1). In all cases, the reaction gave the expected reductive ring expansion product as the
2
sole isomer as observed in the reaction of the corresponding oximes with DIBALH. Thus, the aromatic
ring migrated to the nitrogen atom to form bicyclic compounds having nitrogen attached to the aromatic
ring. Reactions of five- to seven-membered ring substrates 8a, 8b, and 8c provided
1
1
,2,3,4-tetrahydroquinoline
,2,3,4,5,6-hexahydrobenz[b]azocine 9c, respectively (entries 1 to 3). In addition, the reactions were
to the synthesis of 2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine 9d and
,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 9e (entries 4 and 5). Furthermore, a cyclohexyl ring fused to
9a,
2,3,4,5-tetrahydro-1H-benz[b]azepine
6,
and
applicable
2
1
a
thiophene expanded smoothly to give 5,6,7,8-tetrahydrothieno[3,2-b]azepine 9f, which was isolated as a
p-nitrobenzoyl amide 10f owing to the instability of 9f (entry 6).

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HETEROCYCLES, Vol. 82, No. 2, 2011
Table 1. Reductive Rearrangement of Hydroxylamines Derived from Bicyclic Ketoxime with DIBALH
DIBALH
(6 equiv)
X
X
X
NaBH CN
( )n
3
(
)n
( )n
AcOH or
HCl/MeOH
CH Cl2
0 °C to rt
2–5 h;
N
H
2
NOH
NHOH
6
8–80%
7
8
9
aq. NaF
Yield (%)a
49
Entry
1
Hydroxylamine
Product
8a
9a
N
H
NHOH
2b
8
b
c
6
72
62
67
56
N
H
NHOH
8
9c
9d
9e
3
N
H
HOHN
O
O
4
8d
N
H
NHOH
S
S
8
e
5
6
N
H
NHOH
9
f
---
S
S
R = H
8f
1
0f
67
N
R
R = COC H p-NO
6
4
2
NHOH
a
b
Yields are based on hydroxylamine. Ref. 2b
Although the reaction yields of hydroxylamines with DIBALH are slightly lower than those of the
2
b
corresponding oximes with the reagent, one of the advantages of using hydroxylamine instead of an
5
–12
oxime as a substrate should be its broad synthetic accessibility.
Thus, in addition to the reduction of
oximes, hydroxylamines can be prepared from alcohols or primary amines by substitution reactions or

HETEROCYCLES, Vol. 82, No. 2, 2011
1637
oxidation through the regioselective formation of nitrone in a stepwise protocol. For instance, tricyclic
hydroxylamine 8g was prepared by the reaction of alcohol 11 with hydroxylamine hydrochloride in the
8
a,b
presence of sodium acetate and dichloroacetic acid (Scheme 4).
NH OH HCl
2
AcONa, Cl CHCO H
2
2
OH
CH
2
Cl
8
2
, rt, 20 h
NHOH
3%
1
1
8g
Scheme 4. Preparation of Hydroxylamine 8g by Substitution Reaction
On the other hand, N-(9-fluorenyl)hydroxylamine 8h was prepared from primary amine 12 by a stepwise
7
c
protocol including cyanomethylation, regioselective oxidation to nitrone, and hydroxyaminolysis
Scheme 5). The reductive ring expansion reaction of tricyclic hydroxylamines 8g and 8h proceeded
smoothly to give the corresponding secondary amines 9g and 9h (Table 2, entries 1 and 2).
(
Br
CN
i-Pr NEt
MeCN
rt, 2 d
2
NH2
HN
13
CN
1
2
96%
mCPBA, CH Cl
2
2
rt, 30 min
2
NH OH·HCl
MeOH
N
CN
4
3% for 2 steps
NHOH
O
8h
14
Scheme 5. Preparation of Hydroxylamine 8h by Oxidation of Primary Amine
a
Table 2. DIBALH-mediated Rearrangement of Tricyclic Hydroxylamines
Entry
1
Hydroxylamine
Product
Yield (%)
69
8g
9g
HN
NHOH

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HETEROCYCLES, Vol. 82, No. 2, 2011
2
8h
9h
43
N
NHOH
H
a
2 2
Hydroxylamine (1 equiv) and DIBALH (6 equiv) were used in CH Cl at rt for 2–3 h.
Finally, we examined the reaction of linear hydroxylamines, which were easily prepared by reduction of
5
the corresponding ketoximes (Table 3). We observed the specific migration of aryl groups providing the
corresponding aniline derivatives as the sole product. Thus, the reaction of N-(1-phenylethyl)-
1
3
hydroxylamine 8i
and N-(1-phenylpropyl)hydroxylamine 8j afforded N-ethylaniline 9i and
1
4
N-propylaniline 9j via specific aryl migration (entries 1 and 2). N-Diphenylmethanehydroxylamine 8k
was also transformed into benzylaniline 9k in high yield (entry 3). The preferential migratory aptitude of
an aryl group over that of an alkyl chain of hydroxylamines was also observed in the reaction of oximes
2
b
with DIBALH.
a
Table 3. DIBALH-mediated Rearrangement of Linear Hydroxylamines
a
2 2
Hydroxylamine (1 equiv) and DIBALH (6 equiv) were used in CH Cl at rt for 2–3 h.
In summary, we have established the reductive rearrangement reaction of hydroxylamines with DIBALH.
A systematic investigation demonstrated that the N-monosubstituted hydroxylamines serve as a suitable
substrate for the reductive rearrangement reaction. In addition, the reaction gave cyclic or acyclic
secondary amines having nitrogen attached to the aromatic rings specifically owing to the preferential
migratory aptitude of the aromatic rings. Because hydroxylamines can be easily prepared from a various
4
–6
7
8
9,10
11
precursors such as oximes, primary amines, alcohols, nitroalkanes, conjugated nitroalkenes, and
1
2
nitronates, the rearrangement reaction of hydroxylamines with DIBALH should be useful and the
resulted aromatic amines will likely find use in the field of fine and medicinal chemistry.

HETEROCYCLES, Vol. 82, No. 2, 2011
1639
EXPERIMENTAL
General
Column chromatography was performed on silica gel 60N (Kanto, 63-210 μm) and flash column
chromatography was performed on silica gel 60N (40-60 μm) using the indicated solvents. Reactions and
chromatography fractions were monitored by employing pre-coated silica gel 60 F254 plates (0.25 mm).
All melting points were uncorrected. IR spectra were measured with a FT-IR spectrometer and were
-1
reported in wave numbers (cm ). NMR spectra were recorded on 400 MHz or 500 MHz spectrometers
with tetramethylsilane (0 ppm) or chloroform (7.24 ppm) as the internal standard. Chemical shifts were
reported in δ (ppm downfield from tetramethylsilane). Coupling constants were reported in Hz. Mass
spectra were obtained using following ionization techniques: electron impact (EI), fast atom
bombardment (FAB).
General synthetic procedure of hydroxylamines
From representative oxime derivatives: N-4-chromanylhydroxylamine (8d): To a stirred solution of
chroman-4-one oxime (326 mg, 2.00 mmol) in MeOH (4.0 mL) was added NaBH
mmol) at rt and added hydrogen chloride in MeOH (1.0 M, 6.0 mL) at 0 ºC. After stirring for 1.5 h at rt,
the reaction was quenched with saturated aqueous NaHCO . The reaction mixture was extracted with
EtOAc, and the combined extracts were washed with brine, dried over anhydrous Na SO , concentrated
3
CN (624 mg, 9.93
3
2
4
under reduced pressure. The residue was purified by recrystallization (from EtOAc/n-hexane) to give
hydroxylamine 8d (226 mg, 68%) as colorless needles: mp 142-144 °C; IR (KBr) 3258, 3175, 2887, 1491,
-
1 1
1
1
229, 770 cm ; H NMR (400 MHz, CDCl
3
) δ 7.25 (1H, dd, J = 8.8, 1.6 Hz), 7.19 (1H, ddd, J = 8.8, 6.8,
.6 Hz), 6.89 (1H, ddd, J = 8.8, 6.8, 0.8 Hz), 6.84 (1H, dd, J = 8.8, 0.8 Hz), 5.86 (1H, br s), 5.25 (1H, br
s), 4.28-4.21 (2H, m), 4.10 (1H, dd, J = 3.6, 3.6 Hz), 2.22 (1H, ddd, J = 14.8, 6.8, 3.6 Hz), 2.10-1.97 (1H,
1
3
m); C NMR (100 MHz, CDCl
3
) δ 155.7, 130.3, 129.5, 120.3, 119.7, 117.2, 62.0, 54.9, 25.2; LRMS (EI)
+
+
m/z 165 (M ); HRMS m/z Calcd for C
9
H11NO
2
(M ) 165.0790, found 165.0778.
From alcohol derivatives: Preparation of 10,11-dihydro-5-hydroxyamino-5H-dibenzo[a,d]-
cyclopentane (8g): To a stirred solution of dibenzosuberone (1.00 g, 4.80 mmol) in MeOH (12.0 mL)
was added NaBH
temperature, the reaction was quenched with saturated aqueous NH
EtOAc. The combined organic extracts were washed with brine, dried over Na
under reduced pressure. The residue was purified by flash column chromatography (SiO
n-hexane:EtOAc = 85:15) to afford alcohol 11 (1.00 g, quant.) as a colorless oil: IR (neat) 3317, 1483,
4
(545 mg, 14.4 mmol) potionwise at 0 °C. After stirring for 10 min at the same
Cl and the mixture was extracted with
SO , and concentrated
4
2
4
2
,
-1 1
1
456, 1030 cm ; H NMR (400 MHz, CDCl )  7.44 (2H, d, J = 8.0 Hz), 7.22-7.13 (6H, m), 5.96-5.95
3
1
3
(
1H, m), 3.47-3.38 (2H, m), 3.15-3.06 (2H, m), 2.24 (1H, br s); C NMR (100 MHz, CDCl )  140.5,
3
+
1
38.9, 130.2, 127.9, 127.0, 126.2, 76.6, 32.4; LRMS (EI) m/z 210 (M ); HRMS m/z Calcd for C15
H
14
O

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HETEROCYCLES, Vol. 82, No. 2, 2011
2
10.1045, Found 210.1048. To a stirred solution of dichloroacetic acid (4.75 mL, 57.6 mmol), sodium
acetate (394 mg, 4.80 mmol) in CH Cl (5.0 mL) was added hydroxylamine hydrochloride (1.33 g, 19.2
mmol) at rt and stirred for 1 h. To a stirred suspension was added dropwise alcohol 11 (1.00 g, 4.80
mmol) in CH Cl (5.0 mL) at rt. After stirring for 20 h at the same temperature, the reaction was
quenched with saturated aqueous NaHCO at 0 °C and the mixture was extracted with CH Cl . The
combined extracts were washed with brine, dried over Na SO , and concentrated under reduced pressure.
The residue was purified by flash column chromatography (SiO , n-hexane:EtOAc = 85:15) to afford
hydroxylamine 8g (899 mg, 83%) as a colorless oil: IR (neat) 3528, 3260, 3061, 3018, 2928, 2887, 760
2
2
2
2
3
2
2
2
4
2
-1 1
cm ; H NMR (400 MHz, CDCl
3
)  7.31 (2H, d, J = 7.2 Hz), 7.22-7.13 (6H, m), 5.05 (1H, s), 4.21 (1H,
br s), 3.71-3.63 (2H, m), 2.91-2.83 (2H, m) (one proton signal was missing owing to exchanging to
1
3
deuterium); C NMR (100 MHz, CDCl )  141.1, 136.8, 131.3, 130.4, 128.2, 126.0, 74.6, 32.7; LRMS
3
+
+
(
EI) m/z 193 [(M−NHOH) ]; HRMS m/z Calcd for C15
From amine derivatives: N-(9H-fluoren-9-yl)hydroxylamine (8h): To a stirred solution of
N-(9H-fluoren-9-yl)amine 12 (739.5 mg, 4.08 mmol) in MeCN (8.2 mL) and i-Pr NEt (1.42 mL, 8.16
mmol) was added bromoacetonitrile (313 L, 4.49 mmol) dropwise over 15 min. The reaction mixture
was stirred at rt for 2 days and evaporated, diluted with CH Cl . The organic layer was washed with
saturated aqueous NaHCO , dried over Na SO to give the residue, which was purified by flash column
chromatography (SiO , n-hexane:EtOAc = 3:1) to afford 2-(9H-fluoren-9-yl)aminoacetonitrile 13 (858
mg, 95%). To a stirred solution of 13 (192 mg, 873 mol) in CH Cl (2.7 mL) was added
m-chloroperbenzoic acid (471 mg, 2.10 mmol) in portions over 15 min at 0 °C. Stirring was continued at
rt for 20 min and the reaction mixture was quenched with aqueous Na and saturated aqueous
NaHCO , then extracted with CH Cl . The combined extracts were washed with brine, dried over Na SO
H13 [(M−NHOH) ] 193.1018, Found 193.1022.
2
2
2
3
2
4
2
2
2
2 2 3
S O
3
2
2
2
4
and concentrated under reduced pressure to give nitrone 14. To a stirred solution of 14 in MeOH (3.5 mL)
was added hydroxylamine hydrochloride (303 mg, 4.35 mmol). The mixture was heated at 60 °C for 2.5 h.
Then the reaction mixture was diluted with CH
saturated aqueous NaHCO and brine. The organic layer was dried over Na
reduced pressure. The residue was purified by flash column chromatography (SiO
0:1), followed by preparative TLC (SiO , CH Cl :MeOH = 50:1) to afford compound 8h (83.8 mg, 49%
for 2 steps): colorless powder; IR (neat) 3140, 2897, 1448, 1402, 1290, 1063, 1026, 1018, 910, 737, 681
2
Cl
2
(6.0 mL) and filtered. The filtrate was washed with
SO and concentrated under
, CH Cl :MeOH =
3
2
4
2
2
2
5
2
2
2
-1 1
cm ; H NMR (500 MHz, CDCl
3
)  7.75-7.67 (4H, m), 7.40 (2H, dd, J = 7.5, 7.5 Hz), 7.34-7.28 (2H, m),
1
3
6
.08 (1H, brs), 5.10 (1H, s) (one proton signal was missing owing to exchanging to deuterium); C NMR
+
(100 MHz, CDCl
3
)  142.9, 141.1, 128.7, 127.4, 125.6, 120.0, 67.3; LRMS (EI) m/z 197 (M ); HRMS
+
(
EI) m/z Calcd for C13
H
11NO (M ) 197.0841, Found 197.0830.

HETEROCYCLES, Vol. 82, No. 2, 2011
1641
2
1
7
-(9H-Fluoren-9-ylamino)acetonitrile (13): yellow powder; IR (neat) 3329, 3065, 2249, 1448, 1296,
-1 1
200, 743, 667 cm ; H NMR (500 MHz, CDCl
3
) δ 7.70 (2H, d, J = 7.0 Hz), 7.58 (2H, d, J = 7.0 Hz),
.41 (2H, dd, J = 7.5, 7.0 Hz), 7.36 (2H, ddd, J = 7.5, 7.0, 1.2 Hz), 5.02 (1H, s), 3.22 (2H, s), 2.27 (1H,
1
3
brs); C NMR (125 MHz, CDCl
3
) δ 143.0, 141.0, 128.9, 127.6, 125.0, 120.2, 118.2, 62.5, 31.9; LRMS
+
+
(
EI) m/z 220 (M ); HRMS (EI) m/z Calcd for C15
H
12
N
2
(M ) 220.1000, Found 220.1000.
2
-(9H-Fluoren-9-ylimino)acetonitrile N-oxide (14): Trituration with EtOAc, n-hexane and CHCl
3
afforded pure nitrone. colorless powder; IR (KBr) 3096, 2932, 2220, 1541, 1448, 1429, 1275, 1182, 1157,
-
1 1
9
66, 750, 725, 694 cm ; H NMR (500 MHz, CDCl
3
) δ 7.75 (2H, d, J = 7.5 Hz), 7.71 (2H, dd, J = 8.0,
1
3
1
.0 Hz), 7.54 (2H, dd, J = 7.5, 7.5 Hz), 7.41 (2H, ddd, J = 8.0, 7.5, 1.0 Hz), 6.40 (1H, s), 5.93 (1H, s); C
NMR (125 MHz, CDCl
3
) δ 141.2, 137.8, 131.0, 128.8, 125.9, 120.8, 112.1, 104.2, 80.7; LRMS (FAB)
+
+
m/z 235 ([M+H] ); HRMS (FAB) m/z Calcd for C15
H
11
N
2
O ([M+H] ) 235.0871, Found 235.0874.
Data of hydroxylamines
-1 1
N-(1-Indanyl)hydroxylamine (8a): colorless powder; IR (KBr) 3155, 2941, 2882, 760 cm ; H NMR
400 MHz, CDCl )  7.38 (1H, d, J = 7.6 Hz), 7.24-7.14 (3H, m), 4.50 (1H, dd, J = 7.2, 4.0 Hz),
.06-2.99 (1H, m), 2.87-2.80 (1H, m), 2.32-2.23 (1H, m), 2.10-2.01 (1H, m) (two proton signals were
(
3
3
1
3
missing owing to exchanging to deuterium); C NMR (100 MHz, CDCl
3
)  144.7, 141.6, 128.2, 126.3,
+
+
1
1
1
2
25.1, 124.9, 67.1, 30.4, 29.7; LRMS (EI) m/z 149 (M ); HRMS (EI) m/z Calcd for C
9
H
11NO (M )
49.0841, Found 149.0836.
,2,3,4-Tetrahydro-N-hydroxyl-1-naphthaleneamine (8b): colorless powder; IR (KBr) 3155, 2941,
-1 1
3
882, 760 cm ; H NMR (400 MHz, CDCl ) δ 7.32 (1H, dd, J = 6.4, 2.0 Hz), 7.25-7.09 (3H, m), 4.09
(1H, dd, J = 4.0, 4.0 Hz), 2.84-2.68 (2H, m), 2.25-2.20 (1H, m), 1.95-1.89 (1H, m), 1.85-1.75 (2H, m);
1
3
C NMR (100 MHz, CDCl
3
) δ 138.5, 134.3, 129.6, 129.2, 127.4, 125.8, 59.3, 29.4, 25.8, 18.3; LRMS
+
+
(
EI) m/z 163 (M ); HRMS (EI) m/z Calcd for C10
H
13NO (M ) 163.0997, found 163.1015.
N-(6,7,8,9-Tetrahydro-5H-benzocyclohepten-5-yl)hydroxylamine (8c): colorless powder; IR (KBr)
-1 1
3
269, 2914, 1450, 1442, 1364, 1040, 905, 756 cm ; H NMR (400 MHz, CDCl
3
) δ 7.25-7.06 (4H, m),
5.79 (2H, br s), 4.22 (1H, d, J = 8.4 Hz), 2.93 (1H, dd, J = 13.6, 10.0 Hz), 2.81-2.72 (1H, m), 2.02-1.85
1
3
(
2H, m), 1.83-1.65 (3H, m), 1.63-1.50 (1H, m); C NMR (100 MHz, CDCl
3
) δ 142.2, 141.1, 129.8, 127.0,
+
1
26.3, 126.1, 65.8, 35.6, 31.1, 27.7, 27.7; LRMS (EI) m/z 160 ([M–OH] ); HRMS m/z Calcd for
+
C
11
H14N([M–OH] ) 160.1126, Found 160.1101.
N-(Thiochroman-4-yl)hydroxylamine (8e): colorless powder; IR (KBr) 3254, 3167, 2885, 1587, 1562,
-1 1
1
475, 1441, 1408, 1034, 945, 887, 750 cm ; H NMR (500 MHz, CDCl ) δ 7.25-7.00 (4H, m), 5.43 (1H,
3
br s), 4.14 (1H, dd, J = 3.5, 3.5 Hz), 3.33 (1H, ddd, J = 13, 12, 3.5 Hz), 2.81 (1H, dd, J = 13, 4.0, 3.5 Hz),
.60 (1H, dddd, J = 14, 4.0, 3.5, 3.5 Hz), 1.95 (1H, dddd, J = 14, 12, 3.5, 3.5 Hz) (one proton signal was
2
1
3
3
missing owing to exchanging to deuterium); C NMR (100 MHz, CDCl ) δ 134.5, 131.4, 130.4, 128.3,

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HETEROCYCLES, Vol. 82, No. 2, 2011
+
+
1
1
26.8, 124.0, 58.4, 24.4, 21.5; LRMS (EI) m/z 181 (M ); HRMS (EI) m/z Calcd for C
9
H
11NOS (M )
81.0561, Found 181.0562.
N-(4,5,6,7-Tetrahydrobenzo[b]thiophen-4-yl)hydroxylamine (8f): colorless powder; IR (KBr) 3155,
-
1 1
2
4
941, 2882, 760 cm ; H NMR (400 MHz, CDCl
3
) δ 7.08 (1H, d, J = 5.6 Hz), 7.00 (1H, d, J = 5.6 Hz),
.12 (1H, dd, J = 4.8, 4.8 Hz), 2.83 (1H, ddd, J = 16.4, 5.2, 5.2 Hz), 2.77-2.69 (1H, m), 2.08-1.80 (4H, m)
1
3
(
3
two proton signals were missing owing to exchanging to deuterium); C NMR (100 MHz, CDCl ) δ
+
1
39.8, 133.7, 127.0, 122.3, 57.0, 26.1, 25.1, 19.8; LRMS (EI) m/z 169 (M ); HRMS (EI) m/z Calcd for
+
C
8
H11NOS (M ) 169.0561, Found 169.0567.
N-(1-Phenylethyl)hydroxylamine (8i): colorless powder; IR (neat) 3252, 1499, 1452, 988, 760, 698
-1 1
cm ; H NMR (500 MHz, CDCl )  7.37-7.26 (5H, m), 4.11 (1H, q, J = 6.8 Hz), 1.38 (3H, d, J = 6.8 Hz)
3
1
3
(
two proton signals were missing owing to exchanging to deuterium); C NMR (125 MHz, CDCl ) 
3
+
1
42.3, 128.5, 127.6, 127.1, 61.8, 19.4; LRMS (EI) m/z 137 (M ); HRMS (EI) m/z Calcd for C
8
H11NO
+
(
M ) 137.0841, Found 137.0858.
N-(1-Phenylpropyl)hydroxylamine (8j): colorless powder; IR (KBr) 3265, 3144, 2864, 1495, 1452,
-1 1
1
346, 1026, 758, 696 cm ; H NMR (400 MHz, CDCl
3
) δ 7.36-7.24 (5H, m), 3.82 (1H, dd, J = 8.8, 5.6
Hz), 1.93-1.81 (1H, m), 1.68-1.55 (1H, m), 0.81 (3H, t, J = 7.6 Hz) (two proton signals were missing
1
3
owing to exchanging to deuterium); C NMR (100 MHz, CDCl
3
) δ 141.0, 128.4, 127.8, 127.6, 68.7, 26.2,
+
+
1
0.5; LRMS (EI) m/z 151 (M ); HRMS (EI) m/z Calcd for C
9
H
13NO (M ) 151.0997, Found 151.1023.
Diphenylmethylhydroxylamine (8k): colorless powder; IR (KBr) 3252, 3084, 3028, 2880, 1493, 1450,
-1 1
1
3
429, 1085, 1034, 1022, 894, 752, 698, 636 cm ; H NMR (400 MHz, CDCl ) δ 7.52-7.20 (10H, m), 5.17
1
3
(
1H, br s) (two proton signals were missing owing to exchanging to deuterium); C NMR (100 MHz,
+
CDCl ) δ 140.5, 128.5, 127.7, 127.5, 70.6; LRMS (EI) m/z 199 (M ); HRMS (EI) m/z Calcd for
3
+
C
13
H
13NO (M ) 199.0997, Found 199.0992.
General procedure for rearrangement reaction of hydroxylamines with DIBALH
5
,6,11,12-Tetrahydrodibenz[b,f]azocine (9g): To a stirred solution of hydroxylamine 8g (68.9 mg,
0
.306 mmol) in CH Cl (3.1 mL), DIBALH (1.79 mL, 1.83 mmol, 1.02 M in n-hexane) was added
2
2
dropwise at 0 °C under an argon atmosphere. Stirring was continued for 3.5 h at 0 °C. NaF powder (385
mg, 9.18 mmol) and water (100 L) were added at 0 °C, and the resulting mixture was stirred for 30 min
at the same temperature. Then the reaction mixture was filtered through a Celite pad. The filter cake was
washed with CH
2
Cl
2
and Et
2
O, and the combined organic solutions were evaporated under reduced
, n-hexane:EtOAc = 9:1) yielded 9g (44.4
pressure. The residue was purified by preparative TLC (SiO
2
2
b
-1 1
mg, 69%): colorless crystals; mp 128-130 °C; IR (KBr) 3364, 2924, 1603, 1477 cm ; H NMR (400
MHz, CDCl ) δ 7.10-7.05 (3H, m), 7.02 (1H, dd, J = 8.0, 1.6 Hz), 6.97 (1H, dd, J = 7.6, 1.6 Hz), 6.89 (1H,
ddd, J = 8.0, 7.6, 1.6 Hz), 6.68 (1H, ddd, J = 7.6, 7.6, 1.6 Hz), 6.49 (1H, dd, J = 8.0, 1.6 Hz), 4.42 (2H, s),
3

HETEROCYCLES, Vol. 82, No. 2, 2011
1643
1
3
3
1
.93 (1H, br s), 3.29 (2H, t, J = 7.2 Hz), 3.17 (2H, t, J = 7.2 Hz); C NMR (100 MHz, CDCl
3
) δ 147.3,
40.6, 137.3, 131.1, 130.3, 129.5, 129.3, 127.3, 126.8, 126.5, 120.0, 119.0, 51.8, 35.5, 32.5; LRMS (EI)
+
+
m/z 209 (M ); HRMS (EI) m/z Calcd for C15
H15N (M ) 209.1204, Found 209.1179.
5
-12
Similarly, the rearrangement reactions of hydroxylamines 8a-f or 8h-k with DIBALH were carried out
1
5
to afford compounds 6, 9a, 9c-e, 9h-k, or 10f, which were identified with those of the literatures
reported previously.
ACKNOWLEDGEMENTS
This work was supported by the MEXT, the KAKENHI, a Grant-in-Aid for Scientific Research (B)
(20390003), Tohoku University G-COE program ‘IREMC,’ and the JSPS predoctoral fellowship to Y.I.
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8
9
1
1
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1
7
3
3
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1
1
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1
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9
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