Ring-expansion reaction of oximes with aluminum reductants

Article abstract of DOI:10.3390/molecules17067348

The ring-expansion reactions of heterocyclic ketoximes and carbocyclic ketoximes with several reductants such as AlHCl₂, AlH₃ (alane), LiAlH₄, LiAlH(OtBu)₃, and (MeOCH ₂CH₂O)₂AlH₂Na (Red-Al) were examined. Among reductants, AlHCl₂ (LiAlH₄:AlCl ₃ = 1:3) in cyclopentyl methyl ether (CPME) has been found to be a suitable reagent for the reaction, and the rearranged cyclic secondary amines were obtained in good to excellent yields.

Full text of DOI:10.3390/molecules17067348

Molecules 2012, 17, 7348-7355; doi:10.3390/molecules17067348
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Ring-Expansion Reaction of Oximes with Aluminum Reductants
Hidetsura Cho 1,2,*, Yusuke Iwama 2, Nakako Mitsuhashi 2, Kenji Sugimoto 2, Kentaro Okano 2
and Hidetoshi Tokuyama 2,*
1
Graduate School of Science, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku,
Sendai 980-8578, Japan
2
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku,
Sendai 980-8578, Japan
* Authors to whom correspondence should be addressed;
E-Mails: hcho@mail.pharm.tohoku.ac.jp (H.C.); tokuyama@mail.pharm.tohoku.ac.jp (H.T.);
Tel.: +81-22-795-6887 (H.T.); Fax: +81-22-795-6877 (H.T.).
Received: 5 April 2012; in revised form: 4 June 2012 / Accepted: 7 June 2012 /
Published: 14 June 2012
Abstract: The ring-expansion reactions of heterocyclic ketoximes and carbocyclic
ketoximes with several reductants such as AlHCl2, AlH3 (alane), LiAlH4, LiAlH(OtBu)3,
and (MeOCH2CH2O)2AlH2Na (Red-Al) were examined. Among reductants, AlHCl2
(LiAlH4:AlCl3 = 1:3) in cyclopentyl methyl ether (CPME) has been found to be a suitable
reagent for the reaction, and the rearranged cyclic secondary amines were obtained in good
to excellent yields.
Keywords: aluminum reductant; dichloroaluminum hydride (AlHCl2); ring-expansion of
oxime; rearrangement of oxime; cyclopentyl methyl ether (CPME)
1. Introduction
The development of novel synthetic method of constructing basic heterocyclic skeletons is an
important research topic from the viewpoint of both synthetic chemistry and medicinal chemistry.
Specifically, the fundamental skeletons containing a nitrogen functionality attached to an aromatic ring
are of great importance because they are often used as the core structures of medicines or clinical
candidates. In this research area, we have recently reported the synthesis of five- to eight-membered
bicyclic or tricyclic fused heterocycles containing nitrogen attached to an aromatic ring by the

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reductive ring expansion reaction of cyclic ketoximes or hydroxylamines using diisobutylaluminum
hydride [DIBALH: (iBu)2AlH] [1–6]. We also carried out mechanistic studies to prove the
intermediacy of the corresponding hydroxylamines and to obtain mechanistic information about the
ring expansion on the basis of DFT calculations [3].
However, we have not yet performed systematic examinations of suitable reductants and solvents
for the reductive ring expansion reaction. A similar reaction using borane was in fact reported by
Ortiz-Marciales et al. The reductive ring expansion of O-silylated oximes proceeded using borane in
the presence of boron trifluoride [7]. In this report, we disclose our recent results on the reductive
ring-expansion reactions of oximes with a variety of aluminum reductants.
2. Results and Discussion
We selected five reductants, i.e., lithium aluminum hydride (LiAlH4) [8,9], aluminum hydride
(AlH3; alane) [9–11], sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al; Vitride) [12],
dichloroaluminum hydride (AlHCl2) [9–11,13], lithium tri-tert-butoxyaluminum hydride [LiAlH(OtBu)3],
and compared their reactivities using the oxime 1a as the test substrate (Table 1).
Table 1. Rearrangement of oxime with various reductants.
S
S
S
reagent (6 equiv.)
solvent
N
H
NOH
NH2
1a
2a
3a
Entry
Reagent
LiAlH4
Solvent
Et2O
Temp.
0 °C to rt
0 to 50 °C
0 °C to reflux 24 h
Time 2a (%) 3a (%)
1
2
3
4
5
6
5 h
5 h
29
31
0
45
18
0
(MeOCH2CH2O)2AlH2Na toluene
LiAlH(OtBu)3
AlH3
Et2O
Et2O
Et2O
0 °C to rt
0 °C to rt
0 °C to rt
2 h
2 h
2 h
46
72
76
47
6
0
AlHCl2
AlHCl2
CPME
When 1a was treated with six mol equiv. of LiAlH4, the desired ring expansion product, 2,3,4,5-
tetrahydrobenzo[b][1,4]thiazepine (2a) was obtained in only 29% yield and was associated with
substantial amounts of the primary amine 3a [14], which should be generated by the C=N and N–O
reduction of the oxime (Entry 1). Reaction with Red-Al gave similar results providing a mixture of 2a
(31%) and 3a (18%) (Entry 2). LiAlH(OtBu)3, on the other hand, was considerably less reactive and
produced no product (Entry 3). Next, we examined AlH3 and AlHCl2, which possess Lewis acidic
character. When 1a was treated with six mol equiv. of AlH3 in Et2O, a result parallel to those of
LiAlH4 and Red-Al was obtained. Thus, a mixture of 2a and 3a in 46% and in 47% yield, respectively,
was isolated (Entry 4). Interestingly, however, the treatment of the ketoxime 1a with six mol equiv. of
AlHCl2, which was prepared as a suspension in Et2O, afforded 2a in 72% yield associated with only a
small amount of the primary amine 3a (6%) (Entry 5). The smooth ring expansion after 1,2-reduction
may be attributed to the Lewis acidity of AlHCl2 etc., which should coordinate with the oxygen of the

Molecules 2012, 17
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hydroxylamine A to promote a rearrangement process via intermediate B (Scheme 1) [3]. Having
found that AlHCl2 is a suitable reductant to promote the ring expansion reaction, we then investigated
this generality along with solvent effects. As to reaction solvents, several solvents such as Et2O, iPr2O,
THF, cyclopentyl methyl ether (CPME) [15,16] and mixed solvents were examined. Among them, the
use of CPME was found to suppress the formation of undesired 3a to provide 2a in 76% yield (Entry 6).
CPME is an alternative to conventional ethereal solvents, such as THF and diethyl ether, due to a
higher solubility for substrates, the superior handling, and safety for a large-scale production [15].
Scheme 1. Proposed mechanisms of reductive ring expansion reaction of ketoximes with
the aluminum reagent.
The generality of CPME was examined using a variety of cyclic ketoximes (Table 2). Although the
reaction of 1b in CPME provided 2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine (2b) in slightly lower
yield than in Et2O (Entry 2), reactions using 1a, 1c, and 1d in CPME afforded 2,3,4,5-tetrahydro-
benzo[b][1,4]thiazepine (2a), 2,3,4,5-tetrahydro-1H-benz[b]azepine (2c), and 5,6,7,8-tetrahydro-4H-
thieno[3,2-b]azepine (2d) in much better yields (Entries 1, 3, and 4), respectively. In addition, the
reactions of aryl oximes 1e and 1f furnished the desired tetrahydrobenzoazepines 2e and 2f in good to
excellent yields (Entries 5 and 6). Subsequently, we applied the reaction to five- or seven-membered
oximes. While the reaction of 1g in Et2O gave 1,2,3,4-tetrahydroquinoline (2g) in moderate yield
because of the recovered starting material, the reaction in CPME provided 2g in better yields than in
Et2O (Entry 7). The treatment of 1h with AlHCl2 in CPME also gave 1,2,3,4,5,6-hexahydrobenz[b]azocine
(2h) in good yield (Entry 8).
Table 2. Rearrangement of oxime with dichloroaluminum hydride.
X
X
AlHCl2 (6 equiv.)
Y
Ar
Y
Ar
Solvent
0 °C to rt
n
N
H
n
NOH
1
2
n=0, 1, 2
n=0, 1, 2

Molecules 2012, 17
7351
Table 2. Cont.
Entry
Oxime 1
Solvent Rearranged Product 2 Yield of 2
S
S
Et2O
CPME
Et2O
72%
76%
87%
83%
54%
78%
68%
88%
1a
2a
1
N
H
NOH
O
O
1b
1c
1d
2b
2c
2d
2
3
4
N
H
CPME
Et2O
NOH
N
H
CPME
Et2O
NOH
NOH
S
S
N
H
CPME
MeO
MeO
MeO
MeO
1e
1f
2e
2f
5
6
7
CPME
CPME
84%
78%
N
H
NOH
NOH
N
H
Et2O
45%
69%
1g
1h
2g
N
H
CPME
NOH
2h
8
CPME
69%
N
H
HON
3. Experimental
3.1. General
All the melting points were determined with a Yanaco micro melting point apparatus and are
uncorrected. IR spectra were measured with a Shimadzu FTIR-8300 spectrometer. NMR spectra (at
1
13
400 MHz for H and 100 MHz for C) were recorded on a JEOL JNM-Al 400 spectrometer with
tetramethylsilane (0 ppm) or chloroform (7.24 ppm) as the internal standard. Mass spectra were recorded
on JMS-DX303, JMS-700, or JMS-T100GC spectrometers. Elemental analyses were performed with a
Yanaco CHN CORDER MT-6. Column chromatography was performed on silica gel 60N (Kanto,
63–210 μm), and flash column chromatography was performed on silica gel 60N (Kanto, 40–60 μm)
using the indicated solvents. Reactions and chromatography fractions were monitored by using
precoated silica gel 60 F254 plates (Merck).

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3.2. General Preparation of AlHCl2 and AlH3 in Accordance with the Procedure Reported by
Ashby et al. [10,11]
Four mol equiv. of AlHCl2 (containing one mol equiv. of LiCl) was prepared in Et2O or CPME at 0 °C
from one mol equiv. of LiAlH4, and three mol equiv. of AlCl3. Four mol equiv. of AlH3 (containing
three mol equiv. of LiCl) was prepared in Et2O from three mol equiv. of LiAlH4 and one mol equiv.
of AlCl3.
3.2.1. Synthesis of 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine (2a) and 3,4-dihydro-2H-thiochromen-4-
ylamine (3a)
Reaction of 1a with 6.0 mol equiv. of AlHCl2 in CPME (Table 2, Entry 1). A flame-dried 30-mL
two-necked round-bottomed flask equipped with a magnetic stirring bar was charged with LiAlH4
(15.0 mg, 395 µmol). The LiAlH4 in the flask was stirred at 0 °C. A dry CPME (1.5 mL) solution of
AlCl3 (159 mg, 1,190 μmol) from a flame-dried 10-mL two-necked round-bottomed flask was slowly
added to the reaction mixture over a period of 5 min by cannulation. The reaction mixture was stirred
at 0 °C for 2 h. Thiochroman-4-one oxime (1a, 47.3 mg, 264 µmol) in dry CPME (2.5 mL) from a
flame-dried 10-mL two-necked round-bottomed flask was added slowly to the reaction mixture over a
period of 5 min by cannulation. After stirring for 10 min at 0 °C, the reaction mixture was warmed to
room temperature, stirred for another 2 h, cooled to 0 °C, and then treated carefully with wet Et2O (2 mL)
and water (2 mL). The mixture was made basic with 1 M aqueous potassium hydroxide (5 mL) and
extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate
and filtered. The filtrate was concentrated under reduced pressure. The residue was purified twice by
preparative TLC (hexane/EtOAc = 5:1) to afford pure 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine (2a)
(33.2 mg, 201 µmol, 76%) as a yellow oil. To a solution of 2a in Et2O was added hydrochloric acid in
Et2O (1 M) at room temperature. After stirring, Et2O was removed under reduced pressure. The residue
was purified by recrystallization to give the hydrochloric acid salt of 2a as colorless crystals.
2,3,4,5-Tetrahydrobenzo[b][1,4]thiazepine (2a) hydrochloride. M.p.: 138–142 °C (from EtOH), m.p.
1
142–144 °C (from i-PrOH). H-NMR (CD3OD):  7.74 (dd, 1H, J = 1.6 and 7.6 Hz), 7.56 (dd, 1H,
J = 1.6 and 7.6 Hz), 7.51 (ddd, 1H, J = 1.6, 7.6 and 7.6 Hz), 7.46 (ddd, 1H, J = 1.6, 7.6 and 7.6 Hz),
3.51 (t, 2H, J = 5.6 Hz), 2.95 (t, 2H, J = 5.6 Hz), 2.40 (tt, 2H, J = 5.6 and 5.6 Hz). 13C-NMR (CD3OD):
 140.9, 136.0, 132.6, 131.3, 131.0, 124.7, 50.9, 32.7, 29.9. IR (KBr, cm−1): 2914, 2687, 1558, 1456,
764. Elemental analysis: calcd. (%) for C9H12ClNS: C 53.59, H 6.00, N 6.94. Found: C 53.47, H 5.85,
N 6.89.
Orlova et al. carried out the reaction of 1a with the reagent LiAlH4-AlCl3 (1:4, 4 equiv. to 1a) and
described that 2a was obtained in 80.5% yield. The melting point (m.p. 202–204 °C from i-PrOH) of
the HCl salts reported is different from our HCl salts (m.p. 142–144 °C from i-PrOH) [13].
Reaction of 1a with 6.1 mol equiv. of LiAlH4 (Table 1, Entry 1). A flame-dried 10-mL two-necked
round-bottomed flask equipped with a magnetic stirring bar was charged with LiAlH4 (23.2 mg,
610 μmol). The LiAlH4 in the flask was stirred at 0 °C. To the stirred LiAlH4 was added dry Et2O (1.0 mL).
To the suspension was added 1a (18.2 mg, 100 μmol). After stirring for 0.5 h at 0 °C, the reaction
mixture was warmed to room temperature, stirred for another 6 h, cooled to 0 °C, and then treated

Molecules 2012, 17
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carefully with wet Et2O (1 mL) and water (1 mL). The mixture was made basic with 2 M aqueous
NaOH (2 mL) and extracted with Et2O. The combined organic extracts were washed with brine, dried
over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The
residue was purified by preparative TLC (hexane/Et2O = 3:1) to afford 2a (4.8 mg, 29 µmol, 29%) and
3a (7.4 mg, 45 µmol, 45%).
3,4-Dihydro-2H-thiochromen-4-ylamine (3a) [14]; 1H-NMR (CDCl3):  7.32–7.23 (m, 1H), 7.16–7.00
(m, 3H), 4.05 (brs, 1H), 3.31–3.19 (m, 1H), 2.98–2.87 (m, 1H), 2.17–2.05 (m, 2H), 1.62 (br s, 2H).
13C-NMR (CDCl3):  137.4, 132.3, 129.2, 127.4, 126.7, 124.2, 48.4, 31.0, 22.1. IR (neat, cm–1): 2920,
2849, 1583, 1566, 1472, 1435, 1286, 1074, 1042, 887, 754, 731. HRMS-EI calcd. for C9H11NS (M+)
165.0612. Found: 165.0608.
Reaction of 1a with 6.0 mol equiv. of Red-Al (Table 1, Entry 2). A two-necked 10-mL
round-bottomed flask equipped with a magnetic stirring bar was charged with 1a (18.0 mg, 100 μmol)
and dry toluene (1 mL). The solution was cooled to 0 °C. To the solution was added Red-Al (76 μL,
≥65 wt% in toluene, 600 μmol) at 0 °C, and the resulting mixture was stirred at room temperature for
0.5 h. The reaction mixture was heated at 50 °C for 6 h, cooled to 0 °C, and then treated carefully with
wet Et2O (1 mL) and water (1 mL). The mixture was made basic with 2 M aqueous NaOH (2 mL) and
extracted with Et2O. The combined organic extracts were washed with brine, dried over anhydrous
sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was
purified by preparative TLC (hexane/Et2O = 3:1) to afford 2a (5.1 mg, 31 µmol, 31%) and 3a (2.9 mg,
18 µmol, 18%). Orlova and Kucherova reported the reaction of 1a with Red-Al, but they simply noted
the reaction in only 12 lines and no details were given [12].
Reaction of 1a with 5.9 mol equiv. of AlH3 (Table 1, Entry 4). A flame-dried 10-mL two-necked
round-bottomed flask equipped with a magnetic stirring bar was charged with LiAlH4 (16.8 mg, 443 μmol).
The LiAlH4 in the flask was stirred at 0 °C. To the stirred LiAlH4 was added dry Et2O (1.0 mL) and
AlCl3 (23.2 mg, 170 μmol). The reaction mixture was stirred at 0 °C for 1 h. To the suspension was
added 1a (18.2 mg, 100 μmol). After stirring for 0.5 h at 0 °C, the reaction mixture was warmed to
room temperature, stirred for another 2 h, cooled to 0 °C, and then treated carefully with wet Et2O (1 mL)
and water (1 mL). The mixture was made basic with 2 M aqueous NaOH (2 mL) and extracted with
Et2O. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate,
and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by
preparative TLC (hexane/Et2O = 3:1) to afford 2a (7.6 mg, 46 µmol, 46%) and 3a (7.8 mg, 47 µmol, 47%).
3.2.2. Synthesis of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine (2d)
Reaction of 1d with 6.0 mol equiv. of AlHCl2 in CPME (Table 2, Entry 4). To a flame-dried 100-mL
two-necked round-bottomed flask equipped with a magnetic stirring bar were successively added
LiAlH4 (65.1 mg, 1.72 mmol), anhydrous CPME (10 mL), and AlCl3 (682 mg, 5.11 mmol) at 0 °C.
Stirring was continued at 0 °C for 1 h. 6,7-Dihydro-4-benzo[b]thiophenone oxime (1d, 167 mg,
1.00 mmol) was added in a small portion. After stirring for 0.5 h at 0 °C, the reaction mixture was
warmed to room temperature, stirred for another 2.5 h, cooled to 0 °C, and then treated carefully with
wet Et2O (10 mL) and 2 M aqueous NaOH (20 mL). The mixture was extracted with Et2O and the

Molecules 2012, 17
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combined organic extract was washed with brine, dried over anhydrous sodium sulfate, and filtered.
The filtrate was concentrated under reduced pressure to give the residue, which was purified by
silica gel column chromatography (hexanes/EtOAc = 3:1) to afford 5,6,7,8-tetrahydro-4H-thieno[3,2-
b]azepine (2d, 135 mg, 0.881 mmol, 88%) as a yellow oil [1].
4. Conclusions
The examination of the reductive ring-expansion reaction of cyclic ketoximes using a variety of
aluminum reductants, i.e., LiAlH4, LiAlH(OtBu)3, Red-Al, AlHCl2, and AlH3, revealed that
dichloroaluminum hydride (AlHCl2) (LiAlH4/AlCl3 = 1:3) is a suitable reagent for promoting the
reaction and affords ring expansion products in good to excellent yields. In addition, it was clarified
that CPME could be effective solvent than Et2O for the rearrangement of cyclic ketoximes with
AlHCl2. The finding may lead to further synthetic application of variously substituted heterocyclic
compounds and complicated medicine candidates containing a nitrogen functionality attached to an
aromatic ring.
Acknowledgments
This work was supported by KAKENHI, a Grant-in-Aid for Scientific Research (C) (23590001),
the Cabinet Office, Government of Japan through its “Funding Program for Next Generation
World-Leading Researchers”, Tohoku University G-COE program ‘IREMC’, a JSPS predoctoral
fellowship to Y.I., Japan Tobacco Inc. to H.C., and Banyu Life Science Foundation International.
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Sample Availability: Samples of the compounds 2a–h are available from the authors. The primary
amines 3a is reported in the patent [14].
© 2012 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
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