Regiospecific synthesis of unsubstituted basic skeletons of heterocycles containing nitrogen neighboring an aromatic ring by the reductive ring expansion reaction using diisobutylaluminum hydride

Article abstract of DOI:10.3987/COM-08-11629

A systematic investigation of reductive ring expansion reaction of oximes with diisobutylaluminum hydride (DIBAH) was performed. The reaction regiospecifically provided a variety of unsubstituted bicyclic heterocycles 3a-3g or tricyclic heterocycles 3h, 3j-3l that contained nitrogen attached to an aromatic ring.

Full text of DOI:10.3987/COM-08-11629

HETEROCYCLES, Vol. 78, No. 5, 2009
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HETEROCYCLES, Vol. 78, No. 5, 2009, pp. 1183 - 1190. © The Japan Institute of Heterocyclic Chemistry
Received, 16th December, 2008, Accepted, 22nd January, 2009, Published online, 28th January, 2009
DOI: 10.3987/COM-08-11629
REGIOSPECIFIC SYNTHESIS OF UNSUBSTITUTED BASIC
SKELETONS OF HETEROCYCLES CONTAINING NITROGEN
NEIGHBORING AN AROMATIC RING BY THE REDUCTIVE RING
EXPANSION REACTION USING DIISOBUTYLALUMINUM HYDRIDE
Hidetsura Cho,*a,b Yusuke Iwama,b Kenji Sugimoto,b Eunsang Kwon, a,c and
Hidetoshi Tokuyama*b
a Graduate School of Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku,
b
Sendai, 980-8578, Japan E-mail: hcho@mail.pharm.tohoku.ac.jp, Graduate
School
of
Pharmaceutical
Science,
Tohoku
University,
E-mail:
c
tokuyama@mail.pharm.tohoku.ac.jp Research and Analytical Center for Giant
Molecules, Tohoku University
Abstract – A systematic investigation of reductive ring expansion reaction of
oximes with diisobutylaluminum hydride (DIBAH) was performed. The reaction
regiospecifically provided a variety of unsubstituted bicyclic heterocycles 3a-3g
or tricyclic heterocycles 3h, 3j-3l that contained nitrogen attached to an aromatic
ring.
INTRODUCTION
Development of synthetic methods for unsubstituted basic skeletons of heterocycles is important from the
viewpoint of both synthetic chemistry and medicinal chemistry. In particular, synthesis of bicyclic or
tricyclic fused-heterocycles containing nitrogen attached to an aromatic ring (including benzazepine,
benzoxazine, benzoxazepine, benzthiazine, and benzthiazepine) is crucial, since these often form the core
structures of medicines or clinical candidates. However, there are only few synthetic procedures available
to construct heterocycles containing nitrogen attached to an aromatic ring. While Beckmann
rearrangement or Schmidt rearrangement of bicyclic aryl ketones is a possible approach to obtaining these
compounds, such reactions generally produce two isomeric lactam derivatives.1 On the other hand,
structural simplicity means that construction of unsubstituted basic skeletons is relatively difficult and
usually requires lengthy procedures when conventional methods are employed, such as lactamization and

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HETEROCYCLES, Vol. 78, No. 5, 2009
reduction.2 Cho and co-workers devised a method for the construction of heterocyclic fused-azepines by
ring expansion of oxime derivatives with diisobutylaluminum hydride (DIBAH) during the course of
investigating arginine vasopressin antagonists (Scheme 1).3,4
X
X
X
NH2OH·HCl
DIBAH
CH2Cl2
pyridine
N
N
H
O
OH
X = O, S, NH
Scheme 1
Namely, it was found that the regiospecific ring expansion reaction of oximes with DIBAH gave the
corresponding heterocyclic fused-azepines such as 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine,
5,6,7,8-tetrahydro-4H-furo[3,2-b]azepine, and 5,6,7,8-tetrahydro-4H-pyrro[3,2-b]azepine as the sole
product. Yamamoto and Maruoka reported that the rearrangement of aliphatic hydroxylamine carbonates
by trialkylaluminum compounds and the reduction of oximes and oxime sulfonates with DIBAH gave the
corresponding simple amines.5 After Cho’s preliminary report, Torisawa6 and Willand7 more recently
applied the ring expansion reaction with DIBAH to the synthesis of heterocyclic compounds. On the other
hand, Ortiz-Marciales8 reported the synthesis of similar heterocycles by rearrangement of O-silylated
oximes via reduction with boran in the presence of boron trifluoride. Similarly, Naito studied ring
expansion for several azepines by reactions of N-alkoxy(arylmethyl)amines to N-alkyl arylamines with an
organolithium or a magnesium reagent.9 While several applications have been reported, there have been
no investigations about its general applicability. Here we describe a systematic investigation of using the
reductive ring expansion reaction with DIBAH for regiospecific synthesis of unsubstituted basic skeletons
of bicyclic or tricyclic heterocycles.
RESULTS AND DISCUSSION
A series of aryl ketones 1a–1l, which are commercially available or known in the literature,10 were
converted to the corresponding oxime derivatives 2a–2l11 by treatment with two to four equivalents of
hydroxylamine hydrochloride in pyridine (Table 1 and Table 2). Without separation, the E, Z mixture of
o
oximes was reacted with six equivalents of a hexane solution of DIBAH at 0 C to r.t. Then the reaction
mixture was treated with NaF to give the corresponding bicyclic or tricyclic secondary amine compounds
(Table 1 and Table 2) at good to excellent yields. Reaction of a series of oximes 2a, 2b, or 2c, derived
from five-, six-, or seven-membered carbocyclic ketones, resulted in the six-, seven-, or eight-membered
cyclic secondary amines 1,2,3,4-tetrahydroquinoline 3a, 2,3,4,5-tetrahydro-1H-benz[b]azepine 3b,8 and
1,2,3,4,5,6-hexahydrobenz[b]azocine 3c,12 respectively (Table 1; entries 1-3). Similarly, oximes 2d, 2e, 2f,
or 2g prepared from five- or six-membered oxygen- or sulfur-containing cyclic-ketones 1d, 1e, 1f, and 1g

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Table 1. Ring Expansion Reaction of Bicyclic Oximes with DIBAH
Entry
Ketone 1a-1g
Oxime 2a-2g (% yield)a
Aromatic amine 3a-3g (% yield)b
1
1a
1b
2a (85)
3a (92)
3b (80)
N
H
O
NOH
NOH
2
3
4
5
6
7
2b (87)
2c (90)
2d (69)
2e (80)
2f (64)
2g (96)
N
H
O
1c
1d
1e
1f
3c (73)
3d (80)
3e (87)
3f (60)
3g (71)
HN
O
NOH
O
O
O
O
N
NOH
H
O
O
O
O
N
H
NOH
S
S
S
N
O
NOH
H
S
S
S
1g
N
H
O
NOH
aThe reactions were carried out with ketone (1 eq) and hydroxyamine hydrochloride (2 eq) in pyridine at room tempereture for 1-3 h.
bThe reactions were carried out wih oxime (1 eq) and DIBAH (6-9 eq) in CH2Cl2 at room temperature for 2-5 h.

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were converted to six- or seven-membered cyclic secondary amine derivatives, including
3,4-dihydro-2H-benzo[b][1,4]oxazine 3d,13 2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine 3e,8 3,4-dihydro-
2H-benzo[b][1,4]thiazine 3f,14 and 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 3g,14, 15 respectively (Table
1; entries 4-7).
Significantly, the procedure was applicable to performing the ring expansion reaction of oxime 2h11
which was prepared from 1,2,3,4-tetrahydrocarbazol-4-one 1h, leading to the tricyclic compound
1,2,3,4,5,6-hexahydroazepino[3,2-b]indole 3h.
Table 2. Ring Expansion Reaction of Tricyclic Oximes with DIBAH
Entry
Ketone 1h-1l
Oxime 2h-2l (% yield)a
Aromatic amine 3h-3l, 4, 5 (% yield)b
H
H
H
N
N
N
3h (not
isolated)
N
1
1h
2h (91)
4 (63) c
O
O
NOH
NOH
Ar
O
Ar = p-nitrophenyl
H
H
N
N
H
N
H
N
2
3
1i
1j
2i (99)
3i (0)
S
S
S
3j (not
isolated)
5 (21) c
2j (77)
N
O
NOH
Ar
O
Ar = p-nitrophenyl
4
5
1k
1l
2k (99)
3k (69)
N
H
O
NOH
2l (54)d
3l (60)
HN
O
NOH
aThe reactions were carried out with ketone (1 eq) and hydroxyamine hydrochloride (2 eq) in pyridine at room tempereture for 1-3 h.
bThe reactions were carried out wih oxime (1 eq) and DIBAH (6-9 eq) in CH2Cl2 at room temperature for 2-5 h.
cThe yields were based on oximes. dThe reactions were carried out with ketone (1 eq) and hydroxyamine hydrochloride (4 eq) in pyridine under reflux for 11 h.

HETEROCYCLES, Vol. 78, No. 5, 2009
1187
Since the product 3h was unstable, its yield was determined after benzoylation with p-nitrobenzoyl
chloride and Et3N in dichloromethane to afford 4 (Table 2; entry 1). The NMR spectrum of 4 exhibited
only one proton at a lower field (δ 5.11 ppm), apart from the other aliphatic protons. Therefore, the
structure of this tricyclic compound 4 was unambiguously determined by X-ray crystallographic analysis
(Figure 1).16 This also confirmed the regiochemistry of the ring expansion reaction. Thus, the ORTEP
drawing of compound 4 in Figure 1 shows that the product 3h had a nitrogen atom attached to an
aromatic ring, indicating that aryl migration occurred regiospecifically to produce the tricyclic compound.
Despite successful conversion from indole derivative 1h to 3h, reaction of oxime 2i derived from
2,3,4,9-tetrahydrocarbazol-1-one 1i gave a complex mixture under the same reaction conditions and the
desired tricyclic compound 3i was not detected.
H
N
N
O
O2N
4
Figure 1 ORTEP drawing of the molecular structure of compound 4 with thermal ellipsoids at 50 %
probability levels. Hydrogen atoms are omitted for clarity.
Similarly, we tried to synthesize the other tricyclic heterocycle, 2,3,4,5-tetrahydro-1H-
benzothieno[3,2-b]azepine 3j from the corresponding ketone 1j which was obtained by the new synthetic
methods (Scheme 2). As the compound 3j was also unstable, benzoylation was carried out as mentioned
1
13
above to afford compound 5, which was observed as a mixture (6.6:1) of rotamers in H NMR and C
NMR spectra. Next, the possibility of rearrangement on the oximes of the tricyclic ketones; 9-fluorenone
1k and dibenzosuberone 1l was examined. Preparation of oxime 2l from 1l proceeded in pyridine under
reflux for 11 h, and rearrangement from 2k to 5,6-dihydrophenanthridine 3k17 or from 2l to
5,6,11,12-tetrahydrodibenz[b, f]azocine 3l needed longer reaction time (3 h or 4 h), respectively.
The mechanism of the ring expansion reaction using DIBAH has been briefly described in previous
studies.3 We speculate that the reaction is initiated by reduction of the C-N double bond of oximes and
subsequent aromatic ring-assisted N-O bond cleavage, followed by ring expansion to furnish the ring
expansion product with nitrogen attached to the aromatic ring. Further studies on the detailed

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mechanisms are currently under way and will be reported in due course.
In conclusion, we carried out a systematic investigation of the reductive ring expansion reaction of
oximes with DIBAH. It was demonstrated that this procedure was general and useful for constructing a
variety of bicyclic or tricyclic heterocycles containing nitrogen attached to an aromatic ring from the
corresponding aryl ketones. Reactions using a series of substrates revealed that this method is not only
applicable to preparation of the core structures (such as 1,2,3,4-tetrahydroisoquinoline,
2,3,4,5-tetrahydro-1H-benz[b]azepine, 3,4-dihydro-2H-benzo[b][1,4]oxazine, 2,3,4,5- tetrahydrobenzo[b]
[1,4]oxazepine, 3,4-dihydro-2H-benzo[b][1,4]thiazine and 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine
derivatives) of medicines or clinical candidates, but can also be used for the synthesis of
1,2,3,4,5,6-hexahydrobenz[b]azocine, 5,6,11,12-tetrahydrodibenz[b, f]azocine, 2,3,4,5-tetrahydro-1H-
benzothieno[3,2-b]azepine, 1,2,3,4,5,6-hexahydroazepino[3,2-b]indole, and 5,6-dihydrophenanthridine
derivatives which have potential as the core structures of new drugs. Furthermore, this procedure should
be applicable to other bicyclic or tricyclic basic skeletons containing a heteroaryl ring instead of a
benzene ring. This method might be practically useful since it has been possible to employ DIBAH on an
industrial scale.18 Due to its versatility, this synthetic procedure may find widespread use in the fields of
medicinal chemistry and process chemistry for creation of novel drugs as well as for synthesis of the
related natural products.
REFERENCES AND NOTES
1. For Beckmann rearrangement, see: L. G. Danaruma and W. E. Heldt, Org. React., 1960, 11, 1; For
Schmidt rearrangement, see: H. Wolff, Org. React., 1946, 307.
2. C. Kunick, Arch. Pharm. (Weinheim), 1991, 324, 579.
3. H. Cho, K. Murakami, H. Nakanishi, H. Isoshima, K. Hayakawa, and I. Uchida, Heterocycles, 1998,
48, 919.
4. H. Cho, K. Murakami, H. Nakanishi, A. Fujisawa, H. Isoshima, M. Niwa, K. Hayakawa, Y. Hase, I.
Uchida, H. Watanabe, K. Wakitani, and K. Aisaka, J. Med. Chem., 2004, 47, 101; H. Cho, K.
Murakami, A. Fujisawa, M. Niwa, H. Nakanishi, and I. Uchida, Heterocycles, 1998, 48, 1555.
5. K. Hattori, Y. Matsumura, T. Miyazaki, K. Maruoka, and H. Yamamoto, J. Am. Chem. Soc., 1981,
103, 7368; S. Sasatani, T. Miyazaki, K. Maruoka, and H. Yamamoto, Tetrahedron Lett., 1983, 24,
4711; J. Fujisawa, H. Sano, K. Maruoka, and H. Yamamoto, Tetrahedron Lett., 1984, 25, 2367.
6. Y. Torisawa, T. Nishi, and J. Minamikawa, Bioorg. Med. Chem. Lett., 2002, 12, 387.
7. N. Willand, T. Beghyn, G. Nowogrocki, J.-C. Gesquiere, and B. Deprez, Tetrahedron Lett., 2004, 45,
1051.
8. M. Ortiz-Marciales, L. D. Rivera, M. D. Jesús, S. Espinosa, J. A. Benjamin, O. E. Casanova, I. G.

HETEROCYCLES, Vol. 78, No. 5, 2009
1189
Figueroa, S. Rodriguez, and W. Correa, J. Org. Chem., 2005, 70, 10132.
9. O. Miyata, T. Ishikawa, M. Ueda, and T. Naito, Synlett, 2006, 2219.
10. The starting materials 1a, 1b, 1c, 1e, 1g, 1k and 1l are commercially available. Compounds 1d, 1f,
and 1h were prepared according to the procedures in the literatures. For 1d, see: A. Inoue, K.
Kitagawa, H. Shinokubo, and K. Oshima, J. Org. Chem., 2001, 66, 4333. For 1f, see: C. Mukherjee,
S. Kamila, and A. De, Tetrahedron, 2003, 59, 4767. For 1h, see: X. Li and R. Vince, Bioorg. Med.
Chem., 2006, 14, 2942. For cyclization from the carboxylic acid to 1i or 1j, see: H. Cho and S.
Matsuki, Heterocycles, 1996, 43, 127. For new synthesis of 1j, see: Scheme 2 shown below. (As for
the starting material, 2-iodobenzo[b]thiophene, consult ref. 19.)
OH
1) p-TsNHNH2
Pd(PPh3)4 (5 mol%)
CuI (10 mol%), Et3N
1 M NaOAc aq
DME, reflux, 2.5 h
OH
S
S
S
I
OTs
benzene
rt, 30 min
97%
2) p-TsCl, pyridine
CH2Cl2, rt, 2.5 h
57% for 2 steps
6
7
S
S
NaCN
2 M NaOH aq
MsOH, P2O5
1j
CN
CO2H
DMSO
95 °C, 30 min
83%
EtOH
reflux, 6 h
93%
80 °C, 10 min
94%
8
9
Scheme 2
11. The spectral data of oximes 2a, 2b, 2c, 2d, 2e, 2k are identical with those reported previously. For
2a and 2b, see: H. Zhao, C. P. Vandenbossche, S. G. Koenig, S. P. Singh, and R. P, Bakale, Org.
Lett., 2008, 10, 505. For 2c, see: P. A. Bonvallet, E. M. Todd, Y. S. Kim, and R. J. McMahon, J. Org.
Chem., 2002, 67, 9031. For 2d and 2e, see: D. L. J. Clive, M. P. Pham, and R. Subedi, J. Am. Chem.
Soc., 2007, 129, 2713. For 2h, see: S.-I. Bascop, J.-Y. Laronze, and J. Sapi, Monat. Chem., 1999,
130, 1159. For 2k, see: N. Jain, A. Kumar, and S. M. S. Chanhan, Tetrahedron Lett., 2005, 46, 2599.
12. H. Ahlbrecht, E. O. Düber, J. Epsztajn, and R. M. K. Marcinkowski, Tetrahedron, 1984, 40, 1157.
13. K. E. Torraca, S.-I. Kawabe, and S. L. Buchwald, J. Am. Chem. Soc., 2000, 122, 12907.
14. C. Mukheerjee and E. Biehl, Heterocycles, 2004, 63, 2309.
15. General Procedure for the ring expansion reaction using DIBAH: Synthesis of 2,3,4,5-Tetrahydro-
benzo[b][1,4]thiazepine (3g): To a stirred solution of 1-thiochroman-4-one 1g (4.40 g, 26.8 mmol) in
pyridine (50.0 mL) was added hydroxylamine hydrochloride (3.76 g, 54.1 mmol) at rt. After stirring
for 1.5 h, pyridine was removed in vacuo. The residue was diluted with water and extracted with
EtOAc. The aqueous layer was extracted with EtOAc and the combined organic extracts were
washed with brine, dried over MgSO4, and evaporated under reduced pressure to give the crude

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HETEROCYCLES, Vol. 78, No. 5, 2009
material. Chromatography on a silica gel column (EtOAc:n-hexane = 1:3) resulted in oxime 2g (4.61
g, 96%). To a stirred solution of 2g (1.01 g, 5.63 mmol) in CH2Cl2 (56.0 mL) was added DIBAH
(33.0 mL, 33.7 mmol, 1.02 M in n-hexane) over 10 min at 0-5 °C (internal temperature) under Ar.
Stirring was continued for 5 min at 0 °C and for 2 h at rt. NaF powder (6.76 g, 161 mmol) and water
(2.2 mL) 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 pad of Celite. The filter cake was
washed with EtOAc and the combined organic solutions were evaporated to give the crude product.
Purification by chromatography on a silica gel column (Et2O:n-hexane = 1:3) yielded
2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 3g (662 mg, 71%). (1H NMR date was identified with that
reported in ref 14. Although 3 mol eq. of DIBAH is theoretically sufficient in this method, we often
employed 6-9 mol eq. of the reagent to finish each reaction.)
16. Crystal data for 4 C19H17N3O3: MW = 335.36, monoclinic, a = 8.481(2), b = 21.573(6), c =
18.718(5) Å, β = 99.133(3)°, V = 3381.2(16) Å3, T = 173 K, space group P21/c (no. 14), Z = 8,
µ(MoKα) = 0.911 cm-1, Dcalc = 1.317 g/cm3. A total of 49590 reflections were measured, of which
7695 unique (Rint = 0.051) reflections were used for analysis. The structure was refined to a
goodness of fit (GOF) of 0.96 and the final residuals were R = 0.064 and wR = 0.084.
Crystallographic data of 4 have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC-700651. Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB1 1EZ, UK (fax:+44 1223 336033; E-mail:
deposit@ccdc.cam.ac.uk).
17. J. Barluenga, F. J. Fañanas, R. Sanz, and Y. Fernández, Chem. Eur. J., 2002, 8, 2034.
18. For an example to use DIBAH in the process chemistry, see: L. A. Hobson, W. A. Nugent, S. R.
Anderson, S. S. Deshmukh, J. J. Haley III, P. Liu, N. A. Magnus, P. Sheeran, J. P. Sherbine, B. R. P.
Stone, and J. Zhu, Org. Process Res. Develop., 2007, 11, 985. In the case of cyclohexanone oxime,
the large-scale production using DIBAH is also progressing in a chemical corporation.
19. Y. Nicolas, P. Blanchard, E. Levillain, M. Allain, N. Mercier, and J. Roncali, Org. Lett., 2004, 6,
273.