Regioselective synthesis of heterocycles containing nitrogen neighboring an aromatic ring by reductive ring expansion using diisobutylaluminum hydride and studies on the reaction mechanism

Article abstract of DOI:10.1021/jo902177p

(Chemical Equation Presented) A systematic investigation of the reductive ring-expansion reaction of cyclic ketoximes fused to aromatic ringswith diisobutylaluminum hydride (DIBALH) is described. This reaction regioselectively afforded a variety of five- to eight-membered bicyclic heterocycles or tricyclic heterocycles containing nitrogen neighboring an aromatic ring, including indoline, 1,2,3,4,5,6-hexahydrobenz[b]azocine, 3,4-dihydro-2H-benzo[b] [1,4]oxazine, 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine, 1,2,3,4,5,6- hexahydroazepino[3,2-b]-indole, 2,3,4,5-tetrahydro-1H-benzothieno[2,3-b]azepine, 2,3,4,5-tetrahydro-1H-benzothieno[3,2-b]-azepine, 5,6-dihydrophenanthridine, and 5,6,11,12-tetrahydrodibenz[b, f]azocine. The reaction mechanism leading to the rearrangement was investigated on the basis of the restricted Becke three-parameter plus Lee-Yang-Parr (B3LYP) density functional theory (DFT) with the 6-31G (d) basis set. It was found that the reaction proceeds through a three-centered transition state via a stepwise mechanism because the potential energy curve along the intrinsic reaction coordinate (IRC) had twomaxima (saddle points; TS1 and TS2) and the partial phenonium cation intermediate C. In addition to cyclic ketoximes fused to aromatic rings, the reactions of various cyclic and acyclic ketoximeswere examined to investigate preference of migrating group. It was found that themore electron-rich group migrated preferentially to give the corresponding secondary amines.

Full text of DOI:10.1021/jo902177p

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Regioselective Synthesis of Heterocycles Containing Nitrogen
Neighboring an Aromatic Ring by Reductive Ring Expansion Using
Diisobutylaluminum Hydride and Studies on the Reaction Mechanism
Hidetsura Cho,*,†,‡ Yusuke Iwama,‡ Kenji Sugimoto,‡ Seiji Mori,§ and
Hidetoshi Tokuyama*,‡
†Graduate School of Science, and ‡Graduate School of Pharmaceutical Sciences, Tohoku University,
6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan, and §Faculty of Science, Ibaraki University,
2-1-1 Bunkyo, Mito, Ibaraki, 310-8512, Japan
hcho@mail.pharm.tohoku.ac.jp; tokuyama@mail.pharm.tohoku.ac.jp
Received October 9, 2009
A systematic investigation of the reductive ring-expansion reaction of cyclic ketoximes fused to aromatic
rings with diisobutylaluminum hydride (DIBALH) is described. This reaction regioselectively afforded a
variety of five- to eight-membered bicyclic heterocycles or tricyclic heterocycles containing nitrogen
neighboring an aromatic ring, including indoline, 1,2,3,4,5,6-hexahydrobenz[b]azocine, 3,4-dihydro-2H-
benzo[b][1,4]oxazine, 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine, 1,2,3,4,5,6-hexahydroazepino[3,2-b]-
indole, 2,3,4,5-tetrahydro-1H-benzothieno[2,3-b]azepine, 2,3,4,5-tetrahydro-1H-benzothieno[3,2-b]-
azepine, 5,6-dihydrophenanthridine, and 5,6,11,12-tetrahydrodibenz[b, f]azocine. The reaction mechan-
ism leading to the rearrangement was investigated on the basis of the restricted Becke three-parameter
plus Lee-Yang-Parr (B3LYP) density functional theory (DFT) with the 6-31G (d) basis set. It was
found that the reaction proceeds through a three-centered transition state via a stepwise mechanism
because the potential energy curve along the intrinsic reaction coordinate (IRC) had two maxima (saddle
points; TS1 and TS2) and the partial phenonium cation intermediate C. In addition to cyclic ketoximes
fused to aromatic rings, the reactions of various cyclic and acyclic ketoximes were examined to investigate
preference of migrating group. It was found that the more electron-rich group migrated preferentially to
give the corresponding secondary amines.
Introduction
the viewpoint of both synthetic and medicinal chemistry.
Synthesis of five- to eight-membered bicyclic or tricyclic
fused heterocycles containing nitrogen neighboring an aro-
matic ring, such as hydrogenated benzazepine, benzoxazine,
Development of new synthetic methods for the unsubsti-
tuted basic skeletons of heterocycles is important from
DOI: 10.1021/jo902177p
r
Published on Web 12/29/2009
J. Org. Chem. 2010, 75, 627–636 627
2009 American Chemical Society

Cho et al.
JOCArticle
FIGURE 1. Heterocycles containing nitrogen neighboring an aromatic ring.
SCHEME 1. Regiochemical Problem with Beckmann Rearran-
gement
SCHEME 2. Regiochemical Problem with Schmidt Rearrange-
ment
benzoxazepine, benzthiazine, or benzthiazepine (Figure 1), is
particularly important because these are the core structures of
medicines or clinical candidates. In addition, hydrogenated
benzazocine, dibenzoazocine, phenanthridine, azepino[3,2-b]-
indole, and so on are also attractive as partial structures for
medicines, although these compounds have not been widely
used due to lack of synthetic methods.
SCHEME 3. Step-by-Step Synthesis of a Lactam Derivative
Despite their importance, the formation of unsubsti-
tuted core structures of bicyclic or tricyclic heterocycles
containing nitrogen neighboring an aromatic ring has
not yet been well investigated because of the difficulty
in synthesizing these simple structures. There are only
a few straightforward methods available for selective
synthesis of these compounds. While Beckmann rearrange-
ment or Schmidt rearrangement of bicyclic aryl ketones
would be the method of choice, these methods generally
give rise to a mixture of two isomeric lactam derivatives
without high selectivity. For example, Beckmann rear-
oximes with DIBALH2,6 (Scheme 4). Significantly, the
desired bicyclic heterocycle containing nitrogen neighbor-
ing an aromatic ring could be obtained exclusively from
either syn or anti oximes, suggesting that the reaction
mechanisms were different from Beckmann rearrangement.
This method has made it feasible to perform the regioselec-
tive synthesis of a series of unsubstituted basic skeletons
of heterocycles, 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 in good
yield.
As a seminal study in this area, Yamamoto and Maruoka
reported on the reductive rearrangement of oximes
with DIBALH providing the corresponding secondary
amines.7 They also reported several examples of exclusive
generation of secondary amines from unsymmetrical
ketoximes, although the detailed reaction mechanisms
were not described. After Cho’s preliminary report,2a
Torisawa8 and Willand9 more recently applied the
ring-expansion reaction with DIBALH to synthesis
3
rangement of 1 with PPMA1,2 or PCl5 (Scheme 1)
or Schmidt rearrangement of
3
with NaN3-HCl4
(Scheme 2) provides a mixture of two isomeric lactam
derivatives 2a and 2b with low selectivity. In order to
synthesize compound 2a (or 2c) exclusively, conventional
lengthy step-by-step synthesis of ketolactam via Dieckmann
condensation with further transformations are required
(Scheme 3).5
During their investigations into the synthesis of arginine
vasopressin (AVP) antagonists (Figure 2), Cho and co-
workers developed a straightforward method for the synthe-
sis of bicyclic heterocycles containing nitrogen neighbor-
ing an aromatic ring by reductive ring-expansion reaction of
(1) Danaruma, L. G.; Heldt, W. E. Org. React. 1960, 11, 1–156.
(2) (a) Cho, H.; Murakami, K.; Nakanishi, H.; Isoshima, H.; Hayakawa,
K.; Uchida, I. Heterocycles 1998, 48, 919–927. (b) Cho, H.; Matsuki, S.
Heterocycles 1996, 43, 127–131.
(3) Aparajithan, K.; Thompson, A. C.; Sam, J. J. Heterocycl. Chem. 1966,
3, 466–469.
(4) Wolff, H. Org. React. 1946, 307–336.
(5) Kunick, C. Arch. Pharm. (Weinheim) 1991, 324, 579–581.
(6) (a) Cho, H.; Murakami, K.; Nakanishi, H.; Fujisawa, A.; Isoshima,
H.; Niwa, M.; Hayakawa, K.; Hase, Y.; Uchida, I.; Watanabe, H.; Wakitani,
K.; Aisaka, K. J. Med. Chem. 2004, 47, 101–109. (b) Cho, H.; Wakitani, K.
Japan Patent Application, H7-291540 (Nov 9, 1995), WO97/17349. (c) Cho, H.;
Murakami, K.; Fujisawa, A.; Niwa, M.; Nakanishi, H.; Uchida, I. Heterocycles
1998, 48, 1555–1566.
(7) (a) Hattori, K,; Matsumura, Y; Miyazaki, T.; Maruoka, K.; Yama-
moto, H. J. Am. Chem. Soc. 1981, 103, 7368–7370. (b) Sasatani, S.; Miyazaki,
T.; Maruoka, K.; Yamamoto, H. Tetrahedron Lett. 1983, 24, 4711–4712. (c)
Fujiwara, J.; Sano, H.; Maruoka, K.; Yamamoto, H. Tetrahedron Lett. 1984,
25, 2367–2370.
(8) Torisawa, Y.; Nishi, T.; Minamikawa, J. Bioorg. Med. Chem. Lett.
2002, 12, 387–390.
(9) Willand, N.; Beghyn, T.; Nowogrocki, G.; Gesquiere, J.-C.; Deprez,
B. Tetrahedron Lett. 2004, 45, 1051–1054.
628 J. Org. Chem. Vol. 75, No. 3, 2010

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prepared in pyridine from 2-4 equiv of hydroxylamine
hydrochloride and the corresponding aryl ketones, which
are commercially available or reported in the literature,14
and were subjected to reductive rearrangement (Tables 1, 2,
and 4-6). The general procedure involved reaction of an
E, Z mixture of oximes with 6 equiv of a hexane solution of
DIBALH at 0 °C to room temperature, after which the
reaction mixture was treated with NaF to obtain the corres-
ponding linear, bicyclic, or tricyclic secondary amines in
good to excellent yields.
1.1. Reaction of Carbocyclic or Heterocyclic Ketoximes
Fused to a Benzene Ring. The reductive rearrangement reac-
tion was widely applicable, and oximes derived from four- to
seven-membered cyclic ketones could be used to provide the
corresponding ring expanded cyclic secondary amines in good
to excellent yields (Table 1). For instance, reaction of carbo-
cyclic ketoximes 5a, 5b, 5c, or 5d resulted in indoline 6a, 1,2,3,4-
tetrahydroquinoline 6b, 2,3,4,5-tetrahydro-1H-benz[b]azepine
6c,10 and 1,2,3,4,5,6-hexahydrobenz[b]azocine 6d,15 respec-
tively (entries 1-4). Interestingly, the relatively strained
benzocyclobutenone oxime smoothly underwent reductive
rearrangement to give indoline with a small amount (4%) of
an indole byproduct. In addition, a variety of heterocyclic
ketoximes with five- or six-membered oxygen- or sulfur-
containing rings served as good substrates for the reaction.
Thus, coumaran-3-one oxime 5e, chroman-4-one oxime 5f,
thioindoxyl oxime 5g, and thiochroman-4-one oxime 5h were
converted to 3,4-dihydro-2H-benzo[b][1,4]oxazine 6e,16
2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine 6f,10 3,4-dihydro-
2H-benzo[b][1,4]thiazine 6g,17 and 2,3,4,5-tetrahydrobenzo-
[b][1,4]thiazepine 6h,17 respectively (entries 5-8). These com-
pounds should be valuable in the field of medicinal chemistry.
In particular, 3,4-dihydro-2H-benzo[b][1,4]oxazine 6e is im-
portant as a precursor of a human URAT-1 (urate transpor-
ter-1) inhibitor, 2,6-dichloro-4-(2,3-dihydro-1,4-benzoxazin-
4-ylcarbonyl)phenol (Figure 2), which was synthesized in one
step by acylation of 6e with 3,5-dichloro-4-hydroxybenzoyl
chloride.18
FIGURE 2. Structures of an arginine vasopressin (AVP) antago-
nist and a human urate transporter-1 (URAT-1) inhibitor.
SCHEME 4. Preliminary Studies for the Reductive Ring-Ex-
pansion Reaction of Oximes with DIBALH
of heterocyclic compounds. On the other hand, Ortiz-
Marciales10 reported the synthesis of similar hetero-
cycles by rearrangement of O-silylated oximes via
reduction with borane in the presence of boron trifluoride.
In addition, Naito and Miyata described treatment of
oxime ethers with alkyl metal species, such as Grignard
reagents or alkyllithium, to achieve alkylative ring expan-
sion.11
Although several analogous reactions have been
reported, both the general applicability12 and the detailed
reaction mechanisms have not yet been studied. In parti-
cular, there remains some confusion about the mechan-
isms of reductive rearrangement reactions compared
with that of Beckmann rearrangement. In this paper, we
describe the scope and limitation of reductive rearrange-
ment of oximes with DIBALH, including application
to synthesis of five- to eight-membered bicyclic or tricyclic
heterocycles. The results of detailed mechanistic studies
based on density functional theory (DFT) are also
reported.
1.2. Reductive Ring-Expansion Reaction of Tricyclic
Heteroaryl Ketoximes. Next, we examined the reductive
ring-expansion reaction of tricyclic ring systems (Table 2).
(14) The precursor ketones of 5b, 5c, 5d, 5f, 5h, 5k, and 5n are commer-
cially available. Precursor ketones of 5a, 5e, 5g, and 5i were prepared
according to procedures in the literature. (a) For the precursor ketone of
5a, see: Bubb, W. A.; Sternhell, S. Aust. J. Chem. 1976, 29, 1685–1697. (b)
For the precursor ketone of 5e, see: Inoue, A.; Kitagawa, K.; Shinokubo, H.;
Oshima, K. J. Org. Chem. 2001, 66, 4333–4339. (c) For the precursor ketone
of 5g, see: Mukherjee, C.; Kamila, S.; De, A. Tetrahedron 2003, 59, 4767–
4774. (d) For the precursor ketone of 5i, see: Li, X; Vince, R. Bioorg. Med.
Chem. 2006, 14, 2942–2955. (e) For cyclization from the carboxylic acid to
the precursor ketone of 5j, see: Cho, H.; Matsuki, S. Heterocycles 1996, 43,
127–131. Maertens, F.; Toppet, S.; Hoornaert, G. J.; Compernolle, F.
Tetrahedron 2005, 61, 1715–1722. (f) For new synthesis of the precursor
ketone of 5k, see Scheme S1 shown in the Supporting Information. (As for the
starting material, 2-iodobenzo[b]thiophene, consult ref S1 in the Supporting
Information.) (g) For the precursor ketone of 5l, see: Horaguchi, T.; Kubo, T.;
Tanemura, K.; Suzuki, T. J. Heterocyclic. Chem. 1998, 35, 649–653.
Results and Discussion
1. Scope and Limitations of Reductive Rearrangement of
Oximes with DIBALH. A series of oximes 5a-z13 were
ꢀ
(10) Ortiz-Marciales, M.; Rivera, L. D.; Jesus, M. D.; Espinosa, S.;
Benjamin, J. A.; Casanova, O. E.; Figueroa, I. G.; Rodrıguez, S.; Correa,
W. J. Org. Chem. 2005, 70, 10132–10134.
(11) Mukhopadhyay, P. P.; Miyata, O.; Naito, T. Synlett 2007, 1403–
1406.
´
(12) Cho, H.; Iwama, Y.; Sugimoto, K.; Kwon, E.; Tokuyama, H.
Heterocycles 2009, 78, 1183–1190.
€
(15) Ahlbrecht, H.; Duber, E. O.; Epsztajn, J.; Marcinkowski, R. M. K.
Tetrahedron 1984, 40, 1157–1165.
(13) The spectral data of oximes 5a, 5b, 5c, 5d, 5e, 5f, and 5m are identical
with those reported previously. (a) For 5a, see: Bubb, W. A.; Sternhell, S.
Aust. J. Chem. 1976, 29, 1685–1697. (b) For 5b and 5c, see: Zhao, H.;
Vandenbossche, C. P.; Koenig, S. G.; Singh, S. P.; Bakale, R. P. Org. Lett.
2008, 10, 505–507. (c) For 5d, see: Bonvallet, P. A.; Todd, E. M.; Kim, Y. S.;
McMahon, R. J. J. Org. Chem. 2002, 67, 9031–9042. (d) For 5e and 5f, see:
Clive, D. L. J.; Pham, M. P.; Subedi, R. J. Am. Chem. Soc. 2007, 129, 2713–
2717. (e) For 5i, see: Bascop, S.-I.; Laronze, J.-Y.; Sapi, J. Monatsh. Chem.
1999, 130, 1159–1166. (f) For 5m, see: Jain, N.; Kumar, A.; Chauhan, S. M.
S. Tetrahedron Lett. 2005, 46, 2599–2602.
(16) Torraca, K. E.; Kawabe, S.-I.; Buchwald, S. L. J. Am. Chem. Soc.
2000, 122, 12907–12908.
(17) Mukheerjee, C.; Biehl, E. Heterocycles 2004, 63, 2309–2318.
(18) Hirata, K.; Ogawa, N.; Sinagawa, Y.; Kiguchi, T.; Inoue, T.;
Komeda, Y.; Yamashita, I.; Kamiya, Y. Application WO 2007139002,
WO 2007-JP60678, Priority: JP 2006-147261, US 2006-809966. Hirata et.
al. synthesized the human URAT-1 inhibitor in several steps by using
compound 6e obtained from the reaction of 2H-1,4-benzoxazin-3(4H)-one
with sodium bis(2-methoxyethoxy)aluminum hydride in toluene at rt.
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TABLE 1. Reductive Ring-Expansion Reaction of Carbocyclic or
Heterocyclic Ketoximes Fused to a Benzene Ring
TABLE 2. Reductive Ring Expansion of Tricyclic Ketoximes
aKetone (1 equiv) and hydroxylamine hydrochloride (2 equiv) were
used in pyridine at rt for 2-6 h. bOxime (1 equiv) and DIBALH (6 equiv)
were used in CH2Cl2 at 0 °C to rt for 2-4 h. cOxime (1 equiv) and
DIBALH (9 equiv) were used in CH2Cl2/THF (2:1) at 0 °C to rt for 1 h.
dThe yield was based on the oximes. eKetone (1 equiv) and hydroxyla-
mine hydrochloride (6 equiv) were used in pyridine at rt for 3.5 h. fOxime
(1 equiv) and DIBALH (7 equiv) were used in CH2Cl2 at -10 °C for 3 h.
gKetone (1 equiv) and hydroxylamine hydrochloride (4 equiv) were used
in pyridine at 115 °C for 11 h.
aKetone (1 equiv) and hydroxylamine hydrochloride (2 equiv) were
used in pyridine at rt for 1-6 h. bOxime (1 equiv) and DIBALH (6 equiv)
were used in CH2Cl2 at rt for 2-2.5 h. cKetone (1 equiv) and hydroxyl-
amine hydrochloride (4 equiv) were used in pyridine for 4 h.
SCHEME 5. Same Product obtained from Isolated (E)- and
(Z)-Oxime
We found that the reaction was also applicable to cyclic
ketoximes fused to indole and benzothiophene. Reaction of
oxime 5i,14 prepared from 1,2,3,4-tetrahydrocarbazol-4-
one,13 proceeded as expected to furnish 1,2,3,4,5,6-hexa-
hydroazepino[3,2-b]indole 6i as the sole product. Due to its
instability, the yield of 6i was determined after transformation
to 6-(4-nitrobenzoyl)-1,2,3,4,5,6-hexahydroazepino[3,2-b]-
indole 7i by benzoylation with p-nitrobenzoyl chloride and
Et3N in CH2Cl2 (entry 1). The structure of 7i was unambigu-
ously determined by X-ray crystallographic analysis, as
reported previously.12 In contrast, reaction of oxime 5j
derived from 2,3,4,9-tetrahydrocarbazol-1-one gave a com-
plex mixture under the same reaction conditions and the
desired tricyclic compound 6j was not detected. On the other
hand, benzothiophene derivatives behaved in different man-
ner. Thus, reaction of 5l furnished 2,3,4,5-tetrahydro-1H-
benzothieno[2,3-b]azepine 6l in 73% yield, while oxime 5k
derived from the corresponding ketone14f gave 2,3,4,5-tetra-
hydro-1H-benzothieno[3,2-b]azepine 6k in only a modest
yield. Compound 6k was determined after conversion to 7k,
and was found to be a mixture (6.6:1.0) of rotamers according
to 1H NMR and 13C NMR spectra.
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Cho et al.
SCHEME 6. Stepwise Mechanism Proceeding through a Three-Centered Transition State Proposed by the Aid of B3LYP Method
JOCArticle
The reaction was also tested using tricyclic ketoximes
derived from cyclic diaryl ketone derivatives. For example,
9-fluorenone oxime 5m underwent rearrangement to give
5,6-dihydrophenanthridine 6m19 in good yield. The ring-
expansion reaction of the seven-membered ring cyclic
ketoxime 5n prepared from the corresponding ketone under
relatively strong conditions (refluxed in pyridine for 11 h)
required a longer reaction time (3-4 h) but afforded
5,6,11,12-tetrahydrodibenz[b,f]azocine 6n in 73% yield.
2. Theoretical Studies on the Mechanisms of Reductive ring-
expansion Reactions. As mentioned in the Introduction,
the mechanism of the reductive ring-expansion reaction of
oximes with DIBALH has not yet been well investigated,
although it has been suggested to be similar to Beckmann-
type rearrangement. In a previous report,2a we proposed a
mechanism that was different from Beckmann-type rearran-
gement7a based on several experimental findings. For
example, both (E)- and (Z)-oximes derived from 4,5,6,7-
tetrahydro-4-oxobenzo[b]furan were separated, and treat-
ment of each oxime with excess DIBALH gave the same
product, 5,6,7,8-tetrahydrofuro[3,2-b]azepine (Scheme 5).2a
In addition, the same reaction using a mixture of (E)- and
(Z)-oximes derived from 4,5,6,7-tetrahydro-4-oxobenzo-
[b]thiophen gave 5,6,7,8-tetrahydrothieno[3,2-b]azepine as a
single isomer (Scheme 4), while Beckmann rearrangement
gave a mixture of isomeric lactams (Scheme 1). Since
the structure of the reductive ring-expansion product was
independent of the geometry of the oximes, we considered
that the initial step was probably DIBALH reduction of the
C-N double bond, followed by rearrangement involving
N-O bond cleavage assisted by the aromatic ring to furnish
the ring-expansion product with nitrogen attached to the
aromatic ring.2a While the initial step of the reaction is reason-
able, the detailed mechanism of the rearrangement process
SCHEME 7. Rearrangement from Hydroxylamine Derivative 8
to 2,3,4,5-Tetrahydro-1H-benz[b]azepine 6c
remains unclear. Against this background, we carried out an
extensive investigation into the mechanism of the reductive ring-
expansion reaction based on theoretical calculations and even-
tually proved that the reaction proceeds by reduction of the
C-N double bond and subsequent rearrangement by a stepwise
mechanism through a three-centered transition state (Scheme 6).
2.1. Confirmation of Intermediacy of Hydroxylamine Deri-
vative. Before starting the theoretical studies, we confirmed
that hydroxylamine acts as an intermediate in the reductive
ring-expansion reaction. Oxime 5c was chosen as the test
substrate. The corresponding hydroxylamine 8, prepared
by reduction of oxime 5c with NaBH3CN, was treated
with excess DIBALH (Scheme 7). As expected 2,3,4,5-tetra-
hydro-1H-benz[b]azepine 6c was isolated in 72% yield as the
sole product, indicating that the reaction proceeds via initial
formation of aluminum complex (I)-E and Z, followed by 1,2-
reduction of the C-N double bond to generate intermediate II
coordinated by two molecules of dialkyl aluminum (R = i-Bu).
Finally, reductive rearrangement takes place to furnish the
cyclic secondary amine aluminum amide VII (R = i-Bu).
2.2. Theoretical Studies on the Reaction Mechanisms. Sub-
sequently, the reaction processes from II to 6c was investi-
gated by the aid of 3-parameter hybrid Becke exchange/
Lee-Yang-Parr correlation functional (B3LYP) method.20
(20) Hehre, W. J.; Radom, L.; Schleyer, P. V. R.; Pople, J. A. Ab Initio
Molecular Orbital Theory; John Wiley: New York, 1986. References cited
therein.
~
ꢀ
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(19) Barluenga, J.; Fananas, F. J.; Sanz, R.; Fernandez, Y. Chem.;Eur.
J. 2002, 8, 2034–2046.
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For simplicity, (i-Bu)2AlH was modeled as Me2AlH. Two
Me2AlH molecules were added to assess the mechanism,
because at least two equivalents of the molecule are necessary
for completion of the reaction (one for formation of an
aluminum oxide II from (I)-E or (I)-Z, and the other for
reduction of a CdN bond of VI).
The 3D structures of representative intermediates and a
saddle point (TS1) (III) with twist-chair conformation on the
potential energy surface and the potential energy profile are
shown in Figures 3 and 4, respectively. Reduction of E/Z
oxime I by dialkylaluminum hydride led to two possible
conformers II, which were two aluminum-bound hydroxy-
lamine residues (one with pseudoequatorial substitution and
the other with pseudoaxial substitution). The pseudoequa-
torially substituted hydroxylamine A with twist-chair con-
formation of II (R = Me) has a slightly lower energy than the
pseudoaxially substituted hydroxylamine B of II, with the
difference being 0.1 kJ/mol. Since the π-orbital symmetry of
C1 in A does not allow further rearrangement of aromatic
carbon into nitrogen, B is a direct precursor of the rearran-
gement. The transition state (TS1) III of the ring opening has
an energy level 64.2 kJ/mol higher than the conformer A and
64.1 kJ/mol higher than the conformer B based on data
shown in Figures 3 and 4 (see the Experimental Section and
Supporting Information). We performed intrinsic reaction
coordinate (IRC) analysis descending from TS1 toward
two-aluminum-bound hydroxylamine derivative B and alu-
minum-coordinated intermediate C (IV). Calculations follow-
ing the IRC path toward C terminated at a nonstationary
point I1 because the potential surfaces aroundI1 were too flat.
Subsequent geometric optimization from I1 is connected to C.
The other IRC path from TS1 is connected toward B
smoothly. When the benzene C1 atom moves closer to a
nitrogen atom, N-O bond cleavage occurs. During the stage
between B to TS1, electrons from a benzene ring, C2, and N
flow into the O atom (Table 3). The dipole moments at B
and TS1 of 2.3 and 8.8 D, respectively, show that TS1 is more
polar than B. Then, we employed calculations of solvent
polarity effects of CH2Cl2 using polarized continuum model
(PCM)21 at the B3LYP/6-31þG(d) level. We found that the
activation energy of 64.1 kJ/mol decreases to 35.6 kJ/mol.
AtI1, theC1-Ndistance of 1.60A is closer tothe C2-N bond
length of 1.37 A, indicating that the C1-C2-N moiety of I1
more closely resembles an aziridine-like structure than TS1.
During the stage between TS1 and I1, the C1-C2 bond is only
cleaved partially (1.57 A in the TS1 and 1.64 A in I1) and
C1-N bond formation (1.83 A in the TS1 and 1.60 A in I1) is
more advanced. Additional electron flow from the benzene
ring and C2 into N and O then occurs to produce an electron-
deficient imine carbon (Table 3). During ring expansion
(from III to VI), the N-O bond is cleaved along with Al1-O
shortening and N-Al1 bond lengthening (Figure 3 and
Scheme 6). In equilibrium structure C (IV) which is higher
in energy than B by 38.8 kJ/mol, two aluminum atoms interact
with N, and C2 is still interacting with C1. The natural charge
of O changes from -0.861 in B to -1.327 in C (Table 3), and
bonds between O and two Al atoms become stronger. Since
FIGURE 3. Structures of representative intermediates (B, C, and
D), TSs (TS1 and TS2), and representative nonstationary point (I1)
along the IRC. Bond lengths are in angstroms. Total electronic
energies (E) at the B3LYP/6-31G(d) level are shown in a.u. The s
value refers to the reaction coordinate in amu1/2 bohr.
the additional positive charge is developed in the benzene ring
(þ0.400), the intermediate C possesses a partial phenonium
cation structure. The decrease of the natural charge of C2
from TS1 (þ0.003) to C (þ0.202) indicates that C2 changes to
an imine carbon character. Once C1-C2 bond cleavage
occurs with concomitant Al2-N dissociation through the
(21) Cances, M. T.; Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997, 107,
3032–3041. Cossi, M.; Scalmani, G.; Rega, N.; Barone, V. J. Chem. Phys.
2002, 117, 43–54.
632 J. Org. Chem. Vol. 75, No. 3, 2010

Cho et al.
JOCArticle
TABLE 4. Products from 2-Substituted Oximes
FIGURE 4. Potential energy diagram of ring expansion. Relative
energies (kJ/mol) are shown in parentheses (B3LYP/6-31G(d)).
aKetone (1 equiv) and hydroxylamine hydrochloride (2 equiv) were
used in pyridine at rt for 2-6 h. bOxime (1 equiv) and DIBALH (6 equiv)
were used in CH2Cl2 at 0 °C to rt for 2 h. cKetone (1 equiv) and
hydroxylamine hydrochloride (4 equiv) were used in pyridine at rt for
6 h. dKetone (1 equiv) and hydroxylamine hydrochloride (4 equiv) were
used in pyridine at 80 °C for 30 h. eThe yield was based on the oximes.
fThe yields of the regioisomers were determined from 1H NMR spectra
of mixtures of the benzoylamides.
TABLE 3. Natural Charges of Stationary Points (B, TS1, C, TS2, D)
and Representative Nonstationary Points (I1) along the IRC at the B3LYP/
6-31G(d) Level
C1
C2
N
Al1
O
C6H4
B
TS1
I1
C
TS2
D
-0.048
þ0.006
þ0.030
þ0.074
þ0.080
þ0.130
-0.070
þ0.003
þ0.107
þ0.202
þ0.213
þ0.194
-0.707
-0.701
-0.762
-0.820
-0.792
-0.567
þ1.860
þ1.856
þ1.855
þ1.852
þ1.845
þ1.850
-0.861
-1.188
-1.293
-1.327
-1.332
-1.350
-0.008
þ0.300
þ0.389
þ0.400
þ0.368
þ0.172
TABLE 5. Reductive Rearrangement of Diaryl Ketone Oximes
second transition state (TS2), ring expansion takes place
smoothly to furnish D (VI). The activation energy of the step
from C to TS2 is only 1.2 kJ/mol. The exothermic energy of
the nitrogen shift to produce D (VI) relative to A is 204.3 kJ/
mol (Figure 4). Thus, we cannot find aziridine as a local
minimum (point I1 along the IRC s of þ1.82 amu1/2 bohr),
but can indicate that the reaction proceeds through a three-
centered transition state with the stepwise mechanism, be-
cause the potential energy curve along the reaction coordinate
from B to D has two maxima (saddle points; TS1 and TS2).
Subsequently, reduction of a CdN bond of VI with the third
molecule of R2AlH affords compound VII.
3. Preference of the Migrating Group. As shown in Tables 1
and 2, the reductive rearrangement reaction gave exclusive
product due to migration of the aryl group. However, we
found that this was not always the case. The oximes 5c
and 5o22 (Tables 1 and 4) derived from 1-tetralone and
2-methyl-1-tetralone, respectively, provided the expected
products 2,3,4,5-tetrahydro-1H-benz[b]azepine 6c and
3-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine 6o23 due
to exclusive migration of the aryl groups. However, con-
trary to our speculation, rearrangement of oxime 5p pre-
pared from 2,2-dimethyl-1-tetralone gave a mixture of 3,3-
dimethyl-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzo-
aKetone (1 equiv) and hydroxylamine hydrochloride (4 equiv)
were used in pyridine at rt for 8-12 h. bOxime (1 equiv) and DIBALH
(6 equiv) were used in CH2Cl2 at 0 °C to rt for 2 h.
[b]azepine 7p (57%) and 3,3-dimethyl-2-(4-nitrobenzoyl)-
2,3,4,5-tetrahydro-1H-benzo[c]azepine 10p (22%) after ben-
zoylation of 3,3-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]-
azepine 6p and 3,3-dimethyl-2,3,4,5-tetrahydro-1H-benzo-
[c]azepine 9p, respectively. This result prompted us to inves-
tigate the migratory preferences of various substituents.
After choosing unsymmetrical benzophenone oximes bear-
ing different substituents at two para positions each, the
influence of electron density on the preference of the migrating
group was investigated (Table 5). It was found that the
migrating group was clearly dependent on the substituents on
the benzene ring and that only the more electron-rich benzene
ring underwent migration. Thus, in the case of oxime 5q,
exclusive migration of the p-anisyl group took place to give
(22) The spectral data of oximes 5o, 5w, 5x, 5y, and 5z are identical
with those reported previously. (a) For 5o, 5x, and 5y, see: Zhao, H.;
Vandenbossche, C. P.; Koenig, S. G.; Singh, S. P.; Bakale, R. P. Org. Lett.
2008, 10, 505–507. (b) For 5w, see: Hwu, J. R.; Tseng, W. N.; Patel, H. V.;
Wong, F. F.; Horng, D.-N.; Liaw, B. R.; Lin, L. C. J. Org. Chem. 1999, 64,
2211–2218. (c) For 5z, see: Liu, S.; Yu, Y.; Liebeskind, L. S. Org. Lett. 2007,
9, 1947–1950.
(23) The spectral data of amines 6o, 6v, 6w, 6x, and 6y are identical with
those reported previously. (a) For 6o, see: Ventrice, T.; Campi., E. M.; Roy
Jackson, W.; Patti, A. F. Tetrahedron 2001, 57, 7557–7574. (b) For 6v, 6w, 6x,
and 6y, see: Byun, E.; Hong, B.; De Castro, K. A.; Lim, M.; Rhee, H. J. Org.
Chem. 2007, 72, 9815–9817.
J. Org. Chem. Vol. 75, No. 3, 2010 633

Cho et al.
JOCArticle
TABLE 6. Preferred Migrating Group During the Reductive Rearran-
gement of Various Oximes
primary alkyl group migrates in preference to the methyl group
(entry 1). Predominant generation of (N-isopropyl-n-propyl)-
tosylamide 6u by successive reduction and tosylation of ethyl
isopropyl ketone oxime 5u demonstrated that secondary alkyl
group is more likely to migrate than the primary alkyl group
(entry 2). Reactions using benzaldehyde oxime 5v, acetophenone
oxime 5w,22 propiophenone oxime 5x,22 and isopropyl phenyl
ketone oxime 5y22 exclusively gave the corresponding aniline
derivatives, N-methylaniline 6v,23 N-ethylaniline 6w,23 N-n-pro-
pylaniline 6x,23 and N-isobutylaniline 6y,23respectively, due to
migration of the benzene ring, showing that benzene ring
migration was preferred over migration of proton, methyl,
primary, and secondary alkyl groups. Similar to the rearrange-
ment of oxime 5p shown in Table 4, the exceptional example of
generating a mixture of isomeric rearrangement product was
5z,22 which afforded a mixture of 7z (37%) and 10z (31%) after
p-nitrobenzoylation of the resulting secondary amines 2,2-di-
methylpropylaniline 6z and (N-t-butyl)benzylamine 9z. Accord-
ing to the above data, we concluded that the preference for
migration has the following order: phenyl group ≈ tertiary alkyl
group> secondary alkyl group > primary alkyl group. In
addition, an electron-rich phenyl group migrates preferentially
in the case of unsymmetrical benzophenone oximes.
Conclusions
We performed a systematic investigation into the reductive
ring-expansion reaction of oximes with DIBALH. This method
makes it feasible to synthesize a variety of bicyclic or tricyclic
heterocycles containing nitrogen attached to an aromatic ring,
which are the core structures of medicines or clinical candidates
or may have potential as core structure of new drugs. For
instance, compound 6e, obtained by reaction of coumaran-
3-one oxime 5e, is particularly important because it could
be converted to 2,6-dichloro-4-(2,3-dihydro-1,4-benzoxazin-
4-ylcarbonyl)phenol, which is known to inhibit URAT-1
(urate transporter-1) and could be useful for the treatment of
hyperuricemia and gout (Figure 2).18
Both experimental and theoretical studies were performed
to investigate the mechanisms and we obtained some im-
portant information. First, it was demonstrated that the
reaction proceeds through a hydroxylamine intermediate.
Second, DFT calculations revealed that aryl migration
occurred by a stepwise mechanism through a three-centered
transition state (Figures 3 and 4).
We also clarified the preferences of migrating groups
during the reductive rearrangement reaction, and found that
the electronic nature of substituents is a crucial factor
governing migration preference. For example, the electron-
rich phenyl group of unsymmetrical benzophenone migrated
exclusively and alkyl groups with more substituents migrated
more easily, which is similar to the processes observed in
Baeyer-Villiger oxidation. We concluded that the order of
migration was as follows; phenyl ≈ tertiary alkyl group >
secondary alkyl group > primary alkyl group.
aKetone (1 equiv) and hydroxylamine hydrochloride (2 equiv) were
used in pyridine at rt for 2-6 h. bOxime (1 equiv) and DIBALH (6 equiv)
c
were used in CH2Cl2 at 0 °C to rt for 2 h. Ketone (1 equiv), hydro-
xylamine hydrochloride (1.5-2 equiv), and NaOAc (3-5 equiv) were
used in MeOH at rt for 1.5 h. dThe yield was based on the oximes. eThe
yields of the regioisomers were determined from 1H NMR spectra of
mixtures of the tosylamides. fAldehyde (1 equiv), hydroxylamine hydro-
chloride (2 equiv), and pyridine (5 equiv) were used in MeOH at rt for
30 min. gKetone (1 equiv), hydroxylamine hydrochloride (1.5 equiv) and
NaOAc (3 equiv) were used in EtOH at rt for 6 h. hThe yields of the
regioisomers were determined from 1H NMR spectra of mixture of the
benzoylamides.
compound 6q24 in 79% yield. Oxime 5r derived from phenyl
p-anisyl ketone gave 6r25 with complete control due to the
difference between the methoxy group and hydrogen on the
benzene rings. In addition, the CF3 group controlled migration
to furnish 6s24 as the sole product from the reaction of oxime 5s.
We then prepared a variety of oximes and investigated general
trends in the preference of migration. As shown in Table 6,
reaction of ethyl methyl ketone oxime 5t gave a mixture of
diethylamine and N-methyl-n-propylamine, which was deter-
mined as (N-diethyl)tosylamide 6t26 and (N-methyl-N-n-propyl)-
tosylamide 9t (3:2) after tosylation. The results indicate that the
(24) As to determination of the chemical structure of the products, the 1H
NMR data of 6q and 6s were respectively identified with those of the
compounds synthesized by reductive amination of (p-trifluoromethyl)-
benzaldehyde with p-anisidine or aniline, followed by NaBH4 (Supporting
Information, Scheme S2).
(25) Sydnes, M. O.; Kuse, M.; Isobe, M. Tetrahedron 2008, 64, 6406–
6414.
(26) Harmata, M.; Zheng, P.; Huang, C.; Gomes, M. G.; Ying, W.;
Ranyanil, K.-O.; Balan, G.; Calkins, N. L. J. Org. Chem. 2007, 72,
683–685.
Finally, considering the practical utility of DIBALH on an
industrial scale,27 this reaction may find widespread use not
(27) (a) For an example of using DIBALH in process chemistry, see:
Hobson, L. A.; Nugent, W. A.; Anderson, S. R.; Deshmukh, S. S.; Haley, J. J.
III; Liu, P.; Magnus, N. A.; Sheeran, P.; Sherbine, J. P.; Stone, B. R. P.; Zhu,
J. Org. Process Res. Dev. 2007, 11, 985–995. (b) In the case of cyclohexanone
oxime, large-scale production using DIBALH is also underway at a chemical
corporation.
634 J. Org. Chem. Vol. 75, No. 3, 2010

Cho et al.
JOCArticle
only in the field of medicinal chemistry but also in process
chemistry for creation of novel drugs as well as for the
synthesis of related natural products.
(1H, s), 7.90 (2H, d, J = 8.8 Hz), 7.55 (2H, d, J = 8.8 Hz), 7.14
(1H, d, J = 8.0 Hz), 6.98 (1H, t, J = 7.6 Hz), 6.92 (1H, d, J =
8.0 Hz), 6.84 (1H, t, J = 7.6 Hz), 5.11 (1H, m), 3.08 (1H, t, J =
13.8 Hz), 2.91 (1H, m), 2.82 (1H, t, J = 12.2 Hz), 2.16-2.03
(3H, m), 1.61 (1H, m); 13C NMR (100 MHz, CDCl3) δ 167.6,
147.8, 143.1, 133.7, 132.9, 128.7, 123.4, 122.7, 121.8, 120.3,
118.7, 116.6, 110.9, 47.6, 31.1, 28.0, 25.3; LRMS (EI) m/z 335
(Mþ). Anal. Calcd for C19H17N3O3: C, 68.05; H, 5.11; N, 12.53.
Found: C, 67.79; H, 5.36; N, 12.45.
Experimental Section
General Procedure for the Ring-Expansion Reaction Using
DIBALH. Thiochroman-4-one Oxime (5h). To a stirred solution
of 1-thiochroman-4-one(4.40g, 26.8 mmol) in pyridine (50.0 mL)
was added hydroxylamine hydrochloride (3.76 g, 54.1 mmol) at
rt. After the mixture was stirred for 1.5 h, pyridine was removed
under reduced pressure. 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 material. Purification by column chromato-
graphy on a silica gel (EtOAc:n-hexane = 1:3) afforded oxime 5h
(4.61 g, 96%): colorless crystals; mp 98-100 °C; IR (KBr) 3233,
2920, 1587, 1475, 1310 cm-1; 1H NMR (400 MHz, CDCl3) δ 9.13
(1H, brs), 7.87 (1H, dd, J = 1.6 and 8.0 Hz), 7.25 (1H, dd, J = 1.6
and 8.0 Hz), 7.23 (1H, ddd, J = 1.6, 7.2, and 8.0 Hz), 7.13 (1H,
ddd, J = 1.6, 7.2, and 8.0 Hz), 3.19 (2H, t, J = 6.0 Hz), 2.97 (2H,
t, J = 6.0 Hz); 13C NMR (100 MHz, CDCl3) δ 153.6, 136.3,
129.5, 129.3, 128.4, 125.9, 125.5, 26.2, 25.9; LRMS (EI) m/z 179
(Mþ). Anal. Calcd for C9H9NOS: C, 60.31; H, 5.06; N, 7.81.
Found: C, 60.40; H, 5.16; N, 7.72.
2,3,4,5-Tetrahydrobenzo[b][1,4]thiazepine Hydrochloride (6h).
To a stirred solution of 5h (1.01 g, 5.63 mmol) in CH2Cl2
(56.0 mL) was added DIBALH (33.0 mL, 33.7 mmol, 1.02 M
in n-hexane) over 10 min at 0-5 °C (internal temperature) under
an argon atmosphere. 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 Celite pad. The filter cake was
washed with EtOAc, and the combined organic solutions were
evaporated to give the crude product. Purification by column
chromatography on a silica gel (Et2O:n-hexane = 1:3) yielded
2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 6h (662 mg, 71%).
The 1H NMR spectrum was identified with that reported in
ref 17. Although 3 mol equiv of DIBALH is theoretically
sufficient for this method, we often employed 6-9 mol equiv
of the reagent to finish each reaction. To a solution of 6h in Et2O
was added HCl in Et2O (1 M) at rt. After stirring for 20 min,
Et2O was removed under reduced pressure. The residue was
purified by recrystallization (EtOH) to give HCl salts of 6h:
colorless crystals; mp 138-142 °C; IR (KBr) 2914, 2687, 1558,
1456, 764 cm-1; 1H NMR (400 MHz, CD3OD) δ 7.74 (1H, dd,
J = 1.6 and 7.6 Hz), 7.56 (1H, dd, J = 1.6 and 7.6 Hz), 7.51 (1H,
ddd, J = 1.6, 7.6, and 7.6 Hz), 7.46 (1H, ddd, J = 1.6, 7.6, and
7.6 Hz), 3.51 (2H, t, J = 5.6 Hz), 2.95 (2H, t, J = 5.6 Hz), 2.40
(2H, tt, J = 5.6 and 5.6 Hz); 13C NMR (100 MHz, CD3OD) δ
140.9, 136.0, 132.6, 131.3, 131.0, 124.7, 50.9, 32.7, 29.9; LRMS
(FAB) m/z 166 (M - Cl). Anal. Calcd for C9H12ClNS: C, 53.59;
H, 6.00; N, 6.94. Found: C, 53.47; H, 5.85; N, 6.89.
1-(4-Nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzothieno[3,2-b]-
azepine (7k). Compound 7k (rotamers; 6.6:1.0) was synthesized
from 2,3,4,5-tetrahydro-1H-benzothieno[3,2-b]azepine 6k in a
similar manner: pale yellow crystals; mp 180-183 °C; IR (KBr)
2941, 1647, 1522, 1348, 849 cm-1; 1H NMR (400 MHz, CDCl3)
δ 8.26 (0.26H, d, J = 8.8 Hz), 7.90 (1.74H, d, J = 8.8 Hz), 7.68
(0.26H, d, J = 0.8 Hz), 7.58 (0.87H, d, J = 8.4 Hz), 7.48 (1.74H,
d, J = 8.8 Hz), 7.38 (0.13H, d, J = 8.4 Hz), 7.16-7.11 (3H, m),
5.10-5.06 (0.87H, m), 3.87-3.84 (0.13H, m), 3.11-3.04 (2H,
m), 2.87-2.76 (1H, m), 2.20-2.09 (3H, m); 1.63-1.50 (1H, m);
13C NMR (100 MHz, CDCl3) δ 167.8, 148.1, 142.3, 138.3, 136.0,
135.4, 134.8, 133.9, 128.9, 128.4, 127.4, 125.2, 124.5, 124.45,
124.43, 124.0, 123.8, 122.8, 122.7, 120.0, 48.3, 46.8, 37.1, 31.0,
29.1, 25.7, 23.8, 21.7; LRMS (EI) m/z 352 (Mþ); HRMS (EI) m/z
calcd for C19H16N2O3S 352.0882 (Mþ), found 352.0862.
2,3,4,5-Tetrahydro-1H-benzothieno[2,3-b]azepine (6l): color-
less oil; IR (KBr) 3254, 2924, 1645, 1435, 752 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.56 (1H, dd, J = 1.2 and 8.0 Hz), 7.42 (1H,
dd, J = 1.2 and 8.0 Hz), 7.27 (1H, ddd, J = 1.2, 8.0, and 8.0 Hz),
7.11 (1H, ddd, J = 1.2, 8.0, and 8.0 Hz), 4.08 (1H, br s), 3.18 (2H,
t, J = 5.6 Hz), 2.77 (2H, t, J = 6.0 Hz), 1.89 (2H, tt, J = 5.2 and
5.6 Hz), 1.73 (2H, tt, J = 5.2 and 6.0 Hz); 13C NMR (100 MHz,
CDCl3) δ 149.1, 141.4, 132.6, 124.1, 121.65, 121.61, 119.4, 116.8,
49.1, 32.3, 26.7, 26.5; LRMS (EI) m/z 203 (Mþ); HRMS (EI) m/z
calcd for C15H13NO 203.0769 (Mþ), found 203.0753.
Dibenzosuberone oxime (5n): colorless crystals; mp 167-170 °C;
IR (KBr) 3227, 1489, 1445, 1423, 997 cm-1; 1H NMR (400 MHz,
CDCl3) δ 8.86 (1H, br s), 7.56 (1H, d, J = 8.0 Hz), 7.45 (1H, d, J =
7.2 Hz), 7.31-7.23 (4H, m), 7.18 (1H, dd, J = 7.2 and 7.6 Hz), 7.11
(1H, d, J = 7.6 Hz), 3.15-3.12 (4H, m); 13C NMR (100 MHz,
CDCl3) δ158.8, 138.8, 138.4, 134.4, 133.7, 130.4, 129.3, 129.2, 128.6,
128.3, 126.2, 125.6, 33.6, 32.1; LRMS (EI) m/z 223 (Mþ); HRMS
(EI) m/z calcd for C15H13NO 223.0997 (Mþ), found 223.0993.
5,6,11,12-Tetrahydrodibenz[b,f]azocine (6n): colorless crys-
tals; mp 128-130 °C; IR (KBr) 3364, 2924, 1603, 1477 cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.10-7.05 (3H, m), 7.02 (1H, dd,
J = 1.6 and 8.0 Hz), 6.97 (1H, dd, J = 1.6 and 7.6 Hz), 6.89 (1H,
ddd, J = 1.6, 7.6, and 8.0 Hz), 6.68 (1H, ddd, J = 1.6, 7.6, and
7.6 Hz), 6.49 (1H, dd, J = 1.6 and 8.0 Hz), 4.42 (2H, s), 3.93 (1H,
br s), 3.29 (2H, t, J = 7.2 Hz), 3.17 (2H, t, J = 7.2 Hz); 13C NMR
(100 MHz, CDCl3) δ 147.3, 140.6, 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 (Mþ); HRMS (EI) m/z calcd for C15H15N 209.1204
(Mþ), found 209.1179.
1,2,3,4-Tetrahydro-N-hydroxy-1-naphthalenamine (8). To a
stirred solution of tetralone oxime 5c (161 mg, 1.00 mmol) in
MeOH (2.0 mL) was added sodium cyanoborohydride (189 mg,
3.00 mmol) at rt followed by hydrogen chloride in MeOH
(1.0 M, 5.0 mL) at 0 °C. After the mixture was stirred for 5 h
at rt, the reaction was quenched with saturated aqueous NaH-
CO3. The reaction mixture was extracted with EtOAc, and the
combined extracts were washed with brine, dried over anhy-
drous Na2SO4, and concentrated under reduced pressure. The
residue was purified by flash column chromatograpy on silica
gel (EtOAc:n-hexane = 1:1) to give hydroxylamine 8 (124 mg,
6-(4-Nitrobenzoyl)-1,2,3,4,5,6-hexahydroazepino[3,2-b]indole
(7i). 1,2,3,4,5,6-Hexahydroazepino[3,2-b]indole 6i was pre-
pared from oxime 5i, but was unstable. Without purification,
benzoylation of 3i was carried out with p-nitrobenzoyl chloride
(68.7 mg, 0.370 mmol) and Et3N (0.100 mL, 0.717 mmol) in
CH2Cl2 (3.0 mL). Then the reaction mixture was diluted with
water and extracted with CH2Cl2. The combined organic
extracts were washed with brine, dried over anhydrous MgSO4
and evaporated under reduced pressure. The residue was puri-
fied by preparative TLC (EtOAc:n-hexane = 1:1) to afford
compound 7i in 63% yield for two steps: colorless crystals;
mp 216-217 °C (EtOAc/n-hexane); IR (KBr) 3271, 2934, 1632,
1520, 1346, 858, 843 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.02
76%) as a colorless solid: IR (KBr) 3155, 2941, 2882, 760 cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.32 (1H, dd, J = 2.0 and
6.4 Hz), 7.25-7.09 (3H, m), 4.09 (1H, dd, J = 4.0 and 4.0 Hz),
2.84-2.68 (2H, m), 2.25-2.20 (1H, m), 1.95-1.89 (1H, m),
J. Org. Chem. Vol. 75, No. 3, 2010 635

Cho et al.
JOCArticle
1.85-1.75 (2H, m); 13C NMR (100 MHz, CDCl3) 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 (Mþ); HRMS (EI) m/z calcd for C10H13NO (Mþ) 163.0997,
found 163.1015.
CDCl3) δ 157.0, 156.9, 139.7, 136.3, 135.4, 131.9, 131.0 (q, JC-F
=
321 Hz), 131.1 (q, JC-F = 321 Hz), 129.9, 129.7, 129.5, 129.2,
128.6, 128.4, 128.2, 127.7, 125.3 (2C, m), 122.6, 122.5; LRMS (EI)
m/z 265 (Mþ); HRMS (EI) m/z calcd for C14H10F3NO 265.0714
(Mþ), found 265.0707.
2,2-Dimethyl-1-tetralone oxime (5p) (1.4:1.0 mixture of (E)-
and (Z)-isomers): colorless solid; IR (KBr) 3198, 2916, 1456, 949,
770 cm-1; 1H NMR (400 MHz, CDCl3) δ 9.32 (1H, br s), 8.48
(0.42H, d, J = 7.6 Hz), 7.80 (0.58H, d, J = 7.6 Hz), 7.29-7.14
(3H, m), 2.91 (0.83H, t, J = 6.8 Hz), 2.74 (1.17H, t, J = 6.0 Hz),
1.84 (0.83H, t, J = 6.8 Hz), 1.68 (1.17H, t, J = 6.0 Hz), 1.50
(3.50H, s), 1.21 (2.5H, s); 13C NMR (100 MHz, CDCl3) δ 159.3,
158.2, 140.5, 139.4, 132.4, 131.6, 129.4, 128.6, 127.9, 127.3,
126.5, 125.5, 125.3, 40.9, 37.09, 37.05, 36.8, 27.0, 26.5, 26.2,
24.3; LRMS (EI) m/z 189 (Mþ); HRMS (EI) m/z calcd for
C12H15NO (Mþ) 189.1154, found 189.1159.
N-[4-(Trifluoromethyl)benzyl]aniline (6s): pale yellow oil; IR
(neat) 3420, 1605, 1504, 1327, 1163, 1123, 1067 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.56 (2H, d, J = 8.0 Hz), 7.45 (2H, d, J =
8.0 Hz), 7.15 (2H, dd, J = 7.2 and 8.0 Hz), 6.72 (1H, t, J =
7.2 Hz), 6.58 (2H, d, J = 8.0 Hz), 4.38 (2H, s), 4.09 (1H, br s); 13
C
=
NMR (100 MHz, CDCl3) δ 147.6, 143.7, 129.3 (q, JC-F
322 Hz), 129.2, 127.3, 125.5 (q, JC-F = 37 Hz), 122.8, 117.9,
112.8, 47.8; LRMS (EI) m/z 251 (Mþ); HRMS (EI) m/z calcd for
C14H12F3N 251.0922 (Mþ), found 251.0923.
3,3-Dimethyl-2-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzo-
[b]azepine (7p): colorless oil; IR (neat) 2918, 1651, 1524, 1313,
862, 750 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.00 (2H, d, J =
8.0 Hz), 7.39 (2H, d, J = 8.0 Hz), 7.22 (1H, d, J = 7.6 Hz), 7.08
(1H, dd, J = 7.6 and 7.6 Hz), 6.87 (1H, dd, J = 7.6 and 7.6 Hz),
6.54 (1H, d, J = 7.6 Hz), 4.76 (1H, d, J = 13.2 Hz), 3.19 (1H, dd,
J = 13.6 and 14.0 Hz), 2.73 (1H, dd, J = 6.0 and 14.0 Hz), 2.58
(1H, d, J = 13.2 Hz), 1.73 (1H, dd, J = 6.0 and 13.6 Hz), 1.45
Computational Details
All calculations in the present study were performed with the
Gaussian 03 program28 and by using the restricted Becke three-
parameter plus Lee-Yang-Parr (B3LYP) DFT method with the
6-31G(d) basis set.20 Stationary points were optimized without
any symmetry assumption unless otherwise noted. By normal
coordination analyses, zero and one imaginary frequency were
confirmed for all minima and the saddle points, respectively.
Then intrinsic reaction coordinate (IRC) analysis was performed
from the saddle point.29 Reaction coordinate s was based on a
transition state as zero [1 hartree (au) = 2625.4997 kJ/mol].
Cartesian coordinates for representative stationary points are
provided in Table S1 (Supporting Information).
(1H, dd, J = 13.6 and 13.6 Hz), 1.22 (3H, s), 1.02 (3H, s); 13
C
NMR (100 MHz, CDCl3) δ 167.8, 147.9, 143.6, 142.4, 139.3,
130.2, 129.0, 128.0, 127.5, 127.1, 122.9, 56.6, 39.9, 35.7, 30.7,
29.4, 23.2; LRMS (EI) m/z 324 (Mþ); HRMS (EI) m/z Calcd for
C19H20N2O3 (Mþ) 324.1474, found 324.1471.
3,3-Dimethyl-2-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzo-
[c]azepine (10p): pale yellow solid; IR (KBr) 2957, 1651, 1520,
1350, 860, 756 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.11 (2H,
dd, J = 1.2 and 8.0 Hz), 7.34 (2H, d, J = 8.0 Hz), 7.25-7.21 (2H,
m), 7.05 (1H, dd, J = 7.6 and 7.6 Hz), 6.42 (1H, d, J = 7.6 Hz),
4.33 (2H, br s), 3.18 (2H, t, J = 5.2 Hz), 2.11 (2H, t, J = 5.2 Hz),
1.69 (6H, s); 13C NMR (100 MHz, CDCl3) δ 172.0, 148.5, 144.1,
138.7, 135.8, 130.3, 128.7, 128.3, 127.6, 125.9, 123.2, 59.5, 50.5,
40.8, 29.6, 25.0; LRMS (EI) m/z 324 (Mþ); HRMS (EI) m/z calcd
for C19H20N2O3 (Mþ) 324.1474, found 324.1487.
Acknowledgment. The generous allotment of computa-
tional time by the Research Center for Computational
Science (RCCS), the National Institutes of Natural Sciences,
Japan, is gratefully acknowledged.
Supporting Information Available: Additional experimen-
tal, spectral data on compounds 5a, 5g, (E)-5j, (Z)-5j, 5k, 5l, 5r,
6t, 9t, 5u, 6u, 9u, 7z, and 10z, the new synthetic scheme (five
steps) for the precursor ketone of 5k from 2-iodobenzo-
[b]thiophene, the synthetic scheme of authentic samples for 6q
and 6s, and tables of Cartesian coordinates for the representa-
tive stationary points. This material is available free of charge
via the Internet at http://pubs.acs.org.
4-(Methoxyphenyl) 4-(trifluoromethyl)phenyl ketone oxime (5q)
(1:1 mixture of (E)- and (Z)-isomers): colorless solid; IR (KBr)
1
3256, 1605, 1512, 1325, 1256, 1163, 1130, 837 cm-1; H NMR
(400 MHz, CDCl3) δ 7.73 (1H, d, J = 8.0 Hz), 7.58-7.61 (2H, m),
7.51 (1H, d, J = 8.0 Hz), 7.40-7.36 (2H, m), 6.99 (1H, d, J =
9.2 Hz), 6.87 (1H, d, J = 9.2 Hz), 3.87 (1.5H, s), 3.82 (1.5H, s);
13C NMR (100 MHz, CDCl3) δ 161.0, 160.4, 156.54, 156.50, 140.2,
(28) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci,
B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada,
M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.;
Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A.
D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari,
K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.;
Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komar-
omi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.;
Wong, M. W.; Gonzalez, C.; and Pople, J. A. Gaussian 03, revision D.02;
Gaussian Inc.: Wallingford, CT, 2004.
136.6, 131.24 (q, JC-F = 329 Hz), 131.21, 131.0 (q, JC-F
=
329 Hz), 129.6, 129.1, 128.5, 127.8, 125.3-125.2 (2C, m),
123.9, 114.0, 113.7, 55.32, 55.30; LRMS (EI) m/z 295 (Mþ); HRMS
(EI) m/z calcd for C15H12F3NO2 295.0820 (Mþ), found 295.0822.
N-(4-Trifluoromethyl)benzyl-4-methoxyaniline (6q): yellow
solid; IR (KBr) 3406, 1514, 1327, 1236, 1121, 1067, 820 cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.57 (2H, d, J = 8.4 Hz), 7.46
(2H, d, J = 8.4 Hz), 6.76 (2H, d, J = 9.2 Hz), 6.55 (2H, d, J =
9.2 Hz), 4.34 (2H, s), 3.89 (1H, br s), 3.72 (3H, s); 13C NMR
(100 MHz, CDCl3) δ 152.4, 144.0 (d, JC-F = 23 Hz), 141.9,
129.4 (q, JC-F = 329 Hz), 127.5, 125.5 (q, JC-F = 33 Hz), 122.8,
115.0, 114.2, 55.7, 48.7; LRMS (EI) m/z 281 (Mþ); HRMS (EI)
m/z calcd for C15H14F3NO 281.1027 (Mþ), found 281.1032.
Phenyl 4-(trifluoromethyl)phenyl ketone oxime (5s) (mixture of
(E)- and (Z)-isomers): colorless solid; IR (KBr) 3252, 2918, 1616,
(29) (a) Fukui, K. Acc. Chem. Res. 1981, 14, 363–368. (c) Gonzalez, C.;
Schlegel, H. B. J. Chem. Phys. 1989, 90, 2154–2161. (b) Gonzalez, C.;
Schlegel, H. B. J. Phys. Chem. 1990, 94, 5523–5527.
(30) Nicolas, Y; Blanchard, P.; Levillain, E.; Allain, M.; Mercier, N.;
Roncali, J. Org. Lett. 2004, 6, 273–276.
1
1456, 1408, 1323, 1113, 1069, 994 cm-1; H NMR (400 MHz,
CDCl3) δ8.67 (1H, br s), 7.74-7.32 (9H, m); 13CNMR(100 MHz,
636 J. Org. Chem. Vol. 75, No. 3, 2010