High-yield method for the preparation of 1,3,4,5-tetrahydro-7-methoxy-2 H-1-benzazepin-2-one with excellent regio-and stereoselectivity

Article abstract of DOI:10.1080/00397911.2012.680571

We have surveyed the effects of different acid catalysts, reaction times, and temperatures on the yield, regioselectivity, and stereoselectivity and calculated the ketoxime isomerization and activation energy of the title compound. A facile synthetic proc

Full text of DOI:10.1080/00397911.2012.680571

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High-Yield Method for the Preparation
of 1,3,4,5-Tetrahydro-7-methoxy-2H-1-
benzazepin-2-one with Excellent Regio-
and Stereoselectivity
Feng-Yu Piao a , Yu-Zhong Xie a , Wen-Bin Zhang a , Wei Zhang a &
Rong-Bi Han a b
a Department of Chemistry, College of Science, Yanbian University,
Yanji, Jilin Province, China
b Key Laboratory of Natural Resources of Changbai Mountain and
Functional Molecules (Yanbian University), Ministry of Education,
Yanji, Jilin Province, China
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To cite this article: Feng-Yu Piao , Yu-Zhong Xie , Wen-Bin Zhang , Wei Zhang & Rong-Bi Han (2013):
High-Yield Method for the Preparation of 1,3,4,5-Tetrahydro-7-methoxy-2H-1-benzazepin-2-one with
Excellent Regio- and Stereoselectivity, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 43:14, 1920-1930
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Synthetic Communications1, 43: 1920–1930, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.680571
HIGH-YIELD METHOD FOR THE PREPARATION OF
1,3,4,5-TETRAHYDRO-7-METHOXY-2H-
1-BENZAZEPIN-2-ONE WITH EXCELLENT REGIO-
AND STEREOSELECTIVITY
Feng-Yu Piao,1 Yu-Zhong Xie,1 Wen-Bin Zhang,1
Wei Zhang,1 and Rong-Bi Han1,2
1Department of Chemistry, College of Science, Yanbian University, Yanji,
Jilin Province, China
2Key Laboratory of Natural Resources of Changbai Mountain and Functional
Molecules (Yanbian University), Ministry of Education, Yanji, Jilin
Province, China
GRAPHICAL ABSTRACT
Abstract We have surveyed the effects of different acid catalysts, reaction times, and
temperatures on the yield, regioselectivity, and stereoselectivity and calculated the ketoxime
isomerization and activation energy of the title compound. A facile synthetic procedure with
good yields and good regio- and stereoselectivity for Beckmann rearrangement of oxime sul-
fonate with ZnCl2 in the presence of solvent is developed.
Keywords Beckmann rearrangement; ketoxime; regio- and stereoselectivity
INTRODUCTION
Both 2,3,4,5-tetrahydro-7-methoxy-1H-2-benzazepin-1-one and 1,3,4,5-tetra
hydro-7-methoxy-2H-1-benzazepin-2-one are important organic intermediates in
the synthesis of triazolobenzazepine derivatives.[1] These compounds are obtained
via either the Beckmann rearrangement of 6-methoxy-3,4-dihydro-naphthalene-
1(2H)-one oxime[2–6] or the Schmidt rearrangement of 6-methoxy-3,4-dihydro-
naphthalene-1(2H)-one.[7] Beckmann rearrangements usually involve the migration
of the groups in the trans position to the oxime hydroxyl; however, a mixture of
=
two isomers is obtained when the groups at both ends of the C N double bond
are similar in size.[8]
Received February 14, 2012.
Address correspondence to Feng-Yu Piao, Department of Chemistry, College of Science, Yanbian
University, Yanji 133002, Jilin Province, China. E-mail: fypiao4989@yahoo.com.cn
1920

FACILE BECKMANN REARRANGEMENT
1921
6-Methoxy-3,4-dihydronaphthalene-1(2H)-one oxime was synthesized by our
group, and the trans configuration was determined from its single-crystal structure.[9]
According to the mechanism of the Beckmann rearrangement, 6-methoxy-3,4-
dihydro-naphthalene-1(2H)-one oxime should produce the title compound. How-
=
ever, because of the similar size of the groups on both ends of the C N double
bond[8] and the electron-donating methoxy group (CH3O–) in the 6-position of the
oxime,[10] the ring expansion of this ketoxime always forms a mixture of the title
compound and its isomer in poor yield and requires a time-consuming separation.
To obtain good yields as well as high regio- and stereoselectivies for the
rearrangement products, the effect of different acids, solvents, reaction times, and
temperatures on these properties were observed. In addition, both the ketoxime iso-
merization energy and the activation energy of the ring expansion were calculated to
determine which conditions resulted in the title compound with the best yield, regio
selectivity, and stereoselectivity.
RESULTS AND DISCUSSION
Effects of the Reaction Conditions on the Yield, Regioselectivity and
Stereoselectivity of the Rearrangement
At a certain temperature and reaction time in the absence of solvent, both
[12]
[11]
AlCl3
and FeCl3
catalyze the Beckmann rearrangement to produce the title
compound (A) as the primary product along with a small amount of its isomer,
2,3,4,5-tetrahydro-7-methoxy-1H-2-benzazepin-1-one (B). When either CH3SO3H[13]
or polyphosphoric acid (PPA)[14] are used to catalyze this reaction, the product is a
mixture of the two isomers (A=Bꢀ1=2 based on the spot size ratio of the products on
a thin-layer chromatographic, TLC, plate). The effects of the different acids on the
yields and both regio- and stereoselectivities of the rearrangement products are
shown in Table 1.
An important conclusion can be drawn from these experiments: When Lewis
acids, such as FeCl3 and AlCl3, are used to catalyze the Beckmann rearrangement,
A is the primary product; however, when Brønsted acids, such as PPA and
CH3SO3H, are used to catalyze the rearrangement, B is the primary product. The
Table 1. Beckmann rearrangement catalyzed by different acids
Yield (%)
Substances
Oxime
Catalyst
Solvent
Temp. (ꢁC)
Time
A=Ba
A
B
FeCl3
AlCl3
PPA
0
0
0
0
0
80–90
150–160
110–120
17
1.5–3 h
0.5 h
4:1a
4:1a
1:2a
1:2a
1:2a
66.3b
69.1b
22.0c
24.4b
23.1b
Trace
Trace
45.2c
47.9b
47.6b
25 min
16–18 h
16–18 h
CH3SO3H
CH3SO3H, NaN3
Ketone
6–8
aBased on the spot size ratio of the products on a TLC plate.
bGC yield.
cIsolated yield.

1922
F.-Y. PIAO ET AL.
regio- and stereoselectivities of the Beckmann rearrangement catalyzed by FeCl3 and
AlCl3 were much greater.
These experiments demonstrated that both time and temperature have a signifi-
cant impact on the regio- and stereoselectivity of the rearrangement. When anhy-
drous FeCl3 and ketoxime were ground for 1.5–3 h in a mortar at 80–90 ꢁC, A
was the primary product; the proportion of B increased both when the temperature
was increased to greater than 90 ꢁC and when the reaction time was extended at
90 ꢁC. However, when the temperature was too high, a by-product was produced,
which lowered the yield of B. When the temperature was too low, the reaction either
did not occur or only partially occurred. Similar experimental results were obtained
using AlCl3 as the catalyst, and the reaction did not occur under 90 ꢁC, occurred only
partly from 90–110 ꢁC, and went to completion from 110–125 ꢁC, when PPA was
used as the catalyst. The effects of temperature and time on the rearrangement
products using an FeCl3 catalyst are shown in Table 2.
It is important to note that, at the beginning of these reactions, only A was pro-
duced; however, the content of A decreased and B increased when either the reaction
time was extended or the temperature was increased. When the temperature was
90 ꢁC and the reaction time ranged from 1.5 to 3.0 h, the total yield for the two pro-
ducts was maximized. However, when either the reaction time was extended or the
temperature was increased, the amount of impurities also increased, and the yield
decreased. The same trends were observed for reactions using AlCl3 as the catalyst.
Because both of these reactions were conducted in a mortar, a significant amount of
product was lost during the reaction workup. In addition, the separation of the
isomers was troublesome.
The spot ratio on a TLC of the two products from a Schmidt rearrangement
involving a ketone, CH3SO3H, and NaN3 was approximately 1:2 (A=B), with small
amounts of other impurities. Both the yield and stereoselectivity were less than those
of the Beckmann rearrangement.
Beckmann Rearrangement Mechanism for
(1E)-6-Methoxy-3,4-dihydro-naphthalene-1(2h)-one Oxime
To explain these experimental results and obtain both better yields and better
regio- and stereoselectivities for the rearrangement products, the mechanism of the
Beckmann rearrangement was explored. In the presence of acids, the oxime proto-
nates first and then eliminates one molecule of water to form an electron-deficient
nitrogen atom, which is unstable because of its positive charge. The group anti to
Table 2. Effects of temperature and time on the regio- and stereoselectivity of rearrangement catalyzed by
FeCl3
Temp. (90 ꢁC)
Time (3 h)
110 ꢁC
Catalyst
FeCl3
Product
20 min
0.5 h
1.5 h
3.5 h
7 h
24 h
90 ꢁC
130 ꢁC
A=Ba
Trace A
9=1
5=1
4=1
2=1
Trace B
4=1
2.5=1
Trace B
aBased on the spot size ratio of the products on a TLC plate.

FACILE BECKMANN REARRANGEMENT
1923
the hydroxyl migrates to the electron-deficient nitrogen atom and promotes the hydro-
carbon on the ortho-carbon to complete a 1,2-migration. The formed carbocation
reacts with water to produce an amide. This reaction mechanism is shown in Fig. 1.
The direction of the 1,2-migration depends on the stability of the resultant car-
bocation. Therefore, the aryl group preferentially and selectively migrates to the
electron-deficient nitrogen atom, which inserts the nitrogen atom into the ring and
forms an aniline-lactam (A). The migration of the alkyl group is a trans migration
because it can only attack the electron-deficient N atom from the back of the hydroxy
group. Therefore, the products obtained are from trans migration in most cases. In
=
other words, when the C N double bond connects to the aryl and alkyl groups at
both ends, the aryl group migrates first to yield the corresponding products.[15–17]
=
When the groups connected to the two ends of the C N double bond have
similar sizes, a mixture of both the aryl and alkyl migration products will be
obtained.[8,18] In addition, the electron-donating methoxy group (CH3O-) in the
6-position of oxime is conducive to alkyl migration.[10] Therefore, this rearrangement
produces a mixture of the two isomers.
A trans oxime was synthesized by our group,[9] and its isomerization requires a
certain amount of energy. When this externally supplied energy is greater than the
isomerization energy, the configuration changes.[19] The proposed reaction mechan-
isms are shown in Figs. 1 and 2.
Figure 1. Reaction mechanism. (Figure is provided in color online.)

1924
F.-Y. PIAO ET AL.
Figure 2. Reaction path. (Figure is provided in color online.)
Based on the experimental results, the ketoxime requires significant energy to
isomerize when a Lewis acid, such as FeCl3 or AlCl3, catalyzes the rearrangement.
Therefore, the primary product is A. When the temperature is increased to provide
more energy, the content of B in the products increases; extending the reaction time
also increases the content of B because it is the lower energy and more stable. The
energy required for ketoxime isomerization when a Brønsted acid, such as PPA, cat-
alyzes the rearrangement is low. Additionally, B is both lower in energy and more
stable than A, and thus, the primary product is B. These results are consistent with
the theoretical calculations and reasoning.
According to traditional Beckmann rearrangement theory, the cis-ketoxime
generates product B, while the trans-ketoxime generates A. In this study, the theoreti-
cal product should be A because the starting material is purely trans-ketoxime. How-
ever, product B was obtained because of ketoxime isomerization. During the
formation of product A, the alkenyl cation attacks the alkyl cyanide ion; during
the formation of product B, the alkyl cation attacks the alkenyl cyanide ion. The
alkenyl cation is slightly more stable than the alkyl cation (because of the pꢂp

FACILE BECKMANN REARRANGEMENT
1925
=
=
conjugation between the C N and C C p-orbitals). In addition, the alkyl cation is
more stable than a r-type alkenyl cation. Hence, the intermediate of B is more stable
and has lower energy than that of A. Therefore, lower temperatures are conducive to
the formation of A, whereas higher temperatures are conducive to the formation of B.
Because the formation of A does not require isomerization energy, the reaction rate is
much greater; however, increasing the temperature and extending the reaction time
increases the formation of product B because of its stability.[20–22]
Calculation of the Ketoxime Isomerization Energy and the Activation
Energy of Its Rearrangement
Ab initio calculations were used to obtain the ketoxime isomerization energy
and the activation energy of its rearrangement.[23] The obtained results, shown in
Fig. 3, were consistent with the expected results. The rate of formation for A was
significantly greater than that of B because forming A did not require any isomeriza-
tion energy and involved a kinetic process. Therefore, A was always produced first
during these experiments. Isomerizing the oxime to the cis configuration reduces
the activation energy required to generate B, which has lower energy and is more
stable. Therefore, both increasing the reaction temperature and extending the reac-
tion time increases the ratio of B in the products. This reaction is controlled by ther-
modynamics. This finding is consistent with those of previous experiments.
Rearrangement of Oxime Sulfonate Catalyzed by ZnCl2
p-Toluenesulfonic acid (PTSA) and ZnCl2 were both added to a solution of
ketoxime in acetonitrile. This mixture was refluxed at 90 ꢁC to obtain a mixture of
the title compound and its isomer. However, the ketoxime and p-toluenesulfonic acid
reacted to form the oxime sulfonate, ZnCl2 was then added to the acetonitrile sol-
ution, and the mixture was refluxed at 90 ꢁC. The yield of product A was increased
to the point that only A was obtained (see Table 3).
This is because the isomerization energy of oxime sulfonate is greater than that
of ketoxime. In addition, the Lewis acid catalyst, ZnCl2, further increased the iso-
merization energy of the rearrangement relative to the Brønsted acid. Therefore,
Table 3. Rearrangement of Oxime in the presence of both acid and PTSA
Yield (%)
Substances
Oxime
Catalyst
Solvent
Temp. (ꢁC)
Time
A=B
A
B
PPA=PTSA
ZnCl2=PTSA
PPA
0
110–120
Reflux
25 min
6 h
2:1a
2:1a
2:1a
A
49.8b
24.3b
d
d
—
CH3CN
0
CH3CN
—
Oxime sulfonate
110–120
Reflux
25 min
2 h
54.7b
85.2c
28.6b
0
ZnCl2
aBased on the spot size ratio of the products on a TLC plate.
bGC yield.
cIsolated yield.
dNot tested.

1926
F.-Y. PIAO ET AL.
only product A was generated. The product loss of this system is less than that of
the solid-phase catalytic rearrangement because of the acetonitrile solvent. The
Beckmann rearrangement usually possessed a high conversion yield and selectivity
when conducted in the liquid phase.[24–25] This reaction system had a short reaction
time, used mild conditions, and resulted in the generation of the product in good
yield with good regio- and stereoselectivity.
CONCLUSION
The ring expansion rearrangement of (1E)-6-methoxy-3,4-dihydro-
naphthalene-1(2H)-one oxime always produces a mixture of the title compound
=
and its isomer because of the similar sizes of the groups on either end of the C N
double bond and the electron-donating group (CH3O-) at the 6-position of the
oxime. The separation of these two isomers is difficult. The isomerization energy
of ketoxime increased significantly when it was converted into oxime sulfonate while
using the Lewis acid ZnCl2 to catalyze the Beckmann rearrangement in acetonitrile,
which produced only the title compound with good yield.
EXPERIMENTAL
Uncorrected melting points were determined on an X-5 microscope melting
point apparatus. Infrared (IR) spectra were recorded (in KBr) on a Fourier transform
1
(FT)–IR (IR Prestige-21). H NMR spectra were measured on an AV-300 (Bruker,
Switzerland), and all chemical shifts are given in parts per million relative to tetra-
methylsilane (TMS). Mass spectra were measured on an HP1100LC (Agilent Tech-
nologies, USA). Combustion analyses (C, H, and N) were performed on a PE-2400
(Shimadzu). Microanalyses of C, N, and H were performed using a Heraeus CHN
rapid analyzer. The major chemicals were purchased from the Alderich Chemical
Corporation. All other chemicals were of analytical grade.
Rearrangement of (1E)-6-Methoxy-3,4-dihydro-naphthalene-
1(2H)-one Oxime
The Beckmann rearrangements catalyzed by the different acids are shown in
Scheme 1. The starting material, (1E)-6-methoxy-3,4-dihydronaphthalen-1(2H)-one
oxime,[9] was synthesized using a previously described method.[26] The title com-
pound was prepared from ketoxime using different acids.[11–14] The characterization
data for both compounds A and B were consistent with that published in the
literature.[27]
Schmidt Rearrangement of (1E)-6-Methoxy-3,4-dihydro-
naphthalene-1(2H)-one
The Schmidt rearrangement of the ketone using methane sulfonic acid and
sodium azide[7,10,18] is shown in Scheme 2.

FACILE BECKMANN REARRANGEMENT
1927
Scheme 1. Beckmann rearrangement catalyzed by different acids. Reagents: (a) FeCl3, 80–90 ꢁC, 1.5–3 h;
(b) AlCl3, 150–160 ꢁC, 0.5 h; (c) PPA, 120 ꢁC, 25 min; (d) PPA, 200 W, 60 ꢁC, 5–6 h; and (e) CH3SO3H,
17 ꢁC, 16–18 h.
Beckmann Rearrangement of (1E)-6-Methoxy-O-(p-
toluenesulfonyl)-3,4-dihydro-naphthalene-1(2H)-one Oxime
This ketoxime was converted into an oxime sulfonate,[5] which was in the trans
configuration according to the single-crystal structure.[28] Afterward, the oxime
sulfonate was reacted with PPA and ZnCl2 via the Beckmann rearrangement[29–31]
(see Scheme 3).
General Methods
The ketoxime (1.0219 g, 5.8 mmol) and p-toluenesulfonic acid (1.1148 g,
6.5 mmol) were both dissolved in 10 mL acetone at room temperature, and NaOH
(132.6 mg 3.3 mmol) was added. This mixture was stirred for 18 h. After reaching
completion, the acetone was evaporated to dryness. The residue was dissolved in
ethyl acetate, extracted, and washed three times with water. The organic phase
was dried using MgSO4, and the drying reagent was removed via filtration. The ethyl
acetate was concentrated via evaporation, and the solution was left overnight to
precipitate into colorless crystals with a yield of 95.0%.
Zinc chloride (1.0 mmol) was added to a solution of oxime tosylates (1.0 mmol)
in acetonitrile (5 mL). The mixture was heated to reflux (90 ꢁC) for 2 h. The progress
Scheme 2. Schmidt rearrangement of ketone.

1928
F.-Y. PIAO ET AL.
Scheme 3. Reaction of oxime tosylate with acid.
of the reaction was monitored by TLC. After the completion of the reaction, the
acetonitrile was evaporated, and the residue was dissolved in ethyl acetate and
washed with a small amount of water. The combined organic layer was dried over
anhydrous magnesium sulfate and filtered. Ethyl acetate was evaporated under
reduced pressure to give the crude product, which was recrystallized from ethanol
as white crystals, in 85.2% yield.
1,3,4,5-Tetrahydro-7-methoxy-2H-1-benzazepin-2-one (A)
Mp 143.9–144.3 ꢁC. IR (KBr), cmꢂ1: 3176, 1676. 1H NMR (CDCl3, 300 MHz),
d: 2.0–2.3 (m,2H, L -CH2-), 2.34 (t, J ¼ 6.9 Hz, 2H, -CH2-), 2.77(t, J ¼ 7.1 Hz, 2H,
-CH2-), 3.81 (s, 3H, -CH3), 6.5–7.0 (m, 2H, Ar-H), 6.96 (d, J ¼ 1.71 Hz, 1H,
Ar-H), 8.27(s, 1H, -NH-). MS (Mþ) m=z 191.
2,3,4,5-Tetrahydro-7-methoxy-1H-2-benzazepin-1-one (B)
Mp 158.5–159.4 ꢁC. IR (KBr), cmꢂ1: 3186, 1649. 1H NMR (CDCl3, 300 MHz),
d: 1.9–2.1 (m, 2H, -CH2-), 2.86 (t, J ¼ 7.1 Hz, 2H, -CH2-), 3.0–3.2 (m, 2H, -CH2-),
3.86 (s, 3H, -CH3), 6.65 (s, 1H, -NH-), 6.73 (d, J ¼ 2.4 Hz, 1H, Ar-H), 6.86 (dd,
J ¼ 2.4, 8.5 Hz, 1H, Ar-H), 7.68–7.71 (d, J ¼ 8.5 Hz, 1H, Ar-H). MS (Mþ) m=z 191.
ACKNOWLEDGMENT
This work was supported by the National Natural Science Foundation of
China (No. 30860340 and No. 21162031).
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