The application of the schmidt reaction and beckmann rearrangement to the synthesis of bicyclic lactams: Some mechanistic considerations

Article abstract of DOI:10.1071/CH09402

The syntheses of some methoxy-substituted bicyclic lactams, of the types 3 and 4, are reported employing two different conditions for the Schmidt reaction of appropriate ketones and employing two different conditions for the Beckmann rearrangement of the corresponding ketoximes. The alkyl to aryl migration ratios of the reactions were determined by high-performance liquid chromatography analysis of the reactions. The mechanisms of the reactions reported are discussed, some limitations of the reported mechanisms identified, and an alternative mechanism proposed in light of the outcomes of the various reactions. Application of the Schmidt reaction and Beckmann rearrangement was used for the synthesis of some chloro bicyclic lactams, of the types 3 and 4. CSIRO 2010.

Full text of DOI:10.1071/CH09402

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2010, 63, 211–226
The Application of the Schmidt Reaction and Beckmann
Rearrangement to the Synthesis of Bicyclic Lactams:
Some Mechanistic Considerations
Ian T. Crosby,A,B James K. Shin,A and Ben CapuanoA
AMedicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences,
Monash University (Parkville Campus), 381 Royal Parade, Parkville, Vic. 3052, Australia.
BCorresponding author. Email: ian.crosby@pharm.monash.edu.au
The syntheses of some methoxy-substituted bicyclic lactams, of the types 3 and 4, are reported employing two different
conditions for the Schmidt reaction of appropriate ketones and employing two different conditions for the Beckmann
rearrangement of the corresponding ketoximes. The alkyl to aryl migration ratios of the reactions were determined by
high-performance liquid chromatography analysis of the reactions.The mechanisms of the reactions reported are discussed,
some limitations of the reported mechanisms identified, and an alternative mechanism proposed in light of the outcomes
of the various reactions. Application of the Schmidt reaction and Beckmann rearrangement was used for the synthesis of
some chloro bicyclic lactams, of the types 3 and 4.
Manuscript received: 23 July 2009.
Manuscript accepted: 23 September 2009.
Introduction
be obtained depending on the reaction conditions utilized. This
paper aims to examine the influence of the reaction conditions
on the nature of the migration products obtained. In addition to
the reaction conditions, some substituent effects are also inves-
tigated. The substituent investigated in detail is the methoxy
group, a group that in resonance terms is electron-donating and
in inductive terms electron-withdrawing (Hammet substituents
constants;σp-OMe = −0.27;σm-OMe = +0.12).Applicationofthe
insight so gained is used to synthesize lactams derived from
chloro-substituted tetralones and chromanones.
The reaction between hydrazoic acid and carbonyl com-
pounds in the presence of a strong mineral acid is known as
the Schmidt reaction.[9] Although many other functional groups
(carboxylic acids, alcohols, alkenes) are known to react under
the Schmidt reaction conditions, the present investigation is
limited to the conversion of ketones to amides; in particular
cyclic ketones to lactams. The Beckmann rearrangement refers
to the rearrangement of oximes under acidic condition to yield
N-substituted carboxamides.[10] Both ketoximes and aldoximes
react but ketoximes are generally more reactive. Beckmann re-
arrangements have been achieved using acid-type catalysts such
as concentrated sulfuric acid, polyphosphoric acid, phosphorus
oxychloride, phosphorus pentachloride and thionyl chloride, and
success has also been reported using silica gel[11] and microwave
irradiation.[12,13]
Our group has had an interest in the synthesis and testing of
clozapine derivatives[1,2] as a potential for the treatment of
schizophrenia, a debilitating mental illness affecting ∼1% of the
world population.[3] Initial work involved the investigation
of alkylaryl substitution on the distal nitrogen of clozapine
(Fig. 1, 1).[1,2] Progression of this investigation has involved
investigating replacement of the important amino functional
group with a solubilizing aminimide group, as aqueous solu-
bility was beginning to limit the scope of the investigation.[4,5]
Another approach to reducing the lipophilicity of the analogues
has involved pruning the tricycle of clozapine to a bicycle
(Fig. 1, 2).[6]
Owing to stability issues associated with reactions of the
bicyclic lactams 2 to give the amidine clozapine analogues
(possibly due to the cyclic methylene group between two
electron-withdrawing C=N bonds), we desired to explore ana-
logues derived from less unsaturated lactams. As a result, we
desired access to various less unsaturated bicyclic lactams, as
key intermediates for the synthesis of new clozapine analogues
(Fig. 2). Depending on which aromatic ring is pruned, access to
two alternative lactams, 3 and 4, is desired. The replacement of
the nitrogen of clozapine (N5-H), with either methylene or oxy-
gen, is to help address the proposed involvement of the N5-H of
clozapine with its clinically limiting agranulocytosis.[7,8]
This paper explores synthetic approaches to bicyclic lac-
tams derived from a variety of substituted tetralones and
4-chromanones, investigating factors influencing the ratio of the
reaction products to provide optimal conditions for the synthesis
of target bicyclic lactams.
Results
Results from the Schmidt reactions on the five bicyclic ketones
5–9 are tabulated in Table 1. Results from the Beckmann re-
arrangement on the corresponding anti-ketoximes 10–14 are
also shown in Table 1. The alkyl:aryl migration ratio of indi-
vidual reactions was determined and the most efficient route for
the synthesis of the desired bicyclic lactams so determined.
The Schmidt reaction of cyclic ketones, and the Beckmann
rearrangement of their corresponding ketoximes, has provided
a method for the conversion of cyclic ketones to lactams. In the
case of aryl alkyl ketones, a variety of migration product can
© CSIRO 2010
10.1071/CH09402
0004-9425/10/020211

212
I. T. Crosby, J. K. Shin, and B. Capuano
H
N
H
N
H3C
N
Cl
Cl
Cl
Pruning
N
N
N
N
N
N
N
N
N
1
2
H3C
Y
Y
Clozapine
Z
Z
Fig. 1. Initial tricycle to bicycle pruning of clozapine analogues.
H
N
5
Y
Y
Pruning
Pruning
X
X
Cl
N
N
N
N
N
N
Clozapine
N
Z
N
N
Z
Y
Y
X
X
X ϭ H, Cl, OMe
Y ϭ CH2, O
Z ϭ alkylaryl
NH
Bicyclic lactam 3
Fig. 2. Alternative tricycle to bicycle pruning of clozapine analogues.
N
H
O
O
Bicyclic lactam 4
Table 1. The alkyl:aryl migration ratios of the Schmidt reaction and Beckmann rearrangement
6
6
R
R
R
R
X
X
X
X
NH
N
H
O
O
O
N
OH
5 R ϭ CH2, X ϭ H
6 R ϭ O, X ϭ H
10 R ϭ CH2, X ϭ H
11 R ϭ O, X ϭ H
15 R ϭ CH2, X ϭ H
16 R ϭ O, X ϭ H
20 R ϭ CH2, X ϭ H
21 R ϭ O, X ϭ H
7 R ϭ CH2, X ϭ 5-OMe 12 R ϭ CH2, X ϭ 5-OMe 17 R ϭ CH2, X ϭ 6-OMe 22 R ϭ CH2, X ϭ 6-OMe
8 R ϭ CH2, X ϭ 6-OMe 13 R ϭ CH2, X ϭ 6-OMe 18 R ϭ CH2, X ϭ 7-OMe 23 R ϭ CH2, X ϭ 7-OMe
9 R ϭ CH2, X ϭ 7-OMe 14 R ϭ CH2, X ϭ 7-OMe 19 R ϭ CH2, X ϭ 8-OMe 24 R ϭ CH2, X ϭ 8-OMe
Starting material
Reaction
Reagents
Products
Migration ratio (alkyl:aryl)
% Yield of major product
5
5
10
10
6
Schmidt
Schmidt
Beckmann
Beckmann
Schmidt
HCl/NaN3
15, 20
15, 20
15, 20
15, 20
16, 21
16, 21
16, 21
16, 21
17, 22
17, 22
17, 22
17, 22
18, 23
18, 23
18, 23
18, 23
19, 24
19, 24
19, 24
19, 24
96:4
12:88
0:100
92:8
100:0
97:3
52
75
60
48
18
83
56
37
71
21
47
36
53
38
71
31
54
38
47
21
H2SO4/NaN3
Polyphosphoric acid
SOCl2
HCl/NaN3
6
Schmidt
H2SO4/NaN3
Polyphosphoric acid
SOCl2
11
11
7
Beckmann
Beckmann
Schmidt
96:4
100:0
100:0
89:11
0:100
85:15
70:30
67:33
73:27
71:29
95:5
HCl/NaN3
7
Schmidt
H2SO4/NaN3
Polyphosphoric acid
SOCl2
12
12
8
Beckmann
Beckmann
Schmidt
HCl/NaN3
8
Schmidt
H2SO4/NaN3
Polyphosphoric acid
SOCl2
13
13
9
9
14
14
Beckmann
Beckmann
Schmidt
Schmidt
Beckmann
Beckmann
HCl/NaN3
H2SO4/NaN3
Polyphosphoric acid
SOCl2
16:84
0:100
100:0

Application of the Schmidt Reaction and Beckmann Rearrangement to the Synthesis of Bicyclic Lactams
213
concentrated sulfuric acid method, the low product yield detracts
from the usefulness of this method. Similarly, 5-methoxy-1-
tetralone 7 in concentrated hydrochloric acid or in concentrated
sulfuric acid gave the alkyl-migration lactam 17 as the major
product, with the concentrated hydrochloric acid reaction giv-
ing greater selectivity and yield.The use of concentrated sulfuric
acid for the reaction of 7 has not been reported, but polyphospho-
ric acid[19] and trichloroacetic acid[20] have been reported to give
22 as the major product. The Schmidt reaction of 6-methoxy-1-
tetralone 8 also demonstrates the contribution of the steric and
electronic effects on the migration of the adjacent carbon, with a
modest selectivity alkyl:aryl migration ratio compared with that
of 6 and 7 under either reaction conditions. This suggests that
the electronic effects are more influential than the steric effects
and this is in good agreement with the literature reports.[21,22]
7-Methoxy-1-tetralone 9 mirrored that for the Schmidt reaction
of 1-tetralone 5 with the reaction in concentrated hydrochloric
acid, giving mostly alkyl migration and the concentrated sulfuric
acid reaction giving predominately the aryl-migration product,
observations consistent with the literature.[18,23,24]
ϩ
ϩ
NH
N
N
H
O
N
O
O
N
N
5
15
20
25
Scheme 1.
For the Schmidt reaction, concentrated hydrochloric acid and
concentrated sulfuric acid were used, as the Schmidt reaction
was found to behave differently in the two acids. For concen-
trated hydrochloric acid, the methods used by Mach et al.[14] and
MeyersandHutchings[15] werechosen, whereasforconcentrated
sulfuric acid, the method used by Sidhu et al.[16] was adopted.
For the Beckmann rearrangement, the ketoximes were synthe-
sized using hydroxylamine hydrochloride and sodium acetate
in ethanol. The subsequent rearrangement was achieved by stir-
ring the ketoximes in polyphosphoric acid at 95◦C for 2 h, or in
thionyl chloride at 50◦C for 2 h.
Crude samples taken from each reaction were analyzed using
high-performance liquid chromatography (HPLC). Standards
were prepared from the bicyclic lactams previously isolated
and purified. The peaks were identified by comparison of the
retention time and the UV absorption profile with the stan-
dards, and quantitation was achieved by comparing the peak
area with that of the relevant standard. The alkyl:aryl migration
ratio for the Schmidt reaction and the Beckmann rearrangement
are summarized above (Table 1).
For the Beckmann rearrangement, conversion of the ketones
to the ketoximes was achieved by refluxing the ketone with
hydroxylamine hydrochloride and sodium acetate in ethanol for
2 h (Table 2).[25–29]
Literature procedures on the synthesis of ketoximes are not
specific regarding the geometry (syn or anti) of the oxime
group and full characterization is seldom performed as they
are transitory. Hence, the ketoxime intermediates are reported
as either non-specific or are assumed to be in the steri-
cally favoured anti-arrangement. Papers reporting exclusive
syn-ketoxime formation[30–33] are spectroscopically indistin-
guishable from the anti-ketoxime 10,[34–36] adding a significant
amount of uncertainty as far as the geometry is concerned.
No paper identified the orientation of the oxime group for
compounds 11–14.
The Schmidt reaction of 1-tetralone 5 using concentrated sul-
furic acid gave the aryl-migration lactam 20 as the major product
in 75% isolated yield, whereas using concentrated hydrochloric
acid gave the alkyl-migration lactam 15 in 52% isolated yield.
In the concentrated hydrochloric acid reaction, tetrazole 25 was
also isolated in 8% yield, but it was not observed in the sulfuric
acid reaction (Scheme 1).
The two lactams are distinguishable from each other by
comparison of their melting points (15: 99–100◦C; 20: 139–
140◦C) with those from the literature (15: 101◦C;[15] 20: 139–
140◦C[17]). In addition, the splitting pattern of the H3 protons
for lactam 15 shows an apparent quartet resonance at δ 3.12
suggesting that the NH group is at the 2-position, whereas 20
shows a triplet resonance at δ 2.36 for H3 protons, signifying
that the NH is at the 1-position. The integrity of other ring-
substituted bicyclic lactams made in the subsequent reactions
was confirmed principally by comparing the H3 proton reso-
nances. The alkyl:aryl migration ratio of 12:88 in concentrated
sulfuric acid was consistent with that of Tomita et al.,[18] who
reported 80% aryl migration under the same reaction conditions.
The alkyl:aryl migration ratio of 96:4 observed for the concen-
trated hydrochloric acid reaction is a reversal of the selectivity
of the reaction.
Of the five ketoximes synthesized below, X-ray crystal struc-
tures of 13 and 14 were determined (Fig. 3) (C. M. Forsyth,
unpubl. data). As expected, the oxime group was in the ster-
ically less-hindered anti-arrangement. Based on these crystal
structures, it is assumed that other ketoximes are also in the
anti-arrangement.
The Beckmann rearrangement of 1-tetralone oxime 10 in
polyphosphoric acid gave the aryl-migration lactam 20. This is
in agreement with most of the literature but disputes the con-
verse claim made by Mazzocchi et al.[37] that alkyl migration
should predominate. In addition, the ytterbium triflate method
as reported by Yadav et al.[38] was tried but the reaction did not
proceed and failed to produce either of the bicyclic lactams in our
Table 2. Data for the ketoximes synthesized
R
R
NH2OHиHCI
The Schmidt reaction of 4-chromanone 6, 5-methoxy-1-
tetralone 7, 6-methoxy-1-tetralone 8, and 7-methoxy-1-tetralone
9 using concentrated hydrochloric acid or concentrated sulfuric
acid produced alkyl and aryl-migration lactams in the isolated
yields shown in Table 1 with the alkyl:aryl migration ratio
indicated (HPLC).
X
X
NaOAc
Aq. EtOH
O
N
OH
5–9
10–14
Compound
R
X
Yield [%]
mp [◦C]
Lit. mp [◦C]
Reaction of 4-chromanone 6 using concentrated hydrochloric
acid or concentrated sulfuric acid produced the alkyl-migration
lactam 16 as the major product. This shows the importance of
the resonance electronic effects of the ethereal oxygen on the
ortho position relative to the ketone group.Although the reaction
in concentrated hydrochloric acid was more selective than the
10
11
12
13
14
CH2
O
CH2
CH2
CH2
H
H
5-OMe
6-OMe
7-OMe
79
66
74
81
83
100–101
138–140
152–153
124–125
84–85
101–103[25]
139–141[26]
153–155[27]
122–124[28]
86–88[29]

214
I. T. Crosby, J. K. Shin, and B. Capuano
C(11)
C(4)
C(5)
C(6)
C(6)
C(4)
C(7)
C(5)
O(2)
C(7)
C(3)
C(3)
C(8)
C(2)
O(2)
C(10)
C(8)
C(10)
C(2)
C(9)
C(1)
C(9)
C(1)
N(1)
N(1)
C(11)
O(1)
O(1)
13
14
Fig. 3. X-ray crystal structures (ORTEP view) of oximes 13 and 14.
ϩ
ϩ
O
OH
C
OH
OH
HN3
ϪH2O
H
R
C
N
RЈ
ϩ
C
R
R
RЈ
R
RЈ
ϩ
R
RЈ
H
N
N
26
27
28
O
C
R
ϩ
HO
R
H2O
ϪH ϩ
ϪN2
C
N
ϩ
C
N
R
C
N
RЈ
N
H
RЈ
N
RЈ
RЈ
N
29
30
31
32
Fig. 4. Proposed mechanism of the Schmidt reaction.[47]
hands. However, treatment of 10 with thionyl chloride afforded
the alkyl-migration lactam 15 as the major product. The reaction
confirmed the results reported by Sudan et al.,[39] and could be
used as an alternative Beckmann rearrangement method.
Reaction of 4-chromanone oxime 11 in polyphosphoric acid
gave mainly the alkyl-migration lactam 16, which is in agree-
ment with the literature.[40] The reaction of 11 with thionyl
chloride also gave 16 as the major product; no aryl migration
was observed. 5-Methoxy-1-tetralone oxime 12 in polyphospho-
ric acid gave the aryl-migration lactam 22; no alkyl-migration
lactam 17 was observed. This confirmed results reported in the
majority of the literature,[41,42] yet disputes the claim made
by Martinez et al.[43] that the alkyl migration should pre-
dominate. In contrast, the Beckmann rearrangement of 12 in
thionyl chloride gave mostly the alkyl-migration product 17.
6-Methoxy-1-tetralone oxime 13 in both polyphosphoric acid
and thionyl chloride gave alkyl-migration lactam 18 as the major
product. Based on the yield, however, the use of polyphospho-
ric acid is preferred over thionyl chloride, as the former gives
a cleaner reaction and higher yield. Unlike 13, the Beckmann
rearrangement of 7-methoxy-1-tetralone oxime 14 was more
selective. In polyphosphoric acid, the rearrangement of 14 gave
exclusively aryl-migration lactam 24, and in thionyl chloride,
14 yielded exclusively alkyl-migration lactam 19. The Beck-
mann rearrangement of 14 in the literature reports 24 as the
only product[44–46] and the use of thionyl chloride to afford 19
is novel.
Generally, the use of the Schmidt reaction is favoured over
the Beckmann rearrangement, as the former is a one-step proce-
dure, except when the Schmidt reaction does not give the desired
lactam or when the yield of the reaction is unacceptably low. The
majority of the bicyclic lactams were synthesized in moderate
to good yields but some of the aryl-migration lactams (21–24)
suffered a bit from low yields but these were still acceptable for
access to the required lactams. Synthesis of 21 proved to be a
challenge, and in the future, this lactam might require a different
approach.
Mechanistic Discussion: Schmidt Reaction
The mechanism of the Schmidt reaction is not fully elucidated;
however, the mechanism shown above (Fig. 4) has been agreed
on by many researchers as plausible.[47]
Under strongly acidic conditions, protonation of the ketone
26 occurs to give the resonance-stabilized cation 27, and sub-
sequent nucleophilic addition of the hydrazoic acid gives the
hydroxyhydrazidinium intermediate 28. On dehydration, 28 con-
verts to the iminodiazonium ion 29 and a concerted elimination
of the nitrogen and migration of the R-group (the group anti to
the leaving group) afford the nitrilium intermediate 30. Reac-
tion with a water molecule, followed by tautomerization of 31,
gives the final amide 32. Symmetrical ketones (R = Rꢀ) give only
one amide product, but unsymmetrical ketones can give a mix-
ture of the two amide products, where the ratio is determined by

Application of the Schmidt Reaction and Beckmann Rearrangement to the Synthesis of Bicyclic Lactams
215
ϩ
HN3
ϪH2O
H
ϩ
HO
NH
N2
O
OH
OH
ϩ
ϩ
5
34
ϪN2
H2O
N
N
ϩ
N
OH
H
O
N
N2
ϩ
33
35
20
Fig. 5. Proposed Schmidt reaction mechanism of 5 in conc. sulfuric acid to give aryl-migration lactam 20.
15
HN3
ϪN2
20
NH
HO
34
O
N2
ϩ
5
ϪH2O
ϪH2O
ϪN2
H2O
ϪN2
X
NH
N
H
H2O
O
ϩ
H
N
H
N
O
N2
N2
ϩ
15
36 (syn)
33 (anti )
20
Fig. 6. Proposed Schmidt reaction mechanism of 5 under aqueous (conc. hydrochloric acid) and non-aqueous (conc. sulfuric
acid) acids.[54]
the migratory aptitude of the relevant carbons. In the case of an
alkyl aryl ketone, it is generally the aryl group that preferentially
migrates, unless the alkyl group is also bulky.[48]
product in concentrated hydrochloric acid and 20 in concen-
trated sulfuric acid (Fig. 6). The authors[54] have proposed that
under the non-aqueous acid conditions (concentrated sulfuric
acid), dehydration of the hydroxyhydrazidinium intermediate 34
is likely to occur, giving one of the two stereoisomers of the
iminodiazonium intermediates 36 (syn) or 33 (anti). Owing to
the steric hindrance with the peri-proton, the formation of the
syn-iminodiazonium ion 36 is unfavoured and the reaction pro-
ceeds via the anti-iminodiazonium intermediate 33 to give 20.
The two iminodiazonium intermediates are not interchangeable
as the calculation of the energy barrier for nitrogen inversion is
wellabovethatofroomtemperature.[56] However, dehydrationof
34 is not likely to occur in aqueous acid (concentrated hydrochlo-
ric acid).The authors[54] claimed that a concerted rearrangement
of 34 takes place to give 15 as the major product. This proposi-
tion is not supported by a detailed reaction mechanism, as most
of the literature reports aryl migration as the preferred reaction,
in difference with the proposition of Bach and Wolber.[56]
To account for some limitations in the explanation for the
formationof 15undertheaqueousacidconditions, analternative
reaction mechanism is proposed (Fig. 7). Rather than a loss of a
water molecule in the aqueous acid, the hydroxyhydrazidinium
intermediate 34 can undergo a migration of either the alkyl or
aryl carbons, giving the two possible cation intermediates 37
(PathwayA, alkylmigration)and 38(PathwayB, arylmigration).
In either case, subsequent loss of a proton results in formation
of the stable amides 15 or 20, respectively.
In concentrated sulfuric acid, it is predicted from the pro-
posed mechanism of the Schmidt reaction that aryl migration
will predominate over alkyl migration (Fig. 5). The use of con-
centrated sulfuric acid is reported to give the aryl-migration
lactam (20) in 47–92% yield.[49–51] The use of trichloroacetic
acid was also reported to proceed in 57–83% yield in favour of
20.[17,52] Tomita et al.[18] have investigated the alkyl:aryl migra-
tion ratio of various unsymmetrical ketones using different types
and strengths of acid and have found that the reaction of 5 in
trichloroacetic acid, concentrated sulfuric acid and polyphos-
phoric acid gave 30:70, 20:80, and 10:90 for the alkyl:aryl
migration ratios, respectively. The Schmidt reaction mechanism
of 1-tetralone 5 in concentrated sulfuric acid is shown above
(Fig. 5). The key step in the reaction mechanism is the formation
of the anti-iminodiazonium intermediate (33) that is sterically
favoured. Subsequent aryl migration, elimination of molecu-
lar nitrogen, hydration and tautomerization of 35 result in the
formation of 20.
In contrast, the Schmidt reaction of 5 in concentrated
hydrochloric acid reported alkyl-migration lactam 15 as the
major product, with yields ranging from 25 to 84%.[14,15,53] The
low yield (25%) is probably due to the hydrolysis caused by
the 1 M sodium hydroxide solution used during the neutraliza-
tion step.[53] Use of a milder base, such as potassium carbonate,
resulted in higher yields.[14,15] Grunewald and Dahanukar[54,55]
have proposed explanations for the formation of 15 as the major
Comparison of the relative stabilities of the two cations, 37
and 38, indicates that pathway A is energetically favoured over

216
I. T. Crosby, J. K. Shin, and B. Capuano
Hϩ/HN3
ϩ
ϪH
Pathway A
ϩ
A
NH
NH
O
ϪN2
HO
NH
O
B
HO
37
ϩ
N2
5
34
15
ϪN2
Pathway B
ϩ
ϪH
ϩ
N
N
H
H
O
OH
38
20
Fig. 7. Proposed Schmidt reaction mechanism of 5 under conc. hydrochloric acid; Pathway A (alkyl migration
forms lactam 15) and Pathway B (aryl migration forms lactam 20).
O
O
O
O
of the aryl group. Therefore, a more detailed mechanism is pro-
posed showing the full extent of the electronic effects of the
ethereal oxygen on the migration of the alkyl carbon (Fig. 10).
Dehydration of the hydroxyhydrazidinium 42 would occur
in concentrated sulfuric acid to produce the sterically favoured
anti-iminodiazonium intermediate 39. However, the lone pair
of electrons from the oxygen can delocalize into the aromatic
ring and can produce the resonance hybrid structure 43. As
shown, aryl migration would be prohibited owing to the par-
tial double-bond character of the aryl carbon. At the same time,
this partial double bond character reduces the energy barrier
for the anti–syn interconversion and allows rotation of the C–N
bond to produce the syn-iminodiazonium intermediate 44; it can
undergo alkyl migration to give the nitrilium cation 45; subse-
quent hydration and tautomerization result in the formation of
the alkyl-migration lactam 16.
The Schmidt reactions of 5-methoxy-1-tetralone 7 gave a
result consistent with the proposed Schmidt reaction mechanism
in the aqueous acid.As the methoxy group on the 5-position does
not take part in the resonance stabilization of the iminodiazo-
nium intermediate, the formation of the aryl-migration lactam
22 is expected in concentrated sulfuric acid. Contrary to this
expectation, the reaction of 7 in concentrated sulfuric acid gave
17 as the major product.The use of concentrated sulfuric acid for
the reaction of 7 has not been reported in the literature, but the
use of polyphosphoric acid[19] and trichloroacetic acid[20] have
been reported, giving 22 as the major product. The formation of
22 in concentrated sulfuric acid supports the need for the revised
mechanism.
ϩ
NH
Alkyl migration 16
N
H
O
O
4-Chromanone 6
Aryl migration 21
Fig. 8. Schmidt reaction of 6 and its potential products: alkyl (16) and
aryl (21) migration lactams.
pathway B. The aliphatic cation intermediate 38 is resonance-
stabilized by the lone pairs of electrons on two heteroatoms (N
and O) and a remote inductive donation of electrons from the
aromatic ring, whereas the benzylic cation intermediate 37 is
stabilized by the lone pairs of electrons on two heteroatoms (N
and O) and by the benzylic resonance stabilization from the
aromatic ring. As the benzylic resonance-stabilizing effect is
much stronger than a remote inductive effect, 37 is more stable
than 38 and the reaction proceeds to favour the formation of 15.
In contrast to the Schmidt reaction of 1-tetralone 5, there
are many literature reports of the alkyl-migration lactam 16 as
the major reaction when 4-chromanone 6 is subjected to the
Schmidt reaction conditions (Fig. 8). The use of concentrated
sulfuric acid is reported to give 16 in 36–78% yield.[16,40,53,55,57]
A combination of acetic acid and concentrated sulfuric acid was
also used and reported to give 16 in ∼55% yield.[58,59] The use
of concentrated hydrochloric acid has not been reported in the
literature.
Based on steric effects alone the formation of the aryl-
migration lactam 21 is predicted, as the sterically stable anti-
iminodiazonium intermediate 39 is preferred (Fig. 9). The only
reference to the formation of 21 is by Kamei et al.,[60] where
it was isolated as a minor product in 2.6% yield. Evans and
Lockhart[61] proposed that the preference of alkyl migration is
due to the electronic effects of the ‘ortho’ cyclic ether oxygen
and presented a resonance structure of 4-chromanone (Fig. 10),
which shows a partial double-bond character between the two
carbon atoms (C4 and C4a) 40 making it difficult to migrate.
Similar effects 41 were seen with 6-methoxy-1-tetralone 8
where the ether oxygen atom is para with respect to the ketone
functionality.[62]
Compared with other ketones, which showed greater than
95% propensity for the alkyl migration in concentrated
hydrochloric acid, 8 gave an alkyl:aryl migration ratio of 70:30,
with bicyclic lactams 18 and 23 being isolated in 53 and 15%
yield, respectively. This suggests that the Schmidt reaction in
concentrated hydrochloric acid does proceed via two different
reaction mechanisms (Fig. 7), making it difficult to synthesize
23 as the major product.
Mechanistic Discussion: Beckmann Rearrangement
TheresonancestructurespresentedbyEvansandLockhart[61]
below (Fig. 9) do explain the prevention of the aryl migra-
tion in 4-chromanone 6; however, they do little in justifying
why alkyl migration should occur, as the formation of the anti-
iminodiazoniumion 39isstillfavouredbasedonthestericeffects
The Beckmann rearrangement of 46 (Fig. 11) is mechanistically
similar to the Schmidt reaction (Fig. 4); the oxonium intermedi-
ate 47 is analogous to the iminodiazonium intermediate 29, and
the subsequent reaction with water and tautomerization of the
iminol 31 to the amide 32 are identical to the Schmidt reaction

Application of the Schmidt Reaction and Beckmann Rearrangement to the Synthesis of Bicyclic Lactams
217
ϩ
O
O
O
N
O
O
ϩ
rotn
H /HN3
ϪH2O
HO
NH
N2ϩ
N
Ϫ
N2
N2
ϩ
ϩ
6
42
39
43
ϩ
ϩ
O
O
O
O
H2O/ϪH
ϪN2
N
NH
ϩ
ϩ
ϩ
N
N
O
Ϫ
N2
N2
44
45
16
Fig. 9. Proposed Schmidt reaction mechanism of 4-chromanone 6 forming the alkyl-migration lactam 16.
ϩ
ϩ
O
O
O
O
O
O
Ϫ
O
Ϫ
O
6
40
8
41
Fig. 10. Electronic effects of the ether oxygen in 6 and 8.
ϩ
H
R
R
R
ϩ
ϪH2O
ϩ
H2O
ϪH2O
H
C
N
C
N
C
N
ϩ
ϩ
RЈ
OH2
RЈ
OH
RЈ
ϪH
N
O
ϩ
N
N
46
47
30
OH
OH2
ϩ
10
O
C
HO
R
H2O
R
C
N
ϩ
RЈ
N
ϪH
RЈ
H
N
N
H
OH
31
32
20
Fig. 11. Mechanism of the Beckmann rearrangement.[64]
Fig. 12. Beckmann rearrangement mechanism of 10 leading to the aryl-
migration lactam 20.
mechanism. Unlike the Schmidt reaction, however, the geometry
of the oxime group 46 is predetermined, and the migration of the
group that is anti to the leaving group is generally favoured but
it is not always unequivocal.[63]
provided for 15. In addition, of the 11 unsymmetrical ketoximes
studied, all but one proceeded to give aryl-migration product,
which further questions their report. The third paper reporting
the Beckmann rearrangement of 10 using thionyl chloride in 1,4-
dioxan reported 15 in 60% yield.[39] The reported melting point
of 15 (98–99◦C) and spectral data are consistent with the alkyl-
migration lactam. This method appears to provide synthetic
access to 15.
As with the Schmidt reaction of 4-chromanone 6, the Beck-
mann rearrangement of 4-chromanone oxime 11 is driven by
the electronic effects of the cyclic ether oxygen. Presented
below is the proposed Beckmann rearrangement mechanism
of 11 in polyphosphoric acid (Fig. 13). Analogous to the anti-
iminodiazonium intermediate 39, the anti-oxonium intermediate
48 is prohibited from aryl migration owing to the partial double-
bond character of the aryl carbon. Instead, inversion of 48
to the syn-oxonium intermediate 49 occurs through resonance
hybridization structures 50 and 51, which can then undergo an
alkyl migration to give the amide 16.
Most literature on the Beckmann rearrangement of
1-tetralone oxime 10 reported aryl-migration lactam 20 as the
major product. Stirring 10 in polyphosphoric acid for 5 to
10 min at 120–130◦C is reported to give 20 in good yield.[65–68]
Other methods using bismuth chloride,[69] indium chloride,[70]
2,4,6-trichloro[1,3,5]triazine,[71] gallium triflate,[72] aluminium
chloride,[73] and sulfamic acid[74] all reported 20 in good yield
(72–85%). The Beckmann rearrangement mechanism of 10
giving the aryl-migration lactam 20 is presented above (Fig. 12).
A search of the literature revealed only three papers report-
ing alkyl migration of 10. Mazzocchi et al.[37] have reported
the formation of the alkyl-migration lactam 15 in 80% yield
using polyphosphoric acid. However, the reported melting point
of 142.5–143.0◦C is closer to 20 (139–140◦C)[17] than to 15
1
(99–101◦C).[75] The H NMR spectral data provided showed
greater concordance with that of 20 than that of 15. Yadav
et al.[38] have reported alkyl migration of 10 in 70% yield by
using ytterbium triflate as the catalyst. However, their claim in
the short communication is uncertain as no spectral data were
Reports of the Beckmann rearrangement of 11 are
uncommon. The polyphosphoric acid-catalyzed Beckmann

218
I. T. Crosby, J. K. Shin, and B. Capuano
ϩ
O
N
O
O
N
ϩ
rotn
H
N
Ϫ
OH2
ϩ
OH2
ϩ
OH
11
48
50
ϩ
ϩ
O
O
O
O
H2O/ϪH
ϪH2O
N
NH
O
ϩ
N
N
H2O
ϩ
Ϫ
H2O
ϩ
51
49
45
16
Fig. 13. Proposed mechanism of the Beckmann rearrangement of 11 to give the alkyl-migration lactam 16.
5
6
in N,N-dimethylacetamide resulted in the formation of the
intermediate 62. Further addition of excess sodium hydroxide
resulted in the formation of the amide 63 through the Smiles re-
arrangement of 62. Addition of water and heating to reflux gave
6-amino-1-tetralone 60 in 63% yield from 61. The one-pot syn-
thesis of 6-amino-1-tetralone 60 was attempted using the method
reported by Mizuno et al.[79] The 1H NMR spectrum of 60, com-
parison of the melting point (129–131◦C, lit.[80] 129–130◦C) and
electrospray ionization (ESI) mass spectrometry all confirmed
formation of 60. Conversion of the 6-amino-1-tetralone 60 to
52 was achieved under the Sandmeyer conditions (45% yield).
Thetwo-stepmethodforthesynthesisof 53hasbeenreported
by Harris et al.,[81] where Wolff–Kishner reduction of commer-
cially available 3-(4-chlorobenzoyl)propionic acid 64 afforded
65, and subsequent ring closure using polyphosphoric acid
gave 53 (Scheme 3). In our hands, this method gave 65 and
polyphosphoric acid ring closure afforded 53.
X
X
1
1
NH
O
O
52 X ϭ 6-Cl
53 X ϭ 7-Cl
56 X ϭ 7-Cl
57 X ϭ 8-Cl
1
8
6
O
O
X
X
1
NH
O
O
54 X ϭ 6-Cl
55 X ϭ 7-Cl
58 X ϭ 8-Cl
59 X ϭ 7-Cl
Fig. 14. Possible conversion of the chloro ketones (52–55) to the alkyl-
migration lactams (56–59).
Gresham et al.[82] have reported the conversion of
3-cholorophenol 66 to β-phenoxypropionic acid 67 using
β-propiolactone under alkaline conditions, which was readily
reproduced. Ring-closure of the intermediate 67 was achieved
using polyphosphoric acid to afford 55 (Scheme 4).
rearrangement of 11 afforded the alkyl-migration lactam 16 in
33% yield,[40] but an attempt to convert 11 to 21 using
p-toluenesulfonyl chloride was not successful.[76] These results
further support the proposed mechanism of the oxonium inter-
mediate inversion (from anti to syn) arising from the electronic
effects of the cyclic ether oxygen in the ortho position with
respect to the ketone group.
The objective of a second series of bicyclic ring-substituted
analogues (Fig. 2) was to investigate the effect of chlorine
substitution on the eventual 7- and 8-positions of the bicyclic
lactams. Chlorine was chosen as it is present in clozapine and
also other antipsychotic drugs. In addition, analogues with isos-
teric replacement of the N5-H of clozapine with methylene
and oxygen were also targeted. It was envisaged that applying
the Schmidt reaction and Beckmann rearrangement on the
corresponding chlorine-substituted ketones 52–55, the chlorine-
substituted bicyclic lactams (56–59) could be accessed (Fig. 14).
Of the four chlorine-substituted ketones required, only the
6-chloro-4-chromanone 54 was commercially available and the
other chlorine-substituted ketones were synthesized.
Having obtained the required chlorine-substituted 1-
tetralones and 4-chromanones for the bicyclic ring-substituted
analogues, conversion of these ketones to the lactams was
attempted using the Schmidt reaction and Beckmann rearrange-
ment (Fig. 14). The Schmidt reaction of 52 in concentrated
hydrochloric acid gave the alkyl-migration lactam 56 (Fig. 14).
The Schmidt reaction of 53 using concentrated hydrochloric
acid gave the alkyl-migration lactam 57. No aryl migration
product was observed from the reaction of 53 in concentrated
hydrochloric acid but the reaction gave a major by-product that
was identified to be 2,2,7-trichloro-1-tetralone 68, isolated in
53% yield (Scheme 5).
The 1H NMR spectrum of 68, elemental analysis and
electron-impact (EI) mass spectrometry confirmed the pres-
ence of three chlorine atoms. An X-ray crystal structure was
obtained for 68 that confirmed di-chlorination at the 2-position
(Fig. 15).[83]
The Schmidt reaction of 54 in concentrated sulfuric acid gave
the alkyl-migration lactam 58 as the major product. Compar-
ison of the melting point with the literature value showed a
significant difference and accordingly, the identity of 58 was
further supported by elemental analysis. The aryl-migration lac-
tam 69 was isolated in 5% yield by collection of the more mobile
Conversion of 6-amino-1-tetralone 60 to 6-chloro-1-
tetralone 52 has been achieved using the Sandmeyer reaction
(Scheme 2).[77] 6-Amino-1-tetralone 60 can be accessed in
many ways and the use of commercially available 6-hydroxy-
1-tetralone 61 in the one-pot Smiles rearrangement has been
recently reported (Scheme 2).[78,79] Addition of 2-bromo-2-
methylpropanamide to a mixture of 60 and sodium hydroxide

Application of the Schmidt Reaction and Beckmann Rearrangement to the Synthesis of Bicyclic Lactams
219
O
Br
O
NH2
O
NaOH (9 eq.)
HO
Me Me
H2N
50–60ЊC, 2 h
NaOH (3 eq.), DMA
RT, overnight
O
O
61
62
H
N
Cl
H2N
H2O
1. NaNO2, HCl
HO
O
2. CuCl, 0–60ЊC
Reflux, 1 h
O
O
O
63
52
60
Scheme 2.
O
KOH, N2H4иH2O
PPA, 90–95ЊC
COOH
COOH
Ethylene glycol
Reflux, 2 h
20 min
Cl
Cl
Cl
O
64
65
53
Scheme 3.
O
O
Cl
OH
Cl
O
Cl
O
PPA
COOH
75–95ЊC
Aq. NaOH
100ЊC
O
67
55
66
Scheme 4.
NaN3, HCl
Cl
Cl
ϩ
50ЊC, 16 h
NH
Cl
Cl
Cl
O
O
O
53
57 (44%)
68 (53%)
Scheme 5.
O
O
O
O
O(1)
NaN3, H2SO4
ϩ
Toluene
RT, 16 h
NH
Cl
Cl
Cl
CI(2)
N
H
O
O
CI(1)
C(7)
C(6)
54
58 (74%)
69 (5%)
C(8)
C(1)
Scheme 6.
C(5)
C(4)
The Schmidt reaction of 55 in concentrated sulfuric acid gave
CI(3)
the alkyl-migration lactam 59 (Scheme 7); no aryl-migration
lactam was isolated from the reaction. The alkyl-migration 59
was also fully characterized using spectral data and elemental
analyses, as the compound was again novel. Owing to the lim-
ited quantities of the ketone 55, an investigation of the directing
effects of the Schmidt reaction and Beckmann rearrangement
was not pursued.
The Beckmann rearrangement approach was investigated
as an alternative route to the synthesis of 57 (Scheme 8).
Newman and Hung[84] reported the synthesis of 7-chloro-1-
tetralone oxime 71 using the hydroxylamine hydrochloride
method. Using this oxime synthetic method, 71 was obtained.
Comparison of the melting points (114–115◦C, lit.[84] 124–
125◦C) showed some degree of uncertainty, even though the
C(9)
C(10)
C(2)
C(3)
Fig. 15. X-ray crystal structure (ORTEP view) of 2,2,7-trichloro-1-
tetralone 68.
fractions (RF 0.5) from flash chromatography of the above reac-
tion. The aryl-migration product was fully characterized using
spectral data and elemental analyses, as the compound is novel
(Scheme 6).

220
I. T. Crosby, J. K. Shin, and B. Capuano
oxime was recrystallized using the same solvent system and the
characterization of 71 was supported by elemental analysis.
The subsequent Beckmann rearrangement of 71 was carried
out immediately in neat thionyl chloride to afford 57 (Scheme 8).
The use of polyphosphoric acid for the rearrangement of 71
was also investigated and gave the aryl-migration lactam 70
(Scheme 9). In agreement with the literature, 71 acted in a simi-
lar fashion to 1-tetralone oxime 10.[18] Despite the two reaction
steps, the overall yield for the synthesis of 57 using the Beck-
mann rearrangement (50%) is slightly greater than that of the
Schmidt reaction (44%).
5 (10.0 g, 68.4 mmol) and sodium acetate (11.0 g, 134 mmol)
in absolute ethanol (100 mL). Stirring was continued for 2 h
while heating at reflux, after which the resulting solution
was cooled, triturated with water (200 mL), filtered, and dried
under vacuum. Recrystallization (dichloromethane/hexane) of
this material afforded 1-tetralone oxime 10 (8.60 g, 79%) as
white plate-like crystals, mp 100–101◦C (lit.[85] 101–103◦C).
δH ((CD3)2CO) 10.08 (1H, s, NOH), 7.89 (1H, m, H8), 7.25–
7.12 (3H, m, ArH), 2.78–2.72 (4H, m, H2, H4), 1.82 (2H, app
p, J 6.5, H3). δC ((CD3)2CO) 153.1 (Cq), 139.2 (Cq), 131.4
(Cq), 128.5 (CH), 128.4 (CH), 126.0 (CH), 123.8 (CH), 29.5
(CH2), 23.3 (CH2), 21.4 (CH2). m/z (ESI, 70V) 162.0 (11%,
(M + H)+), 157 (16), 144 (27), 128 (25), 117 (67), 116 (100),
115 (70), 89 (71).
Conclusion
We have reported the Schmidt reaction of several unsubstituted
andoxygenatedbicyclicketones(5–9)andBeckmannrearrange-
ment of the corresponding ketoximes (10–14), each reaction
type being carried out using two different experimental con-
ditions. The alkyl to aryl migration ratios were determined by
HPLC. The reported mechanisms of these reactions were exam-
ined and some limitations of these mechanisms discussed. The
syn geometry of two ketoximes (13 and 14) was determined by
X-ray crystallography as part of this investigation; stereochem-
ical assignments had previously been ambiguously either syn or
anti. We proposed modified mechanisms in light of the results
from the various reactions reported. In general, it was found
that the Schmidt reaction method, for the synthesis of the result-
ing bicyclic lactams, was more convenient than the Beckmann
rearrangement approach. We applied the knowledge so gained
to the synthesis of some chloro bicyclic lactams, of the types
3 and 4. We aim to incorporate these chloro bicyclic lactams
(56–59) into some bicyclic analogues of clozapine, with the aim
of producing more stable and accessible bicyclic analogues than
previously reported.[6]
4-Chromanone Oxime 11
4-Chromanone 6 (741 mg, 5.00 mmol) and sodium acetate
(820 mg, 10.0 mmol) in absolute ethanol (50 mL) were
treated with hydroxylamine hydrochloride (417 mg, 6.00 mmol)
and worked up as for the preparation of 10. Recrystal-
lization (dichloromethane/hexane) of this material afforded
4-chromanone oxime 11 (536 mg, 66%) as colourless prisms,
mp 138–140◦C (lit.[26] 139–141◦C). δH ((CD3)2CO) 10.23 (1H,
s, NOH), 7.85 (1H, dd, J 8, 2, H8), 7.23, 6.93–6.85 (1H, 2H,
m, m, H5, H6, H7), 4.21 (2H, t, J 6, H2), 2.93 (2H, t, J 6, H3).
δC ((CD3)2CO) 156.5 (Cq), 148.0 (Cq), 130.3 (CH), 123.8 (Cq),
121.0 (CH), 119.3 (CH), 117.5 (CH), 64.9 (CH2), 23.2 (CH2).
m/z (ESI, 20 V) 164 (100%, (M + H)+).
5-Methoxy-1-tetralone Oxime 12
5-Methoxy-1-tetralone 7 (881 mg, 5.00 mmol) and sodium
acetate (820 mg, 10.0 mmol) in absolute ethanol (50 mL) were
treated with hydroxylamine hydrochloride (417 mg, 6.00 mmol)
and worked up as for the preparation of 10. Recrystallization
(ethyl acetate) of this material afforded 5-methoxy-1-tetralone
oxime 12 (709 mg, 74%) as colourless prisms, mp 152–153◦C
(lit.[27] 153–155◦C). δH ((CD3)2CO) 10.06 (1H, s, NOH), 7.54
(1H, d, J 8, H8), 7.11 (1H, app t, J 8, H7), 6.88 (1H, d, J 8, H6),
3.83 (3H, s, OCH3), 2.75–2.67 (4H, m, H2, H4), 1.79 (2H, app
p, J 6.5, H3). δC ((CD3)2CO) 156.8 (Cq), 153.3 (Cq), 132.4 (Cq),
127.9 (Cq), 126.1 (CH), 116.0 (CH), 109.8 (CH), 54.9 (CH3),
22.7 (CH2), 22.1 (CH2), 20.8 (CH2). m/z (ESI, 70V) 192 (100%,
(M + H)+), 174 (16), 147 (25), 146 (41), 132 (30), 116 (44), 100
(77), 77 (37).
Experimental
Refer to the Accessory Publication file for general experimental
details, and the synthesis of the ketones and their precursors.The
following ketoximes were prepared from commercially avail-
able 1-tetralones and 4-chromanones, and ketones synthesized
in the previous section. The general method is exemplified for
the synthesis of 1-tetralone oxime 10.
1-Tetralone Oxime 10
Hydroxylamine hydrochloride (9.50 g, 137 mmol) was added
in one portion to a magnetically stirred solution of 1-tetralone
O
Cl
O
Cl
NaN3, H2SO4
PPA
Toluene
RT, 16 h
NH
95ЊC, 2 h
Cl
Cl
N
H
O
O
NOH
O
70
71
55
59
Scheme 9.
Scheme 7.
NH2OHиHCl
NaOAc
SOCl2
EtOH
Relux, 4 h
NH
Cl
Cl
Cl
50ЊC, 2 h
O
NOH
O
53
71
Scheme 8.
57

Application of the Schmidt Reaction and Beckmann Rearrangement to the Synthesis of Bicyclic Lactams
221
6-Methoxy-1-tetralone Oxime 13
under vacuum to afford a yellow oil. This material was sub-
jected to flash chromatography (ethyl acetate), and recrystal-
lization (ethyl acetate/hexane) of the major fraction (RF 0.3)
afforded 2,3,4,5-tetrahydro-1H-2-benzazepin-1-one 15 (8.40 g,
52%) as slightly yellow prisms, mp 99–100◦C (lit.[15] 101◦C).
δH (CDCl3) 7.96 (1H, br s, NH), 7.67 (1H, dd, J 7.5, 1.5, H9),
7.35 (1H, app td, J 7.5, 1.5, H7), 7.29 (1H, app td, J 7.5, 1.5,
H8), 7.14 (1H, dd, J 7.5, 1.5, H6), 3.12 (2H, app q, J 6.5, H3),
2.87 (2H, t, J 7, H5), 2.04 (2H, app p, J 6.5, H4). δC (CDCl3)
174.1 (CO), 138.3 (Cq), 134.9 (Cq), 131.2 (CH), 128.5 (CH),
126.9 (CH), 39.5 (CH2), 30.5 (CH2), 30.2 (CH2). m/z (ESI, 70
V) 162 (7%, (M + H)+), 144 (7), 117 (45), 115 (16), 91 (100).
Concentration of the more mobile fraction (RF 0.7) from
the above reaction and recrystallization (ethyl acetate) afforded
6,7-dihydro-5H-tetrazolo[5,1-a][2]benzazepine 25 (1.49 g, 8%)
as pale yellow prisms, mp 98–99◦C (lit.[86] 100–101◦C). δH
(CDCl3) 8.25 (1H, d, J 8, H11), 7.48–7.38 (2H, m, H9, H10),
7.31 (1H, d, J 8, H8), 4.61 (2H, t, J 6.5, H5), 2.99 (2H, br t, J 6,
H7), 2.42 (2H, br app t, J 6.5, H6). δC (CDCl3) 154.4 (Cq), 139.7
(Cq), 131.6 (CH), 130.2 (CH), 130.1 (CH), 127.5 (CH), 123.3
(Cq), 48.6 (CH2), 32.7 (CH2), 26.8 (CH2). m/z (ESI, 20V) 187
(100%, (M + H)+).
6-Methoxy-1-tetralone 8 (881 mg, 5.00 mmol) and sodium
acetate (820 mg, 10.0 mmol) in absolute ethanol (50 mL) were
treated with hydroxylamine hydrochloride (417 mg, 6.00 mmol)
and worked up as for the preparation of 10. Recrystallization
(dichloromethane/hexane) of this material afforded 6-methoxy-
1-tetralone oxime 13 (774 mg, 81%) as colourless rod-like
crystals, mp 124–125◦C (lit.[28] 122–124◦C). δH ((CD3)2CO)
9.83 (1H, s, NOH), 7.84 (1H, d, J 8.5, H8), 6.74 (1H, dd, J 8.5,
2.5, H7), 6.70 (1H, d, J 2.5, H5), 3.78 (3H, s, OCH3), 2.74–2.70
(4H, m, H2, H4), 1.80 (2H, app p, J 6.5, H3). δC ((CD3)2CO)
160.1 (Cq), 152.9 (Cq), 140.9 (Cq), 125.3 (CH), 124.1 (Cq),
112.8 (CH), 112.6 (CH), 54.6 (CH3), 29.8 (CH2), 23.2 (CH2),
21.5 (CH2). m/z (ESI, 70V) 192 (78%, (M + H)+), 175 (22),
147 (100), 132 (22), 117 (19), 91 (16).
7-Methoxy-1-tetralone Oxime 14
7-Methoxy-1-tetralone 9 (881 mg, 5.00 mmol) and sodium
acetate (820 mg, 10.0 mmol) in absolute ethanol (50 mL) were
treated with hydroxylamine hydrochloride (417 mg, 6.00 mmol)
and worked up as for the preparation of 10. Recrystallization
(dichloromethane/hexane) of this material afforded 7-methoxy-
1-tetralone oxime 14 (798 mg, 83%) as colourless prisms, mp
84–85◦C (lit.[29] 86–88◦C). δH ((CD3)2CO) 10.08 (1H, s, NOH),
7.46 (1H, d, J 3, H8), 7.06 (1H, d, J 8.5, H5), 6.82 (1H, dd, J 8.5,
3, H6), 3.75 (3H, s, OCH3), 2.73 (2H, t, J 6.5, H2), 2.67 (2H, t, J
6, H4), 1.79 (2H, app p, J 6.5, H3). δC ((CD3)2CO) 158.1 (Cq),
153.2 (Cq), 132.2 (Cq), 131.6 (Cq), 129.5 (CH), 115.6 (CH),
107.5 (CH), 54.6 (CH3), 28.7 (CH2), 23.2 (CH2), 21.6 (CH2).
m/z (ESI, 70 V) 192 (100%, (M + H)+), 174 (60), 147 (65), 100
(48), 91 (36), 77 (32).
Schmidt Reaction of 1-Tetralone 5 (Method 2)
1,3,4,5-Tetrahydro-2H-1-benzazepin-2-one 20
Sodium azide (650 mg, 10.0 mmol) was added in one por-
tion to a magnetically stirred solution of 1-tetralone 5 (731 mg,
5.00 mmol) in toluene (30 mL) maintained at ∼0◦C (ice-bath).
To this mixture was added concentrated sulfuric acid (2.5 mL)
dropwise over 30 min. It was then warmed up to room tem-
perature and stirring was continued overnight. The reaction
was quenched with water (20 mL), extracted with toluene
(3 × 20 mL), and concentrated under vacuum. This material was
subjected to flash chromatography (60% ethyl acetate in hex-
ane) and recrystallization (dichloromethane/hexane) afforded
1,3,4,5-tetrahydro-2H-1-benzazepin-2-one 20 (604 mg, 75%)
as colourless prisms, mp 139–140◦C (lit.[17] 139–140◦C). δH
(CDCl3) 8.71 (1H, br s, NH), 7.25–7.20 (2H, m, H8, H9), 7.12
(1H, app t, J 7.5, H7), 7.02 (1H, d, J 7.5, H6), 2.80 (2H, t, J 7,
H5), 2.36 (2H, t, J 7, H3), 2.24 (2H, app p, J 7, H4). δC (CDCl3)
175.8 (CO), 138.2 (Cq), 134.3 (Cq), 129.9 (CH), 127.5 (CH),
125.6 (CH), 121.9 (CH), 32.9 (CH2), 30.5 (CH2), 28.7 (CH2).
m/z (ESI, 70 V) 162 (100%, (M + H)+), 85 (23), 79 (75).
7-Chloro-1-tetralone Oxime 71
7-Chloro-1-tetralone 53 (903 mg, 5.00 mmol) and sodium
acetate (820 mg, 10.0 mmol) in absolute ethanol (50 mL) were
treated with hydroxylamine hydrochloride (417 mg, 6.00 mmol)
and worked up as for the preparation of 10. Recrystallization
(ether/petroleum spirit) of this material afforded 7-chloro-1-
tetralone oxime 71 (848 mg, 87%) as slightly yellow crystals
(light-sensitive), mp 114–115◦C (lit.[84] 124–125◦C) (Found:
C 61.4, H 5.2, N 7.2. C10H10ClNO requires C 61.4, H 5.2, N
7.2%.) δH (CDCl3) 8.37 (1H, br s, NOH), 7.88 (1H, d, J 2, H8),
7.22 (1H, dd, J 8, 2, H6), 7.08 (1H, d, J 8, H5), 2.81 (2H, t, J
6.5, H2), 2.73 (2H, t, J 6, H4), 1.86 (2H, app p, J 6.5, H3). δC
(CDCl3) 154.7 (Cq), 138.1 (Cq), 132.3 (Cq), 132.0 (Cq), 130.0
(CH), 129.2 (CH), 124.1 (CH), 29.3 (CH2), 23.6 (CH2), 21.1
(CH2). m/z (ESI, 70V) 198 (17%, (M[37Cl] + H)+), 196 (52,
(M[35Cl] + H)+), 178 (36), 152 (38), 151 (51), 150 (100), 143
(52), 116 (25).
Beckmann Rearrangement of 1-Tetralone Oxime 10
(Method 3)
1,3,4,5-Tetrahydro-2H-1-benzazepin-2-one 20
1-Tetralone oxime 10 (161 mg, 1.00 mmol) in polyphos-
phoric acid (10 mL) was stirred for 2 h at 95◦C and then
poured into water (500 mL) and further stirred for 2 h at
75◦C. The reaction mixture was then cooled, the resulting
precipitate filtered, and dried under vacuum. Recrystalliza-
tion (dichloromethane/hexane) of the crude material afforded
1,3,4,5-tetrahydro-2H-1-benzazepin-2-one 20 (96 mg, 60%),
identical to that prepared by Method 2.
Schmidt Reaction of 1-Tetralone 5 (Method 1)
2,3,4,5-Tetrahydro-1H-2-benzazepin-1-one 15 and
6,7-Dihydro-5H-tetrazolo[5,1-a][2]benzazepine 25
Sodium azide (13.0 g, 200 mol) was added in portions to a
magnetically stirred solution of 1-tetralone 5 (14.6 g, 100 mol)
in concentrated hydrochloric acid (150 mL) maintained at ∼0◦C
(ice-bath). The reaction mixture was warmed up to room tem-
perature and stirring was continued overnight at 50◦C. The
mixture was then poured into ice-water, cautiously neutral-
ized with potassium carbonate, extracted with dichloromethane
(3 × 100 mL), and the combined extracts were concentrated
Beckmann Rearrangement of 1-Tetralone Oxime 10
(Method 4)
2,3,4,5-Tetrahydro-1H-2-benzazepin-1-one 15
1-Tetralone oxime 10 (161 mg, 1.00 mmol) in thionyl chlo-
ride (5 mL) was stirred for 2 h at 50◦C after which excess

222
I. T. Crosby, J. K. Shin, and B. Capuano
thionyl chloride was removed under vacuum and the residue
was partitioned between dichloromethane (20 mL) and saturated
sodium bicarbonate solution (20 mL). The phases were sepa-
rated, the aqueous layer was extracted with dichloromethane
(2 × 20 mL) and the combined extracts were concentrated under
vacuum to give a brown oil. This material was subjected to flash
chromatography (ethyl acetate), and recrystallization (ethyl
acetate/hexane) afforded 2,3,4,5-tetrahydro-1H-2-benzazepin-
1-one 15 (78 mg, 48%), identical to that prepared by Method 1.
of 15 (Method 4). Recrystallization (ethyl acetate/hexane) of
this material afforded 3,4-dihydro-1,4-benzoxazepin-5(2H)-one
16 (60 mg, 37%), identical to that prepared using Method 1.
Schmidt Reaction of 5-Methoxy-1-tetralone 7 (Method 1)
2,3,4,5-Tetrahydro-6-methoxy-1H-2-benzazepin-
1-one 17
5-Methoxy-1-tetralone 7 (881 mg, 5.00 mmol) in concen-
trated hydrochloric acid (10 mL) was treated with sodium azide
(650 mg, 10.0 mmol) and worked up as for the preparation
of 15 (Method 1). Recrystallization (dichloromethane/hexane)
of this material afforded 2,3,4,5-tetrahydro-6-methoxy-1H-2-
benzazepin-1-one 17 (678 mg, 71%) as slightly yellow crystals,
mp 104–106◦C (Found: C 69.1, H 6.8, N 7.4. C11H13NO2
requires C 69.1, H 6.9, N 7.3%.) δH (CDCl3) 7.31–7.24 (2H,
m, H8, H9), 6.98 (1H, dd, J 6.5, 2, H7), 6.51 (1H, br s, NH),
3.84 (3H, s, OCH3), 3.10 (2H, app q, J 6.5, H3), 2.95 (2H, t,
J 7, H5), 1.95 (2H, app p, J 7, H4). δC (CDCl3) 173.6 (CO),
156.2 (Cq), 136.7 (Cq), 127.5 (CH), 126.7 (Cq), 120.7 (CH),
113.2 (CH), 55.9 (CH3), 39.8 (CH2), 29.8 (CH2), 21.0 (CH2).
m/z (ESI, 70V) 214 (19%, (M + Na)+), 192 (58, (M + H)+),
121 (40), 91 (100).
Schmidt Reaction of 4-Chromanone 6 (Method 1)
3,4-Dihydro-1,4-benzoxazepin-5(2H)-one 16
4-Chromanone (148 mg, 1.00 mmol) in concentrated hydro-
chloric acid (7 mL) was treated with sodium azide (130 mg,
2.5 mmol) and worked up as for the preparation of 20
(Method 1). Recrystallization (ethyl acetate/hexane) of this
material afforded 3,4-dihydro-1,4-benzoxazepin-5(2H)-one 16
(30 mg, 18%) as colourless micro-needles, mp 115–116◦C
(lit.[40] 114–116◦C). δH (CDCl3) 7.99 (1H, dd, J 8, 1.5, H6),
7.43 (1H, ddd, J 8, 7, 1.5, H7), 7.13 (1H, m, H8), 7.02 (1H, dd,
J 8, 1.5, H9), 6.76 (1H, br s, NH), 4.40 (2H, t, J 5, H2), 3.51
(2H, app q, J 5, H3). δC (CDCl3) 170.6 (CO), 155.5 (Cq), 133.4
(CH), 131.8 (CH), 123.4 (Cq), 122.7 (CH), 121.2 (CH), 72.9
(CH2), 41.5 (CH2). m/z (ESI, 70 V) 186 (10%, (M + Na)+), 164
(7, (M + H)+), 121 (100), 93 (47), 91 (56), 77 (85), 65 (52).
Schmidt Reaction of 5-Methoxy-1-tetralone 7 (Method 2)
2,3,4,5-Tetrahydro-6-methoxy-1H-2-benzazepin-
1-one 17
Schmidt Reaction of 4-Chromanone 6 (Method 2)
A mixture of 5-methoxy-1-tetralone 7 (881 mg, 5.00 mmol)
and sodium azide (813 mg, 12.5 mmol) in toluene (30 mL)
was treated with concentrated sulfuric acid (2.5 mL) and
worked up as for the preparation of 20 (Method 2).
Recrystallization (dichloromethane/hexane) of this material
afforded 2,3,4,5-tetrahydro-6-methoxy-1H-2-benzazepin-1-one
17 (200 mg, 21%), identical to that prepared using Method 1.
3,4-Dihydro-1,4-benzoxazepin-5(2H)-one 16 and
2,3-Dihydro-1,5-benzoxazepin-4(5H)-one 21
A mixture of 4-chromanone 6 (5.00 g, 33.7 mmol) and
sodium azide (5.60 g, 86.1 mmol) in toluene (150 mL) was
treated with concentrated sulfuric acid (14 mL) and worked
up as for the preparation of 20 (Method 2). Recrystalliza-
tion (ethyl acetate/hexane) of the major fraction (RF 0.3)
afforded 3,4-dihydro-1,4-benzoxazepin-5(2H)-one 16 (4.56 g,
83%) as colourless micro-needles, identical to that prepared
using Method 1.
Beckmann Rearrangement of 5-Methoxy-1-tetralone
Oxime 12 (Method 3)
1,3,4,5-Tetrahydro-6-methoxy-2H-1-benzazepin-
2-one 22
Concentration of the more mobile fraction (RF 0.45) from
the above reaction and recrystallization (ethyl acetate/hexane)
afforded 2,3-dihydro-1,5-benzoxazepin-4(5H)-one 21 (110 mg,
2%) as pale yellow needles, mp 128–129◦C (lit.[40] 126–127◦C).
δH (CDCl3) 8.55 (1H, br s, NH), 7.05–6.98 (4H, m, ArH), 4.46
(2H, t, J 5.5, H2), 2.87 (2H, t, J 5.5, H3). δC (CDCl3) 173.1
(CO), 148.7 (Cq), 129.0 (Cq), 125.4 (CH), 123.8 (CH), 122.2
(CH), 121.8 (CH), 68.8 (CH2), 37.1 (CH2). m/z (EI, 70 eV) 163
(85%, M+•), 120 (13), 109 (100), 80 (18), 55 (37).
5-Methoxy-1-tetralone oxime 12 (176 mg, 1.00 mmol) was
treated with polyphosphoric acid (10 mL) and worked up
as for the preparation of 20 (Method 3). Recrystallization
(dichloromethane/hexane) of this material afforded 1,3,4,5-
tetrahydro-6-methoxy-2H-1-benzazepin-2-one 22 (90 mg, 47%)
as colourless plates, mp 164–165◦C (lit.[19] 162–163◦C). δH
(CDCl3) 7.74 (1H, br s, NH), 7.16 (1H, app t, J 8, H8), 6.72
(1H, d, J 8, H9), 6.61 (1H, d, J 8, H7), 3.83 (3H, s, OCH3), 2.88
(2H, t, J 7, H5), 2.35 (2H, t, J 7, H3), 2.18 (2H, app p, J 7, H4).
δC (CDCl3) 175.3 (CO), 157.7 (Cq), 139.2 (Cq), 127.3 (CH),
122.8 (Cq), 114.3 (CH), 107.8 (CH), 55.8 (CH3), 33.2 (CH2),
27.8 (CH2), 21.9 (CH2). m/z (ESI, 70V) 192 (48%, (M + H)+),
143 (29), 79 (100).
Beckmann Rearrangement of 4-Chromanone Oxime 11
(Method 3)
3,4-Dihydro-1,4-benzoxazepin-5(2H)-one 16
4-Chromanone oxime 11 (163 mg, 1.00 mmol) was treated
with polyphosphoric acid (10 mL) and worked up as for
the preparation of 20 (Method 3). Recrystallization (ethyl
acetate/hexane) of the crude material afforded 3,4-dihydro-
1,4-benzoxazepin-5(2H)-one 16 (91 mg, 56%), identical to that
prepared using Method 1.
Beckmann Rearrangement of 5-Methoxy-1-tetralone
Oxime 12 (Method 4)
2,3,4,5-Tetrahydro-6-methoxy-1H-2-benzazepin-
1-one 17
Beckmann Rearrangement of 4-Chromanone Oxime 11
(Method 4)
12 (176 mg, 1.00 mmol) was treated with thionyl chloride
(5 mL) and worked up as for the preparation of 15 (Method 4).
Recrystallization (dichloromethane/hexane) of this material
afforded 2,3,4,5-tetrahydro-6-methoxy-1H-2-benzazepin-1-one
17 (63 mg, 36%), identical to that prepared using Method 1.
3,4-Dihydro-1,4-benzoxazepin-5(2H)-one 16
4-Chromanone oxime 11 (163 mg, 1.00 mmol) was treated
with thionyl chloride (5 mL) and worked up as for the preparation

Application of the Schmidt Reaction and Beckmann Rearrangement to the Synthesis of Bicyclic Lactams
223
Schmidt Reaction of 6-Methoxy-1-tetralone 8 (Method 1)
Beckmann Rearrangement of 6-Methoxy-1-tetralone
Oxime 13 (Method 4)
2,3,4,5-Tetrahydro-7-methoxy-1H-2-benzazepin-
1-one 18 and 1,3,4,5-Tetrahydro-7-methoxy-
2H-1-benzazepin-2-one 23
2,3,4,5-Tetrahydro-7-methoxy-1H-2-benzazepin-
1-one 18
6-Methoxy-1-tetralone 8 (176 mg, 1.00 mmol) in concen-
trated hydrochloric acid (3 mL) was treated with sodium azide
(130 mg, 2.00 mmol) and worked up as for the preparation of 15
(Method 1). Flash chromatography (5% acetone in chloroform)
and recrystallization (dichloromethane/hexane) of this material
afforded 2,3,4,5-tetrahydro-7-methoxy-1H-2-benzazepin-1-one
18 (100 mg, 53%) as slightly yellow crystals, mp 156–158◦C
(lit.[87] 159–160◦C). δH (CDCl3) 7.68 (1H, d, J 8.5, H9), 6.89
(1H, br s, NH), 6.84 (1H, dd, J 8.5, 2.5, H8), 6.71 (1H, d, J 2.5,
H6), 3.84 (3H, s, OCH3), 3.14 (2H, app q, J 6.5, H3), 2.84 (2H,
t, J 7, H5), 2.01 (2H, app p, J 7, H4). δC (CDCl3) 174.1 (CO),
161.9 (Cq), 140.7 (Cq), 130.9 (CH), 127.5 (Cq), 114.3 (CH),
111.9 (CH), 55.3 (CH3), 39.8 (CH2), 30.8 (CH2), 30.5 (CH2).
m/z (ESI, 20 V) 405 (22%, (2M + Na)+), 232 (29, (M + K)+),
214 (27, (M + Na)+), 192 (100, (M + H)+).
13 (176 mg, 1.00 mmol) was treated with thionyl chloride
(5 mL) and worked up as for the preparation of 15 (Method 4).
Recrystallization (dichloromethane/hexane) of this mate-
rial afforded 2,3,4,5-tetrahydro-7-methoxy-1H-2-benzazepin-
1-one 18 (55 mg, 31%), identical to that prepared using
Method 1.
Schmidt Reaction of 7-Methoxy-1-tetralone 9 (Method 1)
2,3,4,5-Tetrahydro-8-methoxy-1H-2-benzazepin-
1-one 19
7-Methoxy-1-tetralone 9 (881 mg, 5.00 mmol) in concen-
trated hydrochloric acid (10 mL) was treated with sodium azide
(650 mg, 10.0 mmol) and worked up as for the preparation of
15 (Method 1). Recrystallization (diethyl ether) of this material
afforded 2,3,4,5-tetrahydro-8-methoxy-1H-2-benzazepin-1-one
19 (520 mg, 54%) as pale orange prisms, mp 102–104◦C (lit.[18]
100–101◦C). δH (CDCl3) 7.25 (1H, d, J 2.5, H9), 7.10 (1H, d,
J 8.5, H6), 6.95 (1H, dd, J 8.5, 2.5, H7), 6.62 (1H, br s, NH),
3.83 (3H, s, OCH3), 3.13 (2H, app q, J 6, H3), 2.80 (2H, t,
J 7, H5), 1.99 (2H, app p, J 7, H4). δC (CDCl3) 173.7 (CO),
158.7 (Cq), 130.7 (Cq), 130.0 (CH), 124.3 (Cq), 118.0 (CH),
113.0 (CH), 55.5 (CH3), 39.8 (CH2), 30.6 (CH2), 29.4 (CH2).
m/z (ESI, 20V) 405 (40%, (2M + Na)+), 214 (28, (M + Na)+),
192 (100, (M + H)+), 83 (12).
Concentration of the more mobile fraction (RF 0.4) from the
above reaction and recrystallization (dichloromethane/hexane)
afforded 1,3,4,5-tetrahydro-7-methoxy-2H-1-benzazepin-2-one
23 (29 mg, 15%) as slightly brown plate-like crystals, mp 145–
146◦C (lit.[87] 143–144◦C). δH (CDCl3) 8.19 (1H, br s, NH),
6.94 (1H, d, J 7, H9), 6.76–6.73 (2H, m, H6, H8), 3.80 (3H,
s, OCH3), 2.77 (2H, t, J 7, H5), 2.33 (2H, t, J 7, H3), 2.21
(2H, app p, J 7, H4). δC (CDCl3) 175.4 (CO), 157.4 (Cq),
135.9 (Cq), 131.0 (Cq), 123.1 (CH), 115.2 (CH), 112.3 (CH),
55.5 (CH3), 32.6 (CH2), 30.6 (CH2), 28.3 (CH2). m/z (ESI,
20V) 405 (10%, (2M + Na)+), 214 (22, (M + Na)+), 192 (100,
(M + H)+).
Schmidt Reaction of 7-Methoxy-1-tetralone 9 (Method 2)
Schmidt Reaction of 6-Methoxy-1-tetralone 8 (Method 2)
1,3,4,5-Tetrahydro-8-methoxy-2H-1-benzazepin-
2-one 24
2,3,4,5-Tetrahydro-7-methoxy-1H-2-benzazepin-
1-one 18 and 1,3,4,5-Tetrahydro-7-methoxy-2H-
1-benzazepin-2-one 23
A mixture of 7-methoxy-1-tetralone 9 (881 mg, 5.00 mmol)
and sodium azide (813 mg, 12.5 mmol) in toluene (30 mL)
was treated with concentrated sulfuric acid (2.5 mL) and
worked up as for the preparation of 20 (Method 2).
Recrystallization (dichloromethane/hexane) of this material
afforded 1,3,4,5-tetrahydro-8-methoxy-2H-1-benzazepin-2-one
24 (250 mg, 38%) as buff-coloured platelets, mp 132–133◦C
(lit.[44] 131–132◦C). δH (CDCl3) 8.16 (1H, br s, NH), 7.10
(1H, d, J 8.5, H6), 6.68 (1H, dd, J 8.5, 2.5, H7), 6.56 (1H, d,
J 2.5, H9), 3.79 (3H, s, OCH3), 2.73 (2H, t, J 7, H3), 2.36
(2H, t, J 7.5, H5), 2.19 (2H, app p, J 7, H4). δC (CDCl3)
175.5 (CO), 159.1 (Cq), 138.8 (Cq), 130.5 (CH), 126.4 (Cq),
111.0 (CH), 107.8 (CH), 55.5 (CH3), 32.9 (CH2), 29.5 (CH2),
28.7 (CH2). m/z (ESI, 20 V) 405 (17%, (2M + Na)+), 383
(6, (2M + H)+), 214 (36, (M + Na)+), 192 (100, (M + H)+),
83 (33).
8
(881 mg, 5.00 mmol) and sodium azide (813 mg,
12.5 mmol) in toluene (30 mL) were treated with concentrated
sulfuric acid (2.5 mL) and worked up as for the preparation of 20
(Method 2). Flash chromatography (5% acetone in chloroform)
and recrystallization (dichloromethane/hexane) of this mate-
rial afforded 2,3,4,5-tetrahydro-7-methoxy-1H-2-benzazepin-
1-one 18 (360 mg, 38%), identical to that prepared using
Method 1.
Concentration of the more mobile fraction (RF 0.4) from the
above reaction and recrystallization (dichloromethane/hexane)
afforded 1,3,4,5-tetrahydro-7-methoxy-2H-1-benzazepin-2-one
23 (200 mg, 21%), identical to that prepared using
Method 1.
Beckmann Rearrangement of 6-Methoxy-1-tetralone
Oxime 13 (Method 3)
Beckmann Rearrangement of 7-Methoxy-1-tetralone
Oxime 14 (Method 3)
2,3,4,5-Tetrahydro-7-methoxy-1H-2-benzazepin-
1-one 18
1,3,4,5-Tetrahydro-8-methoxy-2H-1-benzazepin-
2-one 24
13(176 mg, 1.00 mmol)wastreatedwithpolyphosphoricacid
(10 mL) and worked up as for the preparation of 20 (Method 3).
Recrystallization (dichloromethane/hexane) of this mate-
rial afforded 2,3,4,5-tetrahydro-7-methoxy-1H-2-benzazepin-
1-one 18 (125 mg, 71%), identical to that prepared using
Method 1.
14(176 mg, 1.00 mmol)wastreatedwithpolyphosphoricacid
(10 mL) and worked up as for the preparation of 20 (Method 3).
Recrystallization (dichloromethane/hexane) of this material
afforded 1,3,4,5-tetrahydro-8-methoxy-2H-1-benzazepin-2-one
24 (83 mg, 47%), identical to that prepared using Method 2.

224
I. T. Crosby, J. K. Shin, and B. Capuano
Beckmann Rearrangement of 7-Methoxy-1-tetralone
Schmidt Reaction of 7-Chloro-1-tetralone 53 (Method 1)
Oxime 14 (Method 4)
8-Chloro-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one 57
and 2,2,7-Trichloro-1-tetralone 68
2,3,4,5-Tetrahydro-8-methoxy-1H-2-benzazepin-
1-one 19
7-Chloro-1-tetralone 53 (1.00 g, 5.54 mmol) in concentrated
hydrochloric acid (50 mL) was treated with sodium azide (1.30 g,
20.0 mmol) and worked up as for the preparation of 15 (Method
1). Recrystallization(acetone)ofthismaterialafforded8-chloro-
2,3,4,5-tetrahydro-1H-2-benzazepin-1-one 57 (472 mg, 44%) as
white micro-needles, mp 159–161◦C (lit.[18] 160–161◦C). δH
(CDCl3) 7.82 (1H, br s, NH), 7.69 (1H, d, J 2, H9), 7.36 (1H, dd,
J 8, 2, H7), 7.14 (1H, d, J 8, H6), 3.13 (2H, app q, J 6.5, H3), 2.84
(2H, t, J 7, H5), 2.02 (2H, app p, J 7, H4). δC (CDCl3) 173.0
(CO), 136.8 (Cq), 136.7 (Cq), 132.9 (Cq), 131.1 (CH), 130.2
(CH), 128.7(CH), 39.4(CH2), 30.3(CH2), 29.8(CH2). m/z (ESI,
70V) 198 (18, (M[37Cl] + H)+), 196 (55, (M[35Cl] + H)+), 178
(33), 153 (60), 151 (86), 125 (100), 116 (21).
Concentration of the more mobile fraction (RF 0.8) from
the above reaction and recrystallization (chloroform/hexane)
afforded 2,2,7-trichloro-1-tetralone 68 (200 mg, 53%) as slightly
brown crystals, mp 162–163◦C (Found: C 48.1, H 2.9, Cl 42.6.
C10H7Cl3O requires C 48.1, H 2.8, Cl 42.6%.) δH (CDCl3) 8.12
(1H, d, J 2.5, H8), 7.52 (1H, dd, J 8, 2.5, H6), 7.23 (1H, d, J
8, H5), 3.18 (2H, t, J 6, H4), 2.95 (2H, t, J 6, H3). δC (CDCl3)
183.0 (Cq), 140.4 (Cq), 134.6 (CH), 133.9 (Cq), 130.3 (CH),
129.8 (Cq), 129.4 (CH), 85.7 (Cq), 43.0 (CH2), 27.0 (CH2). m/z
(EI, 70 eV) 254 (1%, M[37Cl]3+•), 252 (7, M[35Cl][37Cl]2+•),
250 (24, M[35Cl]2[37Cl]+•), 248 (26, M[35Cl]+3 •), 213 (20), 152
(100), 124 (36), 89 (19).
14 (176 mg, 1.00 mmol) was treated with thionyl chloride
(5 mL) and worked up as for the preparation of 15 (Method 4).
Recrystallization (dichloromethane/hexane) of this material
afforded 2,3,4,5-tetrahydro-8-methoxy-1H-2-benzazepin-1-one
19 (37 mg, 21%), identical to that prepared using Method 1.
Schmidt Reaction of 6-Chloro-1-tetralone 52 (Method 1)
7-Chloro-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one 56
6-Chloro-1-tetralone 52 (243 mg, 1.35 mmol) in concen-
trated hydrochloric acid (5 mL) was treated with sodium azide
(195 mg, 3.00 mmol) and worked up as for the preparation
of 15 (Method 1). Recrystallization (ethyl acetate/hexane)
of this material afforded 7-chloro-2,3,4,5-tetrahydro-1H-2-
benzazepin-1-one 56 (153 mg, 58%) as white plate-like crystals,
mp 181–182◦C (lit.[18] 183–184◦C). δH (CDCl3) 7.65 (1H, d, J
8.5, H9), 7.33 (1H, dd, J 8.5, 2, H8), 7.21 (1H, d, J 2, H6), 7.12
(1H, br s, NH), 3.14 (2H, app q, J 6.5, H3), 2.85 (2H, t, J 7,
H5), 2.03 (2H, app p, J 7, H4). δC (CDCl3) 173.2 (CO), 140.3
(Cq), 137.1 (Cq), 133.5 (Cq), 130.4 (CH), 128.8 (CH), 127.2
(CH), 39.5 (CH2), 30.3 (CH2), 30.2 (CH2). m/z (EI, 70 eV) 197
(27%, M[37Cl]+•), 195 (100%, M[35Cl]+•), 166 (75), 138 (43),
102 (28), 77 (24).
Schmidt Reaction of 7-Chloro-1-tetralone 53 (Method 2)
8-Chloro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one 59
Schmidt Reaction of 6-Chloro-4-chromanone 54
(Method 2)
A mixture of 7-chloro-1-tetralone 53 (500 mg, 2.77 mmol)
and sodium azide (450 mg, 6.92 mmol) in toluene (20 mL) was
treated with concentrated sulfuric acid (1.6 mL) and worked up
as for the preparation of 20 (Method 2). Recrystallization (ethyl
acetate/hexane) of the major fraction (RF 0.5) afforded 8-chloro-
1,3,4,5-tetrahydro-2H-1-benzazepin-2-one 59 (438 mg, 81%) as
colourless micro-needles, mp 142–144◦C (lit.[17] 140–142◦C).
δH (CDCl3) 8.44 (1H, br s, NH), 7.15 (1H, d, J 8, H6), 7.10
(1H, dd, J 8, 1.5, H7), 7.03 (1H, d, J 1.5, H9), 2.78 (2H, t, J
7, H3), 2.37 (2H, t, J 7, H5), 2.23 (2H, app p, J 7, H4). δC
(CDCl3) 175.4 (Cq), 139.1 (Cq), 132.8 (Cq), 132.7 (Cq), 130.9
(CH), 125.7 (CH), 122.0 (CH), 32.8 (CH2), 29.9 (CH2), 28.3
(CH2). m/z (ESI, 70V) 198 (32%, (M[37Cl] + H)+), 196 (100,
(M[35Cl] + H)+), 186 (22).
8-Chloro-3,4-dihydro-1,4-benzoxazepin-5(2H)-one 58
and 7-Chloro-2,3-dihydro-1,5-benzoxazepin-
4(5H)-one 69
A mixture of 6-chloro-4-chromanone 54 (4.00 g, 22.0 mmol)
and sodium azide (3.57 mg, 55.0 mmol) in toluene (100 mL)
was treated with concentrated sulfuric acid (12 mL) and worked
up as for the preparation of 20 (Method 2). Recrystallization
(dichloromethane/hexane) of this material afforded 8-chloro-
3,4-dihydro-1,4-benzoxazepin-5(2H)-one 58 (3.16 g, 74%) as
white needle-like crystals, mp 122–124◦C (lit.[16] 109◦C)
(Found: C 54.8, H 4.1, N 7.1. C9H8ClNO2 requires C 54.7, H
4.1, N 7.1%.) δH (CDCl3) 8.17 (1H, br s, NH), 7.95 (1H, d, J
2.5, H6), 7.36 (1H, dd, J 8.5, 2.5, H8), 6.96 (1H, d, J 8.5, H9),
4.39 (2H, t, J 5, H2), 3.52 (2H, app q, J 5, H3). δC (CDCl3)
169.5 (CO), 154.2 (Cq), 133.3 (CH), 131.4 (CH), 128.0 (Cq),
124.6 (Cq), 122.9 (CH), 73.1 (CH2), 41.5 (CH2). m/z (ESI, 70V)
222 (21%, (M[37Cl] + Na)+), 220 (62%, (M[35Cl] + Na)+), 200
(33, (M[37Cl] + H)+), 198 (100, (M[35Cl] + H)+), 180 (15), 157
(23), 155 (83), 153 (34), 127 (30), 91 (45), 70 (77).
Concentration of the more mobile fraction (RF 0.5) from the
reaction of 54 and recrystallization (dichloromethane/hexane)
afforded 8-chloro-2,3-dihydro-1,5-benzoxazepin-4(5H)-one 69
(217 mg, 5%) as pale yellow micro-needles, mp 129–130◦C
(Found: C 54.7, H 4.1, N 7.1. C9H8ClNO2 requires C 54.7,
H 4.1, N 7.1%.) δH (CDCl3) 8.76 (1H, br s, NH), 7.03–6.95
(3H, m, ArH), 4.45 (2H, t, J 5.5, H2), 2.88 (2H, t, J 5.5, H3).
δC (CDCl3) 173.1 (CO), 147.4 (Cq), 130.0 (Cq), 128.6 (Cq),
125.3 (CH), 123.3 (CH), 121.5 (CH), 68.9 (CH2), 37.1 (CH2).
m/z (ESI, 70V) 198 (22%, (M[35Cl] + H)+), 142 (31), 85 (21),
79 (100).
Beckmann Rearrangement of 7-Chloro-1-tetralone
Oxime 71 (Method 3)
8-Chloro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one 59
7-Chloro-1-tetralone oxime 71 (195 mg, 1.00 mmol) was
treated with polyphosphoric acid (10 mL) and worked up
as for the preparation of 20 (Method 3). Recrystallization
(dichloromethane/hexane) of this material afforded 8-chloro-
1,3,4,5-tetrahydro-2H-1-benzazepin-2-one 59 (123 mg, 63%),
identical to that prepared above (Method 2).
Beckmann Rearrangement of 7-Chloro-1-tetralone
Oxime 71 (Method 4)
8-Chloro-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one 57
7-Chloro-1-tetralone oxime 71 (990 mg, 5.06 mmol) was
treated with thionyl chloride (5 mL) and worked up as

Application of the Schmidt Reaction and Beckmann Rearrangement to the Synthesis of Bicyclic Lactams
225
for the preparation of 15 (Method 4). Recrystallization
(dichloromethane/hexane) of this material afforded 8-chloro-
2,3,4,5-tetrahydro-1H-2-benzazepin-1-one 57 (565 mg, 57%),
identical to that prepared above (Method 1).
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7-Chloro-3,4-dihydro-1,4-benzoxazepin-5(2H)-one 59
A mixture of 7-chloro-4-chromanone oxime 55 (300 mg,
1.64 mmol) and sodium azide (270 mg, 4.15 mmol) in toluene
(20 mL) was treated with concentrated sulfuric acid (1 mL) and
worked up as for the preparation of 20 (Method 2). Recrys-
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7-chloro-3,4-dihydro-1,4-benzoxazepin-5(2H)-one 59 (201 mg,
62%) as white needles, mp 161–162◦C (Found: C 54.6, H 4.2, N
7.1. C9H8ClNO2 requires C 54.7, H 4.1, N 7.1%.) δH (CDCl3)
7.96 (1H, d, J 8.5, H6), 7.48 (1H, br s, NH), 7.09 (1H, dd, J 8.5,
2, H7), 7.03 (1H, d, J 2, H9), 4.41 (2H, t, J 4.5, H2), 3.52 (2H,
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133.5 (CH), 123.0 (CH), 121.3 (Cq), 121.2 (CH), 73.0 (CH2),
41.7 (CH2). m/z (ESI, 70 eV) 199 (25%, M[37Cl]+•), 197 (81,
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