Tetrahydro-1,5-benzoxazepines and tetrahydro-1H-1,5-benzodiazepines by a tandem reduction-reductive amination reaction

Article abstract of DOI:10.1002/jhet.5570410617

A tandem reduction-reductive amination reaction has been applied to the synthesis of (±)-4-alkyl-2,3,4,5-tetrahydro-1,5-benzoxazepines and (±)-4-alkyl-1-benzoyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepines. The nitro aldehydes and ketones required for 1,5-be

Full text of DOI:10.1002/jhet.5570410617

Nov-Dec 2004
963
Tetrahydro-1,5-benzoxazepines and Tetrahydro-1H-1,5-benzo-
diazepines by a Tandem Reduction-Reductive Amination Reaction
Richard A. Bunce,* Christopher L. Smith [1] and Jason R. Lewis
Department of Chemistry, Oklahoma State University, Stillwater, OK 74078-3071, USA
Received August 18, 2004
A tandem reduction-reductive amination reaction has been applied to the synthesis of (±)-4-alkyl-2,3,4,5-
tetrahydro-1,5-benzoxazepines and (±)-4-alkyl-1-benzoyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepines. The
nitro aldehydes and ketones required for 1,5-benzoxazepine ring closures were prepared by nucleophilic aro-
matic substitution of the alkoxides from several 3-buten-1-ol derivatives with 2-fluoro-1-nitrobenzene fol-
lowed by ozonolysis. Precursors for the 1,5-benzodiazepines were prepared by similar addition of N-(3-
butenyl)benzamide anions to 2-fluoro-1-nitrobenzene followed by ozonolysis. Catalytic hydrogenation of
the nitro carbonyl compounds using 5% palladium-on-carbon in methanol then gave the target heterocycles
by a tandem reduction-reductive amination sequence. The 1,5-benzoxazepines were isolated in high yield
following chromatographic purification; the 1,5-benzodiazepines were isolated as solids directly from the
hydrogenation mixture and possessed differentiated functionality on the two nitrogen atoms.
J. Heterocyclic Chem., 41, 963 (2004).
methodology was developed to substitute N-(3-butenyl)-
benzamide derivatives onto nitroaromatic systems. We
report here a simple and efficient approach to the synthesis
of tetrahydro-1,5-benzoxazepines and tetrahydro-1H-1,5-
benzodiazepines from homoallylic alcohols and amines
and define the parameters for success in the reaction.
Introduction.
We recently reported a new synthesis of tetrahydroben-
zoxazines and tetrahydroquinoxalines from 1-(2-nitrophe-
noxy)-2-alkanone and N-(2-nitrophenyl)-N-(2-oxoalkyl)-
acetamide derivatives using the tandem reduction-reduc-
tive amination reaction [2]. We have also demonstrated
that this reductive cyclization can be successfully used to
prepare seven-membered heterocycles [3]. The current
project sought to extend this tandem reaction sequence to
the synthesis of (±)-4-alkyl-2,3,4,5-tetrahydro-1,5-ben-
zoxazepines and (±)-4-alkyl-2,3,4,5-tetrahydro-1H-1,5-
benzodiazepines.
Tetrahydro-1,5-benzoxazepines and tetrahydro-1H-1,5-
benzodiazepines are desirable targets for synthesis due to
their potential as pharmaceutical agents. Many structures
incorporating these ring systems are known to have signif-
icant biological activity. For example, benzoxazepines
have been investigated as central nervous system depres-
sants [4], as orexin receptor antagonists for the treatment
of obesity and sleep disorders [5], and as angiotensin con-
verting enzyme inhibitors for the treatment of cardiovascu-
lar disease [6]. Benzodiazepines have proven effective as
arginine vasopressin antagonists for the treatment of
hypertension [7] and have also shown activity as anxiolyt-
ics [8,9], analgesics [10,11], antiaggressives [10], anticon-
vulsants [10,11], antidepressants [12], antimicrobials [13]
and antiinflammatories [14].
Results and Discussion.
The syntheses of our cyclization substrates are summa-
rized in Schemes 1 and 2. Nucleophilic aromatic substitu-
tion of anions derived from 3-buten-1-ol [17] or N-(3-
butenyl)benzamide derivatives [18] with 2-fluoro-1-
nitrobenzene provided an efficient route to nitro alkenes
4a-e and 9a-b. Homoallylic alcohols 3a-b were commer-
cially available. Alcohols 3c-d were prepared from previ-
ously reported allylic halides 1c-d [19] by conversion to the
corresponding Grignard reagents using Rieke magnesium
[20], carboxylation, and reduction with lithium aluminum
hydride. The use of Rieke magnesium was required to min-
imize coupling which occurred during attempts to prepare
the Grignard reagents under standard conditions.
Preparation of the alcohols via the carboxylic acids was
found to be superior to direct synthesis by reaction with
formaldehyde gas and offered a convenient scheme for
purification. Finally, alcohol 3e was prepared by the litera-
ture method [21]. Deprotonation of the alcohols using
sodium hydride in dimethylformamide followed by reac-
tion with 2-fluoro-1-nitrobenzene then gave nitro alkenes
4a-e. N-Benzoyl homoallylic amine derivative 8a was pre-
pared from commercial allyl cyanide by reduction with 1:1
lithium aluminum hydride:aluminum chloride in ether [22]
followed by benzoylation under Schotten-Baumann condi-
tions [23]; 8b-c were prepared by conversion of allylic bro-
mides 1b-c to cyanides 6b-c [24] followed by a similar
reduction and amidation. Deprotonation of the benzamide
derivatives and reaction with 2-fluoro-1-nitrobenzene were
then carried out to introduce the entire pre-fabricated N-(3-
Earlier work by others has described the synthesis of
these ring systems [15,16], but substitution patterns were
limited and yields were generally low. The use of a tan-
dem reduction-reductive amination strategy should permit
greater structural diversity as well as higher yields. As
expected, modification of our previous benzoxazine syn-
thesis, using homoallylic alcohols in place of allylic alco-
hols, provided precursors to the benzoxazepines. Direct
extension of our quinoxaline work to the synthesis of
benzodiazepines, however, was not successful. Thus, new

964
R. A. Bunce, C. L. Smith and J. R. Lewis
Vol. 41
butenyl)-N-benzoyl side chain to the nitroaromatic ring
[25]. This reaction was successful for 8a and 8b, but failed
for 8c, which is more sterically demanding. Despite this
limitation, the current synthesis represents a new approach
to 1˚ and 2˚ benzamide derivatives [18]. Finally, ozonoly-
sis of 4a-e and 9a-b gave clean conversion to the nitro car-
bonyl compounds 5a-e and 10a-b [26]. Overall, from the
homoallylic alcohols and amines, the benzoxazepine pre-
cursors were obtained in 75-95% yields while the benzodi-
azepine precursors were produced in 52-58% yields.
tetrahydro-1,5-benzoxazepines 11a-c and tetrahydro-1H-
1,5-benzodiazepines 15a-b, respectively, in 70-88% yields.
The reaction proceeded best using 4 atmospheres of hydro-
gen and 20 weight percent of 5% palladium-on-carbon (rel-
ative to substrate) in anhydrous methanol at 25-35˚.
Notably among these reactions, cyclization of the parent
1,5-benzoxazepine (e.g. 5a) was found to be concentration
dependent. When the substrate concentration was 3.85 x
-2
10 M, 72% of 11a was formed along with 3.5% of dimer
12. When the concentration of the substrate was reduced
-2
by a factor of three to 1.28 x 10 M, the yield of 11a
increased to 82% and dimer formation was negligible
(<1%). Dimerization did not occur to an appreciable
extent in any of the ketone cyclizations, presumably due to
increased steric hindrance around the carbonyl.
Cyclization of aldehyde 10a was carried out under dilute
-2
conditions (1.32 x 10 M) and did not give a measurable
amount of dimeric product.
The tert-butyl and phenyl substrates were investi-
gated only for the 1,5-benzoxazepine series, but gave
disappointing results in each case. Hydrogenation of 5d
(R = t-C H ) gave heterocycle 11d in only 37% yield. The
4
9
major product, isolated in 49% yield, was amino ketone 13
resulting from reduction without subsequent cyclization.
Apparently, the bulky tert-butyl group impedes approach
of the aniline nitrogen to the side chain carbonyl largely
The results of our cyclization studies are summarized in
Scheme 3. Hydrogenation of 5a-c and 10a-b, initiated the
tandem reduction-reductive amination sequence to give the

Nov-Dec 2004
Tetrahydro-1,5-benzoxazepines and Tetrahydro-1H-1,5-benzodiazepines
965
This compound was prepared on a 20-mmole scale by car-
boxylation of the Grignard reagent from 1c generated using acti-
vated Rieke magnesium [20]. A 250-mL, three-necked, round-
bottomed flask equipped with magnetic stirring and a reflux con-
denser was charged with 100 mL of anhydrous tetrahydrofuran,
3.80 g (40.0 mmoles) of anhydrous magnesium chloride, 3.32 g
(20.0 mmoles) of anhydrous potassium iodide and 2.72 g (70.0
mmoles) of freshly cut potassium metal. The mixture was heated
at reflux with vigorous stirring for 3 hours to give the activated
magnesium as a viscous black suspension. The suspension was
cooled to 0˚ and 3.54 g (20.0 mmoles) of 1c was added dropwise
with vigorous stirring. Stirring was continued for 45 minutes at
0˚ and the Grignard reagent was transferred by cannula under
nitrogen pressure to a large excess of solid carbon dioxide in a
500-mL three-necked round-bottomed flask. The reaction was
stirred for 3 hours, quenched with saturated ammonium chloride,
acidified to pH 2 with 1 M hydrochloric acid and extracted with
ether (three times). The acidic product was extracted into 0.2 M
sodium hydroxide then reacidified with 1 M hydrochloric acid,
and ether extracted (three times). The combined ether extracts
were washed with saturated sodium chloride, dried (magnesium
sulfate) and concentrated under vacuum to afford 1.99 g (70%) of
2c as a colorless oil. The product was spectroscopically pure and
used without further purification; ir: 3686-2287, 1710, 1646, 899
suppressing the final ring closure. Attempts to cyclize 5e
(R = C H ) gave none of the desired heterocyclic product,
6
5
but instead, gave an 84% yield of amino alcohol 14
derived from nitro and carbonyl reduction. It is well
known that phenyl ketones are highly susceptible to reduc-
tion under hydrogenation conditions [27]. In this case,
cyclization of the larger seven-membered ring was suffi-
ciently slow [28] to allow for reduction of the phenyl
ketone before cyclization could occur. By comparison,
closure of the homologous phenyl-substituted benzoxazine
[2] proceeded in 76% yield without significant carbonyl
reduction.
In conclusion, an efficient synthetic route has been
developed for the preparation of substituted tetrahydro-
1,5-benzoxazepine and tetrahydro-1H-1,5-benzodiazepine
derivatives. The tetrahydro-1,5-benzoxazepines were pre-
pared from homoallylic alcohols in three steps with a 66%
average overall yield; the tetrahydro-1H-1,5-benzodi-
azepines were prepared from homoallylic amines in four
steps with a 42% average overall yield. By comparison to
the analogous six-membered ring closures [2], the larger
rings are less readily formed, giving incomplete closure in
substrates that have sterically hindered side chain car-
bonyls and competitive carbonyl reduction from substrates
requiring cyclization on an aromatic ketone. On balance,
however, this approach offers a new entry to uniquely sub-
stituted derivatives of the target heterocycles.
-1 1
cm ; H nmr: δ 11.0 (br s, 1H), 4.96 (m, 1H), 4.93 (m, 1H), 3.08
(d, 2H, J = 0.8), 2.13 (t, 2H, J = 7.1), 1.44 (m, 2H), 1.33 (m, 2H),
13
0.91 (t, 3H, J = 7.4); C nmr: δ 178.2, 142.0, 114.0, 41.7, 35.5,
+
29.5, 22.3, 13.9; ms: m/z 142 (M ).
Anal. Calcd. for C H O : C, 67.61; H, 9.86. Found: C,
8
14 2
67.91; H, 9.92.
3-tert-Butyl-3-butenoic Acid (2d).
This compound (2.04 g, 72%) was isolated as a colorless oil
and used without further purification; ir: 3467-2382, 1710, 1636,
EXPERIMENTAL
-1
1
908 cm ; H nmr: δ 11.6 (br s, 1H), 5.10 (s, 1H), 4.93 (s, 1H),
All reactions (except hydrogenations) were run under dry
nitrogen in oven-dried glassware. Reactions were monitored by
thin layer chromatography on silica gel GF plates (Analtech no.
21521) with ultraviolet detection. Preparative separations were
performed by one of the following methods: (1) flash column
chromatography [29] on silica gel (grade 62, 60-200 mesh) con-
taining ultraviolet-active phosphor (Sorbent Technologies, UV-5)
packed into quartz columns or (2) preparative thin layer chro-
matography on 20-cm x 20-cm silica gel GF plates (Analtech no.
02015). Band elution for both methods was monitored using a
hand-held ultraviolet lamp. Melting points were uncorrected.
Infrared spectra were run as thin films on sodium chloride disks
13
3.11 (s, 2H), 1.09 (s, 9H); C nmr: δ 179.2, 149.8, 112.0, 38.1,
+
36.3, 28.8; ms: m/z 142 (M ).
Anal. Calcd. for C H O : C, 67.61; H, 9.86. Found: C,
8
14 2
67.51; H, 9.92.
Representative Preparation of 3-Buten-1-ols: 3-Butyl-3-buten-1-
ol (3c).
A solution of 2.10 g (14.8 mmoles) of 2c in 20 mL of anhy-
drous ether was added dropwise to a stirred suspension of 0.56 g
(14.8 mmoles) of lithium aluminum hydride in 50 mL of dry
ether. The mixture was refluxed for 30 minutes, then carefully
quenched with water and 5% aqueous sodium hydroxide and
ether extracted (three times). The combined ether extracts were
washed with saturated sodium chloride, dried (magnesium sul-
fate) and concentrated under vacuum to give 1.80 g (95%) of 3c
as a colorless oil. The product was used without further purifica-
1
13
and referenced to polystyrene. H and C Nuclear magnetic res-
onance spectra were measured in deuteriochloroform at 300 MHz
and 75 MHz, respectively, using tetramethylsilane as an internal
standard; coupling constants (J) are given in Hz. Unless other-
wise noted, mass spectra (electron impact/direct probe) were
obtained at 70 electron volts.
-1
1
tion; ir: 3338, 1643, 885 cm ; H nmr: δ 4.86 (s, 1H), 4.81 (s,
1H), 3.71 (br t, 2H, J = 6.6), 2.30 (t, 2H, J = 6.3), 2.03 (t, 2H, J =
Caution: The following operations were carried out in a glove
bag under dry nitrogen to minimize the potential for fires: (1)
cutting and weighing potassium metal used to prepare Rieke
magnesium, (2) weighing lithium aluminum hydride, and (3)
addition of 5% palladium-on-carbon to methanol solutions prior
to hydrogenation.
13
6.9), 1.50-1.24 (complex, 5H), 0.91 (t, 3H, J = 7.2); C nmr: δ
+
146.2, 108.5, 60.3, 39.1, 35.4, 29.9, 22.4, 13.9; ms: m/z 128 (M ).
Anal. Calcd. for C H O: C, 75.00; H, 12.50. Found: C,
8
16
74.94; H, 12.55.
3-tert-Butyl-3-buten-1-ol (3d).
This compound (1.61 g, 96%) was isolated as a colorless oil and
used without further purification; ir: 3339, 1633, 892 cm ; H nmr:
Representative Procedure for the Preparation of 3-Butenoic
Acids: 3-Butyl-3-butenoic Acid (2c).
-1 1

966
R. A. Bunce, C. L. Smith and J. R. Lewis
Vol. 41
This compound (4.80 g, 80%) was prepared from 10.0 g (74
mmoles) of 3-bromo-2-methyl-1-propene by the general proce-
dure outlined for the preparation of allyl cyanide [24]. The tem-
perature required for the substitution reaction was 125˚. The
final product was a colorless oil collected at 60-70˚ (25 mm Hg).
The product was spectroscopically pure and used without further
δ 4.98 (s, 1H), 4.74 (s, 1H), 3.77 (br t, 2H, J = 6.0), 2.35 (t, 2H, J =
13
6.7), 1.59 (br s, 1H), 1.08 (s, 9H); C nmr: δ 154.1, 107.8, 61.9,
+
36.3, 31.0, 29.3 (3); ms: m/z 128 (M ).
Anal. Calcd. for C H O: C, 75.00; H, 12.50. Found: C,
8
16
75.08; H, 12.54.
Representative Procedure for the Preparation of 3-Butenyl
2-Nitroaromatic Ethers: 2-(3-Butenyloxy)-1-nitrobenzene (4a).
-1
1
purification; ir: 2253, 1651, 908 cm ; H nmr: δ 5.10 (m, 1H),
13
5.01 (m, 1H), 3.06 (m, 2H), 1.84 (m, 3H); C nmr: δ 134.3,
+
117.2, 115.0, 25.8, 21.9; ms: m/z 81 (M ).
This compound was prepared on a 5.00-mmole scale by nucle-
ophilic aromatic substitution of the alkoxide derived from 3-butyl-
3-buten-1-ol with 2-fluoro-1-nitrobenzene according to the proce-
dure of Bunce and Easton [17]. The product (0.82 g, 85%) was
purified on a 40 cm x 2.5 cm silica gel column eluted with 5%
ether in hexanes to give 0.82 g (85%) of 4a as a light yellow oil.
The spectral data matched those reported previously [17].
3-Butyl-3-butenenitrile (6c).
This compound (5.70 g, 82%) was prepared from 10.0 g (56.5
mmoles) of 3-bromo-2-butyl-1-propene. The temperature
required for the substitution reaction was 150˚. The final product
was a colorless oil collected at 94-98˚ (30 mm Hg). The product
-1
was used without further purification; ir: 2246, 1653, 902 cm ;
2-(3-Methyl-3-butenyloxy)-1-nitrobenzene (4b).
1
H nmr: δ 5.14 (s, 1H), 5.01 (s, 1H), 3.07 (s, 2H), 2.12 (t, 2H, J =
13
This compound (0.87 g, 84%) was isolated as a light yellow oil;
7.1), 1.40 (m, 4H), 0.92 (t, 3H, J = 7.1); C nmr: δ 138.4, 113.8,
112.7, 35.2, 29.3, 24.5, 22.12, 13.8; ms: m/z 123 (M ).
-1 1
+
ir: 1650, 1525, 1351 cm ; H nmr: δ 7.81 (dd, 1H, J = 8.1, 1.6),
7.51 (ddd, 1H, J = 8.4, 7.5, 1.3), 7.08 (d, 1H, J = 8.4), 7.00 (t, 1H, J
= 8.1), 4.86 (s, 1H), 4.81 (s, 1H), 4.21 (t, 2H, J = 6.8), 2.56 (t, 2H,
Anal. Calcd. for C H N: C, 78.04, H, 10.57; N, 11.38.
8
13
Found: C, 77.97; H, 10.53; N, 11.44.
13
J = 6.8), 1.81 (s, 3H); C nmr: δ 152.2, 141.5, 140.0, 133.9, 125.5,
Representative Procedure for Nitrile Reduction: 3-Butenylamine
(7a).
+
120.2, 114.5, 112.6, 68.4, 36.8, 22.8; ms: m/z 207 (M ).
Anal. Calcd. for C H NO : C, 63.77; H, 6.28; N, 6.76.
11 13
3
Found: C, 63.89; H, 6.34; N, 6.67.
This compound (2.02 g, 48%) was prepared by reduction of
5.78 g (71 mmoles) of 6a according to the procedure of Jacobson
and Williard [22]. The product was isolated as a colorless oil, bp
75-77˚ (literature [30] bp 75-77˚); ir: 3372, 3301, 1640, 991, 908
2-(3-Butyl-3-butenyloxy)-1-nitrobenzene (4c).
This compound (1.09 g, 88%) was isolated as a light yellow
-1 1
oil; ir: 1645, 1358, 1351 cm ; H nmr: δ 7.81 (dd, 1H, J = 8.1,
-1 1
cm ; H nmr: δ 5.78 (ddt, 1H, J = 17.2, 10.3, 6.9), 5.10 (dm, 1H,
1.8), 7.50 (ddd, 1H, J = 8.5, 7.5, 1.8), 7.08 (dd, 1H, J = 8.5, 1.0),
7.01 (ddd, 1H, J = 8.1, 7.5, 1.2), 4.86 (s, 1H), 4.83 (s, 1H), 4.20 (t,
2H, J = 6.9), 2.56 (t, 2H, J = 6.9), 2.09 (t, 2H, J = 7.1), 1.49-1.26
J = 17.2), 5.07 (dm, 1H, J = 10.3), 2.76 (t, 2H, J = 6.6), 2.20
13
(apparent q, 2H, J = 6.6), 1.13 (br s, 2H); C nmr: δ 136.2,
116.6, 41.2, 38.1.
13
(complex, 4H), 0.91 (t, 3H, J = 7.1); C nmr: δ 152.2, 145.6,
3-Methyl-3-butenylamine (7b).
140.2, 133.9, 125.5, 120.2, 114.3, 111.3, 68.6, 36.1, 35.1, 29.8,
+
22.4, 13.9; ms: m/z 249 (M ).
This compound (3.36 g, 64%) was isolated as a colorless oil, bp
Anal. Calcd. for C H NO : C, 67.47; H, 7.63; N, 5.62.
-1 1
14 19
3
93-95˚; ir: 3365, 3290, 1647, 885 cm ; H nmr: δ 4.84 (m, 1H),
Found: C, 67.63; H, 7.71; N, 5.47.
4.76 (m, 1H), 2.84 (t, 2H, J = 6.6), 2.20 (t, 2H, J = 6.6), 1.76 (m,
13
3H), 1.15 (br s, 2H); C nmr: δ 143.2, 111.7, 41.9, 39.7, 22.1.
2-(3-tert-Butyl-3-butenyloxy)-1-nitrobenzene (4d).
This compound (1.07 g, 86%) was isolated as a light yellow
3-Butyl-3-butenylamine (7c).
-1 1
oil; ir: 1638, 1526, 1354 cm ; H nmr: δ 7.81 (dd, 1H, J = 8.1,
This compound (4.75 g, 52%) was isolated as a colorless oil,
1.8), 7.51 (ddd, 1H, J = 8.5, 7.5, 1.8), 7.09 (dd, 1H, J = 8.5, 1.0),
7.01 (ddd, 1H, J = 8.1, 7.5, 1.2), 4.99 (s, 1H), 4.78 (s, 1H), 4.21(t,
-1
1
bp 44-46˚ (7 mm Hg); ir: 3372, 1640, 906 cm ; H nmr: δ 4.80
(m, 1H), 4.75 (m, 1H), 2.80 (t, 2H, J = 6.5), 2.16 (t, 2H, J = 6.5),
2.01 (t, 2H, J = 7.1), 1.41 (m, 4H), 1.11 (br s, 2H), 0.91 (t, 3H, J =
13
2H, J = 7.5), 2.61 (t, 2H, J = 7.5), 1.09 (s, 9H); C nmr: δ 153.4,
152.2, 140.2, 134.0, 125.5, 120.2, 114.5, 108.3, 69.7, 36.2, 30.4,
28.9; ms (30 electron volts): m/z 249 (M ).
13
7.1); C nmr: δ 147.3, 110.4, 40.2, 40.0, 35.5, 29.9, 22.4, 13.9;
+
+
ms: m/z 127 (M ).
Anal. Calcd. for C H NO : C, 67.47; H, 7.63; N, 5.62.
14 19
3
Anal. Calcd. for C H N: C, 75.59; H, 13.38; N, 11.02.
8
17
Found: C, 67.52; H, 7.65; N, 5.57.
Found: C, 75.62; H, 13.41; N, 11.00.
2-(3-Phenyl-3-butenyloxy)-1-nitrobenzene (4e).
This compound (1.21 g, 90%) was isolated as a light yellow
Representative Benzoylation Procedure: N-(3-Butenyl)benza-
mide (8a).
-1 1
oil; ir: 1672, 1525, 1351 cm ; H nmr: δ 7.79 (dd, 1H, J = 8.5,
This compound was prepared on a 34-mmole scale by
Schotten-Baumann benzoylation of 3-butenylamine in benzene
using the procedure of Dewar and co-workers [23]. The product
(5.59 g, 94%) was isolated as a viscous colorless oil by flash col-
umn chromatography on silica gel eluted with 25% ether in hexa-
nes. The spectral data matched those reported previously [31].
1.6), 7.48-7.42 (complex, 3H), 7.37-7.25 (complex, 3H), 7.01-
6.96 (complex, 2H), 5.42 (s, 1H), 5.22 (s, 1H), 4.17 (t, 2H, J =
13
7.1), 3.06 (t, 2H, J = 7.1); C nmr: δ 152.1, 146.0, 143.7, 140.2,
133.9, 128.5, 127.7, 126.1, 125.5, 120.3, 115.2, 114.6, 68.3, 34.9;
+
ms: m/z 269 (M ).
Anal. Calcd. for C H NO : C, 71.38; H, 5.58; N, 5.20.
16 15
3
Found: C, 71.25; H, 5.53; N, 5.26.
N-(3-Methyl-3-butenyl)benzamide (8b).
Representative Procedure for the Preparation of Butenenitriles:
3-Methyl-3-butenenitrile (6b).
This compound (6.17 g, 96%) was isolated as a colorless vis-
cous oil following flash column chromatography on silica gel

Nov-Dec 2004
Tetrahydro-1,5-benzoxazepines and Tetrahydro-1H-1,5-benzodiazepines
967
eluted with 25% ether in hexanes; ir: 3310, 1639, 1542, 889
Attempted Synthesis of N-(3-Butyl-3-butenyl)-N-(2-nitro-
phenyl)benzamide (9c).
-1
1
cm ; H nmr: δ 7.74 (dd, 2H, J = 8.1, 1.3), 7.55-7.39 (complex,
3H), 6.19 (br s, 1H), 4.88 (m, 1H), 4.82 (m, 1H), 3.58 (apparent
Attempted addition of the anion of 8c to 2-fluoro-1-nitroben-
zene on a 5-mmole scale gave 84% of recovered 8c along with
small quantities of products resulting from addition of traces of
water and dimethylamine to the nitroaromatic substrate.
13
q, 2H, J = 6.8), 2.34 (t, 2H, J = 6.7), 1.79 (s, 3H); C nmr: δ
167.3, 142.7, 134.7, 131.3, 128.5, 126.8, 112.6, 37.3, 37.2, 21.9;
+
ms: m/z 189 (M ).
Anal. Calcd. for C
H NO: C, 76.19; H, 7.94; N, 7.41.
12 15
Representative Ozonolysis Procedure: 3-(2-Nitrophenoxy)-
propanal (5a).
Found: C, 76.04; H, 7.99; N, 7.35.
N-(3-Butyl-3-butenyl)benzamide (8c).
A solution of 0.80 g (4.14 mmoles) of 4a in 125 mL of
methanol was cooled to –78º and treated with ozone until thin
layer chromatography indicated complete consumption of the
starting material. Excess ozone was purged with a stream of dry
nitrogen and the reaction was quenched at –78˚ by addition of
5.08 g (84.9 mmoles) of dimethyl sulfide and 200 mg of p-tolu-
enesulfonic acid. The resulting solution was warmed to room
temperature and stirred for 8 hours, then concentrated under
reduced pressure. The crude reaction mixture was diluted with
ether, washed with saturated sodium bicarbonate and sodium
chloride, and dried (magnesium sulfate). Concentration under
reduced pressure gave the dimethyl acetal of 5a containing 5-
10% of the aldehyde. This mixture was dissolved in 25 mL of
tetrahydrofuran, cooled to 0˚, and 25 mL of 3% aqueous perchlo-
ric acid was added dropwise with stirring [25]. The solution was
stirred at 0˚ for 1 hour and at room temperature for 4 hours, then
extracted with dichloromethane (three times). The combined
organic extracts were washed with saturated sodium bicarbonate
and sodium chloride, dried (magnesium sulfate) and concentrated
under vacuum to yield 0.76 g (94%) of 5a. The compound was
spectroscopically pure and used without further purification; ir:
This compound (7.46 g, 95%) was isolated as a colorless vis-
cous oil following flash column chromatography on silica gel
eluted with 25% ether in hexanes; ir: 3310, 1640, 1545, 890 cm ;
-1
1
H nmr: δ 7.74 (m, 2H), 7.51-7.38 (complex, 3H), 6.25 (br s,
1H), 4.87 (m, 1H), 4.84 (m, 1H), 3.58 (td, 2H, J = 6.8, 5.5), 2.34
(t, 2H, J = 6.8), 2.06 (t, 2H, J = 7.1), 1.39 (m, 4H), 0.91 (t, 3H, J
= 7.1); C nmr: δ 167.3, 146.8, 134.7, 131.3, 128.5, 126.8,
111.2, 37.5, 35.6, 35.2, 29.8, 22.4, 13.9; ms: m/z 231 (M ).
13
+
Anal. Calcd. for C
H NO: C, 77.92; H, 9.09; N, 6.06.
15 21
Found: C, 77.76; H, 9.02; N, 6.04.
Representative Procedure for Nucleophilic Aromatic Substitution
of Benzamides to 2-Fluoro-1-nitrobenzene: N-(3-Butenyl)-N-(2-
nitrophenyl)benzamide (9a).
In a 250-mL, three-necked, round-bottomed flask equipped
with magnetic stirring, an addition funnel and a condenser, 0.44 g
of 60% sodium hydride in mineral oil (11.0 mmoles) was washed
with hexanes (three times) and suspended in 15 mL of dimethyl-
formamide. Stirring was started and a solution of 1.75 g (10.0
mmoles) of 8a in 15 mL of dimethylformamide was added drop-
wise at room temperature. The mixture was stirred for 2 hours at
room temperature at which time a solution of 0.71 g (5.0 mmoles)
of 2-fluoro-1-nitrobenzene in 2 mL of dimethylformamide was
added. The reaction became warm and turned brown in color.
The reaction was stirred for 1 hour at room temperature and for
24 hours at 50˚, then cooled, added to saturated ammonium chlo-
ride, and extracted with ether (three times). The combined ether
layers were washed with water and saturated sodium chloride,
dried (magnesium sulfate) and concentrated under vacuum. The
crude product was flash chromatographed on a 40 cm x 2 cm sil-
ica gel column eluted with 10-20% ether in hexanes to afford
1.72 g (58%) of 9a as a yellow oil; ir: 1657, 1528, 1348, 994, 918
-1
1
2840, 2730, 1723, 1528, 1354 cm ; H nmr: δ 9.89 (t, 1H, J =
1.1), 7.83 (dd, 1H, J = 8.1, 1.8), 7.55 (ddd, 1H, J = 8.4, 7.4, 1.8),
7.13 (dd, 1H, J = 8.4, 1.0), 7.06 (ddd, 1H, J = 8.1, 7.4, 1.2), 4.44
13
(t, 2H, J = 6.2), 3.02 (td, 2H, J = 6.2, 1.1); C nmr: δ 199.2,
151.8, 140.1, 134.1, 125.6, 120.9, 114.8, 63.4, 42.8; ms: m/z 195
+
(M ).
Anal. Calcd. for C H NO : C, 55.38; H, 4.62; N, 7.18. Found:
9
9
4
C, 55.51; H, 4.72; N, 7.05.
4-(2-Nitrophenoxy)-2-butanone (5b).
This compound (0.77 g, 95%) was isolated by flash column
chromatography on silica gel using 5-10% ether in hexanes. The
product was a light yellow oil that solidified on cooling to 0˚, mp
-1
1
cm ; H nmr (not coalesced): δ 7.83 (br s, 1H), 7.50 (br s, 1H),
7.43-7.20 (br m, 6H), 7.16 (br s, 1H), 5.79 (br s, 1H), 5.09 (br d,
1H, J = 16.1), 5.05 (br d, 1H, J = 9.6), 4.32 (br s, 1H), 3.55 (m,
-1
1
35-36˚; ir: 1717, 1523, 1353 cm ; H nmr: δ 7.82 (dd, 1H, J =
8.1, 1.8), 7.53 (tm, 1H, J = 8.4), 7.12 (dd, 1H, J = 8.4, 1.0), 7.03
(ddd, 1H, J = 8.1, 7.4, 1.2), 4.37 (t, 2H, J = 6.2), 2.98 (t, 2H, J =
13
1H), 2.47 (br s, 2H); C nmr: δ 165.6, 146.0, 137.5, 134.9,
13
133.7, 131.8, 129.9, 128.2 (2), 127.9 (2), 125.7, 117.1, 49.1, 32.1;
6.2), 2.27 (s, 3H); C nmr: δ 206.0, 152.0, 139.8, 134.1, 125.5,
+
+
ms: m/z 296 (M ).
120.6, 114.7, 64.8, 42.3, 30.8; ms: m/z 209 (M ).
Anal. Calcd. for C H N O : C, 68.92; H, 5.41; N, 9.46.
Anal. Calcd. for C H NO : C, 57.42; H, 5.26; N, 6.70.
17 16
2 3
10 11
4
Found: C, 69.10; H, 5.49; N, 9.33.
Found: C, 57.55; H, 5.31; N, 6.59.
N-(3-Methyl-3-butenyl)-N-(2-nitrophenyl)benzamide (9b).
This compound (1.61 g, 52%) was isolated as a light yellow
1-(2-Nitrophenoxy)-3-heptanone (5c).
This compound (0.75 g, 93%) was isolated as a light yellow oil
by flash column chromatography on silica gel eluted with 5-10%
ether in hexanes; ir: 1714, 1527, 1351 cm ; H nmr: δ 7.81 (dd,
1H, J = 8.1, 1.8), 7.52 (ddd, 1H, J = 8.5, 7.5, 1.8), 7.12 (dd, 1H, J
= 8.5, 1.2), 7.03 (ddd, 1H, J = 8.1, 7.5, 1.2), 4.37 (t, 2H, J = 6.2),
2.95 (t, 2H, J = 6.2), 2.53 (t, 2H, J = 7.5), 1.60 (quintet, 2H, J =
-1
1
solid, mp 65-66˚; ir: 1653, 1529, 1348, 894 cm ; H nmr (not
-1
1
coalesced): δ 7.84 (br s, 1H), 7.51 (br s, 1H), 7.45-7.23 (br m,
6H), 7.14 (br s, 1H), 4.79 (br s, 1H), 4.73 (br s, 1H), 4.38 (br s,
13
1H), 3.59 (m, 1H), 2.41 (br s, 2H), 1.75 and 1.73 (2 s, 3H);
C
nmr: δ 168.4, 145.8, 142.6, 135.3, 133.7, 131.9, 130.0, 128.2 (2),
+
13
128.0 (2), 125.7, 112.1, 49.1, 35.4, 22.5; ms: m/z 310 (M ).
7.4), 1.33 (sextet, 2H, J = 7.4), 0.92 (t, 3H, J = 7.4); C nmr: δ
Anal. Calcd. for C H N O : C, 69.68; H, 5.81; N, 9.03.
208.5, 152.0, 140.0, 134.1, 125.5, 120.5, 114.7, 64.9, 43.5, 41.4,
18 18
2 3
+
Found: C, 69.79; H, 5.87; N, 8.96.
25.6, 22.2, 13.8; ms: m/z 251 (M ).

968
R. A. Bunce, C. L. Smith and J. R. Lewis
Vol. 41
Anal. Calcd. for C H NO : C, 62.15; H, 6.77; N, 5.58.
Found: C, 62.07; H, 6.75; N, 5.59.
catalyst. Concentration of the filtrate produced a light yellow oil
that was purified by preparative thin layer chromatography eluted
with 10% ether in hexanes to give 470 mg (82%) of 11a as a light
yellow oil that solidified on standing at 0˚, mp 35-37˚; ir: 3358
13 17
4
4,4-Dimethyl-1-(2-nitrophenoxy)-3-pentanone (5d).
-1 1
This compound (0.73 g, 91%), was isolated as a light yellow
oil by flash column chromatography on silica gel eluted with
cm ; H nmr: δ 6.96 (dd, 1H, J = 7.8, 1.6), 6.87 (td, 1H, J = 7.4,
1.6), 6.79 (td, 1H, J = 7.5, 1.8), 6.72(dd, 1H, J = 7.5, 1.8), 4.08 (t,
2H, J = 5.4), 3.77 (br s, 1H), 3.24 (t, 2H, J = 5.6), 2.00 (m, 2H);
-1
1
5-10% ether in hexanes; ir: 1710, 1527, 1354 cm ; H nmr: δ
7.81 (dd, 1H, J = 8.2, 1.8), 7.52 (ddd, 1H, J = 8.4, 7.4, 1.8), 7.13
(dd, 1H, J = 8.4, 1.2), 7.02 (ddd, 1H, J = 8.2, 7.5, 1.2), 4.39 (t, 2H,
13
C nmr: δ 150.2, 142.0, 123.4, 121.9, 120.9, 119.6, 71.5, 46.0,
+
31.9; ms: m/z 149 (M ).
13
J = 6.2), 3.03 (t, 2H, J = 6.2), 1.19 (s, 9H); C nmr: δ 213.0,
Anal. Calcd. for C H NO: C, 72.48; H, 7.38; N, 9.40. Found:
9
11
152.2, 140.0, 134.1, 125.5, 120.4, 114.6, 65.0, 44.3, 35.8, 26.0
C, 72.63; H, 7.46; N, 9.32.
+
(3); ms (30 electron volts): m/z 251 (M ).
When the reductive ring closure was run under more concen-
-2
Anal. Calcd. for C H NO : C, 62.15; H, 6.77; N, 5.58.
trated conditions (substrate concentration = 3.85 x 10 M), the
13 17
4
Found: C, 62.28; H, 6.83; N, 5.52.
yield of heterocycle 11a was reduced to 72% and dimer 12 was
produced in 3.5% yield, mp 254-256˚; ir: 3426 cm ; H nmr: δ
6.88 (td, 2H, J = 7.7, 1.3), 6.72 (dd, 2H, J = 8.0, 1.3), 6.65 (td, 2H,
-1
1
3-(2-Nitrophenoxy)-1-phenyl-1-propanone (5e).
This compound (0.76 g, 94%) was isolated as a light yellow
solid by flash column chromatography on silica gel eluted with
5-10% ether in hexanes, mp 103-105˚; ir: 1684, 1525, 1352 cm ;
J = 7.7, 1.5), 6.58 (dd, 2H, J = 8.0, 1.5), 5.13 (br s, 2H), 4.21 (t,
13
4H, J = 5.0), 3.35 (q, 4H, J = 5.0), 2.29 (quintet, 4H, J = 5.1);
C
-1
nmr: δ 145.9, 138.0, 121.3, 116.3, 109.4, 108.7, 69.5, 44.5, 27.9;
1
+
H nmr: δ 8.00 (dd, 2H, J = 7.1, 1.2), 7.81 (dd, 1H, J = 8.1, 1.8),
ms: m/z 298 (M ).
7.62-7.45 (complex, 4H), 7.20 (dd, 1H, J = 8.4, 1.0), 7.04 (ddd,
1H, J = 8.1, 7.5, 1.2), 4.57 (t, 2H, J = 6.6), 3.55 (t, 2 H, J = 6.6);
Anal. Calcd. for C H N O : C, 72.48; H, 7.38; N, 9.40.
18 22
2 2
Found: C, 72.54, H, 7.39; N, 9.33.
13
C nmr: δ 197.2, 152.1, 139.9, 136.4, 134.1, 133.5, 128.7,
(±)-4-Methyl-2,3,4,5-tetrahydro-1,5-benzoxazepine (11b).
+
128.1, 125.5, 120.6, 114.8, 65.1, 42.2; ms: m/z 271 (M ).
Anal. Calcd. for C H NO : C, 66.42; H, 4.80; N, 5.17.
Found: C, 66.59; H, 4.87; N, 5.05.
This compound (473 mg, 87%) was isolated by preparative
thin layer chromatography eluted with 10% ether in hexanes.
The resulting oil crystallized at 0˚ to a yellow solid that darkened
15 13
4
N-(2-Nitrophenyl)-N-(3-oxopropyl)benzamide (10a).
-1 1
on exposure to air, mp 60-62˚; ir: 3351 cm ; H nmr: δ 6.93 (dd,
This compound (0.66 g, 82%) was isolated as a light yellow oil
by flash column chromatography on silica gel eluted with 25%
1H, J = 7.5, 1.6), 6.85 (td, 1H, J = 7.4, 1.6), 6.76 (td, 1H, J = 7.5,
1.8), 6.71 (dd, 1H, J = 7.5, 1.8), 4.38 (ddd, 1H, J = 12.1, 6.2, 3.8),
3.79 (ddd, 1H, J = 11.9, 8.2, 3.5), 3.32 (m, 1H), 3.32 (br s, 1H),
1.96 (ddt, 1H, J = 13.8, 6.3, 3.4), 1.78 (m, 1H), 1.29 (d, 3H, J =
-1
ether in hexanes; ir: 2840, 2731, 1719, 1654, 1628, 1348 cm ;
1
H nmr (not coalesced): δ 9.81 (s, 1H), 7.82 (d, 1H, J = 7.2), 7.59
13
(t, 1H, J = 7.5), 7.39 (apparent t, 2H, J = 8.0), 7.30-7.07 (com-
plex, 4H), 4.36 (m, 1H), 4.07 (quintet, 1H, J = 6.6), 3.03 (br s,
6.5); C nmr: δ 150.3, 140.8, 123.3, 121.7, 120.9, 119.8, 70.6,
+
51.6, 39.4, 22.9; ms: m/z 163 (M ).
13
3H); C nmr: δ 200.4, 170.6, 146.2, 142.6, 134.4, 134.2, 131.2,
Anal. Calcd. for C
H NO: C, 73.62; H, 7.98; N, 8.59.
10 13
+
130.3, 128.4, 128.2, 128.0, 125.7, 45.0, 42.1; ms: m/z 298 (M ).
Found: C, 73.68; H, 8.02; N, 8.56.
Anal. Calcd. for C H N O : C, 64.42; H, 4.70; N, 9.40.
Found: C, 64.61; H, 4.82; N, 9.27.
16 14
2 4
(±)-4-Butyl-2,3,4,5-tetrahydro-1,5-benzoxazepine (11c).
This compound (370 mg, 90%) was isolated by preparative thin
layer chromatography eluted with 10% ether in hexanes. The
resulting oil crystallized at 0˚ to a yellow solid that darkened on
N-(2-Nitrophenyl)-N-(3-oxobutyl)benzamide (10b).
This compound (0.68 g, 84%) was isolated as a light yellow
solid by column chromatography on silica gel eluted with 25%
ether in hexanes, mp 62-64˚; ir: 1711, 1654, 1528, 1348 cm ;
-1 1
exposure to air, mp 28-30˚; ir: 3365 cm ; H nmr: δ 6.92 (dd, 1H,
-1
J = 7.7, 1.6), 6.85 (td, 1H, J = 7.4, 1.6), 6.76 (td, 1H, J = 7.5, 1.8),
6.70 (dd, 1H, J = 7.5, 1.8), 4.39 (ddd, 1H, J = 12.1, 7.1, 3.8), 3.85
(ddd, 1H, J = 12.1, 7.4, 3.8), 3.41 (br s, 1H), 3.19 (ddt, 1H, J = 13.2,
6.5, 3.2), 2.02 (dquintet, 1H, J = 13.8, 3.7), 1.74 (dddd, 1H, J =
13.8, 10.2, 7.4, 3.8), 1.57 (m, 2H), 1.47-1.28 (complex, 4H), 0.93
1
H nmr (not coalesced): δ 7.78 (d, 1H, J = 7.2), 7.60 (t, 1H, J=
7.2), 7.44 (dd, 1H, J = 8.0, 1.3), 7.34 (t, 1H, J = 7.5), 7.31-7.05
(complex, 5H), 4.20 (m, 1H), 4.12 (m, 1H), 3.05 (br s, 2H), 2.16
(br s, 3H); C nmr: δ 208.0, 170.3, 145.7, 138.1, 134.5, 134.1,
131.0, 130.2, 128.3, 128.1, 127.9, 125.7, 46.5, 41.3, 30.0; ms:
13
13
(t, 3H, J = 6.9); C nmr: δ 150.1, 140.7, 123.1, 121.4, 120.8,
+
+
m/z 312 (M ).
119.7, 70.3, 55.8, 37.4, 36.3, 28.4, 22.7, 14.0; ms: m/z 205 (M ).
Anal. Calcd. for C H N O : C, 65.38; H, 5.12; N, 8.97.
Anal. Calcd. for C H NO: C, 76.10; H, 9.27; N, 6.83.
17 16
2
4
13 19
Found: C, 76.02; H, 9.23; N, 6.85.
Found: C, 65.47; H, 5.18; N, 8.93.
(±)-4-tert-Butyl-2,3,4,5-tetrahydro-1,5-benzoxazepine (11d).
Representative Procedure for Reductive Ring Closure: 2,3,4,5-
Tetrahydro-1,5-benzoxazepine (11a).
When the above procedure was run on 300 mg (1.20 mmoles)
of 5d, 240 mg of a mixture of 11d and 13 was isolated.
Purification by preparative thin layer chromatography eluted
with 10% ether in hexanes afforded two bands. Band 1 (fastest
moving) contained 90 mg (37%) of 11d that solidified at 0˚ to a
light yellow solid that darkened on exposure to air, mp 37-38˚;
To a solution of 750 mg (3.85 mmoles) of 5a in 300 mL of
methanol (substrate concentration = 1.28 x 10 M) was added
-2
150 mg of 5% palladium-on-carbon and the mixture was shaken
in a stainless steel vessel under 4 atmospheres of hydrogen for 3
hours at 25˚. The crude reaction mixture was concentrated,
diluted with ether, and vacuum filtered through a pad of Celite
545 topped with a layer of magnesium sulfate to remove the
-1
1
ir: 3399 cm ; H nmr: δ 6.87 (dd, 1H, J = 7.7, 1.6), 6.83 (td, 1
H, J = 7.5, 1.6), 6.73 (td, 1H, J = 7.5, 1.8), 6.66 (dd, 1H, J = 7.5,

Nov-Dec 2004
Tetrahydro-1,5-benzoxazepines and Tetrahydro-1H-1,5-benzodiazepines
969
1.8), 4.46 (ddd, 1H, J = 12.1, 8.2, 4.0), 3.96 (ddd, 1H, J = 11.9,
5.6, 4.6), 3.38 (br s, 1H), 3.07 (dd, 1H, J = 11.2, 3.5), 2.06
(dddd, 1H, J = 13.5, 8.2, 4.7, 3.5), 1.77 (dddd, 1H, J = 13.5,
Acknowledgement.
We wish to thank the Oklahoma Center for the Advancement of
Science and Technology (HR01-015) for support of this research.
Funds for the 300 and 400 MHz NMR spectrometers of the
Oklahoma Statewide Shared NMR Facility were provided by NSF
(BIR-9512269), the Oklahoma State Regents for Higher Education,
the W. M. Keck Foundation, and Conoco, Inc. Partial support for
our mass spectrometer by the NIH and the Oklahoma Center for the
Advancement of Science and Technology is also appreciated.
13
11.2, 5.7, 4.1), 1.02 (s, 9H); C nmr: δ 149.7, 140.8, 122.8,
120.8, 120.4, 119.0, 70.3, 64.6, 33.8, 31.8, 26.4 (3); ms (30
+
electron volts): m/z 205 (M ).
Anal. Calcd. for C
H NO: C, 76.10; H, 9.27; N, 6.83.
13 19
Found: C, 76.17, H, 9.29; N, 6.80.
1-(2-Aminophenoxy)-4,4-dimethyl-3-pentanone (13).
This compound (130 mg, 49%) was isolated as a light yellow
oil from band 2 (above). This oil solidified at 0˚ to a light yellow
solid that darkened on exposure to air, mp 37-38˚; ir: 3468, 3372,
REFERENCES AND NOTES
-1
1
1704 cm ; H nmr: δ 6.81 (m, 2H), 6.70 (m, 2H), 4.26 (t, 2H, J
[*] Corresponding author. E-mail: rab@okstate.edu
[1] Undergraduate research participant, 2003-2004
13
= 6.3), 3.75 (br s, 2H), 2.99 (t, 2H, J = 6.3), 1.18 (s, 9H); C nmr:
[2] R. A. Bunce, D. M. Herron and L. Y. Hale, J. Heterocyclic
Chem., 40, 1031 (2003).
[3] R. A. Bunce, L. B. Johnson and E. M. Holt, J. Heterocyclic
Chem., 41, 563 (2004).
δ 213.5, 146.2, 136.6, 121.6, 118.4, 115.2, 112.6, 63.9, 44.3,
+
36.2, 26.1 (3); ms (30 electron volts): m/z 221 (M ).
Anal. Calcd. for C H NO : C, 70.59; H, 8.60; N, 6.33.
13 19
2
Found: C, 70.78, H, 8.69; N, 6.19.
[4] J. Sam, German Patent DE 2314392 (1973).
(±)-3-(2-Aminophenoxy)-1-phenyl-1-propanol (14).
[5] H. Aissaoui, M. Clozel, T. Weller, R. Koberstein, T. Sifferien
and W. Fischli, International Patent WO 0251838 (2002).
[6] K. Itoh, M. Kori, Y. Inada, K. Nishikawa, Y. Kawamatsu and
H. Sugihara, Chem. Pharm. Bull., 34, 3747 (1986).
[7a] D. M. Ashworth, G. R. W. Pitt, P. Hudson, C. M. Yea, R. J.
Franklin and G. Semple, International Patent WO 2002000626 (2002);
[b] A. Matsuhisa, H. Koshio, K. Sakamoto, N. Taniguchi, T. Yatsu and
A. Tanaka, Chem. Pharm. Bull., 46, 1566 (1998).
[8] A. Ursini, A. M. Capelli, R. A. E. Carr, P. Cassara, M. Corsi,
O. Curcuroto, G. Curotto, M. Dal Cin, S. Davalli, D. Donati, A. Feriani,
H. Finch, G. Finizia, G. Gaviraghi, M. Marien, G. Pentassuglia, S.
Polinelli, E. Ratti, A. Reggiani, G. Tarzia, G. Tedesco, M. E.
Tranquillini, D. G. Trist and F. T. M. Van Amsterdam, J. Med. Chem.,
43, 3596 (2000).
[9] O. E. Fancher, G. Nichols and D. A. Stauffer, U.S. Patent
3021325 (1962).
[10] W. Nawrocka, H. Liszkiewicz, A. Nawojski, M.
Wilimowski, L. Kedzierska-Gozdzik, J. Barczynska, W. Wojewodzki,
E. Duis, A. Szelag and M. Rutkowska, Pol. J. Pharmacol. Pharm., 43,
495 (1991).
[11] A. Nawojski, W. Nawrocka, H. Liszkiewicz, M.
Wilimowski, J. Barczynska, L. Kedzierska, W. Wojewodzki, M.
Rutkowska, E. Duis and A. Szelag, Pol. J. Pharmacol. Pharm., 40, 471
(1988).
[12] E. J. Glamkowski, J. M. Fortunato and H. M. Geyer III, J.
Med. Chem., 23, 1380 (1980).
When the reductive cyclization was carried out on 400 mg
(1.47 mmoles) of 5e, 300 mg (84%) of 14 was isolated as a light
brown oil that crystallized to a tan solid at 0˚. Trituration of the
solid with 1% ether in petroleum ether gave 14 as a light tan
-1
1
solid, mp 55-56˚; ir: 3360 cm ; H nmr: δ 7.40-7.20 (complex,
5H), 6.82-6.65 (complex, 4H), 4.97 (dd, 1H, J = 7.8, 5.1), 4.16
(ddd, 1H, J = 9.6, 7.1, 5.3), 4.04 (m, 1H), 3.30 (br s, 3H), 2.21(m,
13
2H); C nmr: δ 146.4, 144.2, 136.2, 128.5, 127.6, 125.8, 121.4,
+
118.6, 115.2, 111.9, 71.9, 65.5, 38.5; ms: m/z 243 (M ).
Anal. Calcd. for C H NO : C, 74.07; H, 7.00; N, 5.76.
15 17
2
Found: C, 74.22; H, 7.07; N, 5.65.
1-Benzoyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (15a).
This compound (625 mg, 82%) was isolated as a white solid
that was triturated with 2% ether in petroleum ether, mp 137-
-1
1
138˚; ir: 3338, 1632 cm ; H nmr (not coalesced): δ 7.26 (d,
2H, J = 6.8), 7.23-7.07 (complex, 3H), 6.93 (td, 1H, J = 8.0,
1.5), 6.76 (dd, 1H, J = 8.0, 1.2), 6.54 (d, 1H, J = 6.8), 6.50 (t,
1H, J = 7.2), 5.10 and 5.06 (2 br s, 1H), 3.96 (br s, 1H), 3.58 (br
s, 1H), 3.01 (t, 1H, J = 10.3), 2.89 (t, 1H, J = 10.3), 2.10 (br s,
13
1H), 1.97 (br s, 1H); C nmr: δ 169.7, 145.7, 136.5, 134.0,
129.7, 129.3, 127.9, 127.7, 127.5, 120.5, 119.5, 46.1 (2), 29.5;
+
ms: m/z 252 (M ).
[13] D. N. Nagar, M. Tushar and V. H. Shah, Oriental J. Chem.,
18, 543 (2002); Chem. Abstr., 140, 128390 (2004).
Anal. Calcd. for C H N O: C, 76.19; H, 6.35; N, 11.11.
Found: C, 76.23; H, 6.38; N, 11.06.
16 16
2
[14] B. Puodziunaite, R. Janciene, Z. Talaikite, A. Zaks, Y. M.
Rabotnikov and E. A. Usachev, Khim.-Farm. Zh., 19 1195 (1985);
Chem. Abstr., 105, 133861 (1986).
(±)-1-Benzoyl-4-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodi-
azepine (15b).
[15] For earlier syntheses of 1,5-benzoxazepines see: [a] J. von
Braun and O. Braunsdorf, Ber. Dtsch. Chem. Ges., 54B, 685 (1921);
[b] G. S. Sidhu, G. Thyagarajan and U. T. Bhalerao, Indian J. Chem., 2,
211 (1964); [c] K. Nagarajan, J. David, Y. S. Kulkarni, S. B. Hendi, S.
J. Shenoy and P. Upadhyaya, Eur. J. Med. Chem., 21, 21 (1986); [d] H.
M. Nour El-Din and H. D. A. Shawki, Bulletin of the Faculty of
Pharmacy (Cairo University), 9, 253 (1970); Chem. Abstr., 77, 48422
(1972); [e] P. Sebok, A. Levai and T. Timar, Heterocyclic Commun., 4,
547 (1998).
[16] For earlier syntheses of 1,5-benzodiazepines, see: [a] G.
B. Bachman and L. V. Heisey, J. Am. Chem. Soc., 71, 1984 (1949);
[b] S. H. Dandegaonker and G. B. Desai, Indian J. Chem., 1, 298
(1963); [c] M. Hasan, F. Malik, M. C. Garcia Alvarez and Z.
This compound (450 mg, 88%) was isolated as a white solid
that was triturated with 2% ether in petroleum ether, mp 124-
-1
1
125˚; ir: 3325, 1632 cm ; H nmr (not coalesced): δ 7.37 (br s,
1H), 7.30-7.03 (complex, 3H), 6.96 (d, 1H, J = 7.2), 6.83 (d, 1H,
J = 7.5), 6.59 (br s, 2H), 5.13 and 5.19 (2 br s, 0.67H), 4.82 (br s,
0.33H), 4.03 (br s, 0.33H), 3.55 (br s, 0.67H), 3.40 (br s, 0.33H),
3.08 (br s, 0.67H), 2.71 (br s, 0.67H), 2.27 (br s, 0.33H), 1.84 (br
13
s, 2H), 1.37 (d, 3H, J = 6.0), 1.27 (br s, 1H); C nmr: δ 169.5,
145.4, 136.5, 136.0, 129.5, 129.3, 128.4, 127.7, 127.5, 120.8,
+
118.2, 53.1, 45.4, 37.6, 23.8; ms: m/z 266 (M ).
Anal. Calcd. for C H N O: C, 76.69; H, 6.77; N, 10.52.
17 18
2
Found: C, 76.74; H, 6.79; N, 10.47.

970
R. A. Bunce, C. L. Smith and J. R. Lewis
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[25] The alternative approach of adding the amine to the 2-fluoro-