Azepine synthesis from alkyl azide and propargylic ester via gold catalysis

Article abstract of DOI:10.1021/jo300667a

An efficient new method was developed to synthesize multisubstituted 4, 5-dihydro-1H-azepine derivatives through the gold-catalyzed reaction of two molecules of propargylic esters with one molecule of alkyl azide. It was proposed that vinyl gold carbenoid, in situ generated from propargylic ester through gold-catalyzed 1, 2-rearrangement, was trapped by alkyl azide to give vinyl imine intermediate. These, in turn, could undergo a formal [4 + 3] cycloaddition with another molecule of vinyl gold carbenoid to afford the desired azepine product.

Full text of DOI:10.1021/jo300667a

Note
pubs.acs.org/joc
Azepine Synthesis from Alkyl Azide and Propargylic Ester via Gold
Catalysis
Heng Liu,†,‡ Xin Li,† Zili Chen,*,† and Wen-Xiang Hu*,‡
†Department of Chemistry, Renmin University of China, Beijing 100872, P. R. China
‡Capital Normal University, Beijing 100048, P. R. China
S
* Supporting Information
ABSTRACT: An efficient new method was developed to synthesize
multisubstituted 4, 5-dihydro-1H-azepine derivatives through the
gold-catalyzed reaction of two molecules of propargylic esters with
one molecule of alkyl azide. It was proposed that vinyl gold carbenoid,
in situ generated from propargylic ester through gold-catalyzed 1, 2-
rearrangement, was trapped by alkyl azide to give vinyl imine
intermediate. These, in turn, could undergo a formal [4 + 3]
cycloaddition with another molecule of vinyl gold carbenoid to afford
the desired azepine product.
zepine derivatives are important structural elements in
many pharmacologically active compounds and have
continuation of our efforts to develop the gold-catalyzed
tandem reaction, we herein report an efficient new process to
prepare polyfunctionalized 4,5-dihydro-1H-azepine derivatives
from the reaction of propargylic esters with alkyl azides via gold
catalysis.
The reaction of propargylic ester 1a was chosen as the model
system for our initial investigation. As shown in scheme 2, the
reaction of 1a with 2 mol equiv of phenyl azide 2 in the
condition of 5% mol equiv of AuCl3 gave no desired product.24
However, when benzyl azide 3a was used as the carbene
trapper, azepine 5a was obtained in 14% yield, together with
the formation of vinyl aldehyde 4a. Considering vinyl imine
instability, 100 mg 4 Å MS was added to remove the moisture,
which enhanced the yield of 5a slightly (Scheme 2).
These preliminary results prompted us to further explore this
reaction. As shown in Table 1, Au(I) catalysts exhibited poor
activities. AuCl gave 5a in 13% yield (Table 1, entry 2). Use of
the phosphine or N-heterocyclic carbene ligands was also
fruitless (Table 1, entries 3−5). Other Au(III) catalysts were
then tested. AuBr3 provided 5a in 9% yield, while 2-
benzylpyridine-ligated Au(III) catalyst 7 gave 15% yield
(Table 1, entries 6 and 7).25 PicAuCl2 6 performed best,
affording 5a in 25% yield (Table 1, entry 8). Increasing 1a’s
amount enhanced 5a’s yield (Table 1, entry 9). Subsequent
solvent screening proved DCM to be best reaction media
(Table 1, entries 10−14). Under the conditions of 10% molar
equiv of 6, product 5a was obtained in 54% yield (Table 1,
entry 15). When catalyst 6 was added in two batches, 5a’s yield
was further improved to 68% yield (Table 1, entry 16).
Under the conditions from entry 16 in Table 1, the scope
and limitations for this reaction were then explored. At first, we
investigated the reaction of 2-methylbut-3-yn-2-yl benzoate 1a
A
attracted considerable synthetic attention from organic
chemists. Azepine rings can be prepared from intramolecular
cyclization reactions through nucelophilic addition,1 radical
addition,2 condensation reaction,3 olefin metathesis4 and
pyrolysis,5 or ring-expansion reactions through nitrogen
transfer,6 Beckman rearrangement,7 and some related pro-
cesses.8 Despite these achievements, however, examples of
azepine synthesis via intermolecular cycloaddition reaction are
still very scarce.9
As shown in Scheme 1, vinyl gold or platinum carbenoid A,
generated in situ from propargylic ester through gold-catalyzed
1, 2-rearrangement, has been reported to be an important
synthetic intermediate.10 Trapping intermediate A with alkene’s
double bonds,11 sp2 and sp3 C−H bonds,12,13 C−O bonds14
and C−S bonds15 led to the realization of a wide variety of
carbene insertion reactions. Intermediate A can also engaged in
β-elimination16 and intramolecular annulation with neighboring
alkenes,17 pyridine,18 or carbonyl groups.19 Intermolecular
cycloaddition with azomethine imines20 and α,β-unsaturated
imines9b is also documented.
It has been reported that trapping intermediate A by
sulfoxide would give vinyl aldehyde.21 We envisioned that a
similar transformation of intermediate A with azide compound
would provide vinyl imine B, which would further take a
cycloaddition reaction with the second vinyl gold carbenoid
unit A to give azepine product in a one-pot process (routes I
and II, Scheme 1).
Constructing cyclic molecules from two or more acyclic
precursors via tandem reaction is one of the most attractive
strategies in organic synthesis.22 We recently reported a
diastereoselective cascade allylation/enyne cycloisomerization
to construct densely functionalized oxygen hetereocycles from
the reaction of the esters and the propargylic alcohols.23 As a
Received: April 6, 2012
Published: May 14, 2012
© 2012 American Chemical Society
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Note
Scheme 1. Sequential Reactions of Gold Carbenoid A with Azide and Vinyl Imine
A variety of bisubstituted propargylic esters 1a−g (R1, R2 =
alkyl group) were also investigated. A different acyl protection
pattern was first studied. As compared with 1a, pivalate and
acetate substrates 1b and 1c gave relatively lower yields (Table
3, entries 2 and 3). Unsymmertic propargylic esters were then
tested. The reaction of 3-methylpent-1-yn-3-ol benzoate 1d
afforded azepine 5n in 48% yield with a high diastereoselectivity
(trans/cis = 10/1, Table 3, entry 4). Similarly, the reactions of
1e and 1f also gave trans-5o and trans-5p as the major product
in moderate yields (Table 3, entries 5 and 6). No desired
product was obtained in the reaction of substrate 1g and 3a,
possibly because of the increased steric hindrance. However,
when electron-deficient p-fluorobenzyl azide 3d was utilized as
the reactant, the corresponding azpine 5r was obtained in 16%
yield (Table 3, entry 8). Monosubstituted propargylic ester (R1
or R2 = H, Table 3 reaction scheme) was also examined, but no
desired product was obtained.
Scheme 2. Initial Exploration of 1a with Aryl and Alkyl Azide
a
Table 1. Optimization of the Reaction of 1a with 3a
On the basis of the reaction sequence depicted in Scheme 1,
employing two different vinyl gold carbenoids in routes I and II
would provide an unsymmetric azepine product. As shown in
Scheme 3, the reaction of benzyl azide 3a (1.5 equiv) with 2-
methylbut-3-yn-2-yl benzoate 1a (1.0 equiv) and 3-methylhex-
2-yn-3-yl benzoate 1f (2.0 equiv) provided unsymmetric
azepine adduct 8a in 25% yield (Scheme 3). Similarly, in the
reaction of 3a, 1a, and 1h, 8b was obtained in 18% yield
(Scheme 3).
Vinyl aldehyde 4a can be generated from the reaction of vinyl
gold carbenoid with sulfoxide.21 In the reaction of benzyl azide
3a with 1a, 4a was generated as minor product through
hydrolyzation of vinyl imine intermediate B. When 2 equiv of
3a and 1 equiv of 1a was treated with PicAuCl2 at low
temperature, 4a was obtained as major product (scheme 4, eq
1). Further derivation of the azepine product 5b was also
performed. Hydrolyzation of 5k with NaOH in a mixture of
MeOH/THF afforded the azepane-3,6-dione product 9 in 80%
yield (Scheme 4, eq 2).
b
ratio
solution/time
(h)
yield of 3a
catalyst/loading (%)
(3a/1a)
(%)
1
2
AuCl3/5
1/2.5
1/2.5
1/2.5
1/2.5
1/2.5
1/2.5
1/2.5
1/2.5
1/5
DCM/10
DCM/11
DCM/12
DCM/9
21
13
<5
0
AuCl/5
3
Ph3PAuCl/AgSbF6/5
IPrAuCl/AgSbF6/5
SIPrAuCl/AgSbF6/5
AuBr3/5
4
5
DCM/9
0
6
DCM/10
DCM/10
DCM/10
DCM/10
MeNO2/8
THF/8
9
7
7/5
15
25
37
23
12
trace
18
35
54
68
8
PicAuCl2/5
PicAuCl2/5
PicAuCl2/5
PicAuCl2/5
PicAuCl2/5
PicAuCl2/5
PicAuCl2/5
PicAuCl2/10
PicAuCl2/10
9
10
11
12
13
14
15
16
1/5
1/5
1/5
MeCN/8
PhCH3/8
DCE/10
DCM/10
DCM/10
1/5
1/5
1/5
c
1/5
In summary, we have developed an efficient new method to
construct a series of densely functionalized 4,5-dihydro-1H-
azepine products from the intermolecular reaction of alkyl
azides with propargylic esters in which sequential reaction of
vinyl gold carbenoids A with alkyl azides and vinyl imine
intermediates B are involved.
a
Unless noted, all reactions were carried out at 0.1 mmol scale in 2 mL
of solvent at rt with the addition of 100 mg of activated 4 Å MS.
Isolated yields. 10 mol % of catalyst 6 was added in two batches.
b
c
with a number of alkyl azides, including benyl azides with
different substitution patterns. As shown in Table 2, substrates
with electron-rich benzyl groups worked better than their
electron-deficient analogues and gave higher reaction yields
(3a,b,f, Table 2, entries 1, 2, and 6). tButyl benzyl azide 3b gave
the best result. However, the reactions of electron-deficient
substrates proceeded much faster than those of electron-rich
analogues. Compounds 3d and 3g only took 5 h to give the
corresponding products (Table 2, entries 4 and 7). Other alkyl
azides, such as 2-naphthalene methyl azide 3h, 2-phenyl ethyl
azide 3i, and methyl 2-azidoacetate 3j, were also tested. The
desired azepine products 5h, 5i, and 5j were obtained in
moderate yields (Table 2, entries 8−10).
EXPERIMENTAL SECTION
■
All reactions were run under an inert atmosphere (N2) with flame-
dried glassware using standard techniques for manipulating air-
sensitive compounds. CH2Cl2 was obtained by fresh distilled over
Calcium hydride. Commercial reagents were used as supplied or
purified by standard techniques where necessary. Column chromatog-
raphy was performed using 200−300 mesh silica with the proper
solvent system according to TLC analysis using KMnO4 stain and UV
light to visualize the reaction components. Catalyst PicAuCl2,9b alkyl
azides,9a and propargylic esters26 were synthesized according to the
literature procedures.
Typical Procedure for the Gold-Catalyzed Carbocyclization
of Propargylic Esters with Alkyl Azides. In a dry flask under
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Note
a
Table 2. Gold-Catalyzed Intermolecular Reaction of Propargylic Ester 1a with Alkyl Azides
a
Unless noted, all reactions were carried out on a 0.1 mmol scale (1/3 = 5/1) in 2 mL of DCM at rt with the addition of 100 mg of activated 4 Å MS
catalyzed by 10% molar equiv of PicAuCl2 (added in two batches).
nitrogen equipped with a magnetic stir bar were sequentially added
benzyl azide (∼0.1 mmol, 1 equiv), propargyl esters (5 equiv), 100 mg
of activated 4 Å MS, and CH2Cl2 (2 mL). PicAuCl2 (0.1 equiv) was
added in two portions at t = 0 and 4.5 h. The resulting mixture was
stirred at room temperature and monitored periodically by TLC.
Upon consumption of benzyl azide (8 − 20 h), the reaction mixture
was directly subjected to silica gel chromatography (EA/PE) to give
the desired azepine products.
1-Benzyl-4,4,5,5-tetramethyl-4,5-dihydro-1H-azepine-3,6-
diyl Dibenzoate (5a). Obtained as a yellow oil in 68% yield (32.7
mg): 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 7.6 Hz, 4H), 7.57 (t,
J = 7.3 Hz, 2H), 7.45 (t, J = 7.6 Hz, 4H), 7.37−7.25 (m, 5H), 6.04 (s,
2H), 4.38 (s, 2H), 1.35 (s, 6H), 1.09 (s, 6H); 13C NMR (100 MHz,
CDCl3): δ166.7, 137.9, 136.7, 133.1, 130.0, 129.9, 128.7, 128.4, 127.6,
127.2, 125.1, 61.0, 45.5, 26.8, 20.6; IR (neat) 2970, 2955, 1727, 1666,
1451, 1422, 1262, 1203, 1089, 1067, 1001, 705, 629 cm−1; MS (m/z,
rel intensity) 481 (M+, 2), 391 (4), 390 (8), 377 (3), 376 (10), 294
(2), 287 (2), 122 (4), 106 (6), 105 (100), 91 (16), 77 (12), 51 (12);
HRMS (EI) calcd for C31H31NO4 [M]+ 481.2253, found 481.2257.
1-(4-tert-Butylbenzyl)-4,4,5,5-tetramethyl-4,5-dihydro-1H-
azepine-3,6-diyl Dibenzoate (5b). Obtained as a yellow oil in 78%
1
yield (41.8 mg): H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 7.6 Hz,
4H), 7.57 (t, J = 7.4 Hz, 2H), 7.45 (t, J = 7.6 Hz, 4H), 7.37 (d, J = 8.2
Hz, 2H), 7.26−7.24 (m, 2H), 6.04 (s, 2H), 4.36 (d, J = 1.5 Hz, 2H),
1.37 (s, 6H), 1.30 (s, 9H), 1.09 (s, 6H); 13C NMR (100 MHz, CDCl3)
δ166.7, 150.4, 136.5, 134.9, 133.1, 130.0, 129.9, 128.4, 126.7, 125.6,
125.2, 60.6, 45.5, 34.5, 31.3, 26.8, 20.6; IR (neat) 2962, 2941, 1733,
1727, 1262, 1155, 1089, 1068, 1037, 707, 687 cm−1; MS (m/z, rel
intensity) 537 (M+, 2), 390 (11), 350 (5), 161 (40), 147 (26), 132 (5),
106 (5), 105 (100), 77 (9); HRMS (EI) calcd for C35H39NO4 [M]+
537.2879, found 537.2883.
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Note
a,b
Table 3. Gold-Catalyzed Intermolecular Reaction of Substituted Benzyl Azides with Propargylic Alcohols
a
Unless noted, all reactions were carried out on a 0.1 mmol scale (1/3 = 5/1) in 2 mL of DCM at rt with the addition of 100 mg of activated 4 Å MS
b
c
1
catalyzed by 10% molar equiv of PicAuCl2 (added in two batches). The dr value was determined by H NMR spectral data. Substrate 3d was
employed. No syn-product was detected.
d
Scheme 3. Reaction of 3a with Two Different Propargylic Esters
1-(4-Bromobenzyl)-4,4,5,5-tetramethyl-4,5-dihydro-1H-aze-
pine-3,6-diyl Dibenzoate (5c). Obtained as a yellow oil in 65%
yield (36.2 mg): H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 7.2 Hz,
intensity) 391 (6), 390 (20), 186 (3), 184 (22), 182 (21), 170 (5), 168
(3), 156 (3), 106 (6), 105 (100), 77 (10); HRMS (EI) calcd for
C31H30BrNO4 [M]+ 559.1358, found 559.1374.
1
4H), 7.58 (t, J = 7.4 Hz, 2H), 7.49−7.44 (m, 6H), 7.20 (d, J = 8.2 Hz,
2H), 6.00 (s, 2H), 4.31 (s, 2H), 1.34 (s, 6H), 1.08 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ166.6, 137.0, 136.9, 133.2, 131.8, 129.9, 128.9,
128.5, 124.9, 121.5, 60.4, 45.5, 26.8, 20.6; IR (neat) 2977, 2869, 1713,
1420, 1361, 1264, 1221, 1092, 1070, 1039, 713 cm−1; MS (m/z, rel
1-(4-Fluorobenzyl)-4,4,5,5-tetramethyl-4,5-dihydro-1H-aze-
pine-3,6-diyl Dibenzoate (5d). Obtained as a yellow oil in 63%
yield (31.3 mg): H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 7.1 Hz,
4H), 7.58 (t, J = 7.4 Hz, 2H), 7.46 (t, J = 7.6 Hz, 4H), 7.27 (dd, J =
8.6, 5.4 Hz, 2H), 7.04 (t, J = 8.6 Hz, 2H), 6.02 (s, 2H), 4.34 (s, 2H),
1
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Note
Scheme 4. Synthesis of Vinyl Aldehyde 4a and Further Derivation of Azepine 5k
1.31 (s, 6H), 1.09 (s, 6H); 13C NMR (100 MHz, CDCl3) δ166.6,
162.2 (d, J = 243.3 Hz), 136.8, 133.7, 133.2, 129.9, 128.8 (d, J = 8.1
Hz), 128.5, 124.9, 115.6 (d, J = 21.4 Hz), 60.3, 45.4, 26.7, 20.6; IR
(neat) 2962, 2925, 1726, 1666, 1602, 1509, 1450, 1415, 1261, 1224,
1174, 1088, 1067, 1036, 1023, 824, 706 cm−1; MS (m/z, rel intensity)
499 (M+, 4), 395 (4), 394 (15), 390 (16), 268 (2), 138 (2), 123 (8),
109 (24), 105 (100), 77 (11); HRMS (EI) calcd for C31H30FNO4
[M]+ 499.2159, found 499.2163.
125.1, 61.2, 45.5, 26.8, 20.6; IR (neat) 2985, 2932, 1729, 1668, 1452,
1422, 1315, 1264, 1178, 1157, 1070, 1039, 1025, 882, 819, 755, 709,
632 cm−1; MS (m/z, rel intensity) 531 (M+, 9), 426 (15), 390 (31),
142 (8), 141 (100), 105 (30), 147 (66), 77 (6); HRMS (EI) calcd for
C35H33NO4 [M]+ 531.2410, found 531.2412.
4,4,5,5-Tetramethyl-1-phenethyl-4,5-dihydro-1H-azepine-
3,6-diyl Dibenzoate (5i). Obtained as a yellow oil in 52% yield (25.7
mg): 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 7.6 Hz, 4H), 7.59 (t,
J = 7.3 Hz, 2H), 7.48 (t, J = 7.7 Hz, 4H), 7.28 (d, J = 7.8 Hz, 2H),
7.21−7.18 (m, 3H), 5.95 (s, 2H), 3.39 (t, J = 7.7 Hz, 2H), 2.94 (t, J =
7.8 Hz, 2H), 1.35 (s, 6H), 1.09 (s, 6H); 13C NMR (100 MHz, CDCl3)
δ166.7, 138.2, 136.6, 133.1, 133.0, 129.9, 128.8, 128.5, 128.4, 126.4,
124.6, 59.5, 45.4, 37.1, 26.7, 20.6; IR (neat) 2975, 2850, 1729, 1262,
1090, 1068, 705, 668 cm−1; MS (m/z, rel intensity) 495 (M+, 10), 404
(15), 391 (17), 390 (100), 268 (3), 105 (57), 77 (7); HRMS (EI)
calcd for C32H33NO4 [M]+ 495.2410, found 495.2408.
1-(2-Ethoxy-2-oxoethyl)-4,4,5,5-tetramethyl-4,5-dihydro-
1H-azepine-3,6-diyl Dibenzoate (5j). Obtained as a yellow oil in
60% yield (28.6 mg): 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 7.3
Hz, 4H), 7.59 (t, J = 7.4 Hz, 2H), 7.47 (t, J = 7.7 Hz, 4H), 5.89 (s,
2H), 4.21 (q, J = 7.1 Hz, 2H), 3.90 (q, J = 17.4 Hz, 2H), 1.42 (s, 6H),
1.29 (t, J = 7.1 Hz, 3H), 1.10 (s, 6H); 13C NMR (100 MHz, CDCl3):
δ169.6, 166.5, 137.4, 133.2, 129.9, 128.5, 125.0, 61.4, 58.3, 45.4, 26.2,
20.6, 14.1; IR (neat) 2984, 2915, 1730, 1687, 1671, 1451, 1422, 1369,
1313, 1264, 1197, 1157, 1068, 1035, 1024, 709 cm−1; MS (m/z, rel
intensity) 477 (M+, 4), 404 (2), 373 (6), 372 (30), 250 (2), 138(2),
123 (2), 106 (5), 105 (100), 77 (10); HRMS (EI) calcd for
C28H31NO6 [M]+ 477.2151, found 477.2155.
1-(4-tert-butylbenzyl)-4,4,5,5-tetramethyl-4,5-dihydro-1H-
azepine-3,6-diyl Bis(2,2-dimethylpropanoate) (5k). Obtained as
a colorless oil in 55% yield (27.3 mg): 1H NMR (400 MHz, CDCl3) δ
7.37 (d, J = 8.3 Hz, 2H), 7.21 (d, J = 8.2 Hz, 2H), 5.76 (s, 2H), 4.31
(s, 2H), 1.31 (s, 9H), 1.24 (s, 18H), 1.21 (s, 6H), 0.99 (s, 6H); 13C
NMR (100 MHz, CDCl3) δ178.5, 150.2, 136.5, 135.3, 126.4, 125.6,
124.5, 60.4, 45.2, 38.9, 34.5, 31.3, 27.3, 26.5, 20.5; IR (neat) 2964,
2934, 1743, 1666, 1478, 1413, 1276, 1117, 1054, 894, 819 cm−1; MS
(m/z, rel intensity) 497 (M+, 9), 413 (9), 412 (39), 351 (6), 350 (32),
266 (3), 248 (3), 148 (8), 147 (100), 132 (9), 119 (3), 117 (5), 105
(4), 57 (16), 41 (2); HRMS (EI) calcd for C31H47NO4 [M]+
497.3505, found 497.3510.
4,4,5,5-Tetramethyl-1-(4-nitrobenzyl)-4,5-dihydro-1H-aze-
pine-3,6-diyl Dibenzoate (5e). Obtained as a yellow solid in 50%
1
yield (26.3 mg): H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 8.7 Hz,
2H), 8.09 (d, J = 7.2 Hz, 4H), 7.61 (t, J = 7.4 Hz, 2H), 7.52 (d, J = 8.7
Hz, 2H), 7.47 (t, J = 7.5 Hz, 4H), 6.01 (s, 2H), 4.47 (s, 2H), 1.35 (s,
6H), 1.09 (s, 6H); 13C NMR (100 MHz, CDCl3): δ166.6, 147.5,
145.4, 137.4, 133.3, 129.9, 129.7, 128.5, 127.9, 124.8, 124.0, 60.3, 45.5,
26.7, 20.6; IR (neat) 2857, 1728, 1678, 1520, 1450, 1344, 1262, 1174,
1089, 1067, 1001, 800, 708 cm−1; MS (m/z, rel intensity) 526 (M+, 4),
422 (4), 421 (17), 390 (15), 141 (8), 106(10), 105 (100), 77 (11);
HRMS (EI) calcd for C31H30N2O6 [M]+ 526.2104, found 526.2101.
4,4,5,5-Tetramethyl-1-(3-methylbenzyl)-4,5-dihydro-1H-aze-
pine-3,6-diyl Dibenzoate (5f). Obtained as a yellow oil in 72% yield
1
(35.6 mg): H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 7.6 Hz, 4H),
7.58 (t, J = 7.3 Hz, 2H), 7.47 (t, J = 7.7 Hz, 4H), 7.27−7.23 (m, 1H),
7.14−7.07 (m, 3H), 6.04 (s, 2H), 4.35 (s, 2H), 2.36 (s, 3H), 1.37 (s,
6H), 1.10 (s, 6H); 13C NMR (100 MHz, CDCl3) δ166.7, 138.3, 137.9,
136.5, 133.1, 130.0, 129.9, 128.6, 128.4, 128.3, 128.0, 125.2, 124.2,
61.0, 45.5, 26.8, 21.4, 20.7; IR (neat) 2965, 2945, 1727, 1666, 1601,
1450, 1419, 1261, 1175, 1156, 1067, 1037, 1001, 880, 707, 629 cm−1;
MS (m/z, rel intensity) 495 (M+, 2), 404 (1), 391 (4), 390 (9), 308
(3), 286 (2), 122 (3), 119 (8), 106 (6), 105 (100), 91 (2), 77 (10), 51
(2); HRMS (EI) calcd for C32H33NO4 [M]+ 495.2410, found
495.2412.
4,4,5,5-Tetramethyl-1-((perfluorophenyl) methyl)-4,5-dihy-
dro-1H-azepine-3,6-diyl Dibenzoate (5g). Obtained as a yellow
solid in 70% yield (39.9 mg): 1H NMR (400 MHz, CDCl3) δ 8.11 (d,
J = 7.6 Hz, 4H), 7.60 (t, J = 7.3 Hz, 2H), 7.48 (t, J = 7.6 Hz, 4H), 6.06
(s, 2H), 4.47−4.38 (m, 2H), 1.25 (s, 6H), 1.06 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ166.3, 146.5 (m), 143.9 (m), 141.7 (m), 139.2
(m), 138.0, 133.2, 129.9, 128.5, 124.3, 120.0 (m), 111.6 (m), 47.9,
45.3, 26.4, 20.5; IR (neat) 2970, 2120, 1729, 1494, 1264, 1156, 1091,
1069, 1027, 709 cm−1; MS (m/z, rel intensity) 571 (M+, 2), 489 (3),
391 (4), 390 (14), 286 (3), 178 (8), 106 (7), 105 (100), 77 (13), 43
(3); HRMS (EI) calcd for C31H26F5NO4 [M]+ 571.1782, found
571.1784.
1-(4-tert-Butylbenzyl)-4,4,5,5-tetramethyl-4,5-dihydro-1H-
azepine-3,6-diyl Diacetate (5m). Obtained as a colorless oil in 56%
1
yield (23.1 mg): H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 8.3 Hz,
2H), 7.19 (d, J = 8.2 Hz, 2H), 5.85 (s, 2H), 4.29 (d, J = 2.6 Hz, 2H),
2.10 (s, 6H), 1.30 (s, 9H), 1.19 (s, 6H), 1.00 (s, 6H); 13C NMR (100
MHz, CDCl3) δ171.0, 150.4, 136.1, 134.9, 126.6, 125.5, 124.8, 60.5,
45.0, 34.5, 31.3, 26.6, 20.7, 20.4; IR (neat) 2964, 2937, 1753, 1668,
1453, 1402, 1213, 1137, 1088, 1010, 898, 707 cm−1; MS (m/z, rel
intensity) 413 (M+, 11), 371 (8), 370 (7), 328 (5), 312 (6), 266 (28),
224 (12), 187 (20), 164 (11), 161 (19), 147 (100), 132 (17), 131
4,4,5,5-Tetramethyl-1-(naphthalen-2-ylmethyl)-4,5-dihydro-
1H-azepine-3,6-diyl Dibenzoate (5h). Obtained as a yellow oil in
68% yield (36.1 mg): 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 7.3
Hz, 4H), 7.85−7.80 (m, 3H), 7.76(s, 1H), 7.56 (t, J = 7.4 Hz, 2H),
7.47−7.43 (m, 7H), 6.10 (s, 2H), 4.53 (s, 2H), 1.38 (s, 6H), 1.09 (s,
6H); 13C NMR (100 MHz, CDCl3) δ 166.7, 136.7, 135.5, 133.3,
133.1, 132.9, 129.9, 128.6, 128.4, 127.9, 127.7, 126.1, 125.9, 125.2,
5188
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The Journal of Organic Chemistry
Note
(14), 117 (16), 91 (9), 43 (20); HRMS (EI) calcd for C25H35NO4
[M]+ 413.2566, found 413.2567.
1-Benzyl-4,4,5-trimethyl-5-propyl-4,5-dihydro-1H-azepine-
3,6-diyl Dibenzoate (8a). Obtained as a yellow oil in 25% yield
(12.7 mg): H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.4 Hz, 2H),
1
(4R*,5R*)-1-(4-tert-Butylbenzyl)-4,5-diethyl-4,5-dimethyl-
8.07 (d, J = 8.4 Hz, 2H), 7.58 (td, J = 7.2, 1.3 Hz, 2H), 7.46 (t, J = 7.1
Hz, 4H), 7.37−7.25 (m, 5H), 6.09 (s, 1H), 6.04−6.03 (m, 1H), 4.43−
4.34 (m, 2H), 1.77−1.72 (m, 1H), 1.54−1.34 (m, 6H), 1.08 (s, 3H),
1.07 (s, 3H), 0.92 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ166.7, 165.9, 138.2, 135.9, 134.8, 133.1, 133.0, 130.2, 130.1, 129.9,
129.8, 128.7, 128.4, 127.6, 127.1, 127.0, 125.6, 124.7, 61.4, 49.3, 46.3,
42.4, 27.6, 20.9, 18.3, 17.5, 14.9; IR (neat) 2960, 2932, 1728, 1601,
1451, 1422, 1313, 1262, 1174, 1151, 1091, 1068, 1001, 707 cm−1; MS
(m/z, rel intensity) 446 (17), 432 (19), 324 (3), 320 (4), 217 (7), 106
(5), 105 (100), 95 (9), 91 (36), 77 (11), 67 (2); HRMS (EI) calcd for
C33H35NO4 [M]+ 509.2566, found 509.2548.
4,5-dihydro-1H-azepine-3,6-diyl Dibenzoate (5n). Obtained as a
1
colorless oil in 48% yield (27.1 mg, anti/syn = 10/1): H NMR (400
MHz, CDCl3) δ 8.08 (d, J = 7.3 Hz, 4H), 7.57 (t, J = 7.4 Hz, 2H), 7.46
(t, J = 7.8 Hz, 4H), 7.37 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.2 Hz, 2H),
6.10 (s, 2H), 4.37 (s, 2H), 1.98 (dt, J = 20.8, 7.5 Hz, 2H), 1.61 (dt, J =
20.7, 7.4 Hz, 2H), 1.31 (s, 9H), 1.05 (s, 6H), 1.02 (t, J = 7.4 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ166.0, 150.4, 135.3, 133.9, 133.0,
130.2, 129.8, 128.4, 126.5, 125.6, 125.2, 61.3, 50.6, 34.5, 33.4, 31.3,
16.9, 9.4; IR (neat) 2962, 1728, 1666, 1451, 1259, 1174, 1149, 1089,
1067, 1000, 705, 618 cm−1; MS (m/z, rel intensity) 565 (M+, 7), 460
(13), 444 (3), 418 (20), 362 (3), 296 (2), 203 (3), 147 (38), 132 (9),
117 (7), 105 (100), 91 (2), 81 (4), 77 (17), 51 (3); HRMS (EI) calcd
for C37H43NO4 [M]+ 565.3192, found 565.3195.
1-Benzyl-5-(4-methoxyphenyl)-4,4-dimethyl-6-(pivaloy-
loxy)-4,5-dihydro-1H-azepin-3-yl Benzoate (8b). Obtained as a
yellow oil in 18% yield (9.7 mg): 1H NMR (400 MHz, CDCl3) δ 7.90
(d, J = 7.4 Hz, 2H), 7.51 (t, J = 7.4 Hz, 1H), 7.39−7.29 (m, 7H), 7.22
(d, J = 8.6 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 6.15 (s, 1H), 6.07 (s,
1H), 4.45 (s, 2H), 3.81 (s, 3H), 3.42 (s, 1H), 1.54 (s, 3H), 1.12 (s,
9H), 0.83 (s, 3H); 13C NMR (100 MHz, CDCl3) δ177.9, 166.2, 158.2,
137.9, 136.3, 135.4, 133.1, 131.2, 130.4, 129.8, 129.7, 128.8, 128.3,
127.7, 127.1, 125.3, 124.3, 113.1, 61.4, 59.0, 55.2, 41.4, 38.7, 29.9, 27.0,
25.7; IR (neat) 2973, 1732, 1510, 1452, 1265, 1246, 1059, 1025, 827,
706 cm−1; MS (m/z, rel intensity) 539 (M+, 20), 455 (19), 454 (100),
434 (5), 406 (4), 332 (8), 242 (3), 187 (3), 106 (4), 105 (52), 91
(41), 77 (8), 57 (15); HRMS (EI) calcd for C34H37NO5 [M]+
539.2672, found 539.2668.
(4R*,5R*)-1-(4-tert-Butylbenzyl)-4,5-dimethyl-4,5-dipropyl-
4,5-dihydro-1H-azepine-3,6-diyl Dibenzoate (5o). Obtained as a
yellow oil in 54% yield (32.0 mg, only anti-isomer was detected by 1H
NMR): 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 7.3 Hz, 4H), 7.58
(t, J = 7.4 Hz, 2H), 7.46 (t, J = 7.7 Hz, 4H), 7.37 (d, J = 8.2 Hz, 2H),
7.23 (d, J = 8.2 Hz, 2H), 6.11 (s, 2H), 4.41−4.32 (m, 2H), 1.88−1.83
(m, 2H), 1.59−1.38 (m, 6H), 1.31 (s, 9H), 1.08 (s, 6H), 0.93 (t, J =
6.7 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ165.8, 150.4, 135.4,
134.3, 132.9, 130.4, 129.8, 128.4, 126.6, 125.6, 125.2, 61.5, 50.3, 43.2,
34.5, 31.3, 18.3, 17.7, 15.0; IR (neat) 2980, 1731, 1262, 1245, 1065,
1026, 833, 804, 737, 730, 619 cm−1; MS (m/z, rel intensity) 593 (M+,
8), 488 (20), 373 (6), 446 (9), 366 (8), 217(13), 147 (66), 132 (10),
105 (100), 95 (11), 77 (11); HRMS (EI) calcd for C39H47NO4 [M]+
593.3505, found 593.3508.
(4R*,5R*)-1-(4-tert-Butylbenzyl)-4,5-dimethyl-4,5-dipentyl-
4,5-dihydro-1H-azepine-3,6-diyl Dibenzoate (5p). Obtained as a
yellow oil in 40% yield (26.0 mg, only anti-isomer was detected by 1H
NMR): 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 7.3 Hz, 4H), 7.57
(t, J = 7.3 Hz, 2H), 7.46 (t, J = 7.7 Hz, 4H), 7.35 (d, J = 8.2 Hz, 2H),
7.21 (d, J = 8.1 Hz, 2H), 6.09 (s, 2H), 4.38 (s, 2H), 1.96−1.91 (m,
2H), 1.58−1.25 (m, 23H), 1.08 (s, 6H), 0.95−0.92 (m, 6H); 13C
NMR (100 MHz, CDCl3) δ165.8, 150.3, 135.4, 133.9, 132.9, 130.3,
129.8, 128.4, 126.4, 125.5, 125.2, 61.4, 50.2, 40.9, 34.5, 32.8, 31.3, 24.7,
22.9, 17.7, 14.3; IR (neat) 2960, 2954, 1730, 1262, 1174, 1103, 1087,
1068, 1029, 705, 668, 639 cm−1; MS (m/z, rel intensity) 649 (M+, 10),
544 (25), 422 (10), 404 (11), 298 (7), 245 (9), 147 (57), 132 (8), 105
(100), 77 (8); HRMS (EI) calcd for C43H55NO4 [M]+ 649.4131,
found 649.4135.
3-Methyl-1-oxobut-2-en-2-yl Benzoate (4a).21 Obtained as a
1
colorless oil in 55% yield (11.2 mg): H NMR (400 MHz, CDCl3) δ
9.93 (s, 1H), 8.14 (d, J = 7.6 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.48 (t,
J = 7.8 Hz, 2H), 2.31 (s, 3H), 1.95 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ181.7, 164.2, 146.0, 142.8, 133.6, 130.2, 128.9, 128.5, 20.1,
18.0; IR (neat) 2950, 1734, 1678, 1654, 1451, 1374, 1250, 1120, 1064,
1024, 861, 708 cm−1.
Procedure To Synthesize 9 from 5b. To a solution of azepine
(40.0 mg, 0.074 mmol) in methanol/tetrahydrofuran (2/1, 1 mL) at 0
°C was added NaOH (1 M, 0.45 mL, 6 equiv). The resulting mixture
was stirred at room temperature overnight. After consumption of the
starting material, the reaction was diluted with brine and extracted with
diethyl ether (3 × 2 mL). The combined organic extracts were dried
over sodium sulfate, concentrated, and subjected to flash column
chromatography on silica gel. The desired product was isolated as a
white solid (19.6 mg, 80% yield).
1-(4-tert-Butylbenzyl)-4,4,5,5-tetramethylazepane-3,6-
dione: 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.3 Hz, 2H), 7.19
(d, J = 8.2 Hz, 2H), 3.68 (s, 2H), 3.39 (s, 4H), 1.31 (s, 9H), 1.16 (s,
12H); 13C NMR (100 MHz, CDCl3) δ211.0, 150.6, 133.9, 128.6,
125.4, 65.0, 62.8, 51.8, 34.5, 31.3, 20.7; IR (neat) 2963, 1696, 1117,
1023, 820, 720, 623 cm−1; MS (m/z, rel intensity) 329 (M+, 3), 301
(4), 273 (12), 189 (17), 188 (9), 174 (2), 148 (7), 147 (100), 132
(14), 126 (11), 117 (11), 105 (4), 91 (4), 42 (13); HRMS (EI) calcd
for C21H31NO2 [M]+ 329.2355, found 329.2373.
(4R*,5R*)-4,5-Diethyl-1-(4-fluorobenzyl)-4,5-dimethyl-4,5-
dihydro-1H-azepine-3,6-diyl Dibenzoate (5q). Obtained as a
1
yellow oil in 32% yield (16.9 mg, anti/syn = 20/1): H NMR (400
MHz, CDCl3) δ 8.08 (d, J = 7.6 Hz, 4H), 7.58 (t, J = 7.4 Hz, 2H), 7.46
(t, J = 7.7 Hz, 4H), 7.26 (dd, J = 8.3, 5.6 Hz, 2H), 7.04 (t, J = 8.5 Hz,
2H), 6.08 (s, 2H), 4.35 (s, 2H), 1.93 (dt, J = 20.8, 7.3 Hz, 2H), 1.60
(dt, J = 20.7, 7.2 Hz, 2H), 1.04 (s, 6H), 1.01 (t, J = 7.4 Hz, 6H); 13C
NMR (100 MHz, CDCl3): δ165.9, 162.2 (d, J = 244.0 Hz), 134.2,
134.0, 133.1, 130.1, 129.8, 128.6 (d, J = 8.1 Hz), 128.5, 124.9, 115.5
(d, J = 21.5 Hz), 60.9, 50.6, 33.3, 16.9, 9.4; IR (neat) 2877, 1720, 1280,
1130, 1100, 750 cm−1; MS (m/z, rel intensity) 527 (M+, 5), 422 (8),
418 (12), 376 (4), 300 (3), 109 (24), 105 (100), 77 (9); HRMS (EI)
calcd for C33H34FNO4 [M]+ 527.2472, found 527.2479.
ASSOCIATED CONTENT
* Supporting Information
NMR spectral data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org/.
■
S
1-(4-Fluorobenzyl)-4,5-dicyclohexyl-4,5-dihydro-1H-aze-
pine-3,6-diyl Dibenzoate (5r). Obtained as a yellow oil in 16% yield
1
(9.3 mg): H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 7.4 Hz, 4H),
AUTHOR INFORMATION
Corresponding Author
*E-mail: zilichen@ruc.edu.cn; huwx66@163.com.
■
7.58 (t, J = 7.4 Hz, 2H), 7.47 (t, J = 7.7 Hz, 4H), 7.29 (dd, J = 8.4, 5.5
Hz, 2H), 7.02 (t, J = 8.5 Hz, 2H), 6.18 (s, 2H), 4.36 (s, 2H), 1.95−
1.93 (m, 2H), 1.85−1.82 (m, 2H), 1.61−1.26 (m, 14H), 1.10−1.05
(m, 2H); 13C NMR (100 MHz, CDCl3) δ165.9, 162.3 (d, J = 244.2
Hz), 135.3, 134.0, 133.0, 130.7, 129.9, 129.0 (d, J = 8.0 Hz), 128.5,
125.4, 115.5 (d, J = 21.4 Hz), 60.9, 51.9, 33.8, 29.1, 25.9, 24.7, 23.2; IR
(neat) 2980, 2868, 1726, 1261, 1140, 1093, 1068, 701 cm−1; MS (m/z,
rel intensity) 579 (M+, 3), 474 (5), 439 (4), 351 (17), 229 (16), 136
(10), 109 (48), 105 (100), 81(9), 77 (17); HRMS (EI) calcd for
C37H38FNO4 [M]+ 579.2785, found 579.2793.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Support of this work by grants from the National Sciences
Foundation of China (21072224), the Fundamental Research
■
5189
dx.doi.org/10.1021/jo300667a | J. Org. Chem. 2012, 77, 5184−5190

The Journal of Organic Chemistry
Note
Funds for the Central Universities, and the Research Funds of
Renmin University of China (11XNI003) is gratefully acknowl-
edged.
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