Synthesis of 2,3-Dihydro-1H-azepine and 1H-Azepin-2(3H)-one Derivatives from Intramolecular Condensation between Stable Tertiary Enamides and Aldehydes

Article abstract of DOI:10.1021/acs.joc.5b02021

A new strategy to construct 2,3-dihydro-1H-azepine and 1H-azepin-2(3H)-one heterocyclic rings is reported based on emerging tertiary enamide synthons. Under very mild conditions employing BBr₃ as a Lewis acid catalyst and P₂O₅ as an additive, tertiary enamides that contain a formyl group underwent highly efficient and scalable intramolecular cyclic condensation to afford diverse 2,3-dihydro-1H-azepine and 1H-azepin-2(3H)-one derivatives in 71-96% yields. The reaction proceeded most probably through a nucleophilic addition of enamides to aldehyde, deprotonation, and dehydration cascade. Application of the method in the synthesis of dihydro-azepino[2,1-a]isoindol-5-ones, the core structure of naturally occurring lennoxamine, was also demonstrated.

Full text of DOI:10.1021/acs.joc.5b02021

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Article
Synthesis of 2,3-Dihydro-1H-azepine and 1H-Azepin-2(3H)-
one Derivatives From Intramolecular Condensation
between Stable Tertiary Enamides and Aldehydes
Wenju Zhu, Liang Zhao, and Mei-Xiang Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02021 • Publication Date (Web): 09 Nov 2015
Downloaded from http://pubs.acs.org on November 9, 2015
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Synthesis of 2,3-Dihydro-1H-azepine and 1H-Azepin-2(3H)-one Derivatives
From Intramolecular Condensation between Stable Tertiary Enamides and
Aldehydes
Wenju Zhu, Liang Zhao, Mei-Xiang Wang*
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MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology,
Department of Chemistry, Tsinghua University, Beijing, 100084, China
wangmx@mail.tsinghua.edu.cn
Abstract
A new strategy to construct 2,3-dihydro-1H-azepine and 1H-azepin-2(3H)-one
heterocyclic rings is reported based on emerging tertiary enamide synthons. Under
very mild conditions employing BBr3 as a Lewis acid catalyst and P2O5 as an additive,
tertiary enamides that contain a formyl group underwent highly efficient and scalable
intramolecular cyclic condensation to afford diverse 2,3-dihydro-1H-azepine and
1H-azepin-2(3H)-one derivatives in 71% - 96% yields. The reaction proceeded most
probably through a nucleophilic addition of enamides to aldehyde, deprotonation and
dehydration cascade. Application of the method in the synthesis of
dihydro-azepino[2,1-a]isoindol-5-ones, the core structure of naturally occurring
lennoxamine, was also demonstrated.
Introduction
Azepines and especially their partially saturated structures occur frequently in natural
products and synthetic pharmaceuticals (Figure 1). (-)-Balanol (A), for example, is an
azepane containing metabolite from Verticillium balanoids.1,2 It shows potent
ATP-competitive inhibitory activity3 and has served as a template for the development
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of a number of analogues as antitumor agents.4 (±)-Chilenamine (B)5 and
(±)-lennoxamine (C)6 are among a number of isoindolobenzazepine alkaloids isolated
7
8
from
Chilean
Berberis
species.
On
the
other
hand,
9
10-11-dihydro-5H-dibenzo[b,f]azepine compounds such as imipramine (D) and
chlomipramine (E) are inhibitors of monoamine transporters and are used clinically as
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antidepressant
drugs.7
Recently,
a
series
of
substituted
7,8,9,10,11,11a-hexahydro-5H-azepino[2,1-a]isoindol-5-one derivatives including
compound F have been shown to be novel and potent urotensin-II receptor
antagonists.8,9 Because of the interesting conformational structures and wide
applications in the synthesis of natural products and bioactive compounds of
medicinal significance, studies on the construction of azepines and related structures
have always attracted great attentions of organic and medicinal chemists. To access
the seven-membered heterocyclic derivatives, both cyclization of linear precursors
and ring transformation of a three- to six-membered ring reactant are predominant
synthetic methods.10,11 Among various cyclization methods documented in literature,
formation of a C-N bond through displacement reactions and formation of a
C-C-double bond through olefin metathesis constitute the general and widely used
strategies in synthesis. Despite the use of many pre-functionalized materials in
cyclization reactions, construction of azepines and their derivatives with an N-vinyl
component has not yet been reported.10a
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Figure 1. Representative examples of azepine ring-containing natural products and
synthetic pharmaceuticals.
As the N-vinyl-bearing compounds, tertiary enamides are remarkable and useful
chemical entities because of their easy availability, intriguing stability and
reactivity.12-14 In comparison to conventional enamines, secondary and tertiary
enamides and have long been recognized as chemically stable species because of the
electron-withdrawing effect of N-acyl group. In recent years, secondary enamides
have been shown to act as aza-ene components to undergo aza-ene addition reactions
with reactive enophiles.15 On contrary, no reactions occurred when tertiary enamides
were employed instead of secondary enamides.15 However, based on the cross
conjugation system within the molecules, we proposed a few years ago that the
effective tuning of delocalization of lone pair electrons on nitrogen into the
carbon-carbon double bond would reinvigorate the nucleophilic activity of
enamides.12 In line with this working hypothesis, enaminic reactions of tertiary
enamides have been successfully established towards epoxides,16 carbonyls,17
imines18 and nitriliums,19 providing unique and powerful methods for the synthesis of
diverse compounds including five-,16b,17a,b six-16b,17c,18,19a,b and eight-membered
heterocycles.16a To further explore the synthetic utility of this emerging type of
synthons, we undertook the current study of intramolecular cyclization reaction of
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tertiary enamides with aldehydes, envisioning a novel strategy to construct
seven-membered nitrogenous heterocycles. We report herein a highly efficient
synthesis of 2,3-dihydro-1H-azepine and 1H-azepin-2(3H)-one derivatives. Facile
constructions of ring-fused azepine structures that resemble novel and potent
urotensin-II receptor antagonists F are also demonstrated.
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Results and discussion
We have shown in our previous study that tertiary enamides are able to undergo
intramolecular and intermolecular nucleophilic addition to aldehydes to form
4-hydroxy-1,2,3,4-tetrahydropyridine derivatives.17c It was envisioned that the similar
cyclization reaction of 1a would afford hydroxylated 4,5,6,7-tetrahydro-1H-azipne
compound, a key precursor to balanol analogs.1-4 We thus first scrutinized the reaction
of formyl-substituted tertiary enamide 1a. As expected, tertiary enamide 1a was stable
under ambient conditions. No reaction was observed either in refluxing DCM. The
cyclization reaction took place slowly when a Brønsted acid such as TfOH (30 mol%)
was added. Surprisingly, instead of the addition product 2a, a dehydration compound
3a was obtained as the sole product in 24% yield. A number of Lewis acids were then
screened as catalysts (30 mol %) in order to improve the conversion of reactant, the
selective formation of adduct 2a or dehydration product 3a, and the chemical yield of
product. As listed in Table 1, Lewis acids including iron, nickel, copper, zinc and
indium salts were either catalytically inactive or detrimental to reaction leading to no
product or an inseparable mixture, respectively (entries 4 – 11, Table 1). It should be
noted that the use of FeCl3 as a catalyst resulted in the formation of a ketone product
4a (24% yield) in addition to 3a (18% yield). The former compound is most probably
derived from the hydrolysis of the cyclic iminium intermediate that was generated
directly from enaminic addition of tertiary enamide to aldehyde functional group (vide
infra). While AlCl3 and Et2AlCl were effective to catalyzed the reaction (entries 12
and 13), BCl3 (entry 14, Table 1) and especially BBr3 appeared to be more efficient
catalysts. For example, with the loading of BBr3 decreasing from 30 mol % to 3 mol%
or even 1 mol %, the reaction proceeded rapidly to form 3a in moderate yields.
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Notably, solvent played a crucial role in this BBr3-catalyzed cyclization reaction
(entries 17 and 19 – 21, Table 1). For instance, reaction was accelerated in acetonitrile
giving a good yield of 3a in 0.5 h whereas the reaction was completely inhibited in
THF. It should be noted that in all cases using different Lewis acid catalysts, no
5-hydroxy-2,3,4,5-tetrahydro-1H-azepine 2a was obtained. The outcomes were
completely different from the synthesis of 4-hydroxy-1,2,3,4-tetrahydropyridine
derivatives from analogous intramolecular reaction of tertiary enamides with aldehyde
in which no dehydration reaction.17c To account for the difference, we proposed that
intermediate 2a, due to conformational flexibility of seven-membered N-heterocycles,
would adopt a conformational structure that favors considerably the dehydration
reaction to afford a thermodynamically more stable conjugated diene product 3a.
Since the formation of 3a involved a dehydration step, the released water may
deactivate the Lewis acid catalyst causing incomplete conversion of the substrate. To
circumvent this problem, drying agents were examined (entries 22 – 26, Table 1).
Besides, the use of drying agents may also be beneficial to dehydration reaction.
Pleasingly, the presence of a drying agent including CaCl2 and P2O5 did improve the
chemical yield in general. Finally, we found that a combination of BBr3 (3 mol %)
and P2O5 (20 equiv) in anhydrous DCM at ambient temperature worked optimally for
the transformation of tertiary enamide 1a into 1-benzoyl-7-phenyl-
2,3-dihydro-1H-azepine 3a (entry 27, Table 1).
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Table 1. Development of Lewis Acid Catalyzed Cyclization Reaction of 1a
Entry Catalyst (mol %)
Additive (equiv)
Solvent
DCM
DCM
DCM
t (h)
96
3a (%)b
n.r.c
1
2
3
-
-
-
-
TfOH (30)
FeCl3 (30)
96
24
10
18 + 4a (24)
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d
4
Fe(OTf)3 (30)
NiCl2 (30)
Ni(OTf)2 (30)
CuClO4 (30)
CuOTf (30)
ZnCl2 (30)
Zn(OTf)2 (30)
In(OTf)3 (30)
AlCl3 (30)
Et2AlCl (30)
BCl3 (30)
BBr3 (30)
BBr3 (5)
-
DCM
96
96
96
16
96
96
96
96
96
96
16
1
-
5
-
DCM
n.r.c
n.r.c
16
6
-
DCM
7
-
DCM
8
-
DCM
n.r.c
d
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9
-
DCM
-
10
11
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13
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22
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24
25
26
27
-
DCM
n.r.c
n.r.c
66
41
52
68
52
57
49
47
n.r.c
74
63
78
82
88
83
93
-
DCM
-
DCM
-
DCM
-
DCM
-
DCM
-
DCM
1
BBr3 (3)
-
DCM
1
BBr3 (1)
-
DCM
1
BBr3 (3)
-
Toluene
THF
45
45
0.5
3.5
0.5
3.5
0.5
1
BBr3 (3)
-
BBr3 (3)
-
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DCM
BBr3 (3)
MgSO4 (30)
SiO2 (30)
CaCl2 (30)
P2O5 (30)
P2O5 (10)
P2O5 (20)
BBr3 (3)
BBr3 (3)
BBr3 (3)
BBr3 (3)
BBr3 (3)
1
a A mixture of tertiary enamide 1a (0.3 mmol), catalyst and additive was stirred in dry solvent (15
mL) under argon protection. b Isolated yield. c No reaction. d A inseparable mixture was obtained.
Figure 2. Preparation of substrates 1.
To test the scope of BBr3-catalyzed intramolecular condensation between tertiary
enamides and aldehyde, a number of substrates were prepared from ozonolysis19a of
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the terminal olefin moiety of tertiary enamides S1 that were synthesized according to
a literature method20,21 (Figure 2). The results compiled in Table 2 show clearly that
almost all substrates tested underwent cyclization reaction to furnish
2,3-dihydro-1H-azepine products. Various functional groups were tolerated by the
catalytic system. For example, all N-aroyl-substituted tertiary enamides 1a-g,
irrespective of the electronic nature and the substitution pattern of a substituent on
benzene ring, were transformed efficiently into the corresponding products 3a-g in
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excellent yields (entries
1
–
7, Table 2). N-Benzyloxycarbonyl- and
N-ethoxycarbonyl-bearing tertiary enamide substrates 1h and 1i underwent equally
efficient reaction while the reaction of N-acetyl-containing reactant 1j proceeded
sluggishly (entries 8 – 10, Table 2). In these cases, slightly diminished chemical yields
were obtained due to the formation of a polar and unidentified mixture as by-products.
It is worth noting that the slow reaction rate of 1j reflected low nucleophilicity of
N-acetyl-substituted tertiary enamide. Different reaction velocity of tertiary enamides
is indicative of the tuning effect of N-electron-withdrawing group on the nucleophilic
activity of enamides. On the other hand, enamides having an aryl substituent on the
-position behaved as excellent substrates, and all reactants 1k-p underwent similarly
rapid cyclization reaction to produce high yield of products 3k-p (entries 11 – 16,
Table 2). The catalytic reaction was applicable to tertiary enamide that contains an
-heterocyclic
substituent
as
well.
1-Benzoyl-7-(thiophen-2-yl)-2,3-dihydro-1H-azepine 3q was thus prepared readily in
93% yield (entry 17, Table 2).
Table 2. Catalytic synthesis of 2,3-dihydro-1H-azepine derivatives 3a-q
entry
Ar
R
3 (%)a entry Ar
R
3 (%)a
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1b
2
3
4
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7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3a (93) 10c
3b (92) 11
Ph
Me
3j (74)
3k (92)
3l (82)
3m (82)
3n (94)
3o (91)
3p (94)
3q (93)
4-MeOC6H4
4-MeOC6H4 Ph
3,4-(MeO)2C6H3 3c (95) 12
4-MeC6H4
4-FC6H4
Ph
Ph
Ph
Ph
Ph
Ph
4-O2NC6H4
4-ClC6H4
4-BrC6H4
2-BrC6H4
BnO
3d (96) 13
3e (89) 14
3f (90) 15
3g (95) 16d
3h (79) 17
3i (71)
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4-ClC6H4
4-BrC6H4
2-BrC6H4
2-thienyl
9
EtO
a
Isolated yield. b 3a (1.25 g, 91%) was obtained from a gram-scale reaction of 1a (1.49 g, 5
c
d
mmol). Reaction time was 20 h. 3p (1.19 g, 93%) was obtained from a gram-scale reaction of
1p (1.35 g, 3.63 mmol).
The generality of the catalytic reaction was further demonstrated in the synthesis of
1-benzoyl-6-methyl-7-phenyl-2,3-dihydro-1H-azepine
3r
and
7,8-dihydro-5H-azepino[2,1-a]isoindol-5-one 3s. In comparison to its disubstituted
tertiary enamide analog 1a, the trisubstituted tertiary enamide 1r is less reactive.
Nevertheless, in refluxing DCM it was converted smoothly into product 3s in 12 h. In
the case of isoindolin-1-one-derivred enamide 1s, BBr3-catalyzed cyclization under
very mild conditions provided efficiently a straightforward route to fused heterocyclic
ring product 3s, a compound that resembles the core structure of naturally occurring
lennoxamine (Figure 3).
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Figure 3. Synthesis of 3r and 3s.
Figure 4. Preparation of substrates 5.
Following the successful synthesis of various 2,3-dihydro-1H-azepine derivatives 3,
we then attempted the construction of 1H-azepin-2(3H)-one structure by means of
BBr3-catalyzed cyclic condensation reaction of tertiary enamides 5 (Table 3). The
reactants 5 were readily obtained following the reported procedure19a,20,21 depicted in
Figure 4. The shift of the carbonyl moiety of enamide from exo- to endo-position
leads to marginal variation of nucleophilic reactivity. Enaminic addition of enamides
to aldehyde proceeded equally well with tertiary enamides to form intermediates 6.
Although intermediates 6 were not stable and they underwent spontaneous
dehydration reaction to form conjugated diene products 7, in some cases the
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consequent dehydration reaction of 6 appeared slower than that of 2. For example, the
intermediate 2 was never isolated from the reaction of 1. In contrast, under the
identical catalytic conditions, the intramolecular adduct 6b was obtained in 44% yield
along with the formation 7b in 49% yield when the reaction was quenched within 20
min (cf. Experimental Section). Elongated reaction time (3 – 5 h) led to the production
of 7 as the sole products in good yields (entries 1 – 3, Table 3). Intriguingly, tertiary
enamides 5e and 5f underwent very efficient nucleophilic addition and the
consecutive dehydration reaction, furnishing the corresponding products 7e and 7f in
excellent yields.
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Table 3. Synthesis of 1H-azepin-2(3H)-one derivatives 7a-f
entry
Ar
R
t (h)
5
7 (%)a
1
Ph
Bn
7a (85)
7b (88)
7c (87)
7e (84)
7e (94)
7f (94.5)
2
Ph
4-BrC6H4CH2
5
3
Ph
4-MeOC6H4CH2
3
4
4-MeOC6H4
Ph
Me
Me
Me
4
5
1
6
4-ClC6H4
1
a Isolated yield.
Structures of all 2,3-dihydro-1H-azepine and 1H-azepin-2(3H)-one products 3 and 7
were established on the basis of their spectroscopic data. To put the structures beyond
any ambiguity, high quality single crystals of 3a and 7b were obtained from
recrystalization and their X-ray molecular structures were determined (Figures 5 and
1
6). The variable temperature H NMR spectra of these seven-membered nitrogenous
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heterocycles are especially worth addressing. As illustrated in Figures 7 and 8, either
5
6
o
compounds 3 and 7 did not give a complete set of proton signals below 60 C. For
7
8
9
instance, one of the methylenes within heterocycle of 3a (H-6) exhibited a broad peak
at ca. 2.7 ppm while the other (H-7) showed no proton signal (Figure 7). In the case of
7b, the methylene within the ring (H-3) gave a very broad peak at ca. 3.0 ppm. No
resonance signals corresponding to the methylene of benzyl group (H-8) was
observed (Figure 8). The 1H NMR spectra measured at the temperature lower than 60
oC indicated the existence of a mixture of conformers which undergo very slow
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1
inter-conversions in relative to H NMR time scale due to the rigidity of partially
o
saturated medium-sized heterocycles. Upon heating to 150 C in DMSO-d6, the
broadened and unobservable proton signals emerged and all peaks became
well-resolved because of the acceleration of inter-conversion of various conformers
(Figures 7 and 8).
Figure 5. X-ray molecular structure of 3a. The molecular structure is depicted in an
ellipsoid style at 50% probability level.
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Figure 6. X-ray molecular structure of 7b. The molecular structure is depicted in an
ellipsoid style at 50% probability level.
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Figure 7. Variable temperature H NMR spectra of 3a. The signals at ca. 2.5 are
protons of DMSO.
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Figure 8. Variable temperature H NMR spectra of 7b. The signals at ca. 2.5 are
protons of DMSO.
The outcomes of the BBr3-catalyzed cyclization of tertiary enamides 1 or 5 suggest a
nucleophilic addition of enamides to aldehyde, deprotonation and dehydration cascade
as delineated in Figure 9. It is important to address that the use of a Lewis acid
catalyst with a single coordination site is imperative. The enamide substrates 1 and 5
can actually act as a bidentate or tridentate ligand to interact with transition metals.
Competitive formation of stable chelating complexes with Lewis acids would
therefore inhibit the designed enaminic reaction. It is also interesting to note that due
to some subtle conformational differences between intermediates 2 and 6, the former
undergo very fast dehydration reaction to afford directly the intramolecular
condensation products 3. In the case of the later intermediate, however, dehydration
reaction proceeds relatively slowly, allowing the isolation and characterization of 6b.
The heterocyclic iminium intermediates B or B’ is also susceptible to nucleophilic
agents because of its high electrophilic nature. The interception of B by water prior to
deprotonation step results in the generation of ketone compound 4a.
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Figure 9. Plausible reaction mechanism.
The catalytic construction of 2,3-dihydro-1H-azepine and 1H-azepin-2(3H)-one
structures from tertiary enamides is efficient and practically useful. The method can
be easily scaled up to a gram scale. In the gram-scale synthesis, we were delighted to
find out that more than a gram of the products 3a (1.25 g, 91%) or 3p (1.19 g, 93%)
were prepared in 1 h starting from tertiary enamides 1a (5 mmol) or 1p (3.63 mmol)
(entries 1 and 10, Table 2). The acquired 2,3-dihydro-1H-azepine and
1H-azepin-2(3H)-one derivatives are valuable in organic synthesis because they
contain multiple transformable functional groups. Just to demonstrate their synthetic
applications, we conducted the intramolecular Heck reaction of 3g following a
well-established procedure.22 Interestingly, despite several possible cross-coupling
reaction pathways, compound 3g underwent intramolecular coupling reaction between
bromobenzene moiety and the -carbon of tertiary enamide with concomitant shift of
diene bonds to generate 11a-phenyl-7,11a-dihydro-5H-azepino[2,1-a]isoindol-5-one 8
(Scheme 1), a fused heterocyclic compound that is hard to prepare by other means.
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Scheme 1. Synthesis of 8 and its X-ray molecular structure. The molecular structure
of 8 is depicted in an ellipsoid style at 50% probability level.
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Conclusion
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In summary, we have established a new synthetic strategy to construct
2,3-dihydro-1H-azepine and 1H-azepin-2(3H)-one heterocyclic rings. Under very
mild conditions employing BBr3 as a Lewis acid catalyst and P2O5 as an additive,
tertiary enamides underwent efficient and scalable intramolecular cyclic condensation
to afford various 2,3-dihydro-1H-azepine and 1H-azepin-2(3H)-one derivatives in
high yields. The reaction proceeds through a cascade involving nucleophilic addition
of enamides to aldehyde, deprotonation and dehydration. The study along with our
previous ones has demonstrated that tertiary enamides are powerful and versatile
synthons in organic synthesis. Successful exploration of the reactions of stable tertiary
enamides has provided unique and convenient routes to a variety of diverse five- to
eight-membered heterocyclic compounds that are difficult to prepare using other
means. The tandem reactions of tertiary enamides in the synthesis of complex
alkaloids and analogs are being actively pursued in this laboratory and the results will
be reported in due course.
Experimental Section
General procedure for the preparation of 1.19a,20,21
Step 1. The synthesis of secondary enamides was carried out following a literature
method.20 Under N2 protection, methylmagnesium bromide (20 mL, 3.0M in ether, 60
mmol) was added to nitrile (60 mmol). After refluxing for 6 h, the mixture was cooled
down to room temperature and ether (60 mL) was added. After cooling down to 0 oC,
acyl chloride (60 mmol) was added dropwise. The resulting mixture was refluxed for
1 h. After solvent was evaporated in vacuo and the residue was mixed with ethanol
(60 mL) and refluxed for another 1 h. Solvent was removed in vacuo and the residue
was mixed with water (100 mL) and EtOAc (100 mL) and then extracted with EtOAc
(3×60 mL). The combined organic phase was washed with water (30 mL), brine (30
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mL), dried with anhydrous MgSO4. The solvent was evaporated in vacuo and the
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residue was chromatographed on a silica gel column to afford products SS1.
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Step 2. Alkylation of secondary enamides was conducted following a reported
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procedure.21 To a solution of SS1 (10 mmol) in DMF (50 mL) at 0 C under argon
protection was added NaH (600 mg, 60% in mineral oil, 15 mmol). After being stirred
for 0.5 h, a solution of 5-bromopent-1-ene (12 mmol) in DMF (5 mL) was added
dropwise, and the resulting mixture was kept stirring for another 5 h. The mixture was
poured into ice-cold water (60 mL) and EtOAc (40 mL), and extracted with EtOAc
(3×50 mL). The combined organic phase was washed with water (5×30 mL), brine
(30 mL), dried with anhydrous MgSO4. The solvent was evaporated in vacuo and the
residue was chromatographed on a silica gel column to give products S1.
Step 3. Oxidation of alkene into aldehyde was realized using a known method.19a
To a mixture of S1 (6 mmol), 1,4-dioxane (40 mL) and water (20 mL) was added an
aqueous solution of N-methylmorpholine-N-oxide (4.0 mL, 50% w/w) and OsO4 (0.5
mL, 1% in water). After the mixture was stirred for 12 h, NaIO4 (2.56 g, 12 mmol)
was added. The reaction mixture was kept stirring at room temperature for 1 h before
quenching with a saturated thiosulfate solution. The mixture was then extracted with
EtOAc (3×50 mL). The combined organic phase was washed with saturated
thiosulfate solution (3×30 mL), brine (30 mL), dried with anhydrous MgSO4. The
solvent was evaporated in vacuo and the residue was purified by flash silica gel
chromatography to afford the product. All substrates 1 were characterized by means of
spectroscopic data.
N-(4-Oxobutyl)-N-(1-phenylvinyl)benzamide 1a (1.3 g, 68% yield): white solid,
o
1
mp. 92-93 C; Rf = 0.23 (EtOAc / petroleum ether = 1 / 4); H NMR (400 MHz,
CDCl3) δ 9.76 (d, J = 1.0 Hz, 1H), 7.50 – 7.47 (m, 4H), 7.41 – 7.36 (m, 3H), 7.32 –
7.26 (m, 1H), 7.23 – 7.20 (m, 1H), 5.39 (s, 1H), 4.82 (s, 1H), 3.65 (s, 2H), 2.52 (t, J =
13
8 Hz, 2H), 2.02 – 1.94 (m, 2H); C NMR (100 MHz, CDCl3) δ 201.5, 171.4, 147.1,
135.9, 135.8, 130.0, 129.0, 128.9, 127.8, 127.6, 126.3, 114.1, 46.2, 41.1, 20.0; IR
(KBr, cm−1) ν 1717, 1636. HRMS (ESI-ion trap) Calcd for C19H19NO2 (M + Na)+:
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316.1308. Found: 316.1311.
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4-Methoxy-N-(4-oxobutyl)-N-(1-phenylvinyl)benzamide 1b (1.16 g, 64% yield
from 5.6 mmol of S1b): pale yellow oil; Rf = 0.14 (EtOAc / petroleum ether = 1 / 3);
1H NMR (400 MHz, CDCl3) δ 9.76 (d, J = 1.3 Hz, 1H), 7.51 – 7.48 (m, 4H), 7.40 –
7.38 (m, 3H), 6.73 – 6.71 (m, 2H), 5.40 (s, 1H), 4.81 (s, 1H), 3.76 (s, 3H), 3.61 (s,
2H), 2.50 (t, J = 8 Hz, 2H), 2.00 – 1.94 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 201.6,
171.0, 160.9, 147.5, 135.9, 129.8, 129.1, 128.9, 127.8, 126.3, 113.8, 113.0, 55.2, 46.3,
41.2, 20.0; IR (KBr, cm−1) ν 1721, 1638, 1607. HRMS (ESI-ion trap) Calcd for
C20H21NO3 (M + Na)+: 346.1414. Found: 346.1408.
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3,4-Dimethoxy-N-(4-oxobutyl)-N-(1-phenylvinyl)benzamide 1c (380 mg, 47%
o
yield from 2.28 mmol of S1c): white solid, mp. 86-87 C; Rf = 0.25 (EtOAc /
1
petroleum ether = 1 / 2); H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 7.51 – 7.49 (m,
2H), 7.40 – 7.34 (m, 3H), 7.14 (d, J = 8.3 Hz, 1H), 7.07 (s, 1H), 6.68 (d, J = 8.4 Hz,
1H), 5.42 (s, 1H), 4.85 (s, 1H), 3.82 (s, 3H), 3.65 (s, 3H), 3.63 (br, 2H), 2.51 (t, J =
7.4 Hz, 2H), 2.03 – 1.96 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 201.5, 171.0, 150.5,
148.0, 147.4, 135.8, 129.0, 128.9, 127.9, 126.2, 121.1, 113.7, 111.3, 109.8, 55.8, 55.6,
46.5, 41.2, 20.0; IR (KBr, cm−1) ν 1720, 1633. HRMS (ESI-ion trap) Calcd for
C21H23NO4 (M + Na)+: 376.1519. Found: 376.1515.
4-Nitro-N-(4-oxobutyl)-N-(1-phenylvinyl)benzamide 1d (436 mg, 58% yield
o
from 2.22 mmol of S1d): yellow solid, mp. 89-90 C; Rf = 0.12 (EtOAc / petroleum
ether = 1 / 3); 1H NMR (400 MHz, CDCl3) δ 9.76 (d, J = 1.1 Hz, 1H), 8.04 (d, J = 8.0
Hz, 2H), 7.60 (d, J = 7.7 Hz, 2H), 7.42 – 7.36 (m, 5H), 5.43 (s, 1H), 4.87 (s, 1H), 3.67
(t, J = 7.1 Hz, 2H), 2.53 (t, J = 7.3 Hz, 2H), 2.01 – 1.94 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 201.1, 169.1, 148.2, 146.5, 141.9, 135.1, 129.4, 129.0, 128.3, 126.0, 123.0,
114.6, 46.4, 41.0, 19.8; IR (KBr, cm−1) ν 1721, 1644, 1602, 1519. HRMS (ESI-ion
trap) Calcd for C19H18N2O4 (M + Na)+: 361.1159. Found: 361.1150.
4-Chloro-N-(4-oxobutyl)-N-(1-phenylvinyl)benzamide 1e (1.12 g, 66% yield
from 5.2 mmol of S1e): pale yellow oil; Rf = 0.12 (EtOAc / petroleum ether = 1 / 4);
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1H NMR (400 MHz, CDCl3) δ 9.76 (d, J = 0.9 Hz, 1H), 7.46 – 7.36 (m, 7H), 7.19 –
7.17 (m, 2H), 5.41 (s, 1H), 4.83 (s, 1H), 3.63 (s, 2H), 2.50 (t, J = 7.4 Hz, 2H), 1.97 (t,
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J = 7.1 Hz, 2H); C NMR (100 MHz, CDCl3) δ 201.3, 170.3, 147.0, 136.0, 135.5,
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134.1, 129.2, 129.1, 129.0, 128.0, 126.2, 114.2, 46.4, 41.1, 19.9; IR (KBr, cm−1) ν
1723, 1643, 1596. HRMS (ESI-ion trap) Calcd for C19H18NO2Cl (M + Na)+: 350.0918.
Found: 350.0917.
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4-Bromo-N-(4-oxobutyl)-N-(1-phenylvinyl)benzamide 1f (410 mg, 68% yield
from 1.64 mmol of S1f): pale yellow oil; Rf = 0.2 (EtOAc / petroleum ether = 1 / 3);
1H NMR (400 MHz, CDCl3) δ 9.77 (s, 1H), 7.49 – 7.45 (m, 2H), 7.41 – 7.39 (m, 3H),
7.36 (s, 4H), 5.42 (s, 1H), 4.83 (s, 1H), 3.64 (s, 2H), 2.51 (t, J = 7.4 Hz, 2H), 1.99 –
1.95 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 201.4, 170.4, 147.0, 135.5, 134.7, 131.1,
129.3, 129.0, 126.3, 124.5, 114.4, 46.4, 41.2, 20.0; IR (KBr, cm−1) ν 1722, 1641, 1399.
HRMS (ESI-ion trap) Calcd for C19H18BrNO2 (M + Na)+: 394.0413. Found: 394.0412.
2-Bromo-N-(4-oxobutyl)-N-(1-phenylvinyl)benzamide 1g (1.78 g, 68% yield
o
from 7.0 mmol of S1g): white solid, mp. 84-85 C; Rf = 0.19 (EtOAc / petroleum
ether = 1 / 3); 1H NMR (400 MHz, CDCl3, 60 oC) δ 9.77 (s, 1H), 7.43 (d, J = 7.5 Hz,
1H), 7.30 (s, 5H), 7.02 (s, 3H), 5.33 (s, 1H), 5.27 (s, 1H), 3.72 (s, 2H), 2.57 (t, J = 6.8
Hz, 2H), 2.02 (t, J = 6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 201.3, 169.0, 145.5,
138.3, 135.3, 132.5, 129.8, 128.9, 128.6, 126.7, 126.3, 125.8, 120.3, 113.3, 45.2, 40.8,
20.0; IR (KBr, cm−1) ν 1720, 1644, 1627, 1402. HRMS (ESI-ion trap) Calcd for
C19H18NBrO2 (M + Na)+: 394.0413. Found: 394.0405.
Benzyl (4-oxobutyl)(1-phenylvinyl)carbamate 1h (660 mg, 44% yield from 4.6
mmol of S1h): white solid, mp. 95-96 oC; Rf = 0.67 (EtOAc / petroleum ether = 1 / 3);
o
1H NMR (400 MHz, CDCl3, 60 C) δ 9.72 (s, 1H), 7.33 – 7.29 (m, 5H), 7.24 (d, J =
2.9 Hz, 3H), 7.11 (s, 2H), 5.55 (s, 1H), 5.18 (s, 1H), 5.08 (s, 2H), 3.52 (t, J = 7.3 Hz,
13
2H), 2.45 (t, J = 7.3 Hz, 2H), 1.96 – 1.92 (m, 2H); C NMR (100 MHz, CDCl3) δ
201.1, 155.4, 145.7, 136.6, 136.1, 135.8, 128.3, 127.6, 127.3, 125.5, 111.8, 67.0, 47.9,
40.6, 20.7; IR (KBr, cm−1) ν 1703, 1629. HRMS (ESI-ion trap) Calcd for C20H21NO3
(M + Na)+: 346.1414. Found: 346.1412.
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Ethyl (4-oxobutyl)(1-phenylvinyl)carbamate 1i (231 mg, 77% yield from 1.15
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mmol of S1i): pale yellow oil; Rf = 0.67 (EtOAc / petroleum ether = 1 / 3); H NMR
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(400 MHz, CDCl3, 60 C) δ 9.77 (d, J = 1.36 Hz, 1H), 7.36 – 7.30 (m, 5H), 5.54 (s,
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1H), 5.18 (s, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.51 (t, J = 6.8 Hz, 2H), 2.50 – 2.46 (m,
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2H), 1.99 – 1.92 (m, 2H), 1.10 (t, J = 7.1 Hz, 3H); C NMR (100 MHz, CDCl3) δ
201.2, 155.6, 145.8, 136.7, 128.3, 125.5, 111.6, 61.3, 47.6, 40.7, 20.7, 14.1; IR (KBr,
cm−1) ν 1701, 1629. HRMS (ESI-ion trap) Calcd for C18H21NO3 (M + Na)+: 322.1414.
Found: 322.1411.
N-(4-Oxobutyl)-N-(1-phenylvinyl)acetamide 1j (1.54g, 61% yield from 10.9
mmol of S1j): pale yellow oil; Rf = 0.26 (EtOAc / petroleum ether = 1 / 1); 1H NMR
(400 MHz, CDCl3) δ 9.68 (d, J = 1.2 Hz, 1H), 7.34 – 7.32 (m, 5H), 5.72 (s, 1H), 5.17
(s, 1H), 3.40 (t, J = 7.3 Hz, 2H), 2.41 (t, J = 7.4 Hz, 2H), 2.01 (s, 3H), 1.85 – 1.80 (m,
13
2H); C NMR (100 MHz, CDCl3) δ 201.3, 170.7, 146.6, 134.9, 129.1, 128.8, 125.6,
113.8, 45.0, 40.9, 21.8, 20.2; IR (KBr, cm−1) ν 1723, 1658, 1630, 1396. HRMS
(ESI-ion trap) Calcd for C14H17NO2 (M + Na)+: 254.1152; Found: 254.1147.
N-(1-(4-Methoxyphenyl)vinyl)-N-(4-oxobutyl)benzamide 1k (1.09 g, 71% yield
o
from 4.76 mmol of S1k): white solid, mp. 95-96 C; Rf = 0.11 (EtOAc / petroleum
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ether = 1 / 4); H NMR (400 MHz, CDCl3) 9.77 (d, J = 1.4 Hz, 1H), 7.51 – 7.49 (m,
2H), 7.43 – 7.41 (m, 2H), 7.31 – 7.22 (m, 3H), 6.94 – 6.91 (m, 2H), 5.28 (s, 1H), 4.72
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(s, 1H), 3.85 (s, 3H), 3.65 (s, 2H), 2.52 (t, J = 7.3 Hz, 2H), 2.06 – 1.96 (m, 2H); C
NMR (100 MHz, CDCl3) δ 201.6, 171.4, 160.3, 146.6, 135.9, 129.9, 128.1, 127.8,
127.7, 127.5, 114.2, 112.5, 55.3, 46.1, 41.2, 20.0; IR (KBr, cm−1) ν 1723, 1638, 1605.
HRMS (ESI-ion trap) Calcd for C20H21NO3 (M + Na)+: 346.1414. Found: 346.1405.
N-(4-Oxobutyl)-N-(1-(p-tolyl)vinyl)benzamide 1l (1.19 g, 64.5% yield from 6.0
mmol of S1l): pale yellow oil；Rf = 0.19 (EtOAc / petroleum ether = 1 / 3); 1H NMR
(400 MHz, CDCl3) δ 9.76 (d, J = 1.4 Hz, 1H), 7.51 – 7.49 (m, 2H), 7.37 (d, J = 8.0 Hz,
2H), 7.29 – 7.26 (m, 1H), 7.21 (t, J = 7.3 Hz, 4H), 5.34 (s, 1H), 4.75 (s, 1H), 3.63 (s,
2H), 2.50 (t, J = 7.4 Hz, 2H), 2.38 (s, 3H), 1.98 – 1.94 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 201.5, 171.4, 146.8, 139.2, 135.8, 132.8, 129.9, 129.6, 127.7, 127.5, 126.2,
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113.5, 46.0, 41.1, 21.2, 20.0; IR (KBr, cm−1) ν 1722, 1642, 1395. HRMS (ESI-ion
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trap) Calcd for C20H21NO2 (M + Na)+: 330.1465. Found: 330.1459.
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N-(1-(4-Fluorophenyl)vinyl)-N-(4-oxobutyl)benzamide 1m (390 mg, 65% yield
from 1.94 mmol of S1m): colorless oil; Rf = 0.11 (EtOAc / petroleum ether = 1 / 4);
1H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 7.47 – 7.41 (m, 4H), 7.32 – 7.28 (m, 1H),
7.22 (t, J = 7.8 Hz, 2H), 7.06 (t, J = 8.7 Hz, 2H), 5.32 (s, 1H), 4.84 (s, 1H), 3.65 (t, J =
6.9 Hz, 2H), 2.52 (t, J = 7.3 Hz, 2H), 2.02 – 1.95 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 201.3, 171.3, 164.2, 161.7, 146.2, 135.7, 132.0, 132.0, 129.9, 128.0, 128.0,
127.7, 127.4, 115.9, 115.6, 113.5, 46.3, 41.0, 20.0; 19F NMR (376 MHz, CDCl3) δ
-111.9; IR (KBr, cm−1) ν 1722, 1644, 1601, 1507, 1391. HRMS (ESI-ion trap) Calcd
for C19H18NO2F (M + Na)+: 334.1214. Found: 334.1207.
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N-(1-(4-Chlorophenyl)vinyl)-N-(4-oxobutyl)benzamide 1n (994 mg, 62% yield
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from 4.9 mmol of S1n): colorless oil; Rf = 0.2 (EtOAc / petroleum ether = 1 / 3); H
NMR (400 MHz, CDCl3) δ 9.77 (s, 1H), 7.44 (d, J = 7.3 Hz, 2H), 7.39 – 7.28 (m, 5H),
7.22 (t, J = 7.8 Hz, 2H), 5.37 (s, 1H), 4.86 (s, 1H), 3.63 (t, J = 6.8 Hz, 2H), 2.52 (t, J =
13
7.4, 2H), 2.01 – 1.93 (m, 2H); C NMR (100 MHz, CDCl3) δ 201.3, 171.4, 146.3,
135.7, 135.0, 134.5, 130.1, 129.1, 127.9, 127.5, 127.5, 114.3, 46.4, 41.1, 20.0; IR
(KBr, cm−1) ν 1722, 1645, 1392. HRMS (ESI-ion trap) Calcd for C19H18NO2Cl (M +
Na)+: 350.0918. Found: 350.0912.
N-(1-(4-Bromophenyl)vinyl)-N-(4-oxobutyl)benzamide 1o (944 mg,72.5% yield
from 3.5 mmol of S1o): colorless oil; Rf = 0.29 (EtOAc / petroleum ether = 1 / 2); 1H
NMR (400 MHz, CDCl3) δ 9.77 (d, J = 1.2 Hz, 1H), 7.52 – 7.49 (m, 2H), 7.45 – 7.43
(m, 2H), 7.34 – 7.29 (m, 3H), 7.24 – 7.21 (m, 2H), 5.39 (s, 1H), 4.86 (s, 1H), 3.63 (s,
2H), 2.52 (td, J = 7.3, 1.36 Hz, 2H), 2.01 – 1.94 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 201.3, 171.4, 146.3, 135.6, 134.9, 132.0, 130.1, 127.9, 127.8, 127.5, 123.2, 114.4,
46.4, 41.1, 20.0; IR (KBr, cm−1) ν 1721, 1644, 1391. HRMS (ESI-ion trap) Calcd for
C19H18BrNO2 (M + Na)+: 394.0413. Found: 394.0405.
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N-(1-(2-Bromophenyl)vinyl)-N-(4-oxobutyl)benzamide 1p (1.39 g, 63% yield
from 5.94 mmol of S1p): pale yellow oil; Rf = 0.26 (EtOAc / petroleum ether = 1 / 3);
1H NMR (400 MHz, CDCl3) δ 9.80 (s, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.38 (dd, J = 8.2,
1.3 Hz, 2H), 7.27 – 7.24 (m, 1H), 7.21 – 7.17 (m, 2H), 7.12 – 7.00 (m, 3H), 5.26 (s,
1H), 5.16 (s, 1H), 3.76 (t, J = 7.3 Hz, 2H), 2.57 (d, J = 7.3 Hz, 2H), 2.14 – 2.07 (m,
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2H); C NMR (100 MHz, CDCl3) δ 201.5, 171.0, 147.2, 138.0, 136.7, 133.7, 131.0,
129.8, 129.4, 127.9, 127.4, 127.2, 121.5, 113.6, 49.4, 41.3, 21.0; IR (KBr, cm−1) ν
1722, 1650, 1615, 1386. HRMS (ESI-ion trap) Calcd for C19H18NO2Br (M + Na)+:
394.0413. Found: 394.0408.
N-(4-Oxobutyl)-N-(1-(thiophen-2-yl)vinyl)benzamide 1q (1.21 g, 62% yield
from 6.5 mmol of S1q): yellow solid, mp. 109-110 oC; Rf = 0.19 (EtOAc / petroleum
ether = 1 / 3); 1H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 7.50 – 7.48 (m, 2H), 7.31 –
7.28 (m, 1H), 7.26 – 7.20 (m, 3H), 7.12 – 7.11 (m, 1H), 7.00 – 6.98 (m, 1H), 5.33 (s,
13
1H), 4.75 (s, 1H), 3.71 (s, 2H), 2.52 (t, J = 7.4 Hz, 2H), 2.03 – 1.97 (m, 2H); C
NMR (100 MHz, CDCl3) δ 201.4, 171.1, 141.6, 140.9, 135.7, 130.0, 127.8, 127.7,
127.4, 126.4, 125.8, 113.6, 46.6, 41.1, 20.2; IR (KBr, cm−1) ν 1718, 1634. HRMS
(ESI-ion trap) Calcd for C17H17NO2S (M+Na)+: 322.0872. Found: 322.0865.
(E)-N-(4-Oxobutyl)-N-(1-phenylprop-1-en-1-yl)benzamide 1r (277 mg, 60%
yield from 1.5 mmol of S1r): colorless oil; Rf = 0.19 (EtOAc / petroleum ether = 1 / 3);
o
1H NMR (400 MHz, CDCl3, 60 C) δ 9.74 (s, 1H), 7.56 – 7.54 (m, 2H), 7.48 (d, J =
7.8 Hz, 2H), 7.41 – 7.37 (m, 2H), 7.34 – 7.28 (m, 2H), 7.18 (t, J = 7.7 Hz, 2H), 5.85
(q, J = 7.1 Hz, 1H), 4.12 – 4.04 (m, 1H), 3.11 – 3.04 (m, 1H), 2.49 – 2.37 (m, 2H),
13
2.08 – 2.02 (m, 1H), 1.92 – 1.84 (m, 1H), 1.45 (d, J = 7.1 Hz, 1H); C NMR (100
MHz, CDCl3) δ 201.4, 171.0, 140.2, 136.5, 135.7, 130.2, 128.9, 128.3, 127.5, 126.0,
122.8, 46.5, 41.5, 19.9, 14.5; IR (KBr, cm−1) ν 1722, 1637, 1446, 1399. HRMS
(ESI-ion trap) Calcd for C20H21NO2 (M + Na)+: 330.1465. Found: 330.1459.
4-(1-Methylene-3-oxoisoindolin-2-yl)butanal 1s (746 mg, 53% yield from 6.5
1
mmol of S1s): pale yellow oil; Rf = 0.16 (EtOAc / petroleum ether = 1 / 3); H NMR
(400 MHz, CDCl3) δ 9.76 (d, J = 0.8 Hz, 1H), 7.78 (d, J = 7.3 Hz, 1H), 7.66 (d, J =
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7.6 Hz, 1H), 7.55 (t, J = 7.3 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 5.20 (d, J = 1.8 Hz, 1H),
4.93 (d, J = 1.8 Hz, 1H), 3.79 (t, J = 7.0 Hz, 2H), 2.54 (t, J = 7.0 Hz, 2H), 2.03 – 1.94
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 201.2, 167.1, 141.4, 136.1, 131.9, 129.4,
129.0, 122.9, 119.8, 89.0, 40.8, 38.2, 20.5; IR (KBr, cm−1) ν 1705, 1644, 1395. HRMS
(ESI-ion trap) Calcd for C13H13NO2 (M + Na)+: 238.0839. Found: 238.0838.
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Preparation of substrates 5. The aformentioned procedures for the synthesis of
substrates 1 were followed for the preparation of 5.19a,20,21
N-Benzyl-4-oxo-N-(1-phenylvinyl)butanamide 5a (840 mg, 70% yield from 4.1
o
mmol of S5a): yellow solid, mp. 48-49 C; Rf = 0.59 (EtOAc / petroleum ether = 1 /
1); 1H NMR (400 MHz, CDCl3) δ 9.83 (s, 1H), 7.48 – 7.47 (m, 2H), 7.44 – 7.38 (m,
3H), 7.28 – 7.25 (m, 5H), 5.67 (s, 1H), 4.96 (s, 1H), 4.66 (s, 2H), 2.81 (t, J = 6.3 Hz,
2H), 2.68 (t, J = 6.3 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 200.9, 171.5, 145.7,
137.4, 135.1, 129.2, 128.9, 128.9, 128.3, 127.3, 125.9, 115.0, 50.1, 39.0, 26.5; IR
(KBr, cm−1) ν 1708, 1646, 1402. HRMS (ESI-ion trap) Calcd for C19H19NO2 (M +
Na)+: 316.1308. Found: 316.1308.
N-(4-Bromobenzyl)-4-oxo-N-(1-phenylvinyl)butanamide 5b (940 mg, 65% yield
o
from 3.86 mmol of S5b): yellow solid, mp. 85-86 C; Rf = 0.59 (EtOAc / petroleum
ether = 1 / 1); 1H NMR (400 MHz, CDCl3) δ 9.82 (d, J = 0.6 Hz, 1H), 7.46 – 7.38 (m,
7H), 7.11 (d, J = 7.2 Hz, 2H), 5.67 (s, 1H), 4.94 (s, 1H), 4.57 (s, 2H), 2.81 (t, J = 6.3
Hz, 2H), 2.66 (t, J = 6.1 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 200.8, 171.5, 145.5,
136.3, 134.8, 131.3, 130.6, 129.2, 128.9, 125.8, 121.2, 115.0, 49.3, 38.9, 26.3; IR
(KBr, cm−1) ν 1710, 1654, 1630, 1423. HRMS (ESI-ion trap) Calcd for C19H18NO2 Br
(M + Na)+: 394.0413. Found: 394.0405.
N-(4-Methoxybenzyl)-4-oxo-N-(1-phenylvinyl)butanamide 5c (780 mg, 78%
yield from 3.1 mmol of S5c): white solid, mp. 80-81 oC; Rf = 0.19 (EtOAc / petroleum
1
ether = 1 / 3); H NMR (400 MHz, CDCl3) δ 9.83 (s, 1H), 7.46 – 7.39 (m, 5H), 7.16
(d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.3 Hz, 2H), 5.67 (s, 1H), 4.92 (s, 1H), 4.58 (s, 2H),
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3.78 (d, J = 0.9 Hz, 3H), 2.80 (t, J = 6.4 Hz, 2H), 2.65 (t, J = 6.4 Hz, 2H); C NMR
(100 MHz, CDCl3) δ 201.0, 171.3, 158.9, 145.7, 135.3, 130.3, 130.0, 129.2, 129.0,
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125.9, 114.9, 113.6, 55.2, 49.5, 39.1, 26.6; IR (KBr, cm−1) ν 1709, 1651. HRMS
(ESI-ion trap) Calcd for C20H21NO3 (M + Na)+: 346.1414. Found: 346.1413.
4-((1-(4-Methoxyphenyl)vinyl)(methyl)amino)butanal 5d (669 mg, 69% yield
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from 4.28 mmol of S5d): white solid, mp. 74-75 C; Rf = 0.11 (EtOAc / petroleum
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ether = 1 / 2); H NMR (400 MHz, CDCl3) δ 9.58 (s, 1H), 7.21 (d, J = 8.7 Hz, 2H),
6.73 (d, J = 8.8 Hz, 2H), 5.44 (s, 1H), 4.99 (s, 1H), 3.61 (s, 3H), 2.88 (s, 3H), 2.54 (t,
J = 6.1 Hz, 2H), 2.43 (t, J = 5.9 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 200.5, 170.9,
159.9, 147.2, 127.1, 126.6, 113.8, 110.2, 54.7, 38.4, 34.9, 25.8; IR (KBr, cm−1) ν 1709,
1648. HRMS (ESI-ion trap) Calcd for C14H17NO3 (M + Na)+: 270.1101. Found:
270.1098.
N-Methyl-4-oxo-N-(1-phenylvinyl)butanamide 5e (734 mg, 68% yield from 5.0
1
mmol of S5e): pale yellow oil; Rf = 0.19 (EtOAc / petroleum ether = 1 / 2); H NMR
(400 MHz, CDCl3) δ 9.71 (s, 1H), 7.39 (d, J = 7.8 Hz, 2H),7.35 – 7.29 (m, 3H), 5.68
(s, 1H), 5.24 (s, 1H), 3.02 (s, 3H), 2.68 (t, J = 6.3 Hz, 2H), 2.54 (t, J = 6.4 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 200.8, 171.3, 147.9, 134.9, 129.0, 128.7, 125.4, 112.6,
38.8, 35.3, 26.1; IR (KBr, cm−1) ν 1718, 1658, 1387. HRMS (ESI-ion trap) Calcd for
C13H15NO2 (M + Na)+: 240.0995. Found: 240.0993.
4-((1-(4-Chlorophenyl)vinyl)(methyl)amino)butanal 5f (313 mg, 73 % yield from
1
1.8 mmol of S5f): pale yellow oil; Rf = 0.11 (EtOAc / petroleum ether = 1 / 2); H
NMR (400 MHz, CDCl3) δ 9.69 (s, 1H), 7.32 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 8.7 Hz,
2H), 5.65 (s, 1H), 5.23 (s, 1H), 2.97 (s, 3H), 2.68 (t, J = 5.1, 2H), 2.50 (d, J = 5.8 Hz,
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2H); C NMR (100 MHz, CDCl3) δ 201.7, 171.2, 146.9, 134.8, 133.5, 128.9, 126.9,
113.2, 38.7, 35.2, 26.1; IR (KBr, cm−1) ν 1715, 1633. HRMS (ESI-ion trap) Calcd for
C13H14NO2Cl (M + Na)+: 274.0605. Found: 274.0602.
General procedure for the synthesis of 3 and 7. Under argon protection, a solution
of BBr3 (9 μL, 3 mol %, 1.0 M in DCM) was added to a mixture of tertiary enamides
1 or 5 (0.30 mmol) and P2O5 (85 mg, 6 mmol) in DCM (15 mL). The resulting
mixture was stirred at room temperature for a period of time (see Tables 2 and 3 and
Figure 3). The reaction was quenched by adding a saturated NaHCO3 aqueous
solution (10 mL). The aqueous layer was extracted with DCM (3 × 20 mL). The
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combined organic extracts were washed with brine (20 mL), dried over anhydrous
Na2SO4 and concentrated under vacuum to give a crude mixture. Silica gel column
chromatography (200 – 300 mesh) eluted with a mixture of ethyl acetate and
petroleum (1 : 20 to 1 : 3) afforded pure product 3 or 7. All products were fully
characterized and their characterization data are listed below.
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Phenyl(7-phenyl-2,3-dihydro-1H-azepin-1-yl)methanone 3a (77.1 mg, 93% yield):
white solid, mp. 99-100 oC; Rf = 0.3 (EtOAc / petroleum ether = 1 / 5); 1H NMR (400
MHz, DMSO-d6, 150 oC) δ 7.24 – 7.10 (m, 10H), 6.22 – 6.14 (m, 2H), 5.98 (d, J = 6.4
Hz, 1H), 4.02 (s, 2H), 2.73 (dd, J = 8.2, 5.5 Hz, 2H); 13C NMR (100 MHz, DMSO-d6)
δ 169.4, 145.2, 139.5, 137.9, 135.4, 130.7, 129.0, 128.5, 128.4, 128.0, 126.5, 124.0,
116.4, 46.3, 33.4; IR (KBr, cm−1) ν 1643, 1629. HRMS (ESI-ion trap) Calcd for
C19H17NO (M + H)+: 276.1383. Found: 276.1387. A high quality single crystal was
obtained from recrystalization from a mixture of n-hexane and ethyl acetate.
(4-Methoxyphenyl)(7-phenyl-2,3-dihydro-1H-azepin-1-yl)methanone 3b (84
mg, 92% yield): white solid, mp. 139-140 oC; Rf = 0.5 (EtOAc / petroleum ether = 1 /
3); 1H NMR (400 MHz, DMSO-d6, 150 oC) δ 7.20 – 7.12 (m, 7H), 6.70 (d, J = 8.7 Hz,
2H), 6.17 (d, J = 5.0 Hz, 2H), 5.97 (d, J = 6.0 Hz, 1H), 4.01 (s, 2H), 3.73 (s, 3H), 2.71
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(s, 2H); C NMR (100 MHz, DMSO-d6) δ 169.0, 161.3, 145.5, 139.5, 135.4, 130.1,
129.1, 128.6, 126.3, 124.1, 116.1, 113.8, 56.0, 46.5, 33.7; IR (KBr, cm−1) ν 1648,
1265. HRMS (ESI-ion trap) Calcd for C20H19NO2 (M + Na)+: 328.1308. Found:
328.1303.
(3,4-Dimethoxyphenyl)(7-phenyl-2,3-dihydro-1H-azepin-1-yl)methanone
3c
(96 mg, 95% yield): white solid, mp. 92-93 oC, Rf = 0.19 (EtOAc / petroleum ether =
1 / 3); 1H NMR (400 MHz, DMSO-d6,150 oC) δ 7.18 – 7.12 (m, 5H), 6.84 – 6.73 (m,
3H), 6.19 – 6.16 (m, 2H), 5.97 (d, J = 6.4 Hz, 1H), 4.01 (s, 2H), 3.73 (s, 3H), 3.66 (s,
3H), 2.71 (t, J = 2.1 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 169.1, 151.0, 148.5,
145.7, 139.5, 135.4, 130.2, 129.1, 128.6, 126.4, 124.0, 121.7, 115.9, 112.0, 111.3,
56.3, 56.2, 46.5, 33.7; IR (KBr, cm−1) ν 1651, 1626. HRMS (ESI-ion trap) Calcd for
C21H21NO3 (M + Na)+: 358.1414. Found: 358.1407.
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(4-Nitrophenyl)(7-phenyl-2,3-dihydro-1H-azepin-1-yl)methanone 3d (97 mg, 96%
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yield): yellow solid, mp. 93-94 C; Rf = 0.41 (EtOAc / petroleum ether = 1 / 4); H
NMR (400 MHz, DMSO-d6,150 oC) δ 7.95 (d, J = 8.68 Hz, 2H), 7.35 (d, J = 8.72 Hz,
2H), 7.16 (s, 5H), 6.26 – 6.16 (m, 2H), 6.05 (d, J = 6.9 Hz, 1H), 4.04 (s, 2H), 2.78 (d,
J = 4.1 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 167.7, 148.4, 144.1, 143.9, 139.3,
135.9, 129.3, 129.2, 128.7, 126.7, 123.8, 123.8, 117.5, 46.4, 33.2; IR (KBr, cm−1) ν
1652, 1521, 1352. HRMS (ESI-ion trap) Calcd for C19H16N2O3 (M + H)+: 321.1234.
Found: 321.1228.
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(4-Chlorophenyl)(7-phenyl-2,3-dihydro-1H-azepin-1-yl)methanone 3e (82 mg,
88% yield): white solid, mp. 142-143 oC; Rf = 0. 45 (EtOAc / petroleum ether = 1 / 5);
1H NMR (400 MHz, DMSO-d6,150 oC) δ 7.19 – 7.16 (m, J = 4.1 Hz, 9H), 6.23 – 6.16
(m, 2H), 6.01 (t, J = 5.7 Hz, 1H), 4.01 (s, 2H), 2.73 (s, 2H); 13C NMR (100 MHz,
DMSO-d6) δ 168.3, 144.8, 139.3, 136.7, 135.7, 135.4, 129.8, 129.2, 128.7, 128.6,
126.5, 123.9, 116.8, 46.4, 33.4; IR (KBr, cm−1) ν 1652, 1384. HRMS (ESI-ion trap)
Calcd for C19H16ClNO (M + H)+: 310.0993. Found: 310.0993.
(4-Bromophenyl)(7-phenyl-2,3-dihydro-1H-azepin-1-yl)methanone 3f (96 mg,
90% yield): white solid, mp. 139-140 oC; Rf = 0.35 (EtOAc / petroleum ether = 1 / 4);
1H NMR (400 MHz, DMSO-d6,150 C) δ 7.33 (dd, J = 8.2, 1.8 Hz, 2H), 7.20 – 7.17
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(m, 5H), 7.09 (dd, J = 8.7, 1.8 Hz, 2H), 6.23 – 6.13 (m, 2H), 6.01 (d, J = 6.0 Hz, 1H),
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4.01 (s, 2H), 2.73 (d, J = 3.7 Hz, 2H); C NMR (100 MHz, DMSO-d6, 150 C) δ
168.4, 144.8, 139.3, 137.0, 135.7, 131.6, 130.0, 129.2, 128.8, 126.5, 124.2, 123.9,
116.9, 46.4, 33.4; IR (KBr, cm−1) ν 1652. HRMS (ESI-ion trap) Calcd for
C19H16BrNO (M + Na)+: 376.0308. Found: 376.0304.
(2-Bromophenyl)(7-phenyl-2,3-dihydro-1H-azepin-1-yl)methanone 3g (101 mg,
95% yield): white solid, mp. 84-85 oC; Rf = 0.39 (EtOAc / petroleum ether = 1 / 5); 1H
NMR (400 MHz, DMSO-d6, 150 oC) δ 7.33 (s, 1H), 7.17 (s, 5H), 7.09 (s, 2H), 6.90 (s,
1H), 6.19 – 6.08 (m, 2H), 5.88 (d, J = 6.4 Hz, 1H), 3.96 (s, 2H), 2.77 (s, 2H); 13C
NMR (100 MHz, DMSO-d6, 150 oC) δ 166.8, 143.4, 139.3, 138.5, 134.3, 132.4, 130.2,
128.9, 128.1, 127.6, 126.6, 125.9, 123.2, 119.4, 117.5, 45.9, 32.0; IR (KBr, cm−1) ν
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1645, 1629, 1596, 1391. HRMS (ESI-ion trap) Calcd for C19H16BrNO (M + Na)+:
376.0308. Found: 376.0300.
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Benzyl 7-phenyl-2,3-dihydro-1H-azepine-1-carboxylate 3h (72 mg, 79% yield):
white solid, mp. 95-96 oC; Rf = 0.67 (EtOAc / petroleum ether = 1 / 3); 1H NMR (400
MHz, DMSO-d6,150 oC) δ 7.42 (d, J = 7.8 Hz, 2H), 7.37 – 7.29 (m, 3H), 7.26 – 7.22
(m, 3H), 6.98 – 6.96 (m, 2H), 6.03(t, J = 2.7 Hz, 2H), 6.00 – 5.99 (m, 1H), 4.96 (s,
2H), 3.76 (t, J = 5.7 Hz, 2H), 2.67 – 2.64 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ
154.4, 142.6, 139.5, 139.4, 135.7, 133.4, 128.4, 128.0, 127.7, 127.5, 127.2, 125.4,
122.9, 115.5, 67.3, 46.4, 32.5; IR (KBr, cm−1) ν 1698. HRMS (ESI-ion trap) Calcd for
C20H19NO2 (M + Na)+: 328.1308. Found: 328.1305.
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Ethyl 7-phenyl-2,3-dihydro-1H-azepine-1-carboxylate 3i (52 mg, 71% yield):
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colorless oil; Rf = 0.67 (EtOAc / petroleum ether = 1 / 3); H NMR (400 MHz,
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DMSO-d6,150 C) δ 7.42 – 7.30 (m, 5H), 6.03 – 6.02 (m, 2H), 5.95 – 5.94 (m, 1H),
3.92 (q, J = 7.0 Hz, 2H), 3.73 (t, J = 5.5 Hz, 2H), 2.65 – 2.62 (m, 2H), 0.91 (t, J = 7.1
Hz, 3H);13C NMR (100 MHz, DMSO-d6) δ 153.9, 143.4, 139.5, 133.5, 128.5, 127.8,
125.6, 123.5, 115.5, 61.2, 46.6, 32.8, 14.2; IR (KBr, cm−1) ν 2964, 1715, 1261.
HRMS (ESI-ion trap) Calcd for C15H17NO2 (M + Na)+: 266.1152. Found: 266.1150.
1-(7-Phenyl-2,3-dihydro-1H-azepin-1-yl)ethan-1-one 3j (63 mg, 74% yield): pale
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yellow oil; Rf = 0.50 (EtOAc / petroleum ether = 1 / 3); H NMR (400 MHz,
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DMSO-d6,150 C) δ 7.51 – 7.48 (m, 2H), 7.45 – 7.42 (m, 2H), 7.38 – 7.34 (m, 1H),
6.19 (d, J = 5.0 Hz, 1H), 6.07 (s, 2H), 3.74 (s, 2H), 2.66 (s, 2H), 1.66 (s, 3H); 13C
NMR (100 MHz, DMSO-d6) δ 169.3, 143.6, 139.3, 135.5, 130.0, 129.2, 126.2, 123.4,
118.2, 45.9, 32.4, 24.2; IR (KBr, cm−1) ν 1665, 1386. HRMS (ESI-ion trap) Calcd for
C14H15NO (M + Na)+: 236.1046. Found: 236.1041.
(7-(4-Methoxyphenyl)-2,3-dihydro-1H-azepin-1-yl)(phenyl)methanone 3k (84
mg, 92% yield): white solid, mp. 129-130 oC; Rf = 0.36 (EtOAc / petroleum ether = 1
1
o
/ 7); H NMR (400 MHz, DMSO-d6,150 C) δ 7.23 – 7.13 (m, 5H), 7.08 (d, J = 8.7
Hz, 2H), 6.71 (d, J = 8.7 Hz, 2H), 6.14 (d, J = 4.6 Hz, 2H), 5.88 (d, J = 5.0 Hz, 1H),
3.99 (s, 2H), 3.73 (s, 3H), 2.71 (s, 2H); 13C NMR (100 MHz, DMSO-d6) δ 169.4,
159.7, 145.0, 138.0, 134.4, 132.0, 130.7, 128.5, 127.9, 127.8, 124.1, 114.8, 114.5,
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56.0, 46.4, 33.3; IR (KBr, cm−1) ν 1643, 1388. HRMS (ESI-ion trap) Calcd for
C20H19NO2 (M + Na)+: 328.1308. Found: 328.1302.
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Phenyl(7-(p-tolyl)-2,3-dihydro-1H-azepin-1-yl)methanone 3l (71 mg, 82% yield):
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o
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white solid, mp. 129-130 C; Rf = 0.36 (EtOAc / petroleum ether = 1 / 7); H NMR
(400 MHz, DMSO-d6,150 oC) δ 7.24 – 7.13 (m, 5H), 7.05 (d, J = 8.2 Hz, 2H), 6.96 (d,
J = 7.8 Hz, 2H), 6.19 – 6.12 (m, 2H), 5.94 (d, J = 5.5 Hz, 1H), 4.00 (s, 2H), 2.72 (s,
2H), 2.22 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 169.4, 145.3, 137.9, 136.6,
135.0, 130.7, 129.7, 128.4, 128.0, 126.3, 124.0, 115.7, 46.4, 33.4, 21.5; IR (KBr, cm−1)
ν 1643, 1385. HRMS (ESI-ion trap) Calcd for C20H19NO (M + Na)+: 312.1359. Found:
312.1353.
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(7-(4-Fluorophenyl)-2,3-dihydro-1H-azepin-1-yl)(phenyl)methanone 3m (79 mg,
90% yield): white solid, mp. 124-125 oC; Rf = 0. 50 (EtOAc / petroleum ether = 1 / 3);
1H NMR (400 MHz, DMSO-d6,150 C) δ 7.26 – 7.23 (m, 1H), 7.19 – 7.16 (m, 6H),
o
6.95 – 6.89 (m, 2H), 6.22 – 6.15 (m, 2H), 5.94 (d, J = 6.4 Hz, 1H), 4.01 (s, 2H), 2.72
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(d, J = 5.0 Hz, 2H); C NMR (100 MHz, DMSO-d6) δ 169.4, 163.5, 161.1, 144.2,
137.9, 136.1, 135.4, 130.8, 128.7, 128.6, 128.5, 127.9, 123.9, 116.4, 116.0, 115.8,
46.3, 33.4; F NMR (376 MHz, DMSO-d6) δ -114.1; IR (KBr, cm−1) ν 1644, 1383.
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HRMS (ESI-ion trap) Calcd for C19H16NOF (M + H)+: 294.1289. Found: 294.1285.
(7-(4-Chlorophenyl)-2,3-dihydro-1H-azepin-1-yl)(phenyl)methanone 3n (87 mg,
94% yield): white solid, mp. 145-146 oC; Rf = 0.49 (EtOAc / petroleum ether = 1 / 4);
1H NMR (400 MHz, DMSO-d6,150 C) δ 7.25 (q, J = 4.4 Hz, 1H), 7.19 – 7.17 (m,
o
8H), 6.24 – 6.13 (m, 2H), 6.00 (d, J = 6.9 Hz, 1H), 4.00 (s, 2H), 2.73 (d, J = 4.1 Hz,
2H); 13C NMR (100 MHz, DMSO-d6) δ 169.3, 143.9, 138.4, 137.8, 136.0, 132.9,
130.9, 129.0, 128.2, 127.9, 123.9, 117.1, 46.2, 33.4; IR (KBr, cm−1) ν 1649, 1382.
HRMS (ESI-ion trap) Calcd for C19H16NOCl (M + H)+: 310.0993. Found: 310.0990.
(7-(4-Bromophenyl)-2,3-dihydro-1H-azepin-1-yl)(phenyl)methanone 3o (97 mg,
91% yield): white solid, mp. 137-138 oC; Rf = 0.52 (EtOAc / petroleum ether = 1 / 3);
1H NMR (400 MHz, DMSO-d6,150 C) δ 7.31 (d, J = 8.7 Hz, 2H), 7.28 – 7.23 (m,
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1H), 7.18 (d, J = 4.1 Hz, 3H), 7.10 (d, J = 8.2 Hz, 2H), 6.25 – 6.13 (m, 2H), 6.01 (d, J
= 7.3 Hz, 1H), 3.99 (s, 2H), 2.72 (d, J = 4.6 Hz, 2H); 13C NMR (100 MHz, DMSO-d6)
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δ 169.3, 144.0, 138.8, 137.8, 136.1, 132.0, 130.9, 128.6, 128.5, 128.0, 123.9, 121.5,
117.1, 46.3, 33.4; IR (KBr, cm−1) ν 1647, 1381. HRMS (ESI-ion trap) Calcd for
C19H16NOBr (M + H)+: 354.0488. Found: 354.0482.
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(7-(2-Bromophenyl)-2,3-dihydro-1H-azepin-1-yl)(phenyl)methanone 3p (101 mg,
94% yield): white solid, mp. 95-96 oC; Rf = 0.29 (EtOAc / petroleum ether = 1 / 2); 1H
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NMR (400 MHz, DMSO-d6,150 C) δ 7.42 – 7.40 (m, 1H), 7.27 (t, J = 7.3 Hz, 1H),
7.19 (t, J = 7.3 Hz, 2H), 7.07 (d, J = 6.9 Hz, 2H), 7.03 – 7.00 (m, 2H), 6.87 – 6.85 (m,
1H), 6.25 – 6.22 (m, 1H), 6.16 – 6.11 (m, 1H), 5.77 (d, J = 7.3 Hz, 1H), 4.06 (t, J =
5.3 Hz, 2H), 2.72 (d, J = 4.1 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 169.2, 144.0,
139.9, 138.1, 136.1, 133.8, 133.0, 130.6, 130.0, 128.9, 128.0, 127.3, 123.7, 121.4,
119.5, 46.7, 33.7; IR (KBr, cm−1) ν 1649, 1379. HRMS (ESI-ion trap) Calcd for
C19H16NOBr (M + H)+: 354.0488. Found: 354.0482.
Phenyl(7-(thiophen-2-yl)-2,3-dihydro-1H-azepin-1-yl)methanone 3q (80 mg, 93%
o
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yield): white solid, mp. 117-118 C; Rf = 0.39 (EtOAc / petroleum ether = 1 / 5); H
NMR (400 MHz, DMSO-d6,150 oC) δ 7.32 – 7.28 (m, 3H), 7.24 – 7.21 (m, 3H), 6.89
(t, J = 1.8 Hz, 1H), 6.82 – 6.80 (m, 1H), 6.22 – 6.10 (m, 2H), 6.04 (d, J = 6.9 Hz, 1H),
3.97 (s, 2H), 2.71 (d, J = 4.1 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 169.2, 143.5,
139.3, 137.7, 135.7, 130.9, 128.5, 128.5, 127.9, 127.0, 125.8, 123.6, 115.5, 46.3, 33.2;
IR (KBr, cm−1) ν 1642, 1386. HRMS (ESI-ion trap) Calcd for C17H15NOS (M + Na)+:
304.0767. Found: 304.0761.
(6-Methyl-7-phenyl-2,3-dihydro-1H-azepin-1-yl)(phenyl)methanone 3r (73 mg,
84% yield): white solid, mp. 112-113 oC; Rf = 0.43 (EtOAc / petroleum ether = 1 / 4);
1H NMR (400 MHz, DMSO-d6,150 oC) δ 7.27 (t, J = 7.3 Hz, 1H), 7.16 (t, J = 7.6 Hz,
2H), 7.10 (s, 3H), 7.00 (d, J = 7.8 Hz, 2H), 6.86 (d, J = 5.0 Hz, 2H), 6.12 (s, 2H), 4.08
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(s, 2H), 2.68 (s, 2H), 1.86 (s, 3H); C NMR (100 MHz, DMSO-d6) δ 169.7, 140.2,
139.6, 138.4, 133.8, 130.3, 129.9, 129.4, 128.5, 128.3, 127.7, 127.5, 124.0, 48.4, 32.9,
21.2; IR (KBr, cm−1) ν 1652, 1389. HRMS (ESI-ion trap) Calcd for C20H19NO (M +
Na)+: 312.1359. Found: 312.1354.
7,8-Dihydro-5H-azepino[2,1-a]isoindol-5-one 3s (51 mg, 85% yield): yellow oil;
Rf = 0.50 (EtOAc / petroleum ether = 1 / 2); 1H NMR (400 MHz, DMSO-d6) δ 7.95 –
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7.93 (m, 1H), 7.76 (d, J = 7.3 Hz, 1H), 7.68 (t, J = 7.3 Hz, 1H), 7.54 (t, J = 7.6 Hz,
1H), 6.31 (q, J = 2.6 Hz, 1H), 6.16 – 6.15 (m, 2H), 3.94 (t, J = 4.8 Hz, 2H), 2.62 (d, J
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= 4.1 Hz, 2H); C NMR (100 MHz, DMSO-d6) δ 166.0, 138.1, 137.7, 135.4, 133.1,
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129.9, 128.6, 125.4, 123.7, 120.7, 104.2, 41.9, 30.3; IR (KBr, cm−1) ν 1703, 1645.
HRMS (ESI-ion trap) Calcd for C13H11NO (M + H)+: 198.0913. Found: 198.0913.
Formation of N-(4-hydroxy-6-oxo-6-phenylhexyl)benzamide 4a. Under the
catalysis of FeCl3 (30 mol %), 3a was obtained in 18% yield. In addition, product 4a
(22.5 mg, 24% yield) was isolated as a white solid: mp. 95-96 oC; Rf = 0.21 (EtOAc /
petroleum ether = 3 / 2); 1H NMR (400 MHz, CDCl3) δ 8.02 – 7.86 (m, 2H), 7.78 (d,
J = 7.3 Hz, 2H), 7.67 – 7.52 (m, 1H), 7.52 – 7.43 (m, 3H), 7.43 – 7.36 (m, 2H), 6.86
(s, 1H), 4.32 – 4.20 (m, 1H), 3.71 – 3.40 (m, 3H), 3.18 (dd, J = 17.4, 2.7 Hz, 1H),
3.06 (q, J = 8.9 Hz, 1H), 1.93 – 1.74 (m, 2H), 1.67 (q, J = 7.0 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 201.0, 167.6, 136.5, 134.7, 133.7, 131.3, 128.7, 128.5, 128.1, 126.9,
67.6, 45.0, 39.9, 33.7, 25.7; IR (KBr, cm−1) ν 3352, 1682, 1637, 1536. HRMS
(ESI-ion trap) Calcd for C19H21NO3 (M + Na)+: 334.1414. Found: 334.1409.
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1-Benzyl-7-phenyl-1,3-dihydro-2H-azepin-2-one 7a (70 mg, 85% yield): colorless
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oil; Rf = 0.31 (EtOAc / petroleum ether = 1 / 4); H NMR (400 MHz, DMSO-d6,150
oC) δ 7.45 – 7.35 (m, 5H), 7.23 – 7.20 (m, 3H), 6.89 (d, J = 6.9 Hz, 2H), 6.32-6.37 (m,
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2H), 5.91 (q, J = 7.8 Hz, 1H), 4.64 (s, 2H), 3.14 (d, J = 6.4 Hz, 2H); C NMR (100
MHz, DMSO-d6) δ 168.0, 143.8, 138.4, 129.7, 129.4, 129.0, 128.3, 128.2, 127.7,
127.6, 126.0, 121.4, 49.2, 37.8; IR (KBr, cm−1) ν 1668. HRMS (ESI-ion trap) Calcd
for C19H17NO (M + H)+: 276.1383. Found: 276.1384.
1-(4-Bromobenzyl)-7-phenyl-1,3-dihydro-2H-azepin-2-one 7b (93 mg, 88%
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yield): white solid, mp. 101-102 C; Rf = 0.50 (EtOAc / petroleum ether = 1 / 4); H
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NMR (400 MHz, DMSO-d6,150 C) δ 7.44 – 7.37 (m, 7H), 6.84 (d, J = 8.2 Hz, 2H),
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6.33 – 6.30 (m, 2H), 5.92 – 5.89 (m, 1H), 4.60 (s, 2H), 3.14 (d, J = 6.9 Hz, 2H); C
NMR (100 MHz, DMSO-d6) δ 168.0, 143.6, 138.3, 137.8, 132.0, 129.9, 129.8, 129.5,
128.3, 128.2, 126.2, 121.5, 120.9, 48.7, 37.8; IR (KBr, cm−1) ν 1668. HRMS (ESI-ion
trap) Calcd for C19H17NOBr (M + H)+: 354.0488. Found: 354.0479. A high quality
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