Synthesis of Azepines via a [6 + 1] Annulation of Ynenitriles with Reformatsky Reagents

Article abstract of DOI:10.1021/acs.joc.5b01397

A protocol for the direct synthesis of azepines using a hafnium(III)-catalyzed [6 + 1] annulation of N-tethered ynenitriles with Reformatsky reagents is reported. A broad range of 3-amino-2,7-dihydro-1H-azepine-4-carboxylates 4aa-4he were obtained in high yields and with excellent functional group tolerance. The copper-mediated reactions of isolable Blaise intermediates (enamino esters 3), uniquely underwent 5-endo cyclization to afford the β-2,5-dihydropyrrolyl α,β-unsaturated esters 5aa-5fc, which exhibit anticancer activity.

Full text of DOI:10.1021/acs.joc.5b01397

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Article
Synthesis of Azepines via a [6+1] Annulation
of Ynenitriles with Reformatsky Reagents
Mitsuhiro Yoshimatsu, Miki Tanaka, Yu Fujimura, Yukiteru Ito, Yusuke Goto, Yuka
Kobayashi, Hiroaki Wasada, Noriyuki Hatae, Genzoh Tanabe, and Osamu Muraoka
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01397 • Publication Date (Web): 08 Sep 2015
Downloaded from http://pubs.acs.org on September 13, 2015
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Synthesis of Azepines via a [6+1] Annulation of Ynenitriles with Reformatsky
Reagents
Mitsuhiro Yoshimatsu,a* Miki Tanaka,a Yu Fujimura,a Yukiteru Ito,a Yusuke Goto,a
Yuka Kobayashi,a Hiroaki Wasada,b Noriyuki Hatae,c Genzoh Tanabed and Osamu
Muraokad
aDepartment of Chemistry, Faculty of Education, Gifu University, Yanagido 1-1, Japan.
email: yoshimae@gifu-u.ac.jp
bDepartment of Chemistry, Faculty of Regional Study, Gifu University, Yanagido 1-1,
Japan.
cSchool of Pharmaceutical Sciences, Health Sciences University of Hokkaido,
Ishikari-Tobetsu, Hokkaido 061-0293, Japan.
dSchool of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashi-osaka, Osaka
577-8502, Japan.
Table of Contents
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Abstract
A protocol for the direct synthesis of azepines using a hafnium (III)-catalyzed
[6+1]−annulation of N-tethered ynenitriles with Reformatsky reagents is reported. A
broad range of 3-amino-2,7-dihydro-1H-azepine-4-carboxylates 4aa−4he were obtained
in high yields and with excellent functional group tolerance. The copper-mediated
reactions of isolable Blaise intermediates, (enamino esters 3), uniquely underwent
5-endo-mode cyclization to afford -2,5-dihydropyrrolyl -unsaturated esters 5aa-5fc,
which exhibit anti-cancer activity.
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The synthesis of azepines and its derivatives is a subject of continued interest because
of their therapeutic uses, (i.e., antiepileptic, antidepressant, Alzheimer’s disease,
anticancer, and Gram-positive antibacterial agents).1 However, monocyclic azepines
are comparatively rarer than benzazepines and dibenzazepines because it is difficult to
construct the monocyclic 7-membered ring systems.2 The cycloaddition reaction is a
fundamental and powerful tool for the construction of azepine derivatives. However,
approaches using the cycloaddition strategy for azepine derivatives are much less
abundant. The early methods are limited to more specialized substrates derived from
some unique ring expansion reactions of pyrroles with dimethyl
acetylenedicarboxylate.3
Among the recently reported methods, ring-closure
metathesis (RCM) may be one of the most powerful tools for the synthesis of
monocyclic azepines based on its substrate scope and product yields (Scheme 1).4a-d
However, RCM can usually require large amounts of catalyst for successful conversions
of -dienes and enynes to azepines and often have difficulty to remove the residual
metals.4e Recent advances may allow for the direct formation of azepines via a metal
catalyzed [5+2]5 or [4+3]6 cycloaddition reaction of vinylaziridines with electron
deficient alkynes (EDA), reactions of iminocyclopropanes with EDA, and reactions of
4-aminoketones with arylalkynes. Despite the impressive challenge and considerable
efforts in this area, particular focus has been placed on the synthesis of azepines because
of their high potential to exhibit unique biological activities.
Scheme 1. Monocyclic Azepine Syntheses
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Previously, we investigated functionalization-cyclizations (FCs) of 1,6-diynes using
oxygen- and nitrogen-nucleophiles, which led to alkoxymethyl, aryloxymethyl,7a
aminomethyl,7b alkynylmethyl-,7c and deuterium substituted furans and pyrroles,7d-e
which have been utilized to synthesize the tanshinon anticancer derivatives.7f In
continuing studies in this area, we explored the FC process of ynenitriles. Our basic
strategy is shown at the bottom of Scheme 1.8 By treating N-tethered ynenitriles with
Reformatsky reagents, the in situ generated Blaise-type intermediates can undergo a
7-endo-mode cyclization reaction to form azepines that bear both amino and ester
groups. If a protocol for monocyclic azepine synthesis from ynenitriles can be
achieved by using our FC process, new functionalized azepines can be evaluated for
new therapeutic uses. Herein, we report the specific formation of azepines and
2,5-dihydropyrroles from ynenitriles, the results from DFT-calculations, and anticancer
activities.
First, we examined the reaction of ynenitrile 2a with Reformatsky reagent, which was
in situ generated from ethyl bromoacetate/zinc in THF to afford a Blaise intermediate,
(i.e., -enaminoester 3a) in excellent yield. However, the cyclized products were not
obtained (Table 1, entry 1). Therefore, the reaction of 2a in the presence of typical
metal catalysts yielded azepine derivatives 4aa. Screening of the catalysts and
solvents revealed that the use of both hafnium (IV) triflate and 1,4-dioxane reduced the
reaction time while remaining 3aa (entry 8). The use of other catalysts such as
Cu(OAc)2, CuBr, Yb(OTf)3, InCl3, La(OTf)3, GaCl3, Sc(OTf)3 were not satisfied in the
formation of azepine 4aa (entries 2-5, 7, 10-12). Increasing the reaction temperature
significantly reduced the reaction time (entries 6 and 8). The amine additives, such as
phenanthroline, were not effective in the cycloaddition (entries 9).
Table 1. Screening for suitable reaction condition
entry
Condition[a]
Lewis acids (equiv) Yield of 3aa Yield of 4aa
1
2
THF, 75 oC, 0.5 h
THF, 75 oC, 9 h
̶
quant
40
0
Cu(OAc)2 (0.2)
60
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THF, 75 oC, 40 h
THF, 75 oC, 36 h
THF, 75 oC, 42 h
THF, 75 oC, 21 h
THF, 75 oC, 20 h
dioxane, 100 oC, 9 h
THF, 75 oC, 39 h[b]
THF, 75 oC, 22 h
THF, 75 oC
CuBr (0.2)
Cu(OTf)2 (0.2)
Yb(OTf)3 (0.2)
Hf(OTf)4 (0.2)
InCl3 (0.2)
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Hf(OTf)4 (0.2)
Hf(OTf)4 (0.2)
La(OTf)3 (0.2)
GaCl3 (0.2 eq)
Sc(OTf)3 (0.2)
9
15
50
0
10
11
12
THF, 75 oC, 20 h
25
54
aZinc was activated with chlorotrimethylsilane. Each experiment was performed using 2a (0.16 mmol)/Zn (1.6
mmol)/BrCH2CO2Et (0.80 mmol) in THF or dioxane (1.0 mL). b0.1 equiv of phenathroline was used as an additive.
cCompound 2a was recovered in 70% yield.
With the optimized reaction conditions in hand, we examined the scope of the [6+1]
cycloaddition reaction of ynenitriles with Reformatsky reagents, and the results are
shown in Table 2. In general, high yields were obtained with substrates that contained
electron-rich and electron-deficient aryl, alkyl, hydrogen, and phenylsulfanyl groups.
The scope of the bromoester component of the Reformatsky reagents was also
investigated. With a Reformatsky reagent generated from a methyl ester, the reaction
afforded 1H-azepine 4ab in good yield. However, the bulky tert-butyl ester led not to
the desired azepine, but to the adduct, (i.e., Blaise intermediate 3ac). The results
indicated that the [6+1] cycloaddition reaction is affected by steric interaction between
R1 and R2. Next, the scope of the ynenitrile component, (i.e., R1 group at the alkyne
termini), was investigated in the cycloaddition. Substrate 2b (R1=p-MeOC6H4) reacted
with ethyl and methyl bromoacetates, which resulted in azepines 4ba-4bb, respectively.
In addition, the reaction with a tert-butyl derivative also afforded Blaise intermediate
3bc in good yield. Regarding the similar trend in entries 6−15, the steric strain
imposed by the interaction between the R1 and R2 groups most likely prevented the
[6+1] azepine formation. The reactions were tolerant of ynenitriles 2c and 2d bearing
p-chlorophenyl and ethyl groups (entries 6—10). Surprisingly, the reaction of
ynenitrile (R1=Et) with the t-butyl reagent exclusively afforded azepine 4dc (entry 10).
1H-Azepines 4ea-b (R1=H) gave rise to low yields because it gradually decomposed
due to its lability (entries 11-12). This transformation also tolerates substrates bearing
sulfanyl group at the alkyne termini with ethyl, methyl, and tert-butyl esters (entries
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13—15). Fine single crystals of 4fa were obtained, and their structural confirmation
was established based on X-ray crystallographic analysis, revealed that 4fa was the
2,7-dihydro-1H-azepine derivative.
Table 2. Substrate scope for azepine formations
entry
1
R1
Ph
R2
Me
t-Bu
Et
(%yield)a
4ab (80)
3ac (quant)
4ba (78)
4bb (68)
3bc (68)
4ca (98)
4cb (97)
4da (65)
4db (74)
4dc (53)
4ea (37)
4eb (25)
4fa (80)
4fb (32)
4fc (66)
4fd (60)
dioxane, 1 h
THF, 20 min
THF, 33 h
2
3
MeOC6H4
4
Me
t-Bu
Et
THF, 0.5 h
5
dioxane, 12 h
dioxane, 22 h
dioxane, 2 h
dioxane, 1 h
THF, 1.5 h
6
p-ClC6H4
Et
7
Me
Et
8
9
Me
t-Bu
Me
t-Bu
Et
10
11
12
13
14
15
16
dioxane, 3 h
THF, 40 min
THF, 0.5 h
H
PhS
THF, 12 h
Me
t-Bu
Ph
THF, 2 h
dioxane, 2.5 h
dioxane, 19 h
aAll products were isolated. Each reaction was performed under the scale (0.14-1.8
mmol) and the experimental details were described in the supplement data. The reactions of most substrates were
performed under the optimized condition in
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both THF and dioxane. The better result was listed in Table 2.
Scheme 2. Cyclization of enamino ester 3aa
To gain additional insight into the mechanisms for the azepine formation, we carried
out intramolecular cyclization reactions of isolable Blaise intermediate 3aa, which was
easily prepared from the reaction of ynenitrile 2a with a Reformatsky reagent
(Zn/BrCH2CO2Et in THF), under the selected conditions, as shown in Scheme 2. First,
the reaction of 3aa in the presence of hafnium triflate in dioxane was examined.
However, the product was not an azepine, but hydrated ketoester 6aa as an isolable sole
product. This result indicates that the cyclization of 3aa cannot be achieved by only
activating the alkyne with hafnium triflate. In addition, the copper-mediated
cyclization did not afford azepine 4aa, but 2,5-dihydropyrrole 5aa. Analysis of the 1H
NMR spectrum implies a different type of ring closure under the hafnium conditions
compared with that leading to 1H-azepines, such as 4aa. Under the same conditions as
the azepine formation with, Reformatsky reagents generated by ethyl bromoacetate /
zinc / hafnium triflate (0.1 eq), the reaction of 3aa successfully afforded azepine 4aa in
good yield. The result indicated that the completion of the reaction requires both
hafnium triflate and a large excess of the Reformatsky reagent.
Next, we investigated the intramolecular cyclization of the isolable Blaise-type
intermediates 3 to clarify the generality of the results shown in Table 3. Surprisingly,
the copper-mediated reactions of t-butyl esters 3ac-3fc, which did not yield azepines
under the hafnium triflate catalyzed conditions, afforded 2,5-dihydropyrroles 5ac-5fc in
good yields (entries 2, 3, 5, 7, 9). In addition, the reaction of ethyl esters 3aa also
afforded 2,5-dihydropyrrole 5aa, but not azepines (entries 1, 4, 6). However, the
reaction of methyl ester 3fc gave rise to low selectivity. Both azepine 4fc and
2,5-dihydropyrrole 5fc were obtained in nearly the same yield.
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The mechanism outlined in Scheme 3 was proposed. Because the Blaise
intermediate, (i.e., -enaminoesters 3), has already been isolated, from the reactions of
ynenitriles with Reformatsky reagents, the first step involves the nucleophilic attack of
the Reformatsky reagent on the nitrile carbon.9 The formed iminoester 8 would react
with a large excess of Reformatsky reagents to form key intermediate 9, which has a
zinc enolate structure that is activated by hafnium metals, and regioselectively
undergoes carbometalation leading to 1H-azepine 10 (path a). The tautomerization of
10 to intermediate 11 would be accelerated by a large excess of the Reformatsky reagent.
The usual protodemetalation and subsequent hydrolysis of 11 affords azepine 12and
regenerate the hafnium triflate.
Table 3. Copper-mediated 5-endo-mode cyclization of enamino esters 3
entry
R1
Ph
R2
Et
solv, time (h)
dioxane, 1.3
(%yield)a
5aa (80)
5ac (77)
5bc (78)
5da (62)
5dc (76)
5ea (23)
5ec (66)
5fb (56)b
5fc (quant)
1
2
3
4
5
6
7
8
9
t-Bu dioxane, 2.5
t-Bu dioxane, 14
MeOC6H4
Et
Et
t-Bu dioxane, 0.5
Et THF, 12
t-Bu THF, 16
Me dioxane, 2
t-Bu dioxane, 19
dioxane, 2
H
PhS
aAll products were isolated. b4fb was also obtained in 44% yield.
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Fig 1. DFT-calculation for the azepine formation
In the reactions of ynenitriles (R=Ar, Et, H) with Reformatsky reagents (R’=ethyl or
methyl) shown in Table 2, the 7-endo-mode cyclization of 9 would easily proceed due to
the low steric hindrance between the R and R’ groups. A large steric strain that is
imposed by the interaction between R and R’ in intermediate 9 (R’ = tert-BuO) would
prevent the 7-endo-mode cyclization and give rise to the formation of adduct 13.
Under the copper-mediated conditions, the intramolecular cyclization of isolable 13
would produce 2,5-dihydropyrrole 16 via an enamine intermediate 14. The different
reactivity between the hafnium-catalyzed 7-endo-mode cyclization and the
copper-mediated intramolecular 5-endo-mode cyclization appears to be due to the
nature of the metal used. To gain a better understanding this speculation, density
functional theory (DFT) calculations were performed on all of the intermediates (i.e., 9,
TS-7en-Hf, 10, 13, 14, 6ex-Hf, TS-6ex-Hf, TS-Cu-A, TS-Cu-B, and TS-Cu-C) using
Gaussian 09. As shown in Fig 1, the competing 7-endo- and 6-exo-mode pathways
were calculated using Hf (II) triflate models for simplification of calculations. The
barrier of the TS-7en-Hf transition state (9.0 kcal/mol) is nearly the same as that of
TS-6ex-Hf (7.1 kcal/mol) (Fig. 1). In addition, TS-7en-Hf would also afford both
1H-azepine 10 (-20.6 kcal/mol) and piperidine 6-ex-Hf (-20.9 kcal/mol). In addition,
Lee and coworkers reported that the in situ generated Blaise intermediates reacted with
1-alkynes and 1,3-enynes to afford
a
vinylzinc intermediate, whose
deprotonation-isomerization yielded vinyl enaminoesters as the product.9b-d In our
system, the 6-exo-mode cyclization would provide a similar vinylzinc intermediate.
Therefore, the 6-exo-mode pathway also appears to be favorable.10 However, no
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6-exo-mode cyclized products were obtained in the cycloaddition reactions of
ynenitriles with Reformatsky reagents. Based on the Mulliken charge of 9, the
hafnium metal coordinates with the inner carbon of the alkyne, and the exo-carbon of
alkyne bearing the ethyl group would have a positive charge (Fig 2). However, the
Mulliken charge of TS-6ex-Hf indicates that the alkyne has a negative charge.
Therefore, the nucleophilic attack of zinc enamine 9 would occur at the -carbon of the
ethyl group to exclusively afford azepine, and the hafnium-catalyzed azepine formation
was the most favorable process from intermediate 9.
Next, the
isomerization-cyclization of enaminoester 13 was calculated to gain insight into the
formation of dihydropyrroles 16 (Fig 3). The results indicate that the relative free
energy of enamine 14 is lower than that of 13 (ca. 4 kcal/mol), and that the reaction of
13 would proceed toward the dihydropyrrole formation. Therefore, the isomerization
from intermediate 13 to 14 involves a copper-mediated hydride transfer step,11 which
proceeds from the carbon adjacent to the nitrogen of TS-Cu-A to the -carbon to the
ester group to afford TS-Cu-C via TS-Cu-B, as shown in Fig 3. Therefore, the
copper-mediated 5-endo-mode cyclization reaction of enaminoesters would selectively
afford the corresponding dihydropyrrole derivatives 16.
Fig 2. Mulliken charge of 9
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Fig 3. Isomerization of 13 to 14
Scheme 3. Proposed mechanism
Scheme 4. Synthesis of 2,5-dihydro-1H-pyrrole analogs
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The antiproliferative activity of several types of Michael acceptors, including
-unsaturated ketones and esters, against P388 and L1210 leukemias12 have been
reviewed. In the current study, the antiproliferative activity of the synthesized
-amino--pyrrolylenaminoesters against HCT-116 cells was investigated, and the data
are shown in Fig. 4. To prepare these analogs for the anticancer activities, the
transformation of 2,5-dihydropyrroles from compound 5 was examined (Scheme 4).
The reaction of 5aa and 5ac with t-BuOK in t-BuOH afforded
3-amino-3-pyrrolyl--unsaturated esters 17a,b in good yields. The amino group of 5
easily underwent chloroacetylation and the following amination provided amides 19a,b.
2,5-Dihydropyrroles 5ec and 5fc slightly inhibited the tumor cell viability in 10 M
treatments, and nearly all of the tested compounds, except 5dc, exhibited
antiproliferative activity at a 100 M treatment.
Fig 4. Antiproliferative activeties of -amino--pyrrolyl enaminoesters against
HCT-116 cells.
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HCT-116 cells were treated with 10 (gray column) or 100 M (filled column) of
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Data shown are mean ±SEM values (n=3).
In summary, we have developed a hafnium-catalyzed [6+1] cycloaddition reaction for
ynenitriles
2
using
Reformatsky
reagents,
that
afford
3-amino-1H-azepine-4-carboxylates in high yields. In addition, the copper-mediated
reaction of -enaminoesters 3 underwent 5-endo-mode cyclization to afford
2,5-dihydropyrroles with anticancer activity. The mechanistic investigations of the
selective 7-endo-mode and 5-endo-mode cyclization reactions were performed using
DFT calculations.
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Experimental
General Information
All new compounds were fully characterized. NMR-spectra were recorded on a 600
MHz spectrometer. Chemical shifts are expressed in parts per million (ppm) with
respect to tetramethylsilane as an internal standard. Splitting patterns are designated as
follows: s, singlet; d, doublet; q, quartet. IR spectrometer and are expressed in
reciprocal centimeters. EI mass spectra (MS) were obtained with direct-insertion
probe at 70 eV. All high resolution mass determinations were obtained on line system.
Melting points apparatus were determined on a Micro melting point apparatus and
uncorrected. The data of 4fb and 5dc have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication number CCDC 1016452 and
CCDC 1016451, respectively.
Preparations of Ynenitriles.
N-Cyanomethyl-N-[3-phenyl-2-propyn-1-yl]-p-toluenesulfonamide (2a), Typical
Procedure.
To a THF (12.5 mL) solution of N-(p-toluenesulfonyl)aminoacetonitrile13 (1) (2.5 g,
11.9 mmol), phenylpropargyl alcohol (1.9 g, 11.9 mmol) and triphenylphosphine (3.1 g,
11.9 mmol) was added dropwise DEAD (5.4 ml, 11.9 mmol) at room temperature.
The reaction mixture was stirred for 1 h. The solvent was removed under reduced
pressure. The residue was purified by column chromatography on silica gel eluting
with AcOEt-n-hexane (1:10, 1:5). The residue was purified by column chromatography
on silica gel eluting with AcOEt-n-hexane (1:10, 1:5) to give the titled compound 2a
(3.2 g, 82 %) as white powders. mp 95-96 C (from CH2Cl2-n-hexane). IR (KBr, cm-1)
o
 2982, 2925, 2854, 2246, 1598, 1491, 1442, 1357, 1260, 1166, 1121, 1093, 1073, 969,
909, 888, 816; 1H NMR (600 MHz, CDCl3) δ 2.39 (3H, s, Me), 4.37 (2H, s, CH2), 4.38
(2H, s, CH2), 7.22-7.35 (7H, m, ArH), 7.78 (2H, d, J=8.2 Hz, ArH); 13C NMR (150
MHz, CDCl3) δ 21.5 (q), 35.2 (t), 38.5 (t), 79.8 (s), 87.3 (s), 113.6 (s), 121.5 (s), 127.8
(d×2), 128.2 (d×2), 128.9 (d), 130.0 (d×2), 131.6 (d×2), 134.0 (s), 144.9 (s); EIMS m/z
324 (M+), 169 (M+-Tos). Anal. Calcd for C18H16N2O2S: C, 66.65; H, 4.97; N, 8.64.
Found: C, 66.67; H, 5.02; N, 8.43.
N-Cyanomethyl-N-[3-(4-methoxyphenyl)-2-propyn-1-yl]- p-toluenesulfonamide
(2b).
A
triethylamine (2.5 mL) solution of N-cyanomethyl-N-(2-propyn-1-yl)-
p-toluenesulfonamide (2e) (0.30 g, 1.21 mmol), 4-iodoanisole (0.28 g, 1.21 mmol),
copper iodide (23 mg, 1.21 × 10-5 mmol), bis(triphenylphosphine)palladium(II)
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dichloride (24 mg, 2.06×10-3 mmol) was stirred for 2.5 h at 50 C. The reaction
mixture was poured into water (50 mL). The organic layer was separated and the
aqueous layer was extracted with AcOEt. The combined organic layer was dried over
MgSO4. The solvent was removed under reduced pressure. The residue was purified
by preparative TLC on silica gel (AcOEt-n-hexane (1:4) as eluent) to give the titled
compound 2b12 (0.20 g, 46 %) as a pale yellow oil. IR (KBr, cm-1)  2921, 2850, 2223,
1606, 1510, 1457, 1442, 1356, 1293, 1250, 1166, 1093, 1030, 908, 886, 834, 816, 753,
673, 576, 544, 414; 1H NMR (600 MHz, CDCl3) δ 2.39 (3H, s), 3.78 (3H, s), 4.35 (2H,
s), 4.36 (2H, s), 6.79 (2H, d, J=8.2 Hz), 7.16 (2H, d, J=8.9 Hz), 7.32 (2H, d, J=8.2 Hz),
13
7.76 (2H, d, J=8.2 Hz); C NMR (150 MHz, CDCl3) δ 21.5 (q), 35.0 (t), 38.6 (t), 55.2
(q), 78.4 (s), 87.2 (s), 113.4 (s), 113.7 (s), 113.8 (d×2), 127.8 (d×2), 129.9 (d×2), 133.1
(d×2), 133.9 (s), 144.8 (s), 159.9 (s); EIMS m/z 354 (M+), 199 (M+-Tos). High
resolution mass (EI) calcd for C19H18N2O3S: 354.1038, found m/z 354.1043.
N-Cyanomethyl-N-[3-(4-chlorophenyl)-2-propyn-1-yl]-p-toluenesulfonamide (2c).
A
mixture of triethylamine (2.5 mL), N-cyanomethyl-N-(2-propyn-1-yl)-p-
toluenesulfonamide (2e) (0.30 g, 1.21 mmol), 4-chloroiodobenzene (0.30 g, 1.21 mmol),
(23 mg, 1.21 × 10-5 mmol) and bis(triphenylphosphine)palladium(II) dichloride (24
mg, 2.06 × 10-3 mmol) was stirred for 2.5 h at 50 C. The reaction mixture was
o
poured into water (100 mL). The organic layer was separated and the aqueous layer
was extracted with AcOEt. The combined organic layer was washed with sat. NH4Cl
solution (30 mL) and water (30 mL) and then dried over MgSO4. The solvent was
removed under reduced pressure. The residue was purified by preparative TLC on
silica gel eluting with AcOEt-n-hexane (1:4) to give the titled compound 2c14 (0.33 g,
75 %), (mp 112-113 C, from CH2Cl2-n-hexane) as white powders. IR (KBr, cm-1) 
o
2923, 2350, 2252, 1490, 1360, 1263, 1222, 1165, 1092, 1015, 911, 885, 831, 747, 665,
583, 550; 1H NMR (600 MHz, CDCl3) δ 2.39 (3H, s, Me), 3.78 (3H, s, Me), 4.35 (2H, s,
CH2), 4.36 (2H, s, CH2), 6.79 (2H, d, J=8.2 Hz, ArH), 7.16 (2H, d, J=8.9 Hz, ArH),
7.32 (2H, d, J=8.2 Hz, ArH), 7.76 (2H, d, J=8.2 Hz, ArH); 13C NMR (150 MHz,
CDCl3) δ 21.6 (q), 35.3 (t), 38.6 (t), 80.9 (q), 86.1 (s), 113.6 (s), 119.9 (s), 127.9 (d×2),
128.6 (d×2), 130.0 (d×2), 132.9 (d×2), 134.0 (s), 135.1 (s), 145.0 (s); EIMS m/z 358
(M+-1), 203 (M+-Tos), 91 (M+-Tos-C6H4Cl). Anal. Calcd for C18H15N2O2SCl: C,
60.25; H, 4.21; N, 7.80. Found: C, 60.10; H, 3.86; N, 7.74.
N-Cyanomethyl-N-(2-pentyn-1-yl)-p-toluenesulfonamide (2d).
To a THF (2.0 mL) solution of N-(4-methylphenylsulfonyl)aminoacetonitrile (1) (0.61 g,
2.9 mmol), 2-pentyn-1-ol (0.244 g, 2.9 mmol), triphenylphosphine (0.76 g, 2.9 mmol)
was added DEAD (1.3 ml of 2.2 M THF, 2.9 mmol) under an Ar atmosphere. The
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reaction mixture was stirred for 1 h. The solvent was removed under reduced pressure.
The residue was purified by column chromatography on silica gel
(AcOEt-n-hexane=1:10) to give the titled compound 2d (0.474 g, 59 %) as a yellow oil.
IR (KBr, cm-1)  2980, 2939, 2923, 2236, 1598, 1495, 1439, 1417, 1357, 1333, 1255,
1
1167, 1122, 1094, 1018, 908, 888, 816, 745, 661, 574, 544, 424; H NMR (600 MHz,
CDCl3) δ 1.00 (3H, t, J=7.6 Hz, Me), 2.04-2.07 (2H, m, CH2), 2.44 (3H, s, Me), 4.10
(2H, t, J=2.1 Hz, CH2), 4.30 (2H, s, CH2), 7.35 (2H, brd, J=8.3 Hz, ArH), 7.73 (2H, brd,
13
J=8.2 Hz, ArH); C NMR (150 MHz, CDCl3) δ 12.1 (t), 13.3 (q), 21.5 (q), 34.8 (t),
38.1 (t), 70.2 (s), 89.6 (s), 113.6 (s), 127.8 (d×2), 129.9 (d×2), 134.0 (s), 144.7 (s). High
resolution mass (EI) calcd for C14H16N2O2S: 276.0932, found m/z 276.0950.
N-Cyanomethyl-N-(2-propyn-1-yl)-p-toluenesulfonamide (2e).
To a THF (6 mL) solution of N-(p-toluenesulfonyl)aminoacetonitrile (1.0 g, mmol),
propargyl alcohol (1.26 g, 4.8 mmol), triphenylphosphine (0.269 g, 4.8 mmol) was
added DEAD (2.2 ml, 4.8 mmol) under an Ar at mosphere. The solvent was removed
under reduced pressure. The residue was purified by column chromatography on silica
gel (AcOEt-n-hexane=1:10 then 1:5) to give the title compound15 2e (1.00 g, 89 %) as
white needles. 2e: mp 55-56 °C (from CH2Cl2-n-hexane), IR (KBr, cm-1)  3290, 2987,
2925, 2361, 2124, 1709, 1598, 1357, 1167, 1094, 903, 886, 817, 754, 664, 577, 544,
492, 403; 1H NMR (600 MHz, CDCl3) δ 2.30 (1H, t, J=2.1 Hz, CH), 2.45 (3H, s, Me),
4.13 (2H, s, CH2), 4.33 (2H, s, CH2), 7.37 (2H, d, J=8.2 Hz, ArH), 7.73 (2H, d, J=8.2
13
Hz, ArH); C NMR (150 MHz, CDCl3) δ 21.6 (q), 34.8 (t), 37.4 (t), 74.8 (s), 75.7 (s),
113.3 (s), 127.8 (d×2), 130.1 (d×2), 133.8 (s), 145.1 (s); EIMS m/z 248 (M+).
N-Cyanomethyl-N-[3-(phenylsulfanyl)-2-propyn-1-yl]-p-toluenesulfonamide (2f):
To a THF (12.5 mL) solution of N-(p-toluenesulfonyl)aminoacetonitrile (2.50 g, 11.9
mmol), 3-(phenylsulfanyl)propargyl alcohol (1.90 g, 11.9 mmol) and
triphenylphosphine (3.10 g, 11.9 mmol) was added dropwise diethyl azodicarboxylate
(2.2 M, 5.40 mL, 11.9 mmol) under an Ar atmosphere. The reaction mixture was
stirred for 1 h. The solvent was removed under reduced pressure. The residue was
purified by column chromatography on silica gel eluting with AcOEt-n-hexane (1:10,
then 1:5) to give the titled compound 2f (4.20 g, 100 %) as colorless prisms. 2f: mp
o
45-47 C (from CH2Cl2-n-hexane), IR (KBr, cm-1)  2978, 2924, 2188, 1709, 1596,
1582, 1479, 1441, 1356, 1330, 1165, 1094, 908, 886, 815; 1H NMR (600 MHz, CDCl3)
δ 2.39 (s, Me, 3H), 4.32 (s, CH2, 2H), 4.39 (s, CH2, 2H), 7.29-7.34 (m, ArH, 7H), 7.72
(d, J=8.2 Hz, ArH, 2H); 13C NMR (150 MHz, CDCl3) δ 21.6 (q), 35.1 (t), 39.0 (t), 75.4
(s), 89.5 (s), 113.4 (s), 126.6 (d×2), 127.0 (d), 127.7 (d×2), 129.4 (d×2), 130.1 (d×2),
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131.3 (s), 133.7 (s), 145.1 (s); EIMS m/z 356 (M+), 266 (M+-Tol). Anal. Calcd for
C18H16N2O2S2: C, 60.65; H, 4.52; N, 7.86. Found: C, 60.51; H, 4.48; N, 7.83.
Screening for Suitable Reaction Condition, Results of Table 1 and Preparation of
Alkyl 4-(Prop-2-yn-1-ylamino)but-2-enoates (3).
Procedure of entry 1 in Table 1.
N-Cyanomethyl-N-(3-phenyl-2-propyn-1-yl)-p-toluenesulfonamide (3aa) (50 mg, 0.16
mmol) was added to a THF (1 mL) suspension of ethyl bromoacetate (0.134 g, 0.80
mmol) and zinc (0.10 g, 1.60 mmol, activated by two drops of TMSCl) at room
temperature. The reaction mixture was refluxed for 1 h, then, poured into water. The
organic layer was separated and the aqueous layer was extracted with AcOEt. The
combined organic layer was dried over MgSO4. The solvent was removed under
reduced pressure. The residue was separated by the preparative TLC on silica gel
eluting
with
AcOEt-n-hexane
(1:5)
to
give
ethyl
3-amino-4-[N-3-(phenylprop-2-yn-1-yl)-N-(p-toluenesulfonyl)amino]but-2-enoate (3aa)
(65 mg, quant) as colorless prisms. The large scale reaction of 2a (0.50 g, 1.54 mmol)
with zinc (0.50 g, 7.71 mmol) and ethyl bromoacetate (0.77 g, 4.62 mmol) in THF (8.0
mL) and the workup procedure gave a crude residue, which was precipitated from
hexane. The almost pure 3aa was quantitatively obtained as white powders.
mp 127-128 oC, IR (KBr, cm-1) 3459, 2925, 2853, 1733, 1672, 1625, 1569, 1491, 1443,
1
1351, 1284, 1164, 1092, 1041, 903, 814, 794, 758, 662, 586, 549, 417; H NMR (600
MHz, CDCl3) δ 1.26 (3H, t, J=7.6 Hz, Me), 2.35 (3H, s, Me), 3.85 (2H, s, CH2), 4.13
(2H, q, J=7.5 Hz, CH2), 4.33 (2H, s, CH2), 4.62 (1H, s, olefinic H), 5.37 (2H, brs, NH),
7.08 (2H, d, J=7.6 Hz, ArH), 7.25-7.28 (5H, m, ArH), 7.79 (2H, d, J=8.2 Hz, ArH); 13C
NMR (150 MHz, CDCl3) δ 14.5 (q), 21.4 (q), 37.6 (t), 50.1 (t), 59.0 (t), 80.9 (s), 85.4
(q), 86.3 (s), 121.8 (s), 127.8 (d×2), 128.1 (d×2), 128.6 (d), 129.7 (d×2), 131.5 (d×2),
135.4 (s), 144.1 (s), 155.4 (s), 169.6 (s); EIMS m/z 412 (M+), 257 (M+-Tos). Anal.
Calcd for C22H24N2O4S: C, 64.06; H, 5.86; N, 6.79. Found: C, 63.92; H, 5.89; N, 6.71.
Ethyl
3-Amino-2,7-dihydro-5-phenyl-1-(p-toluenesulfonyl)-1H-azepine-4-
carboxylate (4aa), entry 8 in Table 1, Typical Procedure.
N-Cyanomethyl-N-(3-phenyl-2-propyn-1-yl)-p-toluenesulfonamide (2a) (50 mg, 0.16
mmol) was added to a dioxane (1 mL) suspension of ethyl bromoacetate (0.134 g, 0.80
mmol) and zinc (0.10 g, 1.60 mmol, activated by two drops of TMSCl) at room
temperature. To the resulting mixture was then added hafnium(IV) triflate (24.8 mg,
o
0.032 mmol) and the mixture was stirred for 9 h at 100 C. Work-up and purification
by the preparative TLC on silica gel eluting with AcOEt-n-hexane (1:5) gave the titled
compound 4aa (56 mg, 85 %) as white powders, accompanied by a small amount of 2a.
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mp 184–185 C. IR (KBr, cm-1)  3435, 2925, 2854, 1732, 1665, 1615, 1532, 1456,
1
1446, 1330, 1259, 1161, 1092, 915, 756, 548, 446; H NMR (600 MHz, CDCl3) δ 0.63
(3H, t, J=6.9 Hz, Me), 2.40 (3H, s, Me), 3.78-4.14 (6H, m, CH2), 5.01 (1H, s, NH), 5.81
(1H, t, J=7.6 Hz, CH), 7.21-7.26 (5H, m, ArH), 7.28 (2H, d, J=8.3 Hz, ArH), 7.72 (2H,
d, J=8.3 Hz, ArH), 8.26 (1H, s, NH); 13C NMR (150 MHz, CDCl3) δ 13.4 (q), 21.5 (q),
44.2 (t), 50.1 (t), 59.1 (t), 96.8 (s), 117.9 (d), 126.5 (d×2), 127.2 (d×2), 127.3 (d), 127.9
(d×2), 129.9 (d×2), 135.7 (s), 141.8 (s), 143.8 (s), 147.3 (s), 155.6 (s), 168.6 (s); EIMS
m/z 412 (M+), 256 (M+-Tos). Anal. Calcd for C22H24N2O4S: C, 64.06; H, 5.86; N, 6.79.
Found: C, 63.77; H, 5.90; N, 6.69.
Methyl 3-Amino-5-phenyl-1-(p-toluenesulfonyl)-2,7-dihydro-1H-azepine-4-
carboxylate (4ab), Table 2, entry 1.
4ab: N-Cyanomethyl-N-(3-phenylprop-2-ynyl)-p-toluenesulfonamide (2a) (50 mg, 0.15
mmol) was added to a dioxane (1.0 mL) suspension of methyl bromoacetate (0.11 g,
0.75 mmol) and zinc (98 mg, 1.50 mmol, activated by two drops of TMSCl) at room
temperature. To the resulting mixture was then added hafnium(IV) triflate (23 mg, 0.03
o
mmol), and the whole was stirred for 1 h at 100 C. Work-up and purification by
preparative TLC gave a crude residue, which was precipitated from hexane. The titled
o
compound 4ab (48 mg, 80 %) was obtained as pale yellow powders (mp 170–171 C)
(from CH2Cl2-n-hexane). IR (KBr, cm-1)  3437, 3057, 3028, 2949, 2924, 1671, 1615,
1535, 1492, 1458, 1346, 1330, 1264, 1162, 1091, 1064, 905, 810, 756, 700, 681, 665,
756, 700, 681, 665, 624, 580, 548; 1H NMR (600 MHz, CDCl3) δ 2.40 (3H, s, Me), 3.31
(3H, s, OMe), 3.80 (4H, brs, CH2×2), 5.12 (1H, brs, NH), 5.83 (1H, t, J=7.5 Hz),
7.21-7.27 (5H, m, ArH), 7.29 (2H, d, J=8.3 Hz, ArH), 7.72 (2H, d, J=8.2 Hz, ArH),
8.34 (1H, brs, NH); 13C NMR (150 MHz, CDCl3) δ 21.5 (q), 44.1 (t), 50.0 (t), 50.5 (q),
96.2 (s), 118.2 (d), 126.2 (d×2), 127.2 (d×2), 127.4 (d), 128.0 (d×2), 129.9 (d×2), 135.7
(s), 141.3 (s), 144.1 (s), 146.8 (s), 155.6 (s), 169.0 (s). EIMS m/z 398 (M+), 243
(M+-Tos). Anal. Calcd for C21H22N2O4S: C, 63.30; H, 5.56; N, 7.03. Found: C,
63.18; H, 5.60; N, 6.82.
tert-Butyl
3-Amino-4-[N-3-(phenylprop-2-yn-1-yl)-N-(p-toluenesulfonyl)amino]-
but-2-enoate (3ac), entry 2.
N-Cyanomethyl-N-[3-phenyl-2-propyn-1-yl]-p-toluenesulfonamide (2a) (0.40 g, 1.23
mmol) was added to a THF (4.0 mL) suspension of tert-butyl bromoacetate (0.72 g,
3.70 mmol) and zinc (0.40 g, 6.70 mmol, activated by two drops of TMSCl) at room
temperature, and the mixture was stirred for 10 min at 75 °C. Work-up and precipitation
from hexane gave the titled compound 3ac (0.47 g, 87 %) as white needles. mp 97–98
oC (from CH2Cl2-n-hexane). A small scale reaction of 2a (50 mg, 0.15 mmol) with
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tert-butyl bromoacetate under the similar condition afforded 3ac in quantitative yield as
shown in Table 2, entry 2. IR (KBr, cm-1)  3471, 3339, 2926, 1668, 1562, 1491, 1443,
1390, 1351, 1290, 1252, 1163, 1092, 997, 901, 852, 797, 759, 718, 705, 691, 662, 585,
1
549; H NMR (600 MHz, CDCl3) δ 1.47 (9H, s, Me×3), 2.32 (3H, s, Me), 3.82 (2H, s,
CH2), 4.32 (2H, s, CH2), 4.56 (1H, s, olefinic H), 7.05 (2H, d, J=8.2 Hz, ArH),
7.23-7.27 (5H, m, ArH), 7.77 (2H, d, J=8.2 Hz, ArH), two protons of amino group were
not observed. 13C NMR (150 MHz, CDCl3) δ 21.3 (q), 28.4 (q×3), 37.4 (t), 50.0 (t), 78.6
(s), 81.0 (s), 86.1 (s), 87.0 (d), 121.7 (s), 127.6 (d×2), 128.0 (d×2), 128.4 (d), 129.6
(d×2), 131.4 (d×2), 135.3 (s), 143.9 (s), 154.5 (s), 169.3 (s); EIMS m/z 440 (M+), 383
(M+-t-Bu). Anal. Calcd for C24H28N2O4S: C, 65.43; H, 6.41; N, 6.36. Found: C,
65.17; H, 6.54; N, 6.33.
Ethyl 3-Amino-5-(4-methoxyphenyl)-1-(p-toluenesulfonyl)-1H-azepine-4- carboxyl-
ate (4ba), entry 3.
N-Cyanomethyl-N-[3-(4-methoxyphenyl)prop-2-yn-1-yl]-p-toluenesulfonamide
(2b)
(50 mg, 0.14 mmol) was added to dioxane (2.0 mL) suspension of ethyl bromoacetate
(0.12 g, 0.71 mmol) and zinc (92 mg, 1.4 mmol, activated by two drops of TMSCl) at
room temperature. To the resulting mixture was then added hafnium(IV) triflate (22 mg,
o
0.03 mmol), and the mixture was stirred for 33 h at 100 C. Work-up and purification
by preparative TLC gave the titled compound 4ba (48 mg, 78 %) as colorless plates.
o
171–172 C (from CH2Cl2-n-hexane). IR (KBr, cm-1)  3436, 3315, 2926, 2854, 2359,
2342, 1665, 1609, 1540, 1509, 1457, 1365, 1343, 1329, 1292, 1250, 1161, 1091, 1062,
1
1036, 917, 831, 760, 679, 607, 548; H NMR (600 MHz, CDCl3) δ 0.70 (3H, t, J=7.6
Hz, Me), 2.40 (3H, s, Me), 3.79 (3H, s, OMe), 3.84 (6H, brs, CH2×3), 5.17 (1H, brs,
NH), 5.74 (1H, t, J=7.6 Hz, CH), 6.79 (2H, d, J=9.0 Hz, ArH), 7.14 (2H, d, J=9.0 Hz,
ArH), 7.29 (2H, d, J=8.3 Hz, ArH), 7.72 (2H, d, J=8.3 Hz, ArH), 8.26 (1H, brs, NH);
1H NMR (600 MHz, C5D5N) δ 0.69 (3H, t, J=6.9 Hz, Me), 2.06 (3H, s, Me), 3.65 (3H, s,
OMe), 3.90 (2H, brs, CH2), 4.20 (4H, brs, CH2×2), 5.01 (1H, brs, NH), 5.85 (1H, t,
J=7.6 Hz, CH), 6.93 (2H, d, J=8.9 Hz, ArH), 7.35 (2H, d, J=8.9 Hz, ArH), 7.58 (2H, s,
ArH), 8.00 (2H, d, J=6.9 Hz, ArH), 9.19 (1H, brs, NH); 13C NMR (150 MHz, CDCl3) δ
13.6 (q), 21.5 (q), 44.2 (t), 50.1 (t), 55.3 (q), 59.1 (t), 96.8 (s), 113.3 (d×2), 116.5 (d),
127.2 (d×2), 127.5 (d×2), 129.9 (d×2), 134.4 (s), 135.7 (s), 143.7 (s), 146.6 (s), 155.4
(s), 159.1 (s), 168.6 (s); EIMS m/z 442 (M+), 287 (M+-Tos). Anal. Calcd for
C23H26N2O5S: C, 62.42; H, 5.92; N, 6.33. Found: C, 62.09; H, 5.96; N, 6.29.
Methyl
3-Amino-2,7-dihydro-5-(p-methoxyphenyl)-1-(p-toluenesulfonyl)-1H-
azepine-4-carboxylate (4bb), entry 4.
N-Cyanomethyl-N-[3-(4-methoxyphenyl)-2-propynyl]-p-toluenesulfonamide (2b) (50
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mg, 0.14 mmol) was added to a dioxane (1.0 mL) suspension of methyl bromoacetate
(0.134 g, 0.80 mmol) and zinc (79 mg, 1.2 mmol, activated by two drops of TMSCl) at
room temperature. To the resulting mixture was then added hafnium(IV) triflate (24.8
o
mg, 0.032 mmol), and the mixture was stirred for 40 min at 100 C. Work-up and
purification by preparative TLC gave the titled compound 4bb (30 mg, 71 %) as white
o
powders (mp 164–165 C). IR (KBr, cm-1)  3436, 3321, 2949, 1669, 1608, 1510,
1458, 1441, 1345, 1329, 1250, 1161, 1091, 1037, 904, 831, 760, 679, 662, 607, 548; 1H
NMR (600 MHz, CDCl3) δ 2.40 (3H, s, Me), 3.35 (3H, s, OMe), 3.79 (7H, brs, OMe
and CH2×2), 5.04 (1H, brs, NH), 5.77 (1H, t, J=7.5 Hz, ArH), 6.79 (2H, d, J=7.9 Hz,
ArH), 7.15 (2H, d, J=8.3 Hz, ArH), 7.29 (2H, d, J=8.3 Hz, ArH), 7.71 (2H, d, J=7.5 Hz,
13
ArH), 8.34 (1H, brs, NH); C NMR (150 MHz, CDCl3) δ 21.5 (q), 44.1 (t), 50.0 (t),
50.6 (q), 55.2 (q), 96.4 (s), 113.4 (d×2), 116.7 (d), 126.3 (d×2), 127.2 (d×2), 129.9
(d×2), 133.9 (s), 135.8 (s), 143.7 (s), 146.2 (s), 155.5 (s), 159.2 (s), 169.1 (s); EIMS m/z
428 (M+), 337 (M+-Tol), 273 (M+-Tos). Anal. Calcd for C22H24N2O5S: C, 61.70; H,
5.65; N, 6.54. Found: C, 61.45; H, 5.70; N, 6.45.
Preparation of tert-Butyl (Z)-3-Amino-4-[3-(p-methoxyphenyl)-N-(p-toluene-
sulfonylprop-2-ynylamino)but-2-enoate (3bc), entry 5.
N-Cyanomethyl-N-[3-(4-methoxyphenyl)prop-2-yn-1-yl]-4-methylphenylsulfonamide
(7) (3 mg, 0.21 mmol) was added to a THF (2.0 mL) suspension of tert-butyl
bromoacetate (0.172 g, 1.03 mmol) and zinc (135 mg, 2.06 mmol, activated by two
o
drops of TMSCl) at room temperature, and the mixture was stirred for 40 min at 75 C.
Work-up and purification by preparative TLC gave the title compound 6f (76 mg, 78 %)
as pale yellow oil. IR (KBr, cm-1)  3464, 3342, 2974, 2927, 1668, 1623, 1567, 1510,
1
1457, 1350, 1292, 1250, 1163, 1092, 1033, 902, 834, 799, 765, 747, 669, 580, 548; H
NMR (600 MHz, CDCl3) δ 1.47 (9H, s, Me×3), 2.36 (3H, s, Me), 3.79 (3H, s, OMe),
3.81 (2H, s, CH2), 4.31 (2H, s, CH), 4.55 (1H, s, olefinic H), 6.77 (2H, d, J=9.0 Hz,
ArH), 7.01 (2H, d, J=8.2 Hz, ArH), 7.27 (2H, d, J=8.2 Hz, ArH), 7.77 (2H, d, J=8.2 Hz,
1
ArH); the two hydrogen of amino group were not observed in the H NMR spectrum.
13CNMR (150 MHz, CDCl3) δ 21.4 (q), 28.4 (q×3), 37.6 (t), 50.0 (t), 55.2 (q), 78.7 (s),
79.6 (s), 86.0 (s), 87.0 (d), 113.7 (d×2), 113.8 (s), 127.7 (d×2), 129.6 (d×2), 132.9 (d×2),
135.4 (s), 143.9 (s), 154.6 (s), 159.7 (s), 169.4 (s); EIMS m/z 470 (M+), 413 (M+-t-Bu).
Anal. Calcd for C25H30N2O5S: C, 63.81; H, 6.43; N, 5.95. Found: C, 63.63; H, 6.37; N,
5.74.
Ethyl 3-Amino-5-(4-chlorophenyl)-2,7-dihydro-1-(p-toluenesulfonyl)-1H-azepine-
4-carboxylate (4ca), entry 6.
N-Cyanomethyl-N-[3-(4-chlorophenyl)prop-2-yn-1-yl]-p-toluenesulfonamide (2c) (50
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mg, 0.14 mmol) was added to a dioxane (2.0 mL) suspension of ethyl bromoacetate
(0.12 g, 0.70 mmol) and zinc (92 mg, 1.4 mmol, activated by two drops of TMSCl) at
room temperature, and the mixture was stirred for 21.5 h. Work-up and purification by
preparative TLC gave the titled compound 4ca (61.1 mg, 98 %) as colorless prisms (mp
183–184 oC). IR (KBr, cm-1)  3445, 3306, 2926, 2360, 1668, 1615, 1541, 1490, 1457,
1345, 1330, 1259, 1162, 1091, 1062, 1015, 916, 817, 761, 677, 586, 549; 1H NMR (600
MHz, CDCl3) δ 0.70 (3H, t, J=7.6 Hz, Me), 2.41 (3H, s, Me), 3.80 (6H, brs, CH2), 5.15
(1H, brs, NH), 5.76 (1H, t, J=7.6 Hz, olefinic H), 7.13 (2H, d, J=8.3 Hz, ArH), 7.21
(2H, d, J=8.3 Hz, ArH), 7.30 (2H, d, J=8.3 Hz, ArH), 7.72 (2H, d, J=8.2 Hz, ArH), 8.35
(1H, brs, NH); 13C NMR (150 MHz, CDCl3) δ 13.5 (q), 21.5 (q), 44.1 (t), 50.1 (t), 59.2
(t), 96.2 (s), 118.3 (d), 127.2 (d×2), 127.7 (dx2), 128.0 (d×2), 129.9 (d×2), 133.0 (s),
135.5 (s), 140.4 (s), 143.9 (s), 146.1 (s), 155.8 (s), 168.3 (s); EIMS m/z 446 (M+-1), 291
(M+-Tos). Anal. Calcd for C22H23N2O4SCl: C, 59.12; H, 5.19; N, 6.27. Found: C,
58.89; H, 5.16; N, 6.25.
Methyl 3-Amino-5-(4-chlorophenyl)-2,7-dihydro-1-(p-toluenesulfonyl)-1H-azepine-
4-carboxylate (4cb), entry 7.
N-Cyanomethyl-N-[3-(4-chlorophenyl)prop-2-yn-1-yl]-p-toluenesulfonamide (2c) (40
mg, 0.11 mmol) was added to a dioxane (1.0 mL) suspension of methyl bromoacetate
(84 mg, 0.55 mmol) and zinc (73 mg, 1.4 mmol, activated by two drops of TMSCl) at
o
room temperature, and the mixture was stirred for 40 min at 100 C. Work-up and
purification by preparative TLC gave the titled compound 4cb (47 mg, 97 %) as
o
colorless needles (mp 181–183 C) (from CH2Cl2-n-hexane). IR (KBr, cm-1)  3435,
3318, 2949, 1671, 1614, 1532, 1488, 1440, 1402, 1345, 1329, 1263, 1161, 1091, 1063,
1
1013, 1905, 828, 762, 677, 586, 549; H NMR (600 MHz, CDCl3) δ 2.36 (3H, s, Me),
3.33 (3H, s , Me), 3.79 (4H, brs, CH2×2), 5.24 (1H, brs, NH), 5.79 (1H, t, J=7.5 Hz,
olefinic H), 7.14 (2H, d, J=8.3 Hz, ArH), 7.21 (2H, d, J=8.9 Hz, ArH), 7.29 (2H, d,
J=8.2 Hz, ArH), 7.71 (2H, d, J=8.3 Hz, ArH), one hydrogen of amino group was not
1
13
observed in the H NMR spectrum; C NMR (150 MHz, CDCl3) δ 21.5 (q), 44.0 (t),
50.0 (t), 50.6 (q), 95.8 (s), 118.6 (d), 127.2 (d×2), 127.5 (d×2), 128.2 (d×2), 129.9 (d×2),
133.2 (s), 135.6 (s), 139.9 (s), 143.9 (s), 145.8 (s), 156.0 (s), 168.7 (s); EIMS m/z 432
(M+), 277 (M+-Tos). Anal. Calcd for C21H21ClN2O4S: C, 58.30; H, 4.89; N, 6.47.
Found: C, 58.13; H, 4.91; N, 6.36.
Ethyl 3-Amino-5-ethyl-2,7-dihydro-1-(p-toluenesulfonyl)-1H-azepine-4-carboxyl-
ate (4da), entry 8.
N-Cyanomethyl-N-(2-pentyn-1-yl)-p-toluenesulfonamide (2d) (500 mg, 1.80 mmol)
was added to a dioxane (6.0 mL) suspension of ethyl bromoacetate (0.91 g, 5.43 mmol)
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and zinc (0.65 g, 10.0 mmol, activated by five drops of TMSCl) at room temperature.
To the resulting mixture was then added hafnium(IV) triflate (50.0 mg, 0.065 mmol),
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and the mixture was stirred for 1 h at 100 C. Work-up and purification by preparative
TLC gave the titled compound 4da (433 mg, 65 %) as white powders (mp 144–145 oC).
IR (KBr, cm-1)  3328, 2923, 2360, 2342, 1600, 1339, 1257, 1162, 1090, 908, 761, 669;
1H NMR (600 MHz, CDCl3) δ 0.83 (3H, t, J=7.6 Hz, Me), 1.25 (3H, t, J=6.9 Hz, Me),
2.29 (2H, q, J=6.9 Hz, CH2), 2.44 (3H, s, Me), 3.68 (4H, brs, CH2), 4.12-4.14 (2H, m,
CH2), 5.40 (1H, t, J=7.6 Hz, CH), 7.33 (2H, d, J=7.6 Hz, ArH), 7.71 (2H, d, J=8.3 Hz,
ArH), two hydrogens were not observed in the 1H NMR spectrum; 1H NMR (600 MHz,
C5D5N) δ 0.87 (3H, t, J=7.8 Hz, Me), 1.12 (3H, t, J=6.9 Hz, Me), 2.18 (3H, s, Me),
2.43 (2H, d, J=7.4 Hz, CH2), 3.99 (4H, brs, CH2), 4.16 (2H, d, J=6.9 Hz, CH2), 4.60
(1H, s, NH), 5.42 (1H, t, J=7.2 Hz, CH), 7.27 (2H, d, J=7.8 Hz, ArH), 7.99 (2H, d,
13
J=8.2 Hz, ArH), 8.89 (1H, s, NH); C NMR (150 MHz, CDCl3) δ 13.7 (q), 14.2 (q),
21.5 (q), 28.7 (t), 43.8 (t), 50.0 (t), 59.4 (t), 97.0 (s), 116.3 (d), 127.3 (d×2), 129.8 (d×2),
135.5 (s), 143.7 (s), 149.3 (s), 154.4 (s), 168.4 (s); EIMS m/z 364 (M+), 209 (M+-Tos).
Anal. Calcd for C18H24N2O4S: C, 59.32; H, 6.64; N, 7.69. Found: C, 59.51; H, 6.84; N,
7.44.
Methyl 3-Amino-5-ethyl-2,7-dihydro-1-(p-toluenesulfonyl)-1H-azepine-4-carboxyl-
ate (4db), entry 9.
N-Cyanomethyl-N-(2-pentyn-1-yl)-4-methylphenylsulfonamide (2d) (50 mg, 0.18
mmol) was added to a dioxane (1.0 mL) suspension of methyl bromoacetate (0.14 g,
0.91 mmol), and zinc (0.12 g, 1.8 mmol, activated by two drops of TMSCl) at room
temperature. To the resulting mixture was then added hafnium(IV) triflate (28 mg, 0.036
o
mmol), and the mixture was stirred for 1.3 h at 100 C. Work-up and purification by
preparative TLC gave the titled compound 4db (47 mg, 74 %) as white powders (mp
129–130 oC). IR (KBr, cm-1)  3443, 3322, 2964, 2872, 1670, 1615, 1529, 1458, 1439,
1
1347, 1328, 1252, 1186, 1163, 1091, 991, 905, 812, 760, 708, 676, 620, 549; H NMR
(600 MHz, CDCl3) δ 0.82 (3H, t, J=7.5 Hz, Me), 2.27 (2H, q, J=7.5 Hz, CH2), 2.44 (3H,
s, Me), 3.66 (3H, s, OMe), 3.70 (4H, brs, CH2×2), 5.40 (1H, t, J=7.6 Hz, olefinic H),
7.33 (2H, d, J=8.3 Hz, ArH), 7.71 (2H, d, J=8.3 Hz, ArH), two protons of amino group
1
13
were not observed in the H NMR spectrum; C NMR (150 MHz, CDCl3) δ 13.7 (q),
21.5 (q), 28.7 (t), 43.7 (t), 50.0 (t), 50.7 (q), 96.6 (s), 116.4 (d), 127.3 (d×2), 129.8 (d×2),
135.4 (s), 143.7 (s), 149.1 (s), 154.5 (s), 168.8 (s). EIMS m/z 350 (M+), 195 (M+-Tos).
Anal. Calcd for C17H22N2O4S: C, 58.26; H, 6.33; N, 7.99. Found: C, 58.11; H, 6.34; N,
7.94.
tert-Butyl
3-Amino-5-ethyl-2,7-dihydro-1-(p-toluenesulfonyl)-1H-azepine-4-
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carboxylate (4dc), entry 10.
N-Cyanomethyl-N-(2-pentyn-1-yl)-p-toluenesulfonamide (2d) (0.38 g, 1.37 mmol) was
added to a THF (2.0 mL) suspension of tert-butyl bromoacetate (1.33 g, 6.84 mmol) and
zinc (0.89 g, 13.7 mmol, activated by two drops of TMSCl) at room temperature. The
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mixture was stirred for 2 h at 100 C. Work-up and purification by preparative TLC
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gave the titled compound 4dc (0.29 g, 53 %) as white powders (mp 169–170 C)
(colorless prisms from CH2Cl2-n-hexane). IR (KBr, cm-1)  3448, 3308, 3291, 2979,
2931, 2873, 2853, 1658, 1604, 1523, 1456, 1390, 1366, 1341, 1327, 1292, 1277, 1252,
1157, 1089, 1058, 1039, 947, 917, 848, 818, 807, 766, 848, 818, 807, 766, 708, 670,
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618, 548; H NMR (600 MHz, CDCl3) δ 0.83 (3H, t, J=7.5 Hz, Me), 1.45 (9H, s,
tert-Bu), 1.54 (3H, s, Me), 2.28 (2H, q, J=6.9 Hz, CH2), 2.43 (2H, s, CH2), 3.67 (2H,
brd, J=6.9 Hz, CH2), 5.35 (1H, t, J=7.5 Hz, CH), 7.32 (2H, d, J=8.6 Hz, ArH), 7.70 (2H,
1
1
d, J=8.0 Hz, ArH), two hydrogens were not observed in the H NMR spectrum; H
NMR (600 MHz, C5D5N) δ 0.89 (3H, t, J=7.5 Hz, Me), 1.47 (9H, s, tert-Bu), 2.18 (3H,
s, Me), 2.43 (2H, q, J=7.3 Hz, CH2), 3.99 (2H, brd, J=5.6 Hz, CH2), 4.13 (2H, brs, CH2),
4.90 (1H, s, NH), 5.40 (1H, t, J=7.5 Hz, CH), 7.24 (2H, d, J=8.5 Hz, ArH), 7.95 (2H, d,
13
J=8.2 Hz, ArH), 8.73 (1H, s, NH); C NMR (150 MHz, CDCl3) δ 13.6 (q), 21.5 (q),
28.4 (q×3), 28.7 (t), 43.9 (t), 50.2 (t), 79.8 (s), 98.7 (s), 115.9 (d), 127.4 (d×2), 129.7
(d×2), 135.8 (s), 143.6 (s), 149.6 (s), 153.8 (s), 168.2 (s); EIMS m/z 392 (M+), 237
(M+-Tos). Anal. Calcd for C20H28N2O4S: C, 61.20; H, 7.19; N, 7.14. Found: C,
61.06; H, 7.14; N, 7.23.
Methyl 3-Amino-2,7-dihydro-1-(p-toluenesulfonyl)-1H-azepine-4-carboxylate (4ea),
entry 11.
N-Cyanomethyl-N-(2-propyn-1-yl)-p-toluenesulfonamide (2e) (100 mg, 0.40 mmol)
was added to a THF (2.0 mL) suspension of methyl bromoacetate (0.18 mg, 1.20 mmol),
and zinc (0.13 g, 2.0 mmol, activated by two drops of TMSCl) at room temperature. To
the resulting mixture was then added hafnium(IV) triflate (32 mg, 0.04 mmol), and the
mixture was stirred for 2 h at 75 °C. Work-up and purification by preparative TLC gave
o
the titled compound 4ea (49 mg, 37 %) as pale yellow powders (mp 174–176 C). IR
(KBr, cm-1)  3392, 2924, 2854, 1670, 1616, 1540, 1440, 1335, 1259, 1160, 1092, 976,
901, 805, 757, 709, 668, 597, 583; 1H NMR (600 MHz, CDCl3) δ 2.40 (3H, s, Me), 3.64
(3H, s, OMe), 3.93 (2H, s, CH2), 3.97 (2H, dd, J=4.1 and 1.6 Hz, CH2), 5.12 (1H, brs,
NH), 5.25 (1H, dt, J=11.7 and 4.1 Hz, olefinic H), 6.28 (1H, d, J=11.7 Hz, olefinic H),
7.26 (2H, d, J=8.2 Hz, ArH), 7.67 (2H, d, J=8.3 Hz, ArH), 8.43 (1H, brs, NH); 13C
NMR (150 MHz, CDCl3) δ 21.5 (q), 48.7 (t), 50.9 (q), 51.9 (t), 94.8 (s), 118.3 (d), 127.3
(d×2), 127.5 (d), 129.5 (d×2), 135.8 (s), 143.5 (s), 156.8 (s), 168.9 (s); EIMS m/z 322
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(M+). Anal. Calcd for C15H18N2O4S: C, 55.90; 5.63; 8.69. Found: C, 55.77; H, 5.61;
N, 8.51.
tert-Butyl
3-Amino-2,7-dihydro-1-(p-toluenesulfonyl)-1H-azepine-4-carboxylate
(4eb), entry 12.
N-Cyanomethyl-N-(2-propyn-1-yl)-p-toluenesulfonamide (2e) (50 mg, 0.20 mmol) was
added to a THF (1.0 mL) suspension of tert-butyl bromoacetate (0.19 g, 1.0 mmol), and
zinc (0.13 g, 2.0 mmol, activated by two drops of TMSCl) at room temperature. To the
resulting mixture was then added hafnium(IV) triflate (31 mg, 0.04 mmol), and the
mixture was stirred for 0.5 h at 75 °C. Work-up and purification by preparative TLC
gave the titled compound 4eb (19 mg, 25 %) as pale yellow powders (mp 124–126 oC).
IR (KBr, cm-1)  3436, 2976, 2925, 2852, 1664, 1611, 1534, 1455, 1249, 1160, 1092,
967, 903, 849, 815, 753, 709, 668, 549; 1H NMR (600 MHz, CDCl3) δ 1.44 (9H, s, Me),
2.40 (3H, s, Me), 3.89 (2H, brs, CH2), 3.95 (2H, dd, J=1.4 and 4.1 Hz, CH2), 5.20 (1H,
dt, J=4.2 and 12.3 Hz, olefinic H), 6.27 (1H, dt, J=1.4 and 12.4 Hz, olefinic H), 7.26
13
(2H, d, J=8.2 Hz, ArH), 7.67 (2H, d, J=8.3 Hz, ArH); C NMR (150 MHz, CDCl3) δ
21.5 (q), 28.4 (qx3), 48.6 (t), 52.0 (t), 79.5 (d), 96.5 (s), 117.6 (d), 127.3 (dx2), 128.5
(d), 129.5 (dx2), 135.8 (s), 143.4 (s), 156.0 (s), 168.3 (s); EIMS m/z 364 (M+). Anal.
Calcd for C18H24N2O4S: C, 59.32; H, 6.64; N, 7.69. Found: C, 59.28; H, 6.46; N, 7.55.
Synthesis of Ethyl 3-Amino-2,7-dihydro-5-(phenylsulfanyl)-1-(p-toluenesulfonyl)-
1H-azepine-4-carboxylate (4fa), entry 13.
N-Cyanomethyl-N-[3-(phenylsulfanyl)-2-propyn-1-yl]-p-toluenesulfonamide (2f) (50
mg, 0.14 mmol) was added to a THF (1 mL) suspension of ethyl bromoacetate (70 mg,
0.42 mmol) and zinc (46 mg, 0.70 mmol, activated by two drops of TMSCl) at room
temperature. To the resulting mixture was then added copper (II) acetate monohydrate
o
(6 mg, 0.03 mmol), and the mixture was stirred for 7 h at 75 C. After being cooled,
the reaction mixture was poured into a mixture of aqueous solution of NH4Cl (5 mL)
and water (50 mL). The whole was diluted with AcOEt and the organic layer was
separated. The aqueous layer was extracted with AcOEt. The combined organic layer
was dried over MgSO4. The residue was purified by preparative TLC on silica gel
eluting AcOEt-n-hexane (1:4) to give the titled compound 4fa (50 mg, 80 %) as pale
yellow prisms. mp 187-188 oC (from CH2Cl2-n-hexane). IR (KBr, cm-1)  3431, 3315,
1
2980, 1660, 1613, 1528, 1338, 1259, 1162, 1090, 1060, 912, 754, 671, 547; H NMR
(600 MHz, CDCl3) δ 1.29 (3H, t, J=6.8 Hz, Me), 2.45 (3H, s, Me), 3.73 (4H, s, CH2×2),
4.13 (2H, q, J=6.9 Hz, CH2), 5.18 (1H, brs, NH), 5.46 (1H, t, J=7.6 Hz, CH), 7.25 (5H,
d, J=4.9 Hz, ArH), 7.30 (2H, d, J=8.3 Hz, ArH), 7.66 (2H, d, J=8.3 Hz, ArH), 8.24 (1H,
13
brs, NH); C NMR (150 MHz, CDCl3) δ 14.2 (q), 21.6 (q), 44.2 (t), 50.0 (t), 60.0 (t),
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95.8 (s), 119.6 (d), 127.2 (d×2), 127.8 (d), 128.9 (d×2), 129.9 (d×2), 133.4 (d×2), 133.8
(s), 135.3 (s), 143.6 (s), 143.8 (s), 155.1 (s), 167.7 (s). EIMS m/z 444 (M+), 371
(M+-CO2Et), 335 (M+-SPh), 289 (M+-Tos). Anal. Calcd for C22H24N2O4S2: C, 59.44; H,
5.44; N, 6.30. Found: C, 59.39; H, 5.36; N, 6.08.
Synthesis of tert-Butyl 3-Amino-5-(phenylsulfanyl)-1-(p-toluenesulfonyl)-2,7-
dihydro-1H-azepine-4-carboxylate (4fb), entry 14.
N-Cyanomethyl-N-[3-(phenylsulfanyl)-2-propyn-1-yl]-p-toluenesulfonamide (2f) (50
mg, 0.14 mmol) was added to a dioxane (1 mL) suspension of tert-butyl bromoacetate
(137 mg, 0.70 mmol) and zinc (46 mg, 0.70 mmol, activated by two drops of TMSCl) at
room temperature. To the resulting mixture was then added hafnium triflate (22 mg,
o
0.03 mmol), and the mixture was stirred for 2.5 h at 100 C. After being cooled, the
reaction mixture was poured into a mixture of aqueous solution of NH4Cl (5 mL) and
water (50 mL). The whole was diluted with AcOEt and the organic layer was
separated. The aqueous layer was extracted with AcOEt. The combined organic layer
was dried over MgSO4. The residue was purified by preparative TLC on silica gel
eluting AcOEt-n-hexane (1:4) to give the compound 4fb (44 mg, 66 %) as white
o
powders. 4fb: White powders, mp 168-169 C, IR (KBr, cm-1)  3435, 3309, 2978,
2926, 1663, 1611, 1528, 1477, 1457, 1338, 1288, 1252, 1162, 1091, 1063, 911, 816,
1
785, 671, 549; H NMR (600 MHz, CDCl3) δ 1.48 (9H, s, Me×3), 2.44 (3H, s, Me),
3.66 (2H, brs, CH2), 3.71 (2H, brs, CH2), 5.36 (1H, t, J=7.5 Hz, CH), 7.25-7.26 (5H, m,
ArH), 7.29 (2H, d, J=8.3 Hz, ArH), 7.65 (2H, d, J=8.2 Hz, ArH), two hydrogens were
1
13
not observed in the H NMR spectrum; C NMR (150 MHz, CDCl3) δ 21.5 (q), 28.4
(q×3), 37.9 (t), 50.0 (t), 73.5 (s), 78.9 (s), 87.3 (d), 91.0 (s), 126.2 (d×2), 126.7 (d),
127.6 (d×2), 129.2 (d×2), 129.7 (d×2), 131.7 (s), 134.9 (s), 144.2 (s), 154.2 (s), 169.4
(s); EIMS m/z 472 (M+), 317 (M+-Tos). Anal. Calcd for C24H28N2O4S2: C, 60.99; H,
5.97; N, 5.93. Found: C, 60.67; H, 6.01; N, 6.13.
Methyl 3-Amino-5-(phenylsulfanyl)-1-(p-toluenesulfonyl)-2,7-dihydro-1H-azepine-
4-carboxylate (4fc), entry 15.
N-Cyanomethyl-N-[3-(phenylsulfanyl)-2-propynyl]-p-toluenesulfonamide (2f) (50 mg,
0.14 mmol) was added to a THF (1 mL) suspension of methyl bromoacetate (64 mg,
0.42 mmol) and zinc (46 mg, 0.70 mmol, activated by two drops of TMSCl) at room
temperature. To the resulting mixture was then added hafnium(IV) triflate (11 mg,
0.014 mmol), and the mixture was stirred for 3.5 h at 75 oC. Work-up and purification
by preparative TLC gave the titled compound 4fc (21 mg, 32 %) as colorless plates. mp
172–173 °C. IR (KBr, cm-1)  3433, 3318, 2948, 2925, 1671, 1615, 1530, 1440, 1338,
1263, 1163, 1091, 902, 756, 673, 548; 1H NMR (600 MHz, CDCl3) δ 2.45 (3H, s, Me),
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3.67 (3H, s, Me), 3.74 (4H, s, CH2), 5.26 (1H, brs, NH), 5.48 (1H, t, J=7.5 Hz, CH),
7.25 (5H, brs, ArH), 7.30 (2H, d, J=8.2 Hz, ArH), 7.67 (2H, d, J=8.2 Hz, ArH), 8.18
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(1H, brs, NH); H NMR (600 MHz, C5D5N) δ 2.22 (3H, s, Me), 3.69 (3H, s, Me), 4.04
(2H, s, CH2), 4.23 (1H, s, NH), 4.93 (2H, s, CH2), 5.66 (1H, t, J=7.6 Hz, CH), 7.23 (2H,
d, J=8.3 Hz, ArH), 7.26-7.29 (3H, m, ArH), 7.46 (2H, dd, J=1.4 and 8.2 Hz, ArH), 7.91
(2H, d, J=8.2 Hz, ArH), 9.00 (1H, s, NH); 13C NMR (150 MHz, CDCl3) δ 21.6 (q), 44.2
(t), 50.0 (t), 51.0 (q), 95.6 (s), 119.2 (d), 127.3 (d×2), 128.0 (d), 128.9 (dx2), 129.9
(dx2), 133.4 (s), 133.7 (dx2), 135.3 (s), 143.5 (s), 143.9 (s), 155.2 (s), 168.0 (s); EIMS
m/z 430 (M+), 275 (M+-Tos). Anal. Calcd for C21H22N2O4S2: C, 58.59; H, 5.15; N,
6.51. Found: C, 58.28; H, 5.20; N, 6.39.
3-Amino-4-benzoyl-5-(phenylsulfanyl)-1-(p-toluenesulfonyl)-2,7-dihydro-1H-
azepine (4fd), entry 16.
N-Cyanomethyl-N-[3-(phenylsulfanyl)prop-2-ynyl]-p-toluenesulfonamide (2f) (50 mg,
0.14 mmol) was added to a THF (1 mL) suspension of phenacyl bromide (0.14 g, 0.70
mmol) and zinc (92 mg, 1.4 mmol, activated by two drops of TMSCl) at room
temperature. To the resulting mixture was then added copper(II) acetate (6 mg, 0.028
o
mmol), and the mixture was stirred for 19 h at 100 C. Work-up and purification by
preparative TLC gave the titled compound 4fd (40 mg, 60 %) (mp 165-166 oC) as white
powders. mp 165–166 oC. IR (KBr, cm-1)  3399, 3186, 3059, 2922, 2867, 1599, 1475,
1338, 1275, 1162, 1092, 1051, 1026, 973, 921, 875, 815, 750, 689, 666, 631, 614, 574,
548; 1H NMR (600 MHz, CDCl3) δ 2.42 (3H, s, Me), 3.89 (4H, brs, CH2×2), 5.28 (1H, t,
J=7.5 Hz, olefiic H), 6.91 (2H, d, J=6.9 Hz, ArH), 7.20-7.22 (2H, m, ArH), 7.24-7.27
(1H, m, ArH), 7.29 (2H, d, J=8.2 Hz, ArH), 7.33-7.37 (2H, m, ArH), 7.44-7.48 (3H, m,
1
ArH), 7.70 (2H, d, J=8.2 Hz, ArH), two hydrogens were not observed in the H NMR
spectrum; 13C NMR (150 MHz, CDCl3) δ 21.5 (q), 44.6 (t), 50.4 (t), 104.0 (s), 115.8 (d),
127.3 (d×2), 127.4 (d×2), 127.8 (d×2), 128.5 (d), 129.0 (d×2), 129.9 (d×2), 130.6 (d),
131.8 (s), 134.1 (d×2), 135.1 (s), 141.7 (s), 143.9 (s), 146.5 (s), 157.8 (s), 193.7 (s);
EIMS m/z 476 (M+), 321 (M+-Tos). Anal. Calcd for C26H24N2O3S2: C, 65.52; H, 5.08;
N, 5.88. Found: C, 65.42; H, 4.97; N, 5.71.
Preparation of Ethyl 3-Amino-4-[3-(phenyl)-N-(p-toluensulonyl)prop-2-ynyl-
amino]but-2-enoate (3aa), Typical Procedure.
N-Cyanomethyl-N-(3-phenyl-2-propyn-1-yl)-p-toluenesulfonamide (4) (0.37 g, 1.14
mmol) in THF (1.0 mL) was added to a Reformatsky reagent (prepared from zinc (0.37
g, 5.70 mmol) and ethyl bromoacetate (0.57 g, 3.42 mmol) in THF (6.0 mL)). The
reaction mixture was refluxed for 10 min. The cooled mixture poured into water (50
mL). The organic layer was separated and the aqueous layer was extracted with
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AcOEt. The combined organic layer was dried over MgSO4. The solvent was
removed under reduced pressure. The residue was crystalized from n-hexane to give
the title compound (0.55 g, quant) as white powders.
Formation of Ethyl 3-Oxo-4-[N-(3-phenylprop-2-yn-1-yl)-N-(p-toluenesulfonyl)-
amino]butanoate (6aa).
Hafnium(IV) triflate (24.8 mg, 0.032 mmol) was added to a dioxane (1.0 mL) solution
of ethyl 3-amino-4-[3-(phenyl)-N-(p-toluensulonyl)prop-2-ynylamino]but-2-enoate
(3aa) (50 mg, 0.16 mmol). The reaction mixture was refluxed for 3 h. The cooled
reaction mixture was poured into water (50 mL). The organic layer was separated and
the aqueous layer was extracted with ethyl acetate. The combined organic layer was
dried over MgSO4. The solvent was removed under reduced pressure. The residue
was purified by preparative TLC on silica gel eluting with EtOAc-n-hexane (1:3) to the
title compound 6aa (19 mg, 29 %) as white powders. The compound 6aa was
synthesized from another route by the hydrolysis with a catalytic amount of
p-toluenesulfonic acid in 66% yield.
IR (KBr, cm-1) 3440, 2981, 2925, 2594, 2243, 1748, 1727, 1599, 1491, 1443, 1405,
1
1351, 1257, 1164, 1092, 1068, 1029, 927, 816, 759, 717, 693, 663, 586, 546 ; H NMR
(600 MHz, CDCl3) 1.26 (3H, t, J=7.6 Hz, Me), 2.36 (3H, s, Me), 3.69 (2H, s, CH2),
4.13 (2H, s, CH2), 4.17 (2H, q, J=7.5 Hz, CH2), 4.38 (2H, s, CH2), 7.11 (2H, d, J=6.8
Hz, ArH), 7.23-7.26 (3H, m, ArH), 7.29 (2H, d, J=8.3 Hz, ArH), 7.75 (2H, d, J=8.3 Hz,
ArH); 13C NMR (125 MHz, CDCl3)  14.0 (q), 21.4 (q), 39.4 (t), 46.2 (t), 55.7 (t), 61.6
(t), 81.0 (s), 86.4 (s), 121.7 (s), 127.8 (dx2), 128.1 (dx2), 128.6 (d), 129.7 (dx2), 131.5
(dx2), 134.8 (s), 144.2 (s), 166.9 (s), 198.6 (s). The molecular ion peak was not
observed in both EI and TOF mass spectrum. Anal. Calcd for C22H23NO5S: C, 63.91;
H, 5.61; N, 3.39. Found: C, 64.09; H, 5.84; N, 3.37.
Synthesis of (Z)-Ethyl 3-Amino-3-[2,5-dihydro-1-(p-toluenesulfonyl)-3-phenyl-
1H-pyrrol-2-yl]prop-2-enoate (5aa), Typical Procedure.
Copper acetate (0.16 g, 0.82 mmol) was added to a dioxane (2.8 mL) solution of ethyl
3-amino-4-[3-(phenyl)-N-(p-toluensulonyl)prop-2-ynylamino]but-2-enoate (3aa) (283
mg, 0.69 mmol). The cooled reaction mixture was poured into water (50 mL). The
organic layer was separated and the aqueous layer was extracted with ethyl acetate.
The combined organic layer was dried over MgSO4. The solvent was removed under
reduced pressure. The residue was purified by preparative TLC on silica gel eluting
with EtOAc-n-hexane (1:3) to the title compound 5aa (225 mg, 80 %) as white
powders.
o
mp 64-65 C, IR (KBr, cm-1) 3457, 3332, 2980, 2925, 2869, 2869, 2361, 1669, 1625,
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1561, 1496, 1446, 1342, 1164, 1094, 815, 792, 757, 671, 596, 550; 1H NMR (600 MHz,
CDCl3) 1.22 (3H, t, J=7.5 Hz, Me), 2.39 (3H, s, Me), 4.05 (2H, dq, J=7.6 and 1.3 Hz,
CH), 4.27 (1H, dd, J=4.8 and 15.8 Hz, CH), 4.38 (1H, dd, J=4.8 and 15.8 Hz, CH), 4.66
(1H, s, olefinic H), 5.27 (1H, d, J=4.8 Hz, 2-H), 6.16 (1H, brs, olefinic H), 7.26-7.30
(7H, m, ArH), 7.73 (2H, d, J=8.2 Hz, ArH), two hydrogens were not observed in the 1H
NMR spectrum; 13C NMR (125 MHz, CDCl3)  14.4 (q), 21.5 (q), 55.1 (t), 58.9 (t),
69.5 (d), 86.2 (d), 122.4 (d), 126.1 (dx2), 127.3 (dx2), 128.6 (dx3), 129.7 (dx2), 131.9
(s), 134.7 (s), 138.8 (s), 143.9 (s), 158.4 (s), 169.8 (s); EIMS m/z 412 (M+), 367
(M+-EtO), 298 (M+-H2NC=CHCO2Et), 257 (M+-Ts). High-resolution mass calcd for
C22H24N2O4S: 412.1457, found m/z 412.1456.
Hafnium-Catalyzed Reformatsky Reaction of 3aa with Ethyl Bromoacetate/Zinc.
N-Cyanomethyl-N-(3-phenyl-2-propyn-1-yl)-p-toluensulonamide (3aa) (50 mg, 0.16
mmol) was added to a dioxane (1 mL) suspension of ethyl bromoacetate (0.134 g, 0.80
mmol) and zinc (0.10 g, 1.60 mmol, activated by two drops of TMSCl) at room
temperature. To the resulting mixture was then added hafnium(IV) triflate (24.8 mg,
o
0.032 mmol) and the mixture was stirred for 9 h at 100 C. Work-up and purification
by the preparative TLC on silica gel gave the titled compound 4aa (56 mg, 85 %) as
white powders.
Synthesis of 2,5-Dihydropyrroles from Alkyl 3-Aminoprop-2-ynylbutenoates (Table
3).
Preparation of Ethyl-3-Amino-4-[N-(pent-2-ynyl)-N-(p-toluenesulfonyl)amino]-
but-2-enoate (3da).
N-Cyanomethyl-N-[3-(p-chlorophenyl)-2-propyn-1-yl]-p-toluensulonamide (0.50 g,
1.81 mmol) in THF (1.0 mL) was added to a Reformatsky reagent (prepared from zinc
(0.59 g, 9.05 mmol) and ethyl bromoacetate (0.91 g, 5.42 mmol) in THF (10.0 mL).
The reaction mixture was refluxed for 10 min and then poured into water (50 mL).
The organic layer was separated and the aqueous layer was extracted with AcOEt. The
combined organic layer was dried over MgSO4. The solvent was removed under
reduced pressure. The residue was crystalized from n-hexane. The almost pure
compound 3da (0.76 g, quant) was obtained as white powders. IR (KBr, cm-1)  3465,
3340, 2979, 2936, 1672, 1624, 1567, 1444, 1351, 1285, 1163, 1092, 903, 815, 791, 763,
1
661, 576, 549, 405; H NMR (600 MHz, CDCl3)  0.90 (3H, t, J=7.6 Hz, CH3), 1.26
(3H, t, J=6.9 Hz, CH3), 1.93 (2H, t, J=2.0 and 7.5 Hz, CH2), 2.43 (3H, s, Me), 3.76 (2H,
s, CH2), 4.08 (2H, brs, CH2), 4.12 (2H, q, J=6.9 Hz, CH2), 4.57 (1H, s, olefinic H), 5.39
(1H, brs, NH), 7.32 (2H, d, J=7.6 Hz, ArH), 7.75 (2H, d, J=8.3 Hz, ArH), one hydrogen
1
of amino group was not observed in the H NMR spectrum; 13C NMR (150 MHz,
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CDCl3)  12.0 (t), 13.3 (q), 14.4 (q), 21.5 (q), 37.2 (t), 49.7 (t), 58.8 (t), 71.1 (s), 85.0
(d), 88.3 (s), 127.8 (dx2), 129.5 (dx2), 135.5 (s), 143.9 (s), 155.7 (s), 169.5 (s); EIMS
m/z 364 (M+), 209 (M+-Tos). Anal. Calcd for C18H24N2O4S: C, 59.32; H, 6.64; N, 7.69.
Found: C, 59.38; H, 6.70; N, 7.50.
tert-Butyl
3-Amino-4-[N-(pent-2-ynyl)-N-(p-toluenesulfonyl)amino]but-2-enoate
(3dc)
N-Cyanomethyl-N-[3-(p-chlorophenyl)-2-propyn-1-yl]-p-toluensulonamide (2d) (0.40 g,
1.45 mmol) was added to a dioxane (3.0 mL) suspension of tert-butyl bromoacetate
(0.85 g, 4.34 mmol) and zinc (0.47 g, 7.25 mmol, activated by two drops of TMSCl) at
o
room temperature, and the mixture was stirred for 10 min at 100 C. Work-up and
purification by column chromatography gave the titled compound 3dc (0.60 g, quant) as
white powders. mp 61–65 oC (from CH2Cl2-n-hexane). FT-IR (KBr, cm-1): 3468, 3340,
2978, 2926, 1712, 1669, 1625, 1561, 1362, 1351, 1291, 1254, 1162, 1150, 1093, 903,
798, 666, 659, 580, 573, 546; 1H NMR (600 MHz, CDCl3) δ 0.90 (3H, t, J=7.6 Hz, Me),
1.47 (9H, s, Mex3), 1.91-1.93 (2H, m, CH2), 2.43 (3H, s, Me), 3.73 (2H, s, CH2), 4.08
(2H, s, CH2), 4.50 (1H, s, olefinic H), 5.21 (1H, brs, NH), 7.31 (2H, d, J=8.2 Hz, ArH),
7.75 (2H, d, J=8.2 Hz, ArH), one proton of the amino group was not observed. 13C
NMR (150 MHz, CDCl3) δ 12.0 (t), 13.3 (q), 21.5 (q), 28.4 (q×3), 37.2 (t), 49.7 (t), 71.2
(s), 78.7 (s), 86.8 (d), 88.1 (s), 127.8 (d×2), 129.4 (d×2), 135.5 (s), 143.8 (s), 154.8 (s),
169.4 (s); EIMS m/z 335 (M+-t-Bu), 319 (M+-t-BuO). Anal. Calcd for C20H28N2O4S:
C, 61.20; H, 7.19; N, 7.14. Found: C, 60.87; H, 7.37; N, 7.10.
Ethyl 3-Amino-4-[N-(prop-2-ynyl)-N-(p-toluenesulfonyl)amino)but-2-enoate (3ea).
N-Cyanomethyl-N-(2-propyn-1-yl)-p-toluensulonamide (0.25 g, 1.00 mmol) in THF
(1.0mL) was added to a Reformtsky reagent (prepared from zinc (0.33 g, 5.00 mmol)
and methyl bromoacetate in THF (3.0 mL)). The reaction mixture was heated under
o
50 C. The workup procedure gave the title compound 3ea (0.29 g, 86 %) as white
powders. IR (KBr, cm-1)  3487, 3462, 3347, 3288, 3277, 2982, 1666, 1622, 1598,
1561, 1444, 1348, 1280, 1157, 1119, 1092, 1069, 1037, 925, 902, 802, 765, 659, 579,
1
551, 535; H NMR (600 MHz, CDCl3)  1.26 (3H, t, J=6.8 Hz, CH3), 2.05 (2H, m,
CH2), 2.30 (1H, t, J=2.0 Hz, CH), 2.44 (3H, s, Me), 3.78 (2H, brs, CH2), 4.12 (2H, q,
J=7.5 Hz, CH2), 4.59 (1H, s, CH), 7.32 (2H, d, J=8.2 Hz, ArH), 7.75 (2H, d, J=7.2 Hz,
ArH), two hydrogens were not observed in the 1H NMR spectrum; 13C NMR  14.1 (q),
21.5 (q), 36.4 (t), 49.7 (t), 58.9 (t), 74.5 (s), 85.4 (d), 127.7 (dx2), 129.7 (dx2), 130.1 (d),
135.3 (s), 144.2 (s), 155.1 (s), 169.5 (s); EIMS m/z 336 (M+), 181 (M+-Tos). Anal.
Calcd for C16H20N2O4S: C, 57.13; H, 5.99; N, 8.33. Found: C, 56.88; H, 6.23; N, 8.32.
tert-Butyl
3-Amino-4-[N-(prop-2-ynyl)-N-(p-toluenesulfonyl)amino)but-2-enoate
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