Platinum catalyzed 7-endo cyclization of internal alkynyl amides and its application to synthesis of the caprazamycin core

Article abstract of DOI:10.1039/c2ob25111f

The scope and limitations of the platinum catalyzed 7-endo cyclization of internal alkynyl amides were investigated. Substitution of the alkyne with an aryl group gave better results, presumably because it stabilized the transition state. Applying the reaction to a secondary amide, the caprazamycin core was successfully synthesized from commercially available material in eight steps.

Full text of DOI:10.1039/c2ob25111f

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PAPER
Platinum catalyzed 7-endo cyclization of internal alkynyl amides and its
application to synthesis of the caprazamycin core†‡
Chihiro Tsukano, Shinsuke Yokouchi, Anne-Lise Girard, Toshifumi Kuribayashi, Shota Sakamoto,
Taro Enomoto and Yoshiji Takemoto*
Received 15th January 2012, Accepted 9th March 2012
DOI: 10.1039/c2ob25111f
The scope and limitations of the platinum catalyzed 7-endo cyclization of internal alkynyl amides were
investigated. Substitution of the alkyne with an aryl group gave better results, presumably because it
stabilized the transition state. Applying the reaction to a secondary amide, the caprazamycin core was
successfully synthesized from commercially available material in eight steps.
groups (R = aryl) gave a six-membered product 3 rather than a
Introduction
seven-membered one.6c Thus, a reliable method is still required
Transition metal-catalyzed inter- and intramolecular hydro-
amidation is a powerful method for the synthesis of amides,
which are fundamental structures in natural products and pharma-
ceutical compounds.1 Coupling an amide with an alkyne is of par-
ticular interest, because this approach is atom economical and
provides enamides under mild conditions. For example, Goossen
and co-workers described the anti-Markovnikov addition of an
amide to an alkyne.2 The stereochemistry was controlled by a
ruthenium catalyst, Lewis acid, and ligands. Takai and Kuninobu
et al. reported rhenium-catalyzed intermolecular hydroamidation
of unactivated terminal alkynes for synthesis of (E)-enamides.3
Copper-catalyzed intermolecular amidation of alkynes was also
reported by the Evano and Kundu groups.4,5 Intramolecular
hydroamidation of an alkyne was broadly investigated for for-
mation of N-heterocycles using palladium,6 copper,7 gold,8 and
platinum catalysts.9–12 Interestingly, a nitrogen-containing seven-
membered ring could be constructed using these reactions.
Mitchell et al. reported synthesis of benzoazepinone via
palladium-catalyzed intramolecular hydroamidation of internal
alkynes 1 substituted with one alkyl group and one aryl group
(Scheme 1, R = alkyl).6a Liu and co-workers described a gold-
catalyzed 7-endo cyclization of alkynyl amide substituted with
two aryl groups (R = aryl).8 However, these reaction conditions
are not applicable to various substituted alkynyl amides. For
example, Mitchell et al. found that palladium-catalyzed intramo-
lecular hydroamidation of alkynes, substituted with two aryl
for preparing various cyclic enamides, and especially for control-
ling regiochemistry.
We recently reported intramolecular hydroamidation of term-
inal alkynes using PtCl2 and Bi(OTf)3 as catalysts.9,13,14 Starting
from the same alkynyl amide, the 7-endo cyclization using a
platinum catalyst produced 1,4-diazepanone derivatives and the
6-exo cyclization using a bismuth catalyst produced piperazin-2-
one derivatives. These reactions are useful because terminal
alkynes can be used. The obtained structures are found in natural
products and pharmaceutical compounds, such as caprazamycin
A, which could be used to develop new drug candidates for
tuberculosis (Fig. 1).15 For further application, the substrate
scope and limitations of the reaction conditions need to be deter-
mined. In this paper, we will report platinum-catalyzed hydro-
amidation of internal alkynes with various substrates, and
synthetic studies of the caprazamycin core using the developed
reaction.
Results and discussion
Initially, phenyl substituted alkynyl amide 7 was prepared from
L-phenylalanine methyl ester hydrochloride 4 for platinum and
bismuth-catalyzed cyclizations. Ammonolysis of methyl ester
was followed by nosyl (Ns) protection16 to give amide 5
(Scheme 2). After introduction of a propargyl group, the
46-29 Yoshida, Sakyo-ku, Kyoto, Japan. E-mail: takemoto@pharm.
kyoto-u.ac.jp; Fax: +81 75 753 4569; Tel: +81 75 753 4528
†This article is part of the Organic & Biomolecular Chemistry 10th
Anniversary issue.
‡Electronic supplementary information (ESI) available: 1H and 13C
NMR spectral data and crystallographic data of compound 9 in CIF.
CCDC 869849. For ESI and crystallographic data in CIF or other elec-
tronic format see DOI: 10.1039/c2ob25111f
Scheme 1 Transition metal-catalyzed hydroamidation.
6074 | Org. Biomol. Chem., 2012, 10, 6074–6086
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Fig. 1 Caprazamycin A.
Fig. 2 The X-ray structure of compound 9. Thermal ellipsoids are
shown at the 50% probability level.
clearly showed that it contained an enamide moiety.18 Thus, the
cyclized product 9 was hydrolyzed under acidic conditions to
ketocarboxylic acid 13, whose structure was determined by
NMR spectroscopy. These results indicated that the platinum
catalyzed cyclization gave the 7-endo cyclized product 9. The
structure of compound 9 was also unambiguously secured by
X-ray crystal structure analysis (Fig. 2).19 Protection of the
amine was essential for this reaction. Platinum-catalyzed cycliza-
tion of compound 8 prepared from 7 by deprotection of the Ns
group resulted in recovery of the starting material 8, because the
platinum catalyst was probably inactivated by coordination of
the secondary amine.
Scope and limitations of platinum catalyzed 7-endo cyclization
We then investigated the effect of substitution on the 7-endo
cyclization. Aryl alkynyl amides 14a–d with electron rich aro-
matic rings, such as 2,4-dimethoxyphenyl, p-methoxyphenyl,
tolyl and naphthyl, were treated with PtCl2 in dichloroethane at
70 °C. In these cases, the platinum catalyzed 7-endo cyclization
proceeded to give the desired products 15a–d in 70–97% yield
(Table 1, entries 1–4). For diazepanone 15d, the regioselectivity
was confirmed again by hydrolysis under acidic conditions
(Scheme 3). The obtained carboxylic acid 16 indicated that
nucleophilic addition of nitrogen occurred at the sp carbon next
to the naphthyl group. Interestingly, the 7-endo cyclization of
aryl alkynyl amide 14g with a nitrophenyl group did not proceed
at all. The cyclizations of aryl alkynyl amides 14e and 14f with
chlorine and trifluoromethyl groups on the aromatic ring,
respectively, gave the cyclized products in excellent yields
(entries 5–7). These results suggest that electron donating and
weak electron withdrawing groups are tolerated on the aromatic
ring, but strong electron withdrawing groups suppress the 7-endo
cyclization.
Scheme 2 The synthesis of alkynyl amide 7 and its cyclization.
resultant terminal alkyne was treated with PhI, a catalytic
amount of Pd(PPh3)4, and CuI to give the cyclization precursor
7.17 In the platinum and bismuth catalyzed reactions, the four
isomers 9, 10, 11 and 12 might be produced by nucleophilic
addition of the nitrogen or oxygen atom of the amide via 6-exo
or 7-endo cyclization after activation of the alkyne by the metal
catalyst. When the phenyl substituted alkynyl amide 7 was
treated with PtCl2 in dichloroethane at 70 °C, 7-endo cyclized
product 9 was obtained as a single isomer. By contrast, bismuth-
catalyzed cyclization of 7 did not proceed at all. Structural
characterization of the 7-endo cyclized product 9 was confusing,
although spectroscopic analysis, including NMR spectroscopy,
Other substituents on the alkyne were also examined. With
methyl alkynyl amides 14h in the platinum catalyzed cyclization,
the cyclized product 15h was obtained in low yield along with a
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Table 1 7-endo-dig hydroamidation of aryl alkynyl amides 14a–i
Table 2 Effect of substitution at the α-position and protecting group
for the secondary amine of alkynyl amides in the 7-endo-dig
hydroamidation
Entry
Alkyne
R
Product
Yielda (%)
1
2
3
4
5
6
7
8
9
14a
14b
14c
14d
14e
14f
14g
14h
14i
2,4-(MeO)2C6H3
pMeOC6H4
pMeC6H4
1-Naphthyl
pClC6H4
pCF3C6H4
pNO2C6H4
Me
15a
15b
15c
15d
15e
15f
15g
15h
15i
72
82
70
97
99
99
0
Entry
Alkyne
R1
R2
Product
Yielda (%)
1
2
3
4
5
6
7
18a
18b
18c
18d
18e
18f
iBu
iPr
Me
Bn
Bn
Bn
Bn
pNs
pNs
pNs
Ts
CO2 Pr
Cbz
19a
19b
19c
19d
19e
19f
84
84
82
92
98
72
29b
i
33b
0c
TMS
18g
Boc
19g
a Isolated yield. b Methyl ketone 17 was obtained in 63% yield as by-
a Isolated yield. b Starting material (20%) was recovered and 19g′ was
obtained in 50% yield.
product. c No reaction.
Scheme 4 The side reaction with a Boc protecting group.
i
i
alkyne (18a–c, R1 = Bu, Pr and Me). Several protecting groups
could be employed for the secondary amine instead of the Ns
i
group. The reactions of 18d–f protected with tosyl, –CO2 Pr, and
Cbz groups proceeded smoothly to give the 7-endo cyclized pro-
ducts 19d–f in 72–98% yields (entries 4–6). When the Boc pro-
tecting group was used, the reaction gave the desired product
19g (29%) along with a large amount of a 6-endo cyclized
product 19g′ (50%), which was produced via nucleophilic
addition of the oxygen atom of Boc group following loss of a
tert-butyl group (Table 2, entry 7 and Scheme 4).20
These investigations indicate the presence of an aromatic ring
on the alkyne stabilizes the transition state of the 7-endo cycliza-
tion after activation of the alkyne by the platinum catalyst. Con-
sequently, the reaction was accelerated and the yields were
improved with an aromatic substituent compared with cyclization
of a terminal alkyne. These results will be helpful in synthesis of
substituted diazepanones, and we applied the reaction to syn-
thesis of the caprazamycin core.
Scheme 3 The hydrolysis of cyclized products 15d and 15h.
large amount of ketone 17 (Table 1, entry 8). While the 7-endo
cyclized products were generally stable under the reaction con-
ditions, in CDCl3 product 15h was almost fully decomposed to
by-product 17 within a few days (Scheme 3). Thus the by-
product 17 would be produced via hydrolysis of compound 15h
because of its lability under the reaction conditions. The 7-endo
cyclization of trimethylsilyl alkynyl amide 14i was also
attempted, but no reaction was observed, presumably because of
steric hindrance of the silyl group (entry 9).
Next, substituents at the α-position of the amide were exam-
ined. We previously observed a substitution effect at this position
in the reaction of terminal alkynyl amides.9 As the R1 group
became bulkier, the yield increased. In sharp contrast, the plati-
num catalyzed cyclization of internal alkynyl amides 18a, b, and
c substituted with phenyl groups derived from leucine, valine,
and alanine, respectively, proceeded smoothly to give diazepa-
nones 19a–c in 82–84% yield (Table 2, entries 1–3). Compared
with the reactions for the corresponding terminal alkynes, the
selectivity and reactivity increased with a phenyl substituent on
Application to synthesis of the caprazamycin core
Caprazamycins were isolated from Streptomyces sp. MK730-
62F2 by Igarashi et al. when screening drug seeds for tuberculo-
sis (Fig. 1).15 The structure was determined by extensive spectral
analysis, including 2D NMR, derivatization, and X-ray crystallo-
graphy. Caprazamycins are lipo-nucleoside antibiotics, which
have a diazepanone core with amino sugar, uridine, and lipid
6076 | Org. Biomol. Chem., 2012, 10, 6074–6086
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Scheme 5 The synthetic strategy for the caprazamycin core 20.
Scheme 6 Hydroamidation of terminal alkynylamide 25 and attempted
introduction of a methyl group.
Scheme 7 Hydroamidation of secondary alkynyl amides 31a–d and
synthesis of the core structure of caprazamycin 34.
side chains. These compounds show antibacterial activity against
Mycobacterium tuberculosis, including multi-drug resistant
strains (e.g., caprazamycin A: MIC = 3.3 μg mL−1). They are
thought to inhibit MraY for biosynthesis of peptidoglycan.21
Because of their interesting biological activities and structures,
lipo-nucleoside antibiotics, including caprazamycins, have
attracted attention from synthetic chemists and pharmacists. Total
synthesis of caprazole, which is a caprazamycin hemisphere, was
achieved by Matsuda and Ichikawa et al.22 Several attempts have
been made to construct the diazepanone skeleton in these com-
pounds, including reductive amination, intramolecular amidation,
and amination via double epoxide ring opening.23–30 Platinum
catalyzed 7-endo cyclization could provide a concise route for
synthesis of the caprazamycin core, and we designed compound
20 as a model compound for this strategy (Scheme 5).
The synthesis commenced with Ns protection of serine methyl
ester hydrochloride 22 (Scheme 6). After benzylation of the
hydroxyl group using benzyl trichloroacetimidate and a catalytic
amount of TfOH,31 the product 23 was converted to amide 24
by ammonolysis. Propargylation of amide 24 gave the precursor
for the 7-endo cyclization. As expected, treatment of 25 with
20 mol% of PtCl2 in dichloroethane at 70 °C gave diazepanone
26 in 62% yield with excellent regioselectivity. Unfortunately,
methylation of enamide did not give the desired compound 27.
When compound 26 was treated with MeI and NaH in DMF,
alkylation at the α-position of the amide proceeded to give com-
pound 28. N-Alkylation using MeI and potassium carbonate in
acetone gave a complex mixture.
Thus, the synthetic route was revised, and the methyl group
was introduced before construction of the diazepanone core.
Because caprazamycins have a substituent at the C7 position,
internal alkynyl amides were also required. The secondary
alkynyl amide was investigated for the 7-endo cyclization. The
reaction of 23 with aqueous methyl amine proceeded smoothly
to give secondary amide 29, which was coupled with propargyl
bromide and ((4-bromobut-2-yn-1-yl)oxy)(tert-butyl)dimethyl-
silane 30 for preparing alkynyl amides 31a and 31b (Scheme 7).
Aryl substituted amides 31c and 31d were synthesized from
terminal alkynyl amide 31a by Sonogashira coupling.15 The
platinum catalyzed 7-endo cyclizations of these alkynyl amides
were investigated. The reaction of compound 31a under standard
conditions gave diazepanone 32a in 56% yield. While the cycli-
zation of dialkynyl amide 31b had a poor yield, the aryl alkynyl
amide 31c was easily converted to diazepanone 32c. These
results are consistent with our previous observations. The reac-
tion of furyl substituted alkynyl amide 31d gave the desired
cyclized product 32d. Because the furyl group could be con-
verted to carboxylate under oxidizing conditions,32 diazepanone
32d was converted to the model compound 34 via deprotection
of the Ns group by treatment with PhSH and potassium carbon-
ate and introduction of the methyl group to the resultant amine
33 by reductive amination. The synthesis of model compound 34
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was accomplished from commercially available serine methyl
ester hydrochloride 22 in eight steps.
pressure to give (S)-2-amino-3-phenylpropanamide as a white
solid (3 g, 79%).
At 0 °C, to a solution of the above amide (3.00 g,
18.32 mmol) in CH2Cl2 (60 mL, 0.3 M) was added Et3N
(5.1 mL, 36.64 mmol, 2 eq.) and subsequently p-NsCl (4.06 g,
18.32 mmol, 1 eq.). The reaction mixture was warmed to room
temperature and stirred overnight. The precipitate was collected
by filtration and washed with CHCl3 (× 3). The resultant white
solid corresponding to (S)-2-(4-nitrophenylsulfonamido)-3-
phenylpropanamide 5 was used without further purification (6 g,
94%).
At 0 °C, to a solution of the above Ns-amide 5 (3.10 g,
8.87 mmol) in DMF (65 mL, 0.14 M) was added K2CO3
(2.45 g, 17.75 mmol, 2 eq.) and subsequently propargyl bromide
(1.58 mL, 17.75 mmol, 2 eq.). The reaction mixture was warmed
to room temperature and stirred for 10 h. After removal the pre-
cipitate by filtration, the filtrate was concentrated under reduced
pressure. Purification by silica gel chromatography (hexane–
EtOAc, 1 : 1) afforded the corresponding alkynyl amide 6 as a
beige solid (3.22 g, 94%): [α]2D5 −127.6 (c 0.48, CHCl3); 1H
NMR (500 MHz, CDCl3): δ 2.32 (t, 1H, J = 2.4 Hz), 2.89
(dd, 1H, J = 14.8, 6.2 Hz), 3.35 (dd, 1H, J = 14.8, 6.2 Hz), 4.22
(dd, 1H, J = 18.8, 2.4 Hz), 4.50 (dd, 1H, J = 18.8, 2.4 Hz), 4.61
(dd, 1H, J = 8.5, 6.1 Hz), 5.68 (br, 1H, NH2), 6.30 (br, 1H,
NH2), 7.04–7.15 (m, 5H), 7.75 (d, 2H, J = 8.5 Hz), 8.11 (d, 2H,
J = 8.5 Hz); 13C NMR (126 MHz, CDCl3): δ 34.0, 34.6, 62.4,
74.2, 78.2, 123.9 (2C), 126.9, 128.4 (2C), 128.6 (2C), 129.2
(2C), 136.7, 144.9, 149.9, 170.7; Mp: 129–130 °C; IR (ATR) ν
3480, 3370, 3285, 2100, 1670 cm−1; HRMS (FAB) calcd for
C18H18N3O5S [(M + H)+] 388.0967 found 388.0960.
Conclusions
In summary, we examined the platinum catalyzed 7-endo cycli-
zation using various internal alkynyl amides substituted with
aryl and alkyl groups. Compared with terminal alkynes, the
7-endo cyclization of alkynyl amides with aryl substituents pro-
ceeded smoothly, presumably because of stabilization of the tran-
sition state. The developed conditions were tolerant of several
substituents, such as alkyl groups at the α-position and protect-
ing groups for the amine. The reaction was successfully applied
to the synthesis of the caprazamycin core using a secondary
alkynyl amide. The model compound 34 was readily accessed
from commercially available amino acid derivatives in eight
steps. The developed method is a reliable and powerful method
for construction of seven-membered diazepanones, and the syn-
thesis of caprazamycin is currently under investigation.
Experimental
General
All non-aqueous reactions were carried out under a positive
atmosphere of argon in dried glassware. Analytical thin-layer
chromatography was performed with silica gel 60 (Merck).
Silica gel column chromatography was performed with Kanto
silica gel 60 (particle size, 63–210 μm). All melting points were
determined on YAMAMOTO micro melting point apparatus and
are uncorrected. Proton nuclear magnetic resonance (1H NMR)
spectra were recorded on a JEOL JNM-LA 500 at 500 MHz.
Chemical shifts are reported relative to Me4Si (δ 0.00) in CDCl3,
solvent residual peak (δ 2.04) in acetone-d6 and solvent residual
peak (δ 2.49) in DMSO. Multiplicity is indicated by one or more
of the following: s (singlet); d (doublet); t (triplet); q (quartet);
m (multiplet); br (broad). Carbon nuclear magnetic resonance
(13C NMR) spectra were recorded on a JEOL JNM-LA 500 at
126 MHz. Chemical shifts are reported relative to CDCl3
(δ 77.0) and DMSO (δ 39.5). Infrared spectra were recorded on a
FT/IR-4100 Fourier-transform infrared spectrometer ATR (atte-
nuated total reflectance). Low and high resolution mass spectra
were recorded on JEOL JMS-HX/HX 110A mass spectrometer.
Optical rotations were determined with a JASCO P-2200KDT
polarimeter and are the average of five measurements.
(S)-2-(4-Nitro-N-(3-phenylprop-2-ynyl)phenylsulfonamido)-3-
phenylpropanamide 7. A mixture of iodobenzene (0.22 mL,
2.0 mmol), Pd(PPh3)4 (116 mg, 0.1 mmol), and CuI (38 mg,
0.2 mmol) in Et3N (14 mL, 0.3 M) was stirred for 30 min at
room temperature under argon atmosphere. To this mixture was
added 6 (774 mg, 2.0 mmol) in solution in THF (6 mL) and the
resultant mixture was stirred for 5 h. After removal Et3N under
reduced pressure, the residue was dissolved in CHCl3, washed
by brine, dried over Na2SO4 and concentrated under reduced
pressure. Purification by silica gel chromatography (hexane–
EtOAc, 2 : 1) afforded the corresponding phenylacetylene 7 as
1
an orange oil (781 mg, 84%): [α]2D7 −107.8 (c 0.75, CHCl3); H
NMR (500 MHz, CDCl3): δ 2.96 (dd, 1H, J = 14.5, 9.4 Hz),
3.42 (dd, 1H, J = 14.5, 5.7 Hz), 4.39 (d, 1H, J = 18.3 Hz), 4.71
(d, 1H, J = 18.3 Hz), 4.72 (m, 1H), 5.47 (br, 1H, NH2), 6.35 (br,
1H, NH2), 7.08–7.16 (m, 5H), 7.25 (m, 1H), 7.30–7.38 (m, 4H),
7.69 (d, 2H, J = 8.9 Hz), 7.99 (d, 2H, J = 8.9 Hz); 13C NMR
(126 MHz, CDCl3): δ 34.5, 34.9, 62.7, 83.4, 86.0, 121.7, 123.8
(2C), 126.9, 128.4 (2C), 128.5 (2C), 128.6 (2C), 129.1, 129.3
(2C), 131.3 (2C), 137.0, 145.2, 149.7, 170.8; Mp: 152–153 °C;
IR (ATR) ν 3474, 3334, 1664, 1602, 1529 cm−1; HRMS (FAB)
calcd for C24H22N3O5S [(M + H)+] 464.1280 found 464.1284.
Material
Anhydrous CH2Cl2, DMF, CH3CN and 1,2-dichloroethane
(DCE) were purchased from KANTO Chemical Co. Aldrich and
Wako chemicals. Materials were obtained from Tokyo Chemical
Industry Co., Ltd Aldrich Inc., and other commercial suppliers
and used without further purification.
Scheme 1: (S)-2-(4-nitro-N-(prop-2-ynyl)phenylsulfonamido)-
3-phenylpropanamide 6. L-Phenylalanine methyl ester hydro-
chloride (5 g, 23.18 mmol) was dissolved in 28% aqueous
ammonia (50 mL, 0.5 M). After stirring overnight at room temp-
erature, the reaction mixture was concentrated under reduced
(S,Z)-3-Benzyl-4-(4-nitrophenylsulfonyl)-7-phenyl-4,5-dihydro-
1H-1,4-diazepin-2(3H)-one 9. A solution of alkynylamide 7
(93 mg, 0.20 mmol) and PtCl2 (5.3 mg, 0.02 mmol) in
ClCH2CH2Cl (1.4 mL) was stirred at 70 °C for 20 h. After
cooling, the reaction mixture was concentrated under reduced
6078 | Org. Biomol. Chem., 2012, 10, 6074–6086
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pressure. Purification by silica gel chromatography (hexane–
EtOAc = 1 : 1) afforded compound 9 (92 mg, 99%) as a pale
(ATR) ν 3650, 1690, 1606, 1529 cm−1; HRMS (FAB) calcd for
C26H26N3O7S [(M + H)+] 524.1491, found 524.1477.
1
yellow solid: [α]2D5 +25.5 (c 0.83, CHCl3); H NMR (500 MHz,
(S)-2-(N-(3-(4-Methoxyphenyl)prop-2-ynyl)-4-nitrophenylsul-
fonamido)-3-phenylpropanamide 14b. Yellow solid (86%); [α]D26
CDCl3): δ 3.22 (dd, 1H, J = 14.6, 9.4 Hz), 3.32 (dd, 1H,
J = 14.6, 6.5 Hz), 4.14 (dd, 1H, J = 17.7, 4.0 Hz), 4.34 (dd, 1H,
J = 17.7, 5.4 Hz), 5.03 (dd, 1H, J = 9.4, 6.5 Hz), 5.38 (t, 1H, J =
5.5 Hz), 6.66 (br, 1H, NH), 7.18–7.20 (m, 3H), 7.26–7.28 (m,
2H), 7.37–7.39 (m, 5H), 7.88 (d, 2H, J = 8.5 Hz), 8.20 (d, 2H,
J = 8.5 Hz); 13C NMR (126 MHz, CDCl3): δ 35.9, 43.1, 63.6,
107.7, 124.1 (2C), 126.0 (2C), 127.4, 128.5 (2C), 128.8 (4C),
129.1 (2C), 129.7, 135.1, 136.6, 137.1, 144.5, 150.0, 171.3; Mp:
205–206 °C; IR (ATR) ν 3299, 3028, 2922, 1672, 1653,
1528 cm−1; HRMS (FAB) calcd for C24H21N3O5S [M+]
463.1202 found 463.1198.
1
−97.4 (c 0.79, CHCl3); H NMR (500 MHz, CDCl3): δ 2.96
(dd, 1H, J = 14.3, 9.1 Hz), 3.42 (dd, 1H, J = 14.3, 5.1 Hz), 3.83
(s, 3H), 4.36 (d, 1H, J = 18.5 Hz), 4.69 (d, 1H, J = 18.5 Hz),
4.72 (dd, 1H, J = 9.1, 5.1 Hz), 5.47 (br, 1H, NH2), 6.36 (br, 1H,
NH2), 6.83 (d, 2H, J = 8.6 Hz), 7.07–7.26 (m, 7H), 7.68 (d, 2H,
J = 9.1 Hz), 7.97 (d, 2H, J = 9.1 Hz); 13C NMR (126 MHz,
CDCl3): δ 34.4, 35.0, 55.3, 62.7, 82.0, 88.1, 113.6, 114.2 (2C),
123.8 (2C), 126.8, 128.4 (2C), 128.6 (2C), 129.4 (2C), 132.8
(2C), 137.1, 145.2, 149.7, 160.1, 170.9; Mp: 155–156 °C; IR
(ATR) ν 3464, 3367, 1683, 1605, 1527, 1508 cm−1; HRMS
(FAB) calcd for C25H24N3O6S [(M + H)+] 494.1386 found
494.1380.
Hydrolysis
of
(S,Z)-3-benzyl-4-(4-nitrophenylsulfonyl)-7-
phenyl-4,5-dihydro-1H-1,4-diazepin-2(3H)-one 9. To a solution
of 9 (14.1 mg, 0.031 mmol) in THF/H2O (3.0 mL/0.60 mL) was
added conc. HCl (0.60 mL). The resultant mixture was stirred
under reflux overnight and then diluted with water (5 mL) and
extracted with CHCl3 (3 × 3 mL). The combined organic layers
were dried over Na2SO4 and concentrated under reduced
pressure. The residue was purified by GPC (CHCl3) to give 13
(S)-2-(4-Nitro-N-(3-(p-tolyl)prop-2-yn-1-yl)phenylsulfona-
mido)-3-phenylpropanamide 14c. [α]2D5 −91.4 (c 0.93, CDCl3)
1H NMR (500 MHz, CDCl3) δ 7.97 (d, 2H, J = 8.3 Hz), 7.68 (d,
2H, J = 8.3 Hz), 7.17–7.07 (m, 9H), 6.37 (s, 1H), 5.64 (s, 1H),
4.74 (dd, 1H, J = 9.2, 3.8 Hz), 4.70 (d, 1H, J = 18.6 Hz), 4.37
(d, 1H, J = 18.6 Hz), 3.42 (dd, 1H, J = 14.6, 9.2 Hz), 2.96 (dd,
1H, J = 14.6, 5.2 Hz), 2.36 (s, 3H). 13C NMR (125 MHz,
CDCl3) δ 171.0, 149.7, 145.2, 139.4, 137.1, 131.2, 129.4, 129.3,
128.6, 128.4, 126.8, 123.8, 118.6, 86.2, 82.8, 62.7, 35.0, 34.5,
1
(9.0 mg, 62%): H NMR (500 MHz, CDCl3): δ 8.16 (d, 2H, J =
8.6 Hz), 7.87 (d, 2H, J = 8.0 Hz), 7.73 (d, 2H, J = 8.6 Hz), 7.58
(d, 1H, J = 7.5 Hz), 7.46 (d, 2H, J = 7.5 Hz), 7.25–7.22
(m, 3H), 7.20–7.17 (m, 3H), 4.96 (dd, 1H, J = 10.3, 5.2 Hz),
3.81 (ddd, 1H, J = 14.9, 9.1, 5.7 Hz), 3.62 (ddd, 1H, J = 17.8,
8.6, 5.7 Hz), 3.53 (ddd, 1H, J = 14.9, 8.6, 5.7 Hz), 3.41 (dd, 1H,
J = 14.9, 5.2 Hz), 3.19 (ddd, 1H, J = 17.8, 9.1, 5.2 Hz), 3.14
(dd, 1H, J = 14.9, 10.3 Hz); 13C NMR (126 MHz, CDCl3):
δ 198.3, 173.9, 149.9, 144.7, 136.2, 136.0, 133.6, 129.0, 128.9,
128.7, 128.5, 128.0, 127.3, 124.0, 61.7, 40.9, 39.4, 35.5; IR ν
2923, 2854, 1744, 1681, 1531, 1350 cm−1; HRMS (FAB) calcd
for C24H24N3O6S [(M − H)−] 481.1070 found 481.1099.
21.5. IR (ATR) ν 3458, 3362, 2922, 1734, 1685, 1528 cm−1
.
HRMS (FAB) calcd for C25H24N3O5S [(M + H)+] 478.1437,
found 478.1427.
(S)-2-(N-(3-(Naphthalen-1-yl)prop-2-ynyl)-4-nitrophenyl-
sulfonamido)-3-phenylpropanamide 14d. Beige oil (87%);
1
[α]2D6 −99.7 (c 1.44, CHCl3); H NMR (500 MHz, CDCl3): δ
3.04 (dd, 1H, J = 14.5, 9.1 Hz), 3.46 (dd, 1H, J = 14.5, 5.7 Hz),
4.57 (d, 1H, J = 18.3 Hz), 4.79 (dd, 1H, J = 9.1, 5.7 Hz), 4.84
(d, 1H, J = 18.3 Hz), 5.87 (br, 1H, NH2), 6.41 (br, 1H, NH2),
7.08–7.16 (m, 5H), 7.38–7.52 (m, 4H), 7.69 (d, 2H, J = 9.1 Hz),
7.84–7.86 (m, 4H), 8.00 (d, 1H, J = 6.9 Hz); 13C NMR
(126 MHz, CDCl3): δ 34.8, 35.1, 62.5, 84.2, 88.1, 119.3, 123.8
(2C), 125.1, 125.5, 126.6, 126.9, 127.0, 128.4 (2C), 128.5,
128.7 (2C), 129.3 (2C), 129.5, 130.6, 133.0, 133.1, 136.9,
145.2, 149.6, 170.9; Mp: 165–166 °C; IR (ATR) ν 3467, 3370,
1683, 1606, 1526 cm−1; HRMS (FAB) calcd for C28H24N3O5S
[(M + H)+] 514.1437 found 514.1434.
Tables 1 and 2: general procedure for Sonogashira coupling
A mixture of iodobenzene (2.0 mmol), Pd(PPh3)4 (0.1 mmol),
and CuI (0.2 mmol) in Et3N (14 mL) was stirred for 30 min at
room temperature under an argon atmosphere. To this mixture
was added 6 (2.0 mmol) in solution in THF (6 mL) and the
resultant mixture was stirred with TLC monitoring until the start-
ing material disappeared. After removal of Et3N under reduced
pressure, the residue was dissolved in CHCl3, washed with brine,
dried over Na2SO4 and concentrated under reduced pressure.
Purification by silica gel chromatography (hexane–EtOAc)
afforded the corresponding phenylacetylene 14a–g.
(S)-2-(N-(3-(4-Chlorophenyl)prop-2-ynyl)-4-nitrophenyl-
sulfonamido)-3-phenylpropanamide 14e. Beige solid (96%);
1
[α]2D6 −83.1 (c 0.98, CHCl3); H NMR (500 MHz, CDCl3): δ
2.94 (dd, 1H, J = 14.5, 9.1 Hz), 3.40 (dd, 1H, J = 14.5, 5.7 Hz),
4.42 (d, 1H, J = 18.5 Hz), 4.67 (d, 1H, J = 18.5 Hz), 4.72 (dd,
1H, J = 9.1, 5.7 Hz), 5.71 (br, 1H, NH2), 6.37 (br, 1H, NH2),
7.07–7.09 (m, 4H), 7.17–7.19 (m, 3H), 7.26–7.31 (m, 2H, J =
8.5 Hz), 7.68 (d, 2H, J = 9.1 Hz), 8.00 (d, 2H, J = 9.1 Hz); 13C
NMR (126 MHz, CDCl3): δ 34.5, 34.8, 62.4, 84.4, 84.7, 120.1,
123.9 (2C), 126.9, 128.4 (2C), 128.6 (2C), 128.9 (2C), 129.3
(2C), 132.5 (2C), 135.2, 136.9, 145.0, 149.8, 170.9; Mp:
154–155 °C; IR (ATR) ν 3463, 3350, 3108, 2975, 2919, 1684,
1589 cm−1; HRMS (FAB) calcd for C24H21ClN3O5S [(M + H)+]
498.0890 found 498.0878.
(S)-2-(N-(3-(2,4-Dimethoxyphenyl)prop-2-yn-1-yl)-4-nitrophe-
nylsulfonamido)-3-phenylpropanamide
14a. [α]2D4
−82.8
(c 1.02, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.97 (d, 2H, J =
9.2 Hz), 7.79 (d, 2H, J = 9.2 Hz), 7.14–7.06 (m, 6H), 6.44–6.41
(m, 3H), 5.56 (s, 1H), 4.73 (d, 1H, J = 18.9 Hz), 4.69 (dd, 1H,
J = 8.6, 5.8 Hz), 4.38 (d, 1H, J = 18.9 Hz), 3.83 (s, 3H), 3.78
(s, 3H), 3.44 (dd, 1H, J = 14.4, 5.8 Hz), 3.00 (dd, 1H, J = 14.4,
8.6 Hz); 13C NMR (125 MHz, CDCl3) δ 171.0, 161.7, 161.5,
149.7, 145.3, 137.3, 134.1, 129.3, 128.6, 128.5, 126.7, 123.7,
105.0, 103.3, 98.5, 85.8, 83.0, 62.8, 55.6, 55.5, 35.5, 34.5; IR
This journal is © The Royal Society of Chemistry 2012
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7.78 (d, 2H, J = 9.1 Hz), 8.08 (d, 2H, J = 9.1 Hz); 13C NMR
(126 MHz, CDCl3): δ 29.6, 36.4, 43.1, 55.4, 64.0, 106.3, 114.3
(2C), 124.0 (2C), 127.3 (2C), 128.5 (2C), 128.7 (2C), 128.8
(2C), 128.9, 135.2, 136.9, 144.3, 150.0, 160.7, 171.1; IR (ATR)
ν 3210, 3106, 3032, 2919, 2849, 1667, 1606 cm−1; HRMS
(FAB) calcd for C25H23N3O6S [M+] 493.1308 found 493.1293.
(S)-2-(4-Nitro-N-(3-(4-(trifluoromethyl)phenyl)prop-2-ynyl)-
phenylsulfonamido)-3-phenylpropanamide 14f. Beige solid
(95%); [α]2D5 −85.1 (c 0.78, CHCl3); 1H NMR (500 MHz,
CDCl3): δ 2.96 (dd, 1H, J = 14.5, 9.1 Hz), 3.40 (dd, 1H, J =
14.5, 5.7 Hz), 4.47 (d, 1H, J = 18.5 Hz), 4.69 (d, 1H, J = 18.5
Hz), 4.72 (m, 1H), 5.64 (br, 1H, NH2), 6.37 (br, 1H, NH2),
7.08–7.11 (m, 5H), 7.37 (d, 2H, J = 8.0 Hz), 7.58 (d, 2H, J =
8.0 Hz), 7.69 (d, 2H, J = 8.5 Hz), 8.02 (d, 2H, J = 8.5 Hz); 13C
NMR (126 MHz, CDCl3): δ 34.6, 34.7, 62.3, 84.4, 85.9, 123.6
(q, J = 273. 4 Hz), 124.7 (2C), 125.5 (2C), 127.0, 128.4 (2C),
128.6 (2C), 129.2 (2C), 130.8 (q, J = 33.0 Hz), 131.6 (2C),
136.8 (2C), 145.0, 149.8, 170.9; Mp: 167–168 °C; IR (ATR) ν
3475, 3340, 3197, 3117, 1667, 1605, 1530 cm−1; HRMS (FAB)
calcd for C25H21F3N3O5S [(M + H)+] 532.1154 found 532.1160.
(S,Z)-3-Benzyl-4-((4-nitrophenyl)sulfonyl)-7-(p-tolyl)-4,5-dihydro-
1H-1,4-diazepin-2(3H)-one 15c. [α]2D5 +31.7 (c 1.00, CHCl3);
1H NMR (500 MHz, CDCl3) δ 8.20 (d, 2H, J = 8.6 Hz), 7.89 (d,
2H, J = 8.6 Hz), 7.29–7.15 (m, 9H), 6.68 (s, 1H), 5.37 (t, 1H, J
= 4.6 Hz), 5.01 (t, 1H, J = 7.5 Hz), 4.28 (dd, 1H, J = 17.5, 5.5
Hz), 4.13 (dd, 1H, J = 17.5, 4.3 Hz), 3.31 (dd, 1H, J = 14,6, 6.9
Hz), 2.37 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 171.2, 150.0,
144.4, 139.9, 136.7, 135.1, 134.0, 129.7, 128.79, 128.77, 128.5,
127.3, 125.8, 124.1, 107.0, 63.8, 43.1, 36.1, 21.2; IR (ATR) ν
3734, 2981, 2917, 1770, 1670, 1530, 1350 cm−1; HRMS (FAB)
calcd for C25H24N3O5S [(M + H)+] 478.1437, found 478.1436.
(S)-2-(4-Nitro-N-(3-(4-nitrophenyl)prop-2-yn-1-yl)phenyl-
sulfonamido)-3-phenylpropanamide 14g. [α]2D5 −43.5 (c 0.93,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 8.20 (d, 2H, J = 8.0 Hz),
8,05 (d, 2H, J = 7.7 Hz), 7.70 (d, 2H, J = 7.5 Hz), 7.44 (d, 2H, J
= 8.1 Hz), 7.19–7.05 (m, 5H), 6.34 (s, 1H), 5.50 (s, 1H), 4.72
(ddd, 1H, J = 9.2, 5.7, 1.4 Hz), 4.69 (d, 1H, J = 17.8 Hz), 4.53
(dd, 1H, J = 18.6, 1.2 Hz), 3.41 (dd, 1H, J = 14.9, 5.7 Hz), 2.96
(dd, 1H, J = 14.8, 9.2 Hz); 13C NMR (125 MHz, CDCl3) δ 170.9,
149.9, 147.5, 144.8, 136.6, 132.2, 129.2, 128.7, 128.5, 128.3,
127.0, 124.0, 123.7, 88.6, 83.7, 62.1, 34.7, 34.65; IR (ATR) ν
3853, 3734, 3628, 1770, 1685, 1521 cm−1; HRMS (FAB) calcd
for C24H21N4O7S [(M + H)+] 509.1131, found 509.1122.
(S,Z)-3-Benzyl-7-(naphthalen-1-yl)-4-(4-nitrophenylsulfonyl)-
4,5-dihydro-1H-1,4-diazepin-2(3H)-one 15d. Beige solid (87%);
[α]2D5 +7.8 (c 0.76, CHCl3); 1H NMR (500 MHz, CDCl3): δ 3.31
(dd, 1H, J = 14.8, 10.9 Hz), 3.42 (dd, 1H, J = 14.8, 5.1 Hz),
4.12 (dd, 1H, J = 19.7, 2.2 Hz), 4.57 (dd, 1H, J = 19.7, 5.1 Hz),
5.10 (dd, 1H, J = 10.9, 5.1 Hz), 5.16 (t, 1H, J = 2.2 Hz), 6.74
(br, 1H, NH), 7.20–7.27 (m, 6H), 7.41 (t, 1H, J = 6.9 Hz),
7.47–7.50 (m, 2H), 7.69 (br d, 1H), 7.83 (m, 4H), 8.19 (d, 2H, J
= 9.2 Hz); 13C NMR (126 MHz, CDCl3): δ 34.4, 42.7, 62.7,
109.9, 124.1 (3C), 125.2, 126.4, 126.5, 127.0, 127.4, 128.4
(2C), 128.6 (2C), 128.7, 128.8 (2C), 129.7, 130.3, 133.6 (2C),
134.9, 135.6, 144.9, 149.9, 171.8; Mp: 197–198 °C; IR (ATR) ν
3310, 2919, 1700, 1679, 1605, 1520 cm−1; HRMS (FAB) calcd
for C28H24N3O5S [(M + H)+] 514.1437 found 514.1442.
Tables 1 and 2: general procedure for 7-endo cyclization using
PtCl2
A solution of alkynylamide (1 eq.) and PtCl2 (10 mol%) in
ClCH2CH2Cl (0.15 M) was stirred at 70 °C with TLC monitor-
ing. After the starting material disappeared, the reaction mixture
was concentrated under reduced pressure. Purification by silica
gel chromatography (hexane–EtOAc) afforded the corresponding
cyclic enamide.
(S,Z)-3-Benzyl-7-(4-chlorophenyl)-4-(4-nitrophenylsulfonyl)-
4,5-dihydro-1H-1,4-diazepin-2(3H)-one 15e. Beige solid (99%);
1
[α]2D6 +25.4 (c 0.99, CHCl3); H NMR (500 MHz, CDCl3): δ
3.18 (dd, 1H, J = 14.9, 9.5 Hz), 3.27 (dd, 1H, J = 14.9, 6.8 Hz),
4.13 (dd, 1H, J = 17.7, 4.3 Hz), 4.30 (dd, 1H, J = 17.7, 5.7 Hz),
4.95 (dd, 1H, J = 9.5, 6.8 Hz), 5.39 (t, 1H, J = 4.5 Hz), 6.98 (br,
1H, NH), 7.14–7.16 (m, 2H), 7.23–7.26 (m, 5H), 7.33–7.35 (m,
2H), 7.83 (d, 2H, J = 9.1 Hz), 8.17 (d, 2H, J = 9.1 Hz); 13C
NMR (126 MHz, CDCl3): δ 35.8, 43.0, 63.6, 108.3, 124.1 (2C),
127.3, 128.4 (6C), 128.6, 128.8 (2C), 129.3, 135.0, 135.3,
135.6, 135.8, 144.3, 150.0, 171.4; Mp: 197–198 °C; IR (ATR) ν
3297, 3099, 3027, 2922, 1674, 1653, 1598, 1529 cm−1; HRMS
(FAB) calcd for C24H20ClN3O5S [M+] 497.0812 found
497.0822.
(S,Z)-3-Benzyl-7-(2,4-dimethoxyphenyl)-4-((4-nitrophenyl)-
sulfonyl)-4,5-dihydro-1H-1,4-diazepin-2(3H)-one
15a. [α]2D5
1
+20.9 (c 0.97, CHCl3); H NMR (500 MHz, CDCl3) δ 8.24 (d,
2H, J = 8.9 Hz), 7.93 (d, 2H, J = 8.6 Hz), 7.30–7.18 (m, 5H),
7.07 (d, 1H, J = 8.6 Hz), 6.89 (s, 1H), 6.45 (dd, 1H, J = 8.3, 2.3
Hz), 6.42 (d, 1H, J = 2.3 Hz), 5.20 (t, 1H, J = 4.9, 4.0 Hz), 4.99
(t, 1H, J = 9.5, 6.9 Hz), 4.37 (dd, 1H, J = 18.3, 5.2 Hz), 4.10
(dd, 1H, J = 18.3, 4.0 Hz), 3.83 (s, 3H), 3.75 (s, 3H), 3.35 (dd,
1H, J = 14.3, 6.9 Hz), 3.24 (dd, 1H, J = 14.3, 9.5 Hz); 13C
NMR (125 MHz, CDCl3) δ 170.6, 161.8, 157.1, 150.0, 144.6,
135.2, 134.6, 130.5, 128.79, 128.75, 128.6, 127.3, 124.0, 118.7,
109.0, 104.7, 98.8, 63.5, 55.52, 55.49, 43.2, 35.5; IR (ATR) ν
3365, 3105, 2933, 1664, 1607, 1528 cm−1; HRMS (FAB) calcd
for C26H26N3O7S [(M + H)+] 524.1491, found 524.1487.
(S,Z)-3-Benzyl-4-(4-nitrophenylsulfonyl)-7-(4-(trifluoromethyl)-
phenyl)-4,5-dihydro-1H-1,4-diazepin-2(3H)-one 15f. Beige solid
(99%); [α]2D6 +30.0 (c 0.92, CHCl3); 1H NMR (500 MHz,
CDCl3): δ 3.18 (dd, 1H, J = 14.9, 9.7 Hz), 3.29 (dd, 1H, J =
14.9, 6.3 Hz), 4.15 (dd, 1H, J = 18.0, 4.0 Hz), 4.38 (dd, 1H, J =
18.0, 5.1 Hz), 4.97 (dd, 1H, J = 9.7, 6.3 Hz), 5.44 (t, 1H, J = 4.0
Hz), 7.04 (br, 1H, NH), 7.13–7.15 (m, 2H), 7.24–7.26 (m, 3H),
7.42–7.44 (m, 2H), 7.63–7.65 (m, 2H), 7.88 (d, 2H, J = 8.6 Hz),
8.20 (d, 2H, J = 8.6 Hz); 13C NMR (126 MHz, CDCl3): δ 35.5,
43.0, 63.6, 109.7, 123.9 (q, J = 271.0), 124.1 (2C), 126.0, 126.6
(2C), 127.4 (2C), 128.4 (2C), 128.7 (2C), 128.8 (2C), 131.6 (q,
(S,Z)-3-Benzyl-7-(4-methoxyphenyl)-4-(4-nitrophenylsulfonyl)-
4,5-dihydro-1H-1,4-diazepin-2(3H)-one 15b. Yellow oil (82%);
[α]2D5 +28.5 (c 2.20, CHCl3); 1H NMR (500 MHz, CDCl3): δ 3.11
(dd, 1H, J = 14.3, 9.1 Hz), 3.18 (dd, 1H, J = 14.3, 7.4 Hz), 3.72
(s, 3H), 4.04 (dd, 1H, J = 16.9, 5.1 Hz), 4.09 (dd, 1H, J = 16.9,
5.1 Hz), 4.86 (t, 1H, J = 7.4 Hz), 5.29 (t, 1H, J = 5.1 Hz),
6.78 (d, 2H, J = 8.5 Hz), 6.95 (br, 1H, NH), 7.08–7.18 (m, 7H),
6080 | Org. Biomol. Chem., 2012, 10, 6074–6086
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J = 33.0), 134.9, 135.4, 140.6, 144.4, 150.0, 171.6; Mp:
NMR (126 MHz, CDCl3): δ 16.3, 42.8, 58.3, 107.5, 124.1 (2C),
125.9 (2C), 128.6 (2C), 129.0 (2C), 129.6, 136.6, 137.0, 144.5,
150.1, 172.3; IR (ATR) ν 3230, 3104, 2925, 1666, 1606,
1529 cm−1; HRMS (FAB) calcd for C18H18N3O5S [(M + H)+]
388.0967 found 388.0973.
202–203 °C; IR (ATR) ν 3292, 2921, 1676, 1654, 1529 cm−1
;
HRMS (FAB) calcd for C25H20F3N3O5S [M+] 531.1076 found
531.1076.
Hydrolysis of (S,Z)-3-benzyl-7-(4-chlorophenyl)-4-(4-nitro-
phenylsulfonyl)-4,5-dihydro-1H-1,4-diazepin-2(3H)-one 15e. To
a solution of 15e (25.2 mg, 0.031 mmol) in THF/H2O (1.0 mL/
0.20 mL) was added conc. HCl (0.20 mL). The resultant mixture
was stirred reflux overnight and then diluted with water (5 mL)
and extracted with CHCl3 (5 × 3 mL). The combined organic
layers were dried over Na2SO4 and concentrated under reduced
pressure. The residue was purified by GPC (CHCl3) to give 16
(S)-3-Benzyl-7-phenyl-4-tosyl-4,5-dihydro-1H-1,4-diazepin-2-
(3H)-one 19d. [α]D25 +32.4 (c 0.94, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 7.67 (d, 2H, J = 8.3 Hz), 7.42–7.34 (m,
3H), 7.32–7.16 (m, 9H), 6.58 (s, 1H), 5.37 (t, 1H, J = 4.0 Hz),
5.03 (t, 1H, J = 8.1 Hz), 4.26 (dd, 1H, J = 17.8, 5.5 Hz), 4.05
(dd, 1H, J = 17.8, 4.3 Hz), 3.28 (dd, 1H, J = 14.6, 7.5 Hz), 3.18
(dd, J = 14.6, 9.2 Hz), 2.37 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 171.8, 143.7, 137.3, 136.3, 135.8, 135.4, 129.5, 129.4,
128.9, 128.8, 128.7, 127.5, 127.1, 126.0, 108.4, 63.3, 42.8,
1
(24.3 mg, 93%): H NMR (500 MHz, CDCl3): δ 8.66 (d, 1H, J
= 8.0 Hz), 8.08 (d, 2H, J = 8.6 Hz), 7.99 (d, 1H, J = 8.6 Hz),
7.87 (d, 1H, J = 8.0 Hz), 7.83 (d, 1H, J = 6.9 Hz), 7.67 (d, 2H, J
= 8.6 Hz), 7.58 (ddd, 1H, J = 6.9, 6.9, 1.7 Hz), 7.53 (ddd, 1H, J
= 6.9, 6.9, 1.2 Hz), 7.48 (t, 1H, J = 8.0 Hz), 7.24–7.17 (m, 5H),
4.93 (dd, 1H, J = 10.3, 5.6 Hz), 3.85 (m, 1H), 3.67–3.57 (m,
2H), 3.37 (dd, 1H, J = 14.9, 5.6 Hz), 3.25 (m, 1H), 3.14 (dd,
1H, J = 14.9, 10.3 Hz); 13C NMR (126 MHz, CDCl3): δ 201.7,
175.1, 149.9, 144.8, 136.2, 134.3, 134.0, 133.7, 130.2, 129.1,
129.0, 128.9, 127.1, 126.6, 125.6, 124.4, 42.4, 41.0, 35.5; IR ν
2917, 2849, 1713, 1678, 1530, 1349, 1165 cm−1; HRMS (FAB)
calcd for C28H25N2O7S [M − H]− 531.1226 found 531.1229.
36.2, 21.5; IR (ATR) ν 3750, 1770, 1670, 1245, 1162 cm−1
;
HRMS (FAB) calcd for C25H25N2O3S [(M + H)+] 433.1586,
found 433.1555.
(S)-Isopropyl 2-benzyl-3-oxo-5-phenyl-2,3,4,7-tetrahydro-1H-
1
1,4-diazepine-1-carboxylate 19e. [α]2D5 +5.2 (c 0.99, CHCl3); H
NMR (500 MHz, CDCl3) δ 7.43–7.20 (m, 10H), 6.93 (s, 1H),
5.40 (s, 1H), 4.94 (m, 1H), 4.82 (br, 1H), 4.18 (br, 2H), 3.32 (s,
2H), 1.30–1.20 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 172.9,
155.4, 138.1, 137.0, 135.8, 129.6, 129.1, 128.9, 128.5, 126.8,
126.2, 110.5, 69.8, 62.5, 44.3, 35.2, 22.05, 22.00; IR (ATR) ν
3244, 2979, 1686, 1414, 1373, 1246 cm−1; HRMS (FAB) calcd
for C22H25N2O3 [(M + H)+] 365.1865, found 365.1856.
(S,Z)-3-Isobutyl-4-(4-nitrophenylsulfonyl)-7-phenyl-4,5-dihydro-
1H-1,4-diazepin-2(3H)-one 19a. Orange oil (84%); [α]2D6 +8.9
(c 2.0, CHCl3); 1H NMR (500 MHz, CDCl3): δ 0.97 (d, 3H, J =
6.3 Hz), 0.99 (d, 3H, J = 6.3 Hz), 1.70–1.74 (m, 2H), 1.82–1.86
(m, 1H), 4.08 (dd, 1H, J = 18.3, 3.5 Hz), 4.46 (dd, 1H, J = 18.3,
5.1 Hz), 4.77 (br dd, 1H), 5.22 (t, 1H, J = 5.1 Hz), 6.73 (br, 1H,
NH), 7.12–7.15 (m, 2H), 7.27–7.35 (m, 3H), 8.04 (d, 2H, J =
9.2 Hz), 8.27 (d, 2H, J = 9.2 Hz); 13C NMR (126 MHz, CDCl3):
δ 21.5, 22.6, 24.3, 38.3, 42.5, 60.7, 107.3, 124.0 (2C), 125.8
(2C), 128.7 (2C), 128.9 (2C), 129.5, 136.1, 137.1, 144.5, 150.0,
(S)-Benzyl 2-benzyl-3-oxo-5-phenyl-2,3,4,7-tetrahydro-1H-1,4-
diazepine-1-carboxylate 19f. [α]2D5 +10.8 (c 1.00, CHCl3); 1H
NMR (500 MHz, CDCl3) δ 7.49–7.09 (m, 15H), 6.93 (br, 1H),
5.41 (br, 1H), 5.15 (s, 2H), 4.95 (br, 1H), 4.23 (br, 2H), 3.29 (br,
2H); 13C NMR (125 MHz, CDCl3) δ 172.7, 155.5, 138.03,
136.6, 129.1, 128.9, 128.8, 128.6, 128.5, 128.4, 128.2, 128.1,
127.9, 126.8, 126.2, 110.2, 67.8, 62.5, 44.0, 35.0; IR (ATR) ν
3255, 3061, 3029, 2956, 1697, 1419, 1244 cm−1; HRMS (FAB)
calcd for C26H25N2O3 [(M + H)+] 413.1865, found 413.1864.
172.4; IR (ATR) ν 3106, 2959, 2932, 2870, 1661, 1528 cm−1
;
HRMS (FAB) calcd for C21H24N3O5S [(M + H)+] 430.1437
found 430.1418.
(S)-tert-Butyl 2-benzyl-3-oxo-5-phenyl-2,3,4,7-tetrahydro-1H-
1,4-diazepine-1-carboxylate 19g. [α]2D5 +0.40 (c 0.98, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.46–7.20 (m, 10H), 6.79 (s,
1H), 5.38 (s, 1H), 4.70 (br, 1H), 4.27 (br, 1H), 4.02 (br, 1H),
3.31 (br, 2H), 1.28 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
173.2, 154.9, 138.4, 137.4, 135.7, 129.1, 129.0, 128.95, 128.89,
128.5, 126.7, 126.2, 110.8, 62.9, 44.7, 35.3, 28.3; IR (ATR) ν
3256, 2981, 1770, 1697, 1367, 1247 cm−1; HRMS (FAB) calcd
for C23H27N2O3 [(M + H)+] 379.2022, found 379.2000.
(S,Z)-3-Isopropyl-4-(4-nitrophenylsulfonyl)-7-phenyl-4,5-dihydro-
1H-1,4-diazepin-2(3H)-one 19b. Yellow oil (84%); [α]2D5 −50.9
(c1.90, CHCl3); 1H NMR (500 MHz, CDCl3): δ 1.03 (d, 3H, J =
1.4 Hz), 1.05 (d, 3H, J = 1.4 Hz), 2.17–2.22 (m, 1H), 4.11–4.14
(m, 2H), 4.22 (d, 1H, J = 11.4 Hz), 5.40 (t, 1H, J = 5.1 Hz),
7.04 (br, 1H, NH), 7.26–7.28 (m, 2H), 7.36–7.38 (m, 3H), 8.03
(d, 2H, J = 9.1 Hz), 8.26 (d, 2H, J = 9.1 Hz); 13C NMR
(126 MHz, CDCl3): δ 19.6 (2C), 27.5, 43.0, 69.7, 107.4, 124.0
(2C), 125.9 (2C), 128.9 (4C), 129.6, 136.3, 137.6, 143.9, 150.0,
170.8; IR (ATR) ν 3218, 3105, 2968, 2932, 2872, 1667,
1527 cm−1; HRMS (FAB) calcd for C20H21N3O5S [M+]
415.1202 found 415.1200.
(S)-2-(2-Oxo-6-phenyl-2H-1,3-oxazin-3(4H)-yl)-3-phenylpro-
panamide 19g′. [α]D25 −48.9 (c 1.00, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 7.49 (d, 2H, J = 7.5 Hz), 7.35–7.16 (m,
8H), 6.25 (s, 1H), 5.64 (s, 1H), 5,48 (s, 1H), 4.74 (t, 1H, J = 8.6,
7.5 Hz), 4.49 (dd, J = 14.3, 1.8 Hz), 3.32 (dd, 1H, J = 14.3, 7.5
Hz), 3.07 (dd, 1H, J = 14.3, 8.6 Hz); 13C NMR (125 MHz,
CDCl3) δ 170.6, 155.8, 141.6, 135.7, 133.1, 128.9, 128.7, 128.5,
128.2, 127.3, 127.0, 103.5, 57.1, 46.5, 34.8; IR (ATR) ν 3734,
2994, 1770, 1697, 1220 cm−1; HRMS (FAB) calcd for
C19H19N2O3 [(M + H)+] 323.1396, found 323.1384.
(S,Z)-3-Methyl-4-(4-nitrophenylsulfonyl)-7-phenyl-4,5-
dihydro-1H-1,4-diazepin-2(3H)-one 19c. Yellow oil (84%);
1
[α]2D6 −19.8 (c 0.10, CHCl3); H NMR (500 MHz, CDCl3): δ
1.58 (d, 3H, J = 7.4 Hz), 4.15 (dd, 1H, J = 17.7, 4.0 Hz), 4.40
(dd, 1H, J = 17.7, 5.2 Hz), 4.83 (q, 1H, J = 7.4 Hz), 5.29 (t, 1H,
J = 5.2 Hz), 6.74 (br, 1H, NH), 7.17–7.19 (m, 2H), 7.32–7.36
(m, 3H), 8.03 (d, 2H, J = 9.1 Hz), 8.26 (d, 2H, J = 9.1 Hz); 13C
This journal is © The Royal Society of Chemistry 2012
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(S)-2-(N-(But-2-yn-1-yl)-4-nitrophenylsulfonamido)-3-phenyl-
propanamide 14h. At 0 °C, to a solution of Ns-amide 5
(429 mg, 1.23 mmol), 2-butyn-1-ol (0.09 mL, 1.23 mmol) and
PPh3 (322 mg, 1.23 mmol) in THF (10 mL) was added dropwise
DIAD (248 mg, 1.23 mmol). The reaction mixture was warmed
to room temperature and stirred overnight. The resultant solution
was diluted with EtOAc and washed with water and brine. The
organic layer was dried over Na2SO4 and concentrated under
reduced pressure. Purification by silica gel chromatography
(hexane–EtOAc, 1 : 1) afforded the corresponding alkynyl amide
14h (192 mg, 39%) as a white solid: [α]2D5 −104.7 (c 1.13,
= 9.5, 5.1 Hz), 4.55 (d, 1H, 18.8 Hz), 4.15 (d, 1H, J = 18.8 Hz),
3.35 (dd, 1H, J = 14.6, 5.1 Hz), 2.90 (dd, 1H, J = 14.6, 9.5 Hz),
0.15 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 170.8, 149.8,
145.1, 137.2, 129.3, 128.51, 128.46, 126.8, 123.8, 99.7, 91.3,
63.0, 35.0, 34.3, −0.4; IR (ATR): ν 3468, 3365, 2960, 2180,
1682, 1605, 1529, 1348, 1160, 846 cm−1; HRMS (FAB+): Calcd
for C21H26N3O5SSi [(M + H)+]: 460.1362; found: 460.1371.
(S)-Methyl
3-(benzyloxy)-2-(4-nitrophenylsulfonamido)-
propanoate 23. To a solution of 22 (15.4 g, 99.1 mmol) in
CH2Cl2 (500 mL) was added diisopropylethylamine (38 mL,
218 mmol) and pNsCl (23.1 g, 104 mmol) successively at 0 °C,
and the solution was stirred at the same temperature for 3.5 h.
The reaction was quenched with saturated aq. NH4Cl and con-
centrated. The residue was dissolved in H2O and extracted with
EtOAc three times. The organic layer was dried over MgSO4,
filtered, and concentrated. The residue was recrystallized from
EtOAc–hexane to afford Ns amide (28.3 mg, 94%) as a colorless
solid: [α]2D5 −4.2 (c 1.0, acetone); 1H NMR (acetone-d6,
500 MHz): δ 8.43 (d, 2H, J = 9.2 Hz), 8.15 (d, 2H, J = 9.2 Hz),
7.29 (d, 1H, J = 9.2 Hz), 4.24 (t, 1H, J = 5.7 Hz), 4.17 (ddd, 1H,
J = 4.6, 4.6, 9.2 Hz), 3.86 (ddd, 1H, J = 5.2, 5.7, 10.9 Hz), 3.76
(ddd, 1H, J = 5.2, 5.7, 10.9 Hz), 3.49 (s, 3H); 13C NMR
(acetone-d6, 126 MHz): δ 170.7, 150.9, 148.0, 129.3, 125.0
63.8, 59.3, 52.4; IR (ATR) ν 3546, 3261, 3107, 2959, 2894,
1741, 1606, 1526, 1446, 1433, 1349, 1313 cm−1; HRMS
(FAB+) Calcd for C10H12N2O7S [(M + H)+]: 305.0443; found:
305.0440.
1
CHCl3); H NMR (500 MHz, CDCl3): δ 8.08 (d, 2H, J = 8.6
Hz), 7.70 (d, 2H, J = 8.6 Hz), 7.15 (t, 1H, J = 6.9 Hz), 7.10 (t,
2H, J = 6.9 Hz), 7.05 (d, 2H, J = 6.9 Hz), 6.35 (br, 1H), 5.51
(br, 1H), 4.41 (dq, 1H, J = 17.8, 2.3 Hz), 4.13 (dq, 1H, J = 17.8,
2.3 Hz), 3.38 (dd, 1H, J = 14.9, 5.7 Hz), 2.90 (dd, 1H, J = 14.9,
9.2 Hz), 1.73 (t, 3H, J = 2.3 Hz); 13C NMR (126 MHz, CDCl3):
δ 171.0, 149.8, 145.2, 137.2, 129.3, 128.52, 128.45, 126.8,
123.7, 82.4, 73.6, 62.6, 34.7, 34.3, 3.4; IR (ATR): ν 3438, 2920,
2854, 1691, 1607, 1527, 1348, 1152 cm−1; HRMS (FAB+):
Calcd for C19H20N3O5S [(M + H)+] 402.1124; found: 402.1148.
7-endo Cyclization of (S)-2-(N-(but-2-yn-1-yl)-4-nitrophenyl-
sulfonamido)-3-phenylpropanamide 14h using PtCl2. 15h: [α]D25
1
+55.9 (c 0.65, CHCl3); H NMR (500 MHz, CDCl3): δ 8.19 (d,
2H, J = 9.0 Hz), 7.77 (d, 2H, J = 9.0 Hz), 7.24–7.21 (m, 3H),
7.14–7.12 (m, 2H), 6.18 (m, 1H), 4.94 (dd, 1H, J = 10.7, 5.6
Hz), 4.82 (m, 1H), 4.29 (m, 1H), 3.89 (m, 1H), 3.27 (dd, 1H, J
= 14.6, 5.6 Hz), 3.10 (dd, 1H, J = 14.6, 10.7 Hz), 1.76 (d, 1H, J
= 1.2 Hz); 13C NMR (126 MHz, CDCl3): δ 171.9, 148.6, 144.9,
135.0, 128.8, 128.6, 128.4, 127.3, 123.9, 105.4, 62.8, 42.4,
34.8, 23.5; IR (ATR): ν 3103, 2976, 2919, 1666, 1529, 1348,
To a solution of the above Ns amide (4.25 g, 14.0 mmol)
in 1,4-dioxane (75 mL) was added benzyl 2,2,2-trichloro-
acetimidate (3.37 mL, 18.1 m mol) and TfOH (0.185 mL,
2.10 mmol) at room temperature and stirred at the same tempera-
ture for 1.5 h. The resulting mixture was diluted with EtOAc,
and washed with saturated aq. NaHCO3 and brine. The organic
layer was dried over MgSO4, filtered and concentrated. After
purification by silica gel column chromatography (hexane–
EtOAc = 2 : 1), the crude product was recrystallized from
hexane–EtOAc to afford 23 (3.52 g, 64%) as a colorless solid:
1236, 1165, 1091 cm−1
;
HRMS (FAB+): Calcd for
C19H20N3O5S [(M + H)+] 402.1124; found: 402.1148.
17: [α]2D4 −20.2 (c 0.93, CHCl3); 1H NMR (500 MHz,
CDCl3): δ 8.10 (d, 2H, J = 8.8 Hz), 7.60 (d, 2H, J = 8.8 Hz),
7.13–7.07 (m, 3H), 7.00–6.95 (m, 2H), 6.42 (br, 1H), 5.41 (br,
1H), 4.59 (dd, 1H, J = 9.3, 6.1 Hz), 3.74 (m, 1H), 3.62 (ddd,
1H, J = 15.1, 9.3, 5.8 Hz), 3.19 (dd, 1H, J = 14.9, 6.1 Hz),
3.08–2.92 (m, 2H), 2.80 (dd, 1H, J = 14.9, 9.3 Hz); 13C NMR
(126 MHz, CDCl3): δ 206.4, 171.9, 149.8, 144.5, 136.3, 129.0,
128.7, 127.9, 126.9, 124.2, 61.2, 43.3, 39.7, 33.8, 30.1; IR
1
[α]2D5 +8.0 (c 1.0, CHCl3); H NMR (500 MHz, CHCl3): δ 8.28
(d, 2H, J = 8.6 Hz), 8.01 (d, 2H, J = 8.6 Hz), 7.36–7.26 (m,
3H), 7.22–7.17 (m, 2H), 5.66 (br s, 1H), 4.45 (q, 2H, J = 12.0
Hz), 4.24 (ddd, 1H, J = 9.2, 3.4, 3.4 Hz), 3.81 (dd, 1H, J = 9.2,
3.4 Hz), 3.66 (dd, 1H, J = 9.2, 3.4 Hz), 3.61 (s, 3H); 13C NMR
(126 MHz, CHCl3): δ 169.5, 150.0, 146.2, 136.9, 128.5, 128.3,
128.1, 127.7, 124.2, 73.4, 70.2, 56.3, 52.9; IR (ATR): ν 3279,
3106, 2955, 2871, 1745, 1348, 1312, 1167, 1138, 1092 cm−1
HRMS (FAB+): Calcd for C17H18N2O7S [(M + H)+]: 395.0913;
found: 395.0913.
(ATR):
ν 3460, 3362, 2924, 2835, 1692, 1529, 1349,
1160 cm−1; HRMS (FAB+): Calcd for C19H22N3O6S [(M + H)+]
420.1229; found: 420.1221.
(S)-2-(4-Nitro-N-(3-(trimethylsilyl)prop-2-yn-1-yl)phenylsulfo-
namido)-3-phenylpropanamide 14i. At 0 °C, to a solution of
Ns-amide 5 (349 mg, 1.00 mmol) in CH3CN (10 mL) was
added K2CO3 (829 mg, 6.0 mmol) and subsequently TMS-pro-
pargyl bromide (191 mg, 1.0 mmol). The reaction mixture was
warmed to room temperature and stirred overnight. After
removal of the precipitate by filtration, the filtrate was concen-
trated under reduced pressure. Purification by silica gel chrom-
atography (hexane–EtOAc, 1 : 1) afforded the corresponding
TMS-alkynyl amide 14i (161 mg, 35%) as a beige solid: [α]D25
(S)-3-(Benzyloxy)-2-(4-nitrophenylsulfonamido)propanamide
24. To a solution of 23 (2.79 g, 7.08 mmol) in 1,4-dioxane
(18 mL) was added 28% aq. NH3 (18 mL) at room temperature,
and stirred at the same temperature for 20 h. After additional
28% aq. NH3 (9.0 mL) was added, and then the solution was
stirred for 7 h. The solution was added H2O (18 mL), and stirred
for an additional 25 h. The resulting solution was concentrated,
and the resulting residue was recrystallized from MeOH–
toluene–hexane to afford 24 (1.86 g, 69%) as a colorless solid:
1
−113.4 (c 0.98, CHCl3); H NMR (400 MHz, CDCl3): δ 8.05
1
(d, 2H, J = 9.0 Hz), 7.71 (d, 2H, J = 9.0 Hz), 7.13 (m, 1H),
708–7.06 (m, 4H), 6.37 (br, 1H), 5.48 (br, 1H), 4.63 (dd, 1H, J
[α]2D6 +37.4 (c 0.20, CHCl3); H NMR (500 MHz, DMSO-d6):
δ 8.59 (d, 1H, J = 8.6 Hz), 8.34 (dt, 2H, J = 8.6, 1.7 Hz), 8.08
6082 | Org. Biomol. Chem., 2012, 10, 6074–6086
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(dt, 2H, J = 8.6, 1.7 Hz), 7.49 (br s, 1H), 7.38–7.26 (m, 3H),
7.25–7.18 (m, 3H), 4.39 (s, 2H), 4.09 (ddd, 1H, J = 8.6, 7.4, 5.2
Hz), 3.56 (dd, 1H, J = 10.3, 5.2 Hz), 3.51 (dd, 1H, J = 10.3, 7.4
Hz); 13C NMR (126 MHz, DMSO-d6): δ 170.1, 149.2, 147.0,
137.7, 128.0, 127.4, 127.3, 124.1, 71.9, 70.2, 56.2; IR (ATR): ν
3415, 3203, 3095, 2867, 1684, 1673, 1530, 1343, 1165,
1091 cm−1; HRMS (FAB+): Calcd for C16H17N3O6S [(M +
H)+]: 380.0916; found: 380.0922.
[α]2D4 +53.8 (c 1.0, CHCl3); 1H NMR (CDCl3, 500 MHz): δ 8.25
(dt, 2H, J = 2.3, 9.2 Hz), 7.96 (dt, 2H, J = 2.3, 9. 2 Hz),
7.39–7.31 (m, 3H), 7.23–7.16 (m, 2H), 6.62 (d, 1H, J = 3.4 Hz),
5.85 (br s, 1H), 4.50 (d, 1H, J = 12.0 Hz), 4.38 (d, 1H, J = 12.0
Hz), 3.83–3.76 (m, 2H), 3.41 (dd, 1H, J = 6.9, 8. 6 Hz), 2.78 (d,
3H, J = 5.2 Hz); 13C NMR (CDCl3, 126 MHz): δ 168.7, 150.2,
144.8, 136.6, 128.7, 128.5, 128.4, 128.0, 124.4, 73.63, 69.34,
55.5, 26.5; IR (ATR) ν 3398, 3321, 3243, 3102, 2868, 1651,
1605, 1525,1442, 1349, 1311 cm−1; HRMS (FAB+) Calcd for
C17H19N3O6S [(M + H)+]: 394.1073; found: 394.1092.
(S)-3-(Benzyloxy)-2-(4-nitro-N-(prop-2-yn-1-yl)phenylsulfona-
mido)propanamide 25. To a solution of 24 (1.81 g, 4.78 mmol)
and K2CO3 (1.98 g, 14.3 mmol) in DMF (24 mL) was added
propargyl bromide (1.1 mL, 14.6 mmol) at 0 °C. After stirring
for 0.5 h, the mixture was allowed to warm to room temperature,
and stirred for 2.5 h. The resulting mixture was diluted in Et2O,
washed with H2O once and brine four times. The organic layer
was dried over MgSO4, filtered, and concentrated. After purifi-
cation by silica gel column chromatography (CHCl3–MeOH =
30 : 1), the obtained product was recrystallized from MeOH–
toluene–hexane to afford 25 (1.33 g, 69%) as a colorless solid:
(S)-3-(Benzyloxy)-N-methyl-2-(4-nitro-N-(prop-2-yn-1-yl)-
phenylsulfonamido)propanamide 31a. To a solution of 29
(2.63 g, 6.69 mmol) and K2CO3 (2.78 g, 20.1 mmol) in DMF
(34 mL) was added propargyl bromide (1.5 mL, 20 mmol) at
0 °C. After stirring for 0.5 h, the mixture was allowed to warm
to room temperature, and stirred for 17 h. The resulting mixture
was quenched with saturated aq. NH4Cl, and extracted with
CHCl3 three times. The organic layer was dried over MgSO4,
filtered, and concentrated. Purification by silica gel column
chromatography (hexane–EOAc = 2 : 1) afforded 36a (2.35 g,
1
[α]2D6 +8.4 (c 0.50, acetone); H NMR (500 MHz, DMSO-d6): δ
1
8.19 (dt, 2H, J = 8.9, 2.0 Hz), 8.08 (dt, 2H, J = 8.9, 2.0 Hz),
7.52 (br s, 1H), 7.32–7.20 (m, 4H), 7.19–7.14 (m, 2H), 4.61 (dd,
1H, J = 4.9, 7.7 Hz), 4.49–4.29 (m, 4H), 3.83–3.72 (m, 2H),
3.18 (dd, 1H, J = 2.3, 2.3 Hz); 13C NMR (126 MHz, DMSO-
d6): δ 169.4, 149.5, 145.2, 137.6, 128.9, 128.0, 127.7, 127.5,
124.0, 79.7, 74.9, 72.1, 68.3, 59.0, 34.5; IR (ATR): ν 3464,
3282, 1683, 1525, 1362, 1350, 1340, 1311, 1157, 1131, 1095,
1088 cm−1; HRMS (FAB+): Calcd for C19H19N3O6S [(M +
H)+]: 418.1073; found: 418.1074.
81%) as an orange solid: [α]2D4 −29.0 (c 1.0, CHCl3); H NMR
(CDCl3, 500 MHz): δ 8.02–7.92 (m, 4H), 7.31–7.21 (m, 3H),
7.06–6.98 (m, 2H), 6.61 (br s, 1H), 4.64 (dd, 1H, J = 5.2, 9.2
Hz), 4.31–4.21 (m, 4H), 4.27 (d, 1H, J = 10.9 Hz), 4.02 (dd,
1H, J = 5.2, 10.9 Hz), 3.87 (dd, 1H, J = 10.9, 10.9 Hz), 2.83 (d,
3H, J = 5.2 Hz), 2.27 (t, 1H, J = 2.3 Hz); 13C NMR (CDCl3,
126 MHz): δ 168.2, 149.9,144.4, 136.7,129.0, 128.3, 128.2,
128.1, 123.5, 77.6, 73.8, 73.5, 66.9, 60.1, 34.3, 26.3; IR (ATR)
ν 3412, 3389, 3156, 2942, 2872, 1668, 1607, 1527, 1454, 1412,
1403, 1348, 1313 cm−1; HRMS (FAB+) Calcd for C20H21N3O6S
[(M + H)+]: 432.1229; found: 432.1215.
(S)-3-((Benzyloxy)methyl)-4-((4-nitrophenyl)sulfonyl)-4,5-
dihydro-1H-1,4-diazepin-2(3H)-one 26. To a solution of 25
(49.0 mg, 0.117 mmol) in 1,2-DCE (1.2 mL) was added PtCl2
(6.3 mg, 0.024 mmol) one portion. The mixture was stirred at
room temperature for 19 h, and then heated at 50 °C for 24 h,
80 °C for 24 h. After cooling to room temperature, the resulting
mixture was filtrated through Celite and washed with acetone
and MeOH. The filtrate was concentrated. After purification by
silica gel column chromatography (hexane–acetone = 2 : 1 and
3 : 2, twice), the crude product was recrystallized from hexane–
acetone to afford 26 (30.3 mg, 62%) as a colorless oil: [α]D26
+14.4 (c 0.050, acetone); 1H NMR (500 MHz, DMSO-d6): δ
9.05 (d, 1H, J = 5.7 Hz), 8.22 (dt, 2H, J = 9.2, 2.3 Hz), 8.00 (dt,
2H, J = 9.2, 2.3 Hz), 7.29–7.20 (m, 3H), 7.14–7.08 (m, 2H),
5.57–5.49 (m, 1H), 4.88 (ddd, 1H, J = 10.3, 5.2, 2.3 Hz), 4.71
(dd, 1H, J = 9.7, 4.6 Hz), 4.41–4.30 (m, 3H), 3.86–3.74 (m,
2H), 3.68 (dd, 1H, J = 10.9, 4.6 Hz); 13C NMR (126 MHz,
DMSO-d6): δ170.2, 149.6, 144.4, 137.3, 128.5, 128.1, 127.6,
124.2, 122.2, 107.8, 71.8, 65.1, 62.0, 43.1; IR (ATR): ν 3332,
(S)-3-(Benzyloxy)-2-(N-(3-(furan-2-yl)prop-2-yn-1-yl)-4-nitro-
phenylsulfonamido)-N-methylpropanamide 31b. To a solution
of 29 (304 mg, 0.773 mmol) and K2CO3 (320 mg, 2.32 mmol)
in DMF (4.0 mL) was added ((4-bromobut-2-yn-1-yl)oxy)(tert-
butyl)dimethylsilane33 (excess) at 0 °C. After stirring for 0.5 h,
the mixture was allowed to warm to room temperature, and
stirred for 17 h. The resulting mixture was diluted with EtOAc,
washed with H2O twice and brine twice. The organic layer was
dried over Na2SO4, filtered, and concentrated. Purification by
silica gel column chromatography (hexane–EtOAc = 3 : 2)
afforded 31b (253 mg, 57%) as a colorless oil: [α]2D7 −17.7 (c
2.2, CHCl3); 1H NMR (500 MHz, CDCl3): δ 8.00–7.93 (m, 4H),
7.32–7.21 (m, 3H), 7.02 (dd, 2H, J = 7.4, 1.7 Hz), 6.60 (d, 1H, J
= 4.0 Hz), 4.64 (dd, 1H, J = 9.2, 5.2 Hz), 4.28 (d, 1H, J = 10.9
Hz), 4.25 (dd, 1H, J = 4.0, 2.3 Hz), 4.22 (d, 1H, J = 10.9 Hz),
4.18 (dd, 2H, J = 1.7, 1.7 Hz), 4.03 (dd, 1H, J = 10.9, 5.2 Hz),
3.85 (dd, 1H, J = 10.9, 9.2 Hz), 2.84 (d, 3H, J = 4.6 Hz), 0.90
(s, 9H), 0.09 (d, 6H, J = 1.7 Hz); 13C NMR (126 MHz, CDCl3):
δ 168.3, 149.9, 144.5, 136.8, 129.0, 128.3, 128.3, 128.1, 123.5,
84.6, 78.3, 73.5, 67.0, 60.2, 51.4, 34.8, 26.4, 25.7, 18.3, −5.29,
−5.33; IR (ATR): ν 3411, 3106, 2956, 2929, 2858, 1674, 1529,
1348, 1313, 1254, 1164, 1088 cm−1; HRMS (FAB+): Calcd for
C27H37N3O7SSi [(M + H)+]: 576.2200; found: 576.2207.
1692, 1663, 1527, 1368, 1348, 1337, 1310, 1160, 1087 cm−1
;
HRMS (FAB+): Calcd for C19H19N3O6S [(M + H)+]: 418.1073;
found: 418.1078.
(S)-3-(Benzyloxy)-N-methyl-2-(4-nitrophenylsulfonamido)pro-
panamide 29. To a solution of 24 (3.50 g, 8.86 mmol) was
added 40% aq. MeNH2 (45 mL) at room temperature, and stirred
at the same temperature for 18 h. The resulting solution was con-
centrated. The obtained residue was recrystallized from MeOH–
acetone–hexane to afford 29 (2.73 g, 78%) as a yellow solid:
(S)-3-(Benzyloxy)-N-methyl-2-(4-nitro-N-(3-phenylprop-2-yn-
1-yl)phenylsulfonamido)propanamide 31c. To a solution of 29
(764 mg, 2.02 mmol) and K2CO3 (835 mg, 6.04 mmol) in DMF
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 6074–6086 | 6083

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(10 mL) was added propargyl bromide (0.45 mL, 6.0 mmol) at
0 °C. After stirring for 1 h, the mixture was allowed to warm to
room temperature, and stirred for 17.5 h. The resulting mixture
was diluted with Et2O, washed with H2O once and brine five
times. The organic layer was dried over MgSO4, filtered, and
concentrated to give crude product.
and washed with acetone. The filtrate was concentrated. Purifi-
cation by silica gel column chromatography (hexane–acetone =
5 : 2) afforded 32a (56.6 mg, 56%) as a colorless solid: [α]D24
1
−17.1 (c 0.84, CHCl3); H NMR (CDCl3, 500 MHz): δ 8.15 (d,
2H, J = 8.6 Hz), 7.93 (d, 2H, J = 8.6 Hz), 7.31–7.26 (m, 3H),
7.16–7.15 (m, 2H), 5.65 (d, 1H, J = 10.6 Hz), 4.96 (tt, 2H, J =
11.5, 3.9 Hz), 4.44 (d, 1H, J = 11.5 Hz), 4.41–4.37 (m, 1H),
4.36 (d, 1H, J = 11.5 Hz), 3.92–3.89 (m, 2H), 3.82 (dd, 1H, J =
10.6, 5.4 Hz), 2.82 (s, 3H); 13C NMR (CDCl3, 126 MHz) δ
168.8, 149.9, 144.9, 136.8, 129.1, 128.6, 128.4, 128.2, 127.9,
123.8, 109.8, 73.1, 65.7, 62.3, 43.6, 37.2; IR (ATR) ν 3104,
To the mixture of the above alkyne and CuI (38.4 mg,
0.201 mmol) in Et3N (10 mL) and THF (10 mL) was added PhI
(0.34 mL, 3.04 mmol) and Pd(PPh3)4 (233 mg, 0.202 mmol) at
room temperature. After the mixture was stirred for 7 h at 50 °C,
the resulting mixture was concentrated. The residue was filtrated
through Celite, and washed with hexane–EtOAc (3 : 2). Purifi-
cation by silica gel column chromatography (hexane–EtOAc =
3 : 2) afforded 31c (496 mg, 49% over 2 steps) as a yellow amor-
3068, 3036, 2869, 1655, 1606, 1529, 1455, 1376, 1349 cm−1
;
HRMS (FAB+) Calcd for C20H21N3O6S [M+]: 431.1151; found:
431.1142.
1
phous solid: [α]2D7 −25.3 (c 0.99, CHCl3); H NMR (500 MHz,
CDCl3): δ 7.98 (dt, 2H, J = 9.2, 2.3 Hz), 7.90 (dt, 2H, J = 9. 2,
2.3 Hz), 7.37–7.32 (m, 1H), 7.32–7.23 (m, 4H), 7.23–7.15 (m,
4H), 6.94 (d, 2H, J = 6.9 Hz), 6.61 (d, 1H, J = 4.6 Hz), 4.72
(dd, 1H, J = 9.2, 5.2 Hz), 4.45 (d, 1H, J = 1.1 Hz), 4.31 (d,1H, J
= 10.9 Hz), 4.21 (d, 1H, J = 10.9 Hz), 4.09 (dd, 1H, J = 10.9,
5.2 Hz), 3.96 (dd, 1H, J = 10.9, 9.2 Hz), 2.83 (d, 3 H, J = 5.2
Hz); 13C NMR (126 MHz, CDCl3): δ 168.4, 149.83, 144.7,
136.7, 131.5, 129.1, 129.0, 128.4, 128.29, 128.25, 128.1, 123.6,
121.7, 85.9, 82.7, 73.6, 67.1, 60.36, 35.3, 26.5; IR (ATR): ν
3416, 3102, 2938, 2873, 1674, 1528, 1490, 1348, 1313, 1165,
1091 cm−1; HRMS (FAB+): Calcd for C26H25N3O6S [(M +
H)+]: 508.1542; found: 508.1545.
(S)-3-((Benzyloxy)methyl)-7-(furan-2-yl)-1-methyl-4-((4-nitro-
phenyl)sulfonyl)-4,5-dihydro-1H-1,4-diazepin-2(3H)-one 32b. To
a solution of 31b (234 mg, 0.406 mmol) in 1,4-dioxane
(4.0 mL) was added PtCl2 (10.8 mg, 0.0406 mmol) in one
portion. The mixture was stirred at 70 °C for 12 h. After cooling
to room temperature, the resulting mixture was filtrated through
Celite and washed with acetone. The filtrate was concentrated.
Purification by silica gel column chromatography (hexane–
EtOAc = 2 : 1) afforded 32b (17.0 mg, 7%) as a colorless oil:
[α]2D7 −59.9 (c 2.7, CHCl3); 1H NMR (500 MHz, CDCl3): δ 8.36
(dt, 2H, J = 8.6, 2.3 Hz), 8.05 (dt, 2H, J = 8.6, 2.3 Hz),
7.37–7.25 (m, 5H), 5.69 (dd, 1H, J = 7.4, 7.4 Hz), 4.88 (dd, 1H,
J = 9.2, 6.3 Hz), 4.55 (d, 1H, J = 12.0 Hz), 4.48 (d, 1H, J = 12.0
Hz), 4.09 (d, 1H, J = 14.3 Hz), 4.05 (dd, 1H, J = 12.0, 7.4 Hz),
3.97 (d, 1H, J = 14.3 Hz), 3.81–3.69 (m, 2H), 3.27 (dd, 1H, J =
12.0, 7.4 Hz), 2.91 (s, 3H), 0.88 (s, 9H), 0.05 (d, 6H, J = 2.9
Hz); 13C NMR (126 MHz, CDCl3): δ 167.3, 150.3, 145.5,
143.1, 137.6, 128.9, 128.4, 127.82, 127.7, 124.4, 110.4, 72.9,
70.6, 64.4, 61.9, 42.5, 31.7, 25.7, 25.6, 18.2, −5.5; IR (ATR): ν
2956, 2929, 2857, 1662, 1532, 1349, 1170, 1089 cm−1; HRMS
(FAB+): Calcd for C27H37N3O7SSi [(M + H)]+: 576.2200;
found: 576.2203.
(S)-3-(Benzyloxy)-2-(N-(4-((tert-butyldimethylsilyl)oxy)but-2-
yn-1-yl)-4-nitrophenylsulfonamido)-N-methylpropanamide
31d. To the mixture of 31a (2.89 g, 6.70 mmol) and Cul
(128 mg, 0.672 mmol) in Et3N (17 mL) and THF (17 mL) was
added 2-bromofuran34 (1.48 g, 10.1 mmol) and Pd(PPh3)4
(774 mg, 0.670 mmol) at room temperature. After the mixture
was stirred for 5 h at 50 °C, the resulting mixture was concen-
trated. The residue was filtrated through Celite, and washed with
hexane–EtOAc (3 : 2). Purification by silica gel column chrom-
atography (hexane–EtOAc = 3 : 2) afforded 31d (2.34 g, 71%) as
1
a yellow oil: [α]2D7 −17.5 (c 1.2, CHCl3); H NMR (500 MHz,
CDCl3): δ 7.99 (dt, 2H, J = 9.2, 2.3 Hz), 7.90 (dt, 2H, J = 9.2,
2.3 Hz), 7.38–7.36 (m, 1H), 7.29–7.22 (m, 2H), 7.22–7.15 (m,
2H), 6.97–6.91 (m, 2H), 6.52 (d, 1H, J = 4.0 Hz), 6.48 (d, 1H, J
= 3.4 Hz), 6.38 (dd, 1H, J = 3.4, 1.7 Hz), 4.70 (dd, 1H, J = 9.2,
4.6 Hz), 4.57 (d, 1H, J = 18.9 Hz), 4.40 (d, 1H, J = 18.9 Hz),
4.29 (d, 1H, J = 10.9 Hz), 4.21 (d, 1H, J = 10.9 Hz), 4.02 (dd,
1H, J = 10.9, 4.6 Hz), 3.90 (dd, 1H, J = 10.9, 9.2 Hz), 2.84 (d,
3H, J = 5.2 Hz); 13C NMR (126 MHz, CDCl3): δ 168.2, 149.9,
144.6, 144.1, 136.7, 135.7, 129.1, 128.2, 128.2, 123.6, 116.0,
111.0, 87.4, 76.1, 73.6, 67.0, 60.5, 35.0, 26.4; IR (ATR): ν 3417,
3329, 3107, 2945, 2871, 1670, 1528, 1348, 1313, 1212, 1165,
1091 cm−1; HRMS (FAB+): Calcd for C24H23N3O7S [(M +
H)+]: 498.1335; found: 498.1336.
(S)-3-((Benzyloxy)methyl)-1-methyl-4-((4-nitrophenyl)sulfonyl)-
7-phenyl-4,5-dihydro-1H-1,4-diazepin-2(3H)-one 32c. To a sol-
ution of 31c (480 mg, 0.946 mmol) in 1,2-DCE (5.0 mL) was
added PtCl2 (25.2 mg, 0.0947 mmol) in one portion. The
mixture was stirred at 70 °C for 22 h. After cooling to room
temperature, the resulting mixture was filtrated through Celite
and washed with acetone. The filtrate was concentrated. Purifi-
cation by silica gel column chromatography (hexane–EtOAc =
2 : 1) afforded 32c (358 mg, 75%) as a yellow amorphous solid:
[α]2D7 −97.4 (c 2.9, CHCl3); 1H NMR (500 MHz, CDCl3): δ 8.40
(dt, 2H, J = 9.2, 2.3 Hz), 8.10 (dt, 2H, J = 9.2, 2.3 Hz),
7.44–7.38 (m, 1H), 7.38–7.32 (m, 4H), 7.32–7.27 (m, 5H), 5.82
(dd, 1H, J = 8.0, 8.0 Hz), 4.97 (dd, 1H, J = 10.3, 6.3 Hz), 4.51
(dd, 1H, J = 24.6, 12.0 Hz), 4.23 (dd, 1H, J = 11.5, 8.0 Hz),
3.81 (dd, 1H, J = 9.7, 9.7 Hz), 3.71 (dd, 1H, J = 9.7, 6.3 Hz),
3.33 (dd, 1H, J = 11.5, 7.4 Hz), 2.77 (s, 3H); 13C NMR
(126 MHz, CDCl3): δ 167.5, 150.4, 148.0, 142.8, 137.4, 134.3,
129.9, 129.1, 128.9, 128.4, 127.8, 127.6, 127.0, 124.5, 112.0,
73.1, 70.6, 64.2, 42.8, 34.3; IR (ATR): ν 3102, 3068, 3033,
2923, 2866, 1662, 1530, 1383, 1348, 1312, 1169, 1086,
(S)-3-((Benzyloxy)methyl)-1-methyl-4-((4-nitrophenyl)sulfo-
nyl)-4,5-dihydro-1H-1,4-diazepin-2(3H)-one 32a. To a solution
of 31a (102 mg, 0.235 mmol) in 1,4-dioxane (1.2 mL) was
added PtCl2 (12.4 mg, 0.0466 mmol) in one portion. The
mixture was stirred at 70 °C for 72 h. After cooling to room
temperature, the resulting mixture was filtrated through Celite
6084 | Org. Biomol. Chem., 2012, 10, 6074–6086
This journal is © The Royal Society of Chemistry 2012

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1052 cm−1; HRMS (FAB+): Calcd for C26H25N3O6S [(M +
H)+]: 508.1542; found: 508.1528.
7. 7, 7.7 Hz), 4.55 (dd, 2H, J = 28.6, 12.0 Hz), 3.90–3.82 (m,
1H), 3.73–3.65 (m, 2H), 3.25 (dd, 1H, J = 12.0, 7.4 Hz), 3.09 (s,
3H), 3.06 (dd, 1H, J = 12.0, 7.4 Hz), 2.35 (s, 3H); 13C NMR
(126 MHz, CDCl3): δ 171.2, 148.6, 143.2, 138.0, 137.6, 128.3,
128.0, 127.6, 113.7, 111.5, 109.3, 73.5, 68.0, 62.7, 51.6, 40.6,
33.1; IR (ATR): ν 3031, 2946, 2858, 2788, 1668, 1489, 1454,
1377, 1305, 1207, 1154, 1099, 1067, 1015 cm−1: HRMS
(FAB+): Calcd for C19H22N2O3 [M+] 326.1630; found:
326.1630.
(S)-3-((Benzyloxy)methyl)-7-(((tert-butyldimethylsilyl)oxy)methyl)-
1-methyl-4-((4-nitrophenyl)sulfonyl)-4,5-dihydro-1H-1,4-diazepin-
2(3H)-one 32d. To a solution of 31d (405.7 mg, 0.82 mmol) in
1,2-DCE (6 mL) was added PtCl2 (22 mg, 0.082 mmol) in one
portion. The mixture was stirred at 70 °C for 18 h. After cooled
to room temperature, the resulting mixture was filtrated through
Celite and washed with acetone. The filtrate was concentrated.
Purification by silica gel column chromatography (hexane–
EtOAc = 8 : 2) afforded 36d (234 mg, 58%) as a yellow oil, and
recovered starting material 31d (121 mg, 31%). 32d: [α]2D8 −19.0
Acknowledgements
1
This work was supported in part by a Grant-in-Aid for Scientific
Research (B) (Y.T.) and “Targeted Proteins Research Program”
from the Ministry of Education, Culture, Sports, Science and
Technology of Japan (Y.T.) and A.-L. G. thanks the JSPS for a
Postdoctoral Fellowship. The authors are grateful for X-ray crys-
tallography from Dr Akihito Yamano of Rigaku.
(c 0.75, CHCl3); H NMR (500 MHz, CDCl3): δ 8.39 (d, 2H,
J = 8.6 Hz), 8.08 (d, 2H, J = 8.6 Hz), 7.44 (s, 1H), 7.35–7.20
(m, 6H), 6.43 (dd, 1H, J = 2.9, 1.7 Hz), 6.32 (d, 1H, J = 3.4
Hz), 6.02 (dd, 1H, J = 8.0, 8.0 Hz), 4.90 (dd, 1H, J = 9.2, 6.9
Hz), 4.46 (d, 2H, J = 7.4 Hz), 4.22 (dd, 1H, J = 11.5, 8.0 Hz),
3.77–3.62 (m, 2H), 3.32 (dd, 1H, J = 11.5, 7.4 Hz), 2.94 (s, 3H);
13C NMR (126 MHz, CDCl3): δ 167.34, 150.4, 147.8, 144.0,
142.9, 138.1, 137.5, 129.0, 128.4, 127.7, 127.6, 124.5, 111.7,
110.5, 110.5, 73.2, 70.8, 64.3, 42.4, 34.7; IR (ATR): ν 3107,
3033, 2924, 2866, 1664, 1530, 1489, 1400, 1348, 1310, 1219,
Notes and references
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1168, 1086, 1052 cm−1
;
HRMS (FAB+): Calcd for
C24H23N3O7S [(M + H)+]: 498.1335; found: 498.1332.
2 (a) M. Arndt, K. S. M. Salih, A. Fromm, L. J. Goossen, F. Menges and
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(S)-3-((Benzyloxy)methyl)-1-methyl-7-phenyl-4,5-dihydro-1H-
1,4-diazepin-2(3H)-one 33. To a solution of 32d (564 mg,
1.13 mmol) and K2CO3 (314 mg, 2.27 mmol) in MeCN
(10 mL) was added PhSH (0.18 mL, 1.7 mmol) at room temp-
erature. After stirring for 4.5 h, the resulting mixture was diluted
with EtOAc, washed with H2O and brine. The organic layer was
dried over Na2SO4, filtered, and concentrated. Purification by
silica gel column chromatography (hexane–EtOAc = 2 : 1 to
CHCl3–MeOH = 10 : 1) afforded 33 (340 mg, 96%) as a yellow
1
oil: [α]2D8 +94.1 (c 1.4, CHCl3); H NMR (500 MHz, CDCl3):
δ 7.45–7.40 (m, 1H), 7.35–7.23 (m, 5H), 6.44 (dd, 1H, J = 3.4,
1.7 Hz), 6.37 (d, 1H, J = 3.4 Hz), 6.18 (dd, 1H, J = 7.7, 7.7 Hz),
4.56 (d, 2H, J = 4. 9 Hz), 3.89–3.80 (m, 2H), 3.72 (dd, 1H, J =
9.2, 7.4 Hz), 3.50 (dd, 1H, J = 13.2, 7.7 Hz), 3.41(dd, 1H, J =
13.2, 7.7 Hz), 3.07 (s, 3H); 13C NMR (126 MHz, CDCl3):
δ 171.9, 148.8, 143.0, 138.1, 136.6, 128.3, 127.9, 127.6, 115.8,
111.4, 108.9, 73.6, 70.3, 56.4, 41.4, 33.2; IR (ATR): ν 3317,
2925, 2864, 1668, 1559, 1490, 1455, 1374, 1220, 1156, 1100,
1065 cm−1; HRMS (FAB+): Calcd for C18H20N2O3 [(M + H)+]:
313.1552; found: 313.1554.
8 L. Zhang, D. Ye, Y. Zhou, G. Lin, E. Feng, H. Jiang and H. Lin, J. Org.
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9 A.-L. Girard, T. Enomoto, S. Yokouchi, C. Tsukano and Y. Takemoto,
Chem.–Asian J., 2011, 6, 1321.
10 Intramolecular hydroamidation of alkyne and amide without transition
metal: (a) S. K. Sharma, A. K. Mandadapu, B. Kumar and B. Kundu,
J. Org. Chem., 2011, 76, 6798; (b) A. Kondoh, H. Yorimitsu and
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(S)-3-((Benzyloxy)methyl)-1,4-dimethyl-7-phenyl-4,5-dihydro-
1H-1,4-diazepin-2(3H)-one 34. To a solution of 33 (298 mg,
0.953 mmol) in MeOH (5.0 mL), MeCN (5.0 mL) and 35% aq.
CH2O (2.0 mL) was added AcOH (0.27mL, 4.8 mmol) and
NaBH3CN (300 mg, 4.8 mmol) at room temperature. After stir-
ring for 16 h, the resulting mixture was quenched with 2M aq.
NaOH and brine, extracted with EtOAc, and washed with brine.
The organic layer was dried over Na2SO4, filtered, and concen-
trated. Purification by silica gel column chromatography
(hexane–EtOAc = 1 : 3 to 1 : 4) afforded 34 (247 mg, 79%) as a
11 Recent reports of hydroamidation for formation of five-membered rings:
(a) S. Fustero, B. Fernandez, P. Bello, C. del Pozo, S. Arimitsu and
G. B. Hammond, Org. Lett., 2007, 9, 4251; (b) S. Fustero, P. Bello,
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(e) L. M. Pardo, I. Tellitu and E. Dominguez, Synthesis, 2010, 971;
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Asian J., 2009, 4, 1668; (h) S. Mehta, J. P. Waldo and R. C. Larock,
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(k) T. Yao and R. C. Larock, J. Org. Chem., 2005, 70, 1432.
1
colorless oil: [α]2D8 +54.5 (c 0.09, CHCl3); H NMR (500 MHz,
CDCl3): δ 7.44 (d, 1H, J = 1.7 Hz), 7.35–7.23 (m, 5H),
6.46–6.43 (m, 1H), 6.38 (d, 1H, J = 3.4 Hz), 6.19 (dd, 1H, J =
This journal is © The Royal Society of Chemistry 2012
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12 Recent reports of hydroamidation for formation of six-membered rings:
(a) R. Alvarez, C. Martinez, Y. Madich, J. G. Denis, J. M. Aurrecoechea
and A. R. de Lera, Chem.–Eur. J., 2010, 16, 12746; (b) S. F. Vasilevsky,
T. F. Mikhailovskaya, V. I. Mamatyuk, G. E. Salnikov,
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2009, 74, 8106; (c) N. Sakai, K. Annaka, A. Fujita, A. Sato and
T. Konakahara, J. Org. Chem., 2008, 73, 4160; (d) G. Le Bras,
A. Hamze, S. Messaoudi, O. Provot, P.-B. Le Calvez, J.-D. Brion and
M. Alami, Synthesis, 2008, 1607; (e) A. Zulys, M. Dochnahl,
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18 We previously assigned the product via the platinum catalyzed reaction of
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(3–5 Hz) between a olefin proton and methylene protons in compound 9,
it was difficult to distinguish between 6-exo and 7-endo cyclized pro-
ducts. Thus compound 9 was hydrolyzed under acidic conditions as
described. Additionally we re-examined the structure, which was reported
in the same paper and found that the platinum catalyzed cyclization pro-
ceeded in 7-endo ring closing mode in all cases. The paper will soon be
corrected after the gold catalyzed reaction is examined.
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6086 | Org. Biomol. Chem., 2012, 10, 6074–6086
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