Copper-catalyzed reaction of ketenimine and in situ generated immonium ion: Access to α, β-unsaturated amidines

Article abstract of DOI:10.1021/jo402368x

A Cu-catalyzed three-component reaction of alkyne, azides (sulfonyl or phosphoryl azides), and N,N-dialkyloxyformamide dialkyl acetal via electrophilic addition of immonium ion to copper ketenimine is reported. This new protocol for the preparation of α,β-unsaturated amidine derivatives appears to offer high yield, mild conditions, and wide substrate scope. The reaction might involve the processes of copper ketenimine intermediate formation, electrophilic addition, and isomerization.

Full text of DOI:10.1021/jo402368x

Article
pubs.acs.org/joc
Copper-Catalyzed Reaction of Ketenimine and in Situ Generated
Immonium Ion: Access to α,β‑Unsaturated Amidines
Bangben Yao,‡,∥ Chuang Shen,†,∥ Zunjun Liang,† and Yuhong Zhang*,†,§
†ZJU-NHU United R&D Center, Department of Chemistry, Zhejiang University, Hangzhou 310027, People’s Republic of China
‡China National Center for Quality Supervision, Test of Agricultural-Avocation Processed Food, Hefei 230051, People’s Republic of
China
§State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, People’s Republic of China
S
* Supporting Information
ABSTRACT: A Cu-catalyzed three-component reaction of alkyne, azides (sulfonyl or phosphoryl azides), and N,N-
dialkyloxyformamide dialkyl acetal via electrophilic addition of immonium ion to copper ketenimine is reported. This new
protocol for the preparation of α,β-unsaturated amidine derivatives appears to offer high yield, mild conditions, and wide
substrate scope. The reaction might involve the processes of copper ketenimine intermediate formation, electrophilic addition,
and isomerization.
yformamide dialkyl acetal, which might involve an electrophilic
addition of immonium ion to an in situ generated copper
ketenimine intermediate. This transformation results in the
efficient formation of synthetically important and pharmaco-
logically useful amidine derivatives.13
INTRODUCTION
■
Click chemistry1 involving the copper-catalyzed azide−alkyne
cycloaddition (CuAAC) reaction to produce regioselectively
1,4-disubstituted 1,2,3-triazoles2 has aroused considerable
interest because of its countless applications in organic
synthesis,3 material sciences,4 bioconjugation,5 and medical
chemistry.6 Among the azides utilized in the CuAAC reaction,
the employment of sulfonyl azides resulted in apparently
different outcomes and smoothly generated in situ a reactive
ketenimine intermediate by ring-opening rearrangement of N-
sulfonyl copper trizole species.7 This facile and versatile route
to a ketenimine has dramatically broadened the scope and
utility of the CuAAC reaction. Elegant examples of multi-
component reactions8−10 have been developed by trapping in
situ generated ketenimine via this CuAAC process.11 However,
these transformations mainly focused on the addition to the
central carbon of ketenimine, which was reactive toward various
nucleophiles. As could be concluded from the resonance
structures of ketenimine intermediates, they could be captured
by both nucleophiles and electrophiles, while the reaction of
electrophiles with ketenimine generated through the CuAAC
mechanism has not yet been investigated to date (Scheme 1).
Recently we have developed an efficient synthesis of 3-
amino-1,4-diynes via copper-catalyzed coupling reactions of
terminal alkynes with C−OMe bonds adjacent to a nitrogen
atom, which involves an immonium ion intermediate generated
in situ through elimination of MeOH from terminal alkynes
and N,N-dimethylformamide dialkyl acetals.12 Encouraged by
these results, we decided to expand the scope of this reaction by
using sulfonyl azides. Herein, we report a unique Cu-catalyzed
three-component reaction of alkyne, azide, and N,N-dialkylox-
RESULTS AND DISCUSSION
■
Under the protocol used for the synthesis of 3-amino-1,4-
diynes in our previous work, phenylacetylene (1a; 0.6 mmol),
tolylsulfonyl azide (2a; 0.6 mmol), and N,N-dimethylforma-
mide dimethyl acetal (3a; 0.5 mmol) were reacted in toluene at
80 °C in the presence of CuBr (10 mol %), dppp (10 mol %),
and 3 Å MS (molecular sieves). Surprisingly, unsaturated
amidine 4a was obtained in 74% isolated yield (Scheme 2), and
its structure was further confirmed by X-ray structural analysis,
which disclosed that the CN double bond had an E
configuration (Figure 1).
After this seminal experiment, we decided to optimize
reaction conditions. As shown in Table 1, commonly used
solvents, such as acetonitrile (MeCN), dioxane, and THF were
also suitable for this transformation; in comparison, dichloro-
ethane (DCE) gave better yields (Table 1, entries 1−5). The
reaction could run smoothly and efficiently even at room
temperature (Table 1, entries 5−7). The use of phosphine
ligands was crucial to this reaction; both monodentate and
bidentate phosphine ligands showed effects on the trans-
formation, while dppe displayed the best reactivity and afforded
a 91% yield of 4a (Table 1, entries 7−11). Other copper
Received: October 24, 2013
Published: January 6, 2014
© 2014 American Chemical Society
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Scheme 1. Divergent Transformation of Ketenimine Intermediate B
compatible under this reaction conditions (Table 2, entries 10−
13). Functionalized alkynes such as silylacetylene and but-3-yn-
2-one could participate smoothly under the same conditions to
afford the corresponding unsaturated amidines in excellent
yields (Table 2, entries 14 and 15). The scope of the reaction
with respect to the azide component was also investigated. As
can be seen from Table 2, both methyl and aryl substituents of
sulfonyl azides could be involved in the reaction. The nature of
the substituents on the phenylsulfonyl azides affected the
efficiency of the reaction: electron-rich azides led to yields of
amidines higher than those with electron-withdrawing groups
on the phenyl rings (Table 2, entries 16−20).
Scheme 2. Formatiom of Unsaturated Amidine 4a
species, such as CuCl and CuI, were also reactive but provided
a slightly lower yield (Table 1, entries 12 and 13). The addition
of 3 Å MS facilitated the three-component reaction, and the
yield of 4a decreased without the use of 3 Å MS (Table 1,
entries 10 and 14). Thus, the reaction efficiently proceeded
when 10 mol % of CuBr and 10 mol % of dppe were used in
combination with 3 Å MS in DCE at room temperature.
With the optimal reaction conditions in hand, we next
studied the scope and generality of this reaction (Table 2). A
variety of terminal alkynes could be used in the reaction to
produce unsaturated amidines in good to excellent yields. The
use of arylacetylenes provided the desired products in similar
yields with little influence of the steric and electronic variation
on the aromatic moiety (Table 2, entries 1−7). Heteroaromatic
acetylene was also tolerated, and conjugated enynes turned out
to be another viable substrate type for the transformation
(Table 2, entries 8 and 9). Aliphatic alkynes bearing certain
functional groups (cyclopropanyl or phenoxyl) and a sterically
bulky group around the triple bond of alkynes were also
We subsequently explored the application of various N,N-
dialkyloxyformamide dialkyl acetals (Table 3). Both acyclic and
cyclic formamide dimethyl acetals were accommodated with
good efficiency (Table 3, entries 1−4). N,N-dimethylforma-
mide diethyl acetal could afford its corresponding α-phenyl-β-
ethoxyl-α,β-unsaturated amidine 6e in 75% yield (Table 3,
entry 5).
Diphenylphosphoryl azide (DPPA)14 also could be success-
fully employed as a reaction partner in our reaction system to
afford the unsaturated phosphoryl amidine 8 in 49% yield
(Scheme 3), which provided an alternative route for the
synthesis of bioactive phosphoryl amidines.15
On the basis of our previous studies12 and the mechanistic
studies of copper-catalyzed multicomponent reactions involving
Figure 1. ORTEP drawing of compound 4a.
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a
Table 1. Optimization of the Reaction Conditions
Table 3. Multicomponent Reactions with Variation of N,N-
Dialkylformamide Acetal 3
a
b
c
entry
catalyst
ligand
solvent
temp (°C)
yield (%)
1
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuCl
CuI
dppp
dppp
dppp
dppp
dppp
dppp
dppp
toluene
MeCN
dioxane
THF
80
74
69
81
79
91
90
89
75
85
91
87
87
2
80
3
80
4
68
5
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
80
6
60
7
room temp
room temp
room temp
room temp
room temp
room temp
room temp
room temp
room temp
8
9
PPh3
dppe
dppb
dppe
dppe
dppe
10
11
12
13
14
15
89
d
CuBr
CuBr
69
d
35
a
Reaction conditions: 1a (0.6 mmol), 2a (0.6 mmol), 3a (0.5 mmol),
catalyst (0.05 mmol), ligand (0.05 mmol), and solvent (4 mL), under
b
N2, for 12 h. Abbreviations: dppe, 1,2-bis(diphenylphosphino)ethane;
dppp, 1,2-bis(diphenylphosphino)propane; dppb, 1,2-bis-
c
d
(diphenylphosphino)butane. Yields refer to 3a. No 3 Å MS added.
Table 2. Multicomponent Reaction with Variation of
a
Terminal Alkynes and Sulfonyl Azides
a
Reaction conditions: 1a (0.6 mmol), 2a (0.6 mmol), 3 (0.5 mmol),
CuBr (0.05 mmol), dppe (0.05 mmol), and DCE (4 mL), N2, 12 h.
b
Yields refer to 3.
b
entry
R1 of 1
Ph (1a)
R2 of 2
4
yield (%)
1
4-MeC6H4 (2a)
4-MeC6H4 (2a)
4-MeC6H4 (2a)
4-MeC6H4 (2a)
4-MeC6H4 (2a)
4-MeC6H4 (2a)
4-MeC6H4 (2a)
4-MeC6H4 (2a)
4-MeC6H4 (2a)
4-MeC6H4 (2a)
4-MeC6H4 (2a)
4-MeC6H4 (2a)
4-MeC6H4 (2a)
4-MeC6H4 (2a)
4-MeC6H4 (2a)
Ph (2b)
4a
4b
4c
4d
4e
4f
91
92
90
Scheme 3. Synthesis of Phosphoryl Amidines
2
4-MeC6H4 (1b)
3-MeC6H4 (1c)
2-MeC6H4 (1d)
4-MeOC6H4 (1e)
4-ClC6H4 (1f)
4-FC6H4 (1f)
3-thienyl (1h)
1-cyclohexenyl (1i)
CH3(CH2)5 (1j)
cyclopropanyl (1k)
(CH3)3C (1l)
PhOCH2 (1m)
(CH3)3Si (1n)
COCH3 (1o)
Ph (1a)
3
c
4
86
5
88
90
89
87
91
87
84
86
88
90
87
81
91
68
56
90
6
7
4g
4h
4i
8
9
ketenimine intermediate with immonium ion. Several experi-
ments were carried out to test this hypothesis (Scheme 4).
First, ketenimine 10 prepared by the known procedure17 was
treated with N,N-dimethylformamide dimethyl acetal 3a or
iminium salt 11. Though protonated ketenimine 10 could be
trapped with a nucleophilic reagent, none of the desired 4a was
detected whether in the presence or in the absence of CuBr
(Scheme 4, eqs 1 and 2). This result implicated that the
product was not generated via the common nucleophilic attack
process and an unprotonated copper ketenimine intermediate
might be involved. On the other hand, iminium salt 11
participated in the reaction under the standard reaction
conditions to give 4a in 42% yield, demonstrating a possible
electrophilic process (Scheme 4, eq 3).
10
11
12
13
14
15
16
17
18
19
20
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
4t
Ph (1a)
4-MeOC6H4 (2c)
4-ClC6H4 (2d)
4-O2NC6H4 (2e)
CH3 (2f)
Ph (1a)
Ph (1a)
Ph (1a)
a
Reaction conditions: 1 (0.6 mmol), 2 (0.6 mmol), 3a (0.5 mmol),
CuBr (0.05 mmol), dppe (0.05 mmol), and DCE (4 mL), N2, 12 h.
b
c
Yields refer to 3a. In toluene at 80 °C.
We assumed that 4a might be the result of a cascade reaction
of an in situ generated copper ketenimine intermediate with
immonium ion. To verify this hypothesis, we investigated the
intermolecular reaction of metalated ketenimine species10b,18
ketenimine,7b,16 we assumed that unsaturated amidine 4a might
be produced from the reaction of an in situ generated
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reaction. Phosphine ligands help to stabilize copper ketenimine
intermediate D, and 3 Å MS helps to absorb the in situ
generated methanol.
Scheme 4. Control Experiments Carried Out To Investigate
the Reaction Mechanism
CONCLUSION
■
In summary, we have developed a new copper-catalyzed three-
component reaction of alkyne, azide, and N,N-dialkyloxyforma-
mide dialkyl acetal, which might involve an electrophilic
addition of immonium ion to copper ketenimine. The
procedure provided a general and efficient method for the
synthesis of pharmacologically useful unsaturated amidines.
Both sulfonyl and phosphoryl azides underwent the reaction
smoothly; in addition, this new protocol was characterized with
wide substrate scope, mild conditions, and high yield. The
determination of further mechanistic details and applications is
currently underway.
EXPERIMENTAL SECTION
General Considerations. Infrared spectra were recorded with a
FTIR spectrometer. NMR spectra were recorded for H NMR at 400
■
with 3a. Gratifyingly, amidine 4a could be obtained in 25%
yield with the assistance of CuBr (Scheme 5).
1
or 500 MHz and 13C NMR at 100 or 125 MHz using TMS as an
internal standard. The following abbreviations were used to describe
peak patterns where appropriate: singlet (s), doublet (d), doublet of
doublets (dd), triplet (t), quartet (q), multiplet (m), broad resonances
(br). Mass spectroscopy data of the products were collected on an
HRMS-EI-TOF instrument or a low-resolution MS instrument using
EI or ESI ionization.
Scheme 5. Reaction of Metalated Ketenimine Species with
3a
General Procedure for Preparation of α,β-Unsaturated
Amidine Derivatives. To a solution of CuBr (0.05 mmol), dppe
(0.05 mmol), and 3 Å MS (100 mg) in DCE (1.5 mL) protected by
argon was added a solution of alkyne (0.6 mmol), N,N-
dialkyloxyformamide dialkyl acetal (0.5 mmol), and azide (0.6
mmol) in DCE (2.5 mL) via syringe, and the mixture was reacted at
room temperature for 12 h. Then the mixture was filtered, the filtrate
was concentrated, and the resulting residue was purified by flash
column chromatography with ethyl acetate/petroleum ether (1/1, v/
v) as eluent to obtain the desired products.
On the basis of the above experimental observations, a
plausible mechanism is proposed as shown in Scheme 6. The
Scheme 6. Plausible Mechanism for the Formation of
Unsaturated Amidine 4
Characterization Data of the Products. (2E)-3-Methoxy-N,N-
dimethyl-2-phenyl-N′-tosylacrylamidine (4a): new compound; white
1
solid (163 mg, 91% yield); mp 118−120 °C (uncorrected); H NMR
(CDCl3, 400 MHz, TMS) δ 7.68−7.69 (d, J = 6.8 Hz, 2 H), 7.23−7.25
(d, J = 6.0 Hz, 2 H), 7.16−7.19 (t, J = 6.0 Hz, 2 H), 7.09−7.12 (t, J =
5.8 Hz, 1 H), 7.06−7.07 (d, J = 6.4 Hz, 2 H), 6.51 (s, 1 H), 3.84 (s, 3
H), 3.14 (s, 3 H), 2.81 (s, 3 H), 2.28 (s, 3 H) ppm; 13C NMR (CDCl3,
100 MHz, TMS) δ 165.8, 151.9, 141.6, 141.2, 133.1, 128.9, 128.3,
127.6, 127.1, 126.7, 110.6, 61.9, 39.6, 35.6, 21.5 ppm; IR (neat) ν
2919, 2851, 1641, 1598, 1544, 1473, 1397, 1276, 1258, 1140, 1084,
851, 684 cm−1; HRMS (EI) calcd for C19H22N2O3S (M+) 358.1351,
found 358.1359.
(2E)-3-Methoxy-N,N-dimethyl-2-p-tolyl-N′-tosylacrylamidine
(4b): new compound; yellowish solid (171 mg, 92% yield); mp 141−
1
143 °C (uncorrected); H NMR (CDCl3, 400 MHz, TMS) δ 7.68−
7.70 (d, J = 7.6 Hz, 2 H), 7.13−7.15 (d, J = 8.0 Hz, 2 H), 7.06−7.09
(d, J = 8.0 Hz, 2 H), 6.98−7.00 (d, J = 8.0 Hz, 1 H), 6.47 (s, 1 H), 3.83
(s, 3 H), 3.14 (s, 3 H), 2.81 (s, 3 H), 2.30 (s, 3 H), 2.28 (s, 3 H) ppm;
13C NMR (CDCl3, 100 MHz, TMS) δ 165.7, 151.0, 141.3, 141.0,
136.2, 130.0, 128.8, 128.7, 127.2, 126.9, 110.4, 61.6, 39.4, 38.3, 21.3,
21.1 ppm; IR (neat) ν 2921, 1638, 1546, 1475, 1399, 1265, 1139,
1109, 1087, 880, 685 cm−1; HRMS (EI) calcd for C20H24N2O3S (M+)
372.1508, found 372.1515.
reaction of terminal alkynes and N,N-dimethylformamide
dimethyl acetal affords immonium ion intermediate C12 and
copper acetylide. The in situ formation of copper ketenimine
intermediate D from copper acetylide and sulfonyl azide7 reacts
with the immonium ion C to give the intermediate E, which
undergoes intramolecular nucleophilic addition of nitrogen to
the central carbon of E and affords the desired product 4 by
isomerization via C−N bond cleavage. The stability of copper
ketenimine intermediate D is one of the crucial factors for this
(2E)-3-Methoxy-N,N-dimethyl-2-m-tolyl-N′-tosylacrylamidine
(4c): new compound; white solid (167 mg, 90% yield); mp 153−155
1
°C (uncorrected); H NMR (CDCl3, 400 MHz, TMS) δ 7.67−7.69
(d, J = 7.6 Hz, 2 H), 7.05−7.06 (m, 3 H), 6.93 (s, 2 H), 6.51 (s, 1 H),
3.85 (s, 3 H), 3.16 (s, 3 H), 2.85 (s, 3 H), 2.28 (s, 3 H), 2.23 (s, 3 H)
ppm; 13C NMR (CDCl3, 100 MHz, TMS) δ 165.7, 151.6, 141.3,
140.9, 137.4, 132.7, 128.6, 128.0, 127.8, 127.3, 127.0, 124.5, 111.2,
61.7, 39.4, 38.37, 21.5, 21.2 ppm; IR (neat) ν 2929, 1649, 1545, 1482,
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1403, 1264, 1137, 1082, 885, 857, 681 cm−1; HRMS (EI) calcd for
C20H24N2O3S (M+) 372.1508, found 372.1509.
= 8.4 Hz, 2 H), 7.21−7.23 (d, J = 8.0 Hz, 2 H), 6.14 (s, 1 H), 3.66 (s, 3
H), 3.03 (s, 6 H), 2.38 (s, 3 H), 2.21−2.25 (t, J = 8.0 Hz, 2 H), 1.25−
1.37 (m, 8 H), 0.85−0.88 (t, J = 6.6 Hz, 3 H) ppm; 13C NMR (CDCl3,
125 MHz, TMS) δ 166.9, 150.3, 142.2, 141.5, 129.0, 126.6, 111.4, 60.6,
39.9, 38.3, 31.7, 29.9, 28.1, 27.2, 22.8, 21.5, 14.2 ppm; IR (neat) ν
2923, 2855, 1649, 1533, 1483, 1394, 1266, 1136, 1083, 859, 680 cm−1;
HRMS (EI) calcd for C19H30N2O3S (M+) 366.1977, found 366.1987.
(2E)-2-Cyclopropyl-3-methoxy-N,N-dimethyl-N′-tosylacrylami-
dine (4k): new compound; white solid (135 mg, 84% yield); mp 117−
(2Z)-3-Methoxy-N,N-dimethyl-2-o-tolyl-N′-tosylacrylamidine
(4d): new compound; white solid (160 mg, 86% yield); mp 173−175
1
°C (uncorrected); H NMR (CDCl3, 400 MHz, TMS) δ 7.87−7.89
(d, J = 7.2 Hz, 2 H), 7.24−7.26 (d, J = 8.0 Hz, 2 H), 7.10−7.20 (m, 5
H), 3.88 (s, 3 H), 2.97 (s, 3 H), 2.60 (s, 3 H), 2.40 (s, 3 H), 2.27 (s, 3
H) ppm; 13C NMR (CDCl3, 100 MHz, TMS) δ 168.4, 156.0, 142.5,
141.3, 136.7, 132.8, 130.5, 130.2, 129.0, 127.4, 126.1, 125.7, 111.0,
61.5, 39.4, 39.0, 21.4, 20.4 ppm; IR (neat) ν 2924, 1634, 1535, 1476,
1399, 1255, 1140, 1087, 867, 673 cm−1; HRMS (EI) calcd for
C20H24N2O3S (M+) 372.1508, found 372.1512.
1
118 °C (uncorrected); H NMR (CDCl3, 400 MHz, TMS) δ 7.76−
7.78 (d, J = 7.6 Hz, 2 H), 7.21−7.23 (d, J = 8.0 Hz, 2 H), 6.46 (s, 1 H),
3.72 (s, 3 H), 3.09 (s, 3 H), 3.03 (s, 3 H), 2.38 (s, 3 H), 1.44−1.48 (m,
1 H), 0.67−0.69 (m, 4 H) ppm; 13C NMR (CDCl3, 100 MHz, TMS)
δ 165.9, 153.5, 142.2, 141.3, 128.9, 126.3, 111.7, 60.8, 39.5, 38.2, 21.3,
9.1, 5.7 ppm; IR (neat) ν 2924, 1649, 1540, 1475, 1398, 1274, 1240,
1141, 1121, 1086, 879, 679 cm−1; HRMS (EI) calcd for C16H22N2O3S
(M+) 322.1351, found 322.1346.
(2E)-3-Methoxy-2-(4-methoxyphenyl)-N,N-dimethyl-N′-tosylacry-
lamidine (4e): new compound; yellowish solid (171 mg, 88% yield);
mp 148−150 °C (uncorrected); 1H NMR (CDCl3, 400 MHz, TMS) δ
7.69−7.71 (d, J = 8.0 Hz, 2 H), 7.19−7.21 (d, J = 8.4 Hz, 2 H), 7.08−
7.10 (d, J = 8.0 Hz, 2 H), 6.73−6.75 (d, J = 8.4 Hz, 1 H), 6.42 (s, 1 H),
3.81 (s, 3 H), 3.77 (s, 3 H), 3.14 (s, 3 H), 2.83 (s, 3 H), 2.31 (s, 3 H)
ppm; 13C NMR (CDCl3, 100 MHz, TMS) δ 165.8, 158.0, 150.2,
141.4, 141.1, 128.7, 128.69, 126.9, 125.6, 61.5, 55.1, 39.4, 38.3, 21.3
ppm; IR (neat) ν 2920, 1636, 1544, 1509, 1489, 1248, 1138, 1106,
1085, 875, 670 cm−1; HRMS (EI) calcd for C20H24N2O4S (M+)
388.1457, found 388.1451.
(2E)-2-(Methoxymethylene)-N,N,3,3-tetramethyl-N′-tosylbutani-
midamide (4l): new compound; yellow solid (145 mg, 86% yield); mp
1
118−120 °C (uncorrected); H NMR (CDCl3, 400 MHz, TMS) δ
7.80−7.82 (d, J = 7.2 Hz, 2 H), 7.22−7.24 (d, J = 8.0 Hz, 2 H), 5.80 (s,
1 H), 3.59 (s, 3 H), 3.10 (s, 3 H), 3.06 (s, 3 H), 2.39 (s, 3 H), 1.29 (s,
9 H) ppm; 13C NMR (CDCl3, 100 MHz, TMS) δ 166.2, 148.4, 142.4,
141.2, 128.9, 126.3, 118.0, 60.4, 40.2, 38.2, 34.1, 28.8, 21.4 ppm; IR
(neat) ν 2923, 1646, 1533, 1482, 1270, 1123, 1084, 988, 878, 850, 684
cm−1; HRMS (EI) calcd for C17H26N2O3S (M+) 338.1664, found
338.1663.
(2E)-2-(4-Chlorophenyl)-3-methoxy-N,N-dimethyl-N′-tosylacryla-
midine (4f): new compound; white solid (177 mg, 90% yield); mp
1
136−138 °C (uncorrected); H NMR (CDCl3, 400 MHz, TMS) δ
7.66−7.68 (d, J = 7.6 Hz, 2 H), 7.18−7.20 (d, J = 8.8 Hz, 2 H), 7.16−
7.18 (d, J = 9.2 Hz, 2 H), 7.07−7.09 (d, J = 8.0 Hz, 2 H), 6.53 (s, 1 H),
3.86 (s, 3 H), 3.15 (s, 3 H), 2.83 (s, 3 H), 2.31 (s, 3 H) ppm; 13C
NMR (CDCl3, 100 MHz, TMS) δ 165.1, 151.9, 141.7, 140.8, 132.0,
131.3, 128.8, 128.6, 128.3, 126.9, 109.2, 61.9, 39.3, 38.4, 21.7 ppm; IR
(neat) ν 2924, 1638, 1541, 1488, 1401, 1268, 1139, 1086, 861, 821,
682 cm−1; HRMS (EI) calcd for C19H21N2O3SCl (M+) 392.0961,
found 392.0966.
(2Z)-3-Methoxy-N,N-dimethyl-2-(phenoxymethyl)-N′-tosylacryla-
midine (4m): new compound; white solid (171 mg, 88% yield); mp
120−122 °C (uncorrected); 1H NMR (d6-DMSO, 500 MHz, TMS) δ
7.61−7.63 (d, J = 8.0 Hz, 2 H), 7.26−7.31 (m, 4 H), 6.92−6.95 (t, J =
7.3 Hz, 1 H), 6.85−6.87 (d, J = 8.0 Hz, 2 H), 6.19 (s, 1 H), 4.66 (s, 2
H), 3.64 (s, 3 H), 3.05 (s, 3 H), 3.01 (s, 3 H), 2.35 (s, 3 H) ppm; 13C
NMR (d6-DMSO, 125 MHz, TMS) δ 164.6, 158.6, 153.0, 142.2,
141.9, 130.0, 129.6, 126.6, 121.3, 114.9, 106.2, 63.2, 61.3, 40.7, 39.4,
21.4 ppm; IR (neat) ν 2921, 1667, 1554, 1483, 1397, 1273, 1241,
1217, 1143, 1085, 1007, 918, 818, 684 cm−1; HRMS (EI) calcd for
C20H24N2O4S (M+) 388.1457, found 388.1455.
(2E)-2-(4-Fluorophenyl)-3-methoxy-N,N-dimethyl-N′-tosylacryla-
midine (4g): new compound; white solid (167 mg, 89% yield); mp
1
135−137 °C (uncorrected); H NMR (CDCl3, 400 MHz, TMS) δ
7.69−7.71 (d, J = 7.2 Hz, 2 H), 7.24−7.26 (m, 2 H), 7.09−7.11 (d, J =
8.0 Hz, 2 H), 6.87−6.91 (t, J = 8.6 Hz, 2 H), 6.51 (s, 1 H), 3.85 (s, 3
H), 3.14 (s, 3 H), 2.82 (s, 3 H), 2.32 (s, 3 H) ppm; 13C NMR (CDCl3,
125 MHz, TMS) δ 165.59, 161.38 (d, 1JC−F = 244.6 Hz), 151.5, 141.8,
(2Z)-3-Methoxy-N,N-dimethyl-N′-tosyl-2-(trimethylsilyl)-
acrylimidamide (4n): new compound; white solid (159 mg, 90%
1
yield); mp 126−128 °C (uncorrected); H NMR (CDCl3, 400 MHz,
3
4
141.2, 129.4 (d, JC−F = 8.0 Hz), 129.3 (d, JC−F = 2.8 Hz), 129.0,
TMS) δ 7.77−7.79 (d, J = 8.4 Hz, 2 H), 7.21−7.23 (d, J = 8.0 Hz, 2
H), 6.19 (s, 1 H), 3.54 (s, 3 H), 3.09 (s, 3 H), 3.03 (s, 3 H), 2.38 (s, 3
H), 0.22 (s, 9 H) ppm; 13C NMR (CDCl3, 100 MHz, TMS) δ 168.2,
157.9, 142.5, 141.2, 128.8, 126.5, 110.5, 60.1, 39.6, 38.0, 21.3, −1.1
ppm; IR (neat) ν 2924, 1614, 1531, 1461, 1392, 1267, 1229, 1131,
1085, 843, 680 cm−1; HRMS (EI) calcd for C16H26N2O3SSi (M+)
354.1433, found 354.1426.
2
127.1, 115.3 (d, JC−F = 21.6 Hz), 109.8, 61.9, 39.6, 38.6, 21.5 ppm;
19F NMR (CDCl3, 376 MHz) δ −114.9 ppm; IR (neat) ν 2926, 1642,
1544, 1510, 1478, 1278, 1258, 1142, 1086, 843, 687 cm−1; HRMS (EI)
calcd for C19H21N2O3SF (M+) 376.1257, found 376.1267.
(2E)-3-Methoxy-N,N-dimethyl-2-(thiophen-3-yl)-N′-tosylacryla-
midine (4h): new compound; yellowish solid (158 mg, 87% yield); mp
1
135−137 °C (uncorrected); H NMR (CDCl3, 400 MHz, TMS) δ
(2Z)-2-(Methoxymethylene)-N,N-dimethyl-3-oxo-N′-tosylbutani-
midamide (4o): new compound; brown solid (141 mg, 87% yield);
mp 182−184 °C (uncorrected); 1H NMR (d6-DMSO, 500 MHz,
TMS) δ 7.54−7.55 (d, J = 8.0 Hz, 2 H), 7.31 (s, 1 H), 7.28−7.29 (d, J
= 8.0 Hz, 2 H), 3.58 (s, 3 H), 3.03 (s, 3 H), 2.85 (s, 3 H), 2.35 (s, 3H),
2.16 (s, 3 H) ppm; 13C NMR (d6-DMSO, 125 MHz, TMS) δ 192.8,
162.2, 161.8, 141.7, 141.4, 129.3, 126.8, 115.2, 62.6, 38.7, 37.8, 26.4,
21.4 ppm; IR (neat) ν 2922, 1654, 1630, 1555, 1477, 1394, 1300,
1258, 1139, 1084, 967, 850, 694 cm−1; HRMS (EI) calcd for
C15H20N2O4S (M+) 324.1144, found 324.1152.
(2E)-3-Methoxy-N,N-dimethyl-2-phenyl-N′-benzenesulfonylacry-
lamidine (4p): new compound; yellow solid (139 mg, 81% yield); mp
73−75 °C (uncorrected); 1H NMR (CDCl3, 400 MHz, TMS) δ 7.82−
7.84 (d, J = 8.0 Hz, 2 H), 7.26−7.35 (m, 5 H), 7.18−7.22 (t, J = 7.4
Hz, 2 H), 7.10−7.12 (t, J = 7.2 Hz, 1 H), 6.51 (s, 1 H), 3.83 (s, 3 H),
3.14 (s, 3 H), 2.82 (s, 3 H) ppm; 13C NMR (CDCl3, 100 MHz, TMS)
δ 165.8, 151.7, 144.0, 132.9, 131.0, 128.2, 128.2, 127.4, 126.8, 126.6,
110.6, 61.7, 39.4, 38.4 ppm; IR (neat) ν 2922, 1642, 1553, 1478, 1403,
1262, 1134, 1087, 857, 764, 691 cm−1; HRMS (EI) calcd for
C18H20N2O3S (M+) 344.1195, found 344.1190.
7.61−7.63 (d, J = 7.2 Hz, 2 H), 7.09 (s, 2 H), 7.02−7.04 (d, J = 8.0 Hz,
2 H), 6.85−6.86 (t, J = 1.8 Hz, 1 H), 6.39−6.40 (d, J = 4.0 Hz, 1 H),
3.87 (s, 3 H), 3.18 (s, 3 H), 2.87 (s, 3 H), 2.29 (s, 3 H) ppm; 13C
NMR (CDCl3, 100 MHz, TMS) δ 164.9, 150.0, 141.4, 140.5, 132.8,
128.6, 127.0, 126.7, 124.3, 121.9, 106.4, 61.5, 39.4, 38.2, 21.3 ppm; IR
(neat) ν 2922, 1640, 1544, 1480, 1399, 1272, 1230, 1141, 1086, 878,
852, 686 cm−1; HRMS (EI) calcd for C17H20N2O3S2 (M+) 364.0915,
found 364.0923.
(2E)-2-Cyclohexenyl-3-methoxy-N,N-dimethyl-N′-tosylacrylami-
1
dine (4i): new compound; yellow liquid (165 mg, 91% yield); H
NMR (CDCl3, 400 MHz, TMS) δ 7.30−7.50 (d, J = 7.6 Hz, 2 H),
7.18−7.20 (d, J = 8.0 Hz, 2 H), 6.12 (s, 1 H), 5.26 (s, 1 H), 3.70 (s, 3
H), 3.10 (s, 3 H), 2.95 (s, 3 H), 2.37 (s, 3 H), 2.15 (b, 2 H), 1.90 (b, 2
H), 1.44−1.51 (m, 4 H) ppm; 13C NMR (CDCl3, 100 MHz, TMS) δ
166.0, 149.3, 141.2, 141.2, 130.9, 128.6, 127.1, 125.8, 112.8, 61.1, 39.2,
38.1, 27.4, 25.5, 22.7, 21.7, 21.3 ppm; IR (neat) ν 2922, 2853, 1638,
1541, 1476, 1397, 1275, 1246, 1142, 1113, 1086, 878, 683 cm−1;
HRMS (EI) calcd for C19H26N2O3S (M+) 362.1664, found 362.1661.
(2E)-2-(Methoxymethylene)-N,N-dimethyl-N′-tosyloctanamidine
(4j): new compound; white solid (159 mg, 87% yield); mp 73−75 °C
(2E)-3-Methoxy-N,N-dimethyl-2-phenyl-N′-(4-methoxybenzene)-
1
(uncorrected); H NMR (CDCl3, 400 MHz, TMS) δ 7.77−7.79 (d, J
1-sulfonylacrylamidine (4q): new compound; white solid (170 mg,
940
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The Journal of Organic Chemistry
Article
91% yield); mp 92−94 °C (uncorrected); 1H NMR (CDCl3, 400
MHz, TMS) δ 7.71−7.73 (d, J = 8.0 Hz, 2 H), 7.13−7.24 (m, 4 H),
7.09−7.12 (t, J = 7.0 Hz, 1 H), 6.72−6.74 (d, J = 8.8 Hz, 2 H), 6.54 (s,
1 H), 3.87 (s, 3 H), 3.75 (s, 3 H), 3.16 (s, 3 H), 2.82 (s, 3 H) ppm;
13C NMR (CDCl3, 100 MHz, TMS) δ 165.4, 161.6, 151.7, 135.8,
132.8, 128.8, 128.1, 127.2, 126.4, 113.2, 110.1, 61.6, 55.3, 39.4, 38.3
ppm; IR (neat) ν 2922, 1646, 1543, 1491, 1404, 1309, 1268, 1183,
1137, 1117, 1084, 893, 684 cm−1; HRMS (EI) calcd for C19H22N2O4S
(M+) 374.1300, found 374.1300.
(t, J = 4.2 Hz, 2 H), 3.64−3.66 (t, J = 4.6 Hz, 2 H), 3.33 (b, 2 H), 3.25
(b, 2 H), 2.28 (s, 3 H) ppm; 13C NMR (CDCl3, 100 MHz, TMS) δ
164.6, 152.2, 141.7, 140.7, 132.8, 128.8, 128.2, 127.5, 126.9, 126.7,
109.6, 66.3, 66.1, 61.8, 47.7, 45.2, 21.3 ppm; IR (neat) ν 2935, 1640,
1517, 1440, 1360, 1260, 1151, 1131, 1113, 1085, 1029, 825, 675 cm−1;
HRMS (EI) calcd for C21H24N2O4S (M+) 400.1457, found 400.1454.
N-((E)-3-Methoxy-2-phenyl-1-(pyrrolidin-1-yl)allylidene)-4-meth-
ylbenzenesulfonamide (6d): new compound; yellow solid (150 mg,
1
78% yield); mp 135−137 °C (uncorrected); H NMR (CDCl3, 500
MHz, TMS) δ 7.71−7.73 (d, J = 7.2 Hz, 2 H), 7.24−7.26 (d, J = 8.0
Hz, 2 H), 7.16−7.20 (t, J = 7.4 Hz, 2 H), 7.11−7.13 (d, J = 7.2 Hz, 1
H), 7.07−7.09 (d, J = 8.0 Hz, 2 H), 6.59 (s, 1 H), 3.84 (s, 3 H), 3.61−
3.65 (t, J = 6.8 Hz, 2 H), 3.08−3.12 (t, J = 7.0 Hz, 2 H), 2.30 (s, 3 H),
1.84−1.88 (m, 2 H), 1.74−1.77 (m, 2 H) ppm; 13C NMR (CDCl3,
100 MHz, TMS) δ 163.1, 151.6, 141.3, 141.3, 132.5, 128.7, 128.1,
127.5, 126.9, 126.4, 111.7, 61.6, 48.6, 48.5, 25.5, 24.3, 21.3 ppm; IR
(neat) ν 2922, 1640, 1517, 1462, 1271, 1138, 1087, 846, 718, 694
cm−1; HRMS (EI) calcd for C21H24N2O3S (M+) 384.1508, found
384.1516.
(2E)-3-Methoxy-N,N-dimethyl-2-phenyl-N′-(4-chlorobenzene)-1-
sulfonylacrylamidine (4r): new compound; white solid (129 mg, 68%
1
yield); mp 126−128 °C (uncorrected); H NMR (CDCl3, 400 MHz,
TMS) δ 7.71−7.73 (d, J = 8.0 Hz, 2 H), 7.14−7.23 (m, 7 H), 6.57 (s, 1
H), 3.88 (s, 3 H), 3.16 (s, 3 H), 2.85 (s, 3 H) ppm; 13C NMR (CDCl3,
100 MHz, TMS) δ 165.7, 151.8, 142.2, 137.3, 132.5, 128.4, 128.3,
128.27, 127.2, 126.7, 110.2, 61.8, 39.5, 38.4 ppm; IR (neat) ν 2922,
1643, 1546, 1473, 1396, 1290, 1259, 1142, 1083, 884, 753, 670 cm−1;
HRMS (EI) calcd for C18H19N2O3SCl (M+) 378.0805, found
378.0806.
(2E)-3-Ethoxy-N,N-dimethyl-2-phenyl-N′-tosylacrylamidine (6e):
(2E)-3-Methoxy-N,N-dimethyl-2-phenyl-N′-(4-nitrobenzene)-1-
new compound; white solid (140 mg, 75% yield); mp 110−112 °C
sulfonylacrylamidine (4s): new compound; yellow solid (109 mg,
1
1
(uncorrected); H NMR (CDCl3, 400 MHz, TMS) δ 7.68−7.70 (d, J
56% yield); mp 174−176 °C (uncorrected); H NMR (CDCl3, 400
= 8.0 Hz, 2 H), 7.24−7.26 (d, J = 8.0 Hz, 2 H), 7.16−7.20 (t, J = 7.6
Hz, 2 H), 7.10−7.12 (d, J = 7.2 Hz, 1 H), 7.05−7.07 (d, J = 7.6 Hz, 2
H), 6.65 (s, 1 H), 4.05−4.11 (q, J = 5.7 Hz, 3 H), 3.14 (s, 3 H), 2.82
(s, 3 H), 2.28 (s, 3 H), 1.40−1,44 (t, J = 7.4 Hz, 3 H) ppm; 13C NMR
(CDCl3, 100 MHz, TMS) δ 165.8, 150.6, 141.4, 141.0, 133.0, 128.7,
128.1, 127.2, 126.9, 126.3, 110.1, 70.5, 39.4, 38.3, 21.3, 15.4 ppm; IR
(neat) ν 2919, 1636, 1544, 1476, 1399, 1275, 1245, 1138, 1085, 884,
683 cm−1; HRMS (EI) calcd for C20H24N2O3S (M+) 372.1508, found
372.1503.
MHz, TMS) δ 8.05−8.07 (d, J = 8.4 Hz, 2 H), 7.92−7.94 (d, J = 8.4
Hz, 2 H), 7.10−7.18 (m, 5 H), 6.65 (s, 1 H), 3.94 (s, 3 H), 3.18 (s, 3
H), 2.90 (s, 3 H) ppm; 13C NMR (CDCl3, 100 MHz, TMS) δ 165.8,
152.1, 149.1, 148.9, 132.2, 128.3, 128.1, 127.0, 126.9, 123.3, 110.1,
62.0, 39.7, 38.5 ppm; IR (neat) ν 2924, 1645, 1521, 1472, 1395, 1345,
1258, 1137, 1119, 1085, 903, 739 cm−1; HRMS (EI) calcd for
C18H19N3O5S (M+) 389.1045, found 389.1044.
(2E)-3-Methoxy-N,N-dimethyl-2-phenyl-N′-methanesulfonylacry-
lamidine (4t): new compound; yellow solid (127 mg, 90% yield); mp
1
151−153 °C (uncorrected); H NMR (CDCl3, 400 MHz, TMS) δ
(Z)-Diphenyl ((E)-1-(dimethylamino)-3-methoxy-2-
phenylallylidene)phosphoramidate (8): new compound; brown
7.44−7.46 (d, J = 8.4 Hz, 2 H), 7.30−7.34 (t, J = 7.6 Hz, 2 H), 7.17−
7.21 (t, J = 7.2 Hz, 1 H), 6.73 (s, 1 H), 3.88 (s, 3 H), 3.12 (s, 3 H),
2.95 (s, 3 H), 2.83 (s, 3 H) ppm; 13C NMR (CDCl3, 100 MHz, TMS)
δ 165.5, 152.0, 133.1, 128.4, 127.7, 126.8, 110.9, 61.7, 43.3, 39.2, 38.1
ppm; IR (neat) ν 2927, 1642, 1545, 1496, 1402, 1269, 1213, 1118,
982, 854, 766 cm−1; HRMS (EI) calcd for C13H18N2O3S (M+)
282.1038, found 282.1035.
1
liquid (107 mg, 49% yield); H NMR (d6-DMSO, 500 MHz, TMS)
δ 7.29−7.37 (m, 8 H), 7.18−7.21 (m, 1 H), 7.07−7.12 (m, 6 H), 6.60
(s, 1 H), 3.70 (s, 3 H), 3.00 (s, 3 H), 2.81 (s, 3 H) ppm; 13C NMR
(d6-DMSO, 125 MHz, TMS) δ 166.8 (d, JC−P = 13.9 Hz), 152.4 (d,
JC−P = 8.0 Hz), 151.4, 134.0, 130.1, 129.0, 127.9, 127.1, 124.6, 120.8
(d, JC−P = 4.1 Hz), 113.1, 62.0, 38.9, 38.1 ppm; 31P NMR (CDCl3, 162
MHz) δ −25.7 ppm; IR (neat) ν 2935, 1641, 1562, 1488, 1249, 1200,
1117, 1058, 1026, 1000, 917, 762, 691 cm−1; HRMS (EI) calcd for
C24H25N2O4P (M+) 436.1552, found 436.1549.
(2E)-N,N-Diethyl-3-methoxy-2-phenyl-N′-tosylacrylamidine (6a):
new compound; white solid (148 mg, 77% yield); mp 114−116 °C
1
(uncorrected); H NMR (CDCl3, 500 MHz, TMS) δ 7.69−7.70 (d, J
= 6.5 Hz, 2 H), 7.29−7.31 (d, J = 8.5 Hz, 2 H), 7.17−7.20 (m, 2 H),
7.11−7.13 (d, J = 7.5 Hz, 1 H), 7.07−7.09 (d, J = 7.5 Hz, 2 H), 6.48 (s,
1 H), 3.84 (s, 3 H), 3.55 (b, 2 H), 3.19−3.20 (m, 2 H), 2.30 (s, 3 H),
1.19−1.22 (t, J = 7.3 Hz, 3 H), 0.84−0.87 (t, J = 7.0 Hz, 3 H) ppm;
13C NMR (CDCl3, 100 MHz, TMS) δ 164.2, 150.9, 141.3, 141.1,
133.1, 128.7, 128.0, 127.5, 126.7, 126.5, 110.3, 61.6, 44.1, 42.3, 21.3,
13.3, 11.8 ppm; IR (neat) ν 2940, 1641, 1528, 1443, 1274, 1256, 1139,
1120, 1078, 974, 853, 768, 680 cm−1; HRMS (EI) calcd for
C21H26N2O3S (M+) 386.1664, found 386.1667.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Figures and CIF files giving H and 13C NMR spectra for all
new compounds and crystallographic data for compounds 4a,d.
This material is available free of charge via the Internet at
http://pubs.acs.org.
N-((E)-3-methoxy-2-phenyl-1-(piperidin-1-yl)allylidene)-4-meth-
ylbenzenesulfonamide (6b): new compound; yellow solid (159 mg,
AUTHOR INFORMATION
■
1
80% yield); mp 135−137 °C (uncorrected); H NMR (CDCl3, 500
Corresponding Author
*Y.Z.: e-mail, yhzhang@zju.edu.cn; fax, +86-571-87953244; tel,
+86-571-87952723.
MHz, TMS) δ 7.67−7.69 (d, J = 7.6 Hz, 2 H), 7.27−7.29 (d, J = 9.2
Hz, 2 H), 7.17−7.20 (t, J = 7.4 Hz, 2 H), 7.11−7.13 (d, J = 6.8 Hz, 1
H), 7.06−7.08 (d, J = 7.2 Hz, 2 H), 6.51 (s, 1 H), 3.84 (s, 3 H), 3.78−
3.81 (t, J = 5.0 Hz, 2 H), 3.22−3.25 (t, J = 5.2 Hz, 2 H), 2.29 (s, 3 H),
1.56−1.61 (m, 4 H), 1.24−1.26 (m, 2 H) ppm; 13C NMR (CDCl3,
100 MHz, TMS) δ 163.9, 151.3, 141.3, 141.1, 133.1, 128.7, 128.0,
127.6, 126.9, 126.4, 110.2, 61.6, 48.7, 46.0, 25.9, 25.3, 24.0, 21.3 ppm;
IR (neat) ν 2935, 1642, 1524, 1445, 1357, 1271, 1126, 1086, 1024,
853, 813, 677 cm−1; HRMS (EI) calcd for C22H26N2O3S (M+)
398.1664, found 398.1660.
Author Contributions
∥These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
N-((E)-3-Methoxy-1-morpholino-2-phenylallylidene)-4-methyl-
ACKNOWLEDGMENTS
■
benzenesulfonamide (6c): new compound; white solid (180 mg, 90%
1
Funding from Zhejiang Province (No. 2011C11097) and the
NSFC (Nos. 21072169 and 21272205) is highly acknowledged.
The work was also supported by the Program for Zhejiang
Leading Team of S&T Innovation.
yield); mp 130−132 °C (uncorrected); H NMR (CDCl3, 500 MHz,
TMS) δ 7.67−7.69 (d, J = 8.0 Hz, 2 H), 7.26−7.28 (d, J = 8.4 Hz, 2
H), 7.17−7.21 (t, J = 7.8 Hz, 2 H), 7.11−7.13 (d, J = 7.6 Hz, 1 H),
7.07−7.09 (d, J = 8.0 Hz, 2 H), 6.58 (s, 1 H), 3.85 (s, 3 H), 3.81−3.83
941
dx.doi.org/10.1021/jo402368x | J. Org. Chem. 2014, 79, 936−942

The Journal of Organic Chemistry
Article
20, 541. (c) Chang, S.-Y.; Bae, S. J.; Lee, M. Y.; Baek, S.-H.; Chang, S.;
Kim, S. H. Bioorg. Med. Chem. Lett. 2011, 21, 727.
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