Catalyst-free approach to construct C-C bond initiated by N-O bond cleavage under thermal conditions

Article abstract of DOI:10.1021/jo502287y

An unexpected and novel approach to construct the sp² C-sp³ C bond has been developed via N-O bond cleavage without any external catalysts or additives. It is a very simple, efficient, and environmentally friendly method and will be

Full text of DOI:10.1021/jo502287y

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Article
A Catalyst-Free Approach to Construct C-C Bond Initiated
by N-O Bond Cleavage under Thermal Conditions
Dan-Dan Li, Zhong-Yuan Li, and Guan-Wu Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502287y • Publication Date (Web): 25 Nov 2014
Downloaded from http://pubs.acs.org on November 29, 2014
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A CatalystꢀFree Approach to Construct C−C Bond Initiated by
N−O Bond Cleavage under Thermal Conditions
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DanꢀDan Li, ZhongꢀYuan Li, and GuanꢀWu Wang*
CAS Key Laboratory of Soft Matter Chemistry, Hefei National Laboratory for
Physical Sciences at Microscale, and Department of Chemistry, University of Science
and Technology of China, Hefei, Anhui 230026, P. R. China
gwang@ustc.edu.cn
ABSTRACT
An unexpected and novel approach to construct sp2 C−sp3 C bond has been
developed via N–O bond cleavage without any external catalysts or additives. It is a
very simple, efficient, and environmentally friendly method and will be a very
attractive radical process towards new C−C bond formation.
INTRODUCTION
The direct and regioselective formation of C–C bonds via the cleavage of
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unactivated C−H bonds is a longꢀstanding goal in organic chemistry. In particular,
the C–C bond formations are among the most important processes in chemistry,
because they provide key steps to build more complex molecules from simple
precursors. In recent years, transitionꢀmetalꢀcatalyzed C−H bond activations and
subsequent C–C bond formations have attracted great interest. 1 However,
achieving the sp3 C–H bond cleavages to construct C–C bonds for preparing
diverse compounds from simple starting materials remains a challenge due to the
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lack
of
a
πꢀelectron
system.
Over
the
past
decades,
crossꢀdehydrogenativeꢀcoupling (CDC) reaction to construct new C–C bonds has
emerged as a powerful and efficient protocol in organic chemistry.2 Substantial
efforts have been devoted to the construction of numerous C–C bonds via
metalꢀcatalyzed oxidative functionalization of sp3 C–H bonds. However, most of
the works were still limited to arylꢀsubstituted substrates, such as the sp3 C−H
bond
adjacent
to
the
nitrogen
of
N,Nꢀdimethylaniline
and
1,2,3,4ꢀtetrahydroisoquinoline and the sp3 C−H bond adjacent to the oxygen of
isochroman.3, 4 Although considerable efforts have been made to realize the
functionalization of the sp3 C–H bonds of simple aliphatic amides,5 the formation
of C–C bonds using a similar strategy received less attention.5aꢀc, 5i Moreover, most
of the reactions5aꢀc, 5i required metal catalysts and/or additional oxidants and rarely
focused on functionalization of the sp3 C–H bonds to construct C–C bonds without
any external catalysts or additives.
On the other hand, the N−O bond is highly active and easily broken. Usually,
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the N−O bond cleavage could be realized by heating,6 light,7 metal catalysis,8
and reduction. 9 It is worthy to note that the thermal decomposition of
N,Nꢀdialkoxyamides brings out alkoxyl radicals and alkoxyamidyl radicals, of
them the latter are prone to HERON rearrangements to give esters.6 Unexpectedly,
we found that isoindolinones bearing an Eꢀconfigured exocyclic C=C bond could
react with both acyclic N,Nꢀdimethylacetamide (DMAc) and cyclic Nꢀalkyl
pyrrolidones without any external catalysts or oxidants under thermal conditions.
Intriguingly, the reaction involves the construction of sp2 C–sp3 C bond initiated
by the N–O bond cleavage.
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RESULTS AND DISCUSSION
Initially,
we
chose
the
reaction
of
(E)ꢀmethyl
2ꢀ(2ꢀmethoxyꢀ3ꢀoxoisoindolinꢀ1ꢀylidene) acetate (1a) with DMAc (2a) as the
model reaction to explore the optimal conditions. At the outset, when 1a (0.25
o
mmol) and 2.0 mL (86 equiv) of 2a was heated at 100 C for 12 h under an air
atmosphere, product 3aa could be obtained in 42% yield (Table 1, entry 1). When
o
the reaction temperature was elevated to 110 C, the yield of 3aa was slightly
increased to 58% (Table 1, entry 2). Much to our pleasure, when the temperature
was further increased to 120 oC, product 3aa could be isolated in 91% yield after 4
h (Table 1, entry 3). However, when the amount of DMAc was decreased to 1.5
mL (Table 1, entry 4) or 1.0 mL (Table 1, entry 5), the yield of 3aa became lower
even if the reaction time was prolonged to 12 h. Disappointingly, when
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1,2ꢀdichloroethane (DCE), toluene, ethanol, dimethyl sulfoxide (DMSO), and
acetonitrile (CH3CN) were employed as the solvent and 10.0 equiv of DMAc was
added, the reaction failed to give product 3aa (Table 1, entries 6−10).
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Table 1. Optimization of the Reaction Conditionsa
O
O
O
N O
NH
+
O
N
N
MeOOC
MeOOC
1a
2a
3aa
entry temp (oC) t (h)
solvent
yield (%)b
1
2
100
110
120
120
120
120
120
120
12
12
4
DMAc (2.0 mL)
DMAc (2.0 mL)
DMAc (2.0 mL)
DMAc (1.5 mL)
DMAc (1.0 mL)
DCE (2.0 mL)
PhMe (2.0 mL)
EtOH (2.0 mL)
42
58
3
91
4
12
12
4
53
5
45
6c
7c
8c
NR
NR
NR
4
4
9c
120
120
4
4
DMSO (2.0 mL)
CH3CN (2.0 mL)
NR
NR
10c
aReaction conditions: unless otherwise noted, all reactions were carried out with 0.25
b
c
mmol of 1a in 2.0 mL of 2a under an air atmosphere. Isolated yield. 10.0 equiv of
DMAc was used.
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With the optimal conditions in hand, then we investigated various
isoindolinones and aliphatic amides to examine the substrate scope and limitation
of the current reaction. The results are summarized in Table 2. Substrates bearing
either electronꢀdonating or electronꢀwithdrawing groups on the phenyl ring of
isoindolinones could be applied to afford the corresponding products 3aa−3fc in
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moderate
to
good
yields.
(E)ꢀMethyl
2ꢀ(2ꢀmethoxyꢀ3ꢀoxoisoindolinꢀ1ꢀylidene)acetate (1a) generally afforded higher
yields (91% for 3aa, 86% for 3ab, and 82% for 3ac) compared to other substituted
substrates. Interestingly, the oꢀMe on the phenyl ring of 1b proceeded better and
provided higher yields relative to the pꢀ and mꢀsubstituted counterparts (3ba vs
3ca and 3da, 3bb vs 3cb). Similarly, substrates with the electronꢀdonating groups
at the metaꢀ or paraꢀposition of the phenyl ring (1c−1e) were smoothly converted
to the corresponding products. It should be noted that substrates 1f and 1g
containing a halogen atom such as chlorine and bromine could also give fairly
good yields. However, isoindolinones bearing strong electronꢀwithdrawing groups
such as nitro and ester groups on the phenyl ring performed much worse than other
substrates. In general, the substituents on the phenyl ring of isoindolinones had an
obvious
influence
on
the
reaction.
Moreover,
(E)ꢀ3ꢀbenzylideneꢀ2ꢀmethoxyisoindolinꢀ1ꢀone (1h), in which the ester moiety was
replaced by a phenyl group, could also react with DMAc to bring out the desired
product, albeit in a relatively low yield.
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Encouraged by the above results, we next explored the scope of cyclic amides.
Interestingly, when Nꢀmethyl pyrrolidone (NMP, 2b) was subjected to this
procedure, the methylene C–H bond reacted in high regioselectivity to provide
products 3ab, 3bb, 3cb, 3eb, and 3fb in 64ꢀ85% yields. Similarly, Nꢀethyl
pyrrolidone 2c could also react with isoindolinones 1a, 1b, 1e, and 1f smoothly to
give the corresponding products 3ac, 3bc, 3ec, and 3fc in 68ꢀ82% yields. It should
be pointed out that a small amount of byproducts resulting from the reactions at the
Nꢀalkyl group for 2b and 2c could also be observed, yet the reactions still
demonstrated good selectivity of the current procedure and predominantly
furnished the corresponding products in good to excellent yields.
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Table 2. Results for the Construction of sp2 C–sp3 C Bond Initiated by N–O Bond
Cleavagea,b
O
O
R1
N O
∆
R1
NH
R
+
O
N
O
N
R
2
R2
R2
3
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O
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NH
O
N
O
9
O
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3aa; 4 h, 91%
3ba; 4 h, 87%
3ca; 3 h, 74%
O
NH
O
N
O
O
3da; 3 h, 73%
3ga; 6 h, 79%
3bb; 3 h, 81%c
3fb; 6 h, 69%c
3ec; 12 h, 72%c
3ea; 6 h, 72%
3ha; 6 h, 47%
3cb; 6 h, 64%c
3ac; 3 h, 82%c
3fc; 12 h, 68%c
3fa, 6 h, 70%
3ab; 3 h, 86%c
O
MeO
NH
O
N
O
O
3eb; 6 h, 64%c
3bc; 12 h, 79%c
aReaction conditions: all reactions were carried out with 0.25 mmol of 1a in 2.0 mL of 2a at
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120 °C under an air atmosphere. bIsolated yield. c100 °C was employed.
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In addition, we also examined other isoindolinones with different alkoxy
substituent or different exocyclic C=C configuration (Figure 1). (E)ꢀMethyl
2ꢀ(2ꢀisopropoxyꢀ3ꢀoxoisoindolinꢀ1ꢀylidene)acetate 1i, in which the methoxy
moiety was replaced by an isopropoxy group, could also react with DMAc to give
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product
3aa
in
62%
yield.
Meanwhile,
when
(Z)ꢀmethyl
2ꢀ(2ꢀmethoxyꢀ3ꢀoxoisoindolinꢀ1ꢀylidene)acetate 1j, a Z isomer of 1a, was allowed
to react with DMAc, the same product 3aa could be obtained in 59% yield.
Nevertheless, both 1i and 1j showed inferior efficiency and provided lower
product yields than 1a.
O
O
N O
N O
O
O
O
O
1j; 4 h, 59%
1i; 12 h, 62%
Figure 1. Other isoindolinones affording product 3aa.
1
Products 3aaꢀ3fc were fully characterized by H NMR, 13C NMR, IR, and
HRMS. In addition, the molecular structure was unequivocally established by the
Xꢀray crystallography of representative 3da.
To gain more insights into the reaction mechanism, a free radical scavenger,
2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxy (TEMPO), was added to the reaction mixture,
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and no desired product 3aa was obtained, indicating that the reaction probably
proceeded through a free radical process.
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Based on the above results and the previously reported radical reactions, a
plausible reaction mechanism is proposed and shown in Scheme 1. Firstly, thermal
decomposition of the isoindolinone derivative proceeds by homolysis of the N–O
bond, which generates the amidyl radical A and methoxyl radical under the thermal
conditions.6 The electron on the nitrogen atom of the amidyl radical A can delocalize
to the C=C bond to generate the resonance structure B. Meanwhile, the generated
methoxyl radical selectively abstracts a hydrogen atom from the αꢀcarbon of aliphatic
amides to form a nitrogenꢀstabilized Cꢀcentred radical C,5f,6 which subsequently
couples with the radical B to produce the intermediate D. Finally, the intermediate D
undergoes isomerization to give product 3 with an exocyclic C=C Eꢀconfiguration.
The exact reason for the favorable formation of the product with Eꢀconfiguration is
unclear now. The key to success in the radical coupling between B and C should be
ascribed to the absence of an oxidant, which would oxidize C to an iminium
intermediate5dꢀf,hꢀj and thus inhibit the radical coupling process. The above proposed
reaction pathway can also elucidate why the same product 3aa is generated from 1i
bearing a different alkoxyl group attached to the nitrogen atom (N–OiPr for 1i vs
N–OMe for 1a) as well as from 1j containing different exocyclic C=C configuration
(Z isomer for 1j vs E isomer for 1a). It should be noted that a chain mechanism is also
possible: the reaction of the methoxyl radical created in the initiation step with the
amide would generate the radical C, which undergoes addition to substrate 1 to give
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the final product 3, accompanied with generation of a new methoxyl radical to
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propagate the chain.
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Scheme 1. Plausible Reaction Mechanism
CONCLUSION
In summary, we have developed a novel method for the formation of sp2 C–sp3 C
bond without any catalysts or external additives. To the best of our knowledge, there
is still no precedent for a catalystꢀfree radicalꢀbased approach to construct sp2 C–sp3 C
bond just under thermal conditions. Compared with those metalꢀcatalyzed reactions,
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this is a novel, highly effective, and environmentally friendly process. We believe that
this radical process will become a new strategy for the formation of C–C bonds and
will be a very attractive method towards new bond formation.
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EXPERIMENTAL SECTION
General Information. Unless otherwise noted, all commercial materials and
solvents were used without further purification. Isoindolinones 1a−1h were prepared
by the reactions of Nꢀmethoxybenzamides with methyl acrylate or styrene, using
Pd(OAc)2 as the catalyst and benzoquinone (BQ) as the oxidant according to our
previous procedure.10 1H NMR and 13C NMR spectra were referenced to TMS and
residue CHCl3 at 0.00 ppm and 77.16 ppm, respectively. Highꢀresolution mass spectra
(HRMS) were measured with ESIꢀOrbitrap, APCIꢀOrbitrap or EIꢀTOF in positive
mode.
Synthesis of 1i. A mixture of Nꢀisopropoxybenzamide (89.6 mg, 0.5 mmol),
Pd(OAc)2 (5.6 mg, 0.025 mmol), BQ (108.0 mg, 1.0 mmol), and methyl acrylate (90.6
ꢁL, 1.0 mmol) was dissolved in HOAc (5.0 mL). Then the solution was stirred at 100
oC. The reaction was monitored by TLC and stopped after 12 h. Then the solvent was
evaporated to dryness in vacuo. The residual was separated on a silica gel column
with petroleum ether/ethyl acetate (6/1) as the eluent to get product 1i (49.6 mg, 38%):
o
white solid, m.p. 74–75 C; IR ν/cmꢀ1 (KBr) 2983, 2940, 1737, 1639, 1456, 1385,
1
1311, 1146, 982, 838, 763, 682; H NMR (400 MHz, CDCl3) δ 9.00 (d, J = 7.8 Hz,
1H), 7.85 (d, J = 7.3 Hz, 1H), 7.69 ( t, J = 7.7 Hz, 1H), 7.61 ( t, J = 7.4 Hz, 1H), 6.00
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(s, 1H), 4.70–4.63 (m, 1H), 3.83 (s, 3H), 1.39 (d, J = 6.0 Hz, 6H); 13C NMR (100
MHz, CDCl3) δ 166.5, 163.0, 146.3, 133.6, 131.6, 130.4, 128.1, 127.5, 123.4, 97.8,
80.1, 51.8, 21.0 (2C); HRMS (EIꢀTOF) m/z [M+] calcd for C14H15NO4 261.1001,
found 261.1000.
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Synthesis of (Z)ꢀMethyl 2ꢀ(2ꢀmethoxyꢀ3ꢀoxoisoindolinꢀ1ꢀylidene)acetate (1j).
To 50 mL of methanol was added 1a (58.3 mg, 0.25 mmol), the solution was placed in
a Pyrex photoreactor (λ > 290 nm), and irradiated with a 300 W highꢀpressure Hg
lamp while bubbling with high pure N2 for 6 h. Upon completion, the solvent was
evaporated to dryness in vacuo. The residual was separated on a silica gel column
with petroleum ether/ethyl acetate (6/1) as the eluent to get 1j (28.0 mg, 48%): white
o
solid, m.p. 73–74 C; IR ν/cmꢀ1 (KBr) 2940, 1748, 1659, 1471, 1434, 1296, 1191,
1168, 1148, 1130, 997, 907, 814, 767, 682; 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J =
7.2 Hz, 1H), 7.67–7.57 (m, 3H), 5.87 (s, 1H), 4.14 (s, 3H), 3.83 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 165.1, 164.3, 139.4, 133.7, 133.3, 131.3, 126.4, 124.0, 120.4,
94.3, 65.3, 52.1; HRMS (EIꢀTOF) m/z [M+] calcd for C12H11NO4 233.0688, found
233.0686.
General Procedure for the Synthesis of 3aa−3ha. A solution of isoindolinone
1a (1b−1j, 0.25 mmol) in N,Nꢀdimethylacetamide (2a, 2.0 mL) was stirred under an
o
air atmosphere at 120 C for a desired time (monitored by TLC). After the reaction
was finished, the mixture was filtered by a silica gel plug with ethyl acetate (30 mL)
as the eluent. The filtrate was washed with saturated brine (3×10 mL) and the organic
phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The
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residue was separated on a silica gel column with petroleum ether/ethyl acetate (1/3)
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as the eluent to get product 3aa (3ba−3ha).
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(E)ꢀMethyl
3ꢀ(Nꢀmethylacetamido)ꢀ2ꢀ(3ꢀoxoisoindolinꢀ1ꢀylidene)propanoate
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(3aa). By following the general procedure, the reaction of 1a (58.3 mg, 0.25 mmol)
with 2a (2.0 mL) for 4 h afforded 3aa (65.7 mg, 91% yield): white solid, m.p.
131–132 oC; IR ν/cmꢀ1 (KBr) 3103, 3004, 2953, 2813, 1728, 1706, 1620, 1438, 1414,
1
1360, 1293, 1246, 1134, 1082, 771, 694; H NMR (400 MHz, CDCl3) δ 10.62 (bs,
1H), 8.36 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.62ꢀ7.53 (m, 2H), 4.54 (s,
2H), 3.94 (s, 3H), 3.09 (s, 3H), 2.15 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.5,
168.1, 168.0, 147.3, 135.0, 132.7, 131.7, 131.0, 126.8, 123.5, 106.1, 52.3, 46.1, 36.4,
+
21.7; HRMS (APCIꢀOrbitrap) m/z [M+H]+ calcd for C15H17N2O4 289.1183, found
289.1178.
(E)ꢀMethyl
2ꢀ(4ꢀmethylꢀ3ꢀoxoisoindolinꢀ1ꢀylidene)ꢀ3ꢀ(Nꢀmethylacetamido)propanoate (3ba). By
following the general procedure, the reaction of 1b (61.8 mg, 0.25 mmol) with 2a (2.0
o
mL) for 4 h afforded 3ba (65.5 mg, 87% yield): white solid, m.p. 140–141 C; IR
ν/cmꢀ1 (KBr) 3093, 2944, 2814, 1708, 1615, 1437, 1365, 1289, 1243, 1180, 1132,
1
1087, 786, 707; H NMR (400 MHz, CDCl3) δ 10.40 (bs, 1H), 8.15 (d, J = 8.0 Hz,
1H), 7.44 (t, J = 7.8 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 4.52 (s, 2H), 3.91 (s, 3H), 3.07
(s, 3H), 2.70 (s, 3H), 2.13 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.4, 168.8, 168.5,
147.0, 138.0, 135.7, 133.4, 132.2, 128.5, 124.2, 105.0, 52.2, 46.2, 36.4, 21.7, 17.6;
+
HRMS (APCIꢀOrbitrap) m/z [M+H]+ calcd for C16H19N2O4 303.1339, found
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303.1335.
(E)ꢀMethyl
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2ꢀ(5ꢀmethylꢀ3ꢀoxoisoindolinꢀ1ꢀylidene)ꢀ3ꢀ(Nꢀmethylacetamido)propanoate (3ca). By
following the general procedure, the reaction of 1c (61.8 mg, 0.25 mmol) with 2a (2.0
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o
mL) for 3 h afforded 3ca (55.8 mg, 74% yield): white solid, m.p. 115–116 C; IR
ν/cmꢀ1 (KBr) 3095, 2948, 2814, 1731, 1702, 1615, 1484, 1437, 1360, 1291, 1246,
1181, 1146, 1126, 1078, 788, 741; 1H NMR (400 MHz, CDCl3) δ 10.53 (bs, 1H), 8.25
(d, J = 8.4 Hz, 1H), 7.66 (t, J = 0.8 Hz, 1H), 7.40–7.37 (m, 1H), 4.53 (s, 2H),3.92 (s,
3H), 3.07 (s, 3H), 2.46 (s, 3H), 2.14 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.5,
168.22, 168.19, 147.8, 141.9, 133.6, 132.5, 132.1, 126.8, 124.0, 105.3, 52.2, 46.1,
36.4, 21.7, 21.6; HRMS (APCIꢀOrbitrap) m/z [M+H]+ calcd for C16H19N2O4
+
303.1339, found 303.1334.
(E)ꢀMethyl
2ꢀ(6ꢀmethylꢀ3ꢀoxoisoindolinꢀ1ꢀylidene)ꢀ3ꢀ(Nꢀmethylacetamido)propanoate (3da). By
following the general procedure, the reaction of 1d (61.7 mg, 0.25 mmol) with 2a (2.0
o
mL) for 3 h afforded 3da (55.1 mg, 73% yield): white solid, m.p. 159–161 C; IR
ν/cmꢀ1 (KBr) 3114, 2952, 1736, 1704, 1621, 1432, 1358, 1245, 1139, 1077, 783, 710;
1H NMR (400 MHz, CDCl3) δ 10.46 (bs, 1H), 8.17 (s, 1H), 7.74 (d, J = 7.2 Hz, 1H),
7.36 (1H, d, J = 7.2 Hz, 1H), 4.53 (s, 2H), 3.93 (s, 3H), 3.07 (s, 3H), 2.48 (s, 3H),
2.14 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.5, 168.2, 168.1, 147.6, 143.4, 135.5,
132.0, 129.3, 127.4, 123.4, 105.7, 52.2, 46.1, 36.4, 22.4, 21.7; HRMS (APCIꢀOrbitrap)
+
m/z [M+H]+ calcd for C16H19N2O4 303.1339, found 303.1333.
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2ꢀ(5ꢀmethoxyꢀ3ꢀoxoisoindolinꢀ1ꢀylidene)ꢀ3ꢀ(Nꢀmethylacetamido)propanoate (3ea). By
following the general procedure, the reaction of 1e (65.9 mg, 0.25 mmol) with 2a (2.0
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o
mL) for 6 h afforded 3ea (57.5 mg, 72% yield): pale yellow solid, m.p. 106–107 C;
IR ν/cmꢀ1 (KBr) 3106, 2925, 2854, 1728, 1626, 1485, 1438, 1409, 1362, 1290, 1238,
1176, 1124, 1075, 1019, 838, 780, 742; 1H NMR (400 MHz, CDCl3) δ 10.61 (bs, 1H),
8.34 (d, J = 8.8 Hz, 1H), 7.33 (d, J = 2.6 Hz, 1H), 7.10 (dd, J = 8.8, 2.6 Hz, 1H), 4.53
(s, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 3.07 (s, 3H), 2.14 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 172.5, 168.2, 167.9, 162.2, 148.0, 134.2, 128.7, 127.5, 120.0, 106.9, 104.7,
55.9, 52.1, 46.0, 36.4, 21.7; HRMS (APCIꢀOrbitrap) m/z [M+H]+ calcd for
+
C16H19N2O5 319.1289, found 319.1282.
(E)ꢀMethyl
2ꢀ(6ꢀchloroꢀ3ꢀoxoisoindolinꢀ1ꢀylidene)ꢀ3ꢀ(Nꢀmethylacetamido)propanoate (3fa). By
following the general procedure, the reaction of 1f (67.0 mg, 0.25 mmol) with 2a (2.0
o
mL) for 6 h afforded 3fa (56.2 mg, 70% yield): white solid, m.p. 177–178 C; IR
ν/cmꢀ1 (KBr) 3130, 2955, 2814, 1734, 1709, 1616, 1424, 1358, 1249, 1144, 1087, 784,
707; 1H NMR (400 MHz, CDCl3) δ 10.72 (bs, 1H), 8.44 (d, J = 1.8 Hz, 1H), 7.78 (d, J
= 8.0 Hz, 1H), 7.54 (dd, J = 8.0, 1.8 Hz, 1H), 4.54 (s, 2H), 3.95 (s, 3H), 3.08 (s, 3H),
2.15 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.7, 166.7, 166.0, 145.6, 138.2, 135.6,
130.4, 129.1, 126.5, 123.6, 106.1, 51.4, 45.2, 35.6, 20.7; HRMS (APCIꢀOrbitrap) m/z
[M+H]+ calcd for C15H16N2O435Cl+ 323.0793, found 323.0789.
(E)ꢀMethyl
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2ꢀ(6ꢀbromoꢀ3ꢀoxoisoindolinꢀ1ꢀylidene)ꢀ3ꢀ(Nꢀmethylacetamido)propanoate (3ga). By
following the general procedure, the reaction of 1g (78.0 mg, 0.25 mmol) with 2a (2.0
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o
mL) for 6 h afforded 3ga (72.7 mg, 79% yield): white solid, m.p. 154–155 C; IR
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ν/cmꢀ1 (KBr) 3085, 2952, 2808, 1732, 1710, 1616, 1418, 1356, 1251, 1139, 1082, 995,
1
781, 703; H NMR (400 MHz, CDCl3) δ 10.71 (bs, 1H), 8.60 (s, 1H), 7.73–7.68 (m,
2H), 4.54 (s, 2H), 3.95 (s, 3H), 3.08 (s, 3H), 2.15 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 172.8, 167.7, 167.1, 146.5, 136.7, 134.3, 130.6, 130.4, 127.6, 124.9, 107.1,
52.4, 46.2, 36.6, 21.7; HRMS (ESIꢀOrbitrap) m/z [M+H]+ calcd for C15H16N2O479Br+
367.0288, found 367.0290.
(Z)ꢀNꢀMethylꢀNꢀ(2ꢀ(3ꢀoxoisoindolinꢀ1ꢀylidene)ꢀ2ꢀphenylethyl)acetamide (3ha).
By following the general procedure, the reaction of 1h (62.8 mg, 0.25 mmol) with 2a
(2.0 mL) for 6 h afforded 3ha (36.3 mg, 47% yield): white solid, m.p. 230–231 oC; IR
ν/cmꢀ1 (KBr) 3133, 3027, 2788, 1702, 1612, 1418, 1351, 1304, 1279, 1200, 1142,
1
1033, 1018, 766, 702; H NMR (400 MHz, CDCl3) δ 10.01 (bs, 1H), 7.82 (d, J = 7.6
Hz, 1H), 7.51–7.44 (m, 3H), 7.42–7.33 (m, 3H), 7.19 (t, J = 7.6 Hz, 1H), 6.52 (d, J =
8.0 Hz, 1H), 4.48 (s, 2H), 2.82 (s, 3H), 2.13 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
171.8, 168.2, 140.1, 136.6, 135.3, 131.7, 131.5, 129.6 (2C), 129.4 (2C), 129.0, 128.4,
123.49, 123.47, 118.1, 51.8, 37.7, 21.8; HRMS (ESIꢀOrbitrap) m/z [M+H]+ calcd for
+
C19H19N2O2 307.1441, found 307.1443.
General Procedure for the Synthesis of 3ab−3fb. A solution of isoindolinone
1a (1b, 1c, 1e, and 1f, 0.25 mmol) in Nꢀmethyl pyrrolidone (2b, 2.0 mL) was stirred
o
under an air atmosphere at 100 C for a desired time (monitored by TLC). After the
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reaction was finished, the mixture was filtered by a silica gel plug with ethyl acetate
(30 mL) as the eluent. The filtrate was washed with saturated brine (3×10 mL) and the
organic phase was dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was separated on a silica gel column with acetone/ethyl acetate
(1/1) as the eluent to get product 3ab (3bb, 3cb, 3eb, and 3fb).
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(E)ꢀMethyl
2ꢀ(1ꢀmethylꢀ5ꢀoxopyrrolidinꢀ2ꢀyl)ꢀ2ꢀ(3ꢀoxoisoindolinꢀ1ꢀylidene)acetate (3ab). By
following the general procedure, the reaction of 1a (58.3 mg, 0.25 mmol) with 2b (2.0
o
mL) for 3 h afforded 3ab (64.5 mg, 86% yield): white solid, m.p. 200–201 C; IR
ν/cmꢀ1 (KBr) 3183, 3059, 2951, 2827, 1712, 1694, 1650, 1467, 1399, 1359, 1309,
1
1236, 1165, 1082, 960, 773, 715, 695; H NMR (400 MHz, CDCl3) δ 10.62 (bs, 1H),
7.91 (d, J = 6.8 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.64 (t, J = 6.8 Hz, 1H), 7.60 (t, J =
7.6 Hz, 1H), 5.01–4.97 (m, 1H), 3.92 (s, 3H), 2.86 (s, 3H), 2.69–2.45 (m, 3H),
2.30–2.21 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 175.7, 169.9, 167.5, 137.8, 135.0,
133.2, 130.7, 130.5, 124.1, 123.9, 113.5, 59.7, 52.9, 30.2, 28.6, 24.2; HRMS
+
(APCIꢀOrbitrap) m/z [M+H+] calcd for C16H17N2O4 301.1183, found 301.1178.
(E)ꢀMethyl
2ꢀ(4ꢀmethylꢀ3ꢀoxoisoindolinꢀ1ꢀylidene)ꢀ2ꢀ(1ꢀmethylꢀ5ꢀoxopyrrolidinꢀ2ꢀyl)acetate
(3bb). By following the general procedure, the reaction of 1b (61.8 mg, 0.25 mmol)
with 2b (2.0 mL) for 3 h afforded 3bb (63.6 mg, 81% yield): white solid, m.p.
159–160 oC; IR ν/cmꢀ1 (KBr) 3176, 3048, 2955, 1714, 1699, 1652, 1434, 1366, 1310,
1249, 1101, 805, 765, 700, 647; 1H NMR (400 MHz, CDCl3) δ 10.30 (bs, 1H), 7.58 (d,
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J = 8.0 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.32 (d, J = 7.2 Hz, 1H), 4.97–4.93 (m, 1H),
3.90 (s, 3H), 2.85 (s, 3H), 2.70 (s, 3H), 2.64–2.40 (m, 3H), 2.29–2.19 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 175.6, 170.8, 167.7, 138.3, 137.5, 135.5, 132.9, 132.8,
127.4, 121.6, 112.3, 59.8, 52.9, 30.2, 28.6, 24.4, 17.6; HRMS (ESIꢀOrbitrap) m/z
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[M+H]+ calcd for C17H19N2O4 315.1339, found 315.1342.
+
(E)ꢀMethyl
2ꢀ(5ꢀmethylꢀ3ꢀoxoisoindolinꢀ1ꢀylidene)ꢀ2ꢀ(1ꢀmethylꢀ5ꢀoxopyrrolidinꢀ2ꢀyl)acetate
(3cb). By following the general procedure, the reaction of 1c (61.8 mg, 0.25 mmol)
with 2b (2.0 mL) for 6 h afforded 3cb (50.4 mg, 64% yield): brown yellow solid, m.p.
o
230–231 C; IR ν/cmꢀ1 (KBr) 3191, 2972, 2905, 1705, 1652, 1486, 1394, 1350, 1311,
1
1251, 1142, 1072, 895, 827, 693; H NMR (400 MHz, CDCl3) δ 10.23 (bs, 1H), 7.70
(s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 4.93–4.90 (m, 1H), 3.90 (s,
3H), 2.84 (s, 3H), 2.64–2.43 (m, 3H), 2.50 (s, 3H), 2.27–2.18 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 175.7, 170.0, 167.6, 141.5, 138.3, 134.1, 132.5, 130.8, 124.1, 124.0,
112.5, 59.6, 52.8, 30.3, 28.5, 24.2, 21.6; HRMS (ESIꢀOrbitrap) m/z [M+H]+ calcd for
+
C17H19N2O4 315.1339, found 315.1341.
(E)ꢀMethyl
2ꢀ(5ꢀmethoxyꢀ3ꢀoxoisoindolinꢀ1ꢀylidene)ꢀ2ꢀ(1ꢀmethylꢀ5ꢀoxopyrrolidinꢀ2ꢀyl)acetate
(3eb). By following the general procedure, the reaction of 1e (65.8 mg, 0.25 mmol)
with 2b (2.0 mL) for 6 h afforded 3eb (53.2 mg, 64% yield): brown yellow solid, m.p.
o
172–173 C; IR ν/cmꢀ1 (KBr) 2960, 2929, 1725, 1670, 1644, 1493, 1453, 1289, 1138,
1
1071, 820; H NMR (400 MHz, CDCl3) δ 10.33 (bs, 1H), 7.76 (d, J = 8.8 Hz, 1H),
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7.34 (d, J = 2.4 Hz, 1H), 7.15 (dd, J = 8.8, 2.4 Hz, 1H), 4.95–4.91 (m, 1H), 3.94 (s,
3H), 3.90 (s, 3H), 2.84 (s, 3H), 2.65–2.44 (m, 3H), 2.27–2.18 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 175.7, 169.6, 167.6, 162.0, 138.6, 132.6, 127.4, 125.9, 120.9, 111.6,
106.7, 59.7, 56.1, 52.8, 30.3, 28.5, 24.3; HRMS (ESIꢀOrbitrap) m/z [M+H]+ calcd for
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+
C17H19N2O5 331.1289, found 331.1295.
(E)ꢀMethyl
2ꢀ(6ꢀchloroꢀ3ꢀoxoisoindolinꢀ1ꢀylidene)ꢀ2ꢀ(1ꢀmethylꢀ5ꢀoxopyrrolidinꢀ2ꢀyl)acetate (3fb).
By following the general procedure, the reaction of 1f (66.9 mg, 0.25 mmol) with 2b
(2.0 mL) for 6 h afforded 3fb (57.7 mg, 69% yield): pale yellow solid, m.p. 231–232
oC; IR ν/cmꢀ1 (KBr) 3191, 3062, 2952, 1714, 1645, 1429, 1351, 1253, 1165, 1087,
968, 837, 785; 1H NMR (400 MHz, CDCl3) δ 10.15 (bs, 1H), 7.84 (d, J = 8.0 Hz, 1H),
7.83 (s, 1H), 7.57 (dd, J = 8.0, 1.6 Hz, 1H), 4.89–4.85 (m, 1H), 3.94 (s, 3H), 2.83 (s,
3H), 2.67–2.43 (m, 3H), 2.27–2.17 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 175.8,
168.8, 167.1, 139.8, 137.1, 136.4, 131.1, 128.8, 124.9, 124.8, 114.6, 59.7, 53.0, 30.2,
28.6, 24.2; HRMS (ESIꢀOrbitrap) m/z [M+H]+ calcd for C16H16N2O435Cl+ 335.0793,
found 335.0796.
General Procedure for the Synthesis of 3ac−3fc. A solution of isoindolinone
1a (1b, 1e, and 1f, 0.25 mmol) in Nꢀethyl pyrrolidone (2c, 2.0 mL) was stirred under
an air atmosphere at 100 oC for a desired time (monitored by TLC). After the reaction
was finished, the mixture was filtered by a silica gel plug with ethyl acetate (30 mL)
as the eluent. The filtrate was washed with saturated brine (3×10 mL) and the organic
phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The
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residue was separated on a silica gel column with acetone/ethyl acetate (1/1) as the
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eluent to get product 3ac (3bc, 3ec, and 3fc).
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2ꢀ(1ꢀethylꢀ5ꢀoxopyrrolidinꢀ2ꢀyl)ꢀ2ꢀ(3ꢀoxoisoindolinꢀ1ꢀylidene)acetate
(3ac).
By
following the general procedure, the reaction of 1a (58.3 mg, 0.25 mmol) with 2c (2.0
o
mL) for 3 h afforded 3ac (64.7 mg, 82% yield): white solid, m.p. 204–205 C; IR
ν/cmꢀ1 (KBr) 3266, 3122, 2951, 1724, 1668, 1644, 1457, 1421, 1355, 1304, 1244,
1152, 1079, 969, 770, 710; 1H NMR (400 MHz, CDCl3) δ 10.57 (bs, 1H), 7.90 (d, J =
6.8 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.64 (t, J = 7.2 Hz, 1H), 7.59 (t, J = 7.2 Hz, 1H),
5.18–5.14 (m, 1H), 3.92 (s, 3H), 3.83–3.73 (m, 1H), 2.98–2.88 (m, 1H), 2.69–2.44 (m,
3H), 2.33–2.23 (m, 1H), 1.14 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
175.4, 169.8, 167.6, 137.8, 135.0, 133.2, 130.7, 130.5, 124.2, 123.8, 114.0, 57.0, 52.9,
36.1, 30.6, 24.5, 12.4; HRMS (ESIꢀOrbitrap) m/z [M+H]+ calcd for C17H19N2O4
+
315.1339, found 315.1341.
(E)ꢀMethyl
2ꢀ(1ꢀethylꢀ5ꢀoxopyrrolidinꢀ2ꢀyl)ꢀ2ꢀ(4ꢀmethylꢀ3ꢀoxoisoindolinꢀ1ꢀylidene)acetate (3bc).
By following the general procedure, the reaction of 1b (61.8 mg, 0.25 mmol) with 2c
(2.0 mL) for 12 h afforded 3bc (64.5 mg, 79% yield): pale yellow solid, m.p. 150–151
oC; IR ν/cmꢀ1 (KBr) 3178, 3052, 2955, 1715, 1672, 1641, 1459, 1425, 1381, 1360,
1
1311, 1245, 1098, 930, 719, 645; H NMR (400 MHz, CDCl3) δ 10.75 (bs, 1H), 7.57
(d, J = 8.0 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.32 (d, J = 7.2 Hz, 1H), 5.23–5.18 (m,
1H), 3.90 (s, 3H), 3.84–3.74 (m, 1H), 2.97–2.88 (m, 1H), 2.69 (s, 3H), 2.67–2.40 (m,
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3H), 2.32–2.24 (m, 1H), 1.13 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
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175.3, 171.1, 167.7, 138.2, 137.3, 135.6, 132.8, 132.7, 127.5, 121.6, 113.2, 56.8, 52.8,
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36.0, 30.6, 24.6, 17.6, 12.4; HRMS (ESIꢀOrbitrap) m/z [M+H]+ calcd for C18H21N2O4
+
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329.1496, found 329.1502.
(E)ꢀMethyl
2ꢀ(1ꢀethylꢀ5ꢀoxopyrrolidinꢀ2ꢀyl)ꢀ2ꢀ(5ꢀmethoxyꢀ3ꢀoxoisoindolinꢀ1ꢀylidene)acetate
(3ec). By following the general procedure, the reaction of 1e (65.8 mg, 0.25 mmol)
with 2c (2.0 mL) for 12 h afforded 3ec (62.4 mg, 72% yield): pale yellow solid, m.p.
o
192–193 C; IR ν/cmꢀ1 (KBr) 3172, 3112, 2986, 2937, 2809, 1723, 1661, 1623, 1488,
1434, 1349, 1287, 1235, 1172, 1135, 1072, 1021, 814, 735, 674; 1H NMR (400 MHz,
CDCl3) δ 10.33 (bs, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.15 (dd,
J = 8.8, 2.4 Hz, 1H), 5.13–5.08 (m, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 3.80–3.70 (m, 1H),
2.98–2.88 (m, 1H), 2.68–2.44 (m, 3H), 2.30–2.20 (m, 1H), 1.13 t, J = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 175.5, 169.5, 167.6, 161.9, 138.6, 132.6, 127.5, 126.0,
120.8, 112.1, 106.7, 57.0, 56.0, 52.7, 36.1, 30.7, 24.5, 12.4; HRMS (ESIꢀOrbitrap) m/z
[M+H]+ calcd for C18H21N2O5 345.1445, found 345.1452.
+
(E)ꢀMethyl
2ꢀ(6ꢀchloroꢀ3ꢀoxoisoindolinꢀ1ꢀylidene)ꢀ2ꢀ(1ꢀethylꢀ5ꢀoxopyrrolidinꢀ2ꢀyl)acetate (3fc).
By following the general procedure, the reaction of 1f (67.0 mg, 0.25 mmol) with 2c
(2.0 mL) for 12 h afforded 3fc (59.3 mg, 68% yield): pale yellow solid, m.p. 238–239
oC; IR ν/cmꢀ1 (KBr) 3070, 2981, 1705, 1645, 1612, 1454, 1425, 1354, 1253, 1163,
1
1135, 1084, 970, 840, 787, 725, 677; H NMR (400 MHz, CDCl3) δ 10.25 (bs, 1H),
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7.83 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.57 (dd, J = 8.0, 1.6 Hz, 1H), 5.08–5.04 (m,
1H), 3.93 (s, 3H), 3.81–3.72 (m, 1H), 2.95ꢀ2.85 (m, 1H), 2.69–2.43 (m, 3H),
2.29–2.20 (m, 1H), 1.12 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.5,
168.8, 167.1, 139.8, 137.0, 136.4, 131.1, 128.8, 124.94, 124.89, 115.1, 57.0, 53.0,
36.2, 30.6, 24.5, 12.4; HRMS (ESIꢀOrbitrap) m/z [M+H]+ calcd for C17H18N2O435Cl+
349.0950, 349.0959.
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ASSOCIATED CONTENT
Supporting Information
13
1H and C NMR spectra of products 3aa–fc and Xꢀray data of 3da. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: gwang@ustc.edu.cn.
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