Metal-free synthesis of 2-oxindoles via PhI(OAc)2-mediated oxidative C-C bond formation

Article abstract of DOI:10.1021/jo4025539

The series of 3-monofunctionalized 2-oxindoles 2 were conveniently synthesized from reactions between anilide 1 and phenyliodine(III) diacetate (PIDA) through hypervalent iodine mediated C(sp²)-C(sp²) bond formation followed by a subsequent deacylation reaction. This metal-free method, shown to provide direct access to an important oxindole intermediate, could be applied to the total synthesis of naturally occurring horsfiline.

Full text of DOI:10.1021/jo4025539

Article
pubs.acs.org/joc
Metal-Free Synthesis of 2‑Oxindoles via PhI(OAc)2‑Mediated
Oxidative C−C Bond Formation
Jinglei Lv,† Daisy Zhang-Negrerie,† Jun Deng,† Yunfei Du,†,‡,* and Kang Zhao*,†
†Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology,
Tianjin University, Tianjin 300072, People’s Republic of China
‡Collaborative Innovation Center of Chemical Science and Engineering (Tianjin) Tianjin University, Tianjin 300072,
People’s Republic of China
S
* Supporting Information
ABSTRACT: The series of 3-monofunctionalized 2-oxindoles 2 were
conveniently synthesized from reactions between anilide 1 and
phenyliodine(III) diacetate (PIDA) through hypervalent iodine mediated
C(sp2)−C(sp2) bond formation followed by a subsequent deacylation
reaction. This metal-free method, shown to provide direct access to an
important oxindole intermediate, could be applied to the total synthesis
of naturally occurring horsfiline.
ortho aromatic halogen or an α-halogen. Recently, Taylor and Bisai
realized the conversion of anilides to 3,3-disubstituted oxindoles
through Cu- and I2- mediated aromatic C(sp2)−C(sp3) coupling
(Scheme 1, route d).4 Moreover, Ag-, or Rh-catalyzed aromatic C−H
functionalization of α-diazoamides is another effective way to
construct 3-monofunctionalized oxindoles (Scheme 1, route e),5
and starting from N-arylpropiolamides, 3-acyloxindoles can also be
synthesized via Au-mediated aromatic C(sp2)−C(sp) bond
formation (Scheme 1, route f).6 In the past 50 years, hypervalent
iodine reagents, such as phenyliodine diacetate (PIDA) and
phenyliodine bis(trifluoroacetate) (PIFA), have been proven to be
a class of effective and environmentally friendly oxidative reagents in
mediating the formation of C−C bonds, without the involvement of a
toxic, transition-metal-containing reagent.7 To our knowledge, there
are few examples describing the synthesis of 3-monofunctionalized
2-oxindoles via oxidative C(sp2)−C(sp2) bond formation from
anilide derivatives.8 Herein, we report a new application of hypervalent
iodine: that is, in constructing 3-monofunctionalized 2-oxindole
frameworks through its role of facilitating an intramolecular cyclization
of anilide derivatives via an exclusive C(sp2)−C(sp2) bond-forming
reaction.
INTRODUCTION
■
Oxindoles have received enduring synthetic interest from organic
chemists, since they are versatile building blocks for the synthesis
of natural products and biologically active molecules.1
Specifically, 3-monofunctionalized 2-oxindoles have been
identified as indispensible intermediates in the total synthesis
of the naturally occurring horsfiline, welwitindolinone C, CPC-1,
etc.1g−j
According to a literature survey, a handful of strategies have
been established to construct the oxindole skeleton. The most
commonly used approach is through the condensation of
oxindoles with activated ortho esters or acyl derivatives (Scheme 1,
Scheme 1. Existing Routes To Access 3-Functionalized
2-Oxindoles
In our previous work, we successfully realized the construction
of the oxindole scaffold C through PIDA-mediated oxidative
cyclization of anilide A (Scheme 2, eq 1).9 Enthused by this work,
we envisaged the formation of another oxindole compound F
through the same reaction pattern by starting with the
functionalized anilide derivative D, the structure of which bears
a terminal enol functionality (Scheme 2, eq 2).10 We argued that,
upon treatment of D with an iodine(III) oxidant, the analogous
O−I intermediate E should be furnished, which would likely
trigger a similar C(sp2)−C(sp2) bond-forming process and thus
produce the oxindole compound F. The acetyl group in F could
route a).2 Another route is through Ir- or Cu-catalyzed intramolecular
cyclization of β-keto amide derivatives (Scheme 1, routes b and c).3
However, for the cyclization to occur, both methods require
specifically functionalized precursors and the presence of either an
Received: November 18, 2013
© XXXX American Chemical Society
A
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Another modification that drastically improved the reaction
efficiency was the introduction of aqueous NaHCO3 after the
addition of PIDA at room temperature. This modification not
only further reduced the reaction time to only 2 h but also
brought back the yield to 90% (Table 1, entry 11).11
Scheme 2. Proposed Route To Access 3-Functionalized
Oxindoles Based on the Previously Reported PIFA-Mediated
Synthesis of 3-Hydroxy-2-oxindoles
Under the optimal conditions (Table 1, entry 11), a range of
substituted anilide derivatives were studied to explore the scope
as well as limitations of this newly developed method. We were
delighted to see that the method could be well applied to
substrates bearing either electron-donating or electron-
withdrawing aromatic substituents to afford the expected
oxindoles in moderate to good yields (Table 2, entries 2−5, 8,
and 9), with higher yields occurring in the former class of
substrates, giving higher yields of the products. Switching the
methyl group on N to other substituents, such as benzyl and
phenyl groups, did not affect the yield to any significant degree
(Table 2, entries 6 and 7). As expected, meta-substituted substrates
provided two regioisomeric products (Table 2, entries 8 and 9),
the ratio of which implied the cyclization to preferably occur at the
less hindered position. However, total regioselectivity was
observed for 1l, as 2l was obtained as the sole regioisomeric
product (Table 2, entry 12). Because of its strong electron-
withdrawing effect, the cyano group in substrates 1a−j is
understood to be crucial for maintaining the terminal enol structure
through preventing the keto tautomer structure.10 In light of this, we
investigated the functional group tolerance of this methodology by
replacing the cyano group with other electron-withdrawing groups,
such as carboxylic ester (Table 2, entries 11−13) and acetyl groups
(Table 2, entries 14−18).12 To our delight, substrates bearing either
the ester or acetyl group also furnished the desired oxindole
products in satisfactory yields of 72−93%.13
act as a protecting group to avoid overoxidation of the oxindole at
the 3-position.
RESULTS AND DISCUSSION
■
To test the feasibility of the proposed conversion, (Z)-2-cyano-
3-hydroxy-N-methyl-N-phenylbut-2-enamide (1a), readily
prepared via condensation of cyanoacetanilide with acetyl
chloride,10a was selected as the model substrate. However, to
our surprise, 3-cyano-2-oxindole 2a was formed instead, after
mixing 1a and PIDA in MeCN for 72 h at room temperature. The
result showed that an unexpected deacylation reaction had
occurred following the expected C(sp2)−C(sp2) bond for-
mation. Later on, other iodine(III) oxidants, i.e., PIFA and PhIO,
were put to the test and were also found to be effective in
affording the same product, albeit in slightly lower yields (Table 1,
a
Table 1. Optimization of Reaction Conditions
It is worth noting that the method worked equally well for
substrates 1j,m,q, readily derived from tetrahydroquinoline, to
deliver the tricyclic oxindoles 2j,m,q in satisfactory yields,
respectively (Table 2, entries 10, 13, and 17).14
At the early stages, anilide D probably underwent exactly the
pathway we proposed in Scheme 2 and indeed gave the 3-acetyl
oxindole intermediate F through intermediates E and G (Scheme 3).
We believe that intermediate F, bearing an acetyl group and a
strong electron-withdrawing group on the same carbon atom,
should have a strong tendency to undergo deacylation through a
nucleophilic attack on the carbonyl group by the released acetate
anion. Finally, the formed carbanion H captures one proton to
furnish the desired 3-functionalized 2-oxindole.
In order to confirm this assumption, anilide 1s was prepared
and treated with PIDA in TFE, without further treatment with
aqueous NaHCO3 (Scheme 4). In this reaction, intermediate F′
was detected by crude HRMS analysis, although it could not be
purified by silica gel column chromatography due to its extreme
instability.15 As expected, in addition to the desired cyclized
product 2a, the mixed anhydride 3 was also isolated. This result
adequately supports the deacylation mechanism proposed above.
It also led to the conclusion that the presence of NaHCO3 in the
reaction system effectively accelerates the final deacylation
process.
Back in 2006, Trost and Brennan reported a total synthesis of
the oxindole alkaloid horsfiline,1g in which oxindole L acts as an
important intermediate. Here, we report the synthesis of
intermediate L, by applying our newly developed method,
starting from the readily available amine I. As described in
Scheme 5, amine I was conveniently converted to anilide J
through condensation with 2-ethoxycarbonylacetyl chloride,
which was further transformed into K by the general acylation
b
entry
oxidant
solvent
temp
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
10
PIDA
PIFA
PhIO
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
MeCN
MeCN
MeCN
DCM
THF
room temp
room temp
room temp
room temp
room temp
room temp
room temp
room temp
room temp
reflux
72
72
72
72
72
72
48
72
72
7
84
71
72
55
ND
92
74
52
ND
76
88
TFE
DMF
DMSO
MeOH
TFE
c
11
TFE
room temp
2
a
Reaction conditions: 1a (1.0 mmol), oxidant (1.1 mmol) in solvent
unless otherwise stated. Isolated yields. Aqueous NaHCO3 (3.0 mmol)
b
c
was used after the addition of PIDA.
entries 2 and 3). Using PIDA as the oxidant, we next investigated
other solvents, including MeCN, DCM, THF, TFE, DMF,
DMSO, and MeOH (Table 1, entries 4−9). The results revealed
that TFE was the leading solvent for this cyclization reaction
(Table 1, entry 6). Considering the long reaction time of 72 h, we
made further attempts to speed up the reaction, first by raising the
reaction temperature to reflux temperature. The higher temper-
ature indeed resulted in a greatly reduced reaction time, 7 h, but
was unfortunately accompanied by a reduced yield of 76%
(Table 1, entry 10). The cyclized product 2a was obtained in 76% yield.
B
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a
Table 2. Synthesis of 3-Monofunctionalized 2-Oxindoles by PIDA
a
General conditions: 1 (1.0 equiv), PIDA (1.1 equiv) in TFE at room temperature for 1 h unless otherwise stated; then aqueous NaHCO3 (3.0
b
c
d
equiv) was added. Isolated yields. The two regioisomers were inseparable: 2h/2h′ = 2:1. The two regioisomers were inseparable: 2i/2i′ = 1.2:1.
e
1 (1.0 equiv) and PIDA (1.1 equiv) in TFE at room temperature for 72 h without treatment with aqueous NaHCO3.
approach. To our delight, upon treatment with PIDA in
MeCN,16 the expected intramolecular oxidative cyclization/
deacylation occurred in K and gave the oxindole intermediate,
which was captured by TIPSOTf in the presence of Et3N to give
the desired intermediate L in moderate yield. This result
demonstrates that our method can provide an alternative and
effective access to the natural product horsfiline.
reaction. The highlights of the reported method, in comparison
to the currently existing methods for the synthesis of oxindole
products, include the mild reaction conditions, good functional
group tolerance, the metal-free feature, and environmentally
friendly characteristics.
EXPERIMENTAL SECTION
■
I. General Information. All reactions were stirred magnetically
without precaution of air and carried out at room temperature. 1H and
13C NMR spectra were recorded on a 400 or 600 MHz spectrometer at
25 °C. Chemical shift values are given in ppm and referenced to the
internal standard TMS at 0.00 ppm. The peak patterns are indicated as
follows: s, singlet; d, doublet; t, triplet; q, quadruplet; m, multiplet; br,
CONCLUSION
■
In conclusion, we have developed an efficient approach for the
synthesis of 3-monofunctionalized 2-oxindoles via PIDA-
mediated C(sp2)−C(sp2) bond formation and a deacylation
C
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Scheme 3. Proposed Mechanism
Scheme 5. Preparation of a Horsfiline Precursor L
broad; dd, doublet of doublets. The coupling constants J are reported in
hertz (Hz). High-resolution mass spectra (HRMS) were obtained on a
Q-TOF micro spectrometer. Melting points were determined with a
national micromelting point apparatus without corrections. TLC plates
were visualized by exposure to ultraviolet light. Reagents and solvents
were purchased as reagent grade and were used without further
purification. Flash column chromatography was performed over silica
gel 200−300 m, and the eluent was a mixture of ethyl acetate (EA) and
petroleum ether (PE).
13C NMR (100 MHz, CDCl3) δ 161.5, 141.1, 135.6, 132.8 (q, JC−F
32.8 Hz), 132.6, 132.1, 131.0, 129.1, 128.8, 128.2, 126.1 (q, JC−F = 2.8 Hz),
125.4 (q, JC−F = 3.2 Hz), 123.1 (q, JC−F = 274.0 Hz), 113.7, 53.8, 25.9; 19
NMR (566 MHz, CDCl3) δ −62.82 (s, 3F); HRMS (ESI) calcd for
C17H13F3N2NaO+ [M + Na+] 341.0872, found 341.0872; IR (KBr) 1667,
1593, 1410, 1322, 1125 cm−1.
=
II. General Procedure for the Synthesis of 2-Cyano-3-
hydroxy-N-substituted Amides (1a−j,s).10
F
To a suspension of anhydrous MgCl2 (952 mg, 10 mmol) and
cyanoacetanilide (10 mmol) in MeCN (40 mL) was added anhydrous Et3N
(2.79 mL, 20 mmol) at room temperature. Stirring was continued at room
temperature for 45 min, and then acid chloride (11 mmol) was added to the
mixture at 0 °C. The resulting mixture was stirred for another 4 h at room
temperature (the reaction was monitored by TLC). Upon completion of the
reaction, the mixture was acidified with HCl (1 N, 30 mL). The aqueous layer
was extracted with EA (50 mL × 3), and the combined organic layer was
washed with brine (70 mL), dried over Na2SO4, and evaporated under
reduced pressure to remove the solvent. Purification of the crude solid by flash
column chromatography on silica gel (EA/PE) afforded the desired amides.
(Z)-2-Cyano-3-hydroxy-N-methyl-N-phenylbut-2-enamide (1a).
1a was purified by silica gel chromatography (30% EA/PE): yield 1.75 g,
81%, white solid, mp 91−94 °C; 1H NMR (600 MHz, CDCl3) δ 17.04 (s,
1H), 7.48−7.44 (m, 3H), 7.27−7.25 (m, 2H), 3.37 (s, 3H), 2.23 (s, 3H).
(Z)-2-Cyano-3-hydroxy-N-methyl-N-(p-tolyl)but-2-enamide (1b).
1b was purified by silica gel chromatography (30% EA/PE): yield 1.75 g,
76%, white solid, mp 99−100 °C; 1H NMR (600 MHz, CDCl3) δ 17.02
(s, 1H), 7.26 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 7.8 Hz, 2H), 3.33 (s, 3H),
2.41 (s, 3H), 2.23 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 191.0, 169.6,
139.4, 130.6, 127.4, 115.4, 79.1, 39.2, 22.3, 21.3 (one carbon peak was
The cyanoacetanilides were prepared by the known procedures.17 The
novel cyanoacetanilide derivatives Sd, Sh, and Si thus obtained were
characterized as follows.
N-Benzyl-N-(4-bromophenyl)-2-cyanoacetamide (Sd). The amide
was purified by silica gel chromatography (20% EA/PE): yield 84%,
white solid, mp 101−103 °C; 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J =
8.4 Hz, 2H), 7.30 (m, 3H), 7.18 (m, 2H), 6.91 (d, J = 8.4 Hz, 2H), 4.88
(s, 2H), 3.24 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 161.5, 139.5,
135.8, 133.5, 130.0, 129.1, 128.7, 128.1, 123.3, 113.9, 53.7, 25.8; HRMS
(ESI) calcd for C16H13BrN2NaO+ [M + Na+] 351.0103, found
351.0107; IR (KBr) 2251, 1667, 1489, 1455, 1417, 1198, 837 cm−1.
N-Benzyl-2-cyano-N-(3-fluorophenyl)acetamide (Sh). The amide
was purified by silica gel chromatography (40% EA/PE): yield 81%,
1
white solid, mp 119−121 °C; H NMR (400 MHz, CDCl3) δ 7.41
(m, 1H), 7.30 (m, 3H), 7.20 (m, 2H), 7.12 (t, J = 8.0 Hz, 1H), 6.85
(d, J = 8.0 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 4.90 (s, 2H), 3.27 (s, 2H);
13C NMR (100 MHz, CDCl3) δ 163.0 (d, JC−F = 251.8 Hz), 161.8, 161.6,
141.9 (d, JC−F = 8.2 Hz), 135.8, 131.5 (d, JC−F = 9.1 Hz), 129.0, 128.7
128.1, 124.3 (d, JC−F = 2.8 Hz), 116.5 (d, JC−F = 21.4 Hz), 115.8 (d,
JC−F = 22.3 Hz), 113.9, 53.7, 25.8; 19F NMR (566 MHz, CDCl3) δ −108.83
(s, 1F); HRMS (ESI) calcd for C16H13FN2NaO+ [M + Na+] 291.0904,
found 291.0904; IR (KBr) 2250, 1665, 1606, 1487, 1412, 1217 cm−1.
N-Benzyl-2-cyano-N-(3-(trifluoromethyl)phenyl)acetamide (Si).
The amide was purified by silica gel chromatography (30% EA/PE):
+
missing due to overlapping); HRMS (ESI) calcd for C13H14N2NaO2
[M + Na+] 253.0947, found 253.0947; IR (KBr) 2209, 1574, 1512, 1482,
1450, 1380, 1300, 837, 754, 633 cm−1.
(Z)-2-Cyano-3-hydroxy-N-(4-methoxyphenyl)-N-methylbut-2-en-
amide (1c). 1c was purified by silica gel chromatography (30% EA/PE):
1
yield 2.02 g, 82%, white solid, mp 91−92 °C; H NMR (600 MHz,
CDCl3) δ 17.09 (s, 1H), 7.16 (d, J = 9 Hz, 2H), 6.95 (d, J = 9 Hz, 2H),
3.84 (s, 3H), 3.32 (s, 3H), 2.23 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
191.1, 169.8, 160.3, 134.6, 128.9, 115.4, 115.1, 79.0, 55.5, 39.3, 22.4;
1
yield 87%, light yellow solid, mp 122−124 °C; H NMR (400 MHz,
CDCl3) δ 7.69 (d, J = 7.7 Hz, 1H), 7.56 (t, J = 7.9 Hz, 1H), 7.30 (m, 4H),
7.24 (d, J = 7.8 Hz, 1H), 7.18 (m, 2H), 4.92 (s, 2H), 3.23 (s, 2H);
+
HRMS (ESI) calcd for C13H14N2NaO3 [M + Na+] 269.0897, found
Scheme 4. Specific Reaction for Mechanism Elucidation
D
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269.0902; IR (KBr) 2209, 1579, 1510, 1463, 1299, 1254, 1026, 836, 756,
641, 568 cm−1.
III. General Procedure for the Synthesis of Ethyl 3-Hydroxy-2-
(N-substituted carbamoyl)but-2-enoate (1k−m). The ethyl
(Z)-N-Benzyl-N-(4-bromophenyl)-2-cyano-3-hydroxybut-2-enamide
(1d). 1d was purified by silica gel chromatography (40% EA/PE): yield
3.01 g, 81%, white solid, mp 100−102 °C; 1H NMR (600 MHz, CDCl3)
δ 16.82 (s, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.29−7.17 (m, 5H, Harom), 6.93
(d, J = 9 Hz, 2H), 4.90 (s, 2H), 2.24 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 191.6, 169.3, 139.1, 135.6, 133.0, 130.3, 128.9,
128.7, 128.1, 123.5, 115.2, 79.3, 54.6, 22.4; HRMS (ESI) calcd for
C18H1579BrN2NaO2+ [M + Na+] 393.0209, found 393.0209; IR (KBr)
2210, 1591, 1564, 1466, 1218, 1081, 1005, 701, 546 cm−1.
(Z)-N-(4-Chlorophenyl)-2-cyano-3-hydroxy-N-methylbut-2-enamide
(1e). 1e was purified by silica gel chromatography (40% EA/PE): yield
1.98 g, 79%, white solid, mp 110−113 °C; 1H NMR (600 MHz, CDCl3)
δ 16.78 (s, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 3.34
(s, 3H), 2.25 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 191.3, 169.6,
140.5, 135.2, 130.2, 129.0, 115.4, 79.2, 39.1, 22.3; HRMS (ESI) calcd for
C12H1135ClN2NaO2+ [M + Na+] 273.0401, found 273.0403; IR (KBr)
2213, 1587, 1493, 1345, 1299, 1106, 1018, 850, 556 cm−1.
3-(substituted (aryl) amino)-3-oxopropanoates were prepared by the
known procedures.17 The novel ethyl 3-(substituted (aryl) amino)-
3-oxopropanoate (Sl) thus obtained was characterized as follows.
Ethyl 3-(Benzyl(3,4-dimethoxyphenyl)amino)-3-oxopropanoate
(Sl). The amide was purified by silica gel chromatography (40%
1
EA/PE): yield 86%, light yellow oil; H NMR (600 MHz, CDCl3) δ
7.29−7.23 (m, 5H), 6.77 (d, J = 8.5 Hz, 1H), 6.59 (d, J = 8.4 Hz, 1H),
6.42 (s, 1H), 4.88 (s, 2H), 4.14 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 3.68 (s,
3H), 3.24 (s, 2H), 1.24 (t, J = 7.1 Hz, 3H); 13C NMR (150 MHz,
CDCl3) δ 167.9, 166.3, 149.3, 148.9, 137.2, 134.5, 129.1, 128.4, 127.5,
120.5, 111.7, 111.2, 61.2, 55.9, 55.9, 53.1, 41.7, 14.1; HRMS (ESI) calcd
+
for C20H23NNaO5 [M + Na+] 380.1468, found 380.1467; IR (KBr)
(Z)-2-Cyano-3-hydroxy-N,N-diphenylbut-2-enamide (1f). 1f was
purified by silica gel chromatography (30% EA/PE): yield 1.92 g, 69%,
white solid, mp 123−124 °C; 1H NMR (600 MHz, CDCl3) δ 16.45 (s,
1H), 7.43−7.24 (m, 10H, Harom), 2.30 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 191.9, 170.4, 141.6, 129.7, 128.2, 127.6, 114.9, 80.6, 22.5;
2966, 1745, 1650, 1514, 1407, 1260 cm−1.
To a suspension of NaH (60% in mineral oil, 600 mg, 15 mmol) in
THF and MeCN (35 mL, 1/1 vTHF/vMeCN) was added a solution of ethyl
3-(substituted (aryl) amino)-3-oxopropanoate (10 mmol) in THF and
MeCN (35 mL, 1/1 vTHF/vMeCN) dropwise at 0 °C. Stirring was continued
at room temperature for 15 min, and acetyl chloride (778 μL, 11 mmol) was
added to the mixture at 0 °C. The resulting mixture was stirred for another
4 h at room temperature (the reaction was monitored by TLC). Upon
completion, the mixture was acidified with HCl (1 N, 60 mL). The aqueous
layer was extracted with EA (60 mL × 3), and the combined organic layer
was washed with brine (90 mL), dried over Na2SO4, and evaporated under
reduced pressure to remove the solvent. Purification of the crude oil by flash
column chromatography on silica gel (EA/PE) afforded the desired amides.
Ethyl 3-Hydroxy-2-(methyl(phenyl)carbamoyl)but-2-enoate (1k).
1k was purified by silica gel chromatography (30% EA/PE): yield 2.21 g,
84% (enol:ketone = 3:2), light yellow oil; 1H NMR (600 MHz, CDCl3)
major isomer (1k) δ 12.44 (s, 1H), 7.46−7.42 (m, 1H, peak of two
isomers overlapped), 7.32 (t, J = 6.0 Hz, 2H), 7.09 (d, 12 Hz, 2H), 4.13
(q, J = 7.2 Hz, 2H), 3.40 (s, 3H), 2.02 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H),
minor isomer (1k′) δ 7.40−7.38 (m, 1H, peak of two isomers
overlapped), 7.24 (t, J = 7.2 Hz, 2H), 7.20 (d, J = 7.2 Hz, 2H), 4.37 (s,
1H), 4.18−4.16 (q, J = 6.0 Hz, 2H), 3.33 (s, 3H), 2.22 (s, 3H), 1.23
(t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 198.3, 174.6, 169.8,
166.3, 165.5, 164.4, 164.1, 143.9, 142.7, 130.2, 129.9, 129.1, 128.7, 128.3,
127.6, 127.3, 126.1, 102.9, 64.5, 62.0, 60.9, 37.7, 37.3, 29.1, 19.8, 14.2,
+
HRMS (ESI) calcd for C17H14N2NaO2 [M + Na+] 301.0947, found
301.0964; IR (KBr) 2210, 1586, 1493, 1441, 754, 740, 556 cm−1.
(Z)-N-Benzyl-2-cyano-3-hydroxy-N-phenylbut-2-enamide (1g). 1g
was purified by silica gel chromatography (40% EA/PE): yield 2.31 g,
79%, white solid, mp 92−95 °C; 1H NMR (600 MHz, CDCl3) δ 17.04
(s, 1H), 7.42−7.06 (m, 10H, Harom), 4.93 (s, 2H), 2.23 (s, 3H); 13C
NMR (150 MHz, CDCl3) δ 191.5, 169.4, 140.2, 135.9, 129.8, 129.5,
128.9, 128.8, 128.6, 127.9, 115.1, 79.3, 54.8, 22.4; HRMS (ESI) calcd for
C18H16N2NaO2+ [M + Na+] 315.1104, found 315.1107; IR (KBr) 2214,
1569, 1443, 1293, 755, 693, 564 cm−1.
(Z)-N-Benzyl-2-cyano-N-(3-fluorophenyl)-3-hydroxybut-2-enamide
(1h). 1h was purified by silica gel chromatography (20% EA/PE): yield
2.23 g, 72%, white solid, mp 89−90 °C; 1H NMR (600 MHz, CDCl3) δ
16.84 (s, 1H), 7.33−6.81 (m, 9H, Harom), 4.93 (s, 2H), 2.25
(s, 3H); 13C NMR (150 MHz, CDCl3) δ 191.6, 169.4, 163.8
(d, JC−F = 249.2 Hz), 141.5 (d, JC−F = 9.9 Hz), 135.6, 130.9 (d, JC−F
9.4 Hz), 128.8, 128.7, 128.1, 124.7 (d, JC−F = 2.4 Hz), 116.7 (d, JC−F
=
=
21.0 Hz), 116.3 (d, JC−F = 22.7 Hz), 115.0, 79.4, 54.6, 22.4; HRMS (ESI)
+
calcd for C18H15FN2NaO2 [M + Na+] 333.1010, found 333.1010; IR
(KBr) 3072, 2215, 1572, 1445, 1336, 1297, 756, 702, 515 cm−1.
(Z)-N-Benzyl-2-cyano-3-hydroxy-N-(3-(trifluoromethyl)phenyl)-
but-2-enamide (1i). 1i was purified by silica gel chromatography (20%
+
14.0; HRMS (ESI) calcd for C14H17NNaO4 [M + Na+] 286.1050,
found 286.1044; IR (KBr) 3062, 2846, 1741, 1629, 1580, 1492, 1383,
1
EA/PE): yield 2.41 g, 67%, white solid, mp 105−108 °C; H NMR
1069, 846, 666 cm−1.
(600 MHz, CDCl3) δ 16.83 (s, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.49 (t, J =
8.4 Hz, 1H), 7.30−7.29 (m, 4H, Harom), 7.24 (d, J = 9.0 Hz, 1H), 7.18
(m, 2H), 4.95 (s, 2H), 2.24 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
191.9, 169.3, 140.6, 135.4, 132.4 (q, JC−F = 33.2 Hz), 132.3, 130.4, 128.9,
128.7, 128.2, 126.2 (q, JC−F = 3.7 Hz), 126.1 (q, JC−F = 3.8 Hz), 122.4 (q,
JC−F = 272.8 Hz), 114.9, 79.2, 54.7, 22.4; HRMS (ESI) calcd for
Ethyl 2-(Benzyl(3,4-dimethoxyphenyl)carbamoyl)-3-hydroxybut-
2-enoate (1l). 1l was purified by silica gel chromatography (30% EA/
PE): yield 2.65 g, 82% (enol:ketone = 1:1.4), light yellow oil; 1H NMR
(600 MHz, CDCl3) major isomer (1l′) δ7.29−7.24 (m, 5H, Harom, peak
of two isomers overlapped), 6.76 (d, J = 8.4 Hz, 1H), 6.54 (d, J = 8.4 Hz,
1H), 6.32 (d, 1H, peak of two isomers overlapped), 5.22−4.71 (m, 2H,
peak of two isomers overlapped), 4.39 (s, 1H), 4.20 (m, 2H, peak of two
isomers overlapped), 3.86 (s, 3H), 3.66 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H),
minor isomer (1l) δ 12.29 (s, 1H), 7.29−7.24 (m, 5H, Harom, peak of two
isomers overlapped), 6.68 (d, J = 8.4 Hz, 1H), 6.50 (d, J = 8.4 Hz, 1H),
6.32 (d, 1H, peak of two isomers overlapped), 5.22−4.71 (m, 2H, peak
of two isomers overlapped), 4.20 (m, 2H, peak of two isomers overlapped),
3.83 (s, 3H), 3.62 (s, 3H), 2.02 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H); 13C NMR
(150 MHz, CDCl3) δ 198.5, 173.7, 169.7, 166.3, 165.7, 164.5, 149.4, 149.2,
148.7, 148.4, 137.6, 136.9, 135.1, 133.6, 129.0, 128.9, 128.5, 128.4, 127.6,
127.5, 120.8, 119.5, 111.8, 111.3, 111.0, 110.7, 103.1, 64.6, 62.0, 60.9, 56.0,
55.9, 55.8, 55.7, 53.3, 53.1, 29.2, 19.8, 14.2, 14.0; HRMS (ESI) calcd for
C22H25NNaO6+ [M + Na+] 422.1574, found 422.1579; IR (KBr) 2982,
1745, 1631, 1580, 1461, 1241, 1051, 909, 678 cm−1.
+
C19H15F3N2NaO2 [M + Na+] 383.0978, found 383.0984; IR (KBr)
3064, 2207, 1571, 1497, 1426, 1325, 1170, 1136, 787, 704 cm−1.
(Z)-3-Hydroxy-2-(1,2,3,4-tetrahydroquinoline-1-carbonyl)but-2-
enenitrile (1j). 1j was purified by silica gel chromatography (40%
1
EA/PE): yield 2.08 g, 86%, white solid, mp 134−136 °C; H NMR
(600 MHz, CDCl3) δ 16.33 (s, 1H), 7.25−7.20 (m, 4H, Harom), 3.84
(m, 2H), 2.75 (t, J = 6.6 Hz, 2H), 2.32 (s, 3H), 2.01 (m, 2H); 13C NMR
(150 MHz, CDCl3) δ 190.71, 169.8, 137.2, 133.4, 128.7, 126.7, 126.5,
124.6, 115.9, 80.8, 44.7, 26.3, 23.9, 22.3; HRMS (ESI) calcd for
C14H14N2NaO2+ [M + Na+] 265.0947, found 265.0956; IR (KBr) 2962,
2212, 1597, 1493, 1432, 1334, 755, 566 cm−1.
(Z)-2-Cyano-3-hydroxy-N-methyl-N,3-diphenylacrylamide (1s). 1s
was purified by silica gel chromatography (20% EA/PE): yield 2.20 g,
79%, white solid, mp 122−125 °C; 1H NMR (600 MHz, CDCl3) δ 17.07
(s, 1H), 7.78(d, J =6.0Hz, 2H), 7.49−7.46 (m, 3H, Harom), 7.43 (t, J =6.0Hz,
1H), 7.38 (t, J = 6.0 Hz, 2H), 7.32 (d, J = 6.0 Hz, 2H), 3.43 (s, 3H).
Ethyl 3-Hydroxy-2-(1,2,3,4-tetrahydroquinoline-1-carbonyl)but-
2-enoate (1m). 1m was purified by silica gel chromatography
(20% EA/PE): yield 2.43 g, 84% (enol:ketone = 1:0.3), light yellow oil;
E
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1H NMR (600 MHz, CDCl3) major isomer (1m) δ 12.86 (s, 1H), 7.28−
[M + Na+] 256.0944, found 256.0942; IR (KBr) 3063, 1645, 1493, 1425,
1266, 1013, 840 cm−1.
6.89 (m, 4H, Harom, peak of two isomers overlapped), 4.31−3.33 (m, 4H,
peak of two isomers overlapped), 2.86 (m, 2H, peak of two isomers
overlapped), 2.29−1.90 (m, 5H, peak of two isomers overlapped), 0.98
(m, 3H), minor isomer (1m′) 7.28−6.89 (m, 4H, Harom, peak of two
isomers overlapped), 4.31−3.33 (m, 4H, peakoftwo isomersoverlapped),
2.86 (m, 2H, peak of two isomers overlapped), 2.29−1.90 (m, 5H, peak of
two isomers overlapped), 1.22 (m, 3H); 13C NMR (150 MHz, CDCl3) δ
177.1, 169.8, 165.8, 139.1, 132.5, 128.3, 126.0, 125.0, 123.5, 103.2,
60.8, 43.3, 27.3, 23.7, 19.9, 13.8; HRMS (ESI) calcd for C16H19NNaO4+
[M + Na+] 312.1206, found 312.1206; IR (KBr) 2935, 1740, 1630, 1492,
1241, 764 cm−1.
2-Acetyl-3-hydroxy-N-(4-methoxyphenyl)-N-methylbut-2-enamide
(1o). 1o was purified by silica gel chromatography (30% EA/PE): yield
2.13 g, 81% (enol:ketone = 11:1), light yellow oil; 1H NMR
(600 MHz, CDCl3) major isomer 1o δ 16.07 (s, 1H), 7.07 (d, J =
9.0 Hz, 2H), 6.84 (d, J = 9.0 Hz, 2H), 3.79 (s, 3H), 3.41 (s, 3H), 2.09
(s, 6H), isomer 1o′ δ 7.23−6.93 (m, 4H, Harom, peak of three isomers
overlapped), 4.51 (s, 1H), 3.83 (s, 3H), 3.30 (s, 3H), 2.12 (s, 6H); 13C
NMR (150 MHz, CDCl3) δ 189.5, 168.3, 158.4, 136.5, 128.7, 127.0,
126.8, 115.3, 114.6, 113.3, 72.1, 55.5, 55.4, 37.7, 29.6, 23.7, 23.2; HRMS
(ESI) calcd for C14H17NNaO4+ [M + Na+] 286.1050, found 286.1055;
IR (KBr) 2946, 1635, 1577, 1488, 1208, 777 cm−1.
IV. General Procedure for the Synthesis of 2-Acetyl-3-
2-Acetyl-N-(4-chlorophenyl)-3-hydroxy-N-methylbut-2-enamide
(1p). 1p was purified by silica gel chromatography (30% EA/PE): yield
2.09 g, 78%, colorless oil; 1H NMR (600 MHz, CDCl3) δ 16.12 (s, 1H),
7.40 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 7.2 Hz, 2H), 3.43 (s, 3H), 2.07 (s,
6H); 13C NMR (150 MHz, CDCl3) δ 189.7, 168.0, 142.2, 132.9, 130.5,
129.6, 129.0, 127.1, 112.7, 37.4, 23.6; HRMS (ESI) calcd for
hydroxy-N-substituted Amide (1n−r).12a The acetoacetanilides
+
C13H1435ClNNaO3 [M + Na+] 290.0554, found 290.0555; IR (KBr)
3093, 1645, 1493, 1374, 1092, 854, 565 cm−1.
1-(3,4-Dihydroquinolin-1(2H)-yl)-2-(1-hydroxyethylidene)butane-
1,3-dione (1q). 1q was purified by silica gel chromatography (30%
EA/PE): yield 2.28 g, 88%, white solid, mp 80−82 °C; 1H NMR (600
MHz, CDCl3) δ 16.41 (s, 1H), 7.90−6.79 (m, 4H, Harom), 3.93 (m, 2H),
2.77 (m, 2H), 2.16−1.98 (m, 8H); 13C NMR (150 MHz, CDCl3) δ
190.6, 167.4, 138.1, 132.3, 128.7, 126.2, 125.2, 124.2, 113.2, 43.6, 27.2,
23.9, 23.5 (two carbon peaks were missing due to overlapping); HRMS
(ESI) calcd for C15H17NNaO3+ [M + Na+] 282.1101, found 282.1107;
IR (KBr) 2968, 1635, 1488, 1387, 754 cm−1.
were prepared by the known procedures.17 The novel acetoacetanilides
(So, Sq) thus obtained were characterized as follows.
N-(4-Methoxyphenyl)-N-methyl-3-oxobutanamide (So). The
amide was purified by silica gel chromatography (40% EA/PE): yield
69% (ketone:enol = 3.75:1), colorless oil; 1H NMR (600 MHz, CDCl3)
major isomer (ketone) δ 7.11 (d, J = 8.9 Hz, 2H), 6.92 (d, J = 8.9 Hz,
2H), 3.83 (s, 3H), 3.30 (s, 2H), 3.27 (s, 3H), 2.10 (s, 3H), minor isomer
(enol) δ 14.28 (s, 1H), 7.12 (m, 2H, peak of two isomers overlapped),
6.93 (m, 2H, peak of two isomers overlapped), 4.66 (s, 1H), 3.84 (s,
3H), 3.26 (s, 3H), 1.79 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 202.4,
172.1, 167.0, 159.2, 136.4, 128.5, 128.3, 115.0, 114.8, 88.9, 55.6, 49.9, 37.4,
36.4, 30.3, 21.6 (four carbon peaks were missing due to overlapping);
HRMS (ESI) calcd for C12H15NNaO3+ [M + Na+] 244.0944, found
244.0941; IR (KBr) 1655, 1514, 1423, 1357, 1108, 795 cm−1.
1-(3,4-Dihydroquinolin-1(2H)-yl)butane-1,3-dione (Sq). The amide
was purified by silica gel chromatography (30% EA/PE): yield 76%
(ketone:enol = 2:1), colorless oil; 1H NMR (600 MHz, CDCl3) major
isomer δ 7.20−7.06 (m, 4H, peak of two isomers overlapped), 3.81 (m,
2H, peak of two isomers overlapped), 3.69 (s, 2H), 2.72 (m, 2H, peak of
two isomers overlapped), 2.21 (s, 3H), 1.99 (m, 2H, peak of two isomers
overlapped), minor isomer δ 14.38 (s, 1H), 7.29 (d, J = 6.54 Hz, 1H),
7.18−7.06 (m, 3H, peak of two isomers overlapped), 5.37 (s, 1H), 3.81
(m, 2H, peak of two isomers overlapped), 2.72 (m, 2H, peak of two
isomers overlapped), 1.99 (m, 2H, peak of two isomers overlapped),
1.91 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 202.6, 174.9, 171.5, 166.5,
138.3, 133.3, 128.6, 128.6, 126.4, 126.0, 125.2, 124.9, 124.0, 89.2, 50.1, 42.8,
42.4, 30.4, 26.8, 26.7, 24.0, 24.0, 21.9 (three carbon peaks were missing due to
overlapping); HRMS (ESI) calcd for C13H15NNaO2+ [M + Na+] 240.0995,
found 240.0990; IR (KBr) 1716, 1651, 1579, 1444, 1157, 1029 cm−1.
To a suspension of anhydrous MgCl2 (952 mg, 10 mmol) and
acetoacetanilide (10 mmol) in DCM (35 mL) was added anhydrous
pyridine (1.61 mL, 20 mmol) at 0 °C. Stirring was continued at room
temperature for 45 min, and acetyl chloride (778 μL, 11 mmol) was
added to the mixture at 0 °C. The resulting mixture was stirred for
another 4 h at room temperature (the reaction was monitored by TLC).
Upon completion of the reaction, the mixture was treated with HCl
(1 N, 30 mL). The aqueous layer was extracted with DCM (40 mL × 3),
and the combined organic layer was washed with brine (100 mL), dried
over Na2SO4, and evaporated under reduced pressure to remove the
solvent. Purification of the crude oil by flash column chromatography on
silica gel (EA/PE) afforded the desired amides.
1-(6-Chloro-2H-benzo[b][1,4]oxazin-4(3H)-yl)-2-(1-hydroxyethyl-
idene)butane-1,3-dione (1r). 1r was purified by silica gel chromatog-
raphy (20% EA/PE): yield 1.98 g, 67%, white solid, mp 138−140 °C; 1H
NMR (600 MHz, DMSO) δ 16.26 (s, 1H), 8.22 (s, 1H), 7.12 (d, J = 8.4
Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 4.30 (m, 2H), 4.03 (m, 2H), 2.12 (s,
6H); 13C NMR (150 MHz, DMSO) δ 190.0, 166.3, 145.1, 126.1, 125.2,
123.2, 122.7, 118.4, 111.6, 65.8, 44.3, 30.1, 23.4 (one carbon peak was
+
missing due to overlapping); HRMS (ESI) calcd for C14H1435ClNNaO4
[M + Na+] 318.0504, found 318.0512; IR (KBr) 3039, 1650, 1492, 1384,
1045, 823, 740 cm−1.
V. Preparation of 3-Monofunctionalized 2-Oxindole Products
2. Anilide 1 (2 mmol) was dissolved in TFE (30 mL), and then a
solution of PIDA (711 mg, 2.2 mmol) in TFE (10 mL) was added
dropwise over 5 min. The reaction mixture was stirred at room
temperature for 40 min, then aqueous NaHCO3 (5 mL 144 mg, 6
mmol) was added, and the resulting mixture was stirred at room
temperature until TLC indicated the total consumption of anilide 1. The
solvent was removed under vacuum. The residue was extracted with EA
(50 mL), and the combined organic layer was washed with water (50 mL),
dried with anhydrous Na2SO4, and concentrated by a rotary evaporator.
The residue was purified by silica gel chromatography, using a mixture of
PE and EA as eluent, to give the desired product 2.
1-Methyl-2-oxoindoline-3-carbonitrile (2a). 2a was purified by
silica gel chromatography (30% EA/PE): yield 303.1 mg, 88%, white
solid, mp 95−97 °C; 1H NMR (600 MHz, CDCl3) δ 7.46 (d, J = 7.8 Hz,
1H), 7.41 (t, J = 7.8 Hz, 1H), 7.17 (t, J = 7.8 Hz, 1H), 6.90 (d, J = 7.8 Hz,
1H), 4.54 (s, 1H), 3.26 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 167.1,
143.8, 130.5, 124.8, 123.8, 120.1, 114.1, 109.3, 77.3, 77.1, 76.9, 36.6, 27.1.
1,5-Dimethyl-2-oxoindoline-3-carbonitrile (2b). 2b was purified by
silica gel chromatography (30% EA/PE): yield 331.4 mg, 89%, white
1
solid, mp 115−118 °C; H NMR (600 MHz, CDCl3) δ 7.26 (s, 1H),
7.21 (d, J = 8.4 Hz, 1H), 6.78 (d, J = 7.8 Hz, 1H), 4.51 (s, 1H), 3.23 (s,
3H), 2.36 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 167.0, 141.4, 133.7,
130.7, 125.5, 120.1, 114.2, 109.0, 36.7, 27.1, 21.0; HRMS (ESI) calcd for
C11H10N2NaO+ [M + Na+] 209.0685, found 209.0685; IR (KBr) 2947,
2211, 1625, 1558, 1531, 1308, 799 cm−1.
2-Acetyl-3-hydroxy-N-methyl-N-phenylbut-2-enamide (1n). 1n
was purified by silica gel chromatography (30% EA/PE): yield 1.82 g,
78%, light yellow oil; 1H NMR (600 MHz, CDCl3) δ 16.09 (s, 1H), 7.34
(t, J = 7.2 Hz, 2H), 7.33 (t, J = 7.2 Hz, 1H), 7.06 (d, J = 8.4 Hz, 2H), 3.45
(s, 3H), 2.09 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 189.7, 168.1,
143.7, 129.4, 127.3, 125.9, 113.2, 37.5, 23.8 (two carbon peaks were
5-Methoxy-1-methyl-2-oxoindoline-3-carbonitrile (2c). 2c was
purified by silica gel chromatography (30% EA/PE): yield 355.8 mg,
88%, white solid, mp 136−138 °C; 1H NMR (600 MHz, CDCl3) δ 7.05
(s, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 4.53 (s, 1H),
+
missing due to overlapping); HRMS (ESI) calcd for C13H15NNaO3
F
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3.81 (s, 3H), 3.23 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 166.7, 156.7,
2-Oxo-2,4,5,6-tetrahydro-1H-pyrrolo[3,2,1-ij]quinoline-1-carbon-
itrile (2j). 2j was purified by silica gel chromatography (30% EA/PE):
yield 348.8 mg, 88%, white solid, mp 160−165 °C; 1H NMR (600 MHz,
CDCl3) δ 7.27 (d, J = 7.5 Hz, 1H), 7.16 (d, J = 7.7 Hz, 1H), 7.04 (t, J =
7.6 Hz, 1H), 4.51 (s, 1H), 3.75 (m, 2H), 2.79 (m, 2H), 2.04 (m, 2H);
13C NMR (150 MHz, CDCl3) δ 166.0, 139.8, 129.1, 123.2, 122.5, 121.5,
119.0, 114.2, 39.8, 37.3, 24.2, 20.9; HRMS (ESI) calcd for
C12H10N2NaO+ [M + Na+] 221.0685, found 221.0684; IR (KBr)
2969, 2213, 1734, 1555, 1526, 1471, 1303, 743 cm−1.
Ethyl 1-Methyl-2-oxoindoline-3-carboxylate (2k). 2k was purified
by silica gel chromatography (40% EA/PE): yield 368.3 mg, 84%
(ketone:enol = 6:1), tan solid, mp 109−111 °C; 1H NMR (600 MHz,
CDCl3) major isomer (ketone) δ 7.35 (d, J = 7.2 Hz, 1H), 7.34(t, J = 8.4
Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 4.42 (s, 1H),
4.25 (m, 2H), 3.24 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H), minor isomer (enol)
δ 7.74 (m, 1H), 7.21−7.16 (m, 3H), 4.42 (m, 2H, peak of two isomers
overlapped), 3.62 (s, 3H), 1.45 (t, J = 7.2 Hz, 3H).
137.1, 121.2, 115.2, 114.1, 111.8, 109.8, 56.0, 37.0, 27.1; HRMS (ESI)
+
calcd for C11H10N2NaO2 [M + Na+] 225.0634, found 225.0635; IR
(KBr) 2945, 2218, 1689, 1562, 1487, 1268, 1230, 760 cm−1.
1-Benzyl-5-bromo-2-hydroxy-1H-indole-3-carbonitrile (2d). 2d
was purified by silica gel chromatography (30% EA/PE): yield Yield:
1
510.4 mg, 78%, white solid, mp 225−227 °C; H NMR (600 MHz,
DMSO) δ 7.44 (s, 1H), 7.33−7.18 (m, 7H, Harom), 5.27 (s, 2H); 13C
NMR (150 MHz, DMSO) δ 158.4, 136.6, 129.6, 128.7, 128.0, 127.5,
126.9, 123.4, 118.6, 115.8, 113.9, 112.0, 63.3, 44.3; HRMS (ESI) calcd
for C16H1179BrN2NaO+ [M + Na+] 348.9947, found 348.9947; IR (KBr)
2945, 2227, 1612, 1592, 1466, 1183, 800, 700 cm−1.
5-Chloro-2-hydroxy-1-methyl-1H-indole-3-carbonitrile (2e). 2e
was purified by silica gel chromatography (30% EA/PE): yield 264.4
mg, 64%, white solid, mp 195−199 °C; 1H NMR (400 MHz, DMSO) δ
12.80 (s, 1H, OH), 7.27 (d, J = 8.0 Hz, 1H), 7.25 (s, 1H), 7.07 (d, J = 12
Hz, 1H), 3.49 (s, 3H); 13C NMR (101 MHz, DMSO) δ 158.8, 130.4,
127.7, 126.5, 121.0, 116.3, 116.1, 111.4, 63.7, 28.3; HRMS (ESI) calcd
for C10H735ClN2NaO+ [M + Na+] 229.0139, found 229.0137; IR (KBr)
2948, 2218, 1618, 1561, 1531, 1472, 1276, 1108, 844, 798 cm−1.
2-Oxo-1-phenylindoline-3-carbonitrile (2f). 2f was purified by silica
gel chromatography (30% EA/PE): yield 412.3 mg, 88%, white solid,
Ethyl 1-Benzyl-5,6-dimethoxy-2-oxoindoline-3-carboxylate (2l). 2l
was purified by silica gel chromatography (40% EA/PE): yield 402.2 mg,
72% (ketone:enol = 9.6:1), tan solid, mp 142−145 °C; 1H NMR
(600 MHz, CDCl3) major isomer (ketone) δ 7.31−7.26 (m, 5H, Harom
,
peak of two isomers overlapped), 6.95 (s, 1H), 6.30 (s, 1H), 5.07−4.77
(m, 2H), 4.31−4.21 (m, 2H), 3.83 (s, 3H), 3.73 (s, 3H), 1.30 (t, J =
7.2 Hz, 3H), minor isomer (enol) δ 7.29−7.19 (m, 6H, Harom, peak of
two isomers overlapped), 6.65 (s, 1H), 5.20 (s, 2H), 4.44 (m, 2H, peak
of two isomers overlapped), 3.93 (s, 3H), 3.80 (s, 3H), 1.46 (t, J = 7.2
Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 171.3, 167.3, 150.2, 145.3,
137.6, 135.5, 128.8, 127.8, 127.7, 127.1, 126.9, 114.2, 109.4, 95.6, 62.1,
56.8, 56.6, 56.5, 56.3, 52.7, 45.1, 44.0, 14.6, 14.1; HRMS (ESI) calcd for
C20H21NNaO5+ [M + Na+] 378.1312, found 378.1311; IR (KBr) 2973,
1731, 1615, 1510, 1381, 1040, 731 cm−1.
1
mp 154−158 °C; H NMR (600 MHz, CDCl3) δ 7.55 (t, J = 7.8 Hz,
3H), 7.50 (d, J = 7.2 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 7.8 Hz,
2H), 7.33 (t, J = 7.8 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H), 6.82 (d, J = 8.4 Hz,
1H), 4.75 (s, 1H); 13C NMR (150 MHz, CDCl3) δ 166.4, 144.1, 133.4,
130.4, 130.0, 129.0, 126.5, 125.1, 124.2, 120.0, 113.9, 110.5, 37.1; HRMS
(ESI) calcd for C15H10N2NaO+ [M + Na+] 257.0685, found 257.0688;
IR (KBr) 2946, 2810, 2211, 1624, 1558, 1477, 1362, 1109, 760 cm−1.
1-Benzyl-2-oxoindoline-3-carbonitrile (2g). 2g was purified by silica
gel chromatography (30% EA/PE): yield 412.2 mg, 83%, white solid,
1
mp 127−130 °C; H NMR (600 MHz, CDCl3) δ 7.44−6.79 (m, 9H,
Ethyl 2-Oxo-2,4,5,6-tetrahydro-1H-pyrrolo[3,2,1-ij]quinoline-1-
carboxylate (2m). 2m was purified by silica gel chromatography
(30% EA/PE): yield 412.1 mg, 84% (ketone:enol = 8.35:1), tan solid,
mp 58−60 °C; 1H NMR (600 MHz, CDCl3) major isomer 2m δ 7.17 (d,
J = 7.2 Hz, 1H), 7.08 (d, J = 7.2 Hz, 1H), 6.96 (t, J = 7.2 Hz, 1H), 4.40 (s,
1H), 4.25 (m, 2H), 3.74 (t, J = 6.0 Hz, 2H), 2.77 (m, 2H), 2.02 (m, 2H),
1.30 (t, J = 7.2 Hz, 3H), minor isomer 2m′ δ 7.49 (d, J = 7.8 Hz, 1H),
7.09 (m, 1H, peak of two isomers overlapped), 6.88 (d, J = 7.8 Hz, 1H),
4.40 (m, 2H, peak of two isomers overlapped), 4.02 (t, J = 6.0 Hz, 2H),
2.93 (t, J = 6.0 Hz, 2H), 2.18 (m, 2H), 1.43 (t, J = 7.2 Hz, 3H); 13C NMR
(150 MHz, CDCl3) δ 169.6, 167.1, 140.5, 127.9, 122.3, 121.9, 121.0,
120.6, 119.0, 116.8, 84.6, 62.0, 59.9, 53.2, 40.0, 39.2, 24.5, 24.4, 22.0,
Harom), 4.94 (m, 2H), 4.63 (s, 1H); 13C NMR (150 MHz, CDCl3) δ
167.3, 143.0, 134.6, 130.4, 129.0, 128.2, 127.5, 124.9, 123.8, 120.2, 114.0,
110.2, 44.7, 36.7; HRMS (ESI) calcd for C16H12N2NaO+ [M + Na+]
271.0842, found 271.0843; IR (KBr) 2932, 2810, 2221, 1617, 1559,
1523, 1470, 1307, 743 cm−1.
1-Benzyl-6-fluoro-2-hydroxy-1H-indole-3-carbonitrile (2h) and
1-Benzyl-4-fluoro-2-hydroxy-1H-indole-3-carbonitrile (2h′). 2h and
2h′ were purified by silica gel chromatography (30% EA/PE): yield
261.0 mg, 49% (2h:2h′ = 2:1), white solid, mp 160−165 °C; 1H NMR
(600 MHz, DMSO) major isomer 2h δ 7.31−7.18 (m, 6H, Harom, peak
of two isomers overlapped), 7.04 (d, J = 5.4 Hz, 1H), 6.90 (t, J = 9.0 Hz,
1H), 5.28 (s, 2H, peak of two isomers overlapped), minor isomer 2h′ δ
7.31−7.18 (m, 7H, Harom, peak of two isomers overlapped), 6.97 (t, J =
9.0 Hz, 1H), 5.28 (s, 2H, peak of two isomers overlapped); 13C NMR
(150 MHz, DMSO) δ 158.2, 153.9 (d, JC−F = 243.3 Hz), 136.6, 133.1,
128.7, 127.5, 127.0, 126.9, 122.1, 121.6, 117.5, 116.2 (d, JC−F = 31.1 Hz),
113.4, 113.3, 109.0 (d, JC−F = 23.2 Hz), 107.1 (d, JC−F = 18.0 Hz), 106.7,
97.6 (d, JC−F = 25.3 Hz), 63.4, 60.7, 44.6, 44.4 (six carbon peaks were
missing due to overlapping and the extremely poor solubility in NMR
solvents); HRMS (ESI) calcd for C16H11FN2NaO+ [M + Na+]
289.0748, found 289.0744; IR (KBr) 2948, 2810, 2217, 1618, 1561,
1471, 1212, 1065, 844, 693 cm−1.
1-Benzyl-2-hydroxy-6-(trifluoromethyl)-1H-indole-3-carbonitrile
(2i) and 1-Benzyl-2-hydroxy-4-(trifluoromethyl)-1H-indole-3-
carbonitrile (2i′). 2i and 2i′ were purified by silica gel chromatography
(30% EA/PE): yield 272.0 mg, 43% (2i:2i′ = 1.2:1), white solid, mp
175−179 °C; 1H NMR (600 MHz, DMSO) isomer 2i δ 10.31 (s, 1H),
7.77 (s, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.44 (t, J =
8.4 Hz, 1H), 7.37−7.34 (m, 4H, Harom), 5.42 (s, 2H); isomer 2i′ δ 10.31
(s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.30−7.20 (m, 7H, Harom), 5.39 (s,
2H); 13C NMR (150 MHz, DMSO) δ 160.5, 159.7, 136.6, 136.5, 131.7,
+
21.1, 14.6, 14.1; HRMS (ESI) calcd for C14H15NNaO3 [M + Na+]
268.0944, found 268.0944; IR (KBr) 2993, 2943, 1713, 1509, 1452,
1320, 1083, 731, 686 cm−1.
3-Acetyl-1-methylindolin-2-one (2n). 2n was purified by silica gel
chromatography (30% EA/PE): yield 310.3 mg, 82%, white solid, mp
102−106 °C; 1H NMR (600 MHz, CDCl3) δ 13.62 (s, 1H), 7.34 (d, J =
8.4 Hz, 1H), 7.20 (t, J = 8.4 Hz, 1H), 7.08 (t, J = 8.4 Hz, 1H), 6.92 (d, J =
8.4 Hz, 1H), 3.30 (s, 3H), 2.41 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
172.9, 171.0, 138.9, 125.2, 122.2, 122.1, 119.7, 108.6, 101.8, 25.6, 20.3;
+
HRMS (ESI) calcd for C11H11NNaO2 [M + Na+] 212.0682, found
212.0682; IR (KBr) 3025, 1769, 1657, 1491, 1151, 977, 905, 748 cm−1.
(Z)-3-(1-Hydroxyethylidene)-5-methoxy-1-methylindolin-2-one
(2o). 2o was purified by silica gel chromatography (40% EA/PE): yield
1
377.0 mg, 86%, white solid, mp 132−137 °C; H NMR (600 MHz,
CDCl3) δ 13.75 (s, 1H), 6.92 (s, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.76 (d,
J = 8.4 Hz, 1H), 3.82 (s, 3H), 3.29 (s, 3H), 2.40 (s, 3H); 13C NMR (150
MHz, CDCl3) δ 173.1, 170.9, 155.7, 133.1, 123.3, 109.6, 108.4, 107.2,
+
102.0, 55.9, 25.7, 20.2; HRMS (ESI) calcd for C12H13NNaO3 [M +
Na+] 242.0788, found 242.0787; IR (KBr) 2939, 1658, 1589, 1474,
1263, 1145, 1035, 772 cm−1.
130.1, 129.6, 128.7, 128.7, 127.5, 127.5, 126.9, 126.8, 125.0 (q, JC−F
=
(Z)-5-Chloro-3-(1-hydroxyethylidene)-1-methylindolin-2-one
270.0 Hz), 124.4 (q, JC−F = 270.2 Hz), 121.5 (q, JC−F = 33.0 Hz), 120.0,
118.6 (q, JC−F = 3.4 Hz), 118.3 (q, JC−F = 3.3 Hz), 117.3 (q, JC−F = 30.0
Hz), 116.7, 115.9, 115.7, 114.0, 107.1, 107.1, 64.2, 44.4, 44.3 (one
carbon peak was missing due to overlapping); HRMS (ESI) calcd for
C17H11F3N2NaO+ [M + Na+] 339.0716, found 339.0718; IR (KBr)
3024, 2932, 2796, 2221, 1559, 1523, 1496, 1202, 997, 743 cm−1.
(2p). 2p was purified by silica gel chromatography (30% EA/PE): yield
1
335.4 mg, 75%, white solid, mp 130−132 °C; H NMR (600 MHz,
CDCl3) δ 13.70 (s, 1H), 7.28 (s, 1H), 7.17 (d, J = 8.4 Hz, 1H), 6.84 (d,
J = 8.4 Hz, 1H), 3.31 (s, 3H), 2.43 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 174.3, 170.8, 137.2, 127.5, 124.8, 123.6, 119.6, 109.1, 101.1,
+
25.7, 20.4; HRMS (ESI) calcd for C11H1035ClNNaO2 [M + Na+]
G
dx.doi.org/10.1021/jo4025539 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
246.0292, found 246.0292; IR (KBr) 1654, 1609, 1486, 1272, 1154,
808 cm−1.
(Z)-1-(1-Hydroxyethylidene)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]-
quinolin-2(4H)-one (2q). 2q was purified by silica gel chromatography
(30% EA/PE): yield 400.3 mg, 93%, light purple solid, mp 155−157 °C;
1H NMR (600 MHz, CDCl3) δ 13.49 (s, 1H), 7.18 (d, J = 7.2 Hz, 1H),
135.0, 133.6, 131.2, 130.8, 129.7, 128.4, 117.6, 117.1, 114.5, 113.7, 104.1,
104.1, 103.3, 98.2, 98.1, 64.9, 62.0, 60.9, 55.4, 55.3, 55.1, 53.5, 47.3, 47.0,
29.2, 19.7, 14.3, 14.0 (two carbon peaks were missing due to
+
overlapping); HRMS (ESI) calcd for C23H27NNaO7 [M + Na+]
452.1680, found 452.1681; IR (KBr) 2982, 1741, 1628, 1492, 1241,
1112, 678 cm−1.
Ethyl 1-(2,4-Dimethoxybenzyl)-5-methoxy-2-((triisopropylsilyl)-
oxy)-1H-indole-3-carboxylate (L). L was purified by silica gel
chromatography (5% EA/PE): yield 682.6 mg, 63%, colorless oil; H
NMR (600 MHz, CDCl3) δ 7.61 (s, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.70
(d, J = 8.4 Hz, 1H), 6.48 (d, J = 9.0 Hz, 1H), 6.46 (s, 1H), 6.26 (d, J = 8.4
Hz, 1H), 5.15 (s, 2H), 4.38 (m, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 3.72 (s,
3H), 1.49−1.43 (m, 6H), 1.07−1.05 (d, J = 7.8 Hz, 18H); 13C NMR
(150 MHz, CDCl3) δ 164.8, 160.0, 157.2, 155.5, 153.4, 127.3, 125.9,
125.8, 116.9, 110.0, 109.7, 104.0, 103.8, 98.1, 89.2, 58.9, 55.6, 55.2, 39.6,
17.8, 17.6, 14.7, 14.2.
7.00−6.95 (m, 2H), 3.83 (t, J = 6.0 Hz, 2H), 2.83 (t, J = 6.0 Hz, 2H), 2.42
(s, 3H), 2.06 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 172.8, 169.9,
134.9, 123.9, 121.7, 120.7, 120.4, 117.5, 102.6, 38.4, 24.7, 21.4, 20.2;
1
+
HRMS (ESI) calcd for C13H13NNaO2 [M + Na+] 238.0838, found
238.0838; IR (KBr) 2937, 1742, 1661, 1611, 1362, 1305, 1243, 1099,
747 cm−1.
(Z)-7-Chloro-6-(1-hydroxyethylidene)-2,3-dihydro[1,4]oxazino-
[2,3,4-hi]indol-5(6H)-one (2r). 2r was purified by silica gel chromatog-
raphy (30% EA/PE): yield 412.6 mg, 82% (enol:ketone = 5:1) white
solid, mp 153−154 °C; 1H NMR (600 MHz, CDCl3) isomer 2r δ 14.90
(s, 1H), 6.91 (d, J = 9.0 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 4.29 (t, J =
4.8 Hz, 2H), 3.95 (t, J = 4.8 Hz, 2H), 2.78 (s, 3H), isomer 2r′ δ 6.92 (d, J
= 8.4 Hz, 1H), 6.84 (d, J = 9.0 Hz, 1H), 4.64 (s, 1H), 4.27 (t, J = 4.8 Hz,
2H), 3.86−3.78 (m, 2H), 2.45 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
197.6, 178.4, 169.1, 167.4, 140.1, 140.0, 130.3, 124.7, 124.2, 123.2, 123.2,
121.7, 119.7, 117.7, 117.4, 113.0, 102.0, 64.8, 64.4, 61.4, 39.4, 38.6, 29.8,
24.8; HRMS (ESI) calcd for C12H1035ClNNaO3+ [M + Na+] 274.0241,
found 274.0243; IR (KBr) 1623, 1484, 1445, 1358, 1244, 1206,
1035, 770 cm−1.
ASSOCIATED CONTENT
* Supporting Information
■
S
Figures, tables, and a CIF file giving spectral data for all new
compounds and X-ray structural data of 2j. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: duyunfeier@tju.edu.cn (Y.D.); kangzhao@tju.edu.cn
(K.Z.).
■
VI. Preparation of Horsfiline Precursor L. Substrate K was
prepared according to the general procedure above.
Anilide K (859 mg, 2 mmol) was dissolved in MeCN (40 mL), and
then PIDA (711 mg, 2.2 mmol) powder was added in one portion. The
reaction mixture was stirred at room temperature for 20 min. Alcohol
(6 mL) and sodium acetate (1.64 g, 20 mmol) were then added, and the
resulting mixture was stirred at room temperature for 48 h. The solvent
was removed, and the residue was treated with water (40 mL) and
extracted with EA (30 mL × 3). The combined organic layer was dried
with anhydrous Na2SO4 and concentrated by a rotary evaporator. The
residue was dissolved in anhydrous DCM (8 mL). The solution was then
cooled to 0 °C, and TEA (836 μL, 6 mmol) was added followed by
TIPSOTf (538 μL, 2 mmol). The mixture was stirred at 0 °C for 10 min
before being quenched with water (15 mL) and extracted with DCM
(20 mL × 3). The combined organic layer was washed with water
(40 mL) and then dried with anhydrous Na2SO4. The solvent was
removed under vacuum, and the residue was purified by silica gel
chromatography, using a mixture of PE and EA as eluent, to give the
desired product L.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge the National Natural Science Foundation of
China (#21072148), Foundation (B) for Peiyang Scholar-Young
Core Faculty of Tianjin University (2013XR-0144), the
Innovation Foundation of Tianjin University (2013XJ-0005),
and the National Basic Research Project (2014CB932200) of the
MOST for financial support.
REFERENCES
■
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Ethyl 3-((2,4-Dimethoxybenzyl)(4-methoxyphenyl)amino)-3-oxo-
propanoate (J). J was purified by silica gel chromatography (40% EA/
PE): yield 85%, light yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.26 (d,
J = 8.4 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 8.8 Hz, 2H), 6.43
(d, J = 8.4 Hz, 1H), 6.32 (s, 1H), 4.87 (s, 2H), 4.13 (q, J = 7.2 Hz, 2H),
3.77 (s, 6H), 3.55 (s, 3H), 3.20 (s, 2H), 1.23 (t, J = 7.2 Hz, 3H); 13C
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131.1, 129.4, 117.6, 114.3, 104.2, 98.2, 61.1, 55.4, 55.3, 55.1, 47.0, 41.9,
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14.1; HRMS (ESI) calcd for C21H25NNaO6 [M + Na+] 410.1574,
found 410.1574; IR (KBr) 2959, 2838, 1738, 1660, 1511, 1400, 1249,
1036, 838 cm−1.
Ethyl 2-((2,4-Dimethoxybenzyl)(4-methoxyphenyl)carbamoyl)-3-
hydroxybut-2-enoate (K). K was purified by silica gel chromatography
1
(30% EA/PE): yield 78% (enol:ketone = 0.9:1), light yellow oil; H
NMR (600 MHz, CDCl3) isomer K δ 12.33 (s, 1H), 7.25 (d, J = 7.2 Hz,
1H), 6.87−6.82 (m, 2H, peak of two isomers overlapped), 6.69 (d, J =
7.8 Hz, 2H), 6.41 (t, J = 7.8 Hz, 2H), 5.06−4.80 (m, 2H, peak of two
isomers overlapped), 4.18−4.14 (m, 2H, peak of two isomers
overlapped), 3.77- 3.76 (m, 6H, peak of two isomers overlapped),
3.61 (s, 3H), 2.03 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H), isomer K′ δ 7.21
(d, J = 7.8 Hz, 1H), 6.87−6.82 (m, 2H, peak of two isomers overlapped),
6.78 (d, J = 8.4 Hz, 2H), 6.35 (m, 2H), 5.06−4.80 (m, 2H, peak of two
isomers overlapped), 4.35 (s, 1H), 4.18−4.14 (m, 2H, peak of two
isomers overlapped), 3.76 (s, 3H), 3.73 (s, 3H), 3.57 (s, 3H), 2.24
(s, 3H), 1.24 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 198.7,
173.8, 169.8, 166.2, 165.7, 164.4, 160.4, 160.2, 159.3, 158.5, 158.4, 158.4,
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(11) It was found that other bases, including Na2CO3 and NaOAc,
could also improve the reaction efficiency but gave relatively lower
yields.
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(13) When the E group was replaced with a methyl group, the
corresponding anilide substrate afforded no desired cyclized product
under the identical conditions. For our previous work describing this,
see ref 9.
(14) The cyclization reaction in entries 10 and 13 would lead to
decreased yields on treatment with NaHCO3 after the addition of PIDA.
(15) For details of the crude HRMS spectra of intermediate F′, please
see S93 in the Supporting Information.
(16) The reaction run in TFE gave product L in an inferior yield of
37%.
(17) For the preparation of 2-functionalized acetanilide derivatives
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I
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