Cobalt(III)-catalyzed fast and solvent-free C-H allylation of indoles using mechanochemistry

Article abstract of DOI:10.1021/acs.joc.7b01695

Mechanochemical conditions have been applied to a highly efficient cobalt(III)-catalyzed C-H bond activation for the first time. In a subsequent step to the olefin insertion and β-oxygen elimination, N-pyrimidinylindoles were allylated with vinylethylene carbonates in the absence of organic solvent under high-speed ball-milling condition. As the reaction afforded the desired products in up to 98% yields within a short time, this method constitutes an environmentally friendly and powerful alternative to the common solution-based approaches.

Full text of DOI:10.1021/acs.joc.7b01695

Note
pubs.acs.org/joc
Cobalt(III)-Catalyzed Fast and Solvent-Free C−H Allylation of Indoles
Using Mechanochemistry
Xinpeng Jiang,† Jinkang Chen,† Weijie Zhu,† Kang Cheng,† Yong Liu,† Wei-Ke Su,‡
and Chuanming Yu*,†,‡
‡
†College of Pharmaceutical Sciences and Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals,
Zhejiang University of Technology, Hangzhou 310014, P.R. China
S
* Supporting Information
ABSTRACT: Mechanochemical conditions have been applied to a highly efficient cobalt(III)-catalyzed C−H bond activation
for the first time. In a subsequent step to the olefin insertion and β-oxygen elimination, N-pyrimidinylindoles were allylated with
vinylethylene carbonates in the absence of organic solvent under high-speed ball-milling condition. As the reaction afforded the
desired products in up to 98% yields within a short time, this method constitutes an environmentally friendly and powerful
alternative to the common solution-based approaches.
1a).21 Subsequently, in 2016, the same group reported Ir(III)-
he presence of an allylic alcohol building block offers the
catalyzed mechanochemical C−H bond amidation of benza-
Tmolecule tremendous potential for further modification
and great opportunity to transform into a wide variety of
pharmaceutical and biologically active compounds.1 The
integration of allylic alcohol into a privileged scaffold, such as
indole, is of great interest.2 However, traditional synthesis of
allylic aromatic compounds bearing a hydroxyl group at the
allylic position is realized by nucleophilic ring opening of vinyl
epoxides with organometallic reagents, which is restricted by
narrow substrate scope and limited functional group compat-
ibility.3 Over the past decades, noble transition metals such as
rhodium-,4,5 iridium-,6 palladium-,7 and ruthenium8-catalyzed
directed C−H activation have received increasing attention.9
Recently, cost-effective Cp*Co(III) complexes have also been
identified as powerful catalysts in C−H activation, as reported
by Matsunaga and Kanai,10 Ackermann,11 Ellman,12 Glorius,13
Jiao,14 Li,15 Maji,16 Wang,17 Zhang,18 and others.19 Therefore,
transition-metal-catalyzed coupling reactions have been devel-
oped as a new strategy to synthesize allylic aromatic scaffolds.
For instance, Wang4b and Kim4c developed Rh(III)-catalyzed
C−H directed allylation with 4-vinyl-1,3-dioxolan-2-ones. Li
and co-workers developed Rh(III)-4a and Co(III)15a-catalyzed
C−C couplings of arenes with 2-vinyloxirane. However, the
usage of toxic solvents, such as 1,2-dichloroethane (DCE), and
relative long reaction time (typically over 10 h) are still posing
potential limitations for the wide application of such methods.
In recent years, the application of mechanochemistry,
especially ball-milling reaction, has successfully drawn much
attention.20 Bolm and co-workers first reported the Rh(III)-
catalyzed C−H functionalization of acetanilides with acrylate
under solventless conditions in a ball-mill machine (Scheme
Scheme 1. Mechanochemical Functionalization of Arenes in
Ball Mills
mides with sulfonyl azides (Scheme 1b).22 Compared to the
traditional solvent reaction system, ball-milling reactions are
believed to significantly improve the reaction efficiency.23
Inspired by these continuous findings as well as our ongoing
studies of mechanochemistry,24 we herein report a solvent-free
ball-milling approach to synthesize allylic alcohol-substituted
Received: July 6, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.7b01695
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The Journal of Organic Chemistry
Note
indoles more environmentally friendly and efficiently. As far as
we know, this is the first example of Co(III)-catalyzed C−H
bond activation using mechanochemistry (Scheme 1c).
At the commencement, N-pyrimidinylindole 1a was chosen
for primary reaction optimization (Table 1). Considering the
benzyloxy (3g) groups at different positions, all coupled with
vinylethylene carbonate efficiently, and the corresponding
products were obtained in 81−93% yields. The introduction
of a cyano group inhibited the reaction as a result of its
coordination with cobalt complex and lower electron density
on the indole ring (3h). The indoles substituted by the
different type of halogens, such as fluorine, chlorine, and
bromine, at various positions could also give the corresponding
product (3i−3o) in good yields. To extend the scope of this
methodology further, fourth position substituted vinylethylene
carbonates 2b and 2c were synthesized and subjected to the
reaction. We were pleased to find that the corresponding
products 3p and 3q were obtained in excellent yields under
standard reactions condition (Scheme 3). Scaling up of the
model reaction to gram level still gave 94% of 3a, which was
obtained using 0.8 mol % catalytic system and prolonged
grinding time to 60 min (Scheme 4).
a
Table 1. Reaction Optimization
b
entry
catalyst (mol %)
additive
yield of 3a (%)
c
1
Cp*Co(MeCN)3[SbF6]2 (5)
Cp*Co(MeCN)3[SbF6]2 (5)
Cp*Co(MeCN)3[SbF6]2 (5)
Cp*Co(MeCN)3[SbF6]2 (5)
Cp*Co(MeCN)3[SbF6]2 (5)
Cp*Co(MeCN)3[SbF6]2 (5)
Cp*Co(MeCN)3[SbF6]2 (2.5)
CoCl2 (5)
CsOAc
CsOAc
72
92
79
97
98
98
69
0
2
3
4
KOAc
To gain insight into the reaction mechanism, a set of control
experiments were carried out (Scheme 5). When substrate 1a
and CD3OD were subjected to the optimized ball-milling
conditions, H/D scrambling at C-2 and C-3 positions indicated
an organometallic mode of C−H activation (Scheme 5a).
Intermolecular competition experiments of different substituted
N-pyrimidinylindoles revealed a reactivity for the electron-poor
substrate 1i lower than that of the electron-rich 1e. The
5
NaOAc
AgOAc
NaOAc
NaOAc
NaOAc
KOAc
6
7
8
9
Co(acac)2 (5)
0
10
[(p-cymene)RuCl2]2 (2.5)
AgSbF6 (5)
29
a
Unless otherwise noted, all reactions were carried out with 1a (0.6
1
reaction shows 3e and 3i in a 1.9:1 ratio (determined by H
mmol), 2 (1.2 mmol), [Cp*Co(MeCN)3][SbF6]2 (0.03 mmol, 5 mol
%), additives (0.12 mmol, 20 mol %), using stainless steel grinding
balls (4 mm diameter × 36) in a 45 mL stainless steel vial. Cp* =
NMR analysis), indicating cationic cobalt species acted as
electrophiles in the C−H activation process (Scheme 5b). In
addition, the competitive coupling of an equimolar mixture of
1a and 1a-[D] with vinylethylene carbonate determined by the
initial rate gave a kinetic isotope effect (KIE) value of KH/KD =
1.9 under solvent-free mechanochemical conditions. These
findings indicated a base-assisted internal electophilic sub-
stitution (BIES)-type C−H functionalization26 (Scheme 5c).
b
pentamethyl cyclopentadienyl. Isolated yield. All cases provided 2.5:1
c
to 3:1 of Z/E ratio, which were determined by 1H NMR. Balls (6 mm
diameter × 16) at 600 rpm were used.
practicability, inexpensive vinylethylene carbonate (VEC),
which is widely used as a film-forming additive in lithium-ion
batteries, was used as allylation reagent in place of 2-
vinyloxirane. Owing to the inert nature of VEC, monomeric
Co(III) catalyst [Cp*Co(MeCN)3][SbF6]2 (5 mol %) along
with CsOAc (20 mol %) was used to establish the module
reaction. To our delight, 72% of 2-allylated N-pyrimidinylindole
3a was obtained after 30 min grinding at 800 rpm (entry 1).
Smaller balls (4 mm × 36) and higher rotational speed (800
rpm) improved the yield to 92% (entry 2). In the absence of
additive, only 79% of 3a was isolated under the same condition,
indicating the important presence of acetates (entry 3). Several
additives were also examined. It turned out that NaOAc and
AgOAc gave the highest isolated yields (entries 4−6).
Decreasing the loading of [Cp*Co(MeCN)3][SbF6]2 to 2.5
mol %, the yield of 3a dropped to 69% (entry 7). When low-
valent cobalt catalysts Co(acac)2 and CoCl2 were used, 3a was
not detected (entries 9 and 10). Other transition metal
catalysts, such as [(p-cymene)RuCl2]2, produced only 29% of
3a (entry 10). In some cases, such as 3j, AgOAc gave higher
yield (95%) than NaOAc (47%). Therefore, the optimized
reaction conditions were 1 (0.6 mmol), 2 (2 equiv),
[Cp*Co(MeCN)3][SbF6]2 (5 mol %), AgOAc (20 mol %),
and silica gel placed in a 45 mL of stainless steel vial with
stainless steel grinding balls (4 mm diameter × 36) and ball-
milling at 800 rpm for 30 min.25
Based on our mechanistic studies and previous literature,27
a
tentative mechanism has been proposed for this reaction
(Scheme 6). Initially, a cationic cobalt(III) acetate complex I
was generated upon treatment of Cp*Co(MeCN)3[SbF6]2 with
AgOAc. C−H activation at 2-position of indole took place
under the assistance of pyrimidine group leading to a five-
member metal acyclic intermediate II with the elimination of
HOAc. Then vinylethylene carbonate coordinated to the Co
center of II and subsequently generated seven-member
intermediate IV. Subsequently, β-oxygen elimination occurred
to form intermediate V with new double bond bearing an allylic
hydroxyl group while releasing CO2. Protonolysis of
intermediate V regenerated the active cobalt complex and
afforded the desired product.
In summary, by using vinylethylene carbonate as a coupling
partner, we have developed a cobalt(III)-catalyzed mechano-
chemical process for the allylation of indoles under solvent-free
conditions. Mechanochemical strategy possesses two significant
aspects compared to solvent-based methods: first, these
reactions were conducted under solvent-free conditions, kept
away from the usage of highly toxic solvents. Second, high-
speed ball-milling could significantly reduce reaction time (only
30 min) without external heating by contrast to the similar
reactions under solvent condition (typically over 10 h). In view
of these advantages, the applications of such a reaction to
achieve the facile synthesis of bioactive compounds are
currently underway.
With the optimized conditions in hand, the scopes and
limitations of this reaction were then investigated (Scheme 2).
To our delight, N-pyrimidinylindoles bearing electron-donating
groups, including methyl (3b−d), methoxy (3e and 3f), and
B
DOI: 10.1021/acs.joc.7b01695
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Note
a
Scheme 2. Co(III)-Catalyzed C−H Allylation with Vinylethylene Carbonate 2a
a
1
Isolated yield. Z/E ratios were determined by H NMR.
solvent indicated. Chemical shifts are reported downfield from TMS
EXPERIMENTAL SECTION
■
1
(=0) or CDCl3 (=7.26) for H NMR. For 13C NMR, chemical shifts
General Information. All chemicals were obtained from
are reported in the scale relative to CDCl3 (=77.0). Mass spectra were
measured with a low-resolution MS instrument using ESI ionization.
HRMS spectra were recorded on an electrospray ionization quadru-
pole time-of-flight (ESI-Q-TOF) mass spectrometer. Unless otherwise
noted, materials obtained from commercial suppliers were used
without further purification.
General Procedures for the Synthesis of Compound 3. N-
Pyrimidinylindole 1 (0.6 mmol), vinylethylene carbonate 2 (1.2
mmol), [Cp*Co(MeCN)3][SbF6]2 (0.03 mmol, 5 mol %), AgOAc
(0.12 mmol, 20 mol %), and silica gel (600 mg, grinding auxiliary)
commercial soures and were used as received unless otherwise
noted. N-Pyrimidine indole,28 vinylethylene carbonates 2b and 2c,29
1a-[D]1,30 [Cp*Co(CO)I2],10b and [Cp*Co(MeCN)3][SbF6]2
15a
were prepared by following literature reports. All reactions were
performed using grinding vessels in a FRITSCH Planetary micro mill
model “Pulverisette 7 premium line”. Both vessels (45 mL) and balls
were made of stainless steel. Column chromatography was performed
on silica gel (300−400 mesh) using ethyl acetate (EA)/hexane (Hex).
NMR spectra were recorded on a 600 MHz NMR spectrometer in the
C
DOI: 10.1021/acs.joc.7b01695
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The Journal of Organic Chemistry
Note
Scheme 3. Co(III)-Catalyzed C−H Allylation with Substituted Vinylethylene Carbonates
Scheme 4. Gram-Scale Reaction
Scheme 5. Mechanistic Studies
were transferred to a ball-milling vessel (stainless steel, 45 mL) loaded
with 36 grinding balls (stainless steel, 4 mm diameter). The milling
vessel was placed in the ball mill (800 rpm, 30 min). The crude
product was collected by washing the vessel and the balls with EtOAc
(3 × 20 mL). The mixture was concentrated in vacuum and purified
by flash chromatography (Hexane/EtOAc = 4:1 to 1:1).
s, 1H); 13C NMR (151 MHz, CDCl3) major isomer δ 158.1, 158.1,
139.6, 137.0, 131.0, 129.5, 129.1, 122.7, 121.8, 119.8, 117.1, 113.7,
106.4, 63.4, 32.4; minor isomer δ 139.6, 137.0, 130.1, 129.1, 122.8,
121.9, 113.8, 106.3, 58.6, 28.1; HRMS (ESI) m/z calcd for
C16H16N3NaO [M + Na]+ 288.1107, found 288.1100.
Gram-Scale Synthesis of 3a: N-Pyrimidinylindole 1a (1.062 g, 5.4
mmol), vinylethylene carbonate 2a (1.232 g, 10.8 mmol), [Cp*Co-
(MeCN)3][SbF6]2 (32.3 mg, 0.0043 mmol, 0.8 mol %), AgOAc (28.8
mg, 0.173 mmol, 3.2 mol %), and silica gel (2.000 g, grinding auxiliary)
were transferred to a ball-milling vessel (stainless steel, 45 mL) loaded
with 36 grinding balls (stainless steel, 4 mm diameter). The milling
vessel was placed in the ball mill (800 rpm, 30 min ×2 + 10 min
4-(1-(Pyrimidin-2-yl)-1H-indol-2-yl)but-2-en-1-ol (3a). Product 3a
1
was obtained as a colorless oil (156.0 mg, 98%, E/Z = 2.8:1 by H
1
NMR): H NMR (600 MHz, CDCl3) δ 8.77 (d, J = 4.4 Hz, 2H),
8.27−8.21 (m, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.25−7.16 (m, 2H), 7.14
(t, J = 4.4 Hz, 1H), 6.48 (s, 1H), 5.88−5.61 (m, 2H), 4.25 (d, J = 6.0
Hz, 0.52H), 4.03 (d, J = 5.6 Hz, 1.48H), 3.99−3.92 (m, 2H), 1.48 (br
D
DOI: 10.1021/acs.joc.7b01695
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The Journal of Organic Chemistry
Note
Scheme 6. Proposed Mechanism
break). The crude product was collected by washing the vessel and the
balls with EtOAc (3 × 40 mL). The mixture was concentrated in
vacuum and purified by flash chromatography (Hexane/EtOAc = 4:1
to 1:1) to afford 3a as a colorless oil (1.349g, 94%, Z/E = 2.6/1 by 1H
NMR).
2H), 2.47 (s, 3H), 1.56 (br s, 1H); 13C NMR (151 MHz, CDCl3)
major isomer δ 158.2, 158.1, 138.9, 137.4, 132.6, 130.8, 129.8, 126.9,
123.3, 119.4, 117.0, 113.7, 106.3, 63.4, 32.4, 22.0; minor isomer δ
139.0, 137.4, 132.6, 130.0, 129.3, 126.9, 123.4, 119.4, 117.0, 113.8,
106.2, 58.6, 28.1; HRMS (ESI) m/z calcd for C17H17N3NaO [M +
Na]+ 302.1264, found 302.1271.
4-(3-Methyl-1-(pyrimidin-2-yl)-1H-indol-2-yl)but-2-en-1-ol (3b).
Product 3b was obtained as a colorless oil (135.8 mg, 81%, E/Z =
4-(5-Methoxy-1-(pyrimidin-2-yl)-1H-indol-2-yl)but-2-en-1-ol (3e).
1
1
2.8:1 by H NMR): H NMR (600 MHz, CDCl3) δ 8.73 (d, J = 4.8,
2H), 8.25−8.21 (m, 1H), 7.54−7.51 (m, 1H), 7.25−7.18 (m, 2H),
7.07 (t, J = 4.8 Hz, 1H), 5.76−5.44 (m, 1H), 4.18 (d, J = 5.8 Hz,
0.52H), 3.96 (d, J = 5.9 Hz, 0.52H), 3.93 (d, J = 6.0 Hz, 1.48H), 3.88
(d, J = 5.9 Hz, 1.48H), 2.29 (s, 3H), 1.51 (br s, 1H); 13C NMR (151
MHz, CDCl3) major isomer δ 158.1, 136.1, 134.0, 130.2, 129.9, 129.7,
128.6, 122.9, 121.4, 118.0, 116.8, 113.3, 113.3, 63.3, 28.9, 8.8; minor
isomer δ 158.0, 136.2, 134.5, 130.2, 129.8, 123.0, 121.5, 118.0, 116.8,
113.6, 113.4, 58.5, 25.0, 8.8. The NMR data were consistent with those
in a literature report.31
Product 3e was obtained as a colorless oil (150.6 mg, 85%, E/Z = 3.2:1
1
1
by H NMR): H NMR (600 MHz, CDCl3) δ 8.67 (d, J = 3.7 Hz,
2H), 8.20−8.15 (m, 1H), 7.02−6.97 (m,2H), 6.87−6.84 (m, 1H), 6.39
(s, 1H), 5.85−5.57 (m, 2H), 4.20 (d, J = 5.8 Hz, 0.48H), 3.98 (d, J =
5.8 Hz, 1.52H), 3.95−3.88 (m, 2H), 3.82 (s, 3H), 2.37 (br s, 1H); 13C
NMR (151 MHz, CDCl3) major isomer δ 157.8, 157.8, 155.1, 140.3,
131.7, 130.9, 129.7, 129.0, 116.7, 114.7, 111.3, 106.2, 102.1, 62.9, 55.5,
32.5; minor isomer δ 157.8, 155.4, 140.3, 132.0, 130.1, 129.7, 128.5,
116.6, 114.9, 111.4, 106.1, 102.1, 58.2, 28.2; MS (ESI) m/z (relative
intensity) 296.2 (100) [M + H]+, 318.2 (69) [M + Na]+. The NMR
data agree with those in a literature report.31
4-[5-Methyl-1-(pyrimidin-2-yl)-1H-indol-2-yl]but-2-en-1-ol (3c).
Product 3c was obtained as a colorless oil (155.9 mg, 93%, E/Z =
4-(6-Methoxy-1-(pyrimidin-2-yl)-1H-indol-2-yl)but-2-en-1-ol (3f).
1
1
2.8:1 by H NMR): H NMR (600 MHz, CDCl3) δ 8.70 (d, J = 4.8
Hz, 2H), 8.20−8.14 (m, 1H), 7.33 (s, 1H), 7.07 (d, J = 8.4 Hz, 1H),
7.04−6.99 (m, 1H), 6.40 (s, 1H), 5.85−5.58 (m, 2H), 4.21 (d, J = 6.1
Hz, 0.47H), 3.98 (d, J = 5.3 Hz, 1.53H), 3.96−3.87 (m, 2H), 2.46 (s,
3H), 2.26 (br s, 1H); 13C NMR (151 MHz, CDCl3) major isomer δ
157.90, 157.9, 139.6, 135.2, 131.0, 130.8, 129.4, 129.3, 124.0, 119.6,
116.8, 113.5, 106.2, 63.1, 32.5, 21.2; minor isomer δ 158.0, 139.6,
135.2, 131.1, 130.0, 129.4, 128.7, 124.0, 116.7, 113.7, 106.0, 58.4, 28.1;
HRMS (ESI) m/z calcd for C17H17N3NaO [M + Na]+ 302.1264,
found 302.1269.
Product 3f was obtained as a colorless oil (159.5 mg, 90%, E/Z = 3.3:1
1
1
by H NMR): H NMR (600 MHz, CDCl3) δ 8.76 (d, J = 4.8 Hz,
2H), 7.91−7.86 (m, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.11 (t, J = 4.8 Hz,
1H), 6.85 (d, J = 8.5 Hz, 1H), 6.39 (s, 1H), 5.85−5.58 (m, 2H), 4.23
(d, J = 6.0 Hz, 0.46H), 4.01 (d, J = 6.7 Hz, 1.54H), 3.96−3.88 (m,
2H), 3.86 (s, 3H), 1.66 (br s, 1H); 13C NMR (151 MHz, CDCl3)
major isomer 158.2, 158.1, 156.8, 138.6, 137.9, 130.8, 129.7, 123.3,
120.1, 116.9, 110.6, 106.3, 99.0, 63.3, 55.8, 32.5; minor isomer δ 138.6,
137.9, 130.0, 129.3, 123.3, 120.0, 116.9, 110.5, 106.2, 99.2, 58.5, 28.2;
HRMS (ESI) m/z calcd for C17H17N3NaO2 [M + Na]+ 318.1213,
found 318.1221.
4-(6-Methyl-1-(pyrimidin-2-yl)-1H-indol-2-yl)but-2-en-1-ol (3d).
Product 3d was obtained as a colorless oil (159.2 mg, 95%, E/Z =
4-(4-(Benzyloxy)-1-(pyrimidin-2-yl)-1H-indol-2-yl)but-2-en-1-ol
1
1
3.7:1 by H NMR): H NMR (600 MHz, CDCl3) δ 8.79 (d, J = 4.8,
2H), 8.07−8.03 (m, 1H), 7.40 (d, J = 7.9 Hz, 1H), 7.14 (t, J = 4.8 Hz,
1H), 7.01 (d, J = 7.9 Hz, 1H), 6.42 (s, 1H), 5.88−5.61 (m, 2H), 4.25
(d, J = 6.2 Hz, 0.43H), 4.03 (d, J = 6.7 Hz, 1.57H), 3.98−3.89 (m,
(3g). Product 3g was obtained as a colorless oil (193.9 mg, 87%, E/Z =
1
1
4.6:1 by H NMR): H NMR (600 MHz, CDCl3) δ 8.74 (d, J = 4.8
Hz, 2H), 7.91−7.85 (m, 1H), 7.53 (d, J = 7.2 Hz, 2H), 7.44−7.40 (m,
2H), 7.38−7.34 (m, 1H), 6.73−6.67 (m, 2H), 5.85−5.59 (m, 2H),
E
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Note
5.23 (s, 2H), 4.21 (d, J = 6.4 Hz, 0.36H), 3.99 (d, J = 5.7 Hz, 1.64H),
3.96−3.90 (m, 2H), 1.95 (br s, 1H); 13C NMR (151 MHz, CDCl3)
major isomer δ 158.2, 158.1, 151.6, 138.5, 138.3, 137.5, 131.1, 129.4,
128.6, 127.9, 127.5, 123.5, 119.8, 117.4, 107.3, 103.7, 103.5, 70.1, 63.3,
32.5; minor isomer δ 151.5, 138.5, 138.3, 137.5, 130.3, 128.9, 127.5,
123.5, 117.3, 107.5, 103.8, 103.3, 58.5, 28.1; HRMS (ESI) m/z calcd
for C23H21N3NaO2 [M + Na]+ 394.1526, found 394.1524.
1H), 7.09−7.04 (m, 1H), 6.53 (s, 1H), 5.85−5.60 (m, 2H), 4.23 (d, J
= 5.2 Hz, 0.37H), 4.02 (d, J = 5.1 Hz, 1.63H), 3.96−3.89 (m, 2H),
1.79 (br s, 1H); 13C NMR (151 MHz, CDCl3) major isomer δ 158.2,
157.7, 140.5, 137.1, 131.4, 129.5, 128.6, 124.6, 123.5, 117.6, 113.6,
112.8, 105.9, 63.2, 32.4; minor isomer δ 140.6, 137.2, 130.5, 129.5,
128.3, 124.6, 123.5, 117.6, 112.9, 105.8, 58.4, 28.0; MS (ESI) m/z
(relative intensity) 366.2 (100) [M + Na]+. The NMR data agree with
those in a literature report.31
4-(5-Bromo-1-(pyrimidin-2-yl)-1H-indol-2-yl)but-2-en-1-ol (3n).
Product 3n was obtained as a pale yellow oil (183.8 mg, 89%, E/Z
= 4.0:1 by 1H NMR): 1H NMR (600 MHz, CDCl3) δ 8.69 (d, J = 4.7
Hz, 2H), 8.27−8.13 (m, 1H), 7.61−7.56 (m, 1H), 7.29−7.24 (m, 1H),
7.09−7.05 (m, 1H), 6.35 (s, 1H), 5.80−5.55 (m, 2H), 4.18 (d, J = 4.7
Hz, 0.4H), 3.97 (d, J = 5.4 Hz, 1.6H), 3.91−3.80 (m, 2H), 2.26 (br s,
1H); 13C NMR (151 MHz, CDCl3) major isomer δ 158.2, 157.7,
141.2, 135.7, 131.4, 130.9, 128.7, 125.3, 122.3, 117.5, 115.5, 115.0,
105.6, 63.1, 32.5; minor isomer δ 130.6, 128.4, 125.4, 117.5, 115.7,
115.0, 105.5, 58.4, 28.2; HRMS (ESI) m/z calcd for C16H14N3BrNaO
[M + Na]+ 366.0212, found 366.0220.
2-(4-Hydroxybut-2-en-1-yl)-1-(pyrimidin-2-yl)-1H-indole-5-car-
bonitrile (3h). Product 3h was obtained as a colorless sticky oil (48.8
1
1
mg, 28%, E/Z = 2.6:1 by H NMR): H NMR (600 MHz, CDCl3) δ
8.85 (d, J = 4.8, 2H), 8.29−8.23 (m, 1H), 7.85−7.83 (m, 1H), 7.46−
7.43 (m, 1H), 7.31−7.25 (m, 1H), 6.53 (s, 1H), 5.86−5.63 (m, 2H),
4.26 (d, J = 6.3 Hz, 0.55H), 4.06 (d, J = 5.8 Hz, 1.45H), 3.99−3.92 (m,
2H), 1.61 (br s, 1H); 13C NMR (151 MHz, CDCl3) major isomer δ
158.4, 157.4, 142.3, 138.7, 131.7, 128.9, 128.3, 125.7, 124.7, 120.4,
118.2, 114.5, 105.9, 104.7, 63.2, 32.3; minor isomer δ 138.7, 130.8,
128.0, 125.8, 120.3, 118.1, 114.6, 105.8, 104.8, 58.5, 28.0; HRMS
(ESI) m/z calcd for C17H14N4NaO [M + Na]+ 313.1060, found
313.1062.
4-(5-Fluoro-1-(pyrimidin-2-yl)-1H-indol-2-yl)but-2-en-1-ol (3i).
4-(6-Bromo-1-(pyrimidin-2-yl)-1H-indol-2-yl)but-2-en-1-ol (3o).
Product 3i was obtained as a white solid (161.6 mg, 90%, E/Z =
Product 3o was obtained as a colorless oil (179.6 mg, 87%, E/Z =
1
1
1
1
2.7:1 by H NMR): mp 94−96 °C; H NMR (600 MHz, CDCl3) δ
8.74 (d, J = 4.8 Hz, 2H), 8.27−8.15 (m, 1H), 7.16 (d, J = 9.0 Hz, 1H),
7.12 (t, J = 4.8 Hz, 1H), 6.94 (t, J = 9.1 Hz, 1H), 6.42 (s, 1H), 5.86−
5.61(m, 2H), 4.23 (d, J = 5.3 Hz, 0.54H), 4.02 (d, J = 5.8 Hz, 1.46H),
3.97−3.90 (m, 2H), 1.83 (br s, 1H); 13C NMR (151 MHz, CDCl3)
major isomer δ 158.7 (d, JC−F = 269.2 Hz), 158.1, 158.0, 141.4, 133.4,
131.2, 129.8 (d, JC−F = 10.0 Hz), 129.0, 117.2, 114.8 (d, JC−F = 9.1
Hz), 110.3 (d, JC−F = 25.0 Hz), 106.2 (d, JC−F = 4.0 Hz), 105.0 (d, JC−F
= 23.5 Hz), 63.2, 32.6; minor isomer δ 130.3, 128.6, 117.2, 115.0 (d,
JC−F = 9.1 Hz), 110.3 (d, JC−F = 24.9 Hz), 106.0 (d, JC−F = 3.9 Hz),
58.4, 28.2; HRMS (ESI) m/z calcd for C16H14N3FNaO [M + Na]+
306.1013, found 306.1021.
3.5:1 by H NMR): H NMR (600 MHz, CDCl3) δ 8.77 (d, J = 4.8
Hz, 2H), 8.48−8.44 (m, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.30−7.27 (m,
1H), 7.15 (t, J = 4.8 Hz, 1H), 6.43 (s, 1H), 5.86−5.61 (m, 2H), 4.24
(d, J = 4.6 Hz, 0.44H), 4.03 (d, J = 5.5 Hz, 1.56H), 3.96−3.89 (m,
2H), 1.51 (br s, 1H); 13C NMR (151 MHz, CDCl3) major isomer δ
158.2, 157.8, 140.4, 137.6, 131.2, 129.1, 128.0, 125.0, 120.8, 117.4,
116.9, 116.3, 106.2, 63.3, 32.5; minor isomer 137.6, 130.4, 128.7,
125.0, 117.4, 117.1, 116.3, 106.1, 58.5, 28.2; HRMS (ESI) m/z calcd
for C16H14BrN3NaO [M + Na]+ 366.0212, found 366.0206.
2-Phenyl-4-(1-(pyrimidin-2-yl)-1H-indol-2-yl)but-2-en-1-ol (3p).
Product 3p was obtained as a yellow oil (200.5 mg, 98%, E/Z =
1
1
4.0:1 by H NMR): H NMR (600 MHz, CDCl3) δ 8.74 (d, J = 4.8
Hz, 0.4H), 8.66 (d, J = 4.8 Hz, 1.6H), 8.28 (d, J = 8.3 Hz, 0.2H), 8.19
(d, J = 8.4 Hz, 1.8H), 7.52 (d, J = 7.3 Hz, 1H), 7.39−7.15 (m, 7H),
7.09 (t, J = 4.8 Hz, 0.2H), 6.99 (t, J = 4.8 Hz, 0.8H), 6.47 (d, J = 5.6
Hz, 1H), 5.89−5.58 (m, 2H), 5.06 (d, J = 6.8 Hz, 1H), 4.19−4.14 (m,
0.2H), 4.0−3.91 (m, 1.8H), 2.11 (s, 0.2H), 1.98 (s, 0.8H); 13C NMR
(151 MHz, CDCl3) major isomer δ 158.0, 157.9, 142.9, 139.3, 137.0,
134.2, 129.1, 129.0, 128.4, 127.4, 126.1, 122.7, 121.8, 119.8, 117.1,
113.7, 106.6, 74.8, 32.4; minor isomer δ 158.1, 143.3, 139.4, 137.1,
133.5, 129.1, 128.5, 127.5, 126.0, 122.8, 121.9, 119.9, 113.9, 69.6, 28.4;
HRMS (ESI) m/z calcd for C22H19N3NaO [M + Na]+ 364.1420,
found 364.1429.
4-(5-Chloro-1-(pyrimidin-2-yl)-1H-indol-2-yl)but-2-en-1-ol (3j).
Product 3j was obtained as a colorless oil (158.3 mg, 88%, E/Z =
1
1
3.3:1 by H NMR): H NMR (600 MHz, CDCl3) δ 8.78 (d, J = 4.8
Hz, 2H), 8.27−8.13 (m, 1H), 7.47 (d, J = 1.7 Hz, 1H), 7.20−7.11 (m,
2H), 6.41 (s, 1H), 5.89−5.62 (m, 2H), 4.26 (d, J = 4.6 Hz, 0.47H),
4.05 (d, J = 5.6 Hz, 1.53H), 3.99−3.90 (m, 2H), 1.99 (br s, 1H); 13C
NMR (151 MHz, CDCl3) major isomer δ 158.2, 157.9, 141.2, 135.4,
131.3, 130.3, 129.1, 127.3, 122.7, 119.2, 117.4, 115.0, 105.8, 63.3, 32.6;
minor isomer δ 130.4, 128.8, 127.3, 122.8, 119.2, 117.4, 115.2, 105.7,
58.6, 28.2; HRMS (ESI) m/z calcd for C16H14N3ClNaO [M + Na]+
322.0718, found 322.0728.
4-(4-Chloro-1-(pyrimidin-2-yl)-1H-indol-2-yl)but-2-en-1-ol (3k).
2-(4-Fluorophenyl)-4-(1-(pyrimidin-2-yl)-1H-indol-2-yl)but-2-en-
Product 3k was obtained as a colorless oil (156.5 mg, 87%, E/Z =
1-ol (3q). Product 3q was obtained as a yellow oil (202.9 mg, 94%, E/
1
1
1
1
4.0:1 by H NMR): H NMR (600 MHz, CDCl3) δ 8.77 (d, J = 4.8
Hz, 2H), 8.15−8.09 (m, 1H), 7.19−7.11 (m, 3H), 6.59 (s, 1H), 5.88−
5.61 (m, 2H), 4.25 (d, J = 5.4 Hz, 0.4H), 4.03 (d, J = 6.8 Hz, 1.6H),
3.98−3.90 (m, 2H), 1.70 (br s, 1H); 13C NMR (151 MHz, CDCl3)
major isomer δ 158.2, 157.8, 140.5, 137.6, 131.4, 128.8, 127.7, 125.0,
123.2, 121.5, 117.6, 112.3, 104.3, 63.3, 32.4; minor isomer δ 140.5,
137.6, 130.5, 128.5, 123.3, 121.6, 117.6, 112.4, 104.2, 58.5, 28.1;
HRMS (ESI) m/z calcd for C16H14ClN3NaO [M + Na]+ 322.0718,
found 322.0715.
Z = 5.3:1 by H NMR): H NMR (600 MHz, CDCl3) δ 8.78 (d, J =
4.8 Hz, 0.32H), 8.71 (d, J = 4.8 Hz, 1.68H), 8.30 (d, J = 8.3 Hz,
0.16H), 8.22 (d, J = 8.3 Hz, 0.84H), 7.56−7.51 (m, 1H), 7.38−7.12
(m, 5H), 7.08−6.94 (m, 3H), 6.47 (s, 1H), 5.91−5.56 (m, 2H), 5.07
(d, J = 6.8 Hz, 1H), 4.19−4.12 (m, 0.19H), 4.01−3.95 (m, 1.71H),
2.05 (s, 0.16H), 1.88 (s, 0.84H); 13C NMR (151 MHz, CDCl3) major
isomer δ 162.1 (d, JC−F = 245.5 Hz), 158.0, 158.0, 139.2, 138.7 (d, JC−F
= 2.9 Hz), 137.0, 134.0, 129.2, 129.0, 127.7 (d, JC−F = 8.1 Hz), 122.8,
121.9, 119.9, 117.1, 115.2 (d, JC−F = 21.3 Hz), 113.7, 74.2, 32.4; minor
isomer 162.1 (d, JC−F = 245.6 Hz), 158.2, 158.1, 139.3, 139.0 (d, JC−F
= 2.8 Hz), 137.1, 133.4, 129.1, 128.6, 127.6 (d, JC−F = 8.2 Hz), 122.9,
122.0, 119.9, 117.1, 115.3 (d, JC−F = 21.4 Hz), 114.0, 106.7, 69.0, 28.4;
HRMS (ESI) m/z calcd for C22H18FN3NaO [M + Na]+ 382.1326,
found 382.1333.
Experiment of H/D Exchange. Indole 1a (0.6 mmol), CD3OD
(1.2 mmol), [Cp*Co(MeCN)3][SbF6]2 (0.03 mmol, 5 mol %),
AgOAc (0.12 mmol, 20 mol %), and silica gel (600 mg, grinding
auxiliary) were transferred to a ball-milling vessel (stainless steel, 45
mL) loaded with 36 grinding balls (stainless steel, 4 mm). The milling
vessel was placed in the ball mill (800 rpm, 30 min). The crude
product was isolated by washing the vessel and the balls with EtOAc
(3× 20 mL). The mixture was concentrated in vacuum and purified by
flash chromatography (Hexane/EtOAc = 4:1 to 2:1). Recovery: 98%
of 1a and 1a-[D]n.
4-(6-Chloro-1-(pyrimidin-2-yl)-1H-indol-2-yl)but-2-en-1-ol (3l).
Product 3l was obtained as a colorless oil (163.6 mg, 91%, E/Z =
1
1
4.0:1 by H NMR): H NMR (600 MHz, CDCl3) δ 8.79 (d, J = 4.8
Hz, 2H), 8.34−8.29 (m, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.19−7.14 (m,
1H), 6.44 (s, 1H), 5.88−5.63 (m, 2H), 4.26 (d, J = 5.2 Hz, 0.4H) 4.05
(d, J = 5.8 Hz, 1.6H), 3.99−3.90 (m, 2H), 1.59 (br s, 1H); 13C NMR
(151 MHz, CDCl3) major isomer δ 158.2, 157.8, 140.5, 137.3, 131.2,
129.1, 128.5, 127.6, 122.3, 120.4, 117.4, 114.1, 106.2, 63.3, 32.5; minor
isomer δ 157.8, 137.3, 130.3, 128.8, 128.6, 122.4, 117.4, 114.2, 106.0,
58.5, 28.2; HRMS (ESI) m/z calcd for C16H14ClN3NaO [M + Na]+
322.0718, found 322.0706.
4-(4-Bromo-1-(pyrimidin-2-yl)-1H-indol-2-yl)but-2-en-1-ol (3m).
Product 3m was obtained as a colorless oil (175.1 mg, 85%, E/Z =
1
1
4.4:1 by H NMR): H NMR (600 MHz, CDCl3) δ 8.76 (d, J = 4.8
Hz, 2H), 8.18−8.12 (m, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.17−7.13 (m,
F
DOI: 10.1021/acs.joc.7b01695
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Competitive Experiment. Indole 1e (0.6 mmol), indole 1h (0.6
mmol), vinylethylene carbonate 2 (0.6 mmol), [Cp*Co(MeCN)3]-
[SbF6]2 (0.03 mmol, 5 mol %), AgOAc (0.12 mmol, 20 mol %), and
silica gel (600 mg, grinding auxiliary) were transferred to a ball-milling
vessel (stainless steel, 45 mL) loaded with 36 grinding balls (stainless
steel, 4 mm). The milling vessel was placed in the ball mill (800 rpm,
20 min). The crude product was isolated by washing the vessel and the
balls with EtOAc (3× 20 mL). The mixture was concentrated in
vacuum and purified by flash chromatography (Hexane/EtOAc = 4:1
to 2:1) to give mixture (3e and 3h). The ratio of the two products was
determined by the integration of signals in 1H NMR resulting K3e/K3h
= 1.98/1.03 = 1.9:1.
KIE Experiment. Indole 1a (0.3 mmol), indole 1a-[D]1 (0.3
mmol), vinylethylene carbonate 2 (0.6 mmol), [Cp*Co(MeCN)3]-
[SbF6]2 (0.03 mmol, 5 mol %), AgOAc (0.12 mmol, 20 mol %), and
silica gel (600 mg, grinding auxiliary) were transferred to a ball-milling
vessel (stainless steel, 45 mL) loaded with 36 grinding balls (stainless
steel, 4 mm). The milling vessel was placed in the ball mill (800 rpm, 5
min). The crude product was isolated by washing the vessel and the
balls with EtOAc (3 × 20 mL). The mixture was concentrated in
vacuum and purified by flash chromatography (Hexane/EtOAc = 4:1).
Recovery indole 1a and 1a-[D]1 174.6 mg (88%), K(H)/K(D) = (1−
0.457)/0.457 = 1.89:1.
G.; Ellman, J. A. Acc. Chem. Res. 2012, 45, 814. (c) Ye, B.; Cramer, N.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b01695.
(12) (a) Hummel, J. R.; Ellman, J. A. Org. Lett. 2015, 17, 2400.
(b) Hummel, J. R.; Ellman, J. A. J. Am. Chem. Soc. 2015, 137, 490.
(13) (a) Gensch, T.; Klauck, F. J. R.; Glorius, F. Angew. Chem., Int.
Ed. 2016, 55, 11287. (b) Lerchen, A.; Knecht, T.; Daniliuc, C. G.;
Glorius, F. Angew. Chem., Int. Ed. 2016, 55, 15166. (c) Wang, X.;
Lerchen, A.; Glorius, F. Org. Lett. 2016, 18, 2090.
1H and 13NMR spectra of all products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ycm@zjut.edu.cn.
(14) Liang, Y.; Liang, Y.-F.; Tang, C.; Yuan, Y.; Jiao, N. Chem. - Eur. J.
2015, 21, 16395.
ORCID
(15) (a) Kong, L.; Yu, S.; Tang, G.; Wang, H.; Zhou, X.; Li, X. Org.
Lett. 2016, 18, 3802. (b) Kong, L.; Yu, S.; Zhou, X.; Li, X. Org. Lett.
2016, 18, 588. (c) Kong, L.; Zhou, X.; Li, X. Org. Lett. 2016, 18, 6320.
(d) Li, L.; Wang, H.; Yu, S.; Yang, X.; Li, X. Org. Lett. 2016, 18, 3662.
(e) Zhou, X.; Pan, Y.; Li, X. Angew. Chem., Int. Ed. 2017, 56, 8163.
(16) Bera, S. S.; Debbarma, S.; Ghosh, A. K.; Chand, S.; Maji, M. S. J.
Org. Chem. 2017, 82, 420.
Wei-Ke Su: 0000-0001-5072-1509
Chuanming Yu: 0000-0002-1345-0778
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(17) Liu, X.-G.; Zhang, S.-S.; Wu, J.-Q.; Li, Q.; Wang, H. Tetrahedron
Lett. 2015, 56, 4093.
■
This work was supported by the National Natural Science
Foundation of China (NSFC) (Grant Nos. 21676252 and
21506191).
(18) (a) Chen, Z.; Wang, B.; Zhang, J.; Yu, W.; Liu, Z.; Zhang, Y.
Org. Chem. Front. 2015, 2, 1107. (b) Liu, Y.; Wang, C.; Lv, N.; Liu, Z.;
Zhang, Y. Adv. Synth. Catal. 2017, 359, 1351. (c) Yu, W.; Zhang, W.;
Liu, Y.; Liu, Z.; Zhang, Y. Org. Chem. Front. 2017, 4, 77.
(19) (a) Moselage, M.; Li, J.; Ackermann, L. ACS Catal. 2016, 6, 498.
(b) Wei, D.; Zhu, X.; Niu, J.-L.; Song, M.-P. ChemCatChem 2016, 8,
1242. (c) Yoshino, T.; Matsunaga, S. Adv. Synth. Catal. 2017, 359,
1245.
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DOI: 10.1021/acs.joc.7b01695
J. Org. Chem. XXXX, XXX, XXX−XXX