Rh(iii)-catalyzed regioselective hydroarylation of alkynes via directed C-H functionalization of pyridines

Article abstract of DOI:10.1039/c4ob00612g

Rh(iii)-catalyzed C-3 selective alkenylation of pyridine derivatives via hydroarylation of alkynes has been developed. The reaction shows high regioselectivity, high yield and good functional group tolerance, providing a convenient strategy for the synthesis of trisubstituted (pyridin-3-yl)alkenes. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00612g

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Rh(III)-catalyzed regioselective hydroarylation of
alkynes via directed C–H functionalization of
pyridines†
Cite this: Org. Biomol. Chem., 2014,
12, 3594
Received 22nd March 2014,
Accepted 9th April 2014
Zhen-Chao Qian, Jun Zhou, Bo Li, Fang Hu and Bing-Feng Shi*
DOI: 10.1039/c4ob00612g
www.rsc.org/obc
Rh(III)-catalyzed C-3 selective alkenylation of pyridine derivatives
via hydroarylation of alkynes has been developed. The reaction
shows high regioselectivity, high yield and good functional group
tolerance, providing a convenient strategy for the synthesis of tri-
substituted (pyridin-3-yl)alkenes.
Since the pioneering work of Murai on carbonyl-directed alke-
nylation of aromatic ketones with alkynes catalyzed by
Ru(H)2(CO)(PPh3)3, chelation-assisted hydroarylation of internal
alkynes has proven to be a valuable tool for the efficient syn-
thesis of trisubstituted alkenes from readily available arenes
and alkynes.1,2 Mechanically, hydroarylation catalyzed by low-
valent transition metal species generally proceeds via oxidative
addition of transition metals into the ortho C–H bonds, which
could then undergo hydrometallation of alkynes followed by
reductive elimination to provide the alkenylated products.3–5
Alternatively, the hydroarylation of alkynes catalyzed by high-
valent transition metals generally involves the metalation–
deprotonation of ortho C–H bonds, followed by migratory
insertion of the metallacycle into alkynes and subsequently
protodemetalation.6,7 From a synthetic point of view, this pro-
tocol can be complementary to the oxidative olefination
process because trisubstituted olefin products are generated,
and no oxidant is needed.
Despite the significant progress in hydroarylation of simple
arenes, the hydroarylation of pyridines is still limited, likely
due to the electron-deficiency of the ring and the strong
coordination of the nitrogen atom.8 Nakao and Hiyama
demonstrated Ni(0)-catalyzed C-2 selective alkenylation of pyri-
dine-N-oxides (Fig. 1A).4a Shortly after that, the same group
reported C-2 alkenylation of pyridines by Ni(0)-Lewis acid
cooperative catalysis.4b Ong, Nakao and Hiyama independently
reported Ni(0)–Al(III) mediated C-4 selective alkenylation of
Fig. 1 Transition-metal-catalyzed hydroarylation of alkynes with pyri-
dine derivatives.
pyridines using N-heterocyclic carbenes as ligands.4c,d Recently,
Chang realized a bishydroarylation of alkynes with 2,2′-bipyri-
dine under the in situ generated Rh(I)-IMes catalyst (Fig. 1A).5
However, these examples are mechanically limited to low-
valent transition metals via an oxidative addition pathway,
which are usually not completely regio- and stereoselective.
Herein, we report a Rh(III)-catalyzed hydroarylation of alkynes
with pyridines in the presence of HOAc and Cu(OAc)2, proceed-
ing regio- and stereoselectively through a directed C–H clea-
vage to produce the corresponding alkenylated products
(Fig. 1B).9
We commenced our study by investigating the hydroaryla-
tion of 2a with picolinamide 1a under the conditions pre-
viously reported for the oxidative olefination reaction and the
desired product 3a was obtained in 74% yield (Table 1, entry
1).9e Adding 4 equiv. of HOAc improved the yield dramatically
(entry 2, 92%). Control experiments showed that both
[Cp*RhCl2]2 and AgSbF6 were essential for this reaction
(entries 5 and 6). It is surprising that the removal or the use of
a catalytic amount of Cu(OAc)2 resulted in reduced yields
(entries 7 and 8). To determine whether Cu(OAc)2 was just
acting as a source of acetate, Cu(OAc)2 was replaced by CsOAc;
Department of Chemistry, Zhejiang Univers ity, Hangzhou 310027, China.
E-mail: bfshi@zju.edu.cn
†Electronic supplementary information (ESI) available: Fig. S1, experimental
procedures, characterization data, and copies of 1H and 13C NMR spectra. See
DOI: 10.1039/c4ob00612g
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Table 1 Optimization of the reaction conditionsa
Table 2 Hydroarylation of alkynes with picolinamidesa
Entry
Picolinamide 1
Alkyne 2
Product 3, yield (%)
1
1a, R = Br
1b, R = Cl
1c, R = F
1d, R = CO2Me
1e, R = PMP
1f, R = OAc
2a
2a
2a
2a
2a
2a
3a, R = Br, 92
Entry
Additive (equiv.)
HOAc (equiv.)
Solvent
Yield (%)
2
3b, R = Cl, 79
3b
4
3c, R = F, 81 (19c)
3d, R = CO2Me, 91
3e, R = PMP, 56
3f, R = OAc, 57
1
2
3
Cu(OAc)2(1.0)
Cu(OAc)2(1.0)
Cu(OAc)2(1.0)
Cu(OAc)2(1.0)
Cu(OAc)2(1.0)
Cu(OAc)2(1.0)
—
Cu(OAc)2(0.1)
CsOAc(1.0)
CuSO4(1.0)
—
DCE
DCE
t-Amyl-OH
1,4-Dioxane
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
74(15b)
92
58
91
16
0
46
45
<10
79
90
89
0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
5
6
4
5c
6d
7
8
9
10
11
12
13
7
8
9
10
11
1g, R = Me
1k, R = OMe
1h, R = F
1i, R = Cl
1j, R = Br
2a
2a
2a
2a
2a
3g, R = Me, 82
3k, R = OMe, 63 (37d)
3h, R = F, 99
3i, R = Cl, 99
3j, R = Br, 90
Mn(OAc)2(1.0)
Co(OAc)2(1.0)
CuBr2(1.0)
a Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), [Cp*RhCl2]2
(2.5 mol %), AgSbF6 (10 mol%), additive in 2 mL solvent at 120 °C for
24 h. Isolated yield. b Yield of isoquinoline (3a′). c Without AgSbF6.
d Without [Cp*RhCl2]2.
12
13
14
15
16
1l, R = Cl
2a, R1 = Ph
2b, R1 = Me
2b, R1 = Me
2b, R1 = Me
2b, R1 = Me
3l, R = Cl, R1 = Ph, 30
3l, R = Cl, R1 = Me, 87
3m, R = Br, 75
3n, R = OMe, 49
NR
1m, R = Br
1n, R = OMe
1o, R = Me
however, only a trace amount of the product was obtained
(entry 9).10 Other Lewis acids, such as CuSO4, Mn(OAc)2 and
Co(OAc)2·4H2O, gave moderate to high yields (entries 10–12),
while CuBr2 failed to give any product (entry 13). Since this
hydroarylation reaction is redox-neutral and no oxidant is
needed, we hypothesized that Cu(OAc)2 might act as a Lewis
acid to coordinate competitively with the pyridine nitrogen.
With the optimized conditions in hand, we further explored
the substrate scope of picolinamides to test the generality of
this protocol (Table 2). A variety of picolinamides with valuable
functional groups, such as chloro, fluoro, bromo, methoxy-
carbonyl, p-methoxyphenyl and acetoxyl, are compatible with this
protocol, furnishing the desired products in moderate to high
yields. Halogenated picolinamides such as bromide, chloride
and fluoride could react smoothly with alkynes under the stan-
dard or slightly modified conditions to give good yields
(entries 1 and 2, and 9–13). Picolinamides with electron-donat-
ing groups were somewhat less reactive than those with elec-
tron-withdrawing groups (entries 1–3 vs. 4 and 5; entries 7 and
8 vs. 9 and 10), together with the overall electron-deficiency of
pyridines, rendering an electrophilic reaction mechanism less
likely. Interestingly, the Z-isomer was afforded in 37% yield
while the electron-donating methoxy group appeared at the
6-position (entry 8). Additionally, this reaction was sensitive to
steric hindrance; substrates bearing a sterically demanding
group at the 4-position were less reactive or failed under the
reaction conditions (entries 12–16).
a Reaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), [Cp*RhCl2]2
(2.5 mol%), AgSbF6 (10 mol%), Cu(OAc)2 (0.2 mmol), HOAc (0.8 mmol)
in 2 mL DCE at 120 °C for 24 h. Isolated yield. b 0.1 mmol Cu(OAc)2
and 1.6 mmol HOAc were added. c Isolated yield of isoquinoline (3c′)
via oxidative annulation of 1c with 2a. d Isolated yield of the Z isomer
(3k′).
group in the phenyl ring reacted with 1a to afford the Z-isomer
predominantly, which was consistent with the hydroarylation
with 1h (Table 3, entry 5 vs. Table 2, entry 8). Symmetrical
dialkyl alkyne, 4-octyne (2h), could also react with 1a to give 3u
in excellent yield (entry 6). The reaction of unsymmetrical
1-phenyl-1-butyne (2i) and 1-phenyl-1-propyne (2j) with 1a pro-
ceeded smoothly, affording the alkenylated products in excel-
lent yields with the phenyl group distal to the amide group
predominantly (entries 7 and 8). Other N,N-dialkyl substituted
picolinamides reacted efficiently with diphenylacetylene 2a
under current conditions to give the alkenylated products in
good yields (entries 9–11).
To probe the mechanism of the hydroarylation reaction,
further experiments were performed. When picolinamide 1a
was subjected to the reaction conditions in the absence of an
alkyne for 20 min and 4 hours, 5% and 30% deuterium incor-
poration was observed at the 3-position of the recovered start-
ing material 1a, respectively (eqn (1)). These results suggest
the reversibility of C–H activation under the reaction con-
ditions. Interestingly, deuterium incorporation was also
observed at the 6-position. Moreover, a primary KIE value (3.1)
was obtained, indicating that C–H bond cleavage might occur
during the rate-determining step (eqn (2)). Next, deuterated
The scope of internal alkynes was also investigated, and the
results are summarized in Table 3. A variety of bis(p-substi-
tuted phenyl)acetylenes (2c–2g) underwent hydroarylation with
1a to produce desired products in moderate to high yields
(entries 1–5). Alkyne 2g bearing an electron-donating methoxyl
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Table 3 Substrate scope of alkynes and amidesa
Entry
Picolinamide 1
Alkyne 2
Product 3, yield (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
2c, R1, R2 = p-F-C6H4
2d, R1, R2 = p-Cl-C6H4
2e, R1, R2 = p-MeC6H4
2f, R1, R2 = p-tBu-C6H4
2g, R1, R2 = p-OMe-C6H4
2h, R1, R2 = nPr
3p, R1, R2 = p-F-C6H4, 85
3q, R1, R2 = p-Cl-C6H4, 99
3r, R1, R2 = p-Me-C6H4, 94
3s, R1, R2 = p-tBu-C6H4, 51
3t, R1, R2 = p-MeO-C6H4, 36 (62b)
3u, R1, R2 = nPr, 94
2i, R1 = Et, R2 = Ph
2j, R1 = Me, R2 = Ph
3v, R1 = Et, R2 = Ph, 98 (9 : 1)c
3w, R1 = Me, R2 = Ph, 100 (20 : 1)c
9
10
11
1o, R′, R′ = (CH2)5
1p, R′, R″ = Cy
1q, R′, R″ = Bn
2a
2a
2a
3x, R′, R″ = (CH2)5, 87
3y, R′, R″ = Cy, 76
3z, R′, R″ = Bn, 81
a Standard conditions. Isolated yield. b Isolated yield of the Z isomer (Z-3t). c Ratios of regioisomers are given in parentheses, determined by 1H
NMR. Major isomers are shown.
picolinamide 1a-d1 was subjected to the reaction conditions, and Table 3, entry 5). Alkene isomerization occurred when
and no deuterium incorporation was observed in the olefinic E-3h and Z-3h were exposed to the reaction conditions, respecti-
position of the product (eqn (3)). This fact suggests that oxi- vely (eqn (4) and (5)). However, there was no deuterium incor-
dative addition of the ortho C–H bond under current con- poration into the olefinic position when E-3h was subjected to
ditions is improbable.
the hydroarylation conditions in DOAc (eqn (4)). These experi-
ments ruled out the possibility of alkene isomerization via the
resonance structure III (Fig. S1, ESI†).12 We reasoned that an
anti-nucleometallation across the electron-rich alkenes fol-
lowed by the syn-elimination pathway might account for the
occurrence of Z-3h and Z-3t. Based on these experiments and
literature precedents, a plausible mechanism is proposed to
explain both the deuteration experiments and the observed
alkene geometry (Fig. S1, ESI†).13
In summary, we have developed a Rh(III)-catalyzed hydroaryl-
ation of a broad range of internal alkynes with picolinamides
to afford trisubstituted (pyridin-3-yl)alkenes. Given that the
oxidative olefination was limited to terminal activated olefins,
such as styrenes and acrylates, that only give E-linear alkenes,
the current hydroarylation protocol offers a complementary
approach to access the branched products.
ð1Þ
ð2Þ
ð3Þ
Financial support from the NSFC (21142002, 21272206, and
J1210042), the Qianjiang Project (2013R10033) and the
Fundamental Research Funds for the Central Universities
(2014QNA3008) is gratefully acknowledged.
ð4Þ
ð5Þ
The possibility of alkyne activation via cationic catalysts was
ruled out based on the exclusive formation of the E-isomers in
most of the cases via syn-selective addition of the C–C triple
bond, as well as on the high value of the KIE.11 However,
Z-isomers were obtained when electron-rich picolinamide 1h
or alkyne 2g was used as a coupling partner (Table 2, entry 8
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