Ru-catalysed C(sp2)-H vinylation/annulation of benzoic acids and alkynes: rapid access to medium-sized lactones

Article abstract of DOI:10.1039/d0cc07573f

An unprecedented ruthenium catalysed [4+4] annulation of readily available benzoic acids and alkynes is reported for the first time. The carboxylate group acts as both a directing group and an internal nucleophilic reagent to facilitate a C(sp²

Full text of DOI:10.1039/d0cc07573f

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Ru-catalysed C(sp2)–H vinylation/annulation of benzoic acids and
alkynes: rapid access to medium-sized lactones
Xiao-Qiang Hu,*a Zi-Kui Liu,a Ye-Xing Hou,a Guodong Zhang*b and Yang Gao*c
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
An unprecedented ruthenium catalysed [4+4] annulation of readily methods for the synthesis of medium-sized lactones is highly
available benzoic acids and alkynes is reported for the first time. desirable and a long sought-after goal for synthetic chemists.
Carboxylate group acts as both directing group and internal
Fascinated by the ability of transition metal catalysis in
nucleophilic reagent to facilitate C(sp2)–H vinylation/annulation structurally complex molecule synthesis, synthetic chemists
cascade. This reaction avoids the classically oxidative [4+2] long ago recognized the potential of transition metal-catalysed
annulation, allowing the efficient synthesis of a wide array of eight- C–H coupling reactions as a powerful tool for the construction
membered lactones under oxidant-free conditions. Moreover, this of medium-sized rings.8 Recently, the group of Miura reported
catalytic system can be successfully extended to [4+3] and [4+5] nickel-catalysed C–H coupling/annulations of benzamides with
annulations for the assembly of seven- and nine-membered highly reactive epoxides or oxetanes to synthesize 6- or 7-
lactones.
membered benzolactones (Scheme 2b).9 Among these
reactions, the 8-aminoquinoline auxiliary acted as a deciduous
directing group. Carboxylate groups are promising directing
groups in modern organic synthesis due to the inexpensive and
easily available meterials.10 In 2015, Shi et al. demonstrated an
elegant rhodium-catalysed of cross-coupling and aromatic acids
with benzyl thioethers with assistance of AgOAc (2.0 equiv.)
through double C–H activation, offering various seven-
membered dibenzooxepinones at 160 oC (Scheme 2b).11 In
addition, the carboxylate-directed [4+1] and [4+2] annulation
reactions have been widely applied in the preparation of 5- and
6-membered benzolactones.12 However, to our knowledge, the
synthesis of larger-sized (8 or 9-membered) benzolactones from
benzoic acids is still largely unexploited.
Spanning the realm of structurally complex molecules that
often exists in bioactive natural products and pharmaceuticals,
not surprisingly, medium-sized lactones are prominent and
attractive to synthetic community (Scheme 1).1 For instance,
Cephalosporolide D is a naturally occurring macrolides.2
Apicularen exhibits a powerful anticancer activity.3 Branimycin
performs good antibacterial activities against Bacillus subtilis
and Micrococcus luteus etc.4 Conventional methods for the
assembly of lactones mainly rely on intramolecular ring
cyclisation reactions (Scheme 2a).5 The ring cyclisation strategy
turned out to be effective for the synthesis of 5-7 membered
lactones but often pose challenges for other medium-sized
lactones due to their high entropic barriers.6 Ring expansion
reaction provides a useful and alternative access to medium-
sized lactones.7 However, the preparation of specialized
precursors often requires multiple steps and limits their broad
application in practical synthesis. The development efficient
O
O
OH
HO
O
O
O
OH
HO
O
8
OMe
8
8
Me
Me
O
H
O
O
Me
Me
Cehalosporolide D
Prenpenicillide
O
Octalactin A
OMe
OH
O
O
O
O
N
H
aKey Laboratory of Catalysis and Energy Materials Chemistry of Ministry of
Education & Hubei Key Laboratory of Catalysis and Materials Science, School of
Chemistry and Materials Science, South-Central University for Nationalities, Wuhan
430074, China. E-mail: huxiaoqiang@mail.scuec.edu.cn.
H
OH
OMe
H
9
9
O
O
H
HO
MeO
Branimycin
Apicularen
OH
OH
bYangzhou University College of Chemistry and Chemical Engineering, Siwangting
Road 180 Yangzhou, 225002 China. E-mail: guodong.zhang@yzu.edu.cn.
cSchool of Chemical Engineering and Light Industry, Guangdong University of
Technology, Guangzhou, 510006, China. E-mail: gaoyang@gdut.edu.cn.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here. See DOI: 10.1039/x0xx00000x
Scheme 1 Selected examples of bioactive medium-sized lactones.
We recently achieved a C–H amination/annulation reaction
of acrylic acids with anthranils for the construction of
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polysubstituted quinolines in which carboxylate acted as a that the iodide-based ruthenium catalyst Ru-2ViecwanArticslleigOhnltinlye
deciduous directing group.13 The same strategy has been improve the reaction efficiency, whicDhOIm: 1a0y.103p9r/oDm0CoCte075t7h3eF
successfully extended to selective ortho-C–H amination of nucleophilic substitution step through the exchange of Cl with I
aromatic acids.14 In this work, an unexpected esterification (entry 10, 64%). The investigation of organic solvents
product was observed through nucleophilic substitution of Cl- demonstrated 1-butanol is the best choice (entry 11, 69%). We
atom by carboxyl group. Encouraged by our recent work on also tested [RuCl2(p-cymene)]2 catalyst under 1-butanol, while
carboxylate-directed C–H functionalisations and heterocycle product 3aa can be obtained in a slightly lower yield (entry 12,
synthesis,15 we envisioned that an alkyne bearing a leaving 62%). The concentrated solution has a positive effect on the
group could be employed as viable reagents for sequential reaction efficiency and the expected product 3aa was isolated
C(sp2)–H vinylation/annulation of benzoic acids, providing a in 78% yield (entry 13). The alkyne 2a’ bearing a methylsulfonyl
straightforward access to medium-sized lactones (Scheme 2c). group was not suitable for this reaction (entry 14). In addition,
Two main challenges are associated with this transformation: (a) the control experiment demonstrated that ruthenium catalyst
[4+2] annulation of benzoic acids with alkynes; (b) direct is essential for this reaction (entry 15).
substitution of Cl group by nucleophilic carboxyl group. The key Table 1 Optimization of the reaction conditionsa
O
handle to suppress the undesired [4+2] annulation is to avoid
O
O
[Ru] (2 mol%)
base (50 mol%)
X
using external oxidant.12n In addition, we believed that the
direct nucleophilic substitution pathway may be suppressed by
OH
8
solvent/H2O (9:1), 100 o
C
+
Ph
2a, X = Cl, 2a', X = OMs
1a
3aa
adjusting the pH of reaction mixture.14 Herein, we reported
a
Ph
yield b
(%)
49
ruthenium catalysed [4+x] (x = 3, 4 and 5) annulation of readily
available benzoic acids and alkynes to synthesize a wide range of 8-
and 9-membered lactones under oxidant-free conditions.
entry catalyst
base
solvent
1
2
Ru-1
Ru-1
Ru-1
Ru-1
Ru-1
Ru-1
Ru-1
Ru-1
Ru-2
K2CO3
1,4-
dioxane
1,4-
dioxane
1,4-
dioxane
1,4-
dioxane
1,4-
dioxane
1,4-
dioxane
1,4-
dioxane
1,4-
dioxane
1,4-
a) Conventional methods: ring cyclisation and ring expansion strategy (well-established)
Cs2CO3
NaHCO3
CsF
46
42
10
36
20
47
56
60
X
Y
Y
high entropic barriers
X
Y
ring cyclisation
n
n
3
Z
X
Z
X
Y
specialized precursors
ring expansion
Y
X
4
Z
b) [4+3] annulation: C–H coupling/annulation strategy for medium-sized ring synthesis
5
KOAc
Miura's work:
O
O
O
cat. Ni(II)
O
+
N
H
R1
R
7
6
K2HPO4
R
R1
H
7
guanidine
carbonate
K2CO3
R
Shi's work:
O
cat. Rh
S
+
8c
9c
OH
O
R
7
[Ag] oxidant, 160 o
C
O
c) This work: [4+x] annulation of benzoic acids and alkynes
K2CO3
O
O
dioxane
tAmOH
1-butanol
1-butanol
O
cat. Ru
Cl
10c
11c
Ru-2
Ru-2
Ru-1
Ru-2
Ru-2
--
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
64
69
62
OH
R
7, 8, 9
+
R
Ar
n = 1, 2, 3
n = 1, 2, 3
Ar
O
12c
O
13c,d
14c,d,f
15c,d,g
1-butanol 80(78)e
R
Challenges：
a) [4+2] annulation
a) direct nucleophilic substitution
R'
1-butanol
1-butanol
0
0
Ar
undesired [4+2] annulation
Advantages: a) simple operation; b) wide substrate scope; c) without external oxidant
aReaction Conditions ： 1a (0.25 mmol), 2a (0.38 mmol), catalyst (2
mol%), base (50 mol%), solvent/H2O (9:1, 1 mL), 100 oC, 18 h under an
atmosphere of argon. b1H NMR yield using 1,3,5-trimethoxybenzene as
internal standard. cK2CO3 (20 mol%) and guanidine carbonate (30 mol%)
Scheme 2 Conventional methods for the synthesis of medium-sized
lactones
and
reaction
design.
f
were used. d0.5 mmol scale. eIsolated yield. 2a’ was used. gwithout
To test this hypothesis, we started the study with the
reaction of 2-methylbenzoic acid 1a and alkyne 2a in the
presence of [RuCl2(p-cymene)]2 (2 mol%) as the catalyst and
K2CO3 (50 mol%) as the base under 1,4-dioxane at 100 oC (Table
1). To our delight, the desired 8-membered lactone 3aa was
successfully obtained in 49% yield (entry 1). Subsequently, a set of
bases have been examined, but all resulted in inferior yields
(entries 2-7). Notably, the yield of 3aa can be further improved
to 56% by combination of K2CO3 (20 mol%) and guanidine
carbonate (30 mol%) as the basic system (entry 8). It was found
ruthenium catalyst. Ru-1 = [RuCl2(p-cymene)]2, Ru-2 = [RuI2(p-cymene)]2,
tAmOH = 2-methyl-2-butanol.
With the established reaction conditions in hand, we then
investigated the generality of this [4+4] annulation reaction. As
shown in Table 2, under optimal conditions, a broad array of
structurally diverse aromatic acids reacted smoothly with
alkyne 2a. Benzoic acids bearing electron-donating (Me, Et,
MeO, Ph, Bn) and electron-withdrawing (F, Cl, Br) groups at the
ortho-, meta-, and para-positions were well-tolerated,
2 | J. Name., 2012, 00, 1-3
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producing 8-membered lactone products in useful to good yields carboxylate group (Scheme 5a, eq. 1). In addition, Vthiewe AsruticblestOrnalitnee
DOI: 10.1039/D0CC07573F
(3aa-3sa, 40-85%). It is important to note that Br or I group may 5 generated from the direct nucleophilic substitution of 2a by 2-
has a potential utility for further coupling reactions. The simple methylbenzoic acid resulted in no conversion under the
benzoic acid could also participate in this transformation with standard conditions (eq. 2). This outcome indicated that
high efficiency. Both 1-naphthoic acid and 2-naphthoic acid compound 5 may not be the intermediate in this reaction.
could be readily coupled with 2a to generate the corresponding When potassium 2-methylbenzoate 6 was used in this reaction,
3,4,5,6-tetrahydro-1H-naphtho[2,3-c]oxocin-1-one (3pa) and the direct substitution of Cl group by carboxyl group readily
3,4,5,6-tetrahydro-1H-naphtho[1,2-c]oxocin-1-one (3qa and occurred and no lactone product 3aa was observed (eq. 3).
3ra) with satisfying yields. Moreover, thiophene-3-carboxylic However, the reaction proceeded smoothly when 1:1 mixture
acid also proved to be suitable for this catalytic system, of potassium 2-methylbenzoate and 2-methylbenzoic was used,
furnishing the expected product 3sa in 40% yield. However, offering 3aa in 40% yield (eq. 4). These results demonstrated
acrylic acid 1t turned out to be ineffective for this the amount of base has a significance influence on the reaction
transformation. The structure of 3ka was unambiguously efficiency. Deuterium-labeling experiments with [D]-1a were
determined by X-ray analysis (see SI for more details).
conducted at the early stage of this reaction. The kinetic isotope
Given the synthetic versatility of alkynes, we further effect (KIE) of both competitive experiment (Scheme 5b, kH/kD
examined the scope of alkynes. As illustrated in Scheme 4, a = 2.0) and parallel experiment (Scheme 5c, kH/kD = 1.5) indicated
variety of alkynes bearing a Me, Cl or F group proceeded well in that the C–H bond cleavage process may be the rate-limiting
this reaction, offering the desired lactone generally good yields step.
(3ab-3ae, 61-78%). Moreover, the sensitive functional groups,
Ru-2 (2 mol%)
K2CO3 (20 mol%)
guanidine carbonate
(30 mol%)
O
R
O
such as ketone and ester substituents, were compatible with
reaction conditions (3af and 3ag). Significantly, this catalytic
system can be extend to [4+3] and [4+5] annulations, furnishing
O
Cl
n = 1, 2, 3
OH
R
7, 8, 9
Ar
+
1-butanol/H2O, 100 o
C
n = 1, 2, 3
Ar
1a or 1d
3
2
O
7- and 9-membered lactones in satisfied yields (3ah, 3dh and 3di)
.
eight-membered lactones
O
O
O
O
O
O
Ru-2 (2 mol%)
8
8
K2CO3 (20 mol%)
guanidine carbonate
(30 mol%)
O
O
Cl
8
3ab, R = Me, 78%
3ac, R = Cl, 63%
3ad, R = F, 63%
R
8
OH
+
Ph
R
1-butanol/H2O, 100 o
C
Cl
3ae, 61%
3af, 60%
O
1
2
3
Ph
R
eight-membered lactones
O
a)
seven-membered lactone
nine-membered lactones
O
Ph
O
O
O
Ph
O
O
O
Bn
O
Bn
8
O
O
O
O
O
O
O
8
8
8
8
9
7
9
Ph
Ph
Ph
Ph
Ph
3dh, 51%
O
3aa, 78%
3ba, 85%
3ca, 81%
3da, 70%
O
F
3ag, 64%
3ah, 69%
3di, 53%
O
O
O
O
Me
O
O
O
O
Ph
8
8
8
Scheme 4 Scope of alkynes.
8
Ph
Ph
3ea, 50%
Ph
3fa, 62%
Ph
3ga, 56%
Ph
3ha, 60%
a) control experiment
O
O
Cl
O
O
O
O
O
standard conditions
O
O
O
O
O
(1)
Br
+
8
Ph
no reaction
8
8
8
8
4
2
MeO
F
3aa
3aa
O
Ph
Ph
Ph
Ph
standard conditions
Ph
O
(2)
(3)
3ia, 63%
3ja, 85%
3ka, 72%
3la, 77%
no reaction
Ph
5
O
O
O
O
O
O
O
standard conditions
without base
O
O
8
8
+
8
OK
3aa
5
8
direct nucleophilic substitution
Br
trace
91% yield
Cl
6
Ph
Ph
O
standard conditions
O
1a
Ph
3na, 60%
Ph
without base
3ma, 65% (CCDC: 2039860)
3oa, 52%
3pa, 47%
(4)
OK
+
3aa
OH
O
6:1a = 1:1
O
O
O
O
MeO
6
40% yield
O
O
O
b) competitive experiment
8
8
8
OH
O
S
CD3
MeO
CH3
O
CD3
O
OH
OH
standard conditions
kH/kD = 2.0
1t
unsuccessful
D3
+
8
Ph
3sa, 40%
+
Ph
Ph
3ra, 48%
D4
3aa
3qa, 54%
1a
[D]-1a
[D]-3aa
[D]-3aa
c) parallel experiment
Ph
Scheme 3 Scope of aromatic acids.
CD3
O
CH3
O
OH
OH
standard conditions
kH/kD = 1.5
To further understand the mechanism, we firstly conducted
the following control and deuterium-labeling experiments
(Scheme 5). 2-Methylbenzoate 4 proved to be ineffective for
this transformation, suggesting the important role of the
or
D4
3aa
+
1a
[D]-1a
Scheme 5 Mechanistic studies.
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