Rhodium(III)-catalyzed [4+1] annulation of aromatic and vinylic carboxylic acids with allenes: An efficient method towards vinyl-substituted phthalides and 2-furanones

Article abstract of DOI:10.1002/chem.201501106

A highly regio- and stereoselective synthesis of 3,3-disubstituted phthalides from aryl carboxylic acids and allenes using a rhodium(III) catalyst has been demonstrated. The reaction features broad functional group tolerance and provides a simple and straightforward route to the synthesis of various 3-vinyl-substituted phthalides. Furthermore, the catalytic reaction can also be applied to the synthesis of biologically active 5-vinyl-substituted 2-furanones from α,β-unsaturated carboxylic acids and allenes. The reactions proceed through a carboxylate-assisted ortho-C-H activation and [4+1] annulation. The preliminary mechanistic studies suggest that a C-H cleavage is the rate-determining step. An efficient synthesis of highly substituted phthalides and 2-furanones from aryl and vinyl carboxylic acids with allenes by using a Rh^III catalyst is demonstrated (see scheme). The reactions proceed through a carboxylate-assisted ortho-C-H activation and [4+1] annulation.

Full text of DOI:10.1002/chem.201501106

DOI: 10.1002/chem.201501106
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Synthetic Methods |Hot Paper|
Rhodium(III)-Catalyzed [4+1] Annulation of Aromatic and Vinylic
Carboxylic Acids with Allenes: An Efficient Method Towards Vinyl-
Substituted Phthalides and 2-Furanones
Parthasarathy Gandeepan, Pachaiyappan Rajamalli, and Chien-Hong Cheng*[a]
Abstract: A highly regio- and stereoselective synthesis of
3,3-disubstituted phthalides from aryl carboxylic acids and
allenes using a rhodium(III) catalyst has been demonstrated.
The reaction features broad functional group tolerance and
provides a simple and straightforward route to the synthesis
of various 3-vinyl-substituted phthalides. Furthermore, the
catalytic reaction can also be applied to the synthesis of bio-
logically active 5-vinyl-substituted 2-furanones from a,b-un-
saturated carboxylic acids and allenes. The reactions proceed
through a carboxylate-assisted ortho-CÀH activation and
[4+1] annulation. The preliminary mechanistic studies sug-
gest that a CÀH cleavage is the rate-determining step.
Introduction
Transition-metal-catalyzed CÀH activation has evolved as
a promising strategy in organic synthesis and has been widely
employed in the synthesis of natural and unnatural com-
pounds.[1,2] In particular, directing-group (DG)-assisted ortho-CÀ
H cleavage followed by coupling with p components is popu-
lar in the synthesis of hetero- and carbocyclic synthesis.[3]
Among the p-coupling partners, alkyne and alkenes have been
heavily tested, but allenes are less explored.[4] Our continuing
interest in CÀH activation reactions[5] and allene chemistry has
prompted us to explore allenes as p components in CÀH acti-
vation reactions.[6] Herein we report a practical method for the
synthesis of 3,3-disubstituted phthalides from aryl carboxylic
acids and allenes. It is worth mentioning that many CÀH acti-
vation reactions are known involving carboxylic acids with dif-
ferent coupling partners, but allenes have never been
studied.[7]
Figure 1. Phthalides containing natural and bioactive compounds.
Results and Discussion
Phthalide (3H-isobenzofuran-1-one) is an important structur-
al motif found in many natural and bioactive compounds
(Figure 1).[8] They have also proven to be potential building
blocks in organic synthesis.[9] Several strategies for their synthe-
sis using transition-metal catalysts involving addition and cou-
pling reactions have been developed.[8b,10] However, these re-
actions require functionalized starting compounds and are
often limited by the availability of the starting compounds.
Therefore the development of a new CÀH activation route that
employs less functionalized starting compounds for the syn-
thesis of phthalide derivatives is highly sought after.[11]
Reaction optimization
The treatment of benzoic acid (1a; 0.60 mmol) and 2,3-buta-
dienylbenzene (2a; 0.90 mmol) in the presence of 2 mol%
[RhCl2Cp*]2 and AgOAc (1.260 mmol) in CH3CN (3 mL) at 608C
for 20 h gave (E)-3-methyl-3-styrylisobenzofuran-1(3H)-one
(3aa) in an isolated yield of 88% (Table 1, entry 11). This com-
pound was thoroughly characterized by H and 13C NMR spec-
1
troscopy and HRMS. The choice of solvent was crucial for the
success of the reaction (Table 1, entries 1–9). Among the sol-
vents tested, acetonitrile was the most suitable to give product
3aa in high yield. Silver salts were found to be better oxidants
than the other inorganic and organic oxidants tested for this
reaction, with silver acetate being the most desirable for
phthalide formation among the silver oxidants tested (Table 1,
entries 11–16). Control experiments revealed that no product
was obtained in the absence of either the rhodium catalyst or
AgOAc (entries 20 and 21).
[a] Dr. P. Gandeepan, Dr. P. Rajamalli, Prof. Dr. C.-H. Cheng
Department of Chemistry, National Tsing Hua University
Hsinchu 30013 (Taiwan)
E-mail: chcheng@mx.nthu.edu.tw
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201501106.
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Table 1. Optimization of the reaction to give phthalide 3aa.[a]
Table 2. Scope of arenecarboxylic acids in the reactions leading to phtha-
lide formation.[a,b]
Entry
Oxidant (amount [equiv])
Solvent
T [8C]
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Cu(OAc)2 (2.1)
Cu(OAc)2 (2.1)
Cu(OAc)2 (2.1)
Cu(OAc)2 (2.1)
Cu(OAc)2 (2.1)
Cu(OAc)2 (2.1)
Cu(OAc)2 (2.1)
Cu(OAc)2 (2.1)
Cu(OAc)2 (2.1)
Cu(OAc)2 (2.1)
AgOAc (2.1)
AgOAc (2.1)
AgOAc (2.1)
Ag2CO3 (1.1)
Ag2O (1.1)
MeOH
DCE
1,4-dioxane
toluene
DMF
60
60
60
60
60
60
60
60
60
80
60
50
60
60
60
60
60
60
60
60
60
12
16
6
–
–
–
15
40
31
28
91 (88)[c]
68
62
75
36
30
11
THF
EtOAc
CH3CN
CH3NO2
CH3CN
CH3CN
CH3CN
CH3NO2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
AgOCOCF3 (2.1)
K2S2O8 (3.0)
BQ[d] (2.1)
O2 (1 atm)
AgOAc (2.1)
–
–
–
–
–
[e]
[a] All reactions were carried out by using benzoic acid 1a (0.60 mmol),
allene 2a (0.90 mmol), [RhCl2Cp*]2 (0.012 mmol), and oxidant in solvent
(3 mL) at T for 20 h. [b] Yields were determined by the 1H NMR integra-
tion method using mesitylene as the internal standard. [c] The isolated
yield is given in parentheses. [d] BQ=1,4-benzoquinone. [e] No
[RhCl2Cp*]2 was used.
Scope of aryl carboxylic acids in the synthesis of phthalides
To realize the scope of the reaction, we examined the per-
formance of various substituted benzoic acids with 2a under
the optimized reaction conditions and the results are shown in
Table 2. The reaction of p-toluic acid (1b) and p-anisic acid (1c)
gave the desired products 3ba and 3ca in yields of 91 and
86%, respectively. Halo-substituted benzoic acids were well tol-
erated under the reaction conditions, giving the expected
phthalide products. Thus, p-fluoro-, p-chloro, p-bromo, and p-
iodo-substituted benzoic acids (1d–g) gave the corresponding
desired products 3da–3ga in high yields. The bromo- and
iodo-substituted products 3 fa and 3ga are appropriate for fur-
ther functionalization through cross coupling. The reaction
also worked well with benzoic acids bearing electron-with-
drawing groups; p-nitro- and p-cyano-substituted benzoic
acids (1h and 1i) gave the expected [4+1] cycloaddition prod-
ucts 3ha and 3ia in good yields. Sterically hindered ortho-sub-
stituted benzoic acids were also compatible under the reaction
conditions and yielded the expected phthalides. Thus, the re-
actions of 2-methyl- and 2-chloro-substituted benzoic acids (1j
and 1k) with 2a afforded the products 3ja and 3ka in yields
of 92 and 74%, respectively.
[a] All reactions were performed by using arenecarboxylic acid
1
(0.80 mmol), allene 2a (1.20 mmol), [Cp*RhCl2]2 (0.016 mmol), and
AgOAc (1.680 mmol) in CH3CN (4.0 mL) at 608C for 20 h. [b] Isolated
yields. [c] The ratios of regioisomers are given in parentheses and were
1
determined by H NMR analysis.
iodo-substituted benzoic acids (1l–n), selectively functionalized
at the less hindered ortho position, gave the desired phthalides
3la–na in yields of 70–89%. However, 3-methoxy-, 3-chloro-,
and 3-bromo-substituted benzoic acids gave mixtures of re-
gioisomeric products in high yields. A single regioisomeric
product 3ra was obtained from the reaction of 1r with 2a,
but piperonylic acid (1s) delivered two regioisomeric products
3sa and 3sa’ in a ratio of 3:1. The results obtained suggest
that the regioselectivity of the CÀH cleavage in meta-substitut-
ed benzoic acids is controlled by both electronic and steric ef-
fects.[12] Under the optimized reaction conditions, 1- and 2-
naphthoic acid (1t and 1u) also yielded the expected phtha-
lides 3ta and 3ua in yields of 90 and 79%, respectively.
Next, we examined the reactions of a variety of meta-substi-
tuted benzoic acids (1l–q) with 2a. 3-Methyl-, 3-fluoro-, and 3-
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Scope of allenes in the synthesis of phthalides
products 3bj and 3bk, respectively, in moderate yields. Inter-
nal allenes were also reactive under the reaction conditions,
giving the desired phthalides in good yields. The reaction of
1,3-dibenzyl-substituted symmetrical allene 2l with 1b pro-
duced the phthalide product 3bl in a yield of 88%. However,
unsymmetrical internal allenes penta-2,3-dien-1-ylbenzene
(2m) and ethyl hexa-3,4-dienoate (2n) reacted with 1b to give
the regioisomeric products 3bm+3bm’ and 3bn+3bn’, re-
spectively, in good yields with high regioselectivity.
Next, we investigated the scope of allenes in this RhIII-catalyzed
ortho-CÀH activation of aryl carboxylic acids. The reactions of
a variety of allenes were examined with 1b and their results
are shown in Table 3. 3-Methylbenzylallene (2b) gave phthalide
Table 3. Scope of allenes in the reactions leading to phthalide formatio-
n.[a,b]
RhIII-catalyzed [4+1] annulation of vinylic carboxylic acids
and allenes
The reactions of substituted acrylic acids with allenes catalyzed
by the RhIII complex were also investigated.[13] Thus, cinnamic
acid (4a) was treated with 2a under reaction conditions similar
to those shown in Tables 2 and 3 to give 2-furanone derivative
(E)-5-methyl-4-phenyl-5-styrylfuran-2(5H)-one (5aa) in a yield of
28%. Fortunately, the use of Ag2CO3 instead of AgOAc im-
proved the yield of 5aa to 61%. Finally, raising the tempera-
ture to 808C gave 5aa in an isolated yield of 78%. It is worth
mentioning that 2-furanone is an important heterocyclic
moiety found in many natural and biologically active mole-
cules and an intermediate in natural product synthesis.[14] Sev-
eral reports for the synthesis of this type of compounds by
cross-coupling and intramolecular cyclization are known,[15] but
the synthetic method described herein to obtain 5-vinyl-substi-
tuted 2-furanones in a single step from readily available simple
starting compounds is unique.
To probe the scope of the formation of 2-furanone deriva-
tives, we investigated the reactions of different cinnamic acids
with allenes (Table 4). Thus, the treatment of o-, m-, and p-
methylcinnamic acids with 2a afforded the corresponding
[4+1] annulation products 5ba–da in good yields. Owing to
the steric hindrance of the o-methyl substituent, the product
5da was obtained in only a moderate yield. In addition, 4-me-
thoxycinnamic acid (5e) smoothly reacted with 2a to give 5ea
in a yield of 81%. Halogen-substituted cinnamic acids 4 f–h
provided the expected products 5 fa–ha, respectively, in yields
of 73–80%. Furan-substituted acrylic acid 4i was also effective-
ly transformed into lactone 5ia in a yield of 82%. Next, we
treated a-methylcinnamic acid (4j) with 2a under the reaction
conditions, and the expected product 5ja was obtained in
a yield of 92%. Both a- and b-alkyl-substituted acrylic acids
were compatible under the reaction conditions, yielding the
desired products 3ka and 3la in yields of 64 and 83%, respec-
tively. Similarly, a,b-dialkyl-substituted acrylic acids 5m–o un-
derwent [4+1] annulation with 2a to give the corresponding
products 5ma–oa in yields of 83–93%. In a similar manner,
2,3-diphenylacrylic acid (4p) also effectively coupled with 2a
to furnish product 5pa in a yield of 92%. Furthermore, benzo-
thiophene-2-carboxylic acid (4q) underwent the RhIII-catalyzed
[4+1] annulation reaction to give the expected product 5qa in
a yield of 68%.
[a] All reactions were performed by using p-toluic acid (1b; 0.80 mmol),
allene 2 (1.20 mmol), [Cp*RhCl2]2 (0.016 mmol), and AgOAc (1.68 mmol) in
CH3CN (4.0 mL) at 608C for 20 h. [b] Isolated yields. [c] The ratios of re-
gioisomers are given in parentheses and were determined by 1H NMR
analysis.
3bb in a yield of 85%. Similarly, 1-(buta-2,3-dien-1-yl)naphtha-
lene (2c) reacted readily with 1b to give 3bc in a yield of
74%. In addition to benzyl-substituted allenes, alkyl-containing
allenes (2d–f) also underwent the catalytic reaction to afford
the desired [4++1] annulation products in good-to-excellent
yields (Table 3, products 3bd–bf). Penta-3,4-dien-2-ylbenzene
(2g) containing a methyl group at the benzylic position also
afforded the corresponding phthalide 3bg in a yield of 83%
under similar reaction conditions. The reaction of ester-substi-
tuted allene 2h with 1b provided the expected product 3bh
in a yield of 93%. tert-Butyl-substituted allene 2i effectively un-
derwent reaction with 1b to afford the product 3bi in a yield
of 82%. Similarly, hydroxy- and trimethylsilyl-substituted al-
lenes 2j–2k also reacted with 1b to furnish the expected
Next we investigated the scope of allenes in the RhIII-cata-
lyzed vinylic CÀH activation and [4+1] annulation reactions.
Different aryl- and alkyl-substituted terminal allenes efficiently
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corresponding [4+1] annulation products; mixtures of regioi-
someric products were obtained with the unsymmetrical inter-
nal allenes (Table 4, products 5jm and 5jn). The identities of
compounds 5ea, 5ja, and 5jc were further confirmed by
single-crystal X-ray structure analysis.[16]
Table 4. Scope of the RhIII-catalyzed [4++1] annulation of vinylic carboxylic
acids and allenes.[a,b]
Mechanistic studies
To understand the inherent nature of the present CÀH activa-
tion reaction, we determined the inter- and intramolecular ki-
netic isotope effects (KIEs) of the reaction of 1a and 2a. An in-
termolecular KIE (kH/kD) of 2.8 was determined for the reaction
of benzoic acid (1a) and [D5]benzoic acid ([D5]-1a) with 2a
(Scheme 1). Furthermore, an intramolecular competition reac-
tion between [D1]benzoic acid ([D1]-1a) and 2a showed a kH/kD
of 4.5. The large KIEs values observed suggest that the CÀH
cleavage step is the rate-determining step.[17]
Scheme 1. Kinetic isotope experiments.
Based on the experimental results reported herein and exist-
ing literature data,[4,13] a plausible catalytic cycle that describes
the mechanism of this reaction is presented in Scheme 2 with
1a and 2a as the reaction substrates. The catalytic cycle is
likely initiated by the removal of chloride from the RhIII dimer
to form an unsaturated RhIII complex. Next, the coordination of
the carboxylic acid group of 1a to the RhIII center followed by
cyclometalation through ortho-CÀH cleavage leads to five-
membered rhodacycle I. The coordination of allene 2a to I to
give intermediate II and subsequent insertion of the CÀRh
bond into an allene double bond of II provides p-allylic rhoda-
cycle III. Intramolecular nucleophilic addition of the coordinat-
ed carboxylate oxygen to the p-allyl of III followed by protona-
tion gives intermediate IV. b-Hydride elimination of IV leaves
the final product 3aa and RhI. The RhIII-active catalyst is regen-
erated from RhI by AgOAc oxidation.
[a] All reactions were performed by using vinyl carboxylic acid
4
(0.80 mmol), allene 2 (1.20 mmol), [Cp*RhCl2]2 (0.016 mmol), and Ag2CO3
(0.88 mmol) in CH3CN (4.0 mL) at 808C for 20 h. [b] Isolated yields. [c] The
ratios of regioisomers are given in parentheses and were determined by
1H NMR analysis.
Conclusion
participated in the reaction with a-methylcinnamic acid (4j) to
afford the corresponding 2-furanone derivatives in excellent
yields. Both symmetrical and unsymmetrical internal allenes
were compatible under the reaction conditions, affording the
We have developed a novel and efficient method for the syn-
thesis of 3,3-disubstituted phthalides from aryl carboxylic acids
and allenes. The reaction proceeds under mild reaction condi-
tions and has a broad substrate scope. The catalytic reaction
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J=16.0 Hz, 1H), 1.85 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=
169.6 (ester carbonyl), 152.9 (C), 135.5 (C), 134.2 (CH), 130.2 (CH),
129.1 (CH), 128.6 (3 CH), 128.2 (CH), 126.6 (2 CH), 125.8 (CH), 125.1
(C), 121.6 (CH), 86.5 (C), 25.8 ppm (CH3); IR (KBr): n˜ =2923, 1758,
1280, 1126, 1033 and 694 cmÀ1; HRMS (EI+): m/z calcd for C17H14O2:
250.0994; found: 250.1001.
Representative procedure for RhIII-catalyzed 2-furanone for-
mation from vinyl carboxylic acids and allenes
A sealed tube containing cinnamic acid 4a (118 mg, 0.80 mmol),
[Cp*RhCl2]2 (10 mg, 0.016 mmol), and Ag2CO3 (243 mg,
0.880 mmol) was evacuated and purged with nitrogen gas three
times. Then a solution of allene 2a (156 mg, 1.20 mmol) in CH3CN
(4.0 mL) was added to the system by syringe under a nitrogen at-
mosphere and the mixture was stirred at 808C for 20 h. At the end
of the reaction, the mixture was diluted with CH2Cl2 (10 mL) and fil-
tered through a short pad of Celite, which was washed with CH2Cl2
(3”20 mL). The combined filtrates were concentrated under re-
duced pressure and the crude mixture purified by silica gel column
chromatography using n-hexane/EtOAc (80:20) as eluent to afford
the desired pure product 5aa in a yield of 78% (172 mg).
Scheme 2. Proposed reaction mechanism.
occurs through RhIII-catalyzed carboxylic acid assisted ortho-CÀ
H bond activation and annulation reactions. Kinetic isotope ex-
periments revealed that the rate-limiting step involves CÀH
cleavage. This RhIII-catalyzed CÀH activation and [4+1] annula-
tion reaction has been successfully extended to a,b-unsaturat-
ed carboxylic acids to give highly substituted 2-furanone. Fur-
ther extension of this reaction to asymmetric systems and de-
tailed mechanistic studies are now in progress.
(E)-5-Methyl-4-phenyl-5-styrylfuran-2(5H)-one (5aa): Pale-yellow
1
oily liquid (172 mg, 78%); H NMR (400 MHz, CDCl3): d=7.60 (d, J=
6.4 Hz, 2H), 7.46–7.29 (m, 8H), 6.80 (d, J=16.0 Hz, 1H), 6.35 (s, 1H),
6.34 (d, J=16.0 Hz, 1H), 1.85 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=171.5 (ester carbonyl), 170.1 (C), 135.5 (C), 132.9 (CH),
131.0 (CH), 129.9 (C), 129.0 (2 CH), 128.7 (2 CH), 128.6 (CH), 127.8
(2 CH), 127.5 (CH), 126.8 (2 CH), 114.5 (CH), 87.9 (C), 23.7 ppm
(CH3); IR (KBr): n˜ =2923, 1751, 1612, 1450, 1241, 964, 771,
694 cmÀ1; HRMS (EI+): m/z calcd for C19H16O2: 276.1150; found:
276.1152.
Experimental Section
General information
Acknowledgements
Unless otherwise stated, all catalytic reactions were performed
under a nitrogen atmosphere on a dual-manifold Schlenk line and
in oven-dried glassware. All reagents were purchased commercially
and used without further purification. Reagent grade acetonitrile
(J. T. Baker) was distilled and dried over CaH2 prior to use. NMR
spectra (1H and 13C) were measured on a Varian MERCURY 400 MHz
spectrometer. High resolution (HR) mass data were measured with
a Thermo Finnigan MAT 95XL spectrometer. Infrared spectra were
recorded on a HORIBA FT-IR 720 using KBr plates.
We thank the Ministry of Science and Technology of the Re-
public of China (MOST-103–2633M-007-001) for support of this
research.
Keywords: allenes · annulation · carboxylic acids · CÀH
activation · reaction mechanisms · rhodium
Representative procedure for RhIII-catalyzed phthalide for-
mation from aromatic carboxylic acids and allenes
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A sealed tube containing benzoic acid 1a (100 mg, 0.80 mmol),
[Cp*RhCl2]2 (10 mg, 0.016 mmol), and AgOAc (279 mg, 1.680 mmol)
was evacuated and purged with nitrogen gas three times. Then
a solution of allene 2a (156 mg, 1.20 mmol) in CH3CN (4.0 mL) was
added to the system by syringe under a nitrogen atmosphere and
the mixture was stirred at 608C for 20 h. At the end of the reaction,
the mixture was diluted with CH2Cl2 (10 mL) and filtered through
a short pad of Celite, which was washed with CH2Cl2 (3”20 mL).
The combined filtrates were concentrated under reduced pressure
and the crude mixture purified by silica gel column chromatogra-
phy using n-hexane/EtOAc (80:20) as eluent to afford the desired
pure product 3aa in a yield of 88% (176 mg).
(E)-3-Methyl-3-styrylisobenzofuran-1(3H)-one (3aa): Pale-yellow
1
oily liquid (176 mg, 88%); H NMR (400 MHz, CDCl3): d=7.90 (d, J=
8.0 Hz, 1H), 7.69 (t, J=7.6 Hz, 1H), 7.53 (t, J=8.4 Hz, 1H), 7.46 (d,
J=7.6 Hz, 1H), 7.36–7.26 (m, 5H), 6.70 (d, J=16.0 Hz, 1H), 6.37 (d,
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Received: March 21, 2015
Published online on May 11, 2015
Chem. Eur. J. 2015, 21, 9198 – 9203
www.chemeurj.org
9203
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