An aerobic [2 + 2 + 2] cyclization via chloropalladation: From 1,6-diynes and acrylates to substituted aromatic carbocycles

Article abstract of DOI:10.1021/jo200572n

A Pd-catalyzed aerobic [2 + 2 + 2] cyclization of 1,6-diynes and acrylates proceeding through a chloropalladation process has been developed. Polysubstituted five-membered aromatic carbocycles/heterocycles were obtained in good to excellent yields. The re

Full text of DOI:10.1021/jo200572n

NOTE
pubs.acs.org/joc
An aerobic [2 þ 2 þ 2] Cyclization via Chloropalladation: From
1,6-Diynes and Acrylates to Substituted Aromatic Carbocycles
Peng Zhou, Meifang Zheng, Huanfeng Jiang,* Xianwei Li, and Chaorong Qi
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, P. R. China
S Supporting Information
b
ABSTRACT: A Pd-catalyzed aerobic [2 þ 2 þ 2] cyclization of
1,6-diynes and acrylates proceeding through a chloropalladation
process has been developed. Polysubstituted five-membered
aromatic carbocycles/heterocycles were obtained in good to
excellent yields. The results of the mechanistic study are
consistent with the proposed reaction mechanism.
olysubstituted aromatic carbocycles/heterocycles are ubiqui-
tously found in biologically interesting molecules and ther-
alkenes. This chemistry can also provide a versatile synthesis
for polysubstituted aromatic compounds with interesting
properties.6
P
apeutic agents. One of the most versatile and efficient approaches
to synthesize functionalized aromatic carbocycles is the transition-
metal-catalyzed [2 þ 2 þ 2] cycloaddition reaction, which involves
multiple bond formation processes in a single transformation.1
In particular, Rh-, Ru-, Pd-, Ni-, and Co-catalyzed [2 þ 2 þ 2]
cycloaddition reactions have been reported to afford arene scaf-
folds bearing diverse functional groups.2 Generally, these reactions
proceed via a common metallacyclopentadiene intermediate A
(Scheme 1), which is presumably generated from the oxidative
addition of alkynes to metal catalysts, and subsequent reductive
elimination reaction would afford aromatic carbocycle/hetero-
cycle products. However, precious ligands are often required to
improve the turnover numbers of these catalytic processes.
Plus, the reaction scope is limited, and only certain types of
substrates could afford respectful yields of the desired products.
Herein, we report a ligand-free, Pd-catalyzed aerobic [2 þ 2 þ 2]
cyclization reaction for the synthesis of complex aromatic
carbocycles and heterocycles, which provides a highly efficient
strategy to prepare poly substituted Indane, 2,3-dihydro-1H-
isoindole, 1,3-dihydro-isobenzofuran, and 3H-isobenzofuran-
1-one derivatives.
Recently, we have developed novel syntheses of multisubsti-
tuted arenes via palladium-catalyzed aerobic [2 þ 2 þ 2]
cyclizations of alkenes and alkynes. A unique reaction mechanism
which goes through the chloropalladation process has been
proposed to explain the formation of desired products.3 In
addition, a palladium-catalyzed 1:2 linear/cyclic cross-trimeriza-
tion of alkyne with alkenes has been carried out to support the
proposed reaction mechanism (Scheme 1).4 However, our
efforts to detect and separate the key intermediate vinylpalladium
complex B were not fruitful.5 Since we envisioned that the
cyclization reaction of 1,6-diynes through intermediate B might
provide important mechanistic information about this novel
chloropalladation process, we have devoted our efforts to develop
a tandem cycloaddition-cyclization reaction of alkynes and
In order to obtain optimal reaction conditions, 1,7-diphenyl-
hepta-1,6-diyne (1a) and ethyl acrylate (2b) were allowed to
react in the presence of different catalysts, oxidants, and solvents
as shown in Table 1. Initially, the reaction was conducted using
previously reported conditions (5 mol % of PdCl2, 5 atm of
dioxygen in wet DMF at 80 °C for 24 h), and a 34% yield of the
desired product (3ab) was obtained (Table 1, entry 1). When the
pressure of dioxygen was decreased to 1 atm, only a 22% yield of
the indan product was evident as indicated by GCꢀMS analysis
(entry 2). To our delight, when CuCl2 2H2O (5 mol %) was
3
employed as co-oxidant, this transformation afforded a 79% yield
of the desired product (entry 3). Other cooxidants, such as
Cu(OAc)2, CuBr2, Ag2CO3, PIDA (iodosobenzene diacetate),
and BQ (1,4-benzoquinone) had also been examined in this
system, but none of these reactions afforded higher yields
(entries 4ꢀ8). Subsequently, Pd(OAc)2 was employed in this
transformation, but only 13% of the desired product was formed
(entries 9 and 10). We also closely examined the effect of
solvents, and it appears that NMP is the most suitable solvent
for this reaction (entry 11 vs entries 12ꢀ14). For instance, when
CH3CN was employed as solvent, a side reaction involving [2 þ
2 þ 2] cycloaddition of alkyne and acetonitrile proceeds pre-
dominantly (entry 13).7 Using CuCl2 2H2O as the sole oxidant
3
dramatically decreased the reaction efficiency, and a 44% yield of
3ab was obtained (entry 15). Thus, the best conditions for this
novel [2 þ 2 þ 2] cyclizationreaction are:5 mol % PdCl2, 5 mol %
CuCl2 2H2O and 1 atm dioxygen in NMP at 90 °C for 24 h
3
(Table 1, entry 12).8
With the optimal conditions in hand, we next examined the
scope and limitations of this methodology. A variety of 1,6-diynes
and alkenes had been employed in this transformation, and
Received: March 18, 2011
Published: May 02, 2011
r
2011 American Chemical Society
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NOTE
Scheme 1. (a) Transition-Metal-Catalyzed [2 þ 2 þ 2] Cycloaddition through Metalcyclopentadiene. (b) Our Aerobic
Cyclizations Triggered by Chloropalladation
3H-isobenzofuran-1-one 3kb-a and 3kb-b in a 8:92 ratio (entry
15). However, when 3-phenylprop-2-ynyl but-2-ynoate(1l) was
treated with methyl acrylate (2a), the reaction provided a good
yield of 3la but with lower regioselectivity than 3kb, which means
the electron effect of 1,6-diynes cannot effect the reaction’s
selectivity obviously but the steric effect can. In summary, this
novel [2 þ 2 þ 2] cycloaddition reaction provides a viable route to
a variety of substituted five-membered aromatic compounds.
A plausible mechanism for this Pd-catalyzed [2 þ 2 þ 2]
cycloaddition reaction is proposed in Scheme 2. Intermediate B
was first generated by the chloropalladation of diyne 1a with
Pd(II) species. Subsequent intermolecular Heck reaction with
ethyl acrylate would be expected to afford triene C. Vinylpalladium
intermediate D was then generated by the oxidative addition of
triene C to Pd(0) species, and an intramolecular Heck reaction
would lead to the desired product 3ab. Finally, dioxygen and
Table 1. Optimization of Reaction Conditions for the [2 þ 2
þ 2] Cyclization of 1a and 2ba
Pd
yieldb
entry (5 mol %)
oxidant
solvent (%)
1c
2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
O2 (5 atm)
O2 (1 atm)
DMF
DMF
34
22
3
O2 (1 atm)/CuCl2 2H2O (5 mol %) DMF
79
3
CuCl2 2H2O oxidize Pd(0) to Pd(II) to complete the catalytic
4
O2 (1 atm)/Cu(OAc)2 (5 mol %)
O2 (1 atm)/CuBr2 (5 mol %)
O2 (1 atm)/Ag2CO3 (5 mol %)
O2 (1 atm)/PhI(OAc)2 (5 mol %)
O2 (1 atm)/BQ (5 mol %)
DMF
DMF
DMF
DMF
DMF
73
3
cycle. Consequently, the formation of intermediate C appears to
be crucial for the success of the reaction, and it could also provide
insightful information with regard to understand the reaction
mechanism. Indeed, vinyl chloride C has been isolated from the
reaction solution of the controlled experiments (Scheme 3), which
is consistent with the proposed reaction mechanism. Plus, further
study indicated that the formation vinylchloride C could be
5
trace
26
6
7
trace
14
8
9
Pd(OAc)2 O2 (1 atm)/CuCl2 2H2O (5 mol %) DMF
13
3
10
O2 (1 atm)/CuCl2 2H2O (5 mol %) DMF
0
3
11 PdCl2
12 PdCl2
13 PdCl2
14 PdCl2
15 PdCl2
O2 (1 atm)/CuCl2 2H2O (5 mol %) NMP
87
promoted via increasing the amount of CuCl2 2H2O used.
3
3
O2 (1 atm)/CuCl2 2H2O (5 mol %) DMA
81
Additionally, when intermediate C was allowed to react under
standard conditions but in the absence of dioxygen, compound
3ab was obtained in 91% yield, suggesting the involvement of
intermediate C in the catalytic cycle.9 However, when C was
treated under standard conditions but without PdCl2, a trace 3ab
was obtained, which suggests the transformation of C to 3ab
should be a Heck cross-coupling but not an electrocyclic reaction.
In summary, we have developed an aerobic and general [2 þ
2 þ 2] cyclization for the synthesis of polysubstituted aromatic
carbocycles/heterocycles from readily available 1,6-diynes and
acrylates through a tanden process. The key most absorbing point
is the detection of intermediate C had been successfully isolated
and characterized, and which is the first mechanistic evidence in
[2þ 2þ 2] cyclization reactions via chloropalladation process. Plus,
this methodology is highly valuable for the synthesis of substituted
aromatic carbocycles/heterocycles, which had found numerous
applications in theraputic reagents and optoelectronic materials.
3
O2 (1 atm)/CuCl2 2H2O (5 mol %) CH3CN traced
3
O2 (1 atm)/CuCl2 2H2O (5 mol %) dioxane 34
3
CuCl2 2H2O (100 mol %)
NMP
44
3
a Reaction was carried out using 1a (0.5 mmol), 2b (0.6 mmol), [Pd]
catalyst (5 mol %), oxidant, and 2 mL of solution in a capped tube,
heating at 90 °C for 24 h. b Determined by GC. c The reaction was
carried out in a 15 mL autoclave. d With products from the cycloaddition
of 1a and CH3CN.
representative examples are summarized in Table 2. Alkenes
bearing electron-withdrawing groups afford good to excellent
yields of the substituted indan derivatives (Table 2, entries
1ꢀ5). 1,7-Diaryl-1,6-diynes bearing either electron-withdrawing
or electron-donating substituents on the aryl groups afford 79ꢀ91%
yields of the desired products (entries 6ꢀ12). It appears that
N-substituted 1,6-diyne could also be employed in this reaction,
and a 91% yield of 2,3-dihydro-1H-isoindole has been obtained
after chromatography (entry 13). We have successfully extended
this chemistry to the synthesis of 1,3-dihydro-isobenzofuran, and
a 93% yield of the expected product was obtained (entry 14).
Finally, an unsymmetrical 1,6-diyne source, 3-phenylprop-2-
ynyl oct-2-ynoate (1k), afforded a 89% yield of two isomeric
’ EXPERIMENTAL SECTION
General Procedure. To a 25 mL round-bottom flask were added
PdCl2 (4.4 mg, 5 mol %), CuCl2 2H2O (4.2 mg, 5 mol %), and 1a (122
3
mg, 0.5 mmol). The flask was then purged with O2 for three times, followed
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Table 2. [2 þ 2 þ 2] Cyclization of 1,6-Diyne and Alkene via Chloropalladation processa,b
a Reaction conditions: 1,6-diyne (0.5 mmol), alkene (0.6 mmol), PdCl2 (5 mol %), CuCl2 2H2O (5 mol %), and 2 mL of solution in a
3
capped tube with 1 atm of oxygen, heating at 90 °C for 24 h. b Isolated yield. c At 75 °C for 24 h; the ratio of a/b was determined by GCꢀMS and
1H NMR.
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Scheme 2. Proposed Mechanism
Research Program of China (973 Program) (2011CB808600),
Doctoral Fund of Ministry of Education of China
(20090172110014), and Guangdong Natural Science Founda-
tion (10351064101000000) for financial support.
’ REFERENCES
(1) For selected reviews on transition-metal-catalyzed [2 þ 2 þ 2]
cycloadditions, see: (a) Varela, J. A.; Saꢀa, C. Chem. Rev. 2003,
103, 3787–3801. (b) Kotha, S.; Brahmachary, E.; Lahiri, K. Eur. J. Org.
Chem. 2005, 4741–4767. (c) Gandon, V.; Aubert, C.; Malacria, M.
Chem. Commun. 2006, 2209–2217. (d) Chopade, P. R.; Louie, J. Adv.
Synth. Catal. 2006, 348, 2307–2327. (e) Shibata, T.; Tsuchikama, K. Org.
Biomol. Chem. 2008, 6, 1317–1323. (f) Heller, B.; Hapke, M. Chem. Soc.
Rev. 2007, 36, 1085–1094.
(2) For selected examples, see the following references. Rh-
catalyzed: (a) Konno, T.; Moriyasu, K.; Kinugawa, R.; Ishihara, T.
Org. Biomol. Chem. 2010, 8, 1718–1724. (b) Kaloko, J. J.; Teng, Y. -H.
G.; Ojima, I. Chem. Commun. 2009, 4569–4571. (c) Shibata, T.; Otomo,
M.; Tahara, Y. -K.; Endo, K. Org. Biomol. Chem. 2008, 6, 4296–4298.
(d) Sagae, H.; Noguchi, K.; Hirano, M.; Tanaka, K. Chem. Commun.
2008, 3804–3806. (e) Tanaka, K.; Kamisawa, A.; Suda, T.; Noguchi, K.;
Hirano, M. J. Am. Chem. Soc. 2007, 129, 12078–12079. Ru-catalyzed:
(f) Yamamoto, Y.; Takagishi, H.; Itoh, K. Org. Lett. 2001, 3, 2117–2119.
(g) Yamamoto, Y.; Kitahara, H.; Hattori, R.; Itoh, K. Organometallics
1998, 17, 1910–1912. (h) Paih, J. L.; Monnier, F.; Dꢀerien, S.; Dixneuf,
P. H.; Clot, E.; Eisenstein, O. J. Am. Chem. Soc. 2003, 125, 11964–11975.
Pd-catalyzed: (i) Singidi, R. R.; Kutney, A. M.; Gallucc, J. C.; RajanBabu,
T. V. J. Am. Chem. Soc. 2010, 132, 13078–13087. Ni-catalyzed:
(j) Iwayama, T.; Sato, Y. Chem. Commun. 2009, 5245–5247. (k) Saito,
N.; Shiotani, K.; Kinbara, A.; Sato, Y. Chem. Commun. 2009, 4284–4286.
(l) Jeevanandam, A.; Korivi, R. P.; Huang, I.-W.; Cheng, C.-H. Org. Lett.
2002, 4, 807–810. (m) Hsieh, J.-C.; Cheng, C.-H. Chem. Commun.
2008, 2992–2994. (n) Ogoshi, S.; Nishimura, A.; Ohashi, M. Org. Lett.
2010, 12, 3450–3452. Co-catalyzed: (o) Zhou., Y.; Porco, J. A.; Snyder,
J. K. Org. Lett. 2007, 9, 393–396. (p) Chang, H.-T.; Jeganmohan, M.;
Cheng, C.-H. Org. Lett. 2007, 9, 505–508. (q) Bonaga, L. V. R.; Zhang,
H.-C.; Gauthier, D. A.; Reddy, I.; Maryanoff, B. E. Org. Lett. 2003,
5, 4537–4540. (r) Sternberg, E. D.; Vollhardt, K. P. C. J. Org. Chem.
1984, 49, 1564–1573. (s) Gandon, V.; Leca, D.; Aechtner, T.; Vollhardt,
K. P. C.; Malacria, M.; Aubert, C. Org. Lett. 2004, 6, 3405–3407.
(3) (a) Jiang, H.; Shen, Y.; Wang, Z. Tetrahedron Lett. 2007,
48, 7542–7545. (b) Shen, Y.; Jiang, H.; Chen, Z. J. Org. Chem. 2010,
75, 1321–1324.
Scheme 3. Controlled Experiments
by addition of 2b (60 mg, 0.6 mmol) and NMP (2 mL). The formed
mixture was gradually heated from rt to 90 °C under O2 (1 atm keeped with
a balloon) and stirred for 24 h as monitored by TLC. The solution was then
cooled to rt, diluted with ether (30 mL), washed with H2O (3 ꢁ 10 mL),
dried over MgSO4, filtered, and evaporated under vacuum. The crude
product was purified by TLC on silica gel to afford a benzo-fused five-
membered cycle whose structure was determined by 1H NMR, 13C NMR,
MS, NOE. Compound 3ab: colorless oil; 1H NMR (CDCl3, 400 MHz) δ
7.77 (s, 1H), 7.49ꢀ7.51 (m, 2H), 7.43ꢀ7.46 (m, 2H), 7.31ꢀ7.41 (m, 4H),
7.26 (s, 2H), 4.02 (q, J = 6.6 Hz, 2H), δ 3.04 (t, J = 6 Hz, 2H), 2.76 (t, J = 6
Hz, 2H), 1.96ꢀ2.03 (m, 2H), 0.93 (t, J = 8 Hz, 3H); 13C NMR (CDCl3,
100 MHz) δ 168.5, 145.7, 144.8, 140.5, 140.3, 137.6, 137.1, 129.9, 128.5,
128.4, 128.3, 127.9, 127.2, 126.8, 60.6, 33.4, 32.8, 25.6, 13.6; MS (EI, 70 eV)
m/z 342 (Mþ, 100), 297 (60), 269 (40), 252 (29), 149 (20). Anal. Calcd
for C24H22O2: C, 84.18; H, 6.48. Found: C, 84.26; H, 6.40.
(4) Zhou, P.; Huang, L.; Jiang, H.; Wang, A.; Li, X. J. Org. Chem.
2010, 75, 8279–8282.
(5) For a review on chloropalladation, see: (a) Lu, X. Handbook of
Organopalladium Chemistry for Organic Synthesis; Meijere, A. D., Negishi,
E., Ed.; Wiley-Interscience: New York, 2002; Vol. 2, pp 2267ꢀ2288.
For selected examples, see: (b) Ma, S.; Lu, X. J. Org. Chem. 1991,
56, 5120–5125. (c) Zhu, G.; Lu, X. Organometallics 1995,
14, 4899–4904. (d) Ma, S.; Wu, B.; Zhao, S. Org. Lett. 2003,
5, 4429–4432. (e) Huang, X. C.; Wang, F.; Liang, Y.; Li, J. H. Org. Lett.
2009, 11, 1139–1142. (f) Li, Y.; Jardine, K.; Tan, R.; Song, D.; Dong,
V. M. Angew. Chem., Int. Ed. 2009, 48, 9690–9692. (g) Yin, G.; Liu, G.
Angew. Chem., Int. Ed. 2008, 47, 5442–5445.
’ ASSOCIATED CONTENT
S
Supporting Information.
Full experimental details
b
and copies of NMR spectral data. This material is available free
of charge via the Internet at http://pubs.acs.org.
(6) For selected examples on 1,6-diynes, see: (a) Tanaka, K.; Otake,
Y.; Wada, A.; Noguchi, K.; Hirano, M. Org. Lett. 2007, 9, 2203–2206.
(b) Matsuda, T.; Kadowaki, S.; Goya, T.; Murakami, M. Org. Lett. 2007,
9, 133–136.
’ AUTHOR INFORMATION
(7) (a) Yong, L.; Butensch€on, H. Chem. Commun. 2002, 2852–2853.
(b) Bo~naga, L. V. R.; Zhang, H.-C.; Moretto, A. F.; Ye, H.; Gauthier,
D. A.; Li, J.; Leo, G. C.; Maryanoff, B. E. J. Am. Chem. Soc. 2005,
127, 3473–3485. (c) Bo~naga, L. V. R.; Zhang, H.-C.; Gauthier, D. A.;
Reddy, I.; Maryanoff, B. E. Org. Lett. 2003, 5, 4537–4540.
(8) For selected papers using the system of Pd(II)/Cu(II)/O2, see:
(a) Ren, W.; Xia, Y.; Ji, S.; Zhang, Y.; Wan, X.; Zhao, J. Org. Lett. 2009,
11, 1841–1844. (b) Jia, X.; Yang, D.; Zhang, S.; Cheng, J. Org. Lett. 2009,
Corresponding Author
*E-mail: jianghf@scut.edu.cn.
’ ACKNOWLEDGMENT
We are grateful to the National Natural Science Foundation
of China (20625205, 20772034, and 20932002), National Basic
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11, 4716–4719. (c) Jonasson, C.; Horvꢀath, A.; B€ackvall, J. J. Am. Chem.
Soc. 2000, 122, 9600–9609. (d) Aouf, C.; Thiery, E.; Bras, J. L.; Muzart, J.
Org. Lett. 2009, 11, 4096–4099.
(9) C was isolated with TLC. The isolated intermediate C appears to
be a single stereoisomer as indicated by NMR and GCꢀMS. NOE
studies for C:
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