Metal-controlled cycloaddition of 2-alkynyl-1,4-benzoquinones and styrenyl systems: Lewis acid versus π acid

Article abstract of DOI:10.1021/ol400956h

Metal-controlled cycloaddition of 2-alkynyl-1,4-benzoquinones and electron-rich styrenyl systems were investigated. The density functional theory (DFT) calculations revealed that the regioselectivity of the cycloaddition results from the different activat

Full text of DOI:10.1021/ol400956h

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Metal-Controlled Cycloaddition
of 2‑Alkynyl-1,4-benzoquinones and
Styrenyl Systems: Lewis Acid versus π Acid
Li Zhang, Zhiming Li,* and Renhua Fan*
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai, 200433, China
rhfan@fudan.edu.cn; zmli@fudan.edu.cn
Received April 7, 2013
ABSTRACT
Metal-controlled cycloaddition of 2-alkynyl-1,4-benzoquinones and electron-rich styrenyl systems were investigated. The density functional
theory (DFT) calculations revealed that the regioselectivity of the cycloaddition results from the different activation modes of Bi(OTf)3 and AuCl.
Cycloaddition between 1,4-benzoquinones and alkenes
is a valuable transformation in organic synthesis.1 It
has become a classical and commonly used approach to
prepare various dihydrobenzofurans2 and indoles.3 For
substituted 1,4-benzoquinones, regiocontrolled cycloaddi-
tion is essential to make this reaction practically useful.
The Engler group investigated the reaction of alkoxy-1,4-
benzoquinones and styrenes.4 They found that the regio-
selectivity depends on the nature and the number of equiva-
lents of Lewis acid used as promoters. Bidentate binding of
the Lewis acid to the C-1 carbonyl group and the C-2
alkoxy oxygen or monodentate binding of the Lewis acid
to the C-4 carbonyl group leads to different cycloaddition
products.
Recently, we have directed our focus to the synthetic
application of the dearomatization of 2-alkynyl phenols
and 2-alkynyl anilines.5 We found that the oxidation of
2-(2-phenylethynyl)phenol with 2 equiv of PhI(OAc)2 in
methanol formed 2-(2-phenylethynyl)-1,4-benzoquinone
1a.6 Since there are multiple reaction sites in the structure
of 2-alkynyl-1,4-benzoquinones, we were interested in
the regioselectivity of their cycloaddition with alkenes.
The reaction might be promoted via various ways and
form three cycloaddition products 3, 4, and 5 (Scheme 1).
When a Lewis acid was employed, it might coordinate with
(1) (a) Uno, H. J. Org. Chem. 1986, 51, 350. (b) Kraus, G. A.; Shi, J.
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Zh. 2008, 52, 57.
r
10.1021/ol400956h
XXXX American Chemical Society

the C-1 orthe C-4 carbonyl group via a monodentate mode
(intermediates I and II). The Lewis acid might also co-
ordinate with the C-1 carbonyl group and the C-2 triple
bond via a bidentate mode (intermediate III). When a
π acid was used, it might coordinate with the C-2 triple
bond via a monodentate mode (intermediate IV). This
activation might induce the nucleophilic attack of the C-1
carbonyl oxygen on the electron-deficient triple bond to
generate an oxonium ion (intermediate V) or a carbocation
(intermediate VI).7
Table 1. Evaluation of Metal Saltsa
entry
catalyst
3aa (%)b
5aa (%)b
To begin our study, we chose 4-methoxystyrene as the
reaction partner of 2-(2-phenylethynyl)-1,4-benzoquinone
to evaluate the catalytic activities of various metal salts.
The reactions were conducted in acetonitrile at room
temperature in the presence of 0.1 equiv of catalyst, and
representative results are shown in Table 1. The generation
of compound 3aa was observed when gold(I) salts were
used (Table 1, entries 1ꢀ3). Compound 3aa was isolated
in a 33% yield from the reaction using gold(I) chloride as
the catalyst.8 In(III), Fe(III), Ru(III), Pt(II), Cu(II), and
Bi(III) salts exhibited different catalytic activities in the
formation of product 5aa, and Bi(OTf)3 was the best
catalyst. The formation of compound 4aa was not ob-
served in all reactions.
1
Ph3PAuOTf
Ph3PAuSbF6
AuCl
<5
17
33
0
0
2
0
3
0
4
AuCl3
0
5
Pd(OAc)2
PdCl2(CH3CN)2
AgOTf
0
0
6
0
0
7
0
0
8
Rh(PPh3)3Cl
Co(acac)3
CuCl
0
0
9
<5
0
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
0
TiCl4
0
0
InCl3
0
12
63
56
65
28
58
66
0
FeCl3
0
RuCl3
0
PtCl2
0
CuCl2
0
Cu(OTf)2
Bi(OTf)3
Zn(OTf)2
Fe(OTf)2
Ni(OTf)2
Yb(OTf)3
Dy(OTf)3
0
0
Scheme 1. Cycloaddition of 2-Alkynyl-1,4-benzoquinones and
Electron-Rich Alkenes
0
0
0
0
0
0
0
0
0
a General reaction conditions: Reactions performed on 0.2 mmol
scale using 2 equiv of 2a, 10 mol % catalyst in CH3CN (2 mL) at 25 °C.
b Reported yields are of the isolated product based on compound 1a.
To gain more insight into the reaction regioselectivity,
the B3LYP density functional theory (DFT) calculations
were performed with the Gaussian 09 package using the
6-31þG(d,p) basis set for the main group atoms and the
LANL2DZ basis set for Au and Bi atoms.9 The other
calculation details were provided in the Supporting Infor-
mation. The condensed Fukui function, introduced in the
DFT by Parr and Yang,10 is the most important local
(9) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.;
Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.;
Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara,
M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.;
Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, Jr., J. A.;
Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin,
K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.;
Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.;
Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich,
(7) (a) Yao, T.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2004,
126, 11164. (b) Yao, T.; Zhang, X.; Larock, R. C. J. Org. Chem. 2005, 70,
7679. (c) Zhang, G.; Huang, X.; Li, G.; Zhang, L. J. Am. Chem. Soc.
2008, 130, 1814. (d) Xiao, Y.; Zhang, J. Angew. Chem., Int. Ed. 2008, 47,
1903. (e) Liu, F.; Yu, Y.; Zhang, J. Angew. Chem., Int. Ed. 2009, 48, 5505.
(f) Liu, F.; Qian, D.; Li, L.; Zhao, X.; Zhang, J. Angew. Chem., Int. Ed.
2010, 49, 6669.
(8) Mehta, S.; Larock, R. C. J. Org. Chem. 2010, 75, 1652. (b)
Nielsen, C. B.; Brock-Nannestad, T.; Reenberg, T. K.; Hammershøj,
P.; Christensen, J. B.; Stouwdam, J. W.; Pittelkow, M. Chem.;Eur. J.
2010, 16, 13030. (c) Wang, T.; Li, Z.-Y.; Xie, A.-L.; Yao, X.-J.; Cao,
X.-P.; Kuck, D. J. Org. Chem. 2011, 76, 3231.
€
S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.;
Fox, D. J. Gaussian 09, revision A.02; Gaussian, Inc.: Wallingford CT, 2009.
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and Molecules; Oxford University Press: New York, 1999. (b) Yang, W.;
Mortier, W. J. J. Am. Chem. Soc. 1986, 108, 5708.
B
Org. Lett., Vol. XX, No. XX, XXXX

reactivity index. It has become a valuable tool to deal with
the site selectivity in a wide range of organic reactions.11
For the nucleophilic attack of the atom site k of the mole-
cule, the condensed Fukui function is defined as the fol-
lowing equation in terms of the atomic charges:9
reaction is the funan-like intermediate V (Figure 1,
bottom). It is more stable by more than 20 kcal/mol than
the other four intermediates. This result is in line with the
concept of a carbophile π acid. That is to say, the different
favored activation modes for Bi(OTf)3 and AuCl result
inherently from the nature of the metal salts: Bi(OTf)3 acts
as a Lewis acid, and AuCl acts as a π acid.
fkþ ¼ qk(N) ꢀ qk(N þ 1)
On the basis of the NBO (natural bond orbital) analysis
of the intermediate Vin the AuCl catalyzed reaction (Table 2),
the C-3 position is more positively charged (ꢀ0.19) compared
to the C-5 (ꢀ0.26) and the C-6 (ꢀ0.29) position. The con-
densed Fukui function also predicts that the nucleophilic
attack will occur at the C-3 position. At the same time, the
NBO analysis and the condensed Fukui function of the
intermediate II in the Bi(OTf)3 catalyzed reaction reveal
that there is a preference at the C-6 position for the
nucleophilic attack. These results are in good agreement
with the experimental results.
Additionally, all the [3 þ 2] cycloaddition transition
states for the Bi(OTf)3 or the AuCl catalyzed reaction were
located. The potential energy surfaces indicate that both
reactions can proceed with reasonable activation barriers.
The Bi(OTf)3 catalyzed reaction features a highly asyn-
chronous concerted pathway. The AuCl catalyzed reaction
proceeds in a stepwise pathway. For the Bi(OTf)3 catalyzed
reaction, the real catalytic species is not clear. Bi(OTf)2þ is
also a possible catalytic species for this reaction.12
After various solvents, temperatures, and ratios of
reagents were screened, the optimal reaction conditions
were established. Compared with the Bi(OTf)3 catalyzed
reaction (the optimized conditions: 0.1 equiv of Bi(OTf)3,
CH3CN, 0 °C, 3 h), a higher reaction temperature (50 °C)
and a longer reaction time (10 h) with THF as solvent were
required for the AuCl catalyzed reaction. With the optimized
reaction conditions in hand, the reaction scope was investi-
gated (Table 3). Notably, all reactions were regioselective
under the conditions A or B. A variety of electron-rich
styrenyl systems were found to be suitable cycloaddi-
tion partners. For example, when 1-methoxy-4-(prop-1-
en-2-yl)benzene 2e was used, the AuCl catalyzed reaction
produced product 3ae in a 71% yield, and the Bi(OTf)3
catalyzed reaction provided product 5ae in an almost
quantitative yield. When styrene or 4-methylstyrene was
used, no reaction was observed under the standard condi-
tions. 2-Alkynyl-1,4-benzoquinones bearing an electron-
rich or -poor aryl group, a tert-butyl or a n-butyl group, a
cyclopropyl group, or a hydrogen atom were readily
accommodated in both transformations. When substrate
1i bearing a TMS group was employed, the reactions were
complex, and no desired products were isolated. The
structures of products were confirmed by single-crystal
diffraction analysis of compounds 3ee and 5ee.
Figure 1. Optimized structures of intermediate II with Bi(III) as
the catalyst (top) and intermediate V with Au(I) as the catalyst
(bottom). The numbers in parentheses are the NBO charges on
atoms, and the numbers in square brackets are the condensed Fukui
functions. For clarity, the counterion (trifluoromethanesulfonate
anion) is omitted for the Bi(III) catalyst.
For the Bi(OTf)3 catalyzed reaction, we could not locate
the stable structure of intermediate III or IV. The optimi-
zation led to the monodentate mode structure I due to the
apparent Lewis acid character of the Bi(III) salt. However,
this optimized structure is unstable by 3.18 kcal/mol com-
pared with the most favored intermediate II (Figure 1,
top). Although the funan-like intermediate V was
located as well, the relative energy from intermediate II is
9.16 kcal/mol, which means that intermediate V is very
unstable. Meanwhile, the computational results indicated
that the most stable intermediate for the AuCl catalyzed
In conclusion, we have developed a metal-controlled
cycloaddition of 2-alkynyl-1,4-benzoquinones and electron-
rich styrenyl systems. The density functional theory calcula-
tions revealed that the regioselectivity of the cycloaddition
(11) (a) Chattaraj, P. K.; Sarkar, U.; Roy, D. R. Chem. Rev. 2006,
106, 2065. (b) Ayers, P. W.; Parr, R. G. J. Am. Chem. Soc. 2000, 122,
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2010. (c) Perez, P.; Toro-Labbe, A.; Aizman, A.; Contreras, R. J. Org.
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Chem. 2002, 67, 4747. (d) Pinter, B.; De Proft, F.; Veszpremi, T.;
Geerlings, P. J. Org. Chem. 2008, 73, 1243.
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8527.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 2. NBO Charges Based on Electrostatic Potential and Condensed Fukui Function Calculation at B3LYP/6-31G(d)/LANL2DZ
NBO charges
condensed Fukui functions
computationally
experimentally
entry
catalyst
intermediate
C-3
C-5
C-6
C-3
C-5
C-6
preferred carbon preferred carbon
1
2
AuCl
V
ꢀ0.19 ꢀ0.26 ꢀ0.29
ꢀ0.27 ꢀ0.24 ꢀ0.23
0.08
0.04
0.04
0.08
0.02
0.48
C-3
C-6
C-3
C-6
Bi(OTf)3
II
Table 3. Reactions Scope Investigationa
conditions A
conditions B
entry
R1
C6H5
R2
R3
R4
3 (%)b
5 (%)b
1
4-MeOC6H4
3,4-(MeO)2C6H3
C6H5
H
H
H
H
H
H
H
H
H
3aa (45)
3ab (46)
3ac (0)
5aa (71)
5ab (92)
5ac (0)
2
C6H5
H
3
C6H5
H
4
C6H5
4-MeC6H4
H
3ad (0)
3ae (71)
3af (47)
3ag (41)
3ah (38)
3ai (30)
3aj (55)
3be (55)
3ce (67)
3de (52)
3ee (50)
3fe (76)
3ge (45)
3he (41)
3ie (0)
5ad (0)
5ae (99)
5af (72)
5ag (89)
5ah (90)
5ai (72)
5aj (78)
5be (88)
5ce (91)
5de (61)
5ee (65)
5fe (96)
5ge (81)
5he (42)
5ie (0)
5
C6H5
4-MeOC6H4
4-MeC6H4
Me
Me
Et
6
C6H5
7
C6H5
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
2-thiophene
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
2-thiophene
8
C6H5
4-MeOC6H4
9
C6H5
Me
Me
H
10
11
12
13
14
15
16
17
18
19
20
21
22
C6H5
Me
4-MeC6H4
4-ClC6H4
4-FC6H4
cyclopropyl
t-Bu
Me
H
Me
H
Me
H
Me
H
Me
H
n-Bu
Me
H
H
Me
H
TMS
Me
H
t-Bu
Et
H
3fg (63)
3fh (65)
3fi (81)
3fj (65)
5fg (91)
5fh (73)
5fi (95)
5fj (89)
t-Bu
4-MeOC6H4
Me
H
t-Bu
Me
H
t-Bu
Me
a General reaction conditions: Reactions performed on 0.2 mmol scale using 3 equiv of 2 and 10 mol % catalyst. b Reported yields are of the isolated
product based on compound 1.
results from the different activation modes of Bi(OTf)3 and
AuCl. Current efforthasalsobeenmade toextend itsscope
and possible synthetic applications, and these results will
be reported in due course.
Supporting Information Available. Experimental pro-
cedures, characterization data, copies of 1H and 13C
NMR of new compounds, X-ray diffraction structures,
and crystallographic data of compounds 3ee and 5ee in
CIF format. This material is available free of charge via
the Internet at http://pubs.acs.org.
Acknowledgment. Financial support from National
Natural Science Foundation of China (Nos. 21072033
and 21102019) is gratefully acknowledged.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX