PdCl2(HNMe2)2-catalyzed highly selective cross [2 + 2 + 2] cyclization of alkynoates and alkenes under molecular oxygen

Article abstract of DOI:10.1021/jo902636g

(Chemical Equation Presented) In the course of our study on palladium-catalyzed aerobic oxidation synthesis, we found that the PdCl ₂/O₂/ DMF system consistently experienced DMF hydrolysis to afford PdCl₂(HNMe₂)₂, which is the real active catalyst for the aerobic oxidation. Although in situ DMF hydrolysis has been widely used in generating supramolecular assembly architectures, as far as we know, it is the first successful example to utilize PdCl₂- (HNMe₂)₂ in synthetic reactions. The highly selective cross [2 + 2+2] cyclization of alkynoates and different alkenes with electron-withdrawing groups could be smoothly catalyzed by PdCl ₂(HNMe₂)₂/O₂/DMF to afford the corresponding functionalized pentasubstituted benzenes in good to excellent yields (70-97%). The extension of alkyne surrogates for cross [2 + 2 + 2] cyclization from special alkenes with leaving groups to simple alkenes under molecular oxygen led to a paradigm shift in arene synthesis. 2010 American Chemical Society.

Full text of DOI:10.1021/jo902636g

pubs.acs.org/joc
polysubstituted benzenes has been mainly achieved by step-
PdCl2(HNMe2)2-Catalyzed Highly Selective Cross
[2 þ 2 þ 2] Cyclization of Alkynoates and Alkenes
under Molecular Oxygen
wise introduction of the substituents via electrophilic sub-
stitution reactions such as the Friedel-Crafts reaction
(eq 1).2 However, high regioselectivity and yield can only
be achieved by the careful choice of the reagents and
synthetic route which usually is necessary to convert and/
or protect-deprotect the substituents properly.
Yanxia Shen, Huanfeng Jiang,* and Zhengwang Chen
School of Chemistry and Chemical Engineering, South China
University of Technology, 381 Wushan Road, Guangzhou
510640, China
In 1948, Reppe and Schweckendiek3 discovered that
transition metals can catalyze the cycloaddition of alky-
nes to form substituted benzenes. The efficiency, atom-
economy, and ease of transition-metal-catalyzed [2 þ
2 þ 2] cycloaddition reactions are clearly evident, but
the high regioselectivity was inherently limited to attempts
at heterotrimerization using two or more different
alkynes.
jianghf@scut.edu.cn
Received December 17, 2009
The most common strategy used to overcome this limi-
tation has relied on tethering two or three of the alkyne
components, and high regioselectivity may be controlled by
the geometric and entropic restrictions imparted by
the tether. This partially or completely intramolecular
approach was continually studied during the last decades;4
however, it always need much more complicated substrate
precursors and always affords “big molecules” (eqs 2
and 3).
Attempts at “small molecules” by a more general
approach to substituted aromatics requires a fundamen-
tally different strategy, one that completely eliminates
the tether (eq 4), and it has been the focus of more
recent studies.5 The lingering regioselective problem has
been solved by strategies based on different ligands and
transition-metal catalysts,6 strategies based on a covalent
linkage as temporary boron tethers,7 and strategies based
on substrates: alkynes with extreme electronic differentia-
tion of the π components8 or some special alkenes as
alkyne equivalents through dehydration,9 dehydroxy-
lation,10 and dehydrocarboxylation,11 etc. Significant
challenges still remain. Expanding the substrate scope to
include more diverse alkynes and alkyne surrogates as well
In the course of our study on palladium-catalyzed aero-
bic oxidation synthesis, we found that the PdCl2/O2/
DMF system consistently experienced DMF hydrolysis
to afford PdCl2(HNMe2)2, which is the real active
catalyst for the aerobic oxidation. Although in situ
DMF hydrolysis has been widely used in generating
supramolecular assembly architectures, as far as we
know, it is the first successful example to utilize PdCl2-
(HNMe2)2 in synthetic reactions. The highly selective
cross [2 þ 2þ2] cyclization of alkynoates and different
alkenes with electron-withdrawing groups could be
smoothly catalyzed by PdCl2(HNMe2)2/O2/DMF to
afford the corresponding functionalized pentasubsti-
tuted benzenes in good to excellent yields (70-97%).
The extension of alkyne surrogates for cross [2 þ 2 þ 2]
cyclization from special alkenes with leaving groups to
simple alkenes under molecular oxygen led to a para-
digm shift in arene synthesis.
(2) Chopade, P. R.; Louie, J. Adv. Synth. Catal. 2006, 348, 2307–
2327.
(3) Reppe, W.; Schweckendiek, W. J. Justus Liebigs Ann. Chem. 1948,
560, 104–116.
(4) Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100, 2901–2915.
(5) Galan, B. R.; Rovis, T. Angew. Chem., Int. Ed. 2009, 48, 2830–
2834.
(6) (a) Kezuka, S.; Tanaka, S.; Ohe, T.; Nakaya, Y.; Takeuchi, R. J. Org.
Chem. 2006, 71, 543–552. (b) Shibata, T.; Fujimoto, T.; Yokota, K.; Takagi,
K. J. Am. Chem. Soc. 2004, 126, 8382–8383. (c) Novak, P.; Pohl, R.; Kotora,
M.; Hocek, M. Org. Lett. 2006, 8, 2051–2054. (d) Wu, Y. T.; Hayama, T.;
Baldridge, K. K.; Linden, A.; Siegel, J. S. J. Am. Chem. Soc. 2006, 128, 6870–
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Chem.;Eur. J. 2005, 11, 1145–1156. (f) Sato, Y.; Tamura, T.; Mori, M.
Angew. Chem., Int. Ed. 2004, 43, 2436–2440.
Polysubstituted benzenes are highly useful compounds
which are widely used in industry as well as in the labo-
ratory.1 Traditionally, the regioselective construction of
(7) Yamamoto, Y.; Ishii, J.; Nishiyama, H.; Itoh, K. J. Am. Chem. Soc.
2005, 127, 9625–9631.
(8) (a) Takeuchi, R.; Nakaya, Y. Org. Lett. 2003, 5, 3659–3662. (b)
Tanaka, K.; Shirasaka, K. Org. Lett. 2003, 5, 4697–4699.
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Chem. Soc. 2008, 130, 7792–7793. (b) Kuninobu, Y.; Nishi, M.; Yudha, S.;
Takai, K. Org. Lett. 2008, 10, 3009–3011.
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*To whom correspondence should be addressed. Fax: (þ) 8620-8711-
2906.
(1) (a) Ballini, R.; Palmieriand, A.; Barboni, L. Chem. Commun. 2008,
2975–2985. (b) Inglis, A. J.; Sinnwell, S.; Davis, T. P.; Barner-Kowollik, C.;
Stenzel, M. H. Macromolecules 2008, 41, 4120–4126. (c) Connal, L. A.;
Vestberg, R.; Hawker, C. J.; Qiao, G. G. Macromolecules 2007, 40, 7855–
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DOI: 10.1021/jo902636g
r
Published on Web 01/27/2010
J. Org. Chem. 2010, 75, 1321–1324 1321
2010 American Chemical Society

Shen et al.
JOCNote
as solving the regioselectivity problem are still being
investigated.
SCHEME 1
SCHEME 2. Synthesis of Pentakis-Substituted Benzenes from
Alkynoates and Alkenesa
In the course of our study on palladium-catalyzed aerobic
oxidation synthesis, we found that PdCl2/O2/DMF is an
efficient catalyst system for [2 þ 2 þ 2] cyclotrimerization of
alkenes with electron-withdrawing groups to selectively
afford 1,3,5-trisubstituted benzene derivatives (Scheme 1A).12
A few years ago, we also developed a regioselective and
highly chemoselective method for preparing benzene deriva-
tives via palladium chloride-catalyzed cyclotrimerization of
alkynes in the presence of CuCl2 (Scheme 1B).13 Taking into
account these precedents and detailed evaluation of the
palladium-catalyzed aerobic oxidation, we envisaged that
functionalized multisubstituted benzene derivatives could be
directly prepared by controlled cross-cyclization of alkyne
and alkene. Here, we report the extension of this palladium
chemistry to the highly selective cross [2 þ 2 þ 2] cycliza-
tion of alkynoates and alkenes with electron-withdrawing
groups under molecular oxygen (Scheme 2) and disclose for
the first time that the in situ DMF hydrolysis-produced
PdCl2(HNMe2)2 is the key to actively catalyze the oxida-
tive reaction and that the extension of alkyne surrogates
from special alkenes with leaving groups to simple alkenes
under molecular oxygen led to a paradigm shift in arene
synthesis.
DMF, one of the important classes of dipolar and aprotic
amides, is well known for its ability to coordinate transi-
tion-metal ions as unidentate O-donor ligands or lattice
solvates14 and is usually an inert solvent.15 But during our
experiment with DMF as solvent, the result is not good
when the system is strictly dehydrated (Table 1, entry 17).
We finally found that the PdCl2/O2/DMF system consis-
tently experienced DMF hydrolysis during oxidation (eq 5)
and resulted in the formation of PdCl2(HNMe2)2, whose
(12) Jiang, H. F.; Shen, Y. X.; Wang, Z. Y. Tetrahedron Lett. 2007, 48,
7542–7545.
(13) Li, J. H.; Jiang, H. F.; Chen, M. C. J. Org. Chem. 2001, 66, 3627–
3629.
(14) (a) Cejudo, R.; Alzuet, G.; Borras, J.; Liu, G. M.; Sanz-Ruiz, F.
Polyhedron 2002, 21, 1057–1061. (b) Hunt, G. W.; Griffith, E.; Amma, E.
Inorg. Chem. 1976, 15, 2993–2997.
(15) (a) Kim, J.; Cho, J.; Kim, H.; Lough, A. Chem. Commun. 2004,
1796–1797. (b) Kim, J.; Cho, J.; Lough, A. Inorg. Chim. Acta 2001, 317,
252–258. (c) Cho, J.; Kim, J.; Lough, A. Inorg. Chem. Commun. 2003, 6, 284–
287.
aReaction conditions: alkynoate 1 (1 mmol), alkene 2 (1 mmol), PdCl2
(3 mol %), pressure of molecular oxygen (0.8 MPa), 80 °C for 24 h in 1 mL
of DMF without drying. bIsolated yields based on 1.
structure was characterized by X-ray crystal diffraction
measurement.16 Therefore, we believe that PdCl2(HNMe2)2
(16) Bombieri, G.; Bruno, G. Inorg. Chim. Acta 1984, 86, 121–125.
1322 J. Org. Chem. Vol. 75, No. 4, 2010

Shen et al.
JOCNote
TABLE 1. Optimization of Reaction Conditionsa
SCHEME 3. Plausible Reaction Mechanism
cat.b
(%)
1a/
2a
O2
(MPa)
temp
(°C)
time
(h)
GC yieldc
(%)
entry
1
2
3
4
5
6
7
1
3
5
3
3
3
3
2:1
2:1
2:1
3:1
2:2
2:3
1:1
0.6
70
70
70
70
70
70
70
24
24
24
24
24
24
24
27
0.6
0.6
0.6
0.6
0.6
ambient
air
56
58
34
69
62
11
8
9
3
3
3
3
3
3
3
3
3
3
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
0.3
0.8
1
0.8
0.8
0.8
0.8
0.8
0.8
0.8
70
70
70
50
80
100
80
80
80
80
24
24
24
24
24
24
18
30
24
24
23
75
73
35
10
11
12
13
14
15
16e
17f
79 (70)d
72
53
81
47
36
occurred (Table 1, entries 4-6). The reaction exhibits a sharp
dependence on the pressure of molecular oxygen and reaches
a maximum value of 75% at 0.8 MPa (Table 1, entries 7-10).
The optimized temperature and time for the reaction is 80 °C
for 24 h (Table 1, entries 10-15). Entry 16 of Table 1 shows
that extra water was not beneficial for the reaction. As we see
in the reaction of direct utilization of molecular oxygen as the
sole oxidant, water is necessary for the in situ DMF hydro-
lysis to afford the catalyst PdCl2(HNMe2)2; however, it is
also the byproduct of the oxidation, and too much water in
the system inhibits the formation of 3aa.
Under the optimized conditions, the reaction was applied
to a range of different alkenes (Scheme 2). It can be learned
that the PdCl2(HNMe2)2-catalyzed cross [2 þ 2 þ 2] cycliza-
tion of alkynoates and alkenes with electron-withdrawing
groups can be achieved in a highly selective 2:1 cross-
coupling manner to give 3 under molecular oxygen. The
scope of substrates successfully moves beyond acrylates
only, and different alkenes with electron-withdrawing
groups, including acrylonitrile and acrylic acid, etc., could
smoothly and successfully react with alkynoates to afford the
corresponding pentasubstituted benzenes in good to excel-
lent yields (70-97%). Many useful substituting groups, such
as acylamide, aryloxycarbonyl, and cyano, were successfully
introduced into the product, and product 3ag is structurally
characterized by X-ray crystal diffraction measurement. It
should be noticed that the cyano group can be reserved while
in most cases it turns out to form pyridines,19 and the
introduction of an aryl group could find potential utiliza-
tions in all kinds of cross-coupling reactions initiated by
palladium, including well-known Heck, Suzuki, etc.
aReaction conditions: dimethyl but-2-ynedioate 1a (1 mmol), DMF
without drying (1 mL). bDosage of PdCl2 based on 1a. cGC yield based
on 1a. dIsolated yield in the parentheses. e0.1 mL of distilled water was
added. fDryness with anhydrous MgSO4 and then vacuum distillation of
DMF before using.
is the real catalytically active palladium complex in our
system.
HCONðCH3Þ2 þ H2O f HNðCH3Þ2 þ HCOOH
ð5Þ
In situ DMF hydrolysis has been widely used in generating
supramolecular assembly architectures.17 Interestingly, few
references were found about in situ DMF hydrolysis being
utilized in synthetic reactions. As far as we know, only in
1974, in a study of R-olefin oxidations with the Clement-
Selwitz system, Fahey et al. reported that the in situ DMF
hydrolysis produced PdCl2(HNMe2)2 resulted in the com-
plete poison of catalyst PdCl2.18
Our initial efforts were focused on reaction optimization
for the selective cross [2 þ 2 þ 2] cyclization of dimethyl but-
2-ynedioate (1a) and methyl acrylate (2a) in DMF without
drying, including the optimization of dosage of PdCl2, molar
ratio of alkynoates to alkene, pressure of molecular oxygen,
temperature, and reaction time (Table 1). It indicated that
the best dosage of PdCl2 was 3 mol % (Table 1, entries 1-3),
which is a relative small dosage for transition-metal-cata-
lyzed [2 þ 2 þ 2] cyclization reactions, generally ranging
between 5 and 10 mol %. This may be attributed to the high
catalytic activity of the in situ produced catalyst PdCl2-
(HNMe2)2. The molar ratio of 1a to 2a seems to have an
obvious effect on the selective formation of 3aa; when the
ratio was more than 1:1, cyclotrimerization of 1a partially
A plausible mechanism of this cyclization was shown in
Scheme 3. The reaction started with the cis chloropalladation
of the C-C triple bond of alkyne 1 by PdCl2(HNMe2)2
giving vinyl-Pd intermediate 4,20 and the succeeding
(17) (a) Wang, X. Y.; Wei, H. Y.; Wang, Z. M.; Chen, Z. D.; Gao, S.
Inorg. Chem. 2005, 44, 572–583. (b) Wang, X. Y.; Gan, L.; Zhang, S. W.;
Gao, S. Inorg. Chem. 2004, 43, 4615–4625. (c) Burrows, A. D.; Cassar, K.;
Friend, R.; Mahon, M.; Rigby, S.; Warren, J. Cryst. Eng. Commun. 2005, 7,
548–550. (d) Fan, S. R.; Zhu, L. G. Inorg. Chim. Acta 2009, 362, 2962–2976.
(e) Liu, S.; Wang, C.; Zhai, H.; Li, D. J. Mol. Struct. 2003, 654, 215–221. (f)
Ju, C. K.; Jungyun, R.; Lough, A. J. Chem. Crystallogr. 2007, 37, 615–618.
(18) Fahey, D. R.; Zuech, E. A. J. Org. Chem. 1974, 39, 3276–3277.
(19) Heller, B.; Hapke, M. Chem. Soc. Rev. 2007, 36, 1085–1094.
(20) (a) Hosokawa, T.; Calvo, C.; Lee, H. B.; Maithlis, P. M. J. Am.
Chem. Soc. 1973, 95, 4914–4923. (b) Han, X. L.; Liu, G. X.; Lu, X. Y. Chin. J.
Org. Chem. 2005, 10, 1182–1197.
J. Org. Chem. Vol. 75, No. 4, 2010 1323

Shen et al.
JOCNote
insertion reaction into the Pd-vinyl bond afforded inter-
mediate 5. Coordination of 2 to 5 underwent insertion and
then β-H elimination-oxidation in the presence of molecular
oxygen, leading to the new chloropalladation intermediate 6,
where Pd-Cl made a further insertion into the carbon-
carbon double bond generating intermediate 7.21 The pre-
sence of molecular oxygen converted H-PdL2-Cl to Cl-PdL2-
OOH, which released H2O2 and kept the Pd(II) oxidative
state. Finally, β-Cl elimination of 7 yielded the product 3, and
the catalyst PdCl2(HNMe2)2 was regenerated.22
makes an extension of alkyne surrogates from special
alkenes with leaving groups to simple alkenes under mole-
cular oxygen but also opens a brand new way for the
utilization of DMF hydrolysis in synthetic reactions. The
relatively cheap and accessible starting materials, green
oxidant molecular oxygen, and environmentally benign
byproduct made the present atom-economic cycloaddition
more attractive.
Experimental Section
Why was PdCl2(HNMe2)2 so highly efficient a catalyst for
the selective cross coupling [2 þ 2 þ 2] cyclization of
alkynoates and alkenes with electron-withdrawing groups
under oxygen while it failed when 2,2-bipyridine or phenan-
throline was used as ligand to stabilize the reduced palladium
species during oxidation? According to the literature,23
compounds of geometrical rigidity, introduced by a biden-
tate ligand forming a small metallacycle, like the com-
plex (2,2-bipyridine)diethylpalladium, will suppress the β-
hydride elimination, a reaction with an increase in coordina-
tion number and considerable geometry change. In addition,
the (2,2-bipyridine)diethylpalladium has a decomposition
point at 109 °C while we found that the decomposition point
of the PdCl2(HNMe2)2 is between 218 and 219 °C. Due to its
thermal stability and less geometrical rigidity around the
metal center of PdCl2(HNMe2)2, we believe that in situ DMF
hydrolysis to produce PdCl2(HNMe2)2 was an excellent
catalyst for this reaction.
Palladium-Catalyzed Highly Selective Cross [2 þ 2 þ 2]
Cyclization of Dimethyl But-2-ynedioate 1a and Methyl Acrylate
2a: A Representative Procedure. All reactions were carried out in
a HF-15 autoclave with magnetic stir bar. PdCl2 (0.03 mmol, 3
mol %), DMF (1 mL, undrying), dimethyl but-2-ynedioate (1a,
1 mmol), and methyl acrylate (2a, 1 mmol) were added into a 15
mL autoclave in sequence. O2 was pumped into the autoclave to
the desired pressure. The autoclave was then put into an oil bath
under magnetic stirring for the desired reaction time. After the
reaction, the autoclave was allowed to cool to room tempera-
ture. Surplus O2 was vented, and the residual was extracted with
50 mL ether and distilled water (5 ꢀ 2 mL). The combined
extract was dried with anhydrous MgSO4. The solvent was
evaporated to dryness under reduced pressure, and the crude
product was separated by column chromatography to give a
pure sample 3aa.
Acknowledgment. We thank the National Natural Foun-
dation of China (Nos. 20625205, 20772034 and 20932002)
and Doctoral Fund of Ministry of Education of China
(20090172110014) for financial support.
In conclusion, we have established an in situ DMF hydro-
lysis producing PdCl2(HNMe2)2 to catalyze highly selective
cross [2 þ 2 þ 2] cycloaddition of alkynoates and alkenes
with electron-withdrawing groups under molecular oxygen
to synthesize pentakis-substituted benzenes in good to
excellent yields (70-97%). This methodology not only
Note Added after ASAP Publication. Scheme 2 contained an
error in the version published ASAP January 27, 2010; the
corrected version posted January 28, 2010.
(21) (a) Dietl, H.; Moffat, R. J.; Maitlis, P. M. J. Am. Chem. Soc. 1970, 92,
2276–2285. (b) Li, J. H.; Jiang, H. F.; Feng, A. Q.; Jia, L. Q. J. Org. Chem.
1999, 64, 5984–5987.
(22) Jiang, H. F.; Shen, Y. X.; Wang, Z. Y. Tetrahedron 2008, 64, 508–
514.
(23) Zhang, L.; Zetterberg, K. Organometallics 1991, 10, 3806–3813.
Supporting Information Available: Full experimental de-
tails, copies of NMR spectral data, and the ORTEP and CIF
files for the X-ray crystal structures of PdCl2(HNMe2)2 and 3ag.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1324 J. Org. Chem. Vol. 75, No. 4, 2010