Pd-catalyzed π-chelation assisted ortho-C-H activation and annulation of allylarenes with internal alkynes

Article abstract of DOI:10.1021/ol400792y

The synthesis of highly substituted naphthalenes from allylarenes and alkynes is described. This reaction proceeds via π-coordination of an allylic carbon-carbon double bond to the Pd(II) center and is followed by ortho selective C-H bond activation.

Full text of DOI:10.1021/ol400792y

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Pd-Catalyzed π‑Chelation Assisted
ortho-CꢀH Activation and Annulation
of Allylarenes with Internal Alkynes
Parthasarathy Gandeepan and Chien-Hong Cheng*
Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan
chcheng@mx.nthu.edu.tw
Received December 23, 2012
ABSTRACT
The synthesis of highly substituted naphthalenes from allylarenes and alkynes is described. This reaction proceeds via π-coordination of an
allylic carbonꢀcarbon double bond to the Pd(II) center and is followed by ortho selective CꢀH bond activation.
Transition-metal-catalyzed CꢀH bond functionaliza-
tion has become a prevailing method for the construc-
tion of carbonꢀcarbon and carbonꢀheteroatom bonds.1
In general, the selectivity of CꢀH functionalization is
controlled by the chelating functional groups.2 Recently,
Rh(III) and Ru(II)-catalyzed CꢀH functionalization
followed by annulation with unsaturated molecules has
been extensively used for the synthesis of various hetero-
cyclic and carbocyclic compounds.3,4 However, similar
reactions involving palladium(II)-catalyzed CꢀH activa-
tion followed by oxidative coupling with alkynes are less
well-studied, and only limited examples were reported.5
While a variety of functional groups have been intensively
investigated as the directing groups for CꢀH bond activa-
tion,1,2 most of these groups involve σ-coordination to
the metal catalysts. It is known that CꢀC multiple bonds
readily coordinate with metal catalysts through π-chelation
and facilitate selective CꢀH activation and intramolecular
cyclizations.6 Intermolecular CꢀH coupling reactions
assisted by π-chelating CꢀC multiple bonds are rarely
documented in literature.7 Our ongoing interest8 in various
(1) For reviews, see: (a) Alberico, D.; Scott, M. E.; Lautens, M.
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Marder, T. B.; Murphy, J. M.; Hartwig, J. F. Chem. Rev. 2010, 110, 890.
(e) Zhang, M. Adv. Synth. Catal. 2009, 351, 2243.
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Angew. Chem., Int. Ed. 2009, 48, 5094. (b) Lyons, T. W.; Sanford, M. S.
Chem. Rev. 2010, 110, 1147. (c) Ackermann, L. Chem. Rev. 2011, 111, 1315.
(d) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. (e) Neufeldt,
S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936. (f) Engle, K. M.; Mei,
T. S.; Wasa, M.; Yu, J. Q. Acc. Chem. Res. 2012, 45, 788.
€
(3) For reviews on Rh(III), see: (a) Satoh, T.; Miura, M. Chem.;Eur.
J. 2010, 16, 11212. (b) Colby, D. A.; Tsai, A. S.; Bergman, R. G.; Ellman,
J. Acc. Chem. Res. 2012, 45, 814. (c) Song, G.; Wang, F.; Li, X. Chem.
Soc. Rev. 2012, 41, 3651.
(6) (a) Mamane, V.; Hannen, P.; Furstner, A. Chem.;Eur. J. 2004,
10, 4556. (b) Chernyak, N.; Gevorgyan, V. J. Am. Chem. Soc. 2008, 130,
5636. (c) Chernyak, N.; Gorelsky, S. I.; Gevorgyan, V. Angew. Chem.,
Int. Ed. 2011, 50, 2342.
(4) For reviews on Ru(II), see: (a) Arockiam, P. B.; Bruneau, C.;
Dixneuf, P. H. Chem. Rev. 2012, 112, 5879. (b) Kozhushkov, S. I.;
Ackermann, L. Chem. Sci. 2013, 4, 886. (c) Ackermann, L. Acc. Chem.
Res. 2013 DOI: 10.1021/ar3002798.
(5) (a) Shi, Z.; Zhang, C.; Li, S.; Pan, D.; Ding, S.; Cui, Y.; Jiao, N.
Angew. Chem., Int. Ed. 2009, 48, 4572. (b) Shi, Z.; Cui, Y.; Jiao, N. Org.
Lett. 2010, 12, 2908. (c) Ding, S.; Shi, Z.; Jiao, N. Org. Lett. 2010, 12,
1540. (d) Wu, Y.-T.; Huang, K. -H.; Shin, C. -C.; Wu, T.-C. Chem.;
Eur. J. 2008, 14, 6697. (e) Shi, Z.; Ding, S.; Cui, Y.; Jiao, N. Angew.
Chem., Int. Ed. 2009, 48, 7895. (f) Yamashita, M.; Hirano, K.; Satoh, T.;
Miura, M. Org. Lett. 2009, 11, 2337. (g) Yamashita, M.; Horiguchi, H.;
Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2009, 74, 7481. (h) Zhou,
F.; Han, X.; Lu, X. Tetrahedron Lett. 2011, 52, 4681. (i) Zhong, H.;
Yang, D.; Wang, S.; Huang, J. Chem. Commun. 2012, 48, 3236.
(7) (a) Kiyooka, S.-I.; Takeshita, Y. Tetrahedron Lett. 2005, 46, 4279.
(b) Yamada, S.; Obora, Y.; Sakaguchi, S.; Ishii, Y. Bull. Chem. Soc. Jpn.
2007, 80, 1194. (c) Tobisu, M.; Hyodo, I.; Onoe, M.; Chatani, N. Chem.
Commun. 2008, 6013. (d) Gandeepan, P.; Cheng, C.-H. J. Am. Chem.
Soc. 2012, 134, 5738. (e) Minami, Y.; Shiraishi, Y.; Yamada, K.;
Hiyama, T. J. Am. Chem. Soc. 2012, 134, 6124.
(8) (a) Gandeepan, P.; Parthasarathy, K.; Cheng, C.-H. J. Am. Chem.
Soc. 2010, 132, 8569. (b) Karthikeyan, J.; Cheng, C.-H. Angew. Chem.,
Int. Ed. 2011, 50, 9880. (c) Jayakumar, J.; Parthasarathy, K.; Cheng,
C.-H. Angew. Chem., Int. Ed. 2012, 51, 197. (d) Parthasarathy, K.;
Senthilkumar, N.; Jayakumar, J.; Cheng, C.-H. Org. Lett. 2012, 14,
3478. (e) Gandeepan, P.; Hung, C.-H.; Cheng, C.-H. Chem. Commun.
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Lett. 2012, 14, 4262.
r
10.1021/ol400792y
XXXX American Chemical Society

CꢀH bond activation and cyclization and the recent
success in the use of an allylic CꢀC double bond as
a directing group for ortho-alkenylation of arenes7d
prompted us to explore the possibility of employing alkyne
as a coupling partner in this functional group directed
intermolecular CꢀH activation reaction and cyclization.
Here, we report the synthesis of substituted naphthalenes
by Pd-catalyzed reaction of allylarenes with internal
alkynes (Scheme 1). It is noteworthy that substituted
naphthalenes are important units in many bioactive
compounds,9 and the design of new direct CꢀH activation
methods leading to the synthesis of naphthalenes is highly
challenging.10
Table 1. Optimization Studies for the Pd-Catalyzed ortho-CꢀH
Activation and Annulation of Allyl Arenesa
O2 (1 atm) þ
solvent
temp (°C)/
time (h)
yield
(%)b
entry
oxidant/mmol
(1.5 mL)
1
O2
O2
O2
DCM
rt/24
20
2
DCE
50/24
50/24
50/24
50/24
50/24
80/24
100/24
80/24
80/24
80/24
80/24
80/24
80/24
80/24
80/24
80/24
80/30
27
30
35
43
47
67
46
70
81
40
72
47
29
80
67
3
toluene
4
O2 þ Cu(OAc)2/0.125 toluene
5
O2 þ Cu(OAc)2/0.25
Cu(OAc)2/0.25
toluene
toluene
toluene
toluene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
Scheme 1. Modes of Chelation in CꢀH Activation
6
7
Cu(OAc)2/0.25
8
Cu(OAc)2/0.25
9
Cu(OAc)2/0.25
10
11
12
13
14
15
16
17
18
O2 þ Cu(OAc)2/0.25
O2 þ CuCl2/0.25
O2 þ CuO/0.25
O2 þ Cu(BF4)2/0.25
O2 þ Cu(OTf)2/0.25
O2 þ Cu(OAc)2/0.05
O2
c
O2 þ Cu(OAc)2/0.05
ꢀ
O2 þ Cu(OAc)2/0.05 o-xylene
89 (85)d
a Unless otherwise mentioned, all reactions were carried out using 1a
(0.25 mmol) and 2a (0.30 mmol), TFA (2.5 mmol) and other additives.
b Yields were determined by the 1H NMR integration method using
mesitylene as the internal standard. c TFA not used. d Isolated yield
based on 1a.
We started our investigation using allylarene 1a and
diphenylacetylene (2a) as the substrates. Treatment of
1a (0.25 mmol) with 2a (0.30 mmol) in the presence of
Pd(OAc)2 (0.025 mmol) and trifluoroacetic acid (TFA)
(2.5 mmol) in dichloromethane under one oxygen atmo-
sphere at room temperature for 24 h gave substituted
naphthalene derivative 3a in 20% yield (Table 1, entry 1).
The structure of 3a was confirmed by its 1H and 13C NMR,
mass data and single crystal X-ray structural determina-
tion. As a result of our devoted optimization study, we
found that the reaction of 1a (1 equiv), 2a (1.2 equiv),
Pd(OAc)2 (10 mmol %), Cu(OAc)2 (20 mol %) and TFA
(10 equiv) in o-xylene at 80 °C for 30 h under one O2
atmosphere gave 3a in 85% isolated yield (for the detailed
optimization study see Table 1 and the Supporting
Information).
arene rings reacted with 1a under the standard reaction
conditions to give the corresponding products 3 in good
to excellent yields (Table 2). Thus, treatment of p-Me and
p-OMe substituted diphenylacetylenes 2b and 2c with 2a
gave the desired naphthalene derivatives 3b and 3c in 81
and 52% yields, respectively (entries 2ꢀ3). p-Cl, -Br and -F
substituted diphenylacetylenes underwent the reaction
with 1a smoothly to offer products 3d, 3e and 3f in 82, 67
and 74% yields, respectively (entries 5ꢀ7). Trifluoromethyl
and acetyl substituted diarylalkynes gave the desired
naphthalenes 3g and 3h in 76 and 68% yields (entries
7ꢀ8). Electron-deficient diethyl acetylenedicarboxylate
(2i) and aliphatic alkyne 4-octyne (2j) also underwent the
cyclization reaction with 1a to give naphthalene derivatives
in 57 and 56% yield, respectively (entries 9 and 13). Next,
we examined the scope of allyl arenes. Thus, 4-Cl substi-
tuted allylarene 1b reacted with 2a to afford 3j in 63% yield
(Table 2, entry 10). Similarly, 3-Cl and 3-OMe substituted
allyl arenes 1c and 1d gave 3k and 3i in 76 and 79% yields,
respectively (entries 11ꢀ12). For substrates with a substi-
tuent at meta position, the CꢀH activation occurs only at
the less hindered ortho position. Presumably, the regios-
electivity was controlled by the steric effect of meta-
substituent (entries 11ꢀ12). Substrates 1eꢀg without a
methyl group on the aliphatic chain also reacted efficiently
with 2a to give the expected naphthalene products in good
Having the optimized reaction conditions in hand, we
tested the scope of allyl arenes 1 and alkynes 2, and the
results are shown in Table 2. Both diarylalkynes having an
electron-donating and electron-withdrawing group on the
(9) (a) Whiting, D. A. Nat. Prod. Rep. 1985, 2, 191. (b) Ward, R. S.
Nat. Prod. Rep. 1995, 12, 183. (c) Eich, E.; Pertz, H.; Kaloga, M.; Schulz,
J.; Fesen, M. R.; Mazumder, A.; Pommier, Y. J. Med. Chem. 1996, 39,
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J. Am. Chem. Soc. 2010, 132, 17710.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Scope of Symmetrical Alkynes 2 in Pd-Catalyzed CꢀH
Activation of Allylarenes 1a
Table 3. Scope of Unsymmetrical Alkynes 2 in Pd-Catalyzed
CꢀH Activation of Allylarenes 1aa
a Unless otherwise mentioned, all reactions were carried out using 1a
(0.25 mmol), alkyne 2 (0.30 mmol), Pd(OAc)2 (0.025 mmol), Cu(OAc)2
(0.05 mmol), TFA (2.5 mmol) and o-xylene (1.5 mL) at 80 °C under one
O2 atmosphere for 30 h. b Isolated yields. c Regioisomers were deter-
mined by 1H NMR.
Similarly, no expected product was observed for the reac-
tion of 2a with 1,3-diphenylpropane (1i) without an olefinic
CꢀC double bond; the starting materials remain un-
changed (entry 18). These results evidence the assistance
of allylic double bond in the present Pd-catalyzed reaction.
To further explore the scope of the reaction, we tested
the reaction of unsymmetrical alkynes with 1a under the
standard reaction conditions, and the results are given in
Table3. Thereactionof1-phenylpropyne (2k) with1agave
a 4:1 ratio of regioisomers 3q and 3q0 in 69% overall yield
(Table 3, entry 1). Similarly, hex-1-ynylbenzene (2l) and
ethyl phenylpropiolate (2m) reacted with 1a to give 2.6:1
and 1.6:1 mixture of regioisomers3r þ 3r0 and 3s þ 3s0 in 62
and 51% yields (entries 2, 3). Methyl oct-2-ynoate (2n) also
underwent the cyclization reaction with 1a to give the
desired naphthalenes in 68% yield with a 95:5 ratio of
the regioisomers (entry 4). These results suggest that the
electronic effects are playing the major role in the observed
regioselectivity. The arylꢀPd intermediate more likely
adds to the carbonꢀcarbon triple bond with the Pd group
to the more electron rich end, which is in agreement with
the previous annulation reactions.11
a Unless otherwise mentioned, all reactions were carried out using 1
(0.25 mmol), 2 (0.30 mmol), Pd(OAc)2 (0.025 mmol), Cu(OAc)2
(0.05 mmol), TFA (2.5 mmol) and o-xylene (1.5 mL) at 80 °C under
O2 atmosphere for 30 h. b Isolated yields. c No characteristic products
were observed.
yields (entries 14ꢀ16). We also examined the possibility of
a butenylic CꢀC double bond as a director for the CꢀH
bond activation reaction with 2a. However, we did not
observe any CꢀH functionalization product (entry 17).
(11) Huang, Q.; Larock, R. C. Org. Lett. 2002, 4, 2505.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Proposed Mechanism for Pd-Catalyzed CꢀH
Activation and Annulation Reaction
Figure 1. Kinetic isotope effect for the Pd-catalyzed reaction of
allylarene 1a with 2a.
To understand the mechanism of this catalytic reaction,
we measured the inter- and intramolecular kinetic isotopic
effects (KIE) of the catalytic reaction of 1a with 2a. An
intermolecular KIE kH/kD of 2.84 was observed for the
competition reaction of 1a and deuterium-labeled 1a-d5
with 2a (Figure 1). On the other hand, an intramolecular
competition experiment of 1a-d1 with 2a showed a kH/kD
of 3.76. The large difference of inter- and intramolecular
KIE values implies that the CꢀC double bond coordina-
tion occurs prior to CꢀH palladation in the catalytic
cycle.12 If palladation takes place before the CꢀC double
bond coordination, similar KIE values for the inter-
and intramolecular competitions should be observed.12
The large KIE value of 3.76 suggests that cleavage of the
CꢀH bond is the rate-limiting step.
the coordination of the CꢀC double bond in 1a and then
the CꢀC π-bond between the ortho- and ipso-carbons
to Pd(II) center to give intermediate A are expected.14
Subsequent cyclometalation leads to the formation of
Pd(II) σ-aryl complex B. Addition of arylpalladium species
B to the carbonꢀcarbon triple bond of 2a gives the
vinylpalladium intermediate C. Intramolecular cis-addition
of vinylpalladium C to the allylic carbonꢀcarbon double
bond generates an alkylpalladium species D. β-Hydride
elimination of D followed by isomerization gives the final
naphthalene 3.
In summary, we have developed an efficient method
for the synthesis of substituted naphthalenes via a
palladium-catalyzed CꢀH activation and annulation of
allylarenes with alkynes. This reaction proceeds through
the π-coordination of the allylic carbonꢀcarbon double
bond to Pd(II) and ortho-selective CꢀH bond activation.
The reaction has the advantage of using environmentally
friendly oxygen as a terminal oxidant.
On the basis of the experiment results and known transi-
tion-metal-catalyzed CꢀH activation reactions,7d,e,11
a
possible mechanism employing 1a and 2a as the substrates
is proposed to account for the present catalytic reaction
(Scheme 2). The highly electrophilic cationic palladium
species [Pd(TFA)]þ is expected to be generated in the
presence of TFA.13 This cationic species should greatly
facilitate the coordination of CꢀC double bond and
enhance the metalation of aromatic CꢀH bond. Thus,
(12) (a) Jones, W. D.; Feher, F. J. Acc. Chem. Res. 1989, 22, 91.
(b) Lenges, C. P.; Brookhart, M. J. Am. Chem. Soc. 1999, 121, 6616.
(c) Hennessy, E. J.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 12084.
(13) (a) Jia, C.; Piao, D.; Oyamada, J.; Lu, W.; Kitamura, T.;
Fujiwara, Y. Science 2000, 287, 1992. (b) Ferreira, E. M.; Stoltz,
B. M. J. Am. Chem. Soc. 2003, 125, 9578. (c) Delcamp, J. H.; White,
M. C. J. Am. Chem. Soc. 2006, 128, 15076. (d) Young, A. J.; White, M. C.
J. Am. Chem. Soc. 2008, 130, 14090. (e) Shi, Z.; Zhang, C.; Li, S.; Pan,
D.; Ding, S.; Cui, Y.; Jiao, N. Angew. Chem., Int. Ed. 2009, 48, 4572.
(f) Shi, Z.; Cui, Y.; Jiao, N. Org. Lett. 2010, 12, 2908. (g) Bueno, A. C.;
deSouza, A. O.; Gusevskaya, E. V. Adv. Synth. Catal. 2009, 351, 2491.
Acknowledgment. We thank the National Science
Council of the Republic of China (NSC-101-2628-M-
007-004) for support of this research.
Supporting Information Available. General experimen-
tal procedure, characterization details, and crystal data
(CIF) for 3a. This material is available free of charge via
the Internet at http://pubs.acs.org.
ꢀ
(h) Liegault, B.; Lee, D.; Huestis, M. P.; Stuart, D. R.; Fagnou, K.
J. Org. Chem. 2008, 73, 5022.
(14) (a) Liu, C. H.; Li, C. S.; Cheng, C. -H. Organometallics 1994, 13,
18. (b) Li, C. S.; Cheng, C.-H.; Liao, F. L.; Wang, S. L. J. Chem. Soc.,
Chem. Commun. 1991, 10, 710.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX