Nucleophilic dearomatization of chloromethyl naphthalene derivatives via η3-benzylpalladium intermediates: A new strategy for catalytic dearomatization

Article abstract of DOI:10.1021/ol2023278

Palladium-catalyzed nucleophilic dearomatization of chloromethyl naphthalene derivatives to produce ortho- or para-substituted carbocycles in satisfactory to excellent yields has been developed. The unprecedented dearomatization reactions proceeded smoothly under mild conditions via η³-benzylpalladium intermediates.

Full text of DOI:10.1021/ol2023278

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5402–5405
Nucleophilic Dearomatization of
Chloromethyl Naphthalene Derivatives via
η3-Benzylpalladium Intermediates: A New
Strategy for Catalytic Dearomatization
Bo Peng,† Sheng Zhang, Xiaoqiang Yu, Xiujuan Feng, and Ming Bao*
State Key Laboratory of Fine Chemicals, Dalian University of Technology,
Dalian 116023, China
mingbao@dlut.edu.cn
Received August 27, 2011
ABSTRACT
Palladium-catalyzed nucleophilic dearomatization of chloromethyl naphthalene derivatives to produce ortho- or para-substituted carbocycles in
satisfactory to excellent yields has been developed. The unprecedented dearomatization reactions proceeded smoothly under mild conditions via
η3-benzylpalladium intermediates.
Dearomatization of aromatic compounds has attracted
considerable attention because it provides a simple method
to achieve functionalized alicyclic compounds, which can
be utilized as synthetic intermediates for the preparation of
natural products and bioactive compounds.1,2 Either elec-
trophilic or nucleophilic dearomatization requires the
activation of the aromatic system, which can be achieved
by the complexation of the aromatic system to transition
metals.3 The coordination of the aromatic system to the
electron-rich, π-basic metal fragment forms [M(η2-arene)]
(M = Os, Re, Mo, and W; Structure A in Scheme 1)
complexes, which could proceed to electrophilic dearoma-
tization reactions.4 In contrast, the coordination of the
aromatic system to an electron-deficient metal fragment
constructs [M(η6-arene)] (M = Cr, Mn, and Ru; Structure
B in Scheme 1) complexes, which could undergo a nucleo-
philic dearomatization reaction.5 Although these two
principal strategies for arene activation have been widely
investigated and applied in alicyclic carbocycle synthesis,
the required use of stoichiometric amounts of transition
metals remains a limitation.
† Present address: Max-Planck-Institut f€ur Kohlenforschung, Kaiser-
Wilhelm-Platz 1, 45470 M€ulheim an der Ruhr, Germany.
(1) For selected recent reviews, see: (a) Ortiz, F. L.; Iglesias, M. J.;
(4) For transition-metal-mediated electrophilic dearomatization, see:
(a) Harman, W. D. Top. Organomet. Chem. 2004, 7, 95. (b) Ding, F.;
Valahovic, M. T.; Keane, J. M.; Anstey, M. R.; Sabat, M.; Trindle,
C. O.; Harman, W. D. J. Org. Chem. 2004, 69, 2257. (c) Surendranath,
Y.; Welch, K. D.; Nash, B. W.; Harman, W. H.; Myers, W. H.; Harman,
W. D. Organometallics 2006, 25, 5852 and references therein. (d)
Kosturko, G. W.; Graham, P. M.; Myers, W. H.; Smith, T. M.; Sabat,
M.; Harman, W. D. Organometallics 2008, 27, 4513 and references
therein. (f) Harrison, D. P.; Sabat, M.; Myers, W. H.; Harman, W. D.
J. Am. Chem. Soc. 2010, 132, 17282 and references therein.
ꢀ
ꢀ
ꢀ
Fernandez, I.; Sanchez, C. A.; Gomez, G. R. Chem. Rev. 2007, 107, 1580.
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(b) Quideau, S.; Pouysegu, L.; Deffieux, D. Synlett 2008, 467. (c)
Pouysegu, L.; Deffieux, D.; Quideau, S. Tetrahedron 2010, 66, 2235.
ꢀ
(d) Roche, S. P.; Porco, J. A., Jr. Angew. Chem., Int. Ed. 2011, 50, 4068.
(2) For selected recent references, see: (a) Garcıa-Fortanet, J.; Kessler,
´
F.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 6676. (b) Lee, S.;
Chataigner, I.; Piettre, S. R. Angew. Chem., Int. Ed. 2011, 50, 472. (c) Wu,
Q.-F.;Liu, W.-B.; Zhuo, C.-X.; Rong, Z.-Q.; Ye, K.-Y.;You, S.-L. Angew.
Chem., Int. Ed. 2011, 50, 4455 and references therein. (d) Rudolph, A.; Bos,
P. H.; Meetsma, A.; Minnaard, A. J.; Feringa, B. L. Angew. Chem., Int.Ed.
2011, 50, 5834. (e) Green, J. C.; Pettus, T. R. R. J. Am. Chem. Soc. 2011,
(5) For transition-metal-mediated nucleophilic dearomatization, see:
€
(a) Kundig, E. P.; Pape, A. Top. Organomet. Chem. 2004, 7, 71. (b)
Pearson, A. J.; Vickerman, R. J. Tetrahedron Lett. 1998, 39, 5931. (c)
Pigge, F. C.; Coniglio, J. J.; Dalvi, R. J. Am. Chem. Soc. 2006, 128, 3498
and references therein. (d) Eloi, A.; Rose-Munch, F.; Rose, E.; Pille, A.;
Lesot, P.; Herson, P. Organometallics 2010, 29, 3876 and references
therein.
´
133, 1603. (f) Rousseaux, S.; Garcıa-Fortanet, J.; Sanchez, M. A. D. A.;
Buchwald, S. L. J. Am. Chem. Soc. 2011, 133, 9282 and references therein.
€
(3) For a review, see: Pape, A. R.; Kaliappan, K. P.; Kundig, E. P.
Chem. Rev. 2000, 100, 2917.
r
10.1021/ol2023278
Published on Web 09/13/2011
2011 American Chemical Society

Table 1. Substrate Screeninga
Scheme 1. Structures of η2-Arene, η6-Arene, and η3-Benzyl
Complexes
The η3-benzylpalladium complexes, widely employed in
organic synthesis (Structure Cin Scheme 1),6,7 possess similar
electronic properties as η6-arene metal complexes. We hypo-
thesize that the reactions of η3-benzylpalladium complexes
with nucleophiles (TsujiꢀTrost type reaction) may occur on
the benzene ring to yield dearomatization products. Using
this strategy, the present work aimed to achieve a transition-
metal-catalyzed nucleophilic dearomatization.
To test this hypothesis, several benzyl chloride deriva-
tives weretreated with diethylmalonate inthe presence ofa
catalytic amount of Pd(PPh3)4. The results are shown in
Table 1. Initially, the reaction of benzyl chloride (1a), the
simplest substrate, was attempted at room temperature.
A normal nucleophilic substitution reaction took place to
give benzylation product 2a in 64% yield (entry 1). Then,
1-chloromethyl naphthalene (1b), a polycyclic analog of
1a, was employed instead of 1a. The reaction of 1b with
diethyl malonate proceeded smoothly, yielding a benzyla-
tion product 2b in 91% yield (entry 2). The higher reactiv-
ity of 1b compared with that of 1a could be attributed to
the easy formation of an η3-benzylpalladium complex
from 1b.8 If an alkyl or aryl substituent on the benzylic
position can stabilize the η3-benzylpalladium complex
generated in situ, then the desired nucleophilic dearoma-
tization can be facilitated. This inference was proved when
the dearomatization product 2c was obtained in 32% yield
along with a benzylation product in 40% yield from the
reaction of 1-(1-chloropropyl)naphthalene (1c) with
a Reaction conditions: substrate 1aꢀf (0.5 mmol), diethyl malonate
(0.5 mmol), NaH (1.0 mmol), and Pd(PPh3)4 (5 mol %) in THF (5 mL) at
room temperature under a nitrogen atmosphere. b Isolated yield. c 40%
of benzylation product was also isolated. d No reaction.
diethyl malonate (entry 3). Substrate 1c likewise had a
hydrogen atom beta to a chlorine atom. No β-hydride
elimination product could be observed.9 Considering these
positive results, the reaction of 1-[chloro(phenyl)methyl]-
naphthalene (1d) having a phenyl group on the benzylic
position was examined under the same reaction conditions
utilized on 1c. The dearomatization product 2d was ob-
tained as the sole product in 85% yield (entry 4). Finally,
(1-chloropropyl)benzene (1e) and (chloromethylene)-
dibenzene (1f) were examined, and no reactions were
observed (entries 5 and 6). Therefore, 1-[chloro(phenyl)-
methyl]naphthalene derivatives were used for intermolec-
ular nucleophilic dearomatization in the subsequent study.
The intermolecular nucleophilic dearomatization reac-
tions ofvariouschloromethylnaphthalene derivatives with
diethyl malonate in the presence of a palladium catalyst
were examined, and the results are shown in Scheme 2. The
reaction of substrate 1d was completed within 6 h and
produced the desired product 2d in 89% yield. Substrates
1gand 1hbearing a methyl groupand bromine atom on the
para position of the naphthalene ring, respectively, under-
went nucleophilic dearomatization smoothly to furnish
products 2g and 2h in 90% and 71% yields, respectively.
These results indicate that the palladium-catalyzed nucleo-
philic dearomatization is not evidently influenced by the
electronic property of a substituent on the para position of
the naphthalene ring. However, substrate 1i having a
methyl group on the meta position of the naphthalene ring
was found to be challenging in nucleophilic dearomatiza-
tion. This substrate produced only a 30% yield of the
desired product 2i along with a 62% yield of benzylation
(6) For selected recent references for the use of η3-benzylpalladium
complexes in cross-coupling reactions, see: (a) Lindsell, W. E.; Palmer,
D. D.; Preston, P. N.; Rosair, G. M.; Jones, R. V. H.; Whitton, A. J.
Organometallics 2005, 24, 1119. (b) Johns, A. M.; Tye, J. W.; Hartwig,
J. F. J. Am. Chem. Soc. 2006, 128, 16010 and references therein. (c)
Larsen, C. H.; Anderson, K. W.; Tundel, R. E.; Buchwald, S. L. Snylett
2006, 2941 and references therein. (d) Kuwano, R.; Kusano, H. Org.
Lett. 2008, 10, 1979 and references therein. (e) Guan, B.; Xiang, S.;
Wang, B.; Sun, Z.; Wang, Y.; Zhao, K.; Shi, Z. J. Am. Chem. Soc. 2008,
130, 3268. (f) Fields, W. H.; Chruma, J. J. Org. Lett. 2010, 12, 316 and
references therein.
(7) For the allylative and propargylative dearomatization via η3-
benzylpalladium intermediates, see: (a) Bao, M.; Nakamura, H.;
Yamamoto, Y. J. Am. Chem. Soc. 2001, 123, 759. (b) Lu, S.; Xu, Z.;
Bao, M.; Yamamoto, Y. Angew. Chem., Int. Ed. 2008, 47, 4366. (c) Peng,
B.; Feng, X.; Zhang, X.; Zhang, S.; Bao, M. J. Org. Chem. 2010, 75,
2619. (d) Peng, B.; Feng, X.; Zhang, X.; Ji, L.; Bao, M. Tetrahedron2010,
66, 6013.
(8) For selected references, see: (a) Baird, J. M.; Kern, J. R.; Lee,
G. R.; Morgans, D. J., Jr.; Sparacino, M. L. J. Org. Chem. 1991, 56,
1928. (b) See: Reference 6b and references therein.
(9) In the cross-coupling reaction of Csp3ꢀX electrophiles, the
β-hydride elimination often took place to give alkenes in preference to
coupling. See: (a) Luh, T.-Y.; Leung, M.-k.; Wong, K.-T. Chem. Rev.
ꢀ
2000, 100, 3187. (b) Cardenas, D. J. Angew. Chem., Int. Ed. 2003, 42, 384.
Org. Lett., Vol. 13, No. 19, 2011
5403

Scheme 2. Intermolecular Nucleophilic Dearomatization
of Chloromethyl Naphthalene Derivatives with
Diethyl Malonatea,b
Scheme 3. Intermolecular Nucleophilic Dearomatization of
1-Chloromethyl Naphthalene with Various Activated
Methylene Compoundsa,b
a Reaction conditions: 1d (0.5 mmol), activated methylene compound
(0.5 mmol), NaH (1.0 mmol), and Pd(PPh3)4 (5 mol %) in THF (5 mL)
under a nitrogen atmosphere. The reaction progress was monitored by
TLC. bIsolated yield. cDiastereomeric ratio (dr) was determined by 1H
NMR. dA benzylation product was also obtained in 52% yield.
f
eA benzylation product was also obtained in 28% yield. The reaction
was performed at 50 °C.
catalyzed nucleophilic dearomatization. Di-tert-butyl mal-
onate exhibited almost the same high reactivity and good
selectivity as diethyl malonate, producing product 2o in
91% yield. Poor selectivity was observed in the reaction of
1d with ethyl 2-cyanoacetate. Product 2p was obtained in
only 45% yield with 3:2 dr and a benzylation product in
52%yield. Ethylacetoacetateshowed lowerreactivitythan
its analogs. The reaction of 1d with ethyl acetoacetate
required an enhanced temperature (50 °C) and prolonged
time (72 h) to reach completion. Product 2q was isolated in
only 42% yield with 1:1 dr, and a benzylation product in
28% yield. The use of sterically hindered nucleophiles led
to the formation of para-substituted dearomatization pro-
ducts. For example, the reactions of 1d with diethyl
2-methylmalonate, diethyl 2-phenylmalonate, and ethyl
2-oxocyclopentanecarboxylate proceeded under the same
reaction conditions and produced para-substituted dear-
omatization products 2rꢀt in good to excellent yields
(92%, 67%, and 71%, respectively).
These successful investigations encouraged us to exam-
ine intramolecular nucleophilic dearomatization. The re-
sults are showninScheme4. Fromthereactionof substrate
3a, product 4a, a rearomatized product, was isolated in
52% yield along with 25% of dimer 5. The desired product
4b was obtained in excellent yield (95%) from the reaction
of 3b without observation of any rearomatized product.
Finally, the dearomatization product 2d was trans-
formed to tetracyclic compounds 7 and 8 to highlight the
usefulness of the dearomatization products obtained
a Reaction conditions: substrate 1d, 1gꢀn (0.5 mmol), diethyl mal-
onate (0.5 mmol), NaH (1.0 mmol), and Pd(PPh3)4 (5 mol %) in THF
(5 mL) under a nitrogen atmosphere. The reaction progress was mon-
itored by thin layer chromatography (TLC). bIsolated yield.c A benzyla-
tion product was also obtained in 62% yield.
product. This could be due to the steric hindrance of the
meta methyl group. Reactions of substrates 1j and 1k
having a methyl group and fluorine atom on the para
position of the benzene ring, respectively, with diethyl
malonate, proceeded smoothly to produce products 2j
and 2k in 86% and 92% yields, respectively. Substrate 1l
having two methyl groups on the meta positions of the
benzene ring can also be employed in this type of dear-
omatization reaction. The desired product 2l was obtained
in 63% yield. The reaction of substrate 1m having a
bromine atom on the ortho position of the benzene ring
produced the dearomatization product 2m also in satisfac-
toryyield (68%), but a prolonged reaction timewas needed
(24 h). The electronic property of a substituent group, as
well as its place on the benzene ring, did not strongly
influence the substrate reactivity in this type of dearoma-
tization. Bromine atoms remained on the products 2h and
2m, suggesting that further manipulation may produce
useful compounds. Finally, the reaction of substrate 1n
bearing two phenyl groups at the benzylic position was
examined. The product 2n was obtained in 75% yield.
Scheme 3 shows the results of the investigation on the
scope of activated methylene compounds in the palladium-
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Org. Lett., Vol. 13, No. 19, 2011

Scheme 4. Palladium-Catalyzed Intramolecular Nucleophilic
Dearomatization
Scheme 5. Transformation of Dearomatization Product 2d to
Tetracyclic Compounds
through the η3-benzylpalladium complex formation
to undergo nucleophilic dearomatization. Using the
present strategy, chloromethyl naphthalene deriva-
tives can be efficiently transformed to ortho- or para-
substituted carbocycles in satisfactory to excellent
yields. With the exception of 4a0, all the dearomatiza-
tion products are very stable and could be purified by
column chromatography on basic alumina. Further
studies focusing on the extension of the reaction scope
and the application of dearomatization products are
currently underway.
(Scheme 5). Compound 2d was easily hydrogenated to
compound 6, and compound 7 was subsequently obtained
in 54% yield in four steps. Product 8, a tetracyclic fused
ring system, was also obtained, even though the yield was
relatively low (45%). All the new products 2c, 2d, 2gꢀt, 4a,
4b, and 5ꢀ8 were identified through their NMR10 and
HRMS data as well as IR spectra.
In conclusion, we demonstrated that the aromatic
system can be activated by a palladium catalyst
Acknowledgment. We are grateful to the National Nat-
ural Science Foundation of China (Nos. 20972021 and
21072023) for their financial support. This work was also
supported by the Program for Changjiang Scholars and
Innovative Research Teams in Universities (No. IRT0711)
and the Specialized Research Fund for the Doctoral
Program of Higher Education (No. 20090041110012).
(10) The structural assignment was based on the analysis of the 1D
1
(1H and 13C) and 2D (1Hꢀ H COSY and NOESY) spectra. For
example, the connection and configuration of products 2d and 2r were
1
obtained from 1Hꢀ H COSY and NOESY spectra.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 19, 2011
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