Pd(OAc)2-catalyzed Domino reactions of 1-chloro-2-haloarenes and 2-haloaryl tosylates with hindered Grignard reagents via palladium-associated arynes

Article abstract of DOI:10.1021/ol061989i

(Chemical Equation Presented) The palladium-associated aryne generation strategy and Pd(OAc)₂-catalyzed annulative Domino reactions of 1-chloro-2-halobenzenes and 2-haloaryl tosylates with hindered Grignard reagents via palladium-associated arynes are described. The palladium-associated aryne generation strategy described here not only allows the high yield, one-step access to potentially useful substituted fluorenes from readily available 1-chloro-2-halobenzenes and 2-haloaryl tosylates, but may also lead to the development of other tandem reactions based on these readily available ortho leaving group bearing haloarenes.

Full text of DOI:10.1021/ol061989i

ORGANIC
LETTERS
2006
Vol. 8, No. 22
5057-5060
Pd(OAc)2-Catalyzed Domino Reactions
of 1-Chloro-2-haloarenes and 2-Haloaryl
Tosylates with Hindered Grignard
Reagents via Palladium-Associated
Arynes
Cheng-Guo Dong and Qiao-Sheng Hu*
Department of Chemistry, College of Staten Island and the Graduate Center of the
City UniVersity of New York, Staten Island, New York 10314
qiaohu@mail.csi.cuny.edu
Received August 10, 2006
ABSTRACT
The palladium-associated aryne generation strategy and Pd(OAc)2-catalyzed annulative Domino reactions of 1-chloro-2-halobenzenes and 2-haloaryl
tosylates with hindered Grignard reagents via palladium-associated arynes are described. The palladium-associated aryne generation strategy
described here not only allows the high yield, one-step access to potentially useful substituted fluorenes from readily available 1-chloro-2-
halobenzenes and 2-haloaryl tosylates, but may also lead to the development of other tandem reactions based on these readily available ortho
leaving group bearing haloarenes
Arynes are very reactive and have recently been demon-
strated as useful substrates for palladium-catalyzed carbon-
carbon bond forming reactions.1-4 However, the aryne
generation strategy in reported reactions, in which arynes
were generated in situ from expensive o-trimethylsilylaryl
triflates, does not work well with the use of catalytic amounts
of palladium because short-lived arynes are needed to search
for inherently unstable palladium intermediates for reactions
to occur. Consequently, a large excess of o-trimethylsilylaryl
triflates was often required to achieve good yields. It would
thus be synthetically advantageous to generate arynes with
palladium species inherently associating with them, especially
from readily available, cost-effective starting materials.
We have recently reported the Pd(0)/t-Bu3P-catalyzed
annulative tandem reacion of 1,2-dibromobenzenes and
1-bromo-2-iodobenzene with hindered Grignard reagents.5,6
However, readily available, less expensive 1-chloro-2-
(3) Recent examples of Pd-catalyzed cyclotrimerization of arynes: (a)
Jayanth, T. T.; Jeganmohan, M.; Cheng, C.-H. J. Org. Chem. 2004, 69,
8445-8450. (b) Iglesias, B.; Cobas, A.; Perez, D.; Guitian, E.; Vollhardt,
K. P. C. Org. Lett. 2004, 6, 3557-3560. (c) Sato, Y.; Tamura, T.; Mori,
M. Angew. Chem., Int. Ed. 2004, 43, 2436-2440. (d) Pena, D.; Cobas, A.;
Perez, D.; Guitian, E.; Castedo, L. Org. Lett. 2003, 5, 1863-1866. (e) Pen˜a,
D.; Pe´rez, D.; Guitia´n, E.; Castedo, L. Eur. J. Org. Chem. 2003, 7, 1238-
1243. (f) Pena, D.; Cobas, A.; Perez, D.; Guitian, E.; Castedo, L. Org. Lett.
2000, 2, 1629-1632. (g) Yoshikawa, E.; Radhakrishnan, K. V.; Yamamoto,
Y. J. Am. Chem. Soc. 2000, 122, 7280-7286. (h) Pena, D.; Perez, D.;
Guitian, E.; Castedo, L. J. Org. Chem. 2000, 65, 6944-6950.
(4) For recent examples of Pd-catalyzed carbonylation of arynes see:
(a) Chatani, N.; Kamitani, A.; Oshita, M.; Fukumoto, Y.; Murai, S. J. Am.
Chem. Soc. 2001, 123, 12686-12687. (b) Yoshikawa, E.; Radhakrishnan,
K. V.; Yamamoto, Y. Tetrahedron Lett. 2000, 41, 729-732.
(1) (a) Pellissier, H.; Santelli, M. Tetrahedron 2003, 59, 701-730. (b)
Saito, S.; Yamamoto, Y. Chem. ReV. 2000, 100, 2901-2916.
(2) Recent examples of Pd-catalyzed reactions via carbopalladation of
arynes: (a) Liu, Z.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2005,
127, 15716-15717. (b) Jayanth, T. T.; Jeganmohan, M.; Cheng, C.-H. Org.
Lett. 2005, 7, 2921-2924. (c) Jeganmohan, M.; Cheng, C.-H. Org. Lett.
2004, 6, 2821-2824. (d). Matsubara, T. Organometallics 2003, 22, 4297-
4304. (e) Yoshida, H.; Honda, Y.; Shirakawa, E.; Hiyama, T. Chem.
Commun. 2001, 1880-1881. (f) Solin, N.; Narayan, S.; Szabo, K. J. J.
Org. Chem. 2001, 66, 1686-1693. (g) Yoshikawa, E.; Yamamoto, Y.
Angew. Chem., Int. Ed. 2000, 39, 173-175.
(5) Dong, C.-G.; Hu, Q.-S. Angew. Chem., Int. Ed. 2006, 45, 2289-
2292.
10.1021/ol061989i CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/06/2006

halobenzenes were found to be unsuitable substrates for such
a tandem reaction because of the reluctancy of the first-step
cross-coupling product, 2-chlorobiphenyls (I), to undergo
oxidative addition with Pd(0) species.5 During our study, we
reasoned that the initial oxidative addition adduct o-chloro-
arylpalladium(II) halides (II), in addition to undergoing
transmetalation with organometallic reagents to form I
(Scheme 1, Path B), might undergo â-chloro group elimina-
tandem/domino reactions. Herein, we report our preliminary
study on such palladium-associated aryne generation strategy,
specifically, on Pd-catalyzed domino reactions of 1-chloro-
2-halobenzenes and 2-haloaryl tosylates with hindered Grig-
nard reagents to access substituted fluorenes.9,10
As depicted in Scheme 1, the direct transmetalation of
o-chloroarylpalladium(II) halides (II) to form cross-coupling
product I (Scheme 1, Path B) would compete with the
formation of Pd(II)XCl-associated benzynes (Path A). There-
fore, factors that could influence the transmetalation and/or
the â-LG elimination of o-aryl(LG)Pd(II) halides, e.g., the
steric hindrance and nucleophilicity of organometallic re-
agents, LG leaving ability, ligand effect, basicity of the base,
reaction temperature, etc., were expected to affect the
generation of Pd-associated arynes. We reasoned that for a
given type of o-aryl(LG)Pd(II) halides with the same LG
and a given type of organometallic regent such as Grignard
reagents at a certain reaction temperature, the influential
factors could be narrowed down to steric hindrance and
ligand effect. Since increasing the steric hindrance of
Grignard reagents has been established to slow down the
transmetalation, we thus first examined the ligand influence.
The reaction of 1-bromo-2-chlorobenzene with bulky 2-mes-
itylmagnesium bromide was employed as the model reac-
tion.11 As the initial oxidative addition was believed to occur
at the C-Br bond12 and 2-chloro-2′,4′,6′-trimethylbiphenyl
(I) was found to be inert under Pd(OAc)2/Grignard reagent
condition (see the Supporting Information), we exepcted that
the reaction product would be 2,4-dimethylfluorene if the
reaction proceeded via benzyne intermediate (Path A).13 The
reaction product would be 2-chloro-2′,4′,6′-trimethylbiphenyl
if the reaction occurred via transmetalation followed by
reductive elimination (Path B). Our results are listed in Table
1. We found that, with monodentate PPh3, PCy3, t-Bu3P, an
N-heterocyclic carbene (NHC), or bidentate DPPE, DPPB,
and BINAP as ligands, 2-chlorobiaryl was obtained as the
Scheme 1. Outline for 1-Chloro-2-halobenzenes for Domino
Reactions via Palladium(II)ClX-Associated Aryne Intermediates
tion to form Pd(II)ClX associated arynes (Scheme 1, Path
A).7,8 The generated Pd(II)ClX-associated arynes could then
undergo transmetalation followed by carbopalladation to form
intermediate III, which could further undergo other trans-
formations (Scheme 1, Path A). Thus, the sequence of
oxidative addition of Pd(0) with 1,2-dihalobenzenes followed
by â-halo elimination (Path A) could be an interesting
strategy for the generation of palladium-assoicated arynes.
Such an aryne generation strategy would employ widely
available 1,2-dihalobenzenes as substrates with the assurance
that every generated aryne would be associated with a
palladium, and thus would have advantages over the reported
aryne generation strategy from o-trimethylsilylaryl triflates.
Importantly, in this oxidative addition followed by â-halo
elimination aryne generation strategy, because the formation
of III does not involve the oxidative addition of the C-Cl
bond of I with Pd(0) species, the overall reactivity of
o-chlorohalobenzenes would be governed by the reactivity
of C-halo bonds that undergo the initial oxidative addition
with Pd(0) catalysts. Thus, 1-chloro-2-halobenzenes that were
previously unsuitable for tandem reactions5 would now be
suitable ones. In addition, this aryne generation strategy
might also allow other types of o-halo(leaving group)arenes,
e.g., 2-haloaryl tosylates, to be employed as substrates for
(9) Fluorenes are typically prepared via more than one step, for
example: (a) Kashulin, I. A.; Nifant’ev, I. E. J. Org. Chem. 2004, 69, 5476-
5479. For a recent one-step synthesis of fluorenes: Fuchibe, K.; Akiyama,
T. J. Am. Chem. Soc. 2006, 128, 1434-1435. Also see ref 5.
(10) Fluorene is the core structure of biologically active molecules,
sensors, and light-emitting materials. For examples: (a) Rathore, R.; Chebny,
V. J.; Abdelwahed, S. H. J. Am. Chem. Soc. 2005, 127, 8012-8013. (b)
Sulsky, R.; Robl, J. A.; Biller, S. A.; Harrity, T. W.; Wetterau, J.; Connolly,
F.; Jolibois, K.; Kunselman, L. Bioorg. Med. Chem. Lett. 2004, 14, 5067-
5070. (c) Marsitzky, D.; Vestberg, R.; Blainey, P.; Tang, B. T.; Hawker,
C. J.; Carter, K. R. J. Am. Chem. Soc. 2001, 123, 6965-6972.
(11) The direct formation of benzyne from 1-bromo-2-chlorobenzene and
2-mesitylmagnesium bromide has been ruled out. See ref 5.
(12) The initial oxidative addition occurring at the C-Cl bond in Pd-
(OAc)2-catalyzed reaction of 1-chloro-2-bromobenzene with 2-mesitylmag-
niseium bromide was ruled out based on the following experiments:
Pd(OAc)2-catalyzed reaction of 1,2-dichlorobenzene with 2-mesitylmag-
nesium bromide in THF at 60 °C gave a low yield of 2,4-dimethylfluorene
(24%, much lower than the 95% yield observed for 1-bromo-2-chloroben-
zene under the same reaction condition), indicating the initial oxidative
addition at the C-Cl bond occurred very slowly. This observation suggested
with 1-bromo-2-chlorobenzene as substrate that the initial oxidative addition
should take place at the C-Br bond. See the Supporting Information.
(13) Pd-catalyzed cyclizations via sp3 C-H activation are rare: ref 5.
Also see: (a) Baudoin, O.; Herrbach, A.; Gueritte, F. Angew. Chem. 2003,
115, 5914-5918; Angew. Chem., Int. Ed. 2003, 42, 5736-5740. (b) Suau,
R.; Lopez-Romero, J. M.; Rico, R. D. Tetrahedron Lett. 1996, 37, 9357-
9360. (c) Dyker, G. J. Org. Chem. 1993, 58, 6426-6428. (d) Dyker, G.
Angew. Chem. 1994, 106, 117-119; Angew. Chem., Int. Ed. Engl. 1994,
33, 103-105. (e) Dyker, G. Angew. Chem. 1992, 104, 1079-1081; Angew.
Chem., Int. Ed. Engl. 1992, 31, 1023-1025.
(6) For recent general reviews on tandem/Domino reactions see: (a)
Tietze, L. F.; Rackelmann, N. Pure Appl. Chem. 2004, 76, 1967-1983.
(b) Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem. Commun. 2003,
551-564. (c) Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem. ReV. 1996,
96, 195-206. (d) Tietze, L. F. Chem. ReV. 1996, 96, 115-136.
(7) Pd(0)-coordinated benzyne complexes formed from o-Ph[B(OH)2]-
Pd(II)XLn have been reported: (a) Retboll, M.; Edwards, A. J.; Rae, A.
D.; Willis, A. C.; Bennett, M. A.; Wenger, E. J. Am. Chem. Soc. 2002,
124, 8348-8360. (b) Klosin, J.; Abboud, K. A.; Jones, W. M. Organome-
tallics 1996, 15, 2465-2468.
(8) Pd(IV) palladacycles as intermediates might also be possible, for
examples: (a) Zhang, X.; Larock, R. C. Org. Lett. 2005, 7, 3973-3976.
(b) Cardenas, D. J.; Martin-Matute, B.; Echavarren, A. M. J. Am. Chem.
Soc. 2006, 128, 5033-5040.
5058
Org. Lett., Vol. 8, No. 22, 2006

Table 1. Ligand Effect on Pd(0)-Catalyzed Cross-Couplings of
1-Bromo-2-chlorobenzene with Grignard Reagentsa
Table 2. Pd(OAc)2-Catalyzed Cross-Couplings of
1-Chloro-2-halobenzenes with Hindered Grignard Reagentsa
a Reaction conditions: 1-bromo-2-chlorobenzene (1.0 equiv), Grignard
reagent (2.5 equiv), THF (2 mL). b Ratio based on 1H NMR. c 4,4′′-
Dimethyl-(1,1′,2′,1′′)-terphenyl was the product.
major product (Table 1, entries 1-6), suggesting the reactions
proceeded predominately through Path B. However, 2,4-
dimethylfluorene was observed as the major product with
Pd2(dba)3, Pd(OAc)2, or Pd(PhCN)2Cl2 as catalysts (Table
1, entry 7), implying that Pd-associated benzynes were
involved. A similar trend was also observed with sterically
less hindered p-tolylmagnesium bromide, in which 4,4′′-
dimethyl-(1,1′,2′,1′′)-terphenyl would be the tandem reaction
product (Table 1, entries 9 and 10). These results suggested
that the absence of phosphines or NHCs favored the reaction
to occur via palladium-associated intermediates.
With Pd(OAc)2 and Pd2(dba)3 as catalysts, we next
examined other 1-chloro-2-halobenzenes and hindered Grig-
nard reagents. Our results, which are listed in Table 2,
showed that all tested 1-chloro-2-halobenzenes, including
1,2-dichlorobenzene, gave good to excellent yields of domino
reaction products. Since the transmetalation rate for the Pd-
Cl bond has been previously established to be different from
that of Pd-Br or C-I bonds,14 our Pd(II)ClX-associated
aryne generation strategy (Scheme 1) suggested transmeta-
lation of aryne-coordinated Pd(II)ClX complexes (X ) Br,
I) would form more aryne-coordinated ArPd(II)Cl species
than aryne-coordinated ArPd(II)X species (X ) Br, I). In
accord with this hypothesis, we expected that with substrates
such as 3-bromo-4-chlorotoluene and 3-chloro-4-iodotoluene
that would produce unsymmetrical arynes, two isomeric
fluorenes would be obtained in unequal amounts.15 Indeed
that is what was observed (Table 2, entries 6-9). The
observation of the formation of two isomeric fluorenes in a
similar ratio (4-5:1) for these substrates (Table 2, entries
a Reaction conditions (not optimized): dihalide (1.0 equiv), Grignard
reagent (2.5 equiv), Pd(OAc)2 (3%), THF (2 mL). b Isolated yields. c 2-
Chlorobiaryls were observed in less than 5% yields. d 1.5% Pd2 (dba)3 as
catalyst. e Ratio based on 1H NMR. f Refluxing, 40 h, 16% 2-chloro-2′,4′,6′-
trimethylbiphenyl was observed.
6-9) suggested that the transmetalation rates for Pd-Br and
Pd-I bonds with hindered Grignard reagents were compa-
rable to each other.
Our hypothesis also suggested that other types of o-halo-
(LG)arenes, such as 2-haloaryl tosylates which contain very
inert Ar-OTs bonds, should also be suitable substrates for
the domino reaction because the oxidative addition of Pd(0)
with the very inert Ar-OTs bond would not be involved
and the OTs group would only serve as a leaving group.
We thus tested 2-haloaryl tosylates, which are readily
available from 2-halophenols, as substrates for domino
reactions (Table 3). We were pleased to find that with Pd-
(OAc)2 as catalyst, high yields of domino reaction products
were obtained for 2-bromophenyl tosylates, 2-iodoaryl to-
sylates, and 1-bromo-2-naphthyltosylate (Table 3, entries
1-9).16 However, 2-chloro-4-methylphenyl tosylate was
found to be a poor substrate (Table 3, entry 10). These results
suggested that the initial oxidative addition should occur at
the C-X bond, rather than at the C-OTs bond, and the
reluctance of the C-Cl bond in 2-chloro-4-methylphenyl
tosylate to undergo the initial oxidative addition with Pd(0)
species excluded it as a suitable substrate for the domino
reaction. The observation of two isomers, rather than only
one, in similar ratios for 2-bromophenyl tosylates, 2-iodo-
4-methylphenyl tosylate, and 1-bromo-2-naphthyltosylate
(14) (a) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; Wiley-VCH: New York, 2004. (b) Negishi, E.-I.
Handbook of Organopalladium Chemistry for Organic Synthesis; Wiley-
Interscience: New York, 2002.
(15) Two isomeric products in close to 1:1 ratio were always observed
with unsymmetrical arynes in the reported aryne generation strategy from
o-trimethylsilylaryl triflates, see ref 2.
(16) Aryl tosylates have been demonstrated to undergo cross-couplings
with para-substituted phenylmagnesium bromides and o-tolymagnesium
bromide catalyzed by Pd(0)/Josiphos ligand: (a) Limmert, M. E.; Roy, A.
H.; Hartwig, J. F. J. Org. Chem. 2005, 70, 9364-9370. (b) Roy, A. H.;
Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 8704-8705.
Org. Lett., Vol. 8, No. 22, 2006
5059

Scheme 2. Pd-Catalyzed Reaction of
2-(2′,4′,6′-Trimethyl)-4-methylphenyl Tosylate with
2-Mesitylmagnesium Bromide
Table 3. Pd(OAc)2-Catalyzed Cross-Couplings of 2-Haloaryl
Tosylates with Hindered Grignard Reagentsa
toyslates with hindered Grignard reagents did not proceed
through the cross-coupling-oxidative addition-sp3 C-H
activation mechanism.
Scheme 3. Pd(0)/t-Bu3P-Catalyzed Reaction of
2-Bromo-4-methylphenyl Tosylate with 2-Mesitylmagnesium
Bromide
In summary, based on the hypothesis that arynes could
be generated with palladium species associated with them
from ortho leaving groups bearing halobenzenes, we explored
the ligand effect on such aryne generation strategy in Pd-
catalyzed reactions of o-halo(LG)arenes with Grignard
reagents. We found the reaction pathway involving pal-
ladium-associated arynes as intermediates would be favored
in the absence of phosphines and NHCs. Our hypothesis also
gave us the opportunity to employ substrates previously
unsuitable for tandem reaction, e.g., 1-chloro-2-halobenzenes
and readily available 2-haloaryl tosylates, for Pd-catalyzed
domino reactions with hindered Grignard reagents, which
provides an efficient access to substituted fluorenes. The
palladium-associated aryne generation strategy described here
may have potential applications for the development of other
tandem reactions from readily available ortho leaving group
bearing haloarenes. Our future work will thus focus on
determining the scope and limitation of this aryne generation
strategy as well as elucidating a more detailed reaction
mechanism.
a Reaction conditions (not optimized): 2-haloaryl tosylate (1.0 equiv),
Grignard reagent (2.5 equiv), Pd(OAc)2 (3%), THF (2 mL), reflux. b Isolated
1
yields. c Ratio based on H NMR.
(Table 3, entries 4-9) further suggested that the transmeta-
lation occurred with comparable transmetalation rates for
Pd-Br and Pd-I bonds.
To exclude that the cross-coupling-oxidative addition-
sp3 C-H activation mechanism was involved in Pd(OAc)2-
catalyzed domino reactions of 2-haloaryl toyslates with
hindered Grignard reagents, we have carried out the reaction
of phenyl tosylate with 2-mesitylmagnesium bromide in the
presence of 5% Pd(OAc)2 at 60 °C for 20 h.16 We found
less than 5% cross-coupling product was observed, suggest-
ing Pd(OAc)2 cannot catalyze the cross-coupling of aryl
tosylates with hindered Grignard reagents efficiently. We also
found that 2-(2′,4′,6′-trimethyl)-4-methylphenyl tosylate,
intermediate that would be formed if the domino reaction
proceeded via cross-coupling-oxidative addition-sp3 C-H
activation mechanism, was unable to be converted to 2,4,6-
trimethylfluorene under Pd(OAc)2/Grignard reagent or Pd-
(OAc)2/MgCl2/Grignard reagent condition (Scheme 2). We
have further carried out thePd2(dba)3/t-Bu3P-catalyzed reac-
tion of 2-bromo-4-methylphenyl tosylate with 2-mesi-tyl-
magnesium bromide and 2-(2′,4′,6′-trimethyl)-4-methylphe-
nyl tosylate was isolated in 82% yield with no cyclized
fluorene being observed (Scheme 3). These results suggested
that Pd(OAc)2-catalyzed domino reactions of 2-haloaryl
Acknowledgment. We gratefully thank the NIH (GM-
69704) for funding. Partial support from the Petroleum
Research Fund, administered by the American Chemical
Society, and PSC-CUNY Research Award Programs is also
gratefully acknowledged. We also thank Frontier Scientific,
Inc. for its generous gifts of Pd(OAc)2.
Supporting Information Available: General experimen-
tal procedures and characterization of products. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL061989I
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