Water-controlled regioselectivity of Pd-catalyzed domino reaction involving a C-H activation process: Rapid synthesis of diverse carbo- And heterocyclic skeletons

Article abstract of DOI:10.1021/ol902672a

[Chemical equaction presented] palladium-catalyzed domino reaction Involving a C-H activation process to synthesize diverse carbo- and heterocyclic skeletons was developed. H2O (as cosolvent) is used to control the regioselectivlty.

Full text of DOI:10.1021/ol902672a

ORGANIC
LETTERS
2010
Vol. 12, No. 3
480-483
Water-Controlled Regioselectivity of
Pd-Catalyzed Domino Reaction Involving
a C-H Activation Process: Rapid
Synthesis of Diverse Carbo- and
Heterocyclic Skeletons
Zhiyao Lu, Chunmei Hu, Jiajie Guo, Jing Li, Yuxin Cui, and Yanxing Jia*
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical
Sciences, Peking UniVersity, 38 Xueyuan Road, Beijing 100191, China
yxjia@bjmu.edu.cn
Received November 19, 2009
ABSTRACT
A palladium-catalyzed domino reaction involving a C-H activation process to synthesize diverse carbo- and heterocyclic skeletons was
developed. H2O (as cosolvent) is used to control the regioselectivity.
Domino reactions have proven to be of exceptional power
for the construction of complex molecules through the
formation of multiple bonds in one-pot reactions.1 The
importance and reliability of palladium-catalyzed transforma-
tions has made it an ideal basis for devising domino
processes, and indeed, significant progress has been achieved
in this regard.2 In recent years, palladium-catalyzed C-H
activation has received substantial attention because it can
transformotherwiseunreactiveC-Hbondsintocarbon-carbon
or carbon-heteroatom bonds.3 Thus, the development of
palladium-catalyzed domino reactions involving C-H acti-
vation represents an attractive research field of synthetic
organic chemistry.
The cyclopalladation proceeding through alkyl/aryl pal-
ladacycles has proven to be a good model for C-H
activation. Lautens,4 Catellani,2c,5 and others6 have reported
many interesting transformations employing norbornene-
(3) For leading reviews, see: (a) Dyker, G. Handbook of C-H
Transformations; Wiley-VCH: Weinheim, 2005; Vol. 1. (b) Meijere, A.;
Diederich, F. Metal Catalyzed Cross-Coupling Reactions; Wiley-VCH:
Weinheim, 2004; Vols. 1-2. (c) Dyker, G. Angew. Chem., Int. Ed. 1999,
38, 1698. (d) Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439. For
recent examples, see: (e) Ruck, R. T.; Huffman, M. A.; Kim, M. M.; Shevlin,
M.; Kandur, W. V.; Davies, I. W. Angew. Chem., Int. Ed. 2008, 47, 4711.
(f) Pinto, A.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46, 3291.
(g) Ohno, H.; Yamamoto, M.; Iuchi, M.; Tanaka, T. Angew. Chem., Int.
Ed. 2005, 44, 5103.
(1) (a) Tietze, L. F. Chem. ReV. 1996, 96, 115. (b) Denmark, S. E.;
Thorarensen, A. Chem. ReV. 1996, 96, 137. (c) Malacria, M. Chem. ReV.
1996, 96, 289. (d) Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem. ReV.
1996, 96, 195. (e) Padwa, A.; Weingarten, M. D. Chem. ReV. 1996, 96,
223. (f) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int.
Ed. 2006, 45, 7134.
(2) (a) Grigg, R. Pure Appl. Chem. 1999, 70, 1647. (b) Poli, G.;
Giambastiani, G.; Heumann, A. Tetrahedron 2000, 56, 5959. (c) Catellani,
M. Synlett 2003, 298. (d) Balme, G.; Bossharth, E.; Monteiro, N. Eur. J.
Org. Chem. 2003, 4101. (e) Zeni, G.; Larock, R. Chem. ReV. 2004, 104,
2285. (f) Cacchi, S.; Fabrizi, G. Chem. ReV. 2005, 105, 2873. (g) Alberico,
D.; Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107, 174, and references
cited therein.
(4) (a) Thansandote, P.; Gouliaras, C.; Turcotte-Savard, M.-O.; Lautens,
M. J. Org. Chem. 2009, 74, 1791. (b) Thansandote, P.; Hulcoop, D. G.;
Langer, M.; Lautens, M. J. Org. Chem. 2009, 74, 1673. (c) Rudolph, A.;
Rackelmann, N.; Turcotte-Savard, M.-O.; Lautens, M. J. Org. Chem. 2009,
74, 289. (d) Lautens, M.; Piguel, S. Angew. Chem., Int. Ed. 2000, 39, 1045.
10.1021/ol902672a  2010 American Chemical Society
Published on Web 12/23/2009

mediated chemistry. To date, only a few examples of
complete alkyl to aryl palladium rearrangement via intramo-
lecular C-H activation have been reported by Larock and
others without using norbornene, and all reactions occurred
on the aromatic site.7 Moreover, regioselective attack at either
the aromatic or alkyl site of palladacycle 2 remains a
challenging task. Herein, we report for the first time that
five-membered palladacycle 2 could be regioselectively
trapped by Heck, as well as Suzuki cross-coupling or
cyanation to give migration “off” product 3 (path a) or
migration “on” product 4 (path b) by manipulating the
reaction conditions (Scheme 1). Also of note is that these
product, was obtained in 42% yield.10 This unexpected result
promted us to obtain a clear picture of how various reaction
variables affect the C-H activation. A wide variety of
reaction conditions (bases, additives, solvents, and temper-
atures) were examined, and some of the representative results
are shown in Table 1. Interestingly, when 18-crown-6 was
Table 1. Optimization of Pd-Catalyzed Domino Reaction of 1a
and K4[Fe(CN)6]·3H2Oa
Scheme 1. Condition-Controlled Pd-Catalyzed Domino
entry temp (°C)
solvent
additive product (yield, %)b
Reactions from Iodobenzene Derivatives
1
2
3
4
5
6
7
120
120
120
120
90
DMF
DMF
DMF/H2O (95:5)
DMF
DMF
DMF
4a (42)
3a (49)
3a (52)
3a (29), 4a (52)
3a (22), 4a (62)
4a (78)
18-C-6
TBAC
TBAC
TBAC
60
60
DMF/H2O (95:5) TBAC
3a (60)
a General reaction conditions: concentration 0.04 M in solvent, 0.05
equiv of Pd(OAc)2, 1.0 equiv of 1a, 0.22 equiv of K4[Fe(CN)6]·3H2O, 1.0
equiv of Na2CO3, and 1.0 equiv of additive. b Isolated yield.
Pd-catalyzed domino reactions involving intramolecular
C-H activation could be achieved under normal Heck
reaction conditions without ligands. Another advantage of
this method is that a diverse range of carbo- or heterocycles
can be prepared starting from the same substrate, which is
consistent with atom- and step-economy.8
In connection with a total synthesis project using the Heck-
cyanation cascade reaction as key step, compound 1a was
employed as a model.9 To our surprise, compound 4a, an
intramolecular C-H activation via 1,4-palladium migration
added as an additive, only the normal Heck-cyanation product
3a was obtained in 49% yield (entry 2). These results
indicated clearly that the regioselectivity of the palladacycle
could be controlled by manipulating the reaction conditions.
When DMF/H2O (95:5) was used as solvent the sole product
3a was obtained in 52% yield (entry 3).11 We have found
that upon the addition of tert-butylammonium chloride
(TBAC) described by Jeffery,12 the yield of 4a was increased
to 52% (entry 4), along with 29% of 3a. To our delight,
simply lowering the reaction temperature to 60 °C led to an
improvement and gave 4a as an exclusive product in 78%
yield (entry 6). Most interesting, the sole compound 3a was
obtained in 60% yield by using DMF/H2O (95:5) as solvent
(entry 7). Thus, the regioselectiVity of palladacycle could
be controlled in the presence/absence of water.7c,11 It is
noteworthy that TBAC is not essential to the C-H activation,
but its presence could shorten the reaction time and minimize
side reactions.
Having established the optimal reaction conditions, the
scope of the palladium migration “on” process was first
examined. Aryl halides 1b-e, representing different
heterocyclic skeleton types, were smoothly transformed
to the desired products (4b-e) in good to excellent yields
(Figure 1).
An interesting question is whether the arylpalladium
intermediates can be trapped by other traditional palladium-
catalyzed chemistry which could broaden the scope and
(5) (a) Faccini, F.; Motti, E.; Catellani, M. J. Am. Chem. Soc. 2004,
126, 78. (b) Catellani, M.; Mealli, C.; Motti, E.; Paoli, P.; Perez-Carren˜o,
E.; Pregosin, P. S. J. Am. Chem. Soc. 2002, 124, 4336.
(6) Ca´mpora, J.; Gutie´rrez-Puebla, E.; Lo´pez, J. A.; Monge, A.; Palma,
P.; Del R´ıo, D.; Carmona, E. Angew. Chem., Int. Ed. 2001, 40, 3641.
(7) (a) Huang, Q.; Fazio, A.; Dai, G.; Campo, M. A.; Larock, R. C.
J. Am. Chem. Soc. 2004, 126, 7460. (b) Wang, L.; Pan, Y.; Jiang, X.; Hu,
H. Tetrahedron Lett. 2000, 41, 725. (c) Ca´mpora, J.; Lo´pez, J. A.; Palma,
P.; Valerga, P.; Spillner, E.; Carmona, E. Angew. Chem., Int. Ed. 1999, 38,
147. (d) Heck, R. F. J. Organomet. Chem. 1972, 37, 389.
(8) (a) Trost, B. M. Science 1991, 254, 1471. (b) Wender, P. A.; Handy,
S. T.; Wright, D. L. Chem. Ind. 1997, 765. (c) Schreiber, S. L. Science
2000, 287, 1964. (d) Burns, N. Z.; Baran, P. S.; Hoffmann, R. W. Angew.
Chem., Int. Ed. 2009, 48, 2854.
(9) (a) Pinto, A.; Jia, Y.; Neuville, L.; Zhu, J. Chem.sEur. J. 2007, 13,
961. (b) Sundermeier, M.; Zapf, A.; Mutyala, S.; Baumann, W.; Sans, J.;
Weiss, S.; Beller, M. Chem.sEur. J. 2003, 9, 1828.
(10) For leading reviews, see: (a) Ma, S.; Gu, Z. Angew. Chem., Int.
Ed. 2005, 44, 7512. For recent examples, see: (b) Karig, G.; Moon, M.-T.;
Thasana, N.; Gallagher, T. Org. Lett. 2002, 4, 3115. (c) Campo, M. A.;
Larock, R. C. J. Am. Chem. Soc. 2002, 124, 14326. (d) Campo, M. A.;
Huang, Q.; Yao, T.; Tian, Q.; Larock, R. C. J. Am. Chem. Soc. 2003, 125,
11506. (e) Zhao, J.; Campo, M.; Larock, R. C. Angew. Chem., Int. Ed.
2005, 44, 1873. (f) Campo, M. A.; Larock, R. C. J. Am. Chem. Soc. 2007,
129, 6298. (h) Kesharwani, T.; Larock, R. C. Tetrahedron 2008, 64, 6090.
(i) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2005, 127, 4685. (g) Chaumontet, M.; Piccardi, R.; Audic, N.;
Hitce, J.; Peglion, J.-L.; Clot, E.; Baudoin, O. J. Am. Chem. Soc. 2008,
130, 15157.
(11) (a) Chai, D. I.; Lautens, M. J. Org. Chem. 2009, 74, 3054. (b)
Fors, B. P.; Krattiger, P.; Strieter, E.; Buchwald, S. L. Org. Lett. 2008, 10,
3505.
(12) Jeffery, T. Chem. Commun. 1984, 1287.
Org. Lett., Vol. 12, No. 3, 2010
481

utility of this migration progress. To address this issue, aryl
halides 1a-e were allowed to react with methyl acrylate
under the aforementioned optimized conditions. The desired
products 4f-j were generated in good to excellent yield
(Figure 1). When styrene was used as a trapping reagent the
desired products 4k and 4l were obtained in good yield.
Table 2. Synthesis of Fused Polycycles via Pd-Catalyzed
Heck/C-H Activation/Intramolecular Arylation Domino
Processa
a Concentration 0.04 M in DMF, 0.05 equiv of Pd(OAc)2, 1.0 equiv of
substrate, 1.0 equiv of Na2CO3, and 1.0 equiv of TBAC, 60 °C. Isolated
yields.
under optimized conditions (3a-c, 3f-i). However, the
Heck-Heck cascade reaction proved to be problematic. The
migration “on” product 4f and migration “off” product 3d
were obtained in a ratio of 1 to 4. Fortunately, we raised the
water amount in the reaction system to 20%, and then 3d
was obtained exclusively in 62% yield (Figure 2). Similarly,
3e was obtained in 70% yield.
Figure 1. Scope of the Pd-catalyzed domino reaction involving
intramolecular C-H activation process (migration “on”).
To explore the scope of this migration progress, further
trapping of the arylpalladium intermediates was tried by a
Suzuki coupling. To the best of our knowledge, this type of
domino reaction has never been reported in the literature.13
Gratefully, all substrates indeed afforded the aryl function-
alized products in good yields (4m-p, Figure 1).
Larock has reported that complex fused polycycles could
be synthesized via a novel 1,4-palladium alkyl to aryl
migration followed by intramolecular arylation under their
usual palladium migration conditions.7a We envisioned that
this type of domino reaction could similarly occur under our
conditions to generate complex fused polycycles. Compounds
5, 7, and 9 reacted well to afford the corresponding fused
ring systems 6, 8, and 10 in good yields (Table 2).
The scope of the palladium migration “off” process was
alsoexamined(Figure2).TheHeck-cyanationandHeck-Suzuki
cascade reaction proceed well to afford the desired product
Figure 2. Scope of the Pd-catalyzed domino reaction involving
a
intramolecular C-H activation process (migration “off”). DMF
/H2O (80/20).
(13) A related domino reaction with a boronic acid was reported by
Buchwald et al.; see ref 10i.
482
Org. Lett., Vol. 12, No. 3, 2010

To study the mechanism in detail, we carried out the
reaction of 1a and K4[Fe(CN)6]·3H2O using DMF/D2O (95/
5) as solvent (Scheme 2, eq 1), the condition which gives
Scheme 3. Proposed Mechanism for the Transformations
Scheme 2. Deuterium-Labeling Experiments
the alkyl-functionalized product 3a (Table 1, entry 7). Proton
NMR spectroscopic analysis of the product showed that
incorporation of the deuterium occurs only in the aryl
position, and no deuterium incorporation in the methylene
or methyl position was observed. A similar result was
obtained by the reaction of 1a and 4-methoxyphenylboronic
acid in DMF/D2O (95/5) (Scheme 2, eq 2). To understand
this process better, the reaction shown in eq 3 (Scheme 2)
was conducted in the presence of 20 equiv of D2O.14 The
isolated product 4f contained >95% deuterium in one of the
methyl groups (see the Supporting Information). These results
provide strong evidence that the five-membered palladacycle
was formed via intramolecular C-H activation under both
palladium migration “on” and “off” reaction conditions
before being trapped. The two types of products, 3a and 4a,
were formed by direct regioselective cleavage of the
carbon-palladium bond of the resulting palladacycle by
cyanation, Heck, or Suzuki reactions or direct arylation.7c
These results also indicate the palladium migration occurs
inreversibly between the aryl and alkyl positions in the
present cases since incorporation of the deuterium occurs
only in either the aryl or alkyl position.10h
11 can insert into the neighboring C-H bond to form a
palladium(II) intermediate or a palladium(IV) intermediate
12. Palladacycle 12 could be regioselectively protonated and
transmetalated to afford the PdII species 13a or 14a, which
then would give either 3a or 4a upon reductive elimination.15
Alternatively, palladacycle 12 could be also regioselectively
trapped by cyanation, Heck, Suzuki reactions, or direct
arylation by varying reaction conditions to provide either
3a or 4a.
In conclusion, we have reported an efficient palladium-
catalyzed domino reaction involving a C-H activation
process. The palladacycle intermediate was successfully
trapped by cyanation, Heck reaction, secondary C-H activa-
tion and Suzuki coupling. The regioselectivity was controlled
by manipulating the reaction conditions to give either an aryl-
functionalized product with yields in the 47-95% range or
alkyl-functionalized product with yields in the 60-95%
range. Moreover, our conditions avoided using expensive
bases, which are usually employed in C-H activation, and
phosphorus ligands, which are usually not friendly to the
environment. Diverse products can be prepared starting from
the same substrate by using this method.
On the basis of these preliminary results, the mechanism
of these transformations was hypothesized as shown in
Scheme 3. The Pd(0) catalyst undergoes oxidative addition
to the aryl iodide 1 to generate an organopalladium(II)
intermediate, which undergoes 6-exo-trig cyclization to afford
the σ-alkylpalladium complex 11. The resulting intermediate
Acknowledgment. Financial support from Peking Uni-
versity, National Science Foundation of China (Nos. 20972007,
20802005), and SRF for ROCS (SEM) is greatly appreciated.
Supporting Information Available: Detailed experimen-
tal procedures, compound characterization, and copies of
spectral data. This material is available free of charge via
the Internet at http://pubs.acs.org.
(14) Reaction of 1a with methyl acrylate using DMF as solvent in
the presence of 20 equiv of D2O gave the sole 1,4-palladium migration
product.
(15) This mechanism was proposed by one of the reviewers; we are
grateful for this suggestion.
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