Tandem isomerization and C-H activation: Regioselective hydroheteroarylation of allylarenes

Article abstract of DOI:10.1021/ol402644y

The first Ni-promoted prototype reaction based on the tandem C-H activation of heteroarenes with alkene isomerization is demonstrated, leading to the branched hydroheteroarylation products. Simultaneously, the reaction selectivity can be chemically switched to linear adducts through Ni-Al tandem catalysis.

Full text of DOI:10.1021/ol402644y

ORGANIC
LETTERS
2
013
Vol. 15, No. 20
358–5361
Tandem Isomerization and
CꢀH Activation: Regioselective
5
Hydroheteroarylation of Allylarenes
†
Wei-Chih Lee, Chun-Han Wang, Yung-Huei Lin, Wei-Chun Shih, and Tiow-Gan Ong*
†
‡
†
,†,‡
Institute of Chemistry, Academia Sinica, Nangang, Taipei, Taiwan, Republic of China, and
Department of Applied Chemistry, National Chiao Tung University, Hsinchu, Taiwan,
Republic of China
tgong@gate.sinica.edu.tw
Received September 14, 2013
ABSTRACT
The first Ni-promoted prototype reaction based on the tandem CꢀH activation of heteroarenes with alkene isomerization is demonstrated, leading
to the branched hydroheteroarylation products. Simultaneously, the reaction selectivity can be chemically switched to linear adducts through
NiꢀAl tandem catalysis.
Transition-metal-mediated CꢀH bond activation has
emerged as a powerful synthetic tool, avoiding extra steps
associated with prefunctionalized coupling partners. Sur-
Nickel-promoted catalysis has been recognized as an
attractive synthetic manifold because of its low cost and
5
low toxicity. Renowned examples of Ni promoted cata-
lytic process are involved with olefin isomerization rang-
1
prisingly, only a few cases of such tandem processes con-
sisting of alkene isomerization and CꢀH bond activation
are known. For example, Bergman and Ellman have ob-
served olefin isomerization in the Rh-mediated synthesis
of multicyclic pyridine and quinolone via intramolecular
ing from the production of linear R-olefins in the shell
higher olefin process (SHOP) to the hydrocyanation of
6
7
butadiene by DuPont to prepare adiponitrile. Nevertheless,
catalytic CꢀH functionalization in a selective fashion
2
CꢀH bond functionalization. Similarly, Willis exploited
facilitated by nickel catalysts still remains a great chal-
8
lenge, despite the tremendous success of palladium cata-
alkene isomerization in preparing indoles and benzo-
3
9
furans via palladium-mediated arylation of styryl units.
Moore also observed similar tandem process mediated by
lysts for this purpose over the past years.
4
(
4) Moore, E. J.; Pretzer, W. R.; O’Connell, T. J.; Harris, J.;
LaBounty, L.; Chou, L.; Grimmer, S. S. J. Am. Chem. Soc. 1992, 114,
888.
(5) (a) Ogoshi, S. J. Synth. Org. Chem. Jpn. 2009, 67, 507. (b)
Ru (CO) in carbonylation of pyridine.
3 12
5
†
‡
Academia Sinica.
National Chiao Tung University.
Kulkarni, A. A.; Daugulis, O. Synthesis;Stuttgart 2009, 4087. (c)
Yamaguchi, J.; Muto, K.; Itami, K. Eur. J. Org. Chem. 2013, 19. (d)
Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.; Zhang, N.; Resmerita,
A.-M.; Garg, N. K.; Percec, V. Chem. Rev. 2011, 111, 1346. (e) Ar ꢀe valo,
´
A.; Garcıa, J. J. Eur. J. Inorg. Chem. 2010, 2010, 4063. (f) Tobisu, M.;
Chatani, N. Chem. Soc. Rev. 2008, 37, 300. (g) Kakiuchi, F.; Chatani, N.
Adv. Synth. Catal. 2003, 345, 1077.
(6) (a) Peuckert, M.; Keim, W. Organometallics 1983, 2, 594. (b)
Peuckert, M.; Keim, W.; Storp, S.; Weber, R. S. J. Mol. Catal. 1983, 20,
115. (c) Keim, W. Angew. Chem., Int. Ed. Engl. 1990, 29, 235.
(7) van Leeuwen, P. W. N. M. Homogeneous Catalysis: Understand-
ing of the Art; Kluwer Academic Publishers: Dordrecht, The Netherlands,
2004; pp 229ꢀ233.
(
1) Selected review papers on tandem reaction: (a) Haibach, M. C.;
Kundu, S.; Brookhart, M.; Goldman, A. S. Acc. Chem. Res. 2012, 45,
47. (b) Alba, A.-N.; Company oꢀ , X.; Viciano, M.; Rios, R. Curr. Org.
Chem. 2009, 13, 1432. (c) Hussain, M. M.; Walsh, P. J. Acc. Chem. Res.
008, 41, 883. (d) Wasilke, J.-C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C.
9
2
Chem. Rev. 2005, 105, 1001. (e) Fogg, D. E.; dos Santos, E. N. Coord.
Chem. Rev. 2004, 248, 2365. (f) Denmark, S. E.; Thorarensen, A. Chem.
Rev. 1996, 96, 137.
(
2) Yotphan, S.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2010, 12,
978.
3) Yagoubi, M.; Cruz, A. C. F.; Nichols, P. L.; Elliott, R. L.; Willis,
M. C. Angew. Chem., Int. Ed. 2010, 49, 7958.
2
(
1
0.1021/ol402644y r 2013 American Chemical Society
Published on Web 10/02/2013

a
Scheme 1
Table 1. Optimization of Reaction Conditions
In this context, we introduce a proof of principle to
integrate olefin isomerization in a tandem manner with
CꢀH bond activation promoted by only a single-component
Ni catalyst (Scheme 1). We speculate that the tandem CꢀH
activation/alkene isomerization process is possible if one
of the reaction sequences is more facile than the other,
ensuring independence of the two operating catalytic
cycles. Conversely, a particular reactivity or product
selectivity can be reversed from the similar tandem pro-
tocol if one of the facile reaction sequences can be delayed
by chemical intervention. Herein, we unravel the first
Ni-promoted prototype reaction based on hybridizing
the CꢀH activation of heteroarenes with alkene isomer-
ization of allylarenes, leading to the branched hydro-
heteroarylation products. Simultaneously, we are able to
chemically toggle the reaction selectivity toward linear
adducts by delaying the alkene isomerization process
using a chemical trigger (AlMe3).
a
Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), Ni(COD)
2
b
(
0.05 mmol), and ligand in toluene (1 mL) at 130 °C for 16 h. Isolated yield.
a
Table 2. Scope with Various Allylbenzenes: Branched Selectivity
With our previous experience in nickel-mediated CꢀH
8
g,i
bondfunctionalization ofpyridine and heteroarenes, we
are quite optimistic that the alkene isomerization cycle should
proceed relatively fast. First, we examined the isomerization
process of allylbenzene 2a in the presence of Ni(COD)2
(
8) (a) Nakao, Y.; Idei, H.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem.
Soc. 2009, 131, 15996. (b) Nakao, Y.; Kanyiva, K. S.; Hiyama, T. J. Am.
Chem. Soc. 2008, 130, 2448. (c) Nakao, Y.; Idei, H.; Kanyiva, K. S.;
Hiyama, T. J. Am. Chem. Soc. 2009, 131, 5070. (d) Nakao, Y.; Morita,
E.; Idei, H.; Hiyama, T. J. Am. Chem. Soc. 2011, 133, 3264. (e) Nakao,
Y.; Yamada, Y.; Kashihara, N.; Hiyama, T. J. Am. Chem. Soc. 2010,
132, 13666. (f) Shiota, H.; Ano, Y.; Aihara, Y.; Fukumoto, Y.; Chatani,
N. J. Am. Chem. Soc. 2011, 133, 14952. (g) Tsai, C.-C.; Shih, W.-C.;
Fang, C.-H.; Li, C.-Y.; Ong, T.-G.; Yap, G. P. A. J. Am. Chem. Soc.
2
2
010, 132, 11887. (h) Ye, M.; Gao, G.-L.; Yu, J.-Q. J. Am. Chem. Soc.
011, 133, 6964. (i) Shih, W.-C.; Chen, W.-C.; Lai, Y.-C.; Yu, M.-S.; Ho,
a
Reaction conditions: 1a (0.5 mmol), 2 (1.0 mmol), Ni(COD)
(0.05 mmol), and IMes (0.05 mmol) in toluene (1 mL) at 130 °C for
2
J.-J.; Yap, G. P. A.; Ong, T.-G. Org. Lett. 2012, 14, 2046. (j) Clement,
N. D.; Cavell, K. J.; Jones, C.; Elsevier, C. J. Angew. Chem., Int. Ed.
b
c
16 h, unless otherwise noted. Isolated yield (3þ4). Ni(COD)
2
2004, 43, 1277. (k) Clement, N. D.; Cavell, K. J. Angew. Chem., Int. Ed.
2004, 43, 3845. (l) Liu, S.; Sawicki, J.; Driver, T. G. Org. Lett. 2012, 14,
3744. (m) Doster, M. E.; Hatnean, J. A.; Jeftic, T.; Modi, S.; Johnson,
(
0.1 mmol) and IMes (0.1 mmol) were used.
S. A. J. Am. Chem. Soc. 2010, 132, 11923. (n) Shacklady-McAtee, D. M.;
Dasgupta, S.; Watson, M. P. Org. Lett. 2011, 13, 3490. (o) Amaike, K.;
Muto, K.; Yamaguchi, J.; Itami, K. J. Am. Chem. Soc. 2012, 134, 13573.
with various ligands in toluene upon heating (Table S1,
Supporting Information). It was promising to find that
2a was exclusively isomerized to trans-β-methylstyrene
10
(
p) Guihaum ꢀe , J.; Halbert, S.; Eisenstein, O.; Perutz, R. N. Organome-
tallics 2012, 31, 1300. (q) Vechorkin, O.; Proust, V.; Hu, X. Angew.
Chem., Int. Ed. 2010, 49, 3061. (r) Qu, G.-R.; Xin, P.-Y.; Niu, H.-Y.;
Wang, D.-C.; Ding, R.-F.; Guo, H.-M. Chem. Commun. 2011, 47, 11140.
within 1 h at 80 °C using 10 mol % of Ni(COD) and IMes
2
10
combination. We next investigated the nickel-catalyzed
hydroheteroarylation of 2a with N-methylbenzimidazole
(9) Selected review papers: (a) Wang, D. H.; Engle, K. M.; Shi, B. F.;
Yu, J. Q. Science 2010, 327, 315. (b) Daugulis, O.; Do, H.-Q.; Shabashov,
D. Acc. Chem. Res. 2009, 42, 1074. (c) Ackermann, L.; Vicente, R.;
Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792. (d) Lyons, T. W.;
Sanford, M. S. Chem. Rev. 2010, 110, 1147. (e) Alberico, D.; Scott, M. E.;
Lautens, M. Chem. Rev. 2007, 107, 174. (f) Satoh, T.; Miura, M. Chem.
Lett. 2007, 36, 200. (g) Wendlandt, A. E.; Suess, A. M.; Stahl, S. S. Angew.
Chem., Int. Ed. 2011, 50, 11062. (h) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem.
Rev. 2011, 111, 1293. (i) Davies, H. M. L.; Morton, D. Chem. Soc. Rev.
1a with results summarized in Table 1. Nitrogen-contain-
ing ligands, such as bipyridine and 1,10-phenanthroline,
were completely ineffective (entries 1 and 2). The use of
PCy gave a linear (3a) to branched (4a) product ratio of
3
2011, 40, 1857.
(10) See the Supporting Information for further details.
Org. Lett., Vol. 15, No. 20, 2013
5359

15:85 in a 27% yield (entry 3). We found that N-heterocyclic
carbene (NHC) ligands were very effective, giving over 80%
a
Table 4. Scope with Various Heteroarenes: Branched Selectivity
yield (entries 4ꢀ6), and the use of IMes gave the best yield
(97%, entry 4) with a high regioselectivity of linear and
branched products (3a:4a = 6:94). It is worth mentioning
that the other regioisomeric product 5a was not observed,
presumably due to rapid olefin isomerization.
a
Table 3. Scope with Various Allylbenzenes: Linear Selectivity
a
Reaction conditions: 1 (0.5 mmol), 2a (1.0 mmol), Ni(COD)
0.05 mmol), and IMes (0.05 mmol) in toluene (1 mL) at 130 °C for 16 h,
2
(
b
unless otherwise noted. Isolated yield (3 þ 4).
a
Reaction conditions: 1a (0.5 mmol), 2 (1.0 mmol), Ni(COD)
(0.05 mmol) in toluene
2
toward the linear adduct 3. To our delight, through the use
of a more bulky IPr ligand with addition of 10 mol %
(
0.05 mmol), IPr (0.05 mmol), and AlMe
3
b
(
1 mL) at 130 °C for 16 h, unless otherwise noted. Isolated yield (3þ4).
c
10,11
Ni(COD)
2
(0.1 mmol), IPr (0.1 mmol), and AlMe
3
(0.1 mmol) were used.
AlMe3, the regioselectivity toward the linear product
a can be achieved in an excellent yield of 92% (entry 1,
3
Table 3). Allylbenzenes bearing electron-donating groups
With the optimal reaction conditions in hand, myriad
(
2bꢀg, entries 2ꢀ7) were also successfully converted to
allylbenzene substrates were investigated to evaluate the
generality of the reaction. The results are listed in Table 2.
The substrates bearing electron-donating methyl substitu-
ents at the ortho-, meta- and para-positions afforded the
corresponding branched products in excellent yields
with high regioselectivity (∼9:1, entries 2ꢀ4). Moderate
yields (∼60%) were witnessed for mono- or dimethoxy
derivatives (entries 5ꢀ7) at different positions with a slight
decrease of regioselectivity. The presence of strong electron-
withdrawing substituents, such as p-fluoro and trifluoro-
methyl groups (entries 8 and 9), has no adverse effect on the
regioselectivity, illustrating the nonsensitivity of the reaction
toward electronic perturbation. Safrole (2j), a naturally
occurring compound, is also suitable for this reaction with
a high selectivity (entry 10). Hydroheteroarylation of
their corresponding linear (3-phenylpropyl)benzimidazole
adducts with high yield and selectivity. The presence of an
electron-withdrawing substituent like fluoride (2i) gave
a good yield (77%), but the CF group (2h) performed
3
poorly (2h, 33%). Finally, a slight difference to the struc-
tural motif, such as in compounds 2j and k, is also suitable
for this reaction to afford the linear product.
To further demonstrate the catalytic utility of this
protocol, we expanded the scope to a variety of benzimida-
zoles and other heteroarenes toward branched selectivity
(Table 4). High branched selectivity and excellent yields
were consistently observed with benzimidazoles bearing
methyl (1a, entry 1), nonyl (1l, entry 2), pyridin-2-ylmethyl
(
1m, entry 3), and benzyl (1n, entry 4) at the nitrogen side
arm. The substrates having electron-rich and electron-
poor aryl substituents at nitrogen also proceeded well to
afford high yield and regioselectivity (entries 5ꢀ8). Sub-
stitution at the benzene backbone did not interfere with the
hydroheteroarylation process to give the branched pro-
ducts (entries 9ꢀ11). Azoles, including benzoxazole (1v),
(
2-methylallyl)benzene (2k) gave an equal amount (∼1:1) of
branched and linear regioisomers (entry 11). The lack of
selectivity in 2k may be due to the steric hindrance imposed
by the extra methyl substitution on the olefinic moiety.
Decelerating the olefin isomerization sequence using a
chemical trigger should in principle boost the selectivity
1
-methylindole (1w), and 1-methylimidazole (1x), also
underwent hydroheteroarylation to afford branched selec-
tivity with ease (entries 12ꢀ14), albeit with lower yields
than those for 1a. Again, the most striking feature and
utility of this system is that inclusion of the chemical trigger
(
11) Our previous work (ref 8i) on the styrene insertion into the
C2ꢀH bond of N-methylbenzimidazole revealed that addition of AlMe
can create a steric requirement to produce the linear product. However,
the extra effect of AlMe of slowing down the isomerization process still
remained unclear at this stage.
3
3
5
360
Org. Lett., Vol. 15, No. 20, 2013

Scheme 2. Proposed Mechanism
Scheme 3
AlMe completely switched the selectivity to linear 3 (see
3
1
0,11
Table S3, Supporting Information).
To gain preliminary mechanistic insights, we monitored
1
0
the reaction process by GC analysis. Detection of trans-
β-methylstyrene 6 within a few minutes implied a fast
isomerization process of 2a to 6 with respect to the CꢀH
by hydroheteroarylation also occurred with 1-phenyl-3-
butene 10, demonstrating that an additional carbon does
not interfere with the chain-walking of the double bond
1
0
bond activation of 1a as shown in Figure S1. Obviously,
this key factor is responsible for the preferential formation
ofthe branchedproduct4aoverthelinearproduct3ainthe
(Scheme3, eq1). Wenext examineda cyclicnonconjugated
diene, 1,5-cyclooctadiene. The results were extremely en-
couraging (Scheme 3, eq 2). Treatment of 1,5-cycloocta-
diene with benzoxazole in the presence of the Ni catalyst
furnished the corresponding Heck-like product 12a (96%)
with a small amount of other isomeric product 12b within
absence of AlMe . A possible mechanism consisting of two
3
operating catalytic cycles is proposed based on the results
described above and the available literature: an alkene chain-
1
2
walking isomerization mechanism (Scheme 2, cycle A)
8
2
h. This consequence revealed the occurrence of both
CꢀH bond activation of benzoxazole and isomerization of
,5-cyclooctadiene. Similarly, the reaction scope can be
applied to various heteroarenes like azole, benzimidazole
and a CꢀH functionalization mechanism (Scheme 2,
cycle B). In the catalytic cycle A, 2a is isomerized via
3
1
a formal 1,3-hydride shift through a η -allyl Ni hydride
1
2
intermediate 5 to afford the more thermodynamically
stable6. Inthecatalytic cycle B, the CꢀH functionalization
process most likely proceeds through the following
steps: (1) oxidative addition of the CꢀH bond to afford
the NiꢀH species 7, (2) migratory insertion of 6 into
the NiꢀH to give 9, and (3) reductive elimination of 9 to
1
4
and caffeine.
In summary, we have demonstrated the first Ni-
promoted regioselective hydroheteroarylation reaction
incorporating alkene isomerization followed by the CꢀH
activation of heteroarenes, leading to the branched selec-
tivity. Simultaneously, we are able to deactivate the alkene
isomerization to afford linear adducts by NiꢀAl coopera-
tive catalysis through steric control. Remarkably, such a
tandem process can also be performed in a similar manner
with 1,5-cyclooctadiene and 1-phenyl-3-butene to afford
the corresponding coupling product. Further mechanistic
investigations of this tandem CꢀH process and a broader
scope are now the focus of our ongoing efforts.
1
3
afford 4a.
Encouraged by the successful tandem process in allyl-
benzenes, we speculate whether the viability of the tandem
strategy may be applied to olefinic substrates other than
allylbenzenes. Positively, olefin isomerization followed
(
12) Oxidative addition of the allylic CꢀH bond to a metal, resulting
in a π-allyl metal hydride intermediate, has been discussed to produce
the isomerization product in the following selected literature. (a)
Crabtree, R. H. The Organometallic Chemistry of the Transition Metals,
4
th ed.; John Wiley & Sons, Inc.: New York, 2005; pp 236ꢀ241. (b)
Acknowledgment. We thank Professor Jennifer Scott
Royal Military College of Canada, Ontario, Canada)
Krompiec, S.; Krompiec, M.; Penczek, R.; Ignasiak, H. Coord. Chem.
Rev. 2008, 252, 1819. (c) Biswas, S.; Huang, Z.; Choliy, Y.; Wang, D. Y.;
Brookhart, M.; Krogh-Jespersen, K.; Goldman, A. S. J. Am. Chem. Soc.
(
for her insightful suggestions for our work. We are also
grateful to the Taiwan National Science Council (NSC:
101-2628-M-001-004-MY3) and Academia Sinica for their
generous financial support.
2012, 134, 13276. (d) Scarso, A.; Colladon, M.; Sgarbossa, P.; Santo, C.;
Michelin, R. A.; Strukul, G. Organometallics 2010, 29, 1487. (e) Parshall,
G. W. Homogeneous Catalysis; Wiley-VCH: Weimheim, 1980; pp 31ꢀ35.
(
13) The CꢀH bond cleavage and migratory insertion steps are
believed to be reversible (see the Supporting Information for further
details).
Supporting Information Available. Experimental pro-
cedures and characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(
14) It is noteworthy that formation of 12a represented a redox
neutral Heck-like coupling of heteroarenes via CꢀH bond activation,
in which the second embedded olefin moiety in 1,5-cyclooctadiene acts
as a hydrogen acceptor without using external oxidant. Our efforts
utilizing a second embedded olefin moiety act as a hydrogen acceptor
without using external oxidant will be the subject of a future manuscript.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 20, 2013
5361