Palladium-catalyzed alkenylation and alkynylation of ortho-C(sp 2)-H bonds of benzylamine picolinamides

Article abstract of DOI:10.1021/ol301214u

An efficient functionalization of ortho-C(sp²)-H bonds of picolinamide (PA)-protected benzylamine substrates with a range of vinyl iodides as well as acetylenic bromide is reported. ortho-Phenyl benzoic acid (oPBA) acts as an effective promoter in this reaction system. This method provides a practical strategy to access highly functionalized benzylamine compounds for organic synthesis.

Full text of DOI:10.1021/ol301214u

ORGANIC
LETTERS
2012
Vol. 14, No. 12
2948–2951
Palladium-Catalyzed Alkenylation and
Alkynylation of ortho-C(sp2)ꢀH Bonds
of Benzylamine Picolinamides
Yingsheng Zhao, Gang He, William A. Nack, and Gong Chen*
Department of Chemistry, The Pennsylvania State University, University Park,
Pennsylvania 16802, United States
Guc11@psu.edu
Received April 1, 2012
ABSTRACT
An efficient functionalization of ortho-C(sp2)ꢀH bonds of picolinamide (PA)-protected benzylamine substrates with a range of vinyl iodides as well
as acetylenic bromide is reported. ortho-Phenyl benzoic acid (oPBA) acts as an effective promoter in this reaction system. This method provides a
practical strategy to access highly functionalized benzylamine compounds for organic synthesis.
Aryl-substituted olefins are frequently utilized as inter-
mediates in organic synthesis and constitute a prominent
structural motif. Foremost among the modern methods
for their synthesis are metal-catalyzed cross-coupling reac-
tions, such as the MizorokiꢀHeck, Suzuki, Negishi, and
Stille reactions; these reactions couple functionalized arene
and olefin partners to reliably form densely substituted
products.1 In contrast to this reactivity is the palladium-
catalyzed arene CꢀH olefination reaction (so-called
FujiwaraꢀMoritani reaction), which couples unfunction-
alized starting materials and thus has a significant advan-
tage in atom and step economy.2ꢀ4 However, despite
extensive development, FujiwaraꢀMoritani reactions still
have relatively limited applicability; for instance, olefin sub-
strates in these systems have been largely restricted to
the more “activated” terminal olgefins such as acrylates
and styrenes.5 Complementary to these approaches is the
“inverse Heck” reaction which couples unfunctionalized
arenes and functionalized olefins (e.g., vinyl halides).6 This
reactivity could potentially provide valuable alternative
synthetic pathways to aryl olefins, with an overall ex-
panded substrate scope. Over the past few years, several
protocols based on this strategy have been reported for
heteroarene substrates bearing relatively acidic CꢀH
bonds. However, corresponding reactions with unactivated
arene substrates are scarce.7,8
(1) For selected reviews on metal-catalyzed cross-coupling reactions,
see: (a) Metal-Catalyzed Cross-coupling Reactions; de Meijere, A.,
Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004. (b) Handbook of Orga-
nopalladium Chemistry for Organic Synthesis; Negishi, E.-i., Ed.; Wiley
Interscience: New York, 2002.
(2) (a) Fujiwara, Y.; Moritani, I.; Danno, S.; Asano, R.; Teranishi, S.
J. Am. Chem. Soc. 1969, 91, 7166–7169. (b) Jia, C.; Kitamura, T.;
Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633–639.
(3) For selected recent reports on FujiwaraꢀMoritani type reactions,
see: (a) Boele, M. D.; van Strijdonck, G. P.; de Vries, A. H.; Kamer,
P. C.; de Vries, J. G.; van Leeuwen, P. W. J. Am. Chem. Soc. 2002, 124,
1586–1587. (b) Beck, E. M.; Grimster, N. P.; Hatley, R.; Gaunt, M. J.
J. Am. Chem. Soc. 2006, 128, 2528–2529. (c) Cai, G.; Fu, Y.; Li, Y.; Wan,
X.; Shi, Z. J. Am. Chem. Soc. 2007, 129, 7666–7673. (d) Wang, D.-H.;
Engle, K. M.; Shi, B.-F.; Yu, J.-Q. Science 2010, 327, 315–319.
(e) Nishikata, T.; Lipshutz, B. H. Org. Lett. 2010, 12, 1972–1975.
(f) Huang, C.; Chattopadhyay, B.; Gevorgyan, V. J. Am. Chem. Soc.
2011, 133, 12406–12409.
(5) (a) Tsai, A. S.; Brasse, M.; Bergman, R. G.; Ellman, J. A. Org.
Lett. 2011, 13, 540–542. (b) Ye, M.; Gao, G.-L.; Yu, J.-Q. J. Am. Chem.
Soc. 2011, 133, 6964–6967. (c) Kubota, A.; Emmert, M. H.; Sanford,
M. S. Org. Lett. 2012, 14, 1760–1763.
(4) For selected reviews on CꢀH alkenylation reactions, see: (a) Chen,
X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48,
5094–5115. (b) Satoh, T.; Miura, M. Chem.;Eur. J. 2010, 16, 11212–
11222. (c) Sahnoun, S.; Messaoudi, S.; Brion, J. D.; Alami, M. Eur. J. Org.
Chem. 2010, 6097–6102.
(6) For a discussion on “inverse Sonogashira coupling”, see: (a) Dudnik,
A. S.; Gevorgyan, V. Angew. Chem., Int. Ed. 2010, 49, 2096–2098. For other
related discussions, see: (b) Le Bras, J.; Muzart, J. Chem. Rev. 2011, 111,
1170–1214. (c) Zaitsev, V. G.; Daugulis, O. J. Am. Chem. Soc. 2005, 127,
4156–4157.
r
10.1021/ol301214u
Published on Web 06/06/2012
2012 American Chemical Society

Herein, we report an efficient palladium-catalyzed method
for the selective functionalization of ortho-CꢀH bonds of
benzylamine picolinamides with vinyl iodides and acet-
ylenic bromide. Benzylamines are versatile synthetic pre-
cursors which are easily accessible through various pre-
parative methods. Stereochemistry at the benzylic position
of R-substituted benzylamines can also be readily intro-
duced using well-establised asymmetric synthesis technol-
ogy. We envision that direct or directed functionalization
of the C(sp2)ꢀH bonds of the benzylamine precursors
will enable rapid access to a range of highly elaborate
N-containing aromatic compounds. In a recent study, we
reported that the ortho-CꢀH bonds of picolinamide (PA)
protected benzylamines can be efficiently alkylated
with β-H containing alkyl halides under Pd catalysis.9
The PA group, first introduced by the Daugulis labora-
tory in 2005,10 has demonstrated excellent directing
abilities for a number of Pd-catalyzed CꢀH function-
alization reactions in recent investigations.11 Encouraged
by these successes, we have proceeded to investigate
whether ortho-CꢀH bonds of benzylamine picolin-
amides can be alkenylated with vinyl halides in a similar
fashion.
Alkenylation of benzylamine substrate 1 with iodocy-
clohexene 2 was examined under various reaction con-
ditions (Table 1). Initial trials were conducted under
the previously developed conditions for PA-directed
C(sp3)ꢀH arylation (10 mol % Pd(OAc)2 and 1 equiv of
AgOAc at 100 °C). The desired alkenylated product 3 was
obtained in good yield (entry 1).10,11a We then directed our
effortstoward replacingtheAgOAcadditive withacheaper
alternative.12 An experimental survey of reaction condi-
tions revealed that the desired alkenylation could proceed
in the presence of both carboxylate ligands and weak bases
like KHCO3.13 Use of strong bases such as Cs2CO3 and
K2CO3 (entries 7 and 8) or strong carboxylic acids such as
TFA (entry 12) resulted in only trace amounts of product.
Carboxylic acid additives alone were insufficient to pro-
mote alkenylation (entries 3 and 4). Use of 2 equiv of
KHCO3 and 0.2 equiv of carboxylic acids provided con-
sistently improved results (entries 13ꢀ17). Interestingly,
ortho-phenyl benzoic acid (oPBA), originally applied in
our previously reported Pd-catalyzed amidate-directed
intramolecular C(sp3)ꢀH arylation reactions, proved to
be the most effective carboxylate promoter.14 Finally, this
alkenylation can be conveniently carried out under an air
atmosphere; neither an O2 nor Ar atmosphere has a
notable effect on reaction outcome (entries 20ꢀ21).15
Table 1. Pd-Catalyzed ortho-C(sp2)ꢀH Alkenylation Reac-
tionsa
Table 2. Substrate Scope of Benzylamine Substrates
a General condition A, all yields are based on isolated product on a
0.2 mmol scale. b Condition B uses 10 mol % Pd(OAc)2, 110 °C, 24 h.
c Condition C uses 5 equiv of 2, 36 h. d Condition D uses 10 mol %
Pd(OAc)2, 130 °C, 36 h.
a All screening reactions were carried out in a 10 mL glass vial with a
PTFE-lined cap on a 0.2 mmol scale, [1]∼ 0.2 M. b The reaction vial was
flushed with O2 or Ar (1 atm) and then sealed with a PTFE-lined cap.
c Yields are based on 1H-NMR analysis of the reaction mixture.
d Isolated yield on a 1.0 mmol scale.
We then examined the substrate scope of the reaction for
benzylamines (Table 2). Overall, electron-rich substrates
were alkenylated in excellent yield under the optimized
Org. Lett., Vol. 14, No. 12, 2012
2949

reaction conditions (e.g., 4, 10; standard condition A:
2 equiv of 2, 5 mol % of Pd(OAc)2, 2 equiv of KHCO3,
0.2 equiv of oPBA, 1,2-dichloroethane, air, 100 °C). Alke-
nylation reactions of electron-poor substrates could pro-
ceed well under slightly more demanding conditions (e.g.,
6, 7; condition B: 10 mol % of Pd(OAc)2, 125 °C). Bis-
alkenylated products were obtained in good yields from
substrates bearing two identical ortho-CꢀH bonds with
5 equiv of 2 (e.g., 8; condition C). In comparison, highly
regioselective monoalkenylation was achieved at the less
sterically hindered position of substrates bearing two in-
equivalent ortho-CꢀH bonds (e.g., 4, 6, 7). An elevation of
reaction temperature to 130 °C was necessary for sub-
strates bearing a prenylether group (e.g., 11; condition D).
Finally, R-substituted benzylamine substrates were also
alkenylated in excellent yield (e.g., 9; condition A).
We found that cyclic vinyl iodides of various ring sizes
(e.g., 18, 20, 22, 26, and 28),16 with the exception of five-
membered 16, were coupled in good to excellent yields.
Even electron-deficient substrate 24 provided an accepta-
ble yield of product 25. In contrast, acyclic vinyl iodides
including 37, 38, 40, and 41 failed to give a useful level of
CꢀH alkenylation products (<10%). Interestingly, tri-
substituted terminal vinyl iodide 30 gave a moderate yield
of product. trans-2-Iodostyrenes such as 32 and 34 could
undergo the desired CꢀH alkenylation reaction to gener-
ate the trans-substituted products in high yield and stereo-
selectivity, while cis-2-iodostyrene 39 only gave a trace
amount of coupled product.8d The bromo, triflate, and
Table 4. Pd-Catalyzed CꢀH Alkynylation Reactions
Table 3. Substrate Scope of Vinyl Halides
a Yields are based on isolated products on a 0.2 mmol scale using
standard conditions. Reactions of compound 43, 45, 46, 51 were
repeated on a 1.0 mmol scale, and consistent yields were obtained
compared with the 0.2 mmol scale; see Supporting Information. b Con-
dition E is similar to A except the reaction temperature is 110 °C.
c Condition F is similar to A except 10 mol % of Pd(OAc)2 was applied.
(7) For selected examples of CꢀH alkenylation of arenes with vinyl
halides, see: (a) Oi, S.; Aizawa, E.; Ogino, Y.; Inoue, Y. J. Org. Chem. 2005,
70, 3113–3119. (b) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2008, 130,
1128–1129. (c) Geary, L. M.; Hultin, P. G. Org. Lett. 2009, 11, 5478–5481.
(8) For selected examples of CꢀH alkenylation of heteroarenes
with vinyl halides, see: (a) Koubachi, J.; El Kazzouli, S.; Berteina
Raboin, S.; Mouaddib, A.; Guillaumet, G. Synthesis 2008, 2537–2542.
(b) Gottumukkala, A. L.; Derridj, F.; Djebbar, S.; Doucet, H. Tetrahedron
ꢀ
Lett. 2008, 49, 2926–2930. (c) Besselievre, F.; Piguel, S.; Mahuteau-Betzer,
F.; Grierson, D. Org. Lett. 2008, 10, 4029–4032. (d) Verrier, C.; Hoarau, C.;
Marsais, F. Org. Biomol. Chem. 2009, 7, 647–650. (e) Mousseau, J. J.;
Fourtier, A.; Charette, A. B. Org. Lett. 2010, 12, 516–519.
(9) Zhao, Y.; Chen, G. Org. Lett. 2011, 13, 4850–4853.
(10) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2005, 127, 13154–13155.
(11) (a) He, G.; Chen, G. Angew. Chem., Int. Ed. 2011, 50, 5192–5196.
(b) He, G.; Zhao, Y.; Zhang, S.; Lu, C.; Chen, G. J. Am. Chem. Soc.
2012, 134, 3–6. (c) Nadres, E. T.; Daugulis, O. J. Am. Chem. Soc. 2012,
134, 7–9. (d) Zhang, S.-Y.; He, G.; Zhao, Y.; Wright, K.; Nack, W. A.;
Chen, G. J. Am. Chem. Soc. 2012, 134, 7313–7316. (e) He, G.; Lu, X.;
Zhao, Y.; Nack, W. A.; Chen, G. Org. Lett. 2012, 14, DOI: 10.1021/
ol301352v. (f) Gou, F. R.; Wang, X. C.; Huo, P. F.; Bi, H. P.; Guan,
Z. H.; Liang, Y. M. Org. Lett. 2009, 11, 5726–5729.
a Yields are based on isolated product on a 0.2 mmol scale.
Complementary to the collection of olefin substrates
used in typical FujiwaraꢀMoritani reactions, a unique
set of alkene coupling partners has been introduced with
this PA-directed CꢀH alkenylation reaction (Table 3).
(12) Agþ reagents are indispensable to many of the known metal-
catalyzed CꢀH functionalization reaction systems.
2950
Org. Lett., Vol. 14, No. 12, 2012

phosphate analogues of 2 are completely unreactive under
the standard conditions.
the cross-coupling step remains elusive. Although a PdII/IV
catalytic cycle via the oxidative addition of vinyl halide or
acetylene bromide to PdII appears reasonable,18 a migra-
tory insertion followed by a β-heteroatom elimination
pathway could also be operative (Scheme 1B).6,17b,19
In addition to vinyl iodides evaluated above, TIPS
protected acetylenic bromide 4217 was utilized to generate
alkynylated products in excellent yield under our standard
reaction conditions (Table 4). Analogous to Chatani’s
pinoneer studies on the Pd-catalyzed CꢀH alkynylation
reactions, 42 performs much better than any other acet-
ylene substrate tested in this reaction system. Alkynylation
reactivity patterns, regioselectivity, and functional group
tolerance are similar to those observed in the PA-directed
CꢀH alkenylation reactions.
Scheme 2. Revomal of the PA Group
Scheme 1. Prelimilary Mechanistic Studies
Removal of the PA group from functionalized products
has been demonstrated in our previous report.9 For ex-
ample, compound 44 reacts with Boc2O at rt and can then
be cleaved with NaOMe/MeOH to give the Boc protected
product 55 in excellent yield (Scheme 2).
In summary, we have developed a new method to
prepare ortho-alkenylated and alkynylated benzylamine
products via Pd-catalyzed C(sp2)ꢀH functionalization
reactions. A broad substrate scope for benzylamine pico-
linamide has been demonstrated; cyclic vinyl iodides,
2-iodostyrenes, and acetylene bromide substrates can be
effectively utilized as coupling partners. This method
features generally high efficiency, inexpensive reagents,
and convenient operating conditions. We are currently
engaged in further mechanistic studies and application of
this method to organic synthesis.
The mechanism of these reactions has not been firmly
established. Under the catalysis of Pd(OAc)2 and in the
presence of 10 equiv of AcOD, the ortho-CꢀH bond of
substrate 1 was deuterated to provide compound 52
(Scheme 1A). A relatively small kinetic isotope effect
(∼1.4) was observed for the alkenylation of 1 and 52
with 2. The CꢀH functionalization process likely proceeds
through a CꢀH palladation/cross-coupling sequence.
However, our efforts to obtain the speculated PdII pallada-
cycle intermediate have been unsuccessful. The nature of
Acknowledgment. We gratefully acknowledge The
Pennsylvania State University and U.S. National Science
Foundation (CHE-1055795) for generous financial sup-
port of this work.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(13) For selected reviews on carboxylate ligands in transition-metal-
catalyzed CꢀH functionalization reactions, see: (a) Lapointe, D.;
Fagnou, K. Chem. Lett. 2010, 39, 1118–1126. (b) Ackermann, L. Chem.
Rev. 2011, 111, 1315–1345. Weakly basic conditions might allow for the
protonolysis of the PA/Pd complex, thus resulting in the release of the
functionalized product.
(14) Feng, Y.; Wang, Y.; Landgraf, B.; Liu, S.; Chen, G. Org. Lett.
2010, 12, 3414–3417. The functional role of oPBA in this reaction system
remains elusive. In comparison with PivOH, oPBA provides marginally
but consistently better performance in terms of reaction rate and yield.
(15) We observed marked inhibition by O2 in our Pd-catalyzed, PA-
directed, PhI(OAc)2-mediated intramolecular CꢀN cyclization reac-
tion; see ref 11b.
(18) For selected reviews on PdIV chemistry, see: (a) Canty, A. J. Acc.
Chem. Res. 1992, 25, 83–90. (b) Xu, L.; Li, B.; Yang, Z.; Shi, Z. Chem.
Soc. Rev. 2010, 39, 712–733. (c) Racowski, J.; Sanford, M. S. Top.
Organomet. Chem 2011, 53, 61–84. Well charaterized oxidative addition
of vinyl halides to PdII to form vinyl PdIV intermediates is extremely rare
in the literature.
(19) For an elegant study on β-heteroatom elimination, see: Zhu, G.;
Lu, X. Organometallics 1995, 14, 4899–4904. This mechanism seems
well-suited to explain the unique reactivity of cyclic vinyl iodide sub-
strates in this reaction system. The migratory insertion product 54 is well
set-up for the subsequent antiperiplanar β-I elimination, followed by the
regeneration of PdII species. Such elimination is less favored in the
acyclic substrates where β-H elimination would compete and possibly
lead to undesired decomposition to Pd black.
(16) Cyclic vinyl iodides can be readily prepared from the corre-
sponding ketone precursors, see Supporting Information.
(17) For studies on CꢀH alkynylation reactions by Chatani, see:
(a) Tobisu, M.; Ano, Y.; Chatani, N. Org. Lett. 2009, 11, 3250–3252.
(b) Ano, Y.; Tobisu, M.; Chatani, N. J. Am. Chem. Soc. 2011, 133,
12984–12986. (c) Ano, Y.; Tobisu, M.; Chatani, N. Org. Lett. 2012, 14,
354–357. For other selected examples of CꢀH alkynylation reactions,
see: (d) Kobayashi, K.; Arisawa, M.; Yamaguchi, M. J. Am. Chem. Soc.
2002, 124, 8528–8529. (e) Seregin, I. V.; Ryabova, V.; Gevorgyan, V.
J. Am. Chem. Soc. 2007, 129, 7742–7743.
The authors declare no competing financial interest.
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