Rhodium(III)-catalyzed oxidative olefination of pyridines and quinolines: Multigram-scale synthesis of naphthyridinones

Article abstract of DOI:10.1021/ol401540k

A Rh(III)-catalyzed oxidative olefination of pyridines and quinolines has been achieved. This method has a broad substrate scope and has been applied to the expeditious, multigram-scale synthesis of naphthyridinones.

Full text of DOI:10.1021/ol401540k

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Rhodium(III)-Catalyzed Oxidative
Olefination of Pyridines and Quinolines:
Multigram-Scale Synthesis
of Naphthyridinones
Jun Zhou,† Bo Li,† Fang Hu,‡ and Bing-Feng Shi*,†,‡
Department of Chemistry, Zhejiang University, Hangzhou 310027, China, and State Key
Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
bfshi@zju.edu.cn
Received May 31, 2013
ABSTRACT
A Rh(III)-catalyzed oxidative olefination of pyridines and quinolines has been achieved. This method has a broad substrate scope and has been
applied to the expeditious, multigram-scale synthesis of naphthyridinones.
The pyridine ring is a common motif in nature and has
extensive application in pharmaceuticals and agrochem-
icals, as well as material science.1 Consequently, tremen-
dous efforts have been made to construct these scaffolds.
Among them, the expeditious synthesis via direct CÀH
functionalization of pyridine isofbroadinterest in terms of
atom and step economy.2 A number of research groups
have made considerable progress in the transition-metal-
catalyzed direct alkylation and arylation of pyridines.3,4 In
contrast, although transition-metal-catalyzed direct olefi-
nation of CÀH bonds (FujiwaraÀMoritani reaction)5 has
emerged as a powerful method for the introduction of
functional diversity and structural versatility,6,10 relatively
few examples of the direct olefination of pyridyl CÀH
bonds have been reported.7À9 Nakao and Hiyama demon-
strated C-2 selective alkenylation of pyridine-N-oxides
catalyzed by nickel and the direct alkenylation of pyridines
by nickel/Lewis acid catalyst.7a,b Shortly after that, the
same group and the Yap group independently realized the
† Zhejiang University.
‡ Shanghai Institute of Organic Chemistry.
(4) For selected examples of arylation of pyridines, see: (a) Liu, B.;
Huang, Y.; Lan, J.; Song, F.; You, J. Chem. Sci. 2013, 4, 2163. (b) Ye,
M.; Gao, G.-L.; Edmunds, A. J. F.; Worthington, P. A.; Morris, J. A.;
Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 19090. (c) Kwak, J.; Kim, M.;
Chang, S. J. Am. Chem. Soc. 2011, 133, 3780. (d) Wei, Y.; Su, W. J. Am.
Chem. Soc. 2010, 132, 16377. (e) Xi, P.; Yang, F.; Qin, S.; Zhao, D.; Lan,
J.; Gao, G.; Hu, C.; You, J. J. Am. Chem. Soc. 2010, 132, 1822. (f) Wasa,
M.; Worrell, B. T.; Yu, J.-Q. Angew. Chem., Int. Ed. 2010, 49, 1275. (h)
Tobisu, M.; Hyodo, I.; Chatani, N. J. Am. Chem. Soc. 2009, 131, 12070.
(i) Berman, A. M.; Lewis, J. C.; Bergman, R. G. J. A.; Ellman J. Am.
(1) For selected reviews, see: (a) Carey, J. S.; Laffan, D.; Thomson,
C.; Williams, M. T. Org. Biomol. Chem. 2006, 4, 2337. (b) Schlosser, M.;
Mongin, F. Chem. Soc. Rev. 2007, 36, 1161.
(2) For a recent practical CÀH functionalization of heterocyles, see:
(a) Fujiwara, Y.; Dixon, J. A.; O’Hara, F.; Funder, E. D.; Dixon, D. D.;
ꢀ
Rodriguez, R. A.; Baxter, R. D.; Herle, B.; Sach, N.; Collins, M. R.;
Ishihara, Y.; Baran, P. S. Nature 2012, 492, 95. For a review of CÀH
functionalization of pyridines, see: (b) Nakao, Y. Synthesis 2011, 3209.
(3) For selected recent examples of alkylation of pyridines, see: (a)
Xiao, B.; Liu, Z.-J.; Liu, L.; Fu, Y. J. Am. Chem. Soc. 2013, 135, 616. (b)
Kwak, J.; Ohk, Y.; Jung, Y.; Chang, S. J. Am. Chem. Soc. 2012, 134,
17778. (c) Guan, B.-T.; Hou, Z. J. Am. Chem. Soc. 2011, 133, 18086. (d)
Li, B.-J.; Shi, Z.-J. Chem. Sci 2011, 2, 488. (e) Nakao, Y.; Yamada, Y.;
Kashihara, N.; Hiyama, T. J. Am. Chem. Soc. 2010, 132, 13666. (f)
Lewis, J. C.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2007, 129,
5332.
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Chem. Soc. 2008, 130, 14926. (j) Larivee, A.; Mousseau, J. J.; Charette,
A. B. J. Am. Chem. Soc. 2008, 130, 52. (k) Kawashima, T.; Takao, T.;
Suzuki, H. J. Am. Chem. Soc. 2007, 129, 11006. (l) Campeau, L.-C.;
Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc. 2005, 127, 18020.
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Jia, C.; Piao, D.; Oyamada, J.; Lu, W.; Kitamura, T.; Fujiwara, Y.
Science 2000, 287, 1992.
r
10.1021/ol401540k
XXXX American Chemical Society

C-4 selective alkenylation of pyridines by the bimetallic
nickel aluminum catalyst.3f,7c The Chang group reported
the C-2 dehydrative olefination of pyridine N-oxides with
external oxidants.7d Recently, the Yu group developed a
novel C-3 selective olefination catalyzed by Pd/1,10-
phenanthroline.8 There are a few other important discov-
eries in this area;9 however, many of these methods still
suffer from a limited substrate scope, require a large excess
of pyridines, and employ symmetrical alkynes with little
functionality or prefunctionalized alkenyl iodides as the
coupling partners.
Scheme 1. Strategy for the Synthesis of 3,4-Dihydro-1,8-
naphthyridin-2(1H)-ones (4) Using Direct Oxidative
Olefination of Pyridines as a Key Step
Recently there has been great success in the Rh(III)-
catalyzed oxidative CÀH olefination of simple arenes
owing to high efficiency and good functional group
tolerance;10,11 however, reported examples of Rh-catalyzed
oxidative CÀH/CÀH cross-coupling reactions between
pyridines and alkenes are still very limited. To the best
of our knowledge, there are only a few isolated exam-
ples of Rh(III)-catalyzed CÀH activation of pyridines,
except that Li has reported systematic studies of
Rh(III)-catalyzed olefination and oxidative annula-
tion of isonicotinamides.9c,12 Thus, it still remains a
challenge to achieve selective direct functionalization
of pyridines, especially in terms of substrate scope, syn-
thetic versatility, and catalyst loading.
were common synthons to biologically important com-
pounds, such as 1À3.13 It has been reported that com-
pounds 1À3 were a FabI inhibitor,13a an antibacterial
agent,13b and a selective ligand of dopamine D2 receptors,13c
respectively (Scheme 1). We realized that the directed
alkenylation of N-(pyridin-2-yl)pivalamide 6b would allow
the straightforward synthesis of a large family of such
skeletons from abundant 2-aminopyridine derivatives.
Our studies commenced with applying reaction condi-
tions previously established by Glorius for the Rh(III)-
catalyzed oxidative Heck reaction of acetanilide and
styrene.11c However, no desired product was observed
when 6a was used as the substrate (Table 1, entry 1). We
were delighted to find that the reaction of N-(pyridin-2-yl)-
pivalamide 6b with ethyl acrylate resulted in the formation
of the desired product, albeit in low yield (entry 2). DCE was
found to be the ideal solvent for the reaction providing 5c in
quantitative yield (entry 4). Cu(OAc)2 is essential to the
success of this tranformation, while other additives such as
Ag2CO3 and Zn(OAc)2 resulted in low yields (entries 5À6).
Attempts to lower the Cu(OAc)2 loading under the atmo-
spheric pressure of O2 led to reduced yields (entries 7À8).
Notably, N-(pyridin-2-yl)acetamide 6a decomposed to
2-aminopyridine under the optimized reaction conditions
(entry 9).
3-Alkenyl pyridines are valuable building blocks for
pharmaceuticals owing to their functional diversity. For
example, 3-alkenyl-2-aminopyridines (5) were precursors
to 3,4-dihydro-1,8-naphthyridin-2(1H)-ones (4), which
(6) For selected reviews, see: (a) Kozhushkov, S. I.; Ackermann, L.
Chem. Sci. 2013, 4, 886. (b) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H.
Chem. Rev. 2012, 112, 5879. (c) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu,
J.-Q. Acc. Chem. Res. 2012, 45, 788. (d) Yu, D.-G.; Li, B.-J.; Shi, Z.-J.
Tetrahedron 2012, 68, 5130. (e) Yeung, C. S.; Dong, V. M. Chem. Rev.
2011, 111, 1215. (f) Lyons, T. W. M.; Sanford, S. Chem. Rev. 2010, 110,
1147. (g) Ferreira, E. M.; Zhang, H.; Stolz, B. M. Oxidative Heck-Type
Reactions (Fujiwara-Moritani Reactions). In The MizorokiÀHeck Re-
action; Oestreich, M., Ed.; WILEY: Chichester, 2009; pp 345À382.
(7) (a) Kanyiva, K. S.; Nakao, Y.; Hiyama, T. Angew. Chem., Int. Ed.
2007, 46, 8872. (b) Nakao, Y.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem.
Soc. 2008, 130, 2448. (c) Tsai, C.-C.; Shih, W.-C.; Fang, C.-H.; Li, C.-Y.;
Ong, T.-G.; Yap, G. P. A. J. Am. Chem. Soc. 2010, 132, 11887. (d) Cho,
S. H.; Hwang, S. J.; Chang, S. J. Am. Chem. Soc. 2008, 130, 9254.
(8) Ye, M.; Gao, G.-L.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 6964.
(9) (a) Mousseau, J. J.; Bull, J. A.; Charette, A. B. Angew. Chem., Int.
Ed. 2010, 49, 1115. (b) Murakami, M.; Hori, S. J. Am. Chem. Soc. 2003,
125, 4720. (c) Wei, X.; Wang, F.; Song, G.; Du, Z.; Li, X. Org. Biomol.
Chem. 2012, 10, 5521.
(10) For reviews, see: (a) Patureau, F.; Wencel-Delord, W. J.; Glorius,
F. Aldrichimica Acta 2012, 45, 31. (b) Song, G.; Wang, F.; Li, X. Chem.
Soc. Rev. 2012, 41, 3651. (c)Satoh, T.;Miura, M. Chem.;Eur. J. 2010, 16,
11212. (d) Colby, D. A.; Bergman, R. G.; Ellm, J. A. Chem. Rev. 2010,
110, 624.
(11) For selected examples, see: (a) Ueura, K.; Satoh, T.; Miura, M.
Org. Lett. 2007, 9, 1407. (b) Mochida, S.; Hirano, K.; Satoh, T.; Miura,
M. J. Org. Chem. 2009, 74, 6295. (c) Patureau, F. W.; Glorius, F. J. Am.
Chem. Soc. 2010, 132, 9982. (d) Patureau, F. W.; Besset, T.; Glorius, F.
Angew. Chem., Int. Ed. 2011, 50, 1064. (e) Rakshit, S.; Grohmann, C.;
Besset, T.; Glorius, F. J. Am. Chem. Soc. 2011, 133, 2350. (f) Tsai, A. S.;
Brasse, M.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2011, 13, 540. (g)
Chen, J.; Song, G.; Pan, C.-L.; Li, X. Org. Lett. 2010, 12, 5426. (h) Park,
S. H.; Kim, J. Y.; Chang, S. Org. Lett. 2011, 13, 2372. (i) Li, H.; Li, Y.;
Zhang, X.-S.; Chen, K.; Wang, X.; Shi, Z.-J. J. Am. Chem. Soc. 2011,
133, 15244. (j) Zhen, W.; Wang, F.; Zhao, M.; Du, Z.; Li, X. Angew.
Chem., Int. Ed. 2012, 51, 11819.
With the optimized conditions in hand, we further
studied the scope and limitations of this reaction
(Scheme 2). Different acrylates all gave good to excellent
yields (5bÀ5d), while unactivated alkenes such as styrene
failed in this case (5a). A wide range of 2-aminopyridine
derivatives are compatible with this protocol, furnishing
the desired products in good yields. Importantly, halides,
such as chloride, bromide, and iodide, survived under the
standard or slightly modified conditions, affording the
(13) (a) Seefeld, M. A.; Miller, W. H.; Newlander, K. A.; Burgess,
W. J.; DeWolf, W. E., Jr.;Elkins, P. A.; Head, M. S.; Jakas, D. R.; Janson,
C. A.; Keller, P. M.;Manley, P. J.; Moore, T. D.; Payne, D. J.; Pearson, S.;
Polizzi, B. J.; Qiu, X.; Rittenhouse, S. F.; Uzinskas, I. N.; Wallis, N. G.;
Huffman, W. F. J. Med. Chem. 2003, 46, 1627. (b) Alemparte-Gallardo,
C.; Barros-Aguirre, D.; Cacho-Izquierdo, M.; Fiandor-Roman, J. M.;
Remuinan-Blanco, M. J. W.O. Patent No. 2009/141399b, 2009. (c) Jin, J.;
Roth, B.; Frye, S. W.O. Patent No. 2012/003418, 2012.
(12) (a) Fukutani, T.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem.
2011, 76, 2867. (b) Hyster, T. K.; Rovis, T. Chem. Commun. 2011, 47,
11846. (c) Wang, H.; Glrius, F. Angew. Chem., Int. Ed. 2012, 51, 7318. (d)
Song, G.; Gong, X.; Li, X. J. Org. Chem. 2011, 76, 7583.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Optimization of Reaction Conditionsa
Scheme 2. Olefination of 2-Aminopyridine Pivalamidese
entry
R
additive
solvent
yield (%)
1
Ac (6a)
2.0 equiv of Cu(OAc)2 t-AmylOH
0b
2
Piv (6b) 2.0 equiv of Cu(OAc)2 t-AmylOH
Piv (6b) 2.0 equiv of Cu(OAc)2 DCE
Piv (6b) 2.0 equiv of Cu(OAc)2 DCE
6b
3
42
100
58
31
91
49
À
4
5
Piv (6b) 2.0 equiv of Ag2CO3
DCE
6
Piv (6b) 2.0 equiv of Zn(OAc)2 DCE
Piv (6b) 1.0 equiv of Cu(OAc)2 DCE
Piv (6b) 0.5 equiv of Cu(OAc)2 DCE
7c
8c
9
Ac (6a)
2.0 equiv of Cu(OAc)2 DCE
a Conditions: 6 (0.2 mmol), ethyl acrylate (0.3 mmol), [Cp*RhCl2]2
(5 mmol %), AgSbF6 (20 mmol %), additive in solvent (2 mL) for 24 h.
Isolated yield. b Determined by 1H NMR. c Under O2.
corresponding olefinated products in moderate to good
yields (5fÀ5j, 44%À76%); this was a synthetically inter-
esting result as such substituents could serve as versatile
handles for further elaboration using conventional Pd-
mediated cross-coupling (see Scheme 4 for synthetic appli-
cations). 2-Aminopyridine derivatives containing electron-
donating groups at the 6-position and/or 5-position were
generally more reactive and afforded higher yields than
those carrying electron-withdrawing groups (5kÀ5t). The
strong electron-withdrawing cyanide group is also toler-
ated, albeit affording the product in a reduced yield
(5t, 33%). The oxidative CÀH olefination was very sensi-
tive to steric hindrance, since only the 4-F derivative gave
the desired product in lower yield (5v, 39%) while other
substituents failed in this case (5u). Moreover, 5,6-disub-
stitutedsubstrateswere olefinatedeffectivelytogiving even
higher yields (5w, 90%; 5x, quantitative), which suggested
this reaction protocol might be applied to synthetic useful
intermediates with more complicated functional groups.
Furthermore, diolefinated product 5y was obtained in
98% yield by adding 3.0 equiv of ethyl acrylate under this
protocol.
a 100 °C. b3.0 equiv ethyl acrylate was added. cRun for 24 h and ethyl
d
acrylate was added in three portions. 0.1 equiv [Cp*RhCl2]2 and 0.4
equiv AgSbF6 was added. e Conditions: 6 (0.2 mmol), alkene (0.3 mmol),
[Cp*RhCl2]2 (5 mmol %) and AgSbF6 (20 mmol %) in 2 mL of DCE for
24 h. Isolated yield.
Scheme 3. Olefination of Quinoline Pivalamidesa
The nature of the heteroarenes can also be varied to
electron-rich heterocycles such as indole and pyrazole
(Scheme 3, 5zÀ5aa).14 Indeed, the olefination of
4-aminoindole proceeded selectively by N-pivalamide-
directed ortho reactivity rather than either the C2 or C3
olefination. This protocol serves as a complementary
method tothe oxidative C2and C3olefinationof indoles.15
N-Methyl-3-aminopyrozole pivalamide 5aa was very re-
active, and a high yield (96%) was obtained.
a Isolated yield. b100 °C. c3.0 equiv of ethyl acrylate were added.
(Scheme 3). In this case, styrenes bearing either electron-
withdrawing or -donating groups all afforded olefinated
products in good yields (8aÀ8f). Different acrylates read-
ily coupled with 7 in isolated yields ranging from 60% to
94% (8gÀ8i). In addition, other electrophilic alkenes
such as vinyl phosphonate also reacted under these con-
ditions (8j). The generality of the quinoline pivalamide was
next demonstrated. Under the standard conditions, iodo-
substitution in the substrate can be tolerated, enabling
additional modification reactions at the iodogenated posi-
tion. Moreover, both N-(quinolin-2-yl)pivalamide (7l) and
We were delighted to find that oxidative CÀH olefina-
tion also occurred smoothly with quinoline derivatives
(14) Hyster, T. K.; Rovis, T. J. Am. Chem. Soc. 2010, 132, 10565.
(15) Grimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J.
Angew. Chem., Int. Ed. 2005, 44, 3125.
Org. Lett., Vol. XX, No. XX, XXXX
C

N-(benzo[h]quinolin-10-yl)pivalamide (7m) reacted with
ethyl acrylate in high yields (8l, quantitative; 8m, 72%).
Our strategy was then applied to the formal synthesis of
pharmaceuticallyimportant compounds 1À2 (Scheme 4).
Hydrolysis of the olefinated product 5h under acidic
conditions afforded 5ha in 80% yield. 6-Bromo-3,4-
dihydro-1,8-naphthyridin-2(1H)-one (5hc) was achieved
after selective reduction and cyclization. Amide 5hc can
be converted to indole naphthyridinone 1 according to a
literature procedure (Scheme 4A).13a Moreover, under
our optimized conditions, a multigram-scale synthesis of
7-methoxy-3,4-dihydro-1,8-naphthyridin-2(1H)-one 5lb
was achieved in three steps starting from 6l in 76%
overall yield. 5lb was the key building block for the
synthesis of antibacterial agent 2 (Scheme 4B).13b No-
tably, this reaction proceeded smoothly on a multigram
scale with a low catalysis loading (0.1 mol %) and high
turnover (TON = 840). In comparison with previous
approaches, the current method is advantageous for
rapid library synthesis in drug discovery because of its
operational simplicity, tolerance of various functional
groups, and broad availability of starting materials.
Sandmeyer reaction. The biologically important 2-(1H-
pyrrol-1-yl)pyridine (13) was constructed by treatment
with 2,5-dimethoxytetrahydrofuran. In addition, the CdC
double bond can be oxidatively cleaved by KMnO4 to afford
compound 14, which is a precursor of pyrido[2,3-d]-
pyrimidines (15), a potent mGlu5 receptor antagonist.16
Scheme 5. Synthetic Transformations of 5
Scheme 4. Synthetic Applications
In summary, we have achieved the effective oxidative
olefination of both pyridine and quinoline pivalamides at
the ortho-position of the directing group, which involves a
rhodium(III)-catalyzed CÀH activation pathway using
Cu(OAc)2 as a convenient oxidant. This protocol is oper-
ationally simple and has been successfully applied to the
expeditious, multigram-scale synthesis of naphthyridi-
nones with a low catalyst loading (0.1 mol %). The high
reactivity might result from the competitive coordination
of Cu(OAc)2 with the pyridine nitrogen, which may facil-
itate the Rh(III)-catalyzed CÀH activation.10a,12 Further
investigations to study the mechanism of this reaction are
underway.
Acknowledgment. Financial support from the National
Science Foundation of China (21002087, 21272206), the
Fundamental Research Funds for the Central Universities
(2010QNA3033), Zhejiang Provincial NSFC (Z12B02000),
and the Ministry of Education (SRFDP 20110101110005)
is gratefully acknowledged. We also are thankful for the
Scholarship Award for Excellent Doctoral Student granted
by the Ministry of Education to J.Z. (2011).
The significance of this rhodium-catalyzed oxidative
olefination of pyridine derivatives is additionally demon-
strated by its chemoselective transformations to various
synthetic useful intermediates. The pivalamide can be
deprotected under acidic conditions to afford free amine
9. As outlined in Scheme 5, the amino group in compound
9 can be readily coverted into 2-OH compounds 10À11
and 2-fluoro compound 12 by means of the well-known
Supporting Information Available. Experimental de-
tails, spectral data for all new compounds. This material
is available free of charge via the Internet at http://pubs.
acs.org.
(16) Wendt, J. A.; Deeter, S. D.; Bove, S. E.; Knauer, C. S.; Brooker,
R. M.; Augelli-Szafran, C. E.; Schwarz, R. D.; Kinsora, J. J.; Kilgore,
K. S. Bioorg. Med. Chem. Lett. 2007, 17, 5396.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX