Palladium-catalyzed C(sp2)-H pyridocarbonylation of N-aryl-2-aminopyridines: Dual function of the pyridyl moiety

Article abstract of DOI:10.1021/ol501070g

An efficient synthesis of 11H-pyrido[2,1-b]quinazolin-11-one through palladium-catalyzed C(sp²)-H pyridocarbonylation of N-aryl-2-aminopyridines has been developed. The pyridyl group acts as an intramolecular nucleophile for the first time in C

Full text of DOI:10.1021/ol501070g

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed C(sp2)−H Pyridocarbonylation of N‑Aryl-2-
aminopyridines: Dual Function of the Pyridyl Moiety
Dongdong Liang, Yimiao He, and Qiang Zhu*
State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190
Kaiyuan Avenue, Guangzhou 510530, China
S
* Supporting Information
ABSTRACT: An efficient synthesis of 11H-pyrido[2,1-b]-
quinazolin-11-one through palladium-catalyzed C(sp2)−H
pyridocarbonylation of N-aryl-2-aminopyridines has been
developed. The pyridyl group acts as an intramolecular
nucleophile for the first time in C−H carbonylation reactions.
ince seminal work by Heck and co-workers,1 transition-
metal-catalyzed carbonylation reactions of organic
Scheme 1. C(sp2)−H Carbonylation
S
(pseudo)halides using carbon monoxide (CO) as a C1 building
block have been recognized as a powerful method to synthesize
carbonyl derivatives.2 In the past decade, the development of
the direct carbonylation of C−H bonds has resulted in a more
straightforward and atom-economic approach to carbonyl-
containing compounds.3 Due to the ubiquity and robustness of
C−H bonds, chemo- and regioselective activation of a specific
C−H bond is a challenging task. To solve this problem, the
strategy of using a directing group is applied to allow selective
C−H bond activation by the localized transition-metal catalyst.4
In this context, a variety of directing groups, including nitrogen-
containing heterocycles,5 amides,6 carboxylic acids,7 and tertiary
amines,8 have been developed in C−H carbonylations (Scheme
1a). In some cases when the directing groups need to be
removed in intermolecular C−H carbonylations, extra synthetic
steps are required, which sacrifices atom economy. On the
other hand, the intramolecular version of this process, in which
the directing groups act as nucleophiles as well, enables fast
construction of heterocycles9,10 with high step efficiency and
atom economy (Scheme 1b).
The pyridyl group is widely used as a directing group in
transition-metal-catalyzed C−H functionalization reactions,
including Pd-, Rh-, or Ru-catalyzed intermolecular carbon-
ylations.5 A major problem associated with pyridine-directed
C−H functionalization is the difficulty of removal or further
transformation of the pyridyl moiety. In a previous study, we
described a Cu/Fe cocatalyzed intramolecular C−H amination
of N-aryl-2-aminopyridines for the synthesis of pyrido[1,2-
a]benzimidazoles, in which the pyridyl group acted as an
intramolecular nucleophile as well as a directing group.11
Herein, we report an unprecedented C−H pyridocarbonylation
process by using the same N-aryl-2-aminopyridines as
substrates. The C−H pyridocarbonylation reaction proceeds
efficiently under an atmospheric pressure of CO in the presence
of Pd(II) and an oxidant to provide 11H-pyrido[2,1-b]-
quinazolin-11-ones. The pyridyl group acts as both a directing
group and an intramolecular nucleophile which is present in the
final product (Scheme 1c). The major challenge of this reaction
is the potential urea byproduct formation between two aniline
moieties under the oxidative conditions.12
11H-Pyrido[2,1-b]quinazolin-11-one is an important scaffold
found in many synthetic compounds with various biological
activities, including antitumor,13 antiallergy,14 HIV-1 integrase
inhibitory,15 and hypolipenmic activities.16 The general method
for the synthesis of this class of molecules is lactamization of 2-
(pyridin-2-ylamino)benzoic acid derivatives.17 In view of recent
advances in C−H carbonylations,4−10 we envisage that the
scaffold of 11H-pyrido[2,1-b]quinazolin-11-one could be read-
Received: April 12, 2014
Published: May 7, 2014
© 2014 American Chemical Society
2748
dx.doi.org/10.1021/ol501070g | Org. Lett. 2014, 16, 2748−2751

Organic Letters
Letter
a
ily constructed starting from N-aryl-2-aminopyridines via
palladium-catalyzed C−H pyridocarbonylation. The pyridyl
directing group acts as an intramolecular nucleophile as well.
Initially, the reactions of N-phenyl-2-aminopyridine 1a under
the previously reported reaction conditions failed to produce
any of the desired product 2a, 11H-pyrido[2,1-b]quinazolin-11-
one (entries 1−2, Table 1).10d,l When the oxidant was changed
Scheme 2. Scope of N-Aryl-2-aminopyridines
a
Table 1. Optimization of the Reaction Conditions
catalyst
(10 mol %)
oxidant
(1 equiv)
additive
(1 equiv)
yield
b
entry
(%)
c
1
Pd(OAc)2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(OAc)2
Pd(TFA)2
PdCl2
CuO
−
TFA
−
−
51
2
3
4
5
6
7
8
9
Cu(OAc)2
CuCl2
−
−
−
−
TsOH
K2CO3
NH4Cl
KI
CuCl2
41
CuCl2
26
CuCl2
64
PdCl2
CuCl2
60
PdCl2
CuCl2
30
PdCl2
CuCl2
69
d
10
PdCl2
CuCl2
−
11
PdCl2
CuBr2
−
−
−
−
30
e
f
12
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
K2S2O8
Na2S2O8
NH4S2O8
87(78)
56
e
13
e
14
51
a
Reaction conditions: 1a (0.2 mmol), Pd (10 mol %), oxidant (1.0
b
equiv), CO balloon (1 atm), solvent (1.0 mL), 110 °C, 28 h. Isolated
yield of 2a. HOAc as solvent. 1,3-Diphenyl-1,3-di(pyridin-2-yl)urea
was isolated as major product in 63% yield. TFA (1.0 mL) as solvent,
Pd(OAc)2 (5 mol %), 70 °C, 4 h. In 10 mmol scale of 1a, 12 h.
c
d
e
f
to CuCl2, 2a was isolated in 51% yield by applying 10 mol % of
Pd(MeCN)2Cl2 as a catalyst under an atmospheric pressure of
CO (entry 3). A screening of other Pd(II) species identified
PdCl2 as able to catalyze the reaction in a higher yield of 64%
(entries 4−6). Additives such as TsOH, K2CO3, and NH4Cl
were also investigated, and no significant improvement in the
yields was observed (entries 7−9). It was notable that when KI
was added, the major product was changed to 1,3-diphenyl-1,3-
di(pyridin-2-yl)urea (entry 10). Fortunately, when the reaction
was run in TFA in the presence of 5 mol % of Pd(OAc)2 as a
catalyst and 3.0 equiv of K2S2O8 as an oxidant, the yield of 2a
was improved greatly to 87% at much milder conditions (70 °C
for 4 h) (entry 12).18 Other analogous oxidants such as
Na2S2O8 and (NH4)2S2O8 proved to be less effective (entries
13−14). Furthermore, the reaction can be run in 10 mmol scale
(1.70 g) without a significant loss of the yield (78%, entry 12).
With the optimized conditions in hand, the scope of
substituents on the pyridyl ring of N-aryl-2-aminopyridines 1
was investigated first (Scheme 2). A range of functional groups
with varied electronic properties, including Me, F, Cl, CF3, and
Ph, were well-tolerated, providing corresponding substituted
11H-pyrido[2,1-b]quinazolin-11-ones 2b−2g in 46−87%
yields. However, when a Me group was present in the C6
position of the pyridine, only a trace amount of the desired
product was detected. It was notable that a pyrimidine motif
was also compatible with the reaction conditions, providing the
corresponding 6H-pyrimido[2,1-b]quinazolin-6-one 2h in
a
Reaction conditions: 1 (0.2 mmol), Pd(OAc)2 (5 mol %), K2S2O8
(3.0 equiv), CO balloon (1 atm), TFA (1.0 mL), 70 °C, isolated yields
b
c
of 2. K2S2O8 (5.0 equiv). At 60 °C.
moderate yield. Then, the effect of the substituents on the
phenyl ring of N-aryl-2-aminopyridines was studied. Substrates
with both electron-donating groups (Me, MeO, and t-Bu) and
electron-withdrawing ones (F, Cl) on the para-position of the
phenyl ring were carbonylated smoothly to provide corre-
sponding products 2i−2m in 62 to 77% yields. Substitution on
the ortho position was usually unfavorable for aromatic C−H
functionalization due to the steric hindrance. However, in this
C−H pyridocarbonylation reaction, the steric influence was
neglectable (2n−2p). When meta-substituted N-aryl-2-amino-
pyridines were applied to the reaction, the regioselectivity
between the two C−H bonds to be activated was dependent on
the size of the substituent. When the substituent was a methyl
or phenyl group, only the sterically less hindered C−H bond
was reacted, furnishing the sole product 2q and 2r in 59% and
2749
dx.doi.org/10.1021/ol501070g | Org. Lett. 2014, 16, 2748−2751

Organic Letters
Letter
75% yields, respectively. However, in the case of a smaller Cl,
two isomers in a ratio of 5:3 in favor of 2t were obtained.
Further transformation of the pyridoquinazolinone product
2a was also explored (Scheme 3). The reduction of 2a with
Scheme 5. Plausible Mechanism
Scheme 3. Diversification of 2a
product with the concurrent formation of a Pd(0) species,
which is reoxidized to the Pd(II) complex by K2S2O8 in the
presence of CO and TFA.
LiAlH4 gave 2-aminopyridine substituted phenylmethanol 3 as
a result of the amide bond cleavage. The released pyridyl
moiety can act as an intramolecular nucleophile again in a
PIDA-promoted C−H amination reaction, providing C6
In summary, we have developed an efficient catalytic
protocol for the synthesis of 11H-pyrido[2,1-b]quinazolin-11-
ones starting from readily available N-aryl-2-aminopyridines.
This is the first example of using a pyridyl group as both a
directing group and an intramolecular nucleophile in a Pd-
catalyzed C(sp2)−H carbonylation reaction. The C−H
pyridocarbonylation reaction takes place smoothly under an
atmospheric pressure of CO in the presence of Pd(OAc)2 and
K2S2O8 as an oxidant in TFA. A range of substituted 11H-
pyrido[2,1-b]quinazolin-11-ones which can be further trans-
formed to C6 substituted pyrido[1,2-a]benzimidazoles are
obtained in moderate to good yields.
hydroxymethyl substituted pyrido[1,2-a]benzimidazole 5.19
A
similar lactam opening and reclosing process was realized by
Grignard addition followed by C−H cycloamination to give a
tertiary alcohol substituted pyrido[1,2-a]benzimidazole deriva-
tive 6. These transformations demonstrated that the current
C−H pyridocarbonylation products can be served as precursors
of C6 hydroxymethyl substituted pyrido[1,2-a]benzimidazoles.
To gain insight into the mechanism of this C−H
pyridocarbonylation process, reactions with isotope labeled
N-phenyl-2-aminopyridine 1a-D5 were investigated (Scheme
4). When a 1:1 mixture of 1a and 1a-D5 was subjected to the
ASSOCIATED CONTENT
* Supporting Information
■
Scheme 4. Isotop Labeling Experiments
S
Experimental procedures and full analytical data. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: zhu_qiang@gibh.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the National Science Foundation of China
(21202167) for financial support of this work.
■
standard conditions, a 1.9:1 mixture of 2a and 2a-D4 was obtain
1
in 0.5 h as determined by H NMR. In parallel reactions using
REFERENCES
1a and 1a-D5 as substrates respectively, a significant KH/KD
(2.5) value was obtained.20 Partial deuterium scrambling was
also observed in the recovered 1a-D5, showing that a reversible
rate-limiting C−H cleavage was likely involved in the reaction
(see SI).
Based on the observations described above, a plausible
reaction mechanism is proposed in Scheme 5. Initial chelation
of the pyridine nitrogen with the CO ligated Pd(II) complex
and the following electrophilic cyclopalladation on the phenyl
ring form intermediate B, which is probably a rate-limiting step.
Migratory insertion of a coordinated CO into the aryl-Pd bond
produces a seven-numbered palladocycle C. Reductive
elimination leads to the corresponding pyridocarbonylation
■
(1) (a) Schoenberg, A.; Bartoletti, I.; Heck, R. F. J. Org. Chem. 1974,
39, 3318. (b) Schoenberg, A.; Heck, R. F. J. Am. Chem. Soc. 1974, 96,
7761. (c) Schoenberg, A.; Heck, R. F. J. Org. Chem. 1974, 39, 3327.
(2) For general reviews, see: (a) Barnard, C. F. J. Organometallics
2008, 27, 5402. (b) Brennfuhrer, A.; Neumann, H.; Beller, M. Angew.
̈
Chem., Int. Ed. 2009, 48, 4114. (c) Grigg, R.; Mutton, S. P. Tetrahedron
2010, 66, 5515. (d) Wu, X.-F.; Neumann, H.; Beller, M. Chem. Soc.
Rev. 2011, 40, 4986. (e) Wu, X.-F.; Neumann, H.; Beller, M. Chem.
Rev. 2013, 113, 1.
(3) For recent reviews on C−H carbonylation reactions, see:
(a) Brennfuhrer, A.; Neumann, H.; Beller, M. ChemCatChem 2009, 1,
̈
28. (b) Liu, Q.; Zhang, H.; Lei, A. Angew. Chem., Int. Ed. 2011, 50,
10788.
2750
dx.doi.org/10.1021/ol501070g | Org. Lett. 2014, 16, 2748−2751

Organic Letters
Letter
(4) For examples of nondirected C−H carbonylation reactions, see:
(a) Lang, R.; Wu, J.; Shi, L.; Xia, C.; Li, F. Chem. Commun. 2011, 47,
12553. (b) Zhang, H.; Liu, D.; Chen, C.; Liu, C.; Lei, A. Chem.Eur.
J. 2011, 17, 9581. (c) Zhang, H.; Shi, R.; Gan, P.; Liu, C.; Ding, A.;
Wang, Q.; Lei, A. Angew. Chem., Int. Ed. 2012, 51, 5204. (d) Xie, R.;
Xie, Y.; Qian, B.; Zhou, H.; Xia, C.; Huang, H. J. Am. Chem. Soc. 2012,
134, 9902. (e) Gadge, S. T.; Khedkar, M. V.; Lanke, S. R.; Bhanage, B.
R. Adv. Synth. Catal. 2012, 354, 2049. (f) Lang, R.; Shi, L.; Li, D.; Xia,
C.; Li, F. Org. Lett. 2012, 14, 4130. (g) Xie, P.; Xia, C.; Huang, H. Org.
Lett. 2013, 15, 3370. (h) Zeng, F.; Alper, H. Org. Lett. 2013, 15, 2034.
(5) (a) Chatani, N.; Ie, Y.; Kakiuchi, F.; Murai, S. J. Org. Chem. 1997,
62, 2604. (b) Guan, Z.-H.; Ren, Z.-H.; Spinella, S. M.; Yu, S.; Liang,
Y.-M.; Zhang, X. J. Am. Chem. Soc. 2009, 131, 729. (c) Liu, B.; Shi, B.-
F. Synlett 2013, 24, 2274. (d) Liu, B.; Jian, H.-Z.; Shi, B.-F. Org.
Biomol. Chem. 2014, 12, 2538.
Synth. Commun. 1996, 26, 3869. (d) Kovac,
̌
̌
T.; Oklobdzija, M.;
Comisso, G.; Decorte, E.; Fajdiga, T.; Moimas, F.; Angeli, C.; Zonno,
̌
́
F.; Toso, R.; Subjic, V. J. Heterocycl. Chem. 1983, 20, 1339.
(18) Lu, W.; Yamaoka, Y.; Taniguchi, Y.; Kitamura, T.; Takaki, K.;
Fujiwara, Y. J. Organomet. Chem. 1999, 580, 290.
(19) He, Y.; Huang, J.; Liang, D.; Liu, L.; Zhu, Q. Chem. Commun.
2013, 49, 7352.
(20) Simmons, E. M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2012, 51,
3066.
(6) (a) Houlden, C. E.; Hutchby, M.; Bailey, C. D.; Ford, J. G.; Tyler,
́
S. N. G.; Gagne, M. R.; Lloyd-Jones, G. C.; Booker-Milburn, K. I.
Angew. Chem., Int. Ed. 2009, 48, 1830. (b) Giri, R.; Lam, J. K.; Yu, J.-Q.
J. Am. Chem. Soc. 2010, 132, 686.
(7) Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14082.
(8) Li, H.; Cai, G.-X.; Shi, Z.-J. Dalton Trans. 2010, 39, 10442.
(9) (a) Lu, Y.; Leow, D.; Wang, X.; Engle, K. E.; Yu, J.-Q. Chem. Sci.
2011, 2, 967. (b) Ferguson, J.; Zeng, F.; Alwis, N.; Alper, H. Org. Lett.
2012, 14, 5602. (c) Inamoto, K.; Kadokawa, J.; Kondo, Y. Org. Lett.
2013, 15, 3962. (d) Lee, T.-H.; Jayakumar, J.; Cheng, C.-H.; Chuang,
S.-H. Chem. Commun. 2013, 49, 11797. (e) Luo, S.; Luo, F.-X.; Zhang,
X.-S.; Shi, Z.-J. Angew. Chem., Int. Ed. 2013, 52, 10598. (f) Chen, M.;
Ren, Z.-H.; Wang, Y.-Y.; Guan, Z.-H. Angew. Chem., Int. Ed. 2013, 52,
14196.
(10) (a) Orito, K.; Horibata, A.; Nakamura, T.; Ushito, H.; Nagasaki,
H.; Yuguchi, M.; Yamashita, S.; Tokuda, M. J. Am. Chem. Soc. 2004,
126, 14342. (b) Inoue, S.; Shiota, H.; Fukumoto, Y.; Chatani, N. J. Am.
Chem. Soc. 2009, 131, 6898. (c) Yoo, E. J.; Wasa, M.; Yu, J.-Q. J. Am.
Chem. Soc. 2010, 132, 17378. (d) Ma, B.; Wang, Y.; Peng, J.; Zhu, Q. J.
́
Org. Chem. 2011, 76, 6362. (e) Lopez, B.; Rodriguez, A.; Santos, D.;
Albert, J.; Ariza, X.; Garcia, J.; Granell, J. Chem. Commun. 2011, 47,
1054. (f) Haffemayer, B.; Gulias, M.; Gaunt, M. J. Chem. Sci. 2011, 2,
312. (g) Hasegawa, N.; Charra, V.; Inoue, S.; Fukumoto, Y.; Chatani,
N. J. Am. Chem. Soc. 2011, 133, 8070. (h) Wrigglesworth, J. W.; Cox,
B.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. Org. Lett. 2011, 13, 5326.
(i) Ferguson, J.; Zeng, F.; Alwis, N.; Alper, H. Org. Lett. 2013, 15,
1998. (j) Rajeshkumar, V.; Lee, T.-H.; Chuang, S.-C. Org. Lett. 2013,
15, 1468. (k) Liang, Z.; Zhang, J.; Liu, Z.; Wang, K.; Zhang, Y.
Tetrahedron 2013, 69, 6519. (l) Liang, D.; Hu, Z.; Peng, J.; Huang, J.;
Zhu, Q. Chem. Commun. 2013, 49, 173. (m) Li, W.; Liu, C.; Zhang, H.;
Ye, K.; Zhang, G.; Zhang, W.; Duan, Z.; You, S.; Lei, A. Angew. Chem.,
Int. Ed. 2014, 53, 2443.
(11) Wang, H.; Wang, Y.; Peng, C.; Zhang, J.; Zhu, Q. J. Am. Chem.
Soc. 2010, 132, 13217.
(12) (a) Didgikara, M. R.; Joshi, S. S.; Guptea, S. P.; Diwakara, M.
M.; Deshpandeb, R. M.; Chaudhari, R. V. J. Mol. Catal. A: Chem. 2011,
334, 20. (b) Guan, Z.-H.; Lei, H.; Chen, M.; Ren, Z.-H.; Bai, Y.; Wang,
Y.-Y. Adv. Synth. Catal. 2012, 354, 489.
(13) (a) Smith, J. R.; Evans, K. J.; Wright, A.; Willows, R. D.; Jamie, J.
F.; Griffith, R. Bioorg. Med. Chem. 2012, 20, 1354. (b) Ebeid, M. Y.;
Aly, S. M. E. M.; Mikhael, A. N.; Eissa, A. A. H. Egypt. J. Pharm. Sci.
1992, 33, 293.
(14) (a) Schwender, C. F.; Sunday, B. R.; Decker, V. L. J. Med. Chem.
1982, 25, 742. (b) Schwender, C. F.; Sunday, B. R.; Herzig, D. J.;
Kusner, E. K.; Schumann, P. R.; Gawlak, D. L. J. Med. Chem. 1979, 22,
748.
(15) (a) Saiz-Urra, L.; Gonzalez, M. P.; Fall, Y.; Gomez, G. Eur. J.
Med. Chem. 2007, 42, 64. (b) Yuan, H.; Parrill, A. L. Bioorg. Med.
Chem. 2002, 10, 4169.
(16) Matzkies, F.; Stechert, R.; Rauber, G.; Matzkies, F. Arzneim.-
Forsch. 1989, 39, 1171.
(17) (a) Pellon
Commun. 2006, 36, 1715. (b) Docampo, M. L.; Pellon
Commun. 2003, 33, 1777. (c) Pellon, R. F.; Carrasco, R.; Rodes
́
, R. F.; Martín, A.; Docampo, M. L.; Mesa, M. Synth.
, R. F. Synth.
, L.
́
́
́
2751
dx.doi.org/10.1021/ol501070g | Org. Lett. 2014, 16, 2748−2751