Co(III)-Catalyzed Synthesis of Quinazolines via C-H Activation of N-Sulfinylimines and Benzimidates

Article abstract of DOI:10.1021/acs.orglett.6b00227

C-H activation of arenes has been established as an important strategy for heterocycle synthesis via annulations between arenes and unsaturated coupling partners. However, nitriles failed to act as such a coupling partner. Dioxazolones have been employed as a synthon of nitriles, and subsequent coupling with arenes such as N-sulfinylimines and benzimidates bearing a functionalizable directing group provided facile access to two classes of quinazolines under Co(III)-catalysis.

Full text of DOI:10.1021/acs.orglett.6b00227

Letter
pubs.acs.org/OrgLett
Co(III)-Catalyzed Synthesis of Quinazolines via C−H Activation of
N‑Sulfinylimines and Benzimidates
Fen Wang,† He Wang,† Qiang Wang, Songjie Yu, and Xingwei Li*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
S
* Supporting Information
ABSTRACT: C−H activation of arenes has been established
as an important strategy for heterocycle synthesis via
annulations between arenes and unsaturated coupling partners.
However, nitriles failed to act as such a coupling partner.
Dioxazolones have been employed as a synthon of nitriles, and
subsequent coupling with arenes such as N-sulfinylimines and
benzimidates bearing a functionalizable directing group
provided facile access to two classes of quinazolines under
Co(III)-catalysis.
n the past decades, C−H bond functionalization of arenes
significant factor.2b,16 Previously, such DGs are often based on
I
has been extensively employed as a powerful strategy. The
cleavage of N−O, N−N, and other oxidizing bonds, and
applications to Co(III)-catalyzed C−H activation are even
more limited.4e,6b We now report the activation of arenes
assisted by a rare functionalizable N−S bond17 as a DG in the
coupling with dioxazolones that function as a synthon of
nitriles. This represents the first synthesis of quinazolines18 via
a C−H activation pathway. A number of quinazolines are
known to exhibit important biological activities.19 However,
their syntheses are not trivial which required functionalized
substrates and harsh conditions (Scheme 1).
ubiquity of C−H bonds and the high atom- and step-economy
of this strategy render it highly attractive in the synthesis of
natural products and functional organic molecules, particularly
heterocycles.1 Direct C−H activation of arenes has mostly
relied on rather costly second and third row transition metals.1,2
High valent Rh(III) complexes have been widely employed as
catalysts in the activation of a large array of arenes,2 and the
high activity is ascribed to the high propensity to activate C−H
bonds, polarity of the M−C bond, and the Lewis acidity of the
catalyst. Recently, earth abundant and environmentally benign
first row transition metals have been increasingly employed as
catalysts.3 Given the higher Lewis acidity of the Co(III)
congeners and enhanced metal−ligand corporation, efficient
couplings between arenes and unsaturated coupling partners
have been recently established as in the reports by Kanai,4
Glorius,5 Ackermann,6 Ellman,7 Daugulis,8 Chang,9 and
others.10
Scheme 1. Coupling Using Dioxazolone As a Synthon of
Nitrile
In the context of C−H activation, late-transition-metal-
catalyzed annulative couplings of arenes with various π-bond
partners such as alkynes, alkenes, allenes, and carbene/nitrene
precursors have been extensively explored.1j,2a,k,5a,11 However,
to the best of our knowledge, nitriles have not been applied for
this purpose,12 likely due to their inhibitive binding (σ-binding)
and its failure to adopt the reactive π-coordination mode,
although nitriles are well-known to undergo [2 + 2 + 2]
cyclizations.13 Thus, a synthon that is equivalent to nitriles
needs to be identified. Very recently Chang9c,14 and we15 have
independently achieved Co(III)- and Rh(III)-catalyzed, chela-
tion-assisted activation of different types of C−H bonds in
couplings with dioxazolones, leading to simple amidation
without further reaction. We reasoned that dioxazolones may
act as a synthetic equivalent of nitriles provided that the
directing group (DG) of the arene is multifunctional and has
sufficient interactions with the amidated intermediate. Thus,
the design of a readily functionalizable or cleavable DG is a
We embarked on our investigation with the optimization of
the coupling between N-sulfinylimine 1a and dioxazolone 2a
(see Table S1, Supporting Information (SI)). Rhodium(III)
catalysts were initially employed, and both the amidation−
cyclization product quinazoline 3aa and the diamidation−
cyclization product 3aaa (eq 1) were obtained in comparable
ratios under different conditions (entries 1−3). The identity of
Received: January 25, 2016
© XXXX American Chemical Society
A
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Letter
was found that although 100 °C seems optimal for substrate 1a,
extension to other substituted N-sulfinylimines gave lower
yields (see product 3ad). Thus, all the coupling reactions were
performed at 120 °C. N-Sulfinylimines derived from sym-
metrical benzophenones bearing para electron-donating and
-withdrawing groups all coupled smoothly with 2a in good to
high yield (3aa−3ga). Notably, the arene substrate has been
extended to a heterocycle, and a bis(2-thienyl)methanone-
derived imine proved to be a viable substrate (3ha).
Symmetrically meta-substituted imines were also efficient
substrates, and the site selectivity varied with the meta-
substituent. The C−H functionalization was directed to the
less hindered site for relatively bulky meta groups (3ia, 3ka),
while C−H activation occurred at the kinetically more acidic
ortho position when a meta-F was introduced (3ka). Site
selectivity in the coupling of various nonsymmetrical imines
was next explored in terms of both electronic and steric effects.
The electronic bias between the para-CF3 and −CH3 groups
seems insignificant because C−H activation was only slightly
preferred at the electron-poor ring (39% yield of 3ra versus
48% yield of 3ra′). However, pronounced steric bias was
observed. Thus, high site selectivity (≥20:1) has been
consistently secured when an ortho- or meta-methyl was
introduced as a blocking group, and the reaction took place
at the less hindered ring (3la−3oa). The reaction was not
limited to the benzophenone imine system. N-Sulfinylimines of
acetophenone also reacted to afford the desired products (3pa,
3qa), albeit with lower yields due to significant competitive
hydrolysis of the imine. The scope of the amidating reagent was
next explored. Introduction of various substituents into the
ortho, meta, and para positions of the aryldioxazolone was fully
tolerated, and the reaction efficiency was only marginally
affected by the steric or electronic effects of these substituents
(3ab−3an). In all cases consistently good to high yields have
been obtained. The presence of halogen groups in the product
should allow further chemical manipulation. Besides aryl-
substituted dioxazolones, an alkyl-substituted one also reacted
(3ao), but with significantly lower efficiency.
product 3aaa has been secured by X-ray crystallography
(CCDC 1433317). In addition, variable amounts of benzophe-
none were also obtained due to hydrolysis of 1a. The same
scenario applied to Ir(III) catalysis (entry 4). To our delight,
switching the catalyst to the cobalt congener significantly
improved the catalytic efficiency and selectivity, and only 3aa
was obtained (entry 5). Further optimization using CoCp*-
(CO)I2 improved the yield to 78%, and AgNTf2 was identified
as the optimal activator (entry 6). An excellent yield was
realized when the reaction temperature was lowered to 100 °C
(entry 9). In contrast, essentially no desired reaction occurred
when benzoyl azide was used as an amidating reagent (entry
10). Moreover, shifting 1a to the unfunctionalized benzophe-
none imine only afforded 3aa in low yield due to significant
hydrolysis (entry 11).
With the optimized conditions in hand, the scope and
generality of this coupling were next examined (Scheme 2). It
Scheme 2. Synthesis of Quinazolines via C−H Activation of
N-Sulfinylimines (see the SI for detailed reaction
conditions)
During our optimization studies (Table S1, entry 11), the
observation of a small amount of quinazoline 3aa using
benzophenone imine suggested that a protic NH directing
group might be possible. We reasoned that high efficiency was
achievable if the imine is sufficiently stable and is less prone to
hydrolysis. Thus, ethyl benzimidate (4a) was applied as a
special aryl imine substrate. Indeed, the coupling of 4a with 2a
under slightly modified, milder conditions afforded the desired
4-ethoxyquinazoline 5aa in excellent yield (Scheme 3). A broad
scope of substrates was next established. In line with the C−H
activation of N-sulfinylimines, benzimidates bearing different
ortho-, meta-, and para-substituents all coupled smoothly with
high efficiency and selectivity (5aa−5ha), and the electronic
and steric effects of the substituents had only marginal
influence. The arene could be extended to a thiophene ring
in good isolated yield. It was found that other alkyl esters (5ja,
5ka) were also viable although the efficiency was somewhat
lower. Examination of the scope of dioxazolones revealed that
both alkyl and aryl substituents were well tolerated (5ab−5aq),
and in this coupling system alkyl dioxazolones reacted with only
slightly lower yields.
The synthetic utility of the quinazoline products has been
previously reported. Treatment of 3aa with TIPS-EBX under
Rh(III) catalysis afforded the ortho-alkynylated product 6 in
moderate yield (eq 2). The hydrolysis of 5an in HCl/dioxane
B
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duterio isotopologues (benzophenone-dn (n = 0−4)), indicat-
ing relevancy of C−H activation (Scheme 5a). KIE was then
Scheme 3. Synthesis of Quinazolines via C−H Activation of
Benzimidates (see the SI for detailed reaction conditions)
Scheme 5. Proposed Mechanism
measured to gain additional insight. Consistent values of KIE =
1.3 were obtained from both intramolecular competition using
1a-d5 and from intermolecular competitions using an equimolar
mixture of 1a and 1a-d10. These small values suggest that C−H
activation is not involved in the turnover-limiting step.21 To
probe the relevancy of initial C−H amidation, amide 8 was
prepared. Stirring of 8 in DCE in the absence of any catalyst
lead to isolation of product 3aa in 87% yield (Scheme 5b), and
this conversion even starts to be observed at 25 °C (CDCl3).
The mechanism of the coupling of N-sulfinylimine 1a with
dioxazolone 2a is given in Scheme 5. On the basis of our
preliminary results and previous reports,9c,14,15 the reaction
likely involves initial Co(III)-catalyzed C−H activation en route
to amidation to afford intermediate 8. This amide intermediate
is proposed to undergo 6-electron cyclization via the imidic acid
tautomer (8′) to give a dearomatized intermediate A.22 The
product 3aa is released upon elimination of a tert-butanesulfinic
acid. Alternatively, 8′ may undergo intramolecular nucleophilic
attack at the sulfinyl group to provide an ester B. Intra-
molecular nucleophilic addition of B gives C, and subsequent
elimination of a tert-butanesulfinic acid furnishes the product.
In either case, the postamidation processes are uncatalyzed.
In summary, we have realized the first synthesis of
quinazolines via C−H activation of N-sulfinylimines and
benzimidates in the coupling with dioxazolones. The reactions
proceeded with high regio- and mono-/diselectivity, and two
types of quinazolines have been synthesized starting from
different arenes. In the case of N-sulfinylimines, the C−H
activation was assisted by an autocleavable N−S bond, and the
employment of N-sulfinylimine substrates seems to circumvent
the poor reactivity and low stability of the corresponding NH
ketoimines. On the other hand, the stability of benzimidates
allowed direct construction of 4-alkoxyquinazolines. In these
systems, the dioxazolone coupling partner acts as a synthon of
(the oxidized form of) nitrile. These coupling reactions
extended the concept of functionalizable DGs to cobalt
catalysis. This new method offers a new rapid entry to
quinazolines, and it is potentially useful for streamlining the
synthesis of bioactive compounds.
generated 4-quinazolinone 7 (eq 3), which can react with
phosphoryl chloride and anilines to afford quinazoline
compounds as a potent inhibitor of BCRP.20
Experimental mechanistic studies have been briefly carried
out (Scheme 4). To probe the C−H activation process, H/D
exchange between imine 1a and CD3COOD has been
performed. While only benzophenone was obtained as a result
of hydrolysis, GC analyses revealed a mixture of protio and
Scheme 4. Preliminary Mechanistic Studies
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00227.
X-ray data for 3aaa (CIF)
C
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Letter
review on Co-catalyzed C−H activation, see: Moselage, M.; Li, J.;
Ackermann, L. ACS Catal. 2016, 6, 498.
General experimental procedures, characterization data,
1
copies of H and 13C NMR spectra of new compounds,
(7) (a) Hummel, J. R.; Ellman, J. A. Org. Lett. 2015, 17, 2400.
(b) Hummel, J. R.; Ellman, J. A. J. Am. Chem. Soc. 2015, 137, 490.
(8) (a) Grigorjeva, L.; Daugulis, O. Org. Lett. 2015, 17, 1204.
(b) Grigorjeva, L.; Daugulis, O. Angew. Chem., Int. Ed. 2014, 53,
10209.
(9) (a) Pawar, A. B.; Chang, S. Org. Lett. 2015, 17, 660. (b) Patel, P.;
Chang, S. ACS Catal. 2015, 5, 853. (c) Park, J.; Chang, S. Angew.
Chem., Int. Ed. 2015, 54, 14103.
(10) (a) Liang, Y.; Liang, Y.-F.; Tang, C.; Yuan, Y.; Jiao, N. Chem. -
Eur. J. 2015, 21, 16395. (b) Zhang, Z.-Z.; Liu, B.; Wang, C.-Y.; Shi, B.-
F. Org. Lett. 2015, 17, 4094. (c) Liu, X.-G.; Zhang, S.-S.; Jiang, C.-Y.;
Wu, J.-Q.; Li, Q.; Wang, H. Org. Lett. 2015, 17, 5404. (d) Kong, L.; Yu,
S.; Zhou, X.; Li, X. Org. Lett. 2016, 18, 588.
and X-ray data for 3aaa(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xwli@dicp.ac.cn.
Author Contributions
†W.F. and W.H. contributed equally.
Notes
The authors declare no competing financial interest.
(11) (a) Wu, S.; Zeng, R.; Fu, C.; Yu, Y.; Zhang, X.; Ma, S. Chem. Sci.
2015, 6, 2275. (b) Wang, H.; Glorius, F. Angew. Chem., Int. Ed. 2012,
51, 7318. (c) Shi, Z.; Koester, D. C.; Boultadakis-Arapinis, M.; Glorius,
F. J. Am. Chem. Soc. 2013, 135, 12204. (d) Hyster, T. K.; Ruhl, K. E.;
Rovis, T. J. Am. Chem. Soc. 2013, 135, 5364. (e) Yu, D.-G.; Suri, M.;
Glorius, F. J. Am. Chem. Soc. 2013, 135, 8802.
ACKNOWLEDGMENTS
■
Financial support from the NSFC (Nos. 21272231, 21472186,
and 21525208) and from Dalian Institute of Chemical Physics,
Chinese Academy of Sciences is gratefully acknowledged.
(12) For a marginally related oxidative insertion of nitriles leading to
annulation that didn’t proceed via a C−H activation pathway, see:
Neumann, J. J.; Suri, M.; Glorius, F. Angew. Chem., Int. Ed. 2010, 49,
7790.
(13) For reviews, see: (a) Vollhardt, K. P. C. Angew. Chem. 1984, 96,
525; Angew. Chem., Int. Ed. Engl. 1984, 23, 539. (b) Heller, B.; Hapke,
M. Chem. Soc. Rev. 2007, 36, 1085.
REFERENCES
■
(1) (a) Chen, Z.; Wang, B.; Zhang, J.; Yu, W.; Liu, Z.; Zhang, Y. Org.
Chem. Front. 2015, 2, 1107. (b) McMurray, L.; O’Hara, F.; Gaunt, M.
J. Chem. Soc. Rev. 2011, 40, 1885. (c) Cho, S. H.; Kim, J. Y.; Kwak, J.;
Chang, S. Chem. Soc. Rev. 2011, 40, 5068. (d) Arockiam, P. B.;
Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879. (e) Engle, K.
M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788.
(f) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936.
(g) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem., Int. Ed.
2012, 51, 8960. (h) Rouquet, G.; Chatani, N. Angew. Chem., Int. Ed.
2013, 52, 11726. (i) Ackermann, L. Acc. Chem. Res. 2014, 47, 281.
(j) Kuhl, N.; Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F. Angew.
Chem., Int. Ed. 2012, 51, 10236. (k) Chen, X.; Engle, K. M.; Wang, D.-
H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094.
(14) Park, Y.; Park, K. T.; Kim, J. G.; Chang, S. J. Am. Chem. Soc.
2015, 137, 4534.
(15) Wang, H.; Tang, G.; Li, X. Angew. Chem., Int. Ed. 2015, 54,
13049.
(16) For leading reviews, see: (a) Huang, H.; Ji, X.; Wu, W.; Jiang, H.
Chem. Soc. Rev. 2015, 44, 1155. (b) Zhang, F.; Spring, D. R. Chem. Soc.
Rev. 2014, 43, 6906.
(17) For the only example, see: Zhang, Q.-R.; Huang, J.-R.; Zhang,
W.; Dong, L. Org. Lett. 2014, 16, 1684.
(2) (a) Song, G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651.
(b) Song, G.; Li, X. Acc. Chem. Res. 2015, 48, 1007. (c) Kuhl, N.;
(18) For selected metal-catalyzed synthesis of quinazolines, see:
(a) Lv, Y.; Li, Y.; Xiong, T.; Pu, W.; Zhang, H.; Sun, K.; Liu, Q.;
Zhang, Q. Chem. Commun. 2013, 49, 6439. (b) Chen, Z.; Chen, J.; Liu,
M.; Ding, J.; Gao, W.; Huang, X.; Wu, H. J. Org. Chem. 2013, 78,
11342. (c) McGowan, M. A.; McAvoy, C. Z.; Buchwald, S. L. Org. Lett.
2012, 14, 3800.
(19) (a) Nahar, S.; Bose, D.; Panja, S. K.; Saha, S.; Maiti, S. Chem.
Commun. 2014, 50, 4639. (b) Kumar, S.; Shakya, N.; Gupta, S.; Sarkar,
J.; Sahu, D. P. Bioorg. Med. Chem. Lett. 2009, 19, 2542.
(20) Juvale, K.; Gallus, J.; Wiese, M. Bioorg. Med. Chem. 2013, 21,
7858.
(21) Simmons, E.; Hartwig, J. F. Angew. Chem., Int. Ed. 2012, 51,
3066.
(22) (a) Colby, D. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc.
2008, 130, 3645. (b) Duttwyler, S.; Lu, C.; Rheingold, A. L.; Bergman,
R. G.; Ellman, J. A. J. Am. Chem. Soc. 2012, 134, 4064.
(c) Parthasarathy, K.; Jeganmohan, M.; Cheng, C.-H. Org. Lett.
2008, 10, 325.
Schroder, N.; Glorius, F. Adv. Synth. Catal. 2014, 356, 1443.
̈
(d) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010,
110, 624. (k) Satoh, T.; Miura, M. Chem. - Eur. J. 2010, 16, 11212.
(3) (a) Kulkarni, A. A.; Daugulis, O. Synthesis 2009, 4087. (b) Tran,
L. D.; Roane, J.; Daugulis, O. Angew. Chem., Int. Ed. 2013, 52, 6043.
(c) Peng, J.; Xie, Z.; Chen, M.; Wang, J.; Zhu, Q. Org. Lett. 2014, 16,
4702. (d) Xu, H.; Qiao, X.; Yang, S.; Shen, Z. J. Org. Chem. 2014, 79,
4414. (e) Shang, M.; Sun, S.-Z.; Dai, H.-X.; Yu, J.-Q. J. Am. Chem. Soc.
2014, 136, 3354. (f) Matsubara, T.; Asako, S.; Ilies, L.; Nakamura, E. J.
Am. Chem. Soc. 2014, 136, 646. For selected reviews, see: (g) Sun, C.-
L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111, 1293. (h) Su, B.; Cao, Z.-
C.; Shi, Z.-J. Acc. Chem. Res. 2015, 48, 886.
(4) (a) Yoshino, T.; Ikemoto, H.; Matsunaga, S.; Kanai, M. Angew.
Chem., Int. Ed. 2013, 52, 2207. (b) Sun, B.; Yoshino, T.; Matsunaga, S.;
Kanai, M. Adv. Synth. Catal. 2014, 356, 1491. (c) Ikemoto, H.;
Yoshino, T.; Sakata, K.; Matsunaga, S.; Kanai, M. J. Am. Chem. Soc.
2014, 136, 5424. (d) Suzuki, Y.; Sun, B.; Sakata, K.; Yoshino, T.;
Matsunaga, S.; Kanai, M. Angew. Chem., Int. Ed. 2015, 54, 9944.
(e) Sun, B.; Yoshino, T.; Kanai, M.; Matsunaga, S. Angew. Chem., Int.
Ed. 2015, 54, 12968. (f) Sun, B.; Yoshino, T.; Matsunaga, S.; Kanai, M.
Chem. Commun. 2015, 51, 4659.
(5) (a) Zhao, D.; Kim, J. H.; Stegemann, L.; Strassert, C. A.; Glorius,
F. Angew. Chem., Int. Ed. 2015, 54, 4508. (b) Gensch, T.; Vasquez-
Cespedes, S.; Yu, D.-G.; Glorius, F. Org. Lett. 2015, 17, 3714. (c) Yu,
D.-G.; Gensch, T.; de Azambuja, F.; Vas
J. Am. Chem. Soc. 2014, 136, 17722.
́ ́
quez-Cespedes, S.; Glorius, F.
(6) (a) Li, J.; Ackermann, L. Angew. Chem., Int. Ed. 2015, 54, 8551.
(b) Li, J.; Ackermann, L. Chem. - Eur. J. 2015, 21, 5718. (c) Ma, W.;
Ackermann, L. ACS Catal. 2015, 5, 2822. (d) Li, J.; Ackermann, L.
Angew. Chem., Int. Ed. 2015, 54, 3635. (e) Sauermann, N.; Gonzalez,
M. J.; Ackermann, L. Org. Lett. 2015, 17, 5316. (f) For a leading
D
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