N-Bu4NI-catalyzed selective dual amination of sp3 C-H bonds: Oxidative domino synthesis of imidazo[1,5-c]quinazolines on a gram-scale

Article abstract of DOI:10.1039/c4cc01444h

An n-Bu₄NI catalyzed domino reaction that involves selective dual amination of sp³ C-H bonds has been developed. The protocol affords a facile and efficient approach to the synthesis of imidazo[1,5-c] quinazolines under mild conditions.

Full text of DOI:10.1039/c4cc01444h

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n-Bu4NI-catalyzed selective dual amination of
sp3 C–H bonds: oxidative domino synthesis
of imidazo[1,5-c]quinazolines on a gram-scale†
Cite this: Chem. Commun., 2014,
50, 4302
Received 25th February 2014,
Accepted 3rd March 2014
Dan Zhao, Teng Wang, Qi Shen and Jian-Xin Li*
DOI: 10.1039/c4cc01444h
www.rsc.org/chemcomm
An n-Bu4NI catalyzed domino reaction that involves selective dual drug molecules, such as those used clinically as anti-thrombotic and
amination of sp3 C–H bonds has been developed. The protocol affords cardiotonic agents.6 Structural variants of imidazoquinazoline show
a facile and efficient approach to the synthesis of imidazo[1,5-c]- a wide range of biological activities, including anticonvulsants,7a
quinazolines under mild conditions.
antitumor7b and antihypertensive7c,d effects. Despite the high inter-
est, synthetic routes available for these molecules often suffer from
In recent years, considerable achievements have been made in some disadvantages, such as strict reaction conditions, complex
transition-metal-catalyzed C–H bond activation. Direct C–N bond manipulations and inaccessible starting materials.8 Therefore, alter-
formation via C–H bond activation is more preferable than traditional native synthetic approaches for imidazoquinazoline derivatives
synthetic strategies in the construction of nitrogen-containing mole- under mild conditions are desired. Very recently, the analogous
cules.1 Despite the major advances achieved in transition-metal- imidazo-N-heterocycle, imidazo[1,5-a]pyridine, was synthesized from
catalyzed C–H amination, the cost effectiveness as well as the presence electron-withdrawing group substituted 2-methylpyridines and
of heavy transition metal impurities in the final products is a major benzylamines via iodine-mediated benzylic secondary C–H amina-
problem regarding their practical applicability, especially in preparing tion (Scheme 1).9 Encouraged by the above results, and in continua-
pharmaceutical agents. Thus, the alternative metal-free direct C–H tion of our research on quinazoline derivatives,10 we herein report a
amination is highly desirable. Recently, iodine-based catalytic systems direct approach for the synthesis of imidazo[1,5-c]quinazolines from
in C–H bond activation have been established and received much readily available 4-methylquinazolines and benzylamines. To the best
attention.2 Furthermore, these efficient and environmentally friendly of our knowledge, imidazo[1,5-c]quinazolines possess a novel hetero-
strategies also promote the more challenging sp3 C–H amination.3 cyclic skeleton to date. Besides, benzylic primary C–H oxidative
For example, iodine promoted benzylic C–H amination has been amination with primary amines has been scarce until now.
developed by Chang4a and Zhu.4b However, nitrogen sources were
Initially, our studies began from an exploration of the reaction
limited to sulphonamides and benzoazoles. Therefore, the benzylic conditions on 4-methyl-2-phenylquinazoline (1a) and benzylamine
C–H bond, especially the more challenging primary C–H oxidative (2a) (Table S1, see ESI†). In the presence of 20 mol% n-Bu4NI, the
amination with primary amine remains highly desirable.
desired product 3aa was afforded in 36% yield when 4 equiv. of
The domino strategy has been widely applied to the synthesis of TBHP was used as an oxidant (entry 1). In the absence of a catalyst,
organic compounds due to its high atom and synthetic efficiency.5 no 3aa was detected (entry 2). Next, various iodine reagents
A variety of iodine promoted oxidative domino reactions that involve were investigated, but no further improvement in the yield was
C–N bond formation have been demonstrated to date, while the
catalytic variants of iodine-initiated domino reactions are still rarely
documented.2c Thus, we focused our attention on iodine catalyzed
domino sp3 C–H amination.
Nitrogen-containing fused heterocycles constitute an important
class of biologically active agents and play an important role in
medicinal chemistry. Imidazoquinazoline is the critical skeleton in
State Key Lab of Analytical Chemistry for Life Science, School of Chemistry and
Chemical Engineering, Nanjing University, Nanjing, 210093, P. R. China.
Scheme 1 Synthesis of imidazo-N-heterocycles via iodine promoted
E-mail: lijxnju@nju.edu.cn; Fax: +86-25-83686419; Tel: +86-25-83686419
dual benzylic C–H aminations.
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4cc01444h
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Table 2 Substrate scope of 4-methylquinazolinesa
observed (entries 3–6). Among the examination of various oxidants,
gratifyingly, 70% aqueous TBHP gave a yield similar to a decane
solution of TBHP, which indicated that a small amount of water
would not inhibit this reaction (entries 7–11). Further experimental
data suggested that both organic and inorganic acids could facilitate
this reaction and acetic acid improved the yield significantly
(entries 12–20). Performing the reaction in other organic solvents
instead of DMSO did not enhance the yield (entries 21–28). In
addition, the amount of TBHP as well as acetic acid was also
optimized and the results are listed in Table S1, ESI† (entries 29–31
and 37). The investigations on reaction temperature and time showed
that reacting at 90 1C for 10 h was optimal for the process. Finally, the
optimal conditions were 20 mol% n-Bu4NI with 4 equiv. TBHP and
3 equiv. acetic acid in DMSO under air.
With the optimized conditions in hand, various benzylamines
were reacted with 4-methyl-2-phenylquinazoline (1a) to give the
corresponding imidazo[1,5-c]quinazolines (3aa–an) (Table 1). We
found that the steric hindrance had little influence on the reaction
(entries 2–4). In all cases, both electron-donating and withdrawing
substituents in the phenyl ring were well tolerated, and gave good
yields (entries 5–10). Notably, functional groups such as F, Cl and Br
were also compatible with the reaction conditions, which provided an
additional handle for further functionalization of the products. More-
over, naphthalen-1-ylmethanamine and several heterocyclic benzyl-
amines were also proved applicable, giving the desired products in
good yields (entries 11–13). However, pyridin-2-ylmethanamine (2n)
failed to yield the desired product, but gave an unexpected byproduct
via self-condensation and cyclization (for details, see ESI†).
To evaluate the generality of this reaction, a variety of quinazolines
and benzylamine were further tested. As shown in Table 2, 2-position
substituted quinazolines with the benzene ring bearing alkyl,
methoxy, fluoro and chloro groups were well tolerated to give
excellent yields, and those with strong electron-withdrawing
groups, such as trifluoromethyl and nitro group still gave target
products in good yields (3ba–ga). 4-Methylquinazoline with other aryl
Nd = Not detected. a Reaction conditions: 1 (0.3 mmol), 2a (0.6 mmol),
n-Bu4NI (0.06 mmol), 70% aq. TBHP (1.2 mmol), CH3COOH (0.9 mmol),
DMSO (2 mL), 90 1C, 10 h. Isolated yield.
substituents such as furyl, thienyl and pyridyl groups also underwent
the reaction efficiently (3ha–ja). 2,4-Dimethylquinazoline (1k) was
successfully transformed in 76% yield with excellent regioselectivity
probably due in part to the weaker C–H bond of the 4-methyl
substituent.11 Moreover, exclusive selectivity was also observed for
amination at methyl over the methylene sp3 C–H bond (3la). Other
alkyl substituents, such as branched and cycloalkyl groups were also
suitable for the present transformation (3ma–oa). 2-Cl substituted
quinazoline failed to yield the product, but gave a byproduct (3pa0, for
details, see ESI†). Substituted 2-aminoquinazolines (1q and 1r),
substituted phenylquinazoline (1s) and pyridopyrimidine (1t) were
also tested and the corresponding products were afforded in moder-
ate to good yields. However, 4-methylpyrimidine showed no reactivity
under current conditions.
Table 1 Substrate scope of benzylaminesa
Recently, a-amino acids have been applied to the preparation of
nitrogen-containing heterocycles via decarboxylative reaction under
metal-free conditions.12 The success of benzylamines gives us a hint
to further test the scope of this reaction with a-amino acids
(Scheme 2). To our delight, when an aryl or alkyl group was connected
to the a-carbon atom of the amino acid, the corresponding products
were obtained with satisfactory yields. When glycine was employed as
the substrate, the reaction also worked although gave a low yield. We
believe that the wide tolerance of various functional groups in the
imidazolyl ring makes this reaction highly practical and reliable.
The scalability of the method was verified by running the
reaction of 1m with 2a on a 5 mmol scale (Scheme 3), and the
product was isolated in identical high yield.
Entry
R
Product
Yieldb (%)
1
2
3
4
5
6
7
8
Ph (2a)
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
3am
3an
88
83
75
71
76
75
85
76
80
77
90
62
76
Ndc
2-Me-Ph (2b)
3-Me-Ph (2c)
4-Me-Ph (2d)
4-tBu-Ph (2e)
4-OMe-Ph (2f)
4-F-Ph (2g)
4-Cl-Ph (2h)
4-Br-Ph (2i)
4-CF3-Ph (2j)
1-Naphthyl (2k)
2-Furyl (2l)
9
10
11
12
13
14
2-Thienyl (2m)
2-Pyridyl (2n)
a
Reaction conditions: 1a (0.3 mmol), 2 (0.6 mmol), n-Bu4NI (0.06 mmol),
70% aq. TBHP (1.2 mmol), CH3COOH (0.9 mmol), DMSO (2 mL), 90 1C,
10 h. Isolated yield. Nd = Not detected.
b
c
Scheme 2 Synthesis of imidazo[1,5-c]quinazolines from amino acids.
Chem. Commun., 2014, 50, 4302--4304 | 4303
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the methodology in other heterocycle synthesis and bioactive
evaluation of imidazo[1,5-c]quinazolines is currently underway
in our laboratory.
Financial support from National Natural Science Foundation
of China (21272114 and 90913023) and the National Natural
Science Fund for Creative Research Groups (21121091) is grate-
fully acknowledged.
Scheme 3 Large scale synthesis of 3ma.
Further control experiments have been performed to obtain
insights into the mechanism (Scheme S1, see ESI†). It was thought
that iodo product 5 may be the key reaction intermediate derived
from 1a. However, 1a under standard conditions in the absence of
2a and acetic acid did not afford 5 (Scheme S1A, ESI†), suggesting
that an ‘in situ iodination’ based oxidative coupling pathway2c could
be excluded. When 20 mol% PhI(OAc)2 was employed, the reaction
did not work (Scheme S1B, ESI†). This result indicated hypervalent
iodine reagents might not be involved in the transformation. Adding
a radical inhibitor BHT (2,6-di-tert-butyl-4-methylphenol) or TEMPO
(2,2,6,6-tetramethylpiperidine-N-oxyl) to the reaction system, a nega-
tive influence on the yield was observed (Scheme S1C, ESI†). This
result suggested that the reaction probably proceeded via a free
radical process. When 1a was used as a substrate under standard
conditions in the absence of benzylamines, an unexpected benzylic
acetate 6 was obtained (Scheme S1D, ESI†). To help ascertain
whether 6 is a potential intermediate, we explored the coupling of
6 with 2a under standard conditions (Scheme S1E, ESI†). The
desired product was obtained in 76% yield within 5 h, suggesting
that 6 was most likely a possible intermediate for the present
transformation. Additionally, no reaction occurred in the absence
of n-Bu4NI or TBHP, indicating that the proper oxidation state of the
iodine catalyst was an important requirement for reactivity. When
sodium acetate was subjected to the reaction conditions, no benzylic
acetate was detected (Scheme S1F, ESI†). Thus, a benzyl cation is not
involved in this reaction.
On the basis of the above evidence and previously reported
results,9,13 a possible mechanism is proposed as shown in
Scheme S2 (see ESI†). Initially, TBHP decomposes to generate the
tert-butoxyl and tert-butylperoxy radicals in the presence of iodide ions
(Iꢀ). These radicals subsequently abstract hydrogen atoms from the
acetic acid and 1 to provide both the acyloxy and benzylic radical A,
respectively. Then the coupling of these two radicals forms the inter-
mediate 6. B is generated via amination of 6 under current conditions,14
followed by oxidation to give C or C0. Subsequently, C or C0 is oxidized
to E via sp3 C–H functionalization under iodine-catalyzed reaction
conditions. Then E is converted to the product after intramolecular
amination/cyclization and rearrangement in a tandem process.
In summary, a facile and efficient approach to the synthesis
of imidazo[1,5-c]quinazolines was developed via a tandem
reaction following sp3 C–H functionalization under metal-free
conditions. Moreover, the reaction showed a broad scope of
substrates including the common commercially available benzyl-
amines and a-amino acids. The new protocol serves not only as a
method to construct a new class of imidazo-N-heterocycles but also
as a rare example of benzylic primary C–H oxidative amination with
primary amines. The investigation of the mechanism indicated
that benzylic acetate as a possible intermediate was involved in
the reaction. Ongoing research involves further application of
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4304 | Chem. Commun., 2014, 50, 4302--4304
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