Access to Imidazole Derivatives by Silver(I) Carbonate Mediated Coupling of Vinyl Azides with Secondary Amines

Article abstract of DOI:10.1002/ejoc.201600015

An efficient protocol for the synthesis of structurally diverse imidazoles by Ag₂CO₃-mediated coupling of vinyl azides with secondary amines was developed, and 22 different examples were synthesized in good to high yields. This operationally simple synthetic strategy allows the formation of three new C-N bonds by cascade reactions that involve sp³ C-H functionalization.

Full text of DOI:10.1002/ejoc.201600015

DOI: 10.1002/ejoc.201600015
Communication
Heterocycle Synthesis
Access to Imidazole Derivatives by Silver(I) Carbonate Mediated
Coupling of Vinyl Azides with Secondary Amines
Praveen Reddy Adiyala,[a][‡] Satheesh Borra,[a][‡] Ahmed Kamal,[a] and
Ram Awatar Maurya*[a,b]
Abstract: An efficient protocol for the synthesis of structurally simple synthetic strategy allows the formation of three new
C–N bonds by cascade reactions that involve sp3 C–H function-
alization.
diverse imidazoles by Ag2CO3-mediated coupling of vinyl azides
with secondary amines was developed, and 22 different exam-
ples were synthesized in good to high yields. This operationally
Introduction
a co-catalyst or oxidant for numerous challenging transforma-
tions.[12]
Developing newer, cleaner and more efficient synthetic meth-
odologies for valuable heterocycles is an ever present challenge
in organic chemistry. The imidazole ring structure is found in a
large number of synthetic and natural products of medicinal
importance.[1] Imidazole-containing molecules have been re-
ported to possess a plethora of biological activities such as anti-
plasmodium,[2] antitumor,[3] antifungal,[4] antibacterial,[5] and of
being inhibitors of p38 MAP kinase[6] and B-Raf kinase.[7] Conse-
quently, a many efforts have been focused on the development
of newer synthetic strategies for this privileged scaffold.[8] In
this context, we recently developed a visible-light photoredox-
catalyzed synthesis of imidazoles by coupling of vinyl azides
with secondary amines.[9a] The reaction was found to be highly
moisture-sensitive, and imidazoles were obtained in moderate
yields (35–71 %). We, therefore, continued our efforts to de-
velop an air- and moisture-tolerant protocol for the efficient
coupling of vinyl azides with secondary amines to access imid-
azoles in high yields.
Vinyl azides 1 are vital three-atom synthons to construct di-
verse and complex nitrogen heterocycles.[9e,13] They are known
to decompose readily into 2H-azirines 2 under thermal or pho-
tochemical conditions.[13] We envisioned that the 2H-azirines 2
might be attacked by secondary amines 3 to generate interme-
diates 4, which should undergo ring opening and cyclization to
yield intermediates 7 that might be oxidized to imidazoles 8 by
using a suitable oxidant (Scheme 1).
Given our interest towards developing newer synthetic trans-
formations,[9] we report herein a straightforward protocol to ac-
cess structurally diverse imidazoles by Ag2CO3-mediated cou-
pling of vinyl azides with secondary amines. It is worth to note
that the synthetic strategy described herein involves functional-
ization of sp3 C–H bonds adjacent to the secondary nitrogen
atom. Ag2CO3 is a mild oxidant and has long been used in
Scheme 1. Proposed synthesis of imidazoles 8 by coupling of vinyl azides 1
with secondary amines 3.
organic synthesis such as Koenigs–Knorr reactions[10] and Féti- Results and Discussion
zon oxidations.[11] In recent years, it was successfully utilized as
In order to check the feasibility of the concept, coupling of vinyl
azide 1a with 1,2,3,4-tetrahydroisoquinoline 3a was studied un-
der various conditions (Table 1). The reaction did not give the
desired imidazole 8a with several catalyst and oxidant combina-
tions such as CuI/H2O2, CuI/TBHP, AgOTf/TBHP, MnO2, DDQ, and
PhI(OAc)2 (Table 1, Entries 1–6). However, we were pleased to
obtain high yields (91 %) of imidazole 8a using 150 mol-% of
Ag2CO3 as an oxidant/catalyst (Table 1, Entry 8). Use of 100 mol-
% of Ag2CO3 (Table 1, Entry 7) and 50 mol-% of Ag2CO3 along
with an external oxidant (Table 1, Entry 14) gave lower yields
[a] Department of Medicinal Chemistry and Pharmacology, CSIR-Indian
Institute of Chemical Technology,
Hyderabad 500007, India
E-mail: ramaurya.iict@gov.in
http://www.iictindia.org/
[b] Academy of Scientific & Innovative Research (AcSIR),
New Delhi 110025, India
[‡] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600015.
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of imidazole 8a. Among several solvents screened, toluene was
found to be the best in terms of product yield and purity
(Table 1, Entries 12–13). Heating of the reaction mixture in tolu-
ene to reflux gave a lower yield of the product, presumably due
to the increased side reactions at elevated temperatures
(Table 1, Entry 10). The reaction remained incomplete at 60 °C
in toluene, even after 24 h, and gave a low yield of imidazole
8a (Table 1, Entry 11). The reaction also worked well under
nitrogen, but the yield of imidazole 8a was lower by using
150 mol-% of Ag2CO3 (Table 1, Entry 15). However, by using a
higher loading of Ag2CO3 gave high yields of imidazole 8a,
even under nitrogen (Table 1, Entry 16). It indicated that atmos-
pheric oxygen supported the reaction when 150 mol-% of
Ag2CO3 was used (Table 1, Entry 8).
Table 2. Scope of the imidazole synthesis by coupling of vinyl azides 1 with
secondary amines 3.[a]
Table 1. Coupling of vinyl azide 1a with 1,2,3,4-tetrahydroisoquinoline 3a to
yield imidazole 8a.[a]
Entry
Catalyst/oxidant
Solvent T [°C] Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
CuI (10 mol-%)/H2O2 (10 equiv.)
CuI (10 mol-%)/TBHP (10 equiv.)
AgOTf (10 mol-%)/TBHP (10 equiv.) toluene
toluene
toluene
90
90
90
90
90
90
90
90
90
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
45
MnO2 (100 mol-%)
DDQ (100 mol-%)
toluene
toluene
toluene
toluene
toluene
toluene
toluene reflux
toluene
THF
PhI(OAc)2 (100 mol-%)
Ag2CO3 (100 mol-%)
Ag2CO3 (150 mol-%)
Ag2CO3 (200 mol-%)
Ag2CO3 (150 mol-%)
Ag2CO3 (150 mol-%)
Ag2CO3 (100 mol-%)
Ag2CO3 (100 mol-%)
Ag2CO3 (50 mol-%)/TBHP
(10 equiv.)
91
92
75
60
reflux
55[c]
48
CH3CN reflux
toluene
54
31
90
15
16
Ag2CO3 (150 mmol)
Ag2CO3 (300 mmol)
toluene
toluene
90
90
65[d]
91[d]
[a] Reaction conditions: vinyl azide 1a (0.5 mmol), 1,2,3,4-tetrahydroisoquino-
line 3a (0.5 mmol), catalyst/oxidant, solvent (5 mL), stiring in open air, 12 h.
TBHP = tert-butyl hydroperoxide, n.d. = desired product not detected by TLC.
[b] Isolated yields. [c] The reaction was run for 24 h. [d] The reaction was
carried out under nitrogen.
Having optimized reaction conditions at hand (Table 1, En-
try 8), we tried to explore the scope of the Ag2CO3-mediated
coupling of vinyl azides and secondary amines to yield imid-
azoles. Vinyl azides 1a–1j and 1m were obtained by Knoeven-
agel condensations of phenacyl azides with aldehydes, whereas
vinyl azides 1k–1l were obtained from the corresponding sty-
renes (for details, see the Supporting Information). A number of
vinyl azides derived from aromatic aldehydes bearing halogen
atoms and electron-withdrawing functional groups gave very
high yields (90–95 %) of the desired imidazole derivatives
(Table 2, Entries 1–2, 6, 9–10, 19 and 21). Vinyl azides derived
from electron-rich aromatic aldehydes, heteroaromatic alde-
hydes and aliphatic aldehydes gave relatively lower yields (68–
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Table 2. (Continued).
81 %) of the imidazole derivatives (Table 2, Entries 3–5, 7, 8, 11
and 20). Lower yields of the imidazoles with these vinyl azides
might be correlated with the increased side reactions of the
2H-azirines derived from such azides. Vinyl azides derived from
styrene gave very high yields (91–95 %) of the desired imid-
azole derivatives (Table 2, Entries 12–14). Vinyl azides derived
from phenacyl azides bearing halogen atoms, electron-with-
drawing as well as electron-releasing functional groups worked
well leading to high yields of the imidazoles (Table 2, Entries 4–
11 and 19–21).
In terms of secondary amines, the reaction gave high yields
of the imidazoles 8 with 1,2,3,4-tetrahydroisoquinoline 3a and
6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 3b (Table 2, En-
tries 1–14 and 19–21). The reaction also worked well and gave
high yields (79–81 %) of the desired imidazoles by using N-
benzylanilines 3c and 3d (Table 2, Entries 15–17). However, it
gave relatively lower yields (65 %) of imidazoles by using di-
benzylamine (3e) (Table 2, Entry 18).
In order to demonstrate the synthetic competence of our
synthetic strategy, a gram-scale (5 mmol) synthesis of 8a was
performed. Compound 8a was obtained in 90 % yield in the
gram-scale reaction, and we could regenerate 80 % of the
Ag2CO3 used in the reaction according to a literature proce-
dure.[14] The regenerated Ag2CO3 was used for further reactions,
which showed the same catalytic efficiency as the fresh one.
Next, we carried out a control experiment whereby a mixture
of vinyl azides 1m and amine 3a was heated in toluene in the
absence of Ag2CO3 (Scheme 2). The reaction proceeded
smoothly to yield a product the structure of which was tenta-
tively assigned as 9a (rather than 7; see Scheme 1) by analyzing
its 1H and 13C NMR spectra. Formation of compound 9a can
be explained by a plausible mechanism depicted in Scheme 2.
Treatment of crude 9a with Ag2CO3 gave the desired imidazole
8t in 90 % yield. Formation of imidazole 8t from 9a can be
explained by considering an Ag2CO3-mediated oxidation of the
tert-amine to iminium ion 10a.[15] The intermediate 10a is at-
tacked by the neighboring amine (NH2) to yield another inter-
mediate 11a, which is further oxidized to the final product 8t.
Ag2CO3 was found to be very crucial for the success of the
imidazole synthesis as other oxidants such as MnO2 oxidized
9a to a complex mixture in which 4-methoxybenzoic acid could
be isolated after careful purification. Attempts to isolate inter-
mediate 11a by carrying out the reaction under nitrogen were
unsuccessful. It was probably oxidized to imidazole 8t during
the workup process. 2H-Azirines 2 containing a carbonyl group
are very reactive compounds; however, some of them (such as
2n) can be isolated after thermolysis of vinyl azide 1n. Control
reactions suggested that Ag2CO3 does not interfere in the ther-
mal decomposition of the vinyl azide 1n (Scheme 3). Ag2CO3-
mediated oxidation of 1,2,3,4-tetrahydroisoquinoline led to a
mixture of products in which 3,4-dihydroisoquinoline (12) and
3,4-dihydroisoquinolin-1(2H)-one (13) were characterized as
major components (Scheme 4). These experiments suggest the
possibility of an alternative mechanism for the formation of
imidazoles 8 as depicted in Scheme 5. The 2H-azirine 2 is
attacked by 3,4-dihydroisoquinoline (12) to generate an inter-
mediate 14, which rearranges to a dihydroimidazole 15. The
[a] Reaction conditions: vinyl azide 1 (0.5 mmol), amine 3 (0.5 mmol), Ag2CO3
(0.75 mmol), toluene (5 mL), 90 °C, stiring in open air, 12 h. [b] Isolated yields.
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Communication
Scheme 2. Control experiments of vinyl azide 1m with amine 3a and mechanistic rationalization for the formation of imidazole 8t.
dihydroimidazole 15 is oxidized to the final product 8 under Conclusions
the reaction conditions.
We have developed a straightforward methodology for the syn-
thesis of fused imidazoles by Ag2CO3-mediated coupling of
vinyl azides with secondary amines under air- and moisture-
tolerant mild reaction conditions. A series of 22 different imid-
azole derivatives were synthesized in high yields by using the
optimized protocol. A few control experiments were carried out
to reveal mechanistic details of the reaction.
Experimental Section
Scheme 3. Thermal decomposition of vinyl azide 1n to 2H-azirine 2n with
and without Ag2CO3.
Supporting Information (see footnote on the first page of this
article): Experimental details and characterization data for the syn-
thesized compounds.
Acknowledgments
R. A. M. is thankful to the Department of Science & Technology,
India for financial support (GAP 0378 and GAP 0470). Financial
support in part from the 12th Five Year Plan Project “Affordable
Cancer Therapeutics (ACT-CSC-0301)” is also acknowledged.
P. R. A. acknowledges the Council of Scientific and Industrial
Research (CSIR), New Delhi, and S. B. acknowledges the Univer-
sity Grants Commission (UGC), New Delhi for their fellowships.
Scheme 4. Oxidation of 1,2,3,4-tetrahydroisoquinoline with Ag2CO3.
Keywords: C-H activation · Heterocycles · Azides · Synthetic
methods · Silver
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Published Online: February 12, 2016
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