Highly N2-selective coupling of 1,2,3-triazoles with indole and pyrrole

Article abstract of DOI:10.1002/chem.201302761

Hydrogen-bond mediated coupling of 1,2,3-triazoles to indoles and pyrroles results in N2 selective functionalization of the triazole moiety in moderate to excellent yields. The reaction was tolerant of un-, mono- and disubstituted triazoles and was applie

Full text of DOI:10.1002/chem.201302761

DOI: 10.1002/chem.201302761
Communication
&
Regioselective Substitution
Highly N2-Selective Coupling of 1,2,3-Triazoles with Indole and
Pyrrole
Jian Wen, Li-Li Zhu, Qing-Wei Bi, Zhu-Qing Shen, Xiao-Xiao Li, Xin Li, Zhen Wang, and
Zili Chen*[a]
The indole/pyrrole moieties are important heteroaromatic
Abstract: Hydrogen-bond mediated coupling of 1,2,3-tria-
zoles to indoles and pyrroles results in N2 selective func-
structures in biological systems or in many functional materi-
als.[9,10] Direct CÀH functionalization enables rapid access to
tionalization of the triazole moiety in moderate to excel-
complex functionalized indole/pyrrole derivatives while pre-
lent yields. The reaction was tolerant of un-, mono- and
cluding the need for the heteroaromatic core syntheses.[11,12] In
disubstituted triazoles and was applied to synthesize tryp-
this field, iodination induced functionalization is an important
tophan derived fluorescent amino acids.
approach because of its mild reaction conditions and metal-
free nature.[13] Herein, we report the first example of N2-selec-
tive coupling of indole with 1,2,3-triazole through N-iodoph-
The chemistry of N1-substituted 1,2,3-triazoles is the subject of
thalimide (or N-iodosuccinimide) mediation, in which, all sub-
many studies and they have been widely applied in materials
and medicinal chemistry.[1–3] However, its N2-analogs have re-
ceived much less attention,[4,5] partly because of difficulties
with their preparation. Much effort has been made toward the
efficient synthesis of N2-aryl 1,2,3-triazoles.[6–8] In 2008, Shi
group reported a highly N2-selective copper-catalyzed arylation
and SNAr reaction from 4,5-disubstituted 1,2,3-triazoles through
steric control.[6a] Subsequently, Wang and co-workers extended
this SNAr process to prepare 4,5-unsubstituted homologs.[6b] Ex-
panding the substrate scope to mono- and unsubstituted
1,2,3-triazoles was achieved by the Buchwald group through
palladium catalyzed coupling reactions with a very bulky biaryl
phosphine ligand.[6c] Despite these achievements, a facile prep-
aration of N2-substituted triazoles with different substitution
patterns remains challenging (Scheme 1). Moreover, expanding
the scope of N2-aryl conjugated triazoles to heteroaromatic an-
alogs has yet to be explored throughly.
stitution patterns, including mono-, di- and unsubstituted
1,2,3-triazoles worked very well to give the desired coupling
adducts in moderate to good yields with a high degree of N2-
regioselectivity.[14] The reversal of nucleophilic regioselectivity
was achieved through intermolecular hydrogen bonding.[15] In
addition, N2-selective pyrrole–triazole conjugates could also be
synthesized under slightly modified reaction conditions.
Based on previous reports, N2-selective nucleophilic attack of
1,2,3-triazole is typically unfavorable, due to the lower relative
electron density at the internal nitrogen atom (N2) as com-
pared to the two terminal nitrogen atoms (N1 and N3).[8a,16] We
postulated that this problem could be resolved by attaching
the in-situ generated halonium ion to the dinucleophilic tria-
zole by
a hydrogen bonding interaction, as shown in
Scheme 1. A mode A type hydrogen bond would be favored
by the higher electron density at the terminal nitrogen atoms
(N1, N3), which would thus lead to an N2-selective addition.[16]
For this process, we hypothesized that the succinimide moiety
or its analogs may be suitable connectors.
In a preliminary trial, N-methyl indole (1aM) was chosen as
the substrate to avoid the potential activation of the indole NÀ
H bond. At first, a 1:1 mixture of 1aM and 4-phenyl 1,2,3-tri-
azole (2a) was treated with N-iodosuccinimide (3a) in dichloro-
methane at RT for 30 min.[17] The desired N2-selective coupling
adduct 5aM was obtained in 5% yield (Table 1, entry 1) and
no N1-coupling adduct was detected. After optimization of the
solvent, substrate ratio, amount of iodinating agent, base and
amount of base, 5aM (N2/N1 =9:1) could be obtained in 1,4-di-
oxane in a ratio of 1/2a/3a=2:1:3 with 5 equivalents of K2CO3,
(Table 1, entry 2).[18] No N3-substituted product was obtained.
Various N-protection methods were scrutinized (Table 1, en-
tries 3–6), in which, the benzyl group improved the yield of
5aB considerably (Table 1, entry 6). Other halogenation re-
agents were also tested. Whereas N-bromosuccinimide (3b), N-
chlorosuccinimide (3c) or 1, 3-Diiodo-5,5-dimethylhydantoin
(3e) led to decreased reaction yields (Table 1, entries 7–8 and
Scheme 1. Proposed hydrogen bond mediated N2-selective coupling reac-
tion.
[a] J. Wen, L.-L. Zhu, Q.-W. Bi, Z.-Q. Shen, X.-X. Li, X. Li, Z. Wang, Prof. Z. Chen
Department of Chemistry, Renmin University of China
59 Zhongguanchun street, Haidian District
Beijing 100872 (P. R. China)
Fax: (+86)10-62516660
E-mail: zilichen@ruc.edu.cn
Supporting information for this article including experimental procedures,
spectral data, absorption and emission spectra and NMR spectra of all
products and X-ray data for 5a (CIF) is available on the WWW under
http://dx.doi.org/10.1002/chem.201302761.
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zoles 2p and 2q reacted smoothly, providing 5p and
5q in moderate yields with high N2-selectivities.The
benzotriazole coupling adduct 5r could be obtained
with good N2-selectivity (N2/N1 =6.5:1) as compared
with the low N2-selectivities obtained in previous re-
ports. This result significantly improves the potential
application of this iodination mediated reaction.[6,19]
The coupling reactions of 2a with various indoles
were also investigated. It was found that unprotected
alcohol, phenol, amine and carboxylate groups ham-
pered the desired transformation. This might be due
to the oxidizing ability[17] of N-iodophthalimide 3d
and the competitive nucleophilicity of these intramo-
lecular functionalities. Fortunately, suitable and cleav-
able protection could resolve this problem. As shown
in Table 3, both electron-donating and electron-with-
drawing substituents (on phenyl part of the indole)
gave moderate to good yields with high regioselec-
tivities (6b–d, Table 3). Although N-protection was in-
dispensible for the aforementioned indole substrates
(5a–r, Table 2; 6b–d, Table 3), the reaction of unpro-
tected 3-methyl indole 1e proceeded smoothly to
give 6e in 55% yield with N2/N1 =2:1, which was
lower than that of the N-benzyl analog 6 f (Table 3).
Despite poor selectivity, the formation of 6e was
very meaningful for the subsequent derivation of the
tryptophan. The protected indole-3-ethanol and nat-
urally occurring plant auxin indole-3-acetic acid were
Table 1. Optimization of the halogenation mediated coupling of 1a with 2a.[a]
R
1a/2a (equiv)
Mediator (equiv)/
solvent
Yield of 5a [%][b]
(5a/5a’ ratio)[c]
/
1[d]
2
3
4
5
6
7
8
9
10
11
12[d]
Me
Me
Boc
TBS
Ph
Bn
Bn
Bn
Bn
Bn
Bn
Bn
1:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2 :1
2:1
3a (1.5)/CH2Cl2
5aM(5)/(ND)
5aM(64)/(9:1)
NR
3a (3)/1,4-dioxane
3a (3)/1,4-dioxane
3a (3)/1,4-dioxane
3a (3)/1,4-dioxane
3a (3)/1,4-dioxane
3b (3)/1,4-dioxane
3c (3)/1,4-dioxane
3d (3)/1,4-dioxane
3e (3)/1,4-dioxane
I2 (3)/1,4-dioxane
I2 (3), 4 (5%)/
5aT(46)/(5:1)
5aP(60)/(20:1)
5aB(72)/(17:1)
5aB(<5)[e]/(ND)
5aB(50)/(5:1)
5aB(83)/(17:1)
5aB(67)/(17:1)
5aB(0)/5aB’(15)
5aB(7)/(1:1.5)
1,4-dioxane
13
Bn
2:1
I2 (3), succinimde (1)/
1,4-dioxane
5aB(14)/(3.5:1)
[a] Unless noted, all reactions were carried out at 0.1 mmol scale in 2 mL solvent with
the addition of 5 equivalents of K2CO3 at RT for 30 min. [b] Yields are those for the iso-
lated N2-selective coupling product. [c] N2/N1 ratio was determined by 1H NMR spec-
troscopy of the reaction mixture. [d] No K2CO3 was added. [e] A brominated coupling
adduct was obtained in 45% yield.[18] NR=no reaction, ND=not determined.
10), N-iodophthalimide (3d) exhibited better reactivity, giving
5aB in 83% yield with excellent regioselectivity (N2/N1 =17:1,
Table 1, entry 9, condition A). The combination of
3 equivalents of I2 with 5 mol% of racemic 1,1’-bi-
then tested, giving the corresponding coupling adducts 6g
and 6h in moderate yields and good regioselectivities (Table 3)
naphthalene-2,2’-diol (racemic-BINOL) derived phos-
phoric acid 4 or with 1 equivalent of succinimide was
fruitless, affording 5aB in reduced yields with low N2/
N1 ratio (Table 1, entries 12–13). In the control experi-
ments, employing I2 alone in this reaction did not give
any N2-coupling product (Table 1, entry 11).
Table 2. N-Iodophthalimide mediated coupling reaction of 1aB with various 1,2,3-
triazoles.[a,b,c]
With the optimized reaction conditions in hand
(condition A), we then examined the scope of this
transformation by N2-selectively synthesizing a variety
of 2-indolyl 1,2,3-triazole derivatives. As shown in
Table 2, various 1,2,3-triazole substrates were exam-
ined with N-benzyl indole (1a) as the coupling part-
ner. Differently substituted phenyl 1,2,3-triazoles were
initially investigated, which afforded the desired cou-
pling adducts in moderate to good yields with high
N2-regioselectivities (5aB, 5b–i, Table 2). No obvious
electronic effects or site preferences (para-, meta- and
ortho-substitution) were observed. The electron-rich
thiophenyl substituted 1,2,3-triazole 2k and alkyl sub-
stituted triazoles 2m and 2n were then explored,
which give the corresponding adducts in slightly re-
duced yields (5k–n, Table 2). The reaction of unsubsti-
tuted 1,2,3-triazole 2o with 1a yielded only 5o with-
out forming the N1-coupling adduct. Disubstituted
1,2,3-triazoles were also tested. Both aryl and alkyl tria-
[a] Condition A: To a suspension of 3d (3 equiv), K2CO3 (5 equiv) in 1,4-dioxane
(1 mL), was added dropwise a solution of 1a (2 equiv), 2 (1 equiv) in 1,4-dioxane
(1 mL) in 5 min. [b] Yields are those for the isolated N2-selective coupling product.
[c] Unless noted, the N2/N1 ratios were determined by 1H NMR spectral data. [d] The
N2/(N1+N3) ratios of 5q and 5r were calculated from isolated yields.
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N2/N1 =1.8:1, in which, the acetoxyethyl group might ster-
ically inhibit the formation of the intermolecular hydrogen
bond.
Table 3. Coupling reactions of 4-phenyl 1,2,3-triazole 2a with various indole-
s.[a,b,c]
To elucidate the detailed reaction mechanism, N1-iodo
1,2,3-triazole 9, which can be generated through the reac-
tion of 2a with 3a,[21] was then reacted with 1a in 1,4-di-
oxane at RT, which gave no reaction [Eq. (2), Scheme 3].
Addition of protic or aprotic polar solvents (CH3OH and
DMF) or pyridine into the reaction of 1aB with 2a led to
decreased yields and N2/N1 ratios [Eq. (3), Scheme 3].
These results, coupled with the data found in Table 1, en-
tries 11–13 indicated the possible involvement of the N-io-
dosuccinimide (or N-iodophthalimide) unit in the iodo-
functionalization process, the key step of which was fol-
lowed by elimination of HI under basic conditions. The re-
action of 2-methyl indole 11 with 2a was also tested,
which provided a fluorescent indole–triazole conjugate
(12) with a trizole in the indole C3 position [Eq. (4),
Scheme 3].[18] It seems that 2a undergoes an A type
(Scheme 1) nucleophilic addition to the in-situ generated
halonium ion giving the anti-addition intermediate 13,
which therefore, can be transformed into 12 by
a Wagner–Meerwein migration and HI elimination.
[a] Unless noted, all reactions were carried out under condition A. [b] Unless
noted, yields are those for the isolated N2-selective coupling product. [c] The N2/
N1 ratios, determined by 1H NMR spectral data, were given in the parentheses.
[d] 3a was utilized with addition of 0.1 mL CHCl3 additive (1/2a=1:2).
In summary, we have developed an N2-selective cou-
pling reaction of 1,2,3-triazoles with indoles and pyrroles
with tolerance of the competitive nucleophilic ester groups.
N2-selective derivation of tryptophan was then performed.
After a series of additive and sequence of substrate addition
optimizations (Table S2),[18,20] the acetyl protected tryptophan
ester could be transformed into the fluorescent amino acid 6i
in 67% yield under base-free conditions, with N2/N1 selectivity
of 12:1.[21] Similarly, CBz and Boc protected tryptophan esters
could provide 6j and 6k in moderate yields with good N2-se-
lectivities. All N2-selective indole–triazole conjugates were
found to be fluorescent substances, emitting blue to green
fluorescence under UV illumination, with peak emission from
ꢀ440 to ꢀ480 nm.[3]
Scheme 2. N2-Selective derivation of benzotriazole.
This triazole coupling reaction was then extended to other
heteroaromatic molecules. It was found that pyrrole–triazole
conjugates could also be synthesized under a slightly modified
conditions (see Table S4 in the Supporting Information for opti-
mization of condition B).[18] Under condition B, 8a could be ob-
tained from the reaction of N-benzyl pyrrole 7 with 2a in 63%
yield with N2/N1 =7:1. The structure of 8a was found to be
similar to the indole–triazole adducts as determined by
1H NMR spectroscopy. Various triazoles were then examined, in
which, mono-, di- and unsubstituted triazoles reacted smoothly
to give the desired coupling adducts in moderate yields with
good N2-selectivity. Efforts to extend this reaction to furan,
benzofuran, thiophene and benzothiophene were fruitless.
Highly N2-selective derivatization of benzotriazole was not
possible by previously reported methods.[6,19] Therefore, benzo-
triazole–indole coupling was further examined. Whereas good
N2-selectivities were observed in the reactions of 5-fluoro, 5-
acetylamino and 3-methyl substituted indoles 1b, 1d and 1e
[Eq. (1), Scheme 2], 9g was obtained in only 24% yield with
Scheme 3. Further exploration to elucidate the reaction mechanism.
through a N-iodophthalimide (or N-iodosuccinimide) mediated
iodofunctionalization–elimination process. In this reaction, N1-
type intermolecular hydrogen bonding is favored by the
higher electron density at the terminal nitrogens of 1,2,3-tria-
zoles and could result in the N2-coupling adduct selectively. All
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1,2,3-triazoles worked very well, giving highly N2-selective fluo-
resecent coupling adducts in moderate to good yields. In addi-
tion, tryptophan derived fluorescent amino acids could also be
synthesized under slightly modified conditions.
Table 4
Table 4. Coupling reaction of N-benzyl pyrrole 7 with various 1,2,3-triazo-
les.[a,b]
[3] For reviews of the use of N1-1,2,3-triazoles in synthesis, see: a) B. Chat-
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[a] Condition B: To a suspension of 7 (2 equiv), 2 (1 equiv) and K2CO3
(5 equiv) in 1,4-dioxane (1 mL), was added dropwise a solution of 3a
(3 equiv) in 1,4-dioxane (1 mL) in 5 min. [b] Yields are those for the isolat-
ed N2-selective coupling product. [c] The N2/N1 ratios were determined by
the isolated yields.
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Experimental Section
General Procedure for the coupling reaction. Condition A:
A solution of 1a (0.2 mmol) and 2a (0.1 mmol) in 1,4-dioxane
(1 mL) was added to a suspension of N-iodophthalimide (3d;
0.3 mmol) and K2CO3 (0.5 mmol) in dry 1,4-dioxane (1 mL) dropwise
over 5 min. After 30 min, the reaction mixture was diluted with
20 mL EtOAc, and washed with saturated aqueous Na2S2O3 (5 mL),
brine (10 mL) and water (10 mL). The organic phase was dried over
anhydrous sodium sulfate, filtered and concentrated in vacuo. Pu-
rification of the crude product by flash chromatography (petrole-
um ether/EtOAc=50:1) afforded 5a (29 mg, 83% yield) as a white
solid. Condition B: To a suspension of 7 (0.2 mmol), 2a (0.1 mmol)
and K2CO3 (5 equiv) in 1,4-dioxane (1 mL), was added dropwise
a solution of 3a (0.3 mmol) in 1,4-dioxane (1 mL) in 5 min. Work
up by the same procedure as A afforded 8a (19 mg, 63% yield) as
a white solid.
Acknowledgements
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Financial support by the National Science Foundation of China
(21072224 and 21272268), the Fundamental Research Funds
for the Central Universities, and the Research Funds of Renmin
University of China (11XNI003) are gratefully acknowledged.
We thank Professor Zhi-Xiang Yu (Peking University).
Keywords: 1,2,3-triazole
·
heterocycles
·
indole–triazole
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conjugates · iodination mediated reaction · pyrrole–triazole
conjugates · regioselectivity
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[17] Treating the conjugate 5aB with 3a for 24 h led to a mixture of de-
composed product, which might affect the reaction yield.
[18] See supporting information for the detailed reaction condition optimi-
zation, the NOESY spectra of compound 12, the absorption and emis-
sion spectra of all indole conjugates. The structure of 5a was deter-
mined by X-ray diffraction analysis. CCDC-933605 contains the supple-
mentary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
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[19] N2/N1 =1:3 in ref. 6a and N2/N1 =47:53 in ref. [6c].
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[21] Compound 10 can be obtained as an insoluble white solid through the
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Chem. Soc. Perkin Trans. 1 1978, 909.
Received: July 15, 2013
Published online on December 16, 2013
Chem. Eur. J. 2014, 20, 974 – 978
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