Conformational control in the regioselective synthesis of N-2-substituted-1,2,3-triazoles

Article abstract of DOI:10.1039/b805328f

An effective strategy for the synthesis of N-2-substituted-1,2,3-triazoles with excellent yields and regioselectivity has been developed. The Royal Society of Chemistry.

Full text of DOI:10.1039/b805328f

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Conformational control in the regioselective synthesis of
N-2-substituted-1,2,3-triazolesw
Yunfeng Chen,a Yuxiu Liu,b Jeffrey L. Petersena and Xiaodong Shi*a
Received (in College Park, MD, USA) 31st March 2008, Accepted 23rd April 2008
First published as an Advance Article on the web 2nd June 2008
DOI: 10.1039/b805328f
An effective strategy for the synthesis of N-2-substituted-1,2,3-
triazoles with excellent yields and regioselectivity has been
developed.
for regioselective N-2 substitution of 1,2,3-triazoles has been
reported in the literature so far.6
With a strong dipole moment and high electron density on
the nitrogens, the NH-triazoles are good nucleophiles, which
will react with electrophiles under suitable conditions. How-
ever, among the reported examples, including acetylation7 and
Michael addition,8 the N-1 substituted triazoles were the
dominant products. This is caused by the higher electron
density associated with the two terminal nitrogens (N-1 and
N-3) than the internal N-2 nitrogen. Therefore, selective N-2
substitution remains a big challenge in triazole derivatization.
Recently, we reported a metal-free synthesis of 4,5-disub-
stituted NH-1,2,3-triazoles through a three component cas-
cade reaction (Scheme 2).9 This new method produced various
C-4, C-5 substituted NH-triazoles in good to excellent yields.
Driven by the great desire to develop efficient synthetic
strategies for functional triazole derivatives, we then investi-
gated the substitution of this new class of compounds. Herein,
we report a successful strategy for the regioselective synthesis
of N-2 substituted-1,2,3 triazoles.
Since the discovery of the copper-catalyzed alkyne–azide 1,3-
dipolar addition for the synthesis of substituted 1,2,3-triazoles
(often reported as ‘‘click-chemistry’’),1 these compounds have
received considerable attention from scientists in many differ-
ent fields.2 Within the past six years, tremendous efforts have
been made regarding the application of 1,2,3-triazoles in
biological science,3 medicinal chemistry4 and material science.5
Currently, 1,2,3-triazoles are prepared by thermo- or
copper-mediated 1,3-dipolar addition as shown in Scheme 1
(A and B). The thermo-condensation, which was first reported
more than a century ago, required harsh reaction conditions
with limited substrate scope. As a result, the 1,2,3-triazoles did
not receive great attention until the remarkable discovery of
Cu(I)-promoted ‘‘click-chemistry’’. In both approaches, only
terminally substituted triazoles (N-1) can be obtained, due to
the nature of azides. Therefore, any N-2 substituted triazoles
can only be obtained by the conversion of non-substituted
NH-triazoles with appropriate electrophiles (Scheme 1C).
However, to the best of our knowledge, no effective strategy
Our general hypothesis is that the C-4, C-5 substituent
groups may provide the necessary steric hindrance to prevent
nucleophilic substitution on the terminal nitrogens. The new
triazole synthesis mentioned above allows for this investiga-
tion. To evaluate the effectiveness of this strategy, we first
carried out an acetylation reaction on 1a. As expected, the N-2
acetylation product was obtained as the only regioisomer in
nearly quantitative yield and the structure of 2a was charac-
terized by X-ray crystallography (Scheme 3).
The triazole acetate 2a is stable under anhydrous, pH
neutral conditions. However, treatment with acid or base
causes hydrolysis of the amide. An attempt at reducing amide
2a with LiAlH4 led to the dissociation of the N–C bond, giving
1a and ethanol. Although the relatively poor stability of 2a
limits the potential applications of this approach, the success-
ful N-2 substitution confirmed our hypothesis.
Alkylation of 1a was then performed in the expectation of
forming a non-labile N–C bond. Treatment of 1a with benzyl
Scheme 1
a C. Eugene Bennett Department of Chemistry, West Virginia
University, Morgantown, WV 26506, USA.
E-mail: Xiaodong.Shi@mail.wvu.edu; Fax: +1-304-293-4904;
Tel: +1-304-293-3435 x6438
b Institute of Elemento-Organic Chemistry, Nankai University,
Tianjin, China. E-mail: Liuyuxiu@nankai.edu.cn;
Fax: +86-22-2349-9842; Tel: +86-22-2350-4229
w Electronic supplementary information (ESI) available: Experimental
details, X-ray measurement and 1H and 13C NMR spectra for all
compounds. CCDC 682966–682970. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/b805328f
Scheme 2
ꢀc
This journal is The Royal Society of Chemistry 2008
3254 | Chem. Commun., 2008, 3254–3256

View Article Online
Table 1 Screening of reactions for NH-triazole alkylationa
Scheme 3
bromide gave N-benzyl triazoles in excellent yields (495%).
However, all three regioisomers were obtained (the three
isomers can be readily separated by column chromatography.
The N-2 product is of much lower polarity). One big challenge
for further evaluation of the regioselectivity regarding different
C-4, C-5 substituents is the characterization of all three
isomers. This problem was overcome by the successful deri-
vatization of the C-5 vinyl group in 3a as shown in Scheme 4.
Notably, all three regioisomers were stable under the reac-
tion conditions and alkyl rearrangement was not observed.
Moreover, the N-benzyl bond was stable under acidic condi-
tions (AcOH in DMSO, overnight) and basic conditions
(K2CO3 in DMSO, overnight). Successful determination of
N-1-3a and N-2-4a by X-ray crystallography provided the
necessary characterization of all three N-isomers for these
substrates. With this information in hand, we then investigated
the optimal reaction conditions for the selective N-2 alkylation
and the results are summarized in Table 1.
As shown in Table 1, N-3 alkylation was the least favored in
almost all cases. From the crystal structures (N-1-3a, N-2-4a,
N-1-5a), the C-4 aryl group adopted a nearly coplanar con-
formation with the triazole ring (the dihedral angle between
the aryl and triazole rings is larger than 1401).11 Therefore, the
N-3 position was blocked for electrophilic addition. As a
result, 4,5-diaryl triazoles should undergo preferred N-2 alky-
lation to give the dominant product, which is supported by the
literature.6 However, the regioselectivity from non-aryl sub-
stituted groups (more interesting derivatives) was complicated.
The 5-vinyl substituted 1a underwent N-1 substitution to give
the major product, with the formation of a good amount of
N-2 product.12 Increasing the size of the C-5 group resulted in
better N-2 selectivity (1c and 1e).
a
The reaction was carried out by mixing triazole 1 (1.0 equiv.), base (2.0
equiv.) and R0X (1.5 equiv.) with solvent (0.2 M of 1) at room
temperature unless otherwise noted. bRatios and conversions were
determined by 1H NMR integration. Yields (combination of all three
isomers) were determined by NMR spectroscopy with 1,3,5-trimethoxy-
c
benzene as internal standard. dHeating at 45 1C. Yields based on the
consumption of the 1. DCE = 1,2-dichloroethane.
e
f
potential application of this strategy, since the ketone func-
tionality can be readily converted into other functional groups.
The 5-keto-triazole 1b may adopt two conformations, the keto
and enol forms. Since hydroxy-triazole 1d (entry 17) gave only
moderate N-2 selectivity (even with potential intramolecular
H-bonding), the keto isomer was likely the active conforma-
tion under the reaction conditions, considering that triazole
nitrogens are better nucleophiles. Therefore, to avoid the
electronic repulsion between the keto oxygen and the triazole
nitrogen, the benzoyl on C-5 would like to be coplanar with
the triazole ring as shown in Scheme 5.13 As a result, the
phenyl group effectively blocked the N-1 position, leaving N-2
as the preferred nucleophilic site. By taking advantage of our
understanding of the influences of electrophiles, C-5 substi-
tuted groups and reaction conditions on the course of the
Screening of the reaction conditions revealed that the choice
of solvent and base did change the reaction kinetics (different
reaction rates). But the influence on the regioselectivity is
subtle. Application of a stronger base, such as NaH, resulted
in deprotonation of the N–H proton, favoring N-1 substitu-
tion (entries 7 and 8). The electrophiles, on the other hand,
showed more influence on the regioselectivity. Application of
the more hindered cyclohexanyl bromide, resulted in a slower
reaction rate, and gave N-2 isomer as the only product
(entry 14).
To our surprise, the benzyl ketone triazole 1b, which is
expected to be a less hindered substrate than 1a, gave excellent
N-2 selectivity (entry 15). This result significantly improves the
Scheme 5 Electronic repulsion resulted in conformational control for
selective N-2 substitution.
Scheme 4 Derivatization of N-benzyl triazoles.10
ꢀc
This journal is The Royal Society of Chemistry 2008
Chem. Commun., 2008, 3254–3256 | 3255

View Article Online
Table 2 Reaction substrate scopea
characterization of the different N-isomers. With the continu-
ously growing interest in 1,2,3-triazoles, we believe this strat-
egy will greatly benefit researchers in various fields. Studies of
triazole analogues as peptide mimics and transition metal
ligands are currently under investigation in our group and
will be reported in due course.
We greatly appreciate the C. Eugene Bennett Department of
Chemistry, the Eberly College of Arts and Science, WVU
research co-op and WV-Nano Initiative at West Virginia
University for financial support.
Notes and references
1. For reviews, see: (a) Q. Wang, S. Chittaboina and H. N. Barnhill,
Lett. Org. Chem., 2005, 2, 293–301; (b) H. C. Kolb, M. G. Finn
and K. B. Sharpless, Angew. Chem., Int. Ed., 2001, 40, 2004–2021.
2. Recent reviews: (a) J. E. Moses and A. D. Moorhouse, Chem. Soc.
Rev., 2007, 36, 1249–1262; (b) P. Wu and V. V. Fokin,
Aldrichimica Acta, 2007, 40, 7–17.
3. Some recent reports: (a) R. Kumar, A. El-Sagheer, J. Tumpane,
P. Lincoln, L. M. Wilhelmsson and T. Brown, J. Am. Chem. Soc.,
2007, 129, 6859–6864; (b) M. Whiting, J. Muldoon, Y. C. Lin,
S. M. Silverman, W. Lindstrom, A. J. Olson, H. C. Kolb,
M. G. Finn, K. B. Sharpless, J. H. Elder and V. V. Fokin, Angew.
Chem., Int. Ed., 2006, 45, 1435–1439; (c) M. Malkoch,
R. Vestberg, N. Gupta, L. Mespouille, P. Dubois, A. F. Mason,
J. L. Hedrick, Q. Liao, C. W. Frank, K. Kingsbury and
C. J. Hawker, Chem. Commun., 2006, 2774–2776;
(d) R. J. Thibault, K. Takizawa, P. Lowenheilm, B. Helms,
J. L. Mynar and J. M. J. C. J. Hawker, J. Am. Chem. Soc.,
2006, 128, 12084–12085.
4. V. D. Bock, D. Speijer, H. Hiemstra and J. H. van Maarseveen,
Org. Biomol. Chem., 2007, 5, 971–975.
5. (a) C. F. Ye, G. L. Gard, R. W. Winter, R. G. Syvret, B. Twamley
and J. M. Shreeve, Org. Lett., 2007, 9, 3841–3844; (b) V. Aucagne,
J. Berna, J. D. Crowley, S. M. Goldup, K. D. Haenni,
D. A. Leigh, P. J. Lusby, V. E. Ronaldson, A. M. Z. Slawin,
A. Viterisi and D. B. Walker, J. Am. Chem. Soc., 2007, 129,
11950–11963.
6. Reports regarding N-2 substituted triazoles are rare. Some di-aryl
substituted triazole examples are: (a) L. Revesz, F. E. Di Padova,
T. Buhl, R. Feifel, H. Gram, P. Hiestand, U. Manning, R. Wolf
and A. G. Zimmerlin, Bioorg. Med. Chem. Lett., 2002, 12,
2109–2112; (b) D. K. Kim, J. Kim and H. J. Park, Bioorg. Med.
Chem. Lett., 2004, 14, 2401–2405.
a
Reactions were carried out by mixing triazole 1 (1.0 equiv.) and R0X
(1.5 equiv.) with solvent (0.2 M of 1) at room temperature unless
otherwise noted. bSeparated yield of N-2 isomers. cStructures have
been confirmed by X-ray diffraction. dHeating at 45 1C. eRefluxing.
fCy = cyclohexanyl.
reactions, various N-2 substituted triazoles have been synthe-
sized in excellent yields and the results are summarized in
Table 2.
7. A. R. Katritzky and A. Pastor, J. Org. Chem., 2000, 65,
3679–3682.
8. J. Wang, H. Li, L. S. Zu and W. Wang, Org. Lett., 2006, 8,
1391–1394.
9. (a) X. H. Sun, S. Sengupta, J. L. Petersen, H. Wang, J. P. Lewis
and X. D. Shi, Org. Lett., 2007, 9, 4495–4498; (b) S. Sengupta,
H. Duan, W. Lu, J. L. Petersen and X. D. Shi, Org. Lett., 2008, 10,
1493–1496.
10. NMR NOE experiments were performed and the results were not
clear enough for regioisomer assignment. Therefore the X-ray
structures were applied for final characterization.
11. Based on the crystal structures of N-1-3a, N-1-5a and N-2-4a(7a),
the dihedral angles between C-4 Ar and the triazole ring are
157.41, 148.31 and 143.11,respectively.
12. The crystal structure of N-1-3a revealed a dihedral angle of 91.41
between the triazole ring and the C-5 vinyl group. Since the C-5
vinyl is perpendicular to the triazole ring, less steric hindrance will
be observed at the N-1 position. Therefore, poor regioselectivity
has been obtained, as shown.
Notably, the N-2 isomers usually have much lower polarity
than the N-1/N-3 isomers, which allowed the easy separation
of the desired N-2 isomers. The applications of versatile
electrophiles, such as allyl halide, a-chloro esters and DCE,
provide good synthetic handles, which permit further func-
tional group transformations. In addition, besides the 5-aryl-
keto triazoles, the 5-alkyl-keto triazoles also gave excellent
N-2 selectivity (7t), thus extending the scope of our strategy.
Finally, the successful preparation of bis-triazole 7u indicated
the great potential of these compounds as ligands in the
formation of a new class of transition metal complexes.
In conclusion, we have successfully developed a general
approach for the selective N-2 substitution of 1,2,3-triazoles.
To the best of our knowledge, this is the first example of the
selective preparation of N-2 triazole compounds with clear
13. The crystal structure of 7a revealed a dihedral angle of 1691
between the triazole ring and C-5 keto group.
ꢀc
This journal is The Royal Society of Chemistry 2008
3256 | Chem. Commun., 2008, 3254–3256