Mitsunobu reaction of 1,2,3-NH-triazoles: A regio- and stereoselective approach to functionalized triazole derivatives

Article abstract of DOI:10.1002/asia.201100357

The Mitsunobu reaction was used in the preparation of chiral triazole derivatives. The reactions gave good to excellent yields with large substrate scope. Complete stereochemistry inversion was obtained, making this strategy one practical approach for the

Full text of DOI:10.1002/asia.201100357

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DOI: 10.1002/asia.201100357
Mitsunobu Reaction of 1,2,3-NH-Triazoles: A Regio- and Stereoselective
Approach to Functionalized Triazole Derivatives
Wuming Yan, Tao Liao, Odbadrakh Tuguldur, Cheng Zhong, Jeffrey L. Petersen, and
Xiaodong Shi*[a]
On the occasion of the 10th anniversary of click chemistry
The discovery of the copper-catalyzed alkyne/azide cyclo-
addition (“click” chemistry)[1] earlier this century has clearly
advanced the research of 1,2,3-triazoles and made these
five-membered heterocycles among the “hottest” com-
pounds in chemistry-,[2] materials-,[3] and biological[4] re-
search during the last decade.[5] This robust method has
been widely applied to various areas as an efficient strategy
for combining different functionalities under mild condi-
tions. Recently, driven by the great success of the synthesis
of 1,2,3-triazoles, more attentions have been put into investi-
gating the fundamental reactivity of this interesting hetero-
cycle.[6] Various attractive applications have been reported
that are associated with the unique 1,2,3-triazole core struc-
ture, including the formation of carbene intermediates[7] and
adjusting the transition metal reactivity with triazole li-
gands.[8] These studies further extended the versatility of
Scheme 1. The challenge in improving N2 regioselectivity of N1-preferred
1,2,3-triazole building blocks. Fast-growing research in this
area has led to the urgent need for effective syntheses of dif-
ferent triazole analogous, especially those that provide good
regio and stereo-selectivity.
triazoles.
vored” NH-triazoles are highly desirable. Herein, we report
the Mitsunobu reaction of NH-triazoles with alcohols as an
effective method not only for the synthesis of enantiomeric
pure chiral triazole derivatives, but also for selective N2 sub-
stitution through the modification of the carbon electro-
philes instead of changing the substituents on the NH-tria-
zoles.
Our group has recently reported several effective strat-
egies[10] for introducing different functional groups onto the
triazole ring. Through these investigations, a clear reactivity
difference was revealed between N1 and N2 isomers. For ex-
ample, we recently discovered that N2-aryl triazole (NAT)
could provide very efficient UV/blue fluorescence whilst N1
isomers gave almost no emission at all.[11] In addition, we
also applied the 1,2,3-triazoles as ligands to form transition
metal complexes and interesting new reactivities were ob-
tained,[12] which clearly demonstrated the strong potential
applications for 1,2,3-triazole in organic synthesis and transi-
tion metal catalysis. The interesting coordination ability of
1,2,3-triazoles and unique complex activity led to the strong
One challenge for the functionalization of triazoles is the
regioselective synthesis of the N2-isomers. Whilst click-
chemistry techniques give only the N1 isomers, NH-triazole
functionalization relies heavily on the reactivity of the tria-
zoles, and, most of the time, the N1 isomers are still the
major products. Recent reports in the literature have de-
scribed strategies focused on the development of suitable
substitute groups at the C4 and C5 positions to promote
good N2 selectivity (Scheme 1).[9] Therefore, new strategies
that can encourage N2 selectivity from “N1-substitution-fa-
[a] W. Yan, T. Liao, O. Tuguldur, Dr. C. Zhong, Prof. Dr. J. L. Petersen,
Prof. Dr. X. Shi
C. Eugene Bennett Department of Chemistry
West Virginia University
Morgantown, WV 26506 (USA)
Fax : (+1)304-293-4904
E-mail: Xiaodong.Shi@mail.wvu.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100357.
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Chem. Asian J. 2011, 6, 2720 – 2724

Table 1. Reaction substrate scope with benzotriazole (BTA).[a]
desire to prepare enantiomerically pure triazole
derivatives. These two challenges, improving N2
selectivity for a triazole that has an N1-substitu-
tion preference and introducing chiral groups
on the triazole ring, led us to investigate the
Mitsunobu reaction between the NH-triazoles
and alcohols.
Yield[b]
Ratio[c]
Yield[b]
Ratio[c]
A
ACHTUNGTREN(NUNG N1+N2) N2/N1
[%]
97
[%]
88
Considering the usually good stereoselectivity
associated with the Mitsunobu reaction,[13]
where complete inversion of the alcohol stereo-
genic center occurred through SN2 addition, we
postulated that this strategy might be applied
on the introduction of chiral substitute groups
on triazoles. The rather high acidity (pKa 8~10)
and the excellent nucleophilicity of the NH-
1,2,3-triazole makes them suitable coupling
partners with alcohols under Mitsunobu condi-
tions. In addition, although the N1 nitrogen of
the triazole is usually more-basic (higher elec-
tron density) than the N2 nitrogen, the center
nitrogen atom is much-less sterically hindered.
Therefore, N2 substitution is kinetically favored.
As a result, the highly stereochemistry-sensitive
Mitsunobu reactions could potentially favor the
kinetic product and increase the N2 selectivity.
To verify this hypothesis, the reaction between
benzyl alcohol 2a and benzotriazole 1a was per-
formed under standard Mitsunobu conditions
(DIAD, PPh3 in THF, Scheme 2a).
1:1.6
1:1.3
1.6:1
1.6:1
3a
3b
3h
3i
84
95
96
93
1:1.9
2:1
3c
3d
3j
93
96
1:1.8
1:1.7
85
80
1.8:1
1.2:1
3k
3e
3l
94
97
1:1.5
1:1.2
79
2.6:1
3 f
3g
3m
As expected, the dehydration product 3a was
isolated in excellent yields (97% combined N1
and N2 isomers) under Mitsunobu conditions.
Notably, N1 and N2 isomers were readily puri-
fied by column chromatography (significantly
different polarity between the N1 and N2 iso-
mers). Compared with the alkylation conditions,
where only trace amounts of N2-3a were isolat-
[a] Standard reaction condition: 1 equiv of alcohols, 1.2 equiv of triazoles, 1.2 equiv of tri-
phenylphosphine (PPh3) and 1.2 equiv of diisopropyl azodicarboxylate (DIAD) were
mixed in the distilled tetrahydrofuran (THF). [b] Yield of isolated product. [c] Ratios de-
termined by NMR analysis of crude reaction mixtures.
ed (Scheme 2b), the Mitsunobu conditions gave a signifi-
cantly higher overall yield of the N2 isomers. To determine
how different alcohols influenced the reactivity and regiose-
lectivity of the Mitsunobu reaction, various alcohols were
applied to react with 1a (Table 1).
As shown in Table 1, the Mitsunobu conditions were suit-
able for a large group of alcohols, giving the coupling prod-
ucts in generally excellent yields (N1+N2>85%). Signifi-
cantly higher yields of the N2 products (compared with the
alkylation conditions) were obtained in all cases. In addi-
tion, the secondary alcohols, although they required longer
reaction times (8 to 12 h), gave the N2 isomers as the major
products, which supported our hypothesis that the stereo-
chemistry-sensitive Mitsunobu reaction promotes the kinetic
N2 addition even for highly N1-preferred benzotriazoles.
Different NH-triazoles were then considered to further
extend the reaction substrate scope (Table 2).
In all cases, significantly higher N2 selectivity was ob-
tained. For example, as we have reported previously, the re-
action between 4-phenyl-NH-triazole (1b) and benzyl bro-
mide (PhCH2Br) gave N1-substituted benzyl 4a as the
major product (N2/N1=1:5). Under the Mitsunobu condi-
tions, the desired N2 isomer became the major product (N2/
N1=1.7:1). Good to excellent yields of the isolated N2 iso-
mers were obtained. This strategy not only provided an al-
Scheme 2. Mitsunobu reaction and alkylation of benzotriazole.
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X. Shi et al.
COMMUNICATION
Table 2. Reaction substrate scope with various triazoles.[a,b]
with the 4-phenyl-triazole (5b) and derivatives
(5d and 5 f). Notably, only trace amount of the
N2/N2 bis-triazoles were observed from the reac-
tion of 4-phenyl-triazole (PTA) with dichloro/di-
bromo alkanes, owing to the unfavored statistic
discussed above.
Encouraged by the good reactivity of the NH-
triazole under Mitsunobu conditions, we investi-
gated the stereoselectivity of this transformation.
The trans-2-methylcyclohexanol 2b and trans-2-
methylcyclopentanol 2c were used to react with
benzotriazole (BTA) 1a and phenyl-triazole
(PTA) 1b. As expected, excellent stereoselectiv-
ity were achieved, only the corresponding cis-
products were obtained with complete stereo-
chemistry inversion (Scheme 4).[14]
4a
N2: 62%;
N1: 36%
4b
N2: 64%;
N1: 30%
4c
4d
N2: 68%;
N1: 16%
N2: 61%;
N1: 32%
4e
N2: 64%;
N1: 16%
4 f
4g
N2: 67%;
N1: 16%
N2: 72%; N1: 18%
These results were exciting because they pro-
vided a practical approach for the preparation of
enantiomeric pure 1,2,3-triazole derivatives
through the coupling of triazoles and chiral alco-
hols. The enantiomeric pure alcohol 2d and qui-
nine 2e were used for the asymmetric synthesis
of chiral triazole derivatives. As shown in
Scheme 5, the chiral triazoles 7a and 7b were
prepared with excellent stereochemistry control.
Under the Mitsunobu conditions, the enantio-
meric pure alcohol 2d gave near-complete chirali-
ty transfer, forming the chiral triazole 7a in 96%
ee (determine by HPLC analysis).[15] As men-
tioned above, the N1 and N2 isomers were readi-
ly separated by column chromatography owing to
their large difference in polarity, which made this
method very attractive for the preparation of
enantiomerically pure triazoles. As observed
above, the secondary alcohols improved the
4h
N2: 62%;
N1: 21%
4i
4j
N2: 72%; N1: 20%
N2: 80%;
N1: 10%
4k
N2: 77%;
N1: 9%
4l
4m
N2: 80%;
N1: <5%
N2: 72%; N1: <5%
[a] Standard reaction conditions: alcohol (1 equiv), triazoles (1.2 equiv), of triphenylphos-
phine (PPh3; 1.2 equiv) and of diisopropyl azodicarboxylate (DIAD; 1.2 equiv) were
mixed in distilled tetrahydrofuran (THF). [b] Yields determined by NMR spectroscopy
with 1,3,5-trimethoxybenzene as an internal standard; ratios determined by NMR analysis
of the crude reaction mixtures.
ternative approach for NH-triazole functionalization, but
also, more importantly, allowed N2 functionalization
through altering different reaction parameters instead of ad-
justing the substitution groups on 1,2,3-triazoles (currently
the dominant approach in the literature for the synthesis of
N2 isomers). The significance of this strategy in altering the
N1/N2 selectivity was further highlighted in the synthesis of
bis-N2-triazole derivatives (Scheme 3).
In general, N1/N1-bis-triazoles can be readily prepared
using double-click-chemistry reactions from diynes. On the
other hand, the N2/N2-bis-triazoles are extremely challeng-
ing to prepare based on the statistic analysis. For example,
assuming that mono-substitution gave a N1/N2 ratio of 5:1,
the ratio of the bis-functionalization of the same reaction
yields of the N2 isomers, even for the usually N1-dominant
benzotriazoles. The synthesis of 7b (structure confirmed by
X-ray crystallography) highlighted the strength of this
method in the preparation of highly functional triazole ana-
logues. It is expected that these compounds can be applied
as potential building blocks in asymmetric catalysis, especial-
ly considering the interesting reactivity of the 1,2,3-triazoles.
In conclusion, the Mitsunobu reactions between NH-tria-
zoles and alcohols is a practical approach for 1,2,3-triazole
functionalization. Unlike the previously reported strategies,
where different triazoles were required to achieve good
yields of N2 isomers, the Mitsunobu conditions favored the
formation of the kinetic products (N2 isomers), even for
1,2,3-triazoles with high N1-preference (such as benzotria-
zoles). Therefore, this method provides an alternative ap-
proach to N2 substitution without changing the reactivity of
the triazoles. Moreover, with the excellent stereochemical
control, this method allows the asymmetric synthesis of
enantiomerically pure triazole derivatives, which can cer-
tainly help the further development of 1,2,3-triazoles as new
building blocks in chemistry and related research.
ꢀ
ꢀ
ꢀ
would be N1 N1/N1 N2/N2 N2=25:10:1. Therefore, the
ꢀ
theoretical yields for N2 N2 product would be only 2.7%.
The Mitsunobu conditions, by altering the N1/N2 selectivity,
afforded the opportunity to synthesize the N2/N2 isomer for
the first time through simple post-triazole derivatization. As
indicated in Scheme 3, bis-triazole 5a was successfully pre-
pared, even with usually N1 dominant benzotriazole. The
yields of the N2/N2 isomers were significantly improved
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Chem. Asian J. 2011, 6, 2720 – 2724

Mitsunobu Reaction of 1,2,3-NH-Triazoles
Scheme 5. Asymmetric synthesis of chiral triazole derivatives.[16]
at a rate such that the temperature of
the reaction mixture is maintained
below 108C. Upon completion of the
addition, the flask is removed from
the ice bath and the solution is stirred
at room temperature for 3 h, and
monitored by TLC. After the reac-
tion is complete, 30 mL of water is
added to quench the reaction. The
mixture is extracted three times with
ethyl acetate (20 mL). The combined
organic layers are washed twice with
brine (20 mL) and dried over anhy-
drous sodium sulfate (Na2SO4).
Excess solvent and other volatile re-
action components are completely re-
moved under reduced pressure. The
residue is applied to a flash chroma-
tography column on silica gel (n-
hexane/ethyl acetate=10:1) to give
the products.
Scheme 3. Synthesis of challenging N2-bis-triazoles.
Acknowledgements
Scheme 4. Complete stereochemistry inversion.
We thank the NSF (CHE-0844602),
WVU PSCOR for financial support.
Experimental Section
Keywords: 1,2,3-triazoles
·
click
chemistry
·
enantioselectivity · Mitsunobu reaction · regioselectivity
General Procedure for the Mitsunobu Reaction of 1,2,3-NH-Triazoles with
Alcohols
A 25 mL round-bottomed flask is equipped with a stirring bar, nitrogen
inlet, rubber septum. The flask is charged with alcohol (3.0 mmol), NH-
triazole (3.6 mmol), triphenylphosphine (PPh3; 3.6 mmol), and 12 mL of
distilled tetrahydrofuran (THF). The flask is immersed in an ice bath,
and diisopropyl azodicarboxylate (DIAD; 3.6 mmol) is added dropwise
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[15] The ee of N2–7a was not determined owing to the difficulty in sepa-
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Received: April 10, 2011
Published online: June 29, 2011
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Chem. Asian J. 2011, 6, 2720 – 2724