Modular synthesis of N-vinyl benzotriazoles

Article abstract of DOI:10.1021/ol401661j

A modular approach to N1-vinyl benzotriazoles by azide-aryne cycloadditions and Julia-Kocienski reactions is described. Reactions of azidomethyl phenyl-1H-tetrazol-5-yl (PT) sulfide with arynes gave methyl(PT-sulfanyl)- substituted benzotriazoles in 68-89% yields. Oxidation of the sulfides to the sulfones gave the benzotriazole-substituted Julia-Kocienski reagents. Olefination reactions of aldehydes and a ketone with reagents derived from benzyne, 2,3-naphthyne, and 4,5-dimethoxybenzyne precursors proceeded to give various N1-vinyl benzotriazole derivatives. Olefination stereoselectivities are tunable for electron-rich aldehydes, but not for electron-deficient aldehydes and alkanals, where they proceed with good to excellent Z-stereoselectivity.

Full text of DOI:10.1021/ol401661j

ORGANIC
LETTERS
2013
Vol. 15, No. 16
4086–4089
Modular Synthesis of N‑Vinyl
Benzotriazoles
Govindra Singh, Rakesh Kumar, Jorge Swett, and Barbara Zajc*
Department of Chemistry, The City College and The City University of New York,
160 Convent Avenue, New York, New York 10031-9198, United States
barbaraz@sci.ccny.cuny.edu
Received June 12, 2013
ABSTRACT
A modular approach to N1-vinyl benzotriazoles by azideꢀaryne cycloadditions and JuliaꢀKocienski reactions is described. Reactions of
azidomethyl phenyl-1H-tetrazol-5-yl (PT) sulfide with arynes gave methyl(PT-sulfanyl)-substituted benzotriazoles in 68ꢀ89% yields. Oxidation of
the sulfides to the sulfones gave the benzotriazole-substituted JuliaꢀKocienski reagents. Olefination reactions of aldehydes and a ketone with
reagents derived from benzyne, 2,3-naphthyne, and 4,5-dimethoxybenzyne precursors proceeded to give various N1-vinyl benzotriazole
derivatives. Olefination stereoselectivities are tunable for electron-rich aldehydes, but not for electron-deficient aldehydes and alkanals,
where they proceed with good to excellent Z-stereoselectivity.
Benzotriazole derivatives are versatile synthetic inter-
mediates that can undergo multiple transformations.1
Severalbenzotriazole derivativeswere alsofound to possess
biological activity, such as Vorozole that was in clinical
testing as an antineoplastic agent.2a Other examples include
tubulin inhibitors2b and compounds with antitubercular,2c
antimicrobial,2d antiproliferative,2e and anti-inflammatory2f
activities (Figure 1).
Current approaches to N-vinyl benzotriazoles are based
on reactions of benzotriazole or benzotriazole derivatives,
for example, addition of 1-chlorobenzotriazole to alkenes,
followed by elimination,3a,b or N-alkylation of benzotria-
zole with chloroethanol, followed by bromination and
elimination.4 However, alkylation reactions of benzotria-
zoles tend to form N1 and N2 regioisomers.
In light of the high pharmacological importance as well
as synthetic utilities of benzotriazoles, we became inter-
ested in delineating a highly modular approach to N-vinyl
benzotriazoles.
(1) (a) Katritzky, A. R.; Lan, X. Chem. Soc. Rev. 1994, 23, 363–373.
(b) Katritzky, A. R.; Lan, X.; Yang, J. Z.; Denisko, O. V. Chem. Rev.
1998, 98, 409–548. (c) Katritzky, A. R.; Rogovoy, B. V. Chem.;Eur. J.
2003, 9, 4586–4593. (d) Katritzky, A. R.; Manju, K.; Singh, S. K.;
Meher, N. K. Tetrahedron 2005, 61, 2555–2581. (e) Kale, R. R.; Prasad,
V.; Mohapatra, P. P.; Tiwari, V. K. Monatsh. Chem. 2010, 141, 1159–
1182.
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E.; Paneni, M. S.; Posocco, P.; Fermeglia, M.; Pricl, S. Eur. J. Med.
Chem. 2011, 46, 4151–4167. (c) Sanna, P.; Carta, A.; Nikookar, M. E. R.
Eur. J. Med. Chem. 2000, 35, 535–543. (d) Swamy, S. N.; Basappa;
Sarala, G.; Priya, B. S.; Gaonkar, S. L.; Prasad, J. S.; Rangappa, K. S.
Bioorg. Med. Chem. Lett. 2006, 16, 999–1004. (e) Zhang, S.-S.; Zhang,
H.-Q.; Li, D.; Sun, L.-H.; Ma, C.-P.; Wang, W.; Wan, J.; Qu, B. Eur. J.
Pharmacol. 2008, 584, 144–152. (f) Dawood, K. M.; Abdel-Gawad, H.;
Rageb, E. A.; Ellithey, M.; Mohamed, H. A. Bioorg. Med. Chem. 2006,
14, 3672–3680.
Figure 1. Biologically active benzotriazole derivatives.
(3) (a) Rees, C. W.; Storr, R. C. J. Chem. Soc. (C) 1969, 1478–1483.
(b) Wender, P. A.; Cooper, C. B. Tetrahedron 1986, 42, 2985–2991.
r
10.1021/ol401661j
Published on Web 08/05/2013
2013 American Chemical Society

More recent examples involve synthesis of Wittig
reagents from 1-(1-chloroalkyl)benzotriazoles followed
by olefination,5a the HornerꢀWadsworthꢀEmmons ap-
proach via diethyl-(1-benzotriazolmethyl)phosphonate,5b
and a Peterson reaction via desilylative-olefination of
1-[1,1-bis(trimethylsilyl)alkyl]benzotriazoles.5a,c Among
these various methods, only a single example involving
the olefination of an enolizable alkanal has been reported
in a low 30% yield.5a
Alternatively, N1-(1-substituted-ethenyl) benzotriazoles
were synthesized from N1-ethenyl benzotriazole via metala-
tion, followed by reaction with an electrophile.6 An example
of Cu-catalyzed reaction of (E)-β-bromostyrene with benzo-
triazole has been reported as well, giving an E-olefin, but a
mixture of N1 (major) and N2 regioisomers was formed.7
To date, there is no approach to N-vinyl benzotriazoles,
wherein both the benzotriazole unit aswellasthe vinyl sub-
stituents can be varied in a facile manner. An uncatalyzed
azideꢀaryne [3 þ 2] cycloaddition8 offers efficient access
to benzotriazoles, with variable aryl and N-substituents.
Herein, we report a new and highly modular approach to
N-vinyl benzotriazoles. Notably, this involves development of
a novel bifunctionalizable building block, containing both a
JuliaꢀKocienski9,10 olefination handle and an azide moiety.
phenyltetrazolyl derivative. Reaction of 1-phenyl-1H-tetra-
zole-5-thiol (PT-thiol) with bromochloromethane gave
chloromethyl derivative 1, which was converted to the
more reactive iodo derivative 2. Reaction of 2 with NaN3
in DMF gave the desired 5-(azidomethylthio)-1-phenyl-
1H-tetrazole (3, Scheme 1). Notably, only 1needed chroma-
tographic purification, whereas crude 2 and 3 were used in
the subsequent steps.
Next, the azideꢀaryne cycloaddition was utilized to as-
semble the benzotriazole core. Initially, as a cost-economical
approach, the reaction of 3 with benzyne derived from
anthranilic acid was evaluated. However, only a complex
reaction mixture was obtained. We therefore evaluated
the use of o-(trimethylsilyl)phenyl triflate.8 Generation
of benzyne from this precursor and reaction with 3 led to
the desired benzotriazole derivative 4 in 85% yield after
purification (Scheme 2). Oxidation of 4, using H5IO6/CrO3
or Mo7O24(NH4)6 4H2O/H2O2, gave the JuliaꢀKocienski
3
reagent 5 (Scheme 2).
Scheme 2. Cycloaddition/Oxidation to the Benzotriazole
JuliaꢀKocienski Reagent
Scheme 1. Synthesis of the Azidomethyl PT-Sulfide
Olefination conditions were screened in the reactions of
p-methoxybenzaldehyde with 5 (Table 1). First, the effect
of the base counterion was assessed, and LHMDS gave the
highest yield and E-selectivity (entries 1ꢀ3). Lowering of
the reaction temperature reversed the selectivity (entry 4),
Synthesis of the requisite azido derivative with a handle
for the JuliaꢀKocienski olefination is shown in Scheme 1.
Our initial substrate, azidomethyl benzothiazolyl sulfide,
gave complex reaction mixtures in the reactions with
benzyne. This prompted us to focus on the more stable11
Table 1. Screening of Olefination Conditionsa
€
(4) Marky, M.; Schmid, H.; Hansen, H.-J. Helv. Chim. Acta 1979, 62,
2129–2153.
(5) (a) Katritzky, A. R.; Offerman, R. J.; Cabildo, P.; Soleiman, M.
Recl. Trav. Chim. Pays-Bas 1988, 107, 641–645. (b) Qian, H.; Huang, X.
Synth. Commun. 2000, 30, 1413–1417. (c) Katritzky, A. R.; Lam, J. N.
Heteroatom Chem. 1990, 1, 21–31.
(6) Katritzky, A. R.; Li, J.; Malhotra, N. Liebigs Ann. Chem. 1992,
843–853.
rxn
base
t
time
(h)
E/Z
entry
(molar equiv)
solvent
(°C)
yieldb ratioc
(7) Taillefer, M.; Ouali, A.; Renard, B.; Spindler, J.-F. Chem.;Eur.
J. 2006, 12, 5301–5313.
1
2
3
4
5
6
7
NaHMDS (2.4)
KHMDS (2.4)
LHMDS (2.4)
LHMDS (4.0)
LHMDS (2.4)
LHMDS (3.0)
LHMDS (2.4)
THF
THF
0
0.5
0.5
4
45%
66%
76%
60/40
60/40
79/21
28/72
70/30
77/23
57/43
(8) (a) Shi, F.; Waldo, J. P.; Chen, Y.; Larock, R. C. Org. Lett. 2008,
10, 2409–2412. (b) Campbell-Verduyn, L.; Elsinga, P. H.; Mirfeizi, L.;
Dierckx, R. A.; Feringa, B. L. Org. Biomol. Chem. 2008, 6, 3461–3463.
(9) (a) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Bull. Soc.
Chim. Fr. 1993, 130, 336–357. (b) Baudin, J. B.; Hareau, G.; Julia, S. A.;
Lorne, R.; Ruel, O. Bull. Soc. Chim. Fr. 1993, 130, 856–878.
(10) For reviews on JuliaꢀKocienski olefination, see: (a) Blakemore,
P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563–2585. (b) Plesniak, K.;
0
THF
0
d
THF
ꢀ78
66e
rt
32
2
ꢀ
THF
81%
30%
THFf
DMF/
DMPUg
THF
5
d
ꢀ50
20
ꢀ
Zarecki, A.; Wicha, J. Top. Curr. Chem. 2007, 275, 163–250. (c) Aıssa, C.
¨
Eur. J. Org. Chem. 2009, 1831–1844. (d) Blakemore, P. R. Olefination of
Carbonyl Compounds by Main-Group Element Mediators. In Compre-
hensive Organic Synthesis, 2nd ed.; Knochel, P., Molander, G., Eds.; Oxford:
Elsevier Ltd., 2013, in press. (e) For a review on fluoro JuliaꢀKocienski
olefination, see: Zajc, B.; Kumar, R. Synthesis 2010, 1822–1836.
(11) (a) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A.
Synlett 1998, 26–28. (b) Kocienski, P. J.; Bell, A.; Blakemore, P. R.
Synlett 2000, 365–366.
8
DBU (2.0)
66e
2
47%
26/74
a Conditions: sulfone 5 (1 molar equiv), pMeO-C6H4-CHO (1.5 molar
equiv). b Yields are of isolated and purified products. c E/Z ratio was
determined by 1H NMR. d Reaction was incomplete; 6 was not isolated.
e At reflux. f MgBr2 OEt2 additive. g DMF/DMPU (1:1 v/v).
3
Org. Lett., Vol. 15, No. 16, 2013
4087

Table 2. Synthesis of Vinyl Benzotriazolesa
Table 3. Reactions of 3 with Various Aryne Precursors
a Conditions: Method A: sulfone 5 (1 molar equiv), carbonyl com-
pound (1.2ꢀ1.5 molar equiv), LHMDS (2.4 molar equiv), THF, 0 °C.
Method B: sulfone 5 (1 molar equiv), carbonyl compound (1.5 molar
equiv), DBU (2.0 molar equiv), THF, reflux. b Yields are of isolated and
purified products. c E/Z ratio was determined by 1H NMR.
a Yields are of isolated and purified products. b Determined by 1H
NMR. c Structures of regioisomeric products were determined by
NOESY. d Combined yield of the two regioisomers.
A ketone, N-benzyl-4-piperidone, reacted as well and gave
product 18 in a good 77% yield (entry 12). The bulkier and
conjugated acetophenone, on the other hand, did not give
good results under these conditions. No further attempts
were made to improve the condensation of acetophenone.
DBU-mediated reactions were Z-selective in all cases
tested. As compared to Method A, this is a reversal of
selectivity with electron-rich aldehydes (Table 1, entry 8,
and Table 2 entries 1, 5) and a substantial improvement in
Z-selectivity for the electron-deficient aldehyde, thiophene-
2-carboxaldehyde, and alkanal (entries 2, 4, 9).
Azidomethyl (phenyl)tetrazolyl sulfide 3 was also re-
acted with substituted benzynes and 2,3-naphthyne, gen-
erated in situ from the corresponding o-(trimethylsilyl)aryl
triflates. Cycloaddition reactions proceeded in yields of
76ꢀ89% (entries 1, 2, 4ꢀ6 in Table 3), except for 3-methoxy
benzyne, where the yield was lower (68%, entry 3), but here
formation of only a single regioisomer was observed. For-
mation of a single regioisomer in the reaction of 3-methoxy
benzyne with benzyl azide has previously been reported.8
Sulfides 19ꢀ21 were oxidized to the JuliaꢀKocienski
reagents. Oxidation of naphthotriazole derivative 19 with
H5IO6/CrO3 led to the quinone 25,12 but not to the sulfone
but the reaction was incomplete after 32 h. A higher yield
was obtained with LHMDS at reflux, with a somewhat
lower E-selectivity (entry 5). Neither MgBr2 OEt2 nor
3
DMPU additives improved the E-selectivity (entries 6, 7).
Condensation also proceeded under mild, DBU mediated
conditions, with Z-selectivity and in a moderate yield (entry 8).
The effect of substrate structure on the yields and stereo-
selectivities was evaluated in reactions of 5 with a series
of aldehydes and a ketone (Table 2). All reactions were
performed using Method A (LHMDS, THF, 0 °C). The
mild, but lower yielding, Z-selective Method B (DBU,
THF, reflux) was evaluated against five representative
aldehydes. Using Method A, vinyl benzotriazoles were
formed in moderate to good yields with a wide range of
aldehydes. The E-isomer predominated with electron-rich
aromatic aldehydes (Table 1, entry 3 and Table 2 entries 1,
5, 6). The exceptions are five-membered heterocycles with
the carboxaldehyde in an ortho position to the heteroatom
(entries 4, 7). Condensations with electron-deficient alde-
hydes (entries 2, 3) and alkanals (entries 8ꢀ11) proceeded
with Z-stereoselectivity. Selectivity was highest with
n-octanal (entry 8), and branching at the R- (entries 9, 10)
or β-position (entry 11) slightly decreased the selectivity.
26 (Scheme 3). On the other hand, use of Mo7O24(NH4)6
4H2O/H2O2 gave the desired sulfone 26.
3
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Org. Lett., Vol. 15, No. 16, 2013

Table 4. Synthesis of N-Vinyl 5,6-Dimethoxy Benzotriazoles
and N-Vinyl Naphthotriazoles
Scheme 3. Oxidation of Naphthotriazole Derivative 19
Similarly, 4-methoxy-substituted benzotriazole deriva-
tive 21 gave the corresponding sulfone 27 upon oxida-
tion with Mo7O24(NH4)6 4H2O/H2O2. 5,6-Dimethoxy-
3
substituted benzotriazole derivative 20 was converted
to sulfone 28 via mCPBA oxidation (see the Supporting
Information (SI) for details).
Condensations of sulfones 26 and 28 with aldehydes
proceeded smoothly under LHMDS-mediated condi-
tions (Method A) to give N-vinyl naphthotriazoles and
5,6-dimethoxybenzotriazoles (Table 4). Since sulfone 26
exhibited poor solubility in THF at 0 °C, it was used as a
crude material (entries 3, 6, and 8) or DMF was used as the
solvent (entries 4, 7, 9). Product yields were higher in DMF
than in THF (entries 4, 7, and 9). The E/Z selectivity was
comparable in THF and DMF for p-trifluoromethylben-
zaldehyde and was lower in DMF for 2-ethylbutanal. With
3,4,5-trimethoxybenzaldehyde, opposite stereoselectivities
were observed in the two solvents. The highest Z-selectivity
was observed with the use of DBU-mediated conditions
(Method B, entry 5); however, the yield was the lowest
(compare entries 3, 4, 5).
a Conditions: Method A: sulfone (1 molar equiv), carbonyl com-
pound (1.2ꢀ2.2 molar equiv, see the SI), LHMDS (2.4 molar equiv),
THF or DMF, 0 °C. Method B: sulfone (1 molar equiv), carbonyl
compound (1.5 molar equiv), DBU (2.0 molar equiv), THF, reflux. b Yields
1
are of isolated and purified products. c E/Z ratio was determined by H
NMR. d Due to poor solubility, crude sulfone 26 was used (see the SI).
In summary, a modular and facile approach to N1-vinyl
benzo-, substituted benzo-, and naphthotriazoles has been
reported. The method is highly flexibile for introduction
of substituents, at both the vinyl and the benzotriazolyl
moieties, and circumvents the N1/N2 regioisomer problem
encountered in alkylation reactions. The stereoselectivity
of olefinations is tunable for electron-rich aldehydes,
whereas reactions with electron-deficient aldehydes and
alkanals proceed with good to excellent Z-stereoselectivity.
Other reactions of bifunctional building block 3 are cur-
rently being pursued and will be published in due course.
Possible isomerization of the alkene mixtures was
then considered. Exposure of E/Z-6 to I2 in CHCl3,13a to
(CH3CN)2PdCl2 in CH2Cl2,13b and to LHMDS in THF
at reflux did not cause isomerization. An isomerization
attempt using a 450 W medium-pressure Hg lamp in PhH
caused decomposition (see the SI).
Acknowledgment. This work was supported by NSF Grant
CHE-1058618 and a PSC CUNY award. Infrastructural sup-
port was provided by NIH NCRR Grant 2G12RR03060-26A1
and by NIMHD Grant 8G12MD007603-27.
(12) Oxidation of naphthalene and methyl substituted naphthalenes,
phenanthrene, anthracene, and trimethoxy substituted benzene to qui-
nones using CrO3/H5IO6 has been reported: Yamazaki, S. Tetrahedron
Lett. 2001, 42, 3355–3357.
(13) (a) Gaukroger, K.; Hadfield, J. A.; Hepworth, L. A.; Lawrence,
N. J.; McGown, A. T. J. Org. Chem. 2001, 66, 8135–8138 and references
therein. (b) Yu, J.; Gaunt, M. J.; Spencer, J. B. J. Org. Chem. 2002, 67,
4627–4629.
Supporting Information Available. Experimental details
and copies of 1H and 13C NMR spectra. This information is
available free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 16, 2013
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