Organoallylaluminum reagents promote easy access to trihalomethyl triazolyl homoallylic alcohols analogous to rufinamide

Article abstract of DOI:10.1016/j.tetlet.2014.02.091

The results of allylation reactions employing allylaluminum reagents are described for 5-substituted (2,6-difluorobenzyl)-4-trifluoro(chloro)acetyl-1H-1, 2,3-triazoles (1), in which the 5-substituents are H, Me, and Ph. The allylating reagents were generated in situ by the catalytic insertion of aluminum into allyl and crotyl bromides (2), in order to furnish a new series of twelve trihalomethyl triazolyl homoallylic alcohols (3) at yields of up to 94%. The excellent reactivity of these organoallyl reagents is highlighted as an economical alternative to the indium-mediated reactions to produce homoallylic alcohols, which are important building blocks in organic synthesis.

Full text of DOI:10.1016/j.tetlet.2014.02.091

Tetrahedron Letters 55 (2014) 2283–2285
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Organoallylaluminum reagents promote easy access to trihalomethyl
triazolyl homoallylic alcohols analogous to rufinamide
⇑
Helio G. Bonacorso , Carson W. Wiethan, Chaiene R. Belo, Maiara C. Moraes, Marcos A. P. Martins,
Nilo Zanatta
Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
The results of allylation reactions employing allylaluminum reagents are described for 5-substituted (2,6-
difluorobenzyl)-4-trifluoro(chloro)acetyl-1H-1,2,3-triazoles (1), in which the 5-substituents are H, Me,
and Ph. The allylating reagents were generated in situ by the catalytic insertion of aluminum into allyl
and crotyl bromides (2), in order to furnish a new series of twelve trihalomethyl triazolyl homoallylic
alcohols (3) at yields of up to 94%. The excellent reactivity of these organoallyl reagents is highlighted
as an economical alternative to the indium-mediated reactions to produce homoallylic alcohols, which
are important building blocks in organic synthesis.
Received 20 December 2013
Revised 20 February 2014
Accepted 24 February 2014
Available online 3 March 2014
Keywords:
Aluminum
Indium
Ó 2014 Elsevier Ltd. All rights reserved.
Organometallic reagents
Allylation
Heterocycles
The direct construction of carbon skeletons containing func-
tional groups capable of being transformed in adjacent steps has
a growing importance in organic synthesis. Among the several
Recently, our research group described the synthesis of 5-alky-
l(aryl)-1-(2,6-difluorobenzyl)-4-trihaloacetyl-1H-1,2,3-triazoles.7
These heterocycles, which have a triazole core and a trihalomethyl
group like many substances with high applicability in various
branches of the pharmacological and agricultural fields, are analo-
gous structures of Rufinamide, a commercial drug employed for
the treatment of Lennox–Gaustaut syndrome, which is a severe
form of epilepsy.
Thus, in view of the importance of the molecules afore
mentioned, as well as few examples of allylation reactions
involving trihalomethyl ketones found in the literature, in this
work we wish to disclose the chemical behavior of these
trifluoro(chloro)acetyl-1H-1,2,3-triazoles (1a–f) in allylation reac-
tions, by employing an inexpensive procedure in order to obtain
a series of trihalomethyl triazolyl homoallylic alcohols (3a–l). We
also wish to compare the effect of the fluorine, chlorine, and
hydrogen atoms of the CX3 groups (Scheme 1). As a starting point
for the study, we investigated the Barbier procedure, described by
Preite et al.8 for inserting allyl bromide into triazole 1a. Unfortu-
nately, for this method, a long reaction time was required to obtain
the desired homoallylic alcohol. This suggests that, in this case, the
aluminum only acts as a reducing agent, and the indium is respon-
sible for the conversion. This supposition is anchored in the high
oxophilicity of the organoalluminun reagents, which show low sta-
bility when exposed to air—conditions employed in Preite’s meth-
od. After this disappointing result, we decided to replace the
ways to perform it, the c-insertion of allylic organometallic nucle-
ophiles into carbonyl compounds is one of the most remarkable
tools found in the literature.1 The homoallylic alcohols obtained
from these reactions are highly featured in synthetic procedures
for building many biologically active molecules such as macrolides,
polyhydroxylated natural products, and polyether antibiotics.2
Although indium-mediated allylation reactions have become
very popular, mainly due to the possibility of performing Barbier
procedures in aqueous media,3 the high cost of this metal makes
the process expensive. In this context, aluminum is a metal that
has several attractive features such as low toxicity, low cost, and
tolerance of a wide number of important functional groups, due
to the low ionic character of the carbon–aluminum bond.4 Unfortu-
nately, the direct insertion of aluminum into organohalides is dif-
ficult, due to the presence of an oxidized layer covering the metal
surface, being the proper activation required to occur the reaction.5
As an alternative, in 2002, Takai and Ikawa described the prep-
aration of allylaluminum reagents under very mild conditions,
employing indium metal as the catalyst.6
Upon searching the literature, we found that most of the studies
of allylation reactions involve aldehydes or simple ketones.
⇑
Corresponding author. Tel.: +55 55 3220 8867; fax: +55 55 3220 8031.
E-mail address: heliogb@base.ufsm.br (H.G. Bonacorso).
http://dx.doi.org/10.1016/j.tetlet.2014.02.091
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

2284
H. G. Bonacorso et al. / Tetrahedron Letters 55 (2014) 2283–2285
F
R1
N
F
R1
HO
O
CX3
R
Al2Br3
N
N
N
N
+
CX3
N
3
F
F
R
1a-f
2a-b
3a-l
Scheme 1. Addition of the allyl and crotyl aluminum to trihaloacetyl ketones (1a–f).
reaction methodology with an improvement of Takai’s method,
disclosed by Knochel et al.9
CX3
CX3
OH
MLn
O
R
Thus, under argon atmosphere, the allyl bromide was reacted
with aluminum flakes and In0 in anhydrous THF, at 0 °C for 1 h.
The corresponding allylic aluminum reagent (2a) was obtained
with a conversion rate of up to 90% (determined by GC–MS from
iodolyzed aliquots). For the less reactive (E)-crotyl bromide, 2 h
were necessary to obtain the crotyl aluminum (2b) at a similar rate
of conversion. In the next step, the solution containing the respec-
tive organometallic reagent was added to each trihaloacetyl ketone
solution (1a–f) in anhydrous THF and an argon atmosphere that
had been previously cooled to À78 °C, and then stirred at this tem-
perature for 2 h.12 The results from these reactions are summarized
in Table 1.
H
e
t
O
H
e
t
R
MLn
+
R
CX3
H
H
e
t
(E)-isomer
anti-homoallylic
alcohol
CX3
CX3
OH
MLn
O
H
O
H
e
t
MLn
H
e
t
+
R
R
H
e
t
CX3
R
Although the yields were good, the compounds derived from
(E)-crotyl bromide (3g–l) still showed low diastereoselectivity.
Explanations in the literature rely on the fact that the addition
(Z)-isomer
syn-homoallylic
alcohol
of allylic nucleophiles, which have small groups at the
c
Scheme 2. Plausible reaction mechanism.
positions, to carbonyl compounds, occurs via a six-membered
chair-like transition state (Zimmerman–Traxler transition state
model).10 This configuration, which is responsible for the very
high stereodifferentiation level, that is, normally observed for
these reactions, implies that anti-homoallylic alcohol is obtained
when the (E)-allylic nucleophile is employed, while the (Z)-
F
F
O
O
O
i
+
N3
N
85%
N
N
F
F
allylic nucleophile provides
(Scheme 2).
a
syn-homoallylic alcohol
4
5
6
Additionally, other studies show that, even starting from (E)-al-
lyl halides, the allylic organometallics generated in situ by a reduc-
tive process can be in equilibrium between the two possible
species, and the most thermodynamic trans-isomer is at the high-
est concentration.11 Thus, due to the low energy barrier necessary
for the metallotropic rearrangement of the crotyl aluminum to oc-
cur, even performing the organometallic synthesis in an ice bath
was not enough to prevent the equilibration of allyl aluminum re-
agents. On the other hand, when lower temperatures were applied,
F
OH
ii
N
90%
N
N
F
7
Scheme 3. Synthesis of the compounds
i = K2CO3, EtOH, reflux, 24 h; ii = 2a, THF, À78 °C, 2 h.
6
and 7.13 Reagents and conditions:
Table 1
Yields and melting points for the new trihalomethyl triazolyl homoallylic alcohols (3a–l)
F
R1
F
R1
HO
O
CX3
THF, -78 °C, 2h
R
Al2Br3
N
N
N
N
+
CX3
N
N
3
F
F
R
Compound
R
R1
X
Mp (°C)
Yielda (%)
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
H
H
H
H
H
H
F
F
F
Cl
Cl
Cl
F
F
F
75–76
78–80
90
94
91
88
92
94
89
86
90
85
90
91
Me
Ph
H
Me
Ph
H
Me
Ph
H
Me
Ph
123–124
143–144
131–133
171–173
85–87
Me
Me
Me
Me
Me
Me
65–66
103–105
116–118
118–120
190–191
3j
3k
3l
Cl
Cl
Cl
a
The compounds derived from crotyl bromide (3g–l) were attained as a mixture of two diastereoisomers in the proportion of 70:30 (determined by 1H NMR).

H. G. Bonacorso et al. / Tetrahedron Letters 55 (2014) 2283–2285
2285
Supplementary data
Supplementary data associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2014.02.091.
References and notes
1. Yamamoto, H.; Oshima, K. Main Group Metals in Organic Synthesis; Wiley-VCH:
Weinheim, 2004.
2. (a) Nicolaou, K. C.; Kim, D. W.; Baati, R. Angew. Chem., Int. Ed. 2002, 41, 3701; (b)
Nicolaou, K. C.; Ninkovic, S.; Sarabia, F.; Vourloumis, D.; He, Y.; Valllberg, H.;
Finlay, M. R. V.; Yang, Z. J. Am. Chem. Soc. 1997, 119, 7974; (c) Bartlett, P. A.
Tetrahedron 1980, 36, 3; (d) Paterson, I.; Mansuri, M. M. Tetrahedron 1985, 41,
3569; (e) Germay, O.; Kumar, N.; Thomas, E. J. Tetrahedron Lett. 2001, 42, 4969;
(f) Romo, D.; Meyer, S. D.; Johnson, D. D.; Schreiber, S. L. J. Am. Chem. Soc. 1993,
115, 9345.
3. Li, C. J. Chem. Rev. 2005, 105, 3095.
4. (a) Negishi, E.-i.; Takahashi, T.; Baba, S.; Van Horn, D. E.; Okukado, N. J. Am.
Chem. Soc. 1987, 109, 2393; (b) Negishi, E.-i. Acc. Chem. Res. 1982, 15, 340; (c)
Ku, S.-L.; Hui, X.-P.; Chen, C.-A.; Kuo, Y.-Y.; Gau, H.-M. Chem. Commun. 2007,
3847; (d) Zweifel, G.; Miller, J. A. In Inorganic Reactions; Dauben, W. G., Ed.;
Wiley: New York, 1984.
5. (a) Rieke, R. D. Top. Curr. Chem. 1975, 59, 1; (b) Rieke, R. D. Aldrichimica Acta
2000, 33, 52.
6. Takai, K.; Ikawa, Y. Org. Lett. 2002, 4, 1727.
7. Bonacorso, H. G.; Moraes, M. C.; Wiethan, C. W.; Luz, F. M.; Meyer, A. R.;
Zanatta, N.; Martins, M. A. P. J. Fluorine Chem. 2013, 156, 112.
8. Preite, M. D.; Geroldi, H. A. J.; Carvajal, A. P. ARKIVOC 2011, vii, 380.
9. Peng, Z.; Blümke, T. D.; Mayer, P.; Knochel, P. Angew. Chem., Int. Ed. 2010, 49,
8516.
Figure 1. Influence of the CX3 in the H-3 and H-5 chemical shifts.
10. (a) Mejuch, T.; Gilboa, N.; Gayon, E.; Wang, H.; Houk, K. N.; Marek, I. Acc. Chem.
Res. 2013, 46(7), 1659; (b) Denmark, S. E.; Weber, E. J. Helv. Chim. Acta 1983, 66,
1655.
11. (a) Roush, W. R. In Comprehensive Organic Synthesis; Heathcock, C. H., Ed.;
Pergamon: Oxford, 1990; Vol. 2, (b) Yamamoto, Y.; Asao, N. Chem. Rev. 1993,
93, 2207; (c) Kennedy, J. W. J.; Hall, D. G. Angew. Chem., Int. Ed. 2003, 42, 4732;
(d) Denmark, S. E.; Fu, J. Chem. Rev. 2003, 103, 2763.
12. General procedure for preparation of trihalomethyl triazolyl homoallylic alcohols
(3a–l) and (7): Aluminum flakes (3 mmol–0.081 g) and In (0.1 mmol–0.011 g)
were placed in a 50 ml Schlenk flask and dried under vacuum (1 mbar) for 5 min
with a heat gun. After returning to room temperature, the system was backfilled
with argon and a solution of allylic bromide (1.5 mmol) in anhydrous THF
(5 mL) was added. The reaction mixture was stirred at 0 °C for 1 h for the allyl
bromide and 2 h for the crotyl bromide. The resulting solution was then quickly
low concentrations of organometallics were observed, even after
long reaction times.
An interesting characteristic observed for the compounds 3a–f
was the influence of the CX3 group at the chemical shift of the
allylic moiety hydrogens, mainly at both H-5, located six bonds
away from the fluorines and chlorine atoms. In the substituted
trichoromethyl compounds, the sets of signals corresponding to
these hydrogens appear to be more separated than in the substi-
tuted trifluoromethyl. In order to compare this effect, we per-
formed the synthesis of the hydrogenated analog (7) for the
compounds 3b and 3e (Scheme 3).
added to
a glass flask containing a solution of the respective triazole 1
(1.0 mmol) in anhydrous THF (3 mL) at À78 °C and in an argon atmosphere. The
resulting mixture was stirred in these conditions for 2 h. The reaction was then
quenched with 5 ml of aqueous HCl solution (10% v/v) and the mixture was
extracted with ether (3 Â 20 mL). The combined extracts were washed with
brine (3 Â 15 mL), dried over Na2CO3, and then concentrated in vacuum. The
crude products 3 and 7 were purified by column chromatography, employing
silica gel as the stationary phase and hexane/EtOAc 1:1 (v/v) as the eluent. The
products were attained as white powders in all cases. Data for 2-(1-(2,6-
difluorobenzyl)-1H-1,2,3-triazolo-4-yl)-1,1,1-trifluoropent-4-en-2-ol (3a): Please
see the atoms numbering for NMR data at the supporting information: 1H NMR
Comparing the results of the NMR 1H analyses, it is possible
to recognize that, although the fluorine is the most electronega-
tive among the three atoms, the highest shift separation was ob-
served for the chlorine-substituted molecules. This fact suggests
that the larger the steric size of the CX3 group, the more rigid
the conformation adopted by the molecule. The preferred confor-
mation appears to place the hydrogen atoms closer to the hydro-
xyl group, and this is reflected in the difference in the chemical
shifts (Fig. 1).
In summary, we have reported the efficient preparation of triha-
lomethyl triazolyl homoallylic alcohols from the addition of allylic
aluminum reagents to trihaloacetyl groups. This economical proto-
col, although showing limitations for allyl halides substituted with
small groups, was able to furnish the desired compounds at consid-
erable yields and under very mild conditions.
4
3
(400 MHz, DMSO-d6, 25 °C) d = 8.13 (s, 1H, H-9), 7.51 (tt, JH-F = 6.8 Hz, JH-
H = 8.3 Hz, 1H, H-4), 7.16–7.20 (m, 2H, H-3, H-5), 6.72 (s, 1H, OH), 5.70 (s, 2H, H-
7), 5.60 (ddt, 3JH-H = 16.9 Hz, 3JH-H = 10.0 Hz, 3JH-H = 6.80 Hz, 1H, H-12), 5.08 (dd,
3
3
3
3JH-H = 17.4 Hz, JH-H = 1.7 Hz, 1H, H-13a), 5.00 (dd, JH-H = 10.2 Hz, JH-
2
3
H = 1.7 Hz, 1H, H-13b), 2.94 (dd, JH-H = 14.3 Hz, JH-H = 7.2 Hz, 1H, H-11a),
2.76 (dd, 2JH-H = 14.3 Hz, 3JH-H = 7.2 Hz, 1H, H-11b). 13C NMR (100 MHz, DMSO-
d6, 25 °C) d = 160.5 (dd, 1JC-F = 250 Hz, 3JC-F = 7 Hz, C-2, C-6); 144.9 (s, C-8), 131.4
(t, 3JC-F = 10 Hz, C-4), 130.9 (s, C-12), 125,0 (q, 1JC-F = 287 Hz, CF3), 124.3 (s, C-9),
118.7 (s, C-13), 111.5 (dd, JC-F = 19 Hz, JC-F = 6 Hz, C-3, C-5), 110.9 (t, JC-
F = 19 Hz, C-1), 72.9 (q, 2JC-F = 28 Hz, C-10), 40.7 (t, 3JC-F = 4 Hz, C-7), 37.9 (s, C-
11). GC–MS (EI, 70 eV): m/z (%) 333 (M+, 23), 316 (10), 292 (47), 264 (10), 127
(100), 101 (12). Anal. Calcd. for C14H12F5N3O (333): C, 50.46; H, 3.63; N, 12.61.
Found: C, 50.43; H, 3.62; N, 12.51.
2
4
2
13. Procedure for preparation of 4-acetyl-1-(2,6-difluorobenzyl)-5-methyl-1H-1,2,3
triazole (6): Sodium carbonate (10 mmol) was added to a solution of 2,6-
difluorobenzyl azide (5 mmol) and acetylacetone (5 mmol) in ethanol (10 ml).
The reaction mixture was stirred under reflux for 24 h. Subsequently, distilled
water (10 mL) was added and the solution was neutralized with aqueous HCl
(30% v/v). The organic fraction was extracted with diethyl ether and dried with
anhydrous sodium sulfate. The organic fraction was extracted with diethyl
ether, dried with anhydrous sodium sulfate, and then concentrated under a
rotary evaporator to yield the crude product. The crude product was purified
by column chromatography, employing silica gel as the stationary phase and
hexane/EtOAc as the eluent, to give a white solid.
Acknowledgments
The authors thank the financial support from Conselho Nacional
de Desenvolvimento Científico
303.013/2011-7 and 470.788/2010-0 - Universal) and Fundação
de Amparo a Pesquisa do Estado do RGS – FAPERGS (Proc. PqG nr.
12/0982-1). Fellowships from CAPES and CNPq are also
acknowledged.
e Tecnológico–CNPq (Proc. nr.