regioselective fashion with respect to the two nitrogen
centers of 6 on the basis of the better reactivity of the se-
condary amine over the primary amine to obtain the
required intermediate 7 which would be conveniently
attached to the benzothiazole moiety to form 9, the
immediate precursor of 1 (Scheme 2).
Table 1. Influence of Solvent on Epoxide Ring-Opening of 3
with 6a
entry
solvent
temp (°C)
yieldb (%)
1
neat
rt
10
rt
15c
trace
60d
90
2
neat
3
water
4
water
10
10
10
10
10
10
10
10
10
10
10
10
Scheme 2. Design of Protecting Group-Free Synthetic Plan for 1
5
DCM
trace
trace
0
6
MeCN
toluene
THF
7
8
0
9
1,4-dioxane
MeNO2
MeOH
EtOH
iPrOH
tBuOH
TFE
0
10
11
12
13
14
15
0
10
11
15
18
40e
a Compound 3 (1 mmol) was treated with 6 (1 mmol, 1 equiv) in the
indicated solvent (1 mL) (except for entries 1 and 2) for 2 h. b Isolated
yield of 7. c The side product 7a was formed in 5% yield. d ESI-MS of the
crude product revealed 17% conversion to 7a.10 e ESI-MS of the crude
product revealed 20% conversion to 7a.10
In implementing the synthetic plan (Scheme 2), it was
realized that although the aminolysis of epoxide is pro-
7
moted by Lewis/Bronsted acid catalysts, in view of the
€
requirement of regioselectivity, a milder electrophilic acti-
vation of the epoxide ring is desirable and attention was
focused toward the ability of water to accelerate the
organic reaction through hydrogen-bond (HB) mediated
electrophilic activation.8
Thus, the 1,2-epoxy-3-(3,4-difluorophenoxy)propane (3),
prepared by a modified procedure,7b was treated with 6 in
various reaction media (Table 1) in the absence of any Lewis/
high cohesive energy density of water, and HB effect.11
Although the HB effect appears to have gained popularity
to account for “on water” catalysis,8,12 the non-HB effect
also has been invoked.13 The excellent yields in water are
attributed to its HB donor (HBD) ability in forming the
supramolecular assembly (Figure 1). Hydrogen-bonded
clusters involving the reactants and water molecule(s) have
beenpostulated invariousorganictransformations,8 water
catalysis of radical-molecule gas-phase reactions,14 and
epoxide-opening cascades.15 The poor results in alco-
hols could be due to their inferior HBD values.16 How-
ever, the use of TFE17 with a better HBD value com-
pared to that of water led to competitive formation of
the side product 7a (entry 15, Table 1). The amount of
water is also very important and 0.36 mL per mmol of 3
was found to be the optimal amount.10 No improve-
ment of the product yield was observed in using larger
volume (1 mL) of water, but the yield decreased upon
decreasing the amount of water.
€
Bronsted acid catalyst to synthesize the 1-(4-aminopiperidin-
1-yl)-3-(3,4-difluorophenoxy)propan-2-ol (7). The best
results were obtained in (demineralized) water at 10 °C
(entry 4). The reaction at rt (∼25À30 °C)9 resulted in
competitive formation of the side product 7a10 (entry 3)
generated due to the reaction of 7 with 3.
The poor results in organic solvents (entries 5À15) or
under neat conditions (entries 1 and 2) highlighted the
beneficial effects of water. The rate enhancement in water
has been the subject of investigation and attributed to
various factors such as enforced hydrophobic interactions,
(7) Selective examples: (a) Pujala, B.; Rana, S.; Chakraborti, A. K.
J. Org. Chem. 2011, 76, 8768. (b) Shivani, Pujala, B.; Chakraborti, A. K.
J. Org. Chem. 2007, 72, 3713. (c) Chakraborti, A. K.; Kondaskar, A.;
Rudrawar, S. Tetrahedron 2004, 60, 9085. (d) Chakraborti, A. K.;
Rudrawar, S.; Kondaskar, A. Eur. J. Org. Chem. 2004, 3597. (e)
Chakraborti, A. K.; Rudrawar, S.; Kondaskar, A. Org. Biomol. Chem.
2004, 2, 1277. (f) Chakraborti, A. K.; Kondaskar, A. Tetrahedron Lett.
2003, 44, 8315.
(8) (a) Kommi, D. N.; Jadhavar, P. S.; Kumar, D.; Chakraborti,
A. K. Green Chem. 201310.1039/C3GC37004F. (b) Kommi, D. N.; Kumar,
D.; Chakraborti, A. K. Green Chem. 201310.1039/C3GC36997H. (c) Kommi,
D. N.; Kumar, D.; Bansal, R.; Chebolu, R.; Chakraborti, A. K. Green Chem.
2012, 14, 3329. (d) A Chankeshwara, S. V.; Chakraborti, A. K. Org. Lett.
2006, 8, 3259. (e) Khatik, G. L.; Kumar, R.; Chakraborti, A. K. Org. Lett.
2006, 8, 2433. (f) Chakraborti, A. K.; Rudrawar, S.; Jadhav, K. B.; Kaur,
G.; Chankeshwara, S. V. Green Chem. 2007, 9, 1335.
(11) Mellouli, S.; Bousekkine, L.; Theberge, A. B.; Huck, W. T. S.
Angew. Chem., Int. Ed. 2012, 51, 7981.
(12) Zheng, Y.; Zhang, J. ChemPhysChem 2010, 11, 65.
(13) (a) Norcott, P.; Spielman, C.; Mcerlean, C. S. P. Green Chem.
2012, 14, 605. (b) Beattie, J. K.; Mcerlean, C. S. P.; Phippen, C. B. W.
Chem.;Eur. J. 2010, 16, 8972. (c) Phippen, C. B. W.; Beattie, J. K.;
Mcerlean, C. S. P. Chem. Commun. 2010, 46, 8234.
(14) Vohringer-Martinez, E.; Hansmann, B.; Hernandez, Francisco,
J. S.; Troe, J.; Abel, B. Science 2007, 315, 497.
(15) Viotijevic, I.; Jamison, T. F. Science 2007, 317, 1189.
i
t
(16) The HBD values (R) of water, MeOH, EtOH, PrOH, BuOH,
and TFE are 1.17, 0.93, 0.83, 0.76, 0.68, and 1.51, respectively. Kamlet,
M. J.; Abboud, J.-M.; Abraham, M. H.; Taft, R. W. J. Org. Chem. 1983,
48, 2877.
(9) (a) Azizi, N.; Saidi, M. R. Org. Lett. 2005, 7, 3649. (b) Bonollo, S.;
Fringuelli, F.; Pizzo, F.; Vaccaro, L. Green Chem. 2006, 8, 960.
(10) For details (structure, IUPAC name, and mass spectrometry
based identification and estimation of this side product), see the
Supporting Information.
(17) (a) Chebolu, R.; Kommi, D. N.; Kumar, D.; Bollineni, N.;
Chakraborti, A. K. J. Org. Chem. 2012, 77, 10158. (b) Das, U.; Crousse,
ꢀ
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B
Org. Lett., Vol. XX, No. XX, XXXX