Al(OTf)3-mediated epoxide ring-opening reactions: Toward piperazine-derived physiologically active products

Article abstract of DOI:10.1021/jo9020437

(Chemical Equation Presented) Al(OTf)₃ is a good catalyst for the ring opening of epoxides, forming β-amino alcohols bearing the piperazine motif. Two different strategies were examined, where the glycidyl ether resided on one-half of the molec

Full text of DOI:10.1021/jo9020437

pubs.acs.org/joc
which has to be neutralized with an equimolar amount of
Al(OTf)3-Mediated Epoxide Ring-Opening
Reactions: Toward Piperazine-Derived
Physiologically Active Products
base, generating significant amounts of salts in the process
and rendering the separation of water-soluble amino alco-
hols from the salts nontrivial. In organic-soluble amino
alcohols the purification is not particularly onerous, but salt
byproduct are generated nevertheless.
D. Bradley G. Williams* and Adam Cullen
Piperazine-based β-amino alcohols are known for their
biological activity. They find applications as positive ino-
tropic agents, increasing myocardial contractivity, in the
treatment of cardiac disorders such as congestive heart failure.5-8
Examples include Carsatrin5 and DPI201-1066 (1 and 2,
Figure 1). A notable β-amino alcohol is propranolol (3,
Figure 1), one of the first non-selective β-blockers developed
finding widespread use in the treatment of hypertension.
They have also found applications as Ca2þ antagonists4a-d
and dopamine uptake inhibitors.4a-d The quinoline-based
β-amino alcohols similar to 4 bearing the piperazine motif
(Figure 1) have even found application in the reversal of
multidrug resistance in cancer cells.9 Piperazine 4 showed
activity four times higher than Verapamil, a calcium channel
blocking drug that is known to reverse multidrug resistance
in cancerous cells.9
Department of Chemistry, University of Johannesburg, P.O.
Box 524, Auckland Park 2006, South Africa
bwilliams@uj.ac.za
Received September 22, 2009
In all cases the synthesis included the reaction of a
chlorohydrin with a nucleophile in the presence of stoichio-
metric amounts of base or by the ring opening of an epoxide,
where the epoxide was heated in the presence of the
nucleophile.4a-d,5-9 Obvious advantages of using an epoxide
as a substrate in the generation of 1,2-amino alcohols are the
general atom efficiency of the reaction.
Previous work performed in our laboratories reported the
use of Al(OTf)3 as an efficient Lewis acid catalyst for the ring
opening of epoxides by various alcohols as well as by
aliphatic and aromatic amines (Scheme 1).10 The aminolysis
reaction was found to be regioselective for nucleophilic
attack at the less hindered carbon atom of the epoxide ring,
a feature of SN2-type reaction mechanisms as opposed to a
borderline SN2-type mechanism, which may favor attack at
the more hindered carbon center.10 Catalyst reuse was also
accomplished by simple extraction of the catalyst with water,
once the reaction had been completed, and subsequently
removing the water under reduced pressure and elevated
temperatures. The catalyst was found to retain its activity
through three cycles. Other Lewis acids reported to be active
toward the ring opening of epoxides include Ti(OiPr)4,11
Al(OTf)3 is a good catalyst for the ring opening of ep-
oxides, forming β-amino alcohols bearing the piperazine
motif. Two different strategies were examined, where the
glycidyl ether resided on one-half of the molecule or the
other, allowing insight into a best-case approach for the
ring-opening step. Each half of the molecule contained an
heteroatom that could be used either to attach the glycidyl
moiety or as the nucleophile in the ring-opening reaction,
for the same set of reagents, allowing this approach.
1,2-Amino alcohols represent an important class of organic
molecules. They have found application in medicinal chem-
istry,1 organic synthesis in general, and particularly in asym-
metric synthesis as chiral ligands and auxiliaries.2 These
molecules are usually prepared by reacting an epoxide at
elevated temperatures in the presence of an excess of
an amine.3 Alternatively, a preformed halohydrin can be
reacted with an amine in the presence of a stoichiometric
amount of a base.4a-d The apparent disadvantage of this
method is the generation of undesired hydrohalous acid,
(5) Press, J. B.; Falotico, R.; Hajos, Z. G.; Sawyers, R. A.; Kanojia,
R. M.; Williams, L.; Haertlein, B.; Kauffman, J. A.; Lakas-Weiss, C.; Salata,
J. J. J. Med. Chem. 1992, 35, 4509–4515.
(1) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835–875.
(2) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986–2012.
(3) Deyrup, J. A.; Moyer, C. L. J. Org. Chem. 1969, 34, 175–179.
(4) (a) Kimura, M.; Masuda, T.; Yamada, K.; Mitani, M.; Kubota, N.;
Kawakatsu, N.; Kishii, K.; Inazu, M.; Kiuchi, Y.; Oguchi, K.; Namiki, T.
Bioorg. Med. Chem. 2003, 11, 3953–3963. (b) Kimura, M.; Masuda, T.;
Yamada, K.; Mitani, M.; Kubota, N.; Kawakatsu, N.; Kishii, K.; Inazu, M.;
Kiuchi, Y.; Oguchi, K.; Namiki, T. Bioorg. Med. Chem. 2003, 11, 1621–1630.
(c) Kimura, M.; Masuda, T.; Yamada, K.; Mitani, M.; Kubota, N.;
Kawakatsu, N.; Kishii, K.; Inazu, M.; Kiuchi, Y.; Oguchi, K.; Namiki, T.
Bioorg. Med. Chem. 2004, 12, 3069–3078. (d) Kimura, M.; Masuda, T.;
Yamada, K.; Mitani, M.; Kubota, N.; Kawakatsu, N.; Kishii, K.; Inazu, M.;
Kiuchi, Y.; Oguchi, K.; Namiki, T. Bioorg. Med. Chem. Lett. 2004, 14, 4287–
4290.
(6) Barton, D. L.; Press, J. B.; Hajos, Z. G.; Sawyers, R. A. Tetrahedron:
Asymmetry 1992, 3, 1189–1196.
(7) Butrous, G. S.; Debbas, N. M. G.; Erwin, J.; Davies, D. W.; Keller,
H. P.; Lunnon, M. W.; Nathan, A. W.; Camm, A. J. Eur. Heart J. 1988, 9,
489–497.
(8) Sircar, I.; Haleen, S. J.; Burke, S. E. J. Med. Chem. 1992, 35, 4442–
4449.
(9) Suzuki, T.; Fukazawa, N.; San-nohe, K. J. Med. Chem. 1997, 40,
2047–2052.
(10) (a) Williams, D. B. G.; Lawton, M. Tetrahedron Lett. 2006, 47, 6557–
6560. (b) Williams, D. B. G.; Lawton, M. Org. Biomol. Chem. 2005, 3, 3269–
3272.
(11) Sagawa, S.; Abe, H.; Hase, Y.; Inaba, T. J. Org. Chem. 1999, 64,
4962–4965.
DOI: 10.1021/jo9020437
r
Published on Web 11/16/2009
J. Org. Chem. 2009, 74, 9509–9512 9509
2009 American Chemical Society

Williams and Cullen
JOCNote
FIGURE 2. Key bond disconnections for target β-amino alcohols.
SCHEME 2. Synthesis of S-Glycidyl Ethers
FIGURE 1. Biologically active piperazine-based compounds.
SCHEME 1. Aminolysis of Epoxides Using Al(OTf)3
TaCl5,12 Bi salts,13 ZrCl4,14 Sm(OTf)3,15 CoCl2,16 CuBF4,17
ZnCl2,18 and Sc(OTf)3.5
The present work describes and compares two epoxide
ring-opening approaches to β-amino alcohols containing
piperazine moieties. In the first, the N-C bond (Figure 2,
bond a) is formed in the ring-opening reaction, whereas in
the second the C-X bond (X=O, S, N, Figure 2, bond b) is
formed by this step. In both cases, Al(OTf)3 is used as a
catalyst for the key bond-forming step.
FIGURE 3. O-Glycidyl ethers.
SCHEME 3. Synthesis of O-Glycidyl Ethers
Synthesis of Glycidyl Derivatives. The S-glycidyl ether
substrates (Scheme 2) were prepared according to a literature
procedure.19 Reaction of the thiol with epichlorohydrin in
the presence of KOH as base in a biphasic 1,4-dioxane/water
mixture yielded the desired S-glycidyl ether in good yields.
The O-glycidyl aryl ether substrates 6a-6c (Figure 3) are
commercially available but can be prepared according to a
literature method,20 whereby the phenol is dissolved in
epichlorohydrin and stirred in the presence of K2CO3 and
a phase transfer catalyst (n-Bu4NBr) to give the desired
products. Application of this method to l-menthol resulted
only in low yields (<20%) of the corresponding glycidyl
ether. However, a modification of a two-step protocol set out
in a patent21 led to significant improvements being realized
(40% over two steps, Scheme 3). Here, Al(OTf)3-catalyzed
chlorohydrin formation followed by base-promoted cycliza-
tion led to the desired glycidyl ether 6d. The Al(OTf)3 used as
catalyst could be readily recycled by simple extraction with
water and drying the aqueous layer under vacuum with
heating.22 In this way, the catalyst could be recycled four times
with no loss of activity (the yield of 40% cited is the average of
four runs, using recycled catalyst in the last three runs).
When preparing the glycidyl amines, some problems were
encountered. Synthesis of compound 7a was initially accom-
plished through a method similar to that used for synthesis of
theS-glycidylethers,19 withthemain variationbeingthe use of
acetonitrile as solvent instead of 1,4-dioxane. However, upon
extension of this methodology to the aromatic amines (Table 1,
see entries 2-6 for the structures of the desired compounds),
low yields and mixed reaction products were encountered with
quaternization of the amine being a serious issue. In an
attempt to overcome this problem, a two-step approach was
adopted whereby epichlorohydrin was ring-opened by the
desired amine in an Al(OTf)3-catalyzed reaction to give the
(12) Chandrasekhar, S.; Ramachandar, T.; Prakash, S. J. Synthesis 2000,
1817–1818.
(13) Chakraborti, A. K.; Kondaskar, A. Tetrahehron Lett. 2003, 44,
8315–8317.
(14) Yadav, J. S.; Reddy, A. R.; Narsaiah, A. V.; Reddy, B. V. S. J. Mol.
Catal. A: Chem. 2007, 261, 207–212.
(15) Sundararajan, G.; Vijayakrishna, K.; Varghese, B. Tetrahedron Lett.
2004, 45, 8253–8256.
(16) Kamal, A.; Ramu, R. R.; Azhar, M. A; Khanna, G. B. R. Tetra-
hedron Lett. 2005, 46, 2675–2677.
(17) Pachon, L. D.; Gamez, P.; van Brussel, J. J.; Reedijk, J. Tetrahedron
Lett. 2003, 44, 6025–6027.
(18) Placzek, A. T.; Donelson, J. L.; Trivedi, R.; Gibbs, R. A.; De, S. K.
Tetrahedron Lett. 2005, 46, 9029–9034.
(19) Liu, C.; Kudo, K.; Hashimoto, Y.; Saigo, K. J. Org. Chem. 1996, 61,
494–502.
(20) Zhen-Zhong, L.; Heng-Chang, C.; Sheng-Li, C.; Run-Tao, L. Synth.
Commun. 1994, 24, 833–838.
(21) Akira, A.; Teruyoshi, A.; Takashi, M.; Toshimitsu, H. EP1201635 to
Takasogo Perfumery Co. Ltd., May 02, 2002.
(22) The catalyst was recycled by extracting the organic phase with water
(3 ꢀ 2 mL), removing the water under vacuum by heating to 80 °C, and
drying under high vacuum at 140 °C. Final drying may also be effected at
120 °C under a flow of dry nitrogen.
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Williams and Cullen
JOCNote
TABLE 1. Yields of N-Glycidyl Amines for the Two-Step Process
TABLE 2. Comparison of Methods A and B for Obtaining β-Amino
Alcohols
a5 mol % Al(OTf)3 catalyst. b1 mol % Al(OTf)3 catalyst.
a10 mol % Al(OTf)3 catalyst. b5 mol % Al(OTf)3 catalyst.
SCHEME 4. Synthesis of N-Glycidyl Amines
FIGURE 4. Proposed metal chelate structure of aluminum catalyst
and heteroatom glycidyl ether.
Inspection of the comparative results detailed in Table 2
reveals that use of a piperazine-based amine to ring-open an
heteroatom glycidyl ether (Method A) is the favored method
for the preparation of the desired β-amino alcohols. The
improved activity of the catalyst under these conditions may
be rationalized by invoking the formation of a deactivated
metal-glycidyl epoxide chelate species (Figure 4). Here,
the positive charge that is transferred to the R-carbon of
the oxirane is diminished by chelation of the heteroatom of
the glycidyl ether to the aluminum ion, as has been pre-
viously suggested.10 This effect is pronounced with glycidyl
ethers bearing a more strongly basic (harder Lewis base)
heteroatom functionality. In the case of entries 1-4 in
Table 2 where sulfur is the heteroatom, the N-glycidyl ether
bearing a basic nitrogen (Table 2, entries 2 and 4) would
significantly deactivate the catalyst in the intermediate
chelated state compared to the analogous the S-glycidyl
ethers (Table 2, entries 1 and 3). This is because of unfavor-
able hard-soft Lewis acid-Lewis base interactions in
the latter instance, which demonstrates the hard-soft
acid-base theory set forth by Pearson.23 The difference
in outcome is more pronounced when the O-glycidyl ethers
are compared to the N-glycidyl ethers (Table 2, entries
5-8), and it becomes clear that Method A is superior to
Method B.
SCHEME 5. Approaches for Obtaining β-Amino Alcohols
intermediate halohydrin, which was subsequently dehydroha-
logenated with an aqueous base to yield the desired N-glycidyl
amine, in a one-pot process (Scheme 4). The use of Al(Otf)3 as
a catalyst for the aminolysis of epoxides has recently been
reported.10 This method yielded the desired N-glycidyl amines
in moderate to excellent yields (Table 1) after two steps. The
two-step process was found to be a significant improvement
on the direct one-step KOH-mediated glycidyl amine forma-
tion for aromatic amines.
Epoxide Aminolysis Method Evaluation. Two different
approaches for obtaining the desired β-amino alcohol were
examined (Scheme 5). The first involved reaction of the
glycidyl ether or amine with a piperazine-based amine
nucleophile (Scheme 5, Method A). The second involved
the reaction of an heteroatom nucleophile with a preformed
piperazine-based glycidyl amine (Scheme 5, Method B).
The difference in the two methods employed to obtain the
desired β-amino alcohols is somewhat less obvious when
N-glycidyl amines and nitrogen nucleophiles are used
(Table 2, entries 9 and 10), but Method A still dominates.
(23) Pearson, R. G.; Songstad, J. J. Am. Chem. Soc. 1967, 89, 1827–1836.
J. Org. Chem. Vol. 74, No. 24, 2009 9511

Williams and Cullen
JOCNote
TABLE 3. Ring-Opening of Various Epoxides with Piperazine-Based
Nucleophiles
attached to the less nucleophilic heteroatom while retaining
the more nucleophilic heteroatom free for the ring-opening
reaction (i.e., a preference for Method A over Method B,
Scheme 5). This technique tolerates a range of nucleophiles
that includes those bearing S, O, and N atoms and is shown
to be readily scalable.
entry glycidyl substrate
8
XR
R
yield (%)
1a
5a
5a
5b
5b
6a
6b
8a SPh
8b SPh
8a SBn
8b SBn
8a OPh
8a O-1-naphthyl
8a O-4-C6H4Cl
8a O-tBu
H
F
H
F
9a: 82
9f: 75
9b: 86
9g: 66
9c: 73
9h: 88
9d: 85
9i: 88
9j: 79
9k: 72
9e: 78
9l: 86
9m: 88
9n: 81
9o: 67
2a
3a
4a
5b
H
H
H
H
H
H
H
H
H
H
H
Experimental Section
6b
7b
6c
Typical Procedure for the Preparation of N-Glycidyl Ethers.
(4-Isopropyl-phenyl)-oxiranylmethyl-amine (7f). To a mixture of
Al(OTf)3 (0.024 g, 50 μmol) and 4-isopropyl-aniline (0.137 mL,
1 mmol) in toluene (5 mL) was added epichlorohydrin (0.081 mL,
1 mmol). The mixture was stirred at 70 °C for 30 min, after which
it was cooled to room temperature and KOH (0.112 g, 20 mmol)
and (n-Bu)4NBr (0.032 g, 100 μmol) dissolved in water (5 mL)
were added. The mixture was stirred for 2.5 h at room tempera-
ture, after which it was extracted with DCM (3ꢀ 5 mL) and the
combined organic layers washed with water (2ꢀ5 mL) and then
dried with magnesium sulfate. The excess organic solvent was
removed under reduced pressure, and the resulting residue was
purified by column chromatography (silica gel, Merck Kieselgel
60 230-400 mesh, 4:1 hexane/ethyl acetate) to afford 7f (0.115 g,
60%) as a yellow oil: TLC Rf=0.31 (4:1 hexane/ethyl acetate); 1H
NMR (300 MHz, CDCl3) δ 7.06 (d, 2H, J=8.7 Hz), 6.60 (d, 2H,
J = 8.7 Hz), 3.78 (br s, 1H), 3.51 (dd, 1H, J = 15.5, 4.7 Hz),
3.24-3.18 (m, 2H), 2.86-2.77 (m, 2H), 2.69 (dd, 1H, J=5.1,
2.4 Hz), 1.21 (d, 6H, J=7.2 Hz); 13C NMR (75 MHz, CDCl3) δ
145.8, 138.4, 127.1, 113.0, 51.0, 45.4, 45.3, 33.1, 24.2; IR νmax
(ATR) 3305, 2957, 1614, 1518, 1361, 1196 cm-1; ESI-MS m/z
(relativeintensity) 192([M þ H]þ, 5), 167(30), 149 (65), 138 (100),
117 (25), 110 (15); ESI HRMS [M þ H]þ calcd for C12H18ON,
192.1388; found, 192.1385.
Typical Procedure for the Ring Opening of Epoxides. 1-(4-
Benzhydryl-piperazin-1-yl)-3-(4-isopropyl-phenylamino)-propan-2-
ol (9o). To a mixture of 8a (0.2 g, 0.792 mmol) and Al(OTf)3
(0.038 g, 0.079 mmol) in toluene(2 mL) was added 7f (0.151 g,
0.792 mmol). The reaction mixture was allowed to stir at 70 °C
for 5 h. The reaction was then quenched by the addition of
aqueous sodium bicarbonate (5 mL). The reaction mixture was
extracted with DCM (3 ꢀ 5 mL), and the combined organic
layers were washed with water (2 ꢀ 5 mL) and dried with
magnesium sulfate. The excess organic solvent was removed
under reduced pressure, and the resulting residue purified
by column chromatography (silica gel, Merck Kieselgel 60
230-400 mesh, 1:1 hexane/ethyl acetate-9:1 DCM/MeOH) to
afford 9o (0.236 g, 67%) as a yellow oil: TLC Rf = 0.41 (1:1
hexane/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.46
(d, 4H, J=7.4 Hz), 7.31 (t, 4H, J=7.4 Hz), 7.24-7.19 (t, 2H,
J=7.4 Hz), 6.95 (d, 2H, J=8.4 Hz), 6.48 (d, 2H, J=8.4 Hz),
4.12 (s, 1H), 3.87-3.79 (m, 1H), 3.13 (dd, 1H, J=12.4, 3.6 Hz),
2.92 (dd, 1H, J = 12.4, 6.5 Hz), 2.71 (sp, 1H, J = 6.9 Hz),
2.60-2.50 (m, 2H), 2.45-2.25 (m, 8H), 1.11 (d, 6H, J=6.9 Hz);
13C (75 MHz, CDCl3) δ 146.3, 142.6, 138.1, 128.5, 127.8, 127.0,
126.9, 113.1, 76.1, 65.1, 61.4, 53.4, 51.9, 47.9, 33.1; IR (ATR)
3411, 2963, 2797, 1615, 1519, 1451, 1138 cm-1; ESI-MS m/z
(relative intensity) 444 ([M þ H]þ, 100), 167 ([Ph2CH]þ, 10);
ESI HRMS [M þ H]þ calcd for C29H38ON3, 444.3015; found,
444.3007
8b
c
9b
8a O-allyl
c
10b
11b
12a
13a
14a
15a
6d
7b
7c
7d
7e
7f
8a O-menthyl
8a N(CH3)Ph
8a NH-4-C6H4Cl
8a NHPh
8a NH-4-C6H4OCH3
8a NH-4-C6H4-iPr
a10 mol % Al(OTf)3 catalyst. b5 mol % Al(OTf)3 catalyst. cCommer-
cially available glycidyl ethers.
SCHEME 6. General Method for Obtaining Piperazine-Based
β-Amino Alcohols
The difference in yields that is observed can be explained by
the basicity and nucleophilicity of the two types of amines
used, i.e., aromatic as opposed to aliphatic amines. To
elaborate, an aromatic amine with significantly reduced
basicity would be best suited for use as the heteroatom
functionality of the N-glycidyl amine, leading to a less-
deactivated intermediate chelate state (Figure 4), whereas
an aliphatic amine with better nucleophilicity would be best
suited for use as the nucleophile.
Epoxide Aminolysis Method Application. Application of
Method A (Scheme 5) to the ring opening of various epoxides
bearing different heteroatom functionalities provided a range
of β-amino alcohols in good yields (Scheme 6, Table 3).
The reaction to produce 9e was scaled up and also
subjected to recycling of the Al(Otf)3 catalyst. When the
scale was increased to 10.00 g (0.040 mol) of the piperazine
substrate 8a and 6.45 g (0.40 mol) of N-glycidyl ether 7b,
the average yield of three runs was 81%. The second and
third runs were performed with recycled catalyst.22
To place these results into context, the reactions to gen-
erate sulfide products 9a, 9b, 9g, and 9f from the correspond-
ing S-glycidyl ethers according to Method A were performed
in the absence of catalyst, yielding the products in yields of
only 3%, 13%, 9%, and 8%, respectively, under otherwise
identical conditions. These results clearly exemplified the
need for the catalyst.
To summarize, aluminum(III) triflate was found to be an
effective recyclable catalyst for the ring opening of hetero-
atom-substituted glycidyl ethers to give the corresponding
piperazine-based β-amino alcohols. This work establishes
that the optimum approach (determined on the basis of
comparisons of two synthetic directions toward the same
target molecules) involves the use of the glycidyl entity
Acknowledgment. We thank the University of Johannesburg,
Sasol, and THRIP for generous funding.
Supporting Information Available: Analytical characteriza-
tion data, 1H and 13C NMR spectra of all compounds, and
reference list for known compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
9512 J. Org. Chem. Vol. 74, No. 24, 2009