Microwave-assisted ring opening of epoxides in solvent-free conditions

Article abstract of DOI:10.1080/00397910500522025

The reaction of aryloxymethyl epoxide with anilines under solvent-free conditions and microwave irradiation affords high yields of 1-arylamino-3- aryloxypropan-2-ols. The reaction was rapid and completely regioselective. Copyright Taylor & Francis Group,

Full text of DOI:10.1080/00397910500522025

Synthetic Communicationsw, 36: 1353–1359, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500522025
Microwave-Assisted Ring Opening of
Epoxides in Solvent-Free Conditions
Wei Tan, Bao-Xiang Zhao, Lei Sha, Pei-Fu Jiao,
and Mao-Sheng Wan
Institute of Organic Chemistry, School of Chemistry and Chemical
Engineering, Shandong University, Jinan, China
Lei Su
Institute of Pesticide, Shandong, Jinan, China
Dong-Soo Shin
Department of Chemistry and Research Institute of Natural Sciences,
Changwon National University, Changwon, Korea
Abstract: The reaction of aryloxymethyl epoxide with anilines under solvent-free con-
ditions and microwave irradiation affords high yields of 1-arylamino-3-aryloxypropan-
2-ols. The reaction was rapid and completely regioselective.
Keywords: b-Amino alcohols, epoxide, microwave irradiation, ring opening
INTRODUCTION
b-Amino alcohols are a very important class of organic compounds and have
considerable application in medicinal chemistry.[1] The conventional route for
the synthesis of these compounds involves ring opening of epoxides at
elevated temperatures.[1,2] These reactions are usually carried out in a
solvent, requiring a large excess of amines or anilines and many hours of
reflux temperature, which is environmentally unfriendly. Furthermore, the
Received in Japan May 30, 2005
Address correspondence to Bao-Xiang Zhao, Institute of Organic Chemistry,
School of Chemistry and Chemical Engineering, Shandong University, Jinan
250100, China. E-mail: bxzhao@sdu.edu.cn
1353

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W. Tan et al.
cleavage of epoxides by aniline to obtain N-aryl-b-aminoalcohol is much
more difficult using classical procedures.
Recently, the use of catalysts to carry out these reactions under mild con-
ditions has been developed, but this still needs expensive catalysts and large
excess of anilines and solvents.[3–6] We have reported earlier regioselective
ring opening of aryloxymethyl epoxide by anilines in the presence of
alumina to afford N-aryl aminoalcohol in moderate to good yields.[7]
However, the scope of the reaction is limited as it requires prolonged
heating in a solvent, and the yield is much lower when deactivated aniline
is used. Because of these reasons, further investigation was necessary to
overcome these difficulties, and here we have chosen microwave as the
energy source to carry out this reaction.
RESULTS AND DISCUSSION
The application of microwave-assisted reactions in organic synthesis is well
documented in the literature.[8,9] Compared to conventional heating,
microwave irradiation often gives greatly enhanced reaction rates and fewer
by-products. In this article, we report a simple and fast procedure for ring
opening of epoxides by anilines under microwave irradiation in solvent-free
conditions. These reactions are performed in a domestic microwave oven
because of its low cost and ready availability. Gratifyingly, we obtained the
desired N-aryl-b-aminoalcohol in good yields in only 10 min using the
microwave-assisted protocol. It is interesting that Kamal reported recently a
similar reaction system, the cleavage of epoxides with aromatic amines by
ultrasonic activated method.[10]
In a typical experiment aryloxymethyl epoxide 1 and anilines 2 were
mixed in an open vessel and irradiated at 380 W for 10 min without
any solvent; the complete reaction took place, leading to 1-arylamino-3-ary-
loxypropan-2-ols 3 (Scheme 1). The reaction was completely regioselective
because no other isomer was detected. The different entries and isolated
yields in comparison with earlier reports are given in Table 1.
As it can be seen from Table 1, the reaction was carried out using five
different aromatic amines. This process worked well for all types of
Scheme 1.

Epoxide Ring Opening
1355
Table 1. 1-Arylamino-3-aryloxypropan-2-ols prepared by the microwave-irradiation
method
Entry
R1
R2
Major product
Yielda (%)
Yieldb (%)
1
2
H
4-Cl
4-Cl
3a
3b
3c
3d
3e
3f
49
66
46
77
67
50
74
69
57
54
61
82
76
76
70
43
60
—
—
50
61
51
—
—
50
—
—
—
—
—
4-OMe
3-Cl
3
4-Cl
4-Cl
4
2-OMe
4-Cl
5
4-Cl
6
H
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
2-OMe
2-OMe
2-OMe
2-OMe
2-OMe
7
4-OMe
3-Cl
3g
3h
3i
8
9
2-OMe
4-Cl
10
11
12
13
14
15
3j
H
3k
3l
4-OMe
3-Cl
3m
3n
3o
2-OMe
4-Cl
aIsolated yields of 3.
bYields reported in Ref.[7]
aromatic amines, regardless of their electronic and steric nature, giving the
desired products with complete regioselectivity. The yields are better than
or as good as our previously reported results.[7] The moderate yields of 3a,
3c, and 3f may be partially due to the evaporation of the starting epoxide
during microwave heating, because no epoxide was found in the product
after microwave irradiation.
In summary, we have achieved an efficient microwave-assisted protocol
for the regioselective ring-opening reaction of aryloxymethyl epoxides with
anilines to afford 1-arylamino-3-aryloxypropan-2-ols. Compared to previous
methods, this procedure uses more friendly reaction conditions and shorter
reaction times, generally gives higher yields, and is applied to a larger set
of substrates. We are currently engaged in investigating other nucleophiles
for the ring-opening reactions of aryloxymethyl epoxides.
EXPERIMENTAL
General
IR spectra were recorded with an IR spectrophotometer Nicolet-20Sx FT-IR.
1H NMR spectra were recorded on Bruker Avance 400 M spectrometer using

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W. Tan et al.
TMS as internal reference and CDCl3 as solvent. The chemical shifts are
expressed as d ppm, and coupling constants are in Hz. MS spectra were
obtained on an API4000 mass spectrograph. Elemental analyses were
obtained on an Elementar VarioEL-3 elemental analyzer.
General Method for the Preparation of 1-Arylamino-3-
aryloxypropan-2-ol
A mixture of aryloxymethyl epoxide (1 mmol) and aromatic amine (1.3 mmol)
was placed in an open vessel. Then the mixture was irradiated with mid-power
(380 W) in a conventional microwave oven for 10 min. After the mixture was
cooled to room temperature, the residue was purified by flash-column chrom-
atography using silica gel to afford compound 3. The structures of all the
newly synthesized compounds were assigned by IR, NMR, and mass
spectral data.
Data
1-(4-Chlorophenoxy)-3-(phenylamino)propan-2-ol (3a): White solid; mp
1
75–788C; H NMR: d ¼ 3.30 (dd, J ¼ 13.0 and 7.2 Hz, 1H, CH2-N), 3.45
(dd, J ¼ 13.0 and 4.3 Hz, 1H, CH2-N), 4.05 (m, 2H, CH2-O), 4.28 (m, 1H,
CH-OH), 6.72 (m, 2H, Ar), 6.78 (m, 1H, Ar), 6.85 (m, 2H, Ar), 7.23
;
(m, 4H, Ar); IR (KBr) y: 3414, 3265, 2924, 1601, 1492, 1245, 1092 cm21
EI-MS (m/z): 278.1 (Mþ þ H); anal. calcd. for C15H16ClNO2: C, 64.87; H,
5.81; N, 5.04. Found C, 64.68; H, 5.98; N, 5.10.
1-(4-Chlorophenoxy)-3-(4-methoxyphenylamino)propan-2-ol (3b): White
1
solid; mp 89–918C; H NMR: d ¼ 3.25 (dd, J ¼ 12.9 and 7.3 Hz, 1H, CH2-
N), 3.39 (dd, J ¼ 12.9 and 4.1 Hz, 1H, CH2-N), 3.75 (s, 3H, O-CH3), 4.02
(m, 2H, CH2-O), 4.25 (m, 1H, CH-OH), 6.70 (m, 2H, Ar), 6.80 (m, 2H, Ar),
6.85 (m, 2H, Ar), 7.24 (m, 2H, Ar); IR (KBr) y: 3438, 3259, 2936, 1515,
1492, 1248, 1038 cm21; EI-MS (m/z): 308.2 (Mþ þ H); anal. calcd. for
C16H18ClNO3: C, 62.44; H, 5.89; N, 4.55. Found C, 62.32; H, 5.98; N, 4.63.
1-(4-Chlorophenoxy)-3-(3-chlorophenylamino)propan-2-ol (3c): White
1
solid; mp 76–778C; H NMR: d ¼ 3.28 (dd, J ¼ 13.0 and 7.2 Hz, 1H, CH2-
N), 3.41 (dd, J ¼ 13.0 and 4.2 Hz, 1H, CH2-N), 4.00 (dd, J ¼ 9.4 and
6.1 Hz, 1H, CH2-O), 4.03 (dd, J ¼ 9.4 and 4.2 Hz, 1H, CH2-O), 4.25
(m, 1H, CH-OH), 6.58 (m, 1H, Ar), 6.68 (t, J ¼ 2.0, 1H, Ar), 6.73 (m, 1H,
Ar), 6.85 (m, 2H, Ar), 7.10 (t, J ¼ 8.0, 1H, Ar), 7.30 (m, 2H, Ar); IR (KBr)
y: 3414, 3289, 2927, 1598, 1490, 1246, 1088 cm21; EI-MS (m/z): 313.1
(Mþ þ H); anal. calcd. for C15H15Cl2NO2: C, 57.71; H, 4.84; N, 4.49.
Found C, 57.86; H, 4.79; N, 4.43.

Epoxide Ring Opening
1357
1-(4-Chlorophenoxy)-3-(2-methoxyphenylamino)propan-2-ol (3d): Oil;
1H NMR: d ¼ 3.30 (dd, J ¼ 13.1 and 7.3 Hz, 1H, CH2-N), 3.45 (dd,
J ¼ 13.1 and 4.3 Hz, 1H, CH2-N), 3.85 (s, 3H, O-CH3), 4.05 (m, 2H, CH2-
O), 4.28 (m, 1H, CH-OH), 6.73 (m, 2H, Ar), 6.80 (m, 1H, Ar), 6.87 (m, 3H,
Ar), 7.25 (m, 2H, Ar); IR (film) y: 3414, 2935, 1601, 1492, 1246
1028 cm21; EI-MS (m/z): 308.7 (Mþ þ H); anal. calcd. for C16H18ClNO3:
C, 62.44; H, 5.89; N, 4.55. Found C, 62.49; H, 5.76; N, 4.61.
1-(4-Chlorophenoxy)-3-(4-chlorophenylamino)propan-2-ol (3e): White
1
solid; mp 83–848C; H NMR: d ¼ 3.25 (dd, J ¼ 12.9 and 7.2 Hz, 1H, CH2-
N), 3.40 (dd, J ¼ 12.9 and 4.3 Hz, 1H, CH2-N), 4.05 (m, 2H, CH2-O), 4.20
(m, 1H, CH-OH), 6.58 (m, 2H, Ar), 6.90 (m, 2H, Ar), 7.10 (m, 2H, Ar),
7.30 (m, 2H, Ar); IR (KBr) y: 3551, 3381, 2927, 1599, 1495, 1243,
1092, 755, 692 cm21; EI-MS (m/z): 313.1 (Mþ þ H); anal. calcd. for
C15H15Cl2NO2: C, 57.71; H, 4.84; N, 4.49. Found C, 57.76; H, 4.90; N, 4.42.
1-(4-Nitrophenoxy)-3-(phenylamino)propan-2-ol (3f): White solid; mp
1
125–1278C; H NMR: d ¼ 3.35 (dd, J ¼ 13.2 and 7.1 Hz, 1H, CH2-N),
3.47 (dd, J ¼ 13.2 and 4.3 Hz, 1H, CH2-N), 4.15 (m, 2H, CH2-O), 4.33
(m, 1H, CH-OH), 6.72 (m, 2H, Ar), 6.80 (m, 1H, Ar), 7.00 (m, 2H, Ar),
7.20 (m, 2H, Ar), 8.20 (m, 2H, Ar); IR (KBr) y: 3438, 3268, 2926, 1593,
1501, 1349, 1265, 1114, 1016, 751, 698 cm21; EI-MS (m/z): 289.4
(Mþ þ H); anal. calcd. for C15H16N2O4: C, 62.49; H, 5.59; N, 9.72. Found
C, 62.28; H, 5.68; N, 9.79.
1-(4-Methoxyphenylamino)-3-(4-nitrophenoxy)propan-2-ol (3g): White
1
solid; mp 123–1248C; H NMR: d ¼ 3.25 (dd, J ¼ 12.9 and 7.4 Hz, 1H,
CH2-N), 3.40 (dd, J ¼ 12.9 and 4.0 Hz, 1H, CH2-N), 3.75 (s, 3H, O-CH3),
4.15 (m, 2H, CH2-O), 4.30 (m, 1H, CH-OH), 6.80 (m, 4H, Ar), 6.97 (m, 2H,
Ar), 8.20 (m, 2H, Ar); IR (KBr) y: 3440, 3263, 2931, 1594, 1507, 1352,
1274, 1030, 751, 665 cm21; EI-MS (m/z): 319.3 (Mþ þ H); anal. calcd. for
C16H18N2O5: C, 60.37; H, 5.70; N, 8.80. Found C, 60.28; H, 5.69; N, 8.71.
1-(3-Chlorophenylamino)-3-(4-nitrophenoxy)propan-2-ol (3h): White
1
solid; mp 95–978C; H NMR: d ¼ 3.33 (dd, J ¼ 12.9 and 6.7 Hz, 1H, CH2-
N), 3.42 (dd, J ¼ 12.9 and 3.1 Hz, 1H, CH2-N), 4.15 (m, 2H, CH2-O), 4.32
(m, 1H, CH-OH), 6.58 (d, J ¼ 8.2 Hz, 1H, Ar), 6.66 (s, 1H, Ar), 6.74
(d, J ¼ 7.9 Hz, 1H, Ar), 7.00 (d, J ¼ 8.9 Hz, 2H, Ar), 7.10 (t, J ¼ 7.9 Hz,
1H, Ar), 8.21 (d, J ¼ 8.7 Hz, 2H, Ar); IR (KBr) y: 3439, 3278, 2923, 1592,
1509, 1340, 1264, 1109, 752, 666 cm21; EI-MS (m/z): 295.7 (Mþ þ H);
anal. calcd. for C15H15ClN2O4: C, 55.82; H, 4.68; N, 8.68. Found C, 55.98;
H, 4.59; N, 8.63.
1-(2-Methoxyphenylamino)-3-(4-nitrophenoxy)propan-2-ol (3i): Oil; 1H
NMR: d ¼ 3.38 (dd, J ¼ 13.2 and 7.0 Hz, 1H, CH2-N), 3.48 (dd, J ¼ 13.2

1358
W. Tan et al.
and 4.6 Hz, 1H, CH2-N), 3.87 (s, 3H, O-CH3), 4.18 (m, 2H, CH2-O), 4.35
(m, 1H, CH-OH), 6.78 (m, 3H, Ar), 6.89 (m, 1H, Ar), 7.0 (m, 2H, Ar), 8.21
(m, 2H, Ar); IR (film) y: 3410, 2936, 1592, 1510, 1341, 1261, 1111,
741 cm21; EI-MS (m/z): 319.2 (Mþ þ H); anal. calcd. for C16H18N2O5: C,
60.37; H, 5.70; N, 8.80. Found C, 60.21; H, 5.83; N, 8.83.
1-(4-Chlorophenylamino)-3-(4-nitrophenoxy)propan-2-ol (3j): White
1
solid; mp 100–1028C; H NMR: d ¼ 3.30 (dd, J ¼ 13.1 and 7.1 Hz, 1H,
CH2-N), 3.42 (dd, J ¼ 13.1 and 4.3 Hz, 1H, CH2-N), 4.15 (m, 2H, CH2-O),
4.31 (m, 1H, CH-OH), 6.62 (m, 2H, Ar), 6.98 (m, 2H, Ar), 7.15 (m, 2H,
Ar), 8.20 (m, 2H, Ar); IR (KBr) y: 3415, 3304, 2923, 1592, 1509, 1268,
1111, 819, 752 cm21; EI-MS (m/z): 323.5 (Mþ þ H); anal. calcd. for
C15H15ClN2O4: C, 55.82; H, 4.68; N, 8.68. Found C, 55.99; H, 4.63; N, 8.60.
1-(2-Methoxyphenoxy)-3-(phenylamino)propan-2-ol (3 k): White solid;
1
mp 64–668C; H NMR: d ¼ 3.34 (dd, J ¼ 12.7 and 6.4 Hz, 1H, CH2-N),
3.50 (dd, J ¼ 12.7 and 4.3 Hz, 1H, CH2-N), 4.15 (m, 2H, CH2-O), 4.31
(m, 1H, CH-OH), 6.52 (m, 1H, Ar), 6.60 (m, 2H, Ar), 6.94 (m, 4H, Ar),
7.07 (m, 2H, Ar); IR (KBr) y: 3414, 3301, 2923, 1592, 1509, 1268, 1085,
821, 749 cm21; EI-MS (m/z): 274.4 (Mþ þ H); anal. calcd. for C16H19NO3:
C, 70.31; H, 7.01; N, 5.12. Found C, 70.26; H, 7.03; N, 5.16.
1-(2-Methoxyphenoxy)-3-(4-methoxyphenylamino)propan-2-ol
(3l):
1
White solid; mp 66–688C; H NMR: d ¼ 3.26 (dd, J ¼ 12.6 and 6.4 Hz,
1H, CH2-N), 3.42 (dd, J ¼ 12.6 and 4.4 Hz, 1H, CH2-N), 3.76 (s, 3H,
O-CH3), 3.88 (s, 3H, O-CH3), 4.08 (dd, J ¼ 9.8 and 6.3 Hz, 1H, CH2-O),
4.16 (dd, J ¼ 9.8 and 3.6 Hz, 1H, CH2-O), 4.28 (m, 1H, CH22OH), 6.72
(m, 2H, Ar), 6.81 (m, 2H, Ar), 6.95 (m, 4H, Ar); IR (KBr) y: 3435, 3379,
2933, 1593, 1514, 1253, 1124, 822, 746 cm21;EI-MS (m/z): 304.2
(Mþ þ H); anal. calcd. for C17H21NO4: C, 67.31; H, 6.98; N, 4.62. Found
C, 67.19; H, 7.03; N, 4.68.
1-(3-Chlorophenylamino)-3-(2-methoxyphenoxy)propan-2-ol (3m): White
solid; mp 53–548C; 1H NMR: d ¼ 3.24 (dd, J ¼ 12.7 and 6.4 Hz, 1H, CH2-N),
3.42 (dd, J ¼ 12.7 and 4.5 Hz, 1H, CH2-N), 3.88 (s, 3H, O-CH3), 4.05 (dd,
J ¼ 9.8 and 6.3 Hz, 1H, CH2-O), 4.16 (dd, J ¼ 9.8 and 3.6 Hz, 1H, CH2-O),
4.23 (m, 1H, CH-OH), 6.52 (m, 1H, Ar), 6.66 (m, 2H, Ar), 6.91 (m, 3H, Ar),
6.99 (m, 1H, Ar), 7.07 (m, 1H, Ar); IR (KBr) y: 3421, 3300, 2912, 1601,
1508, 1256, 1127, 822, 738 cm21; EI-MS (m/z): 308.8 (Mþ þ H); anal. calcd.
for C16H18ClNO3: C, 62.44; H, 5.89; N, 4.55. Found C, 62.29; H, 5.95; N, 4.61.
1-(2-Methoxyphenoxy)-3-(2-methoxyphenylamino)propan-2-ol (3n): Oil;
1HNMR: d ¼ 3.50 (dd, J ¼ 12.6 and 7.1 Hz, 1H, CH2-N), 3.65 (dd,
J ¼ 12.6 and 3.7 Hz, 1H, CH2-N), 3.85 (s, 3H, O-CH3), 4.10 (m, 2H, CH2-
O), 4.50 (m, 1H, CH22OH), 6.95 (m, 4H, Ar), 7.13 (m, 1H, Ar), 7.29

Epoxide Ring Opening
1359
(m, 1H, Ar), 7.38 (m, 1H, Ar), 7.50 (m, 1H, Ar); IR (film) y: 3438, 3396, 2935,
1594, 1505, 1254, 826, 746 cm21; EI-MS (m/z): 304.3 (Mþ þ H); anal. calcd.
for C17H21NO4: C, 67.31; H, 6.98; N, 4.62. Found C, 67.19; H, 7.26; N, 4.61.
1-(4-Chlorophenylamino)-3-(2-methoxyphenoxy)propan-2-ol (3o): White
1
solid; mp 70–728C; HNMR: d ¼ 3.25 (dd, J ¼ 12.7 and 6.4 Hz, 1H, CH2-
N), 3.40 (dd, J ¼ 12.7 and 4.4 Hz, 1H, CH2-N), 3.89 (s, 3H, O-CH3), 4.07
(dd, J ¼ 9.8 and 6.4 Hz, 1H, CH2-O), 4.15 (dd, J ¼ 9.8 and 3.5 Hz, 1H,
CH-OH), 4.24 (m, 1H, CH-OH), 6.62 (m, 2H, Ar), 6.92 (m, 3H, Ar), 7.00
(m, 1H, Ar), 7.13 (m, 2H, Ar); IR (KBr) y: 3433, 3387, 2931, 1599, 1505,
1253, 1125, 744 cm21; EI-MS (m/z): 308.8 (Mþ þ H); anal. calcd. for
C16H18ClNO3: C, 62.44; H, 5.89; N, 4.55. Found C, 62.58; H, 5.83; N, 4.39.
ACKNOWLEDGMENT
Financial support from the key program of Ministry of Education of China is
gratefully acknowledged.
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