Efficient preparation of biologically important 1,2-amino alcohols

Article abstract of DOI:10.1080/00397911.2011.603876

An efficient three-step methodology developed for the preparation of 1,2-amino alcohols. In the first step a rapid coupling between bromoketones and potassium phthalimide in ionic liquid produced-phthalimido ketones in quantitative yields, which is followed by a facile reduction using NaCNBH ³ in acetic acid to give corresponding phthalimido alcohols and finally effecting hydrazinolysis in water at 60C to yield biologically important 1,2-amino alcohols.

Full text of DOI:10.1080/00397911.2011.603876

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Efficient Preparation of Biologically
Important 1,2-Amino Alcohols
Pankaj Gupta a b , Abdul Rouf a , Bhahwal A. Shah a , Debaraj
Mukherjee a & Subhash C. Taneja a
a Indian Institute of Integrative Medicine (CSIR), Jammu, India
b Department of Chemistry, Govt. Degree College, Kathua, J & K,
India
Accepted author version posted online: 13 Feb 2012.Version of
record first published: 08 Nov 2012.
To cite this article: Pankaj Gupta , Abdul Rouf , Bhahwal A. Shah , Debaraj Mukherjee & Subhash
C. Taneja (2013): Efficient Preparation of Biologically Important 1,2-Amino Alcohols, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
43:4, 505-519
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Synthetic Communications1, 43: 505–519, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.603876
EFFICIENT PREPARATION OF BIOLOGICALLY
IMPORTANT 1,2-AMINO ALCOHOLS
Pankaj Gupta,1,2 Abdul Rouf,1 Bhahwal A. Shah,1
Debaraj Mukherjee,1 and Subhash C. Taneja1
1Indian Institute of Integrative Medicine (CSIR), Jammu, India
2Department of Chemistry, Govt. Degree College, Kathua, J & K, India
GRAPHICAL ABSTRACT
Abstract An efficient three-step methodology developed for the preparation of 1,2-amino alco-
hols. In the first step a rapid coupling between bromoketones and potassium phthalimide in ionic
liquid produced a-phthalimido ketones in quantitative yields, which is followed by a facile
reduction using NaCNBH3 in acetic acid to give corresponding phthalimido alcohols and finally
effecting hydrazinolysis in water at 60 ꢀC to yield biologically important 1,2-amino alcohols.
Keywords b-Amino alcohols; hydrazinolysis; ionic liquid; NaCNBH3; a-phthalimidoke-
tones
INTRODUCTION
The b-amino alcohol moiety is a widespread structural motif in natural and
synthetic biologically active molecules.[1] This can also be used as versatile chiral
building block and chiral catalyst or ligand in a variety of asymmetric synthesis, such
as enantioselective dialkylzinc addition to aldehydes[2] and in Henry reactions.[3] In
view of their high requirements in organic synthesis, numerous methods have been
reported for their preparation. Prominent among them are epoxide ring opening
with an amine in the presence of catalysts,[4,5] selective reduction of oxazolidinones,[6]
and intermolecular Pd-catalyzed aminoacetoxylation of alkenes with phthalimide.[7]
The amino ketone reduction strategy is undoubtedly more attractive than epoxide
ring opening, because it avoids the handling of the transition-metal catalysts.
The selective reduction of protected amino ketone derivatives is preferred
because of their good stability.[8] However, their precursors (amino ketones) are dif-
ficult to isolate as free amines because of the formation of Schiff bases. One way of
Received April 7, 2011.
Address correspondence to Subhash C. Taneja, Indian Institute of Integrative Medicne (CSIR),
Canal Road, Jammu 180001, India. E-mail: sctaneja@iiim.ac.in
505

506
P. GUPTA ET AL.
overcoming the difficulty of isolation is to protect the amino alcohols with a suitable
protecting group such as phthalimide, which is a comparatively stable. Moreover,
the phthalimide analogs are reported to have anti-inflammatory,[9] analgesic,[10]
anticonvulsant,[11] herbicidal,[12] and insecticidal[13] activities.
Most of the methodologies used for the reduction of a-phthalimido ketones
suffer from the formation of side products because of the labile phthalimide moiety.
The hydride attack on the phthaloyl moiety leads to the formation of major side pro-
ducts during sodium borohydride reduction.[14] However, transition-metal catalysts
at higher temperature and pressure may be used for this purpose.[15]
RESULTS AND DISCUSSION
Our three-step strategy for the preparation of 1,2-amino alcohols was initiated
with the preparation of a-phthalimido ketones via coupling of a-bromoketones and
potassium phthalimide in dimethylformamide (DMF) (Scheme 1).[15] The method-
ology required longer duration (ꢁ12 h) and the final yields in our hands varied
between 70 and 85%. Therefore, the present strategy also envisaged the development
of a more efficient method for preparation of a-phthalimido ketones. The improved
methodology involves the coupling of bromoketones with potassium phthalimide in
an ionic liquid (1-butyl-3-methylimidazoliumtetrafluoroborate) [bmim]PF4.[16]
In this method the coupling reaction was completed within 10–15 min of stir-
ring at room temperature (Scheme 1), and the product 2 was easily extracted in tetre-
hydrofuran (THF) in almost quantitative yield. The ionic liquid after washing and
drying under vacuum could be reused for the reaction up to four to five cycles with-
out any loss in activity (Table 1). The coupling reaction thus demonstrated the
Scheme 1. Synthesis of 1,2-amino alcohols; Reagents and conditions: (i) ionic liquid [bmim]BF4, rt,
10–15 min, >95%; (ii) method A: Pd=C hydrogenation, 40–50 psi; method B: NaCNBH3 in acetic acid;
method C: NaCNBH3 in methanol at pH 4 (3 N HCl in MeOH); (iii) NH2NH2ꢂH2O, H2O, 60 ꢀC.

PREPARATION OF 1,2-AMINO ALCOHOLS
507
Table 1. Coupling reaction using ionic liquid
Product 2 (reaction 1)
Entry
a
Y(%)=T (min)
95=15
b
c
97=12
96=13
d
e
97=15
98=12
f
95=15
97=13
g
h
i
95=14
96=15
95=14
j
k
96=14
—
—
—
Notes. Phth, phthalimide; T (min), time in minutes; Y (%), isolated yield in %.
importance of ionic liquids as reusable reaction media for the rapid chemical
transformations at ambient temperature.[17]
In the next step of reduction of carbonyl function, a-phthalimido ketones (2)
were subjected to hydrogenation under Pd=C and hydrogen gas at high pressure
(method A). However, this method was more applicable to the reduction of the
carbonyl function in an activated aromatic ring only, whereas carbonyl compounds
with deactivated aromatic rings including aliphatic ketones gave lower yields after

508
P. GUPTA ET AL.
Table 2. Reaction conditions for the selective reduction of a-phthalimido ketones
Method A
Method B
Method C
Entry
a
Product (3) reaction 2
T (h)
Y (%)
95
T (h)
Y (%)
95
T (h)
Y (%)
ND
10
40
48
24
24
24
60
60
60
b
c
85
90
95
96
ND
ND
d
70
10
24
97
60
ND
e
f
70
70
12
10
24
24
48
96
92
88
60
60
60
ND
85
ND
ND
g
ND
ha
70
12
70
ND
80
36
48
48
90
85
80
60
60
60
75
ia
ND
ND
jb
ND
kc
70
ND
36
96
60
65
Notes. Phth, phthalimide; T (h), time in hours; Y (%), isolated yield in %; ND, not detected. The struc-
tures of the products were established from their spectral (1H, 13C NMR, and MS) and analytical data.
aanti=syn ¼ > 99 (using NMR).
banti=syn ¼ 43:57.
canti=syn ¼ 1:1.

PREPARATION OF 1,2-AMINO ALCOHOLS
509
Table 3. Deprotection of phthalimides 3 to amines 4 by hydrazine hydrate
Entry
a
Substrate (3)
Product (4)
Time (h)
3
Yield (%)
97
b
c
3
3
95
90
d
3
93
e
f
3
3
3
95
40
95
g
h
i
3
3
3
3
65
96
60
j
k
55
(Continued )

510
P. GUPTA ET AL.
Table 3. Continued
Product (4)
Entry
l
Substrate (3)
Time (h)
3
Yield (%)
94
2-eq. of hydrazine hydrate was used and yield mentioned was isolated yield; structures of the final pro-
ducts were confirmed by spectroscopic analysis.
a long reaction time. These problems were eliminated by opting for more effec-
tive reduction procedure using acetic acid and NaCNBH3 for the reduction of
a-phthalimido ketones (Table 2).
Earlier NaCNBH3–acetic acid[18] and NaCNBH3–TMSCl[19] combinations
have been used to convert acyl to alkyl derivatives. In the present study it has been
demonstrated that among other reducing agents used for a-phthalimido ketones,
NaCNBH3 in acetic acid (method B) (also a chemoselective reducing agent)[20] was
found to be the most effective, whereas other mild reducing agents such as NaBH4
and Pd=C-H2 were not so successful. We also attempted to use the mild reducing sys-
tem such as NaCNBH3 in MeOH at pH 4, which gave lower yields of secondary
alcohols yet proved to be highly chemoselective as it could reduce only a nonenoliz-
able aliphatic carbonyl after a longer reaction time (2–3 days, method C), leaving
aromatic ketones or enolizable ketones intact. Another interesting observation made
during the use of method B was high diastereoselectivity (anti, 99%) of products in
the case of cyclic amino alcohol intermediates (entries 3h and 3i, Table 2). However,
poor diastereoselectivity was recorded during reduction of acyclic molecules (entries
3j and 3k, Table 2).
Despite the beneficial properties of phthalimide protection, removal of the
phthaloyl group can often be problematic. Literature study revealed that generally
deprotection of N-substituted phthalimides can be effected at elevated temperatures
using large access of hydrazine hydrate,[21] butylamine,[22] hydroxylamine[23] or
diamine[24] as amine bases in protic solvents. Over the years, many experimental
procedures for phthalimido deprotection have been documented with different
N-alkylphthalimide substrates, with variations in the molar proportions of amine
bases, solvent, reaction temperature, time, and workup procedures (i.e., acid=
alkaline conditions).[25]
Recently, interest has been emerging in organic reactions in water because of
water’s natural abundance and its environmental friendliness, using it as a sole reac-
tion medium. Indeed, industry prefers to use water as a solvent rather than hazard-
ous organic solvents, and therefore deprotection of N-substituted phthalimides
under greener condition is desirable.
The present improved methodology involves stirring phthalimido derivatives 3
in water at moderately elevated temperature (60 ꢀC) in the presence of 2 equivalent of
hydrazine hydrate (Table 3). The products 4a–l are easily isolated in 99% purity
(NMR) simply by ethyl acetate extraction without any further column purification.
The comparatively poor yields of 4f, 4h, 4j, and 4k can be attributed to the loss of

PREPARATION OF 1,2-AMINO ALCOHOLS
511
some free amino alcohols in the aqueous phase during workup. It is worth mention-
ing that during hydrazinolysis of compound 3l, the initially formed free amine got
acetylated probably because of in situ O-Ac to N-Ac migration[26] under basic con-
ditions. The formation of N-acetyl derivative (4l) was confirmed by spectroscopic
analysis.
CONCLUSIONS
In conclusion, an efficient three-step methodology for the preparation of
1,2-amino alcohols in good yields has been demonstrated that involved a rapid coup-
ling between bromoketones and potassium phthalimide, followed by selective
reduction using NaCNBH3–acetic acid, and finally efficient removal of phthalimido
protection in water at 60 ꢀC.
EXPERIMENTAL
1H NMR spectra in CDCl3 were recorded on Bruker 200-MHz spectrometers
with tetramethylsilane (TMS) as the internal standard. Chemical shifts were
expressed in parts per million (d ppm). Reagents and solvents used were mostly lab-
oratory reagent (LR) grade. Silica gel–coated aluminum plates coated on alumina
from M=s Merck were used for thin-layer chromatography (TLC). Mass Spectra
(MS) were recorded on Jeol MSD-300 and Bruker Esquire 3000 GC-mass spectro-
meters. Infrared (IR) was recorded on a Fourier transform (FT)–IR Bruker
(270-30) spectrophotometer. Melting points were determined on a Buchi B-542
apparatus by the open capillary method and are uncorrected.
a-Phthalimido Ketones
A mixture of potassium phthalimide (1.1 mmol) and bromo ketone (1 mmol) in
a 10-mL conical flask was added to 1 mL ionic liquid [1-butyl-3-methylimidazolium
tetrafluoroborate], and the resulting reaction mixture was stirred at room tempera-
ture for 10–15 min. The reaction mixture was extracted from the ionic liquid phase
with tetrahydrofuran (THF) (2 ꢃ 5 mL). The organic layer was concentrated and
evaporated under reduced pressure. The residue was purified by column chromato-
graphy to obtain the corresponding product. The ionic liquid left in the flask was
further washed with ethylacetate, dried under vacuum, and reused in four to five
subsequent reactions without loss in activity.
2-(2-Oxo-2-phenyl-ethyl)-isoindole-1,3-dione (2a) (C16H11NO3). Pale
1
yellow crystals; mp 168–170 ꢀC; IR (KBr) cmꢄ1: 1419.8, 1914.1, 1962.3. H NMR,
d: 5.14 (s, 2H, CH2), 7.51–7.56 (m, 3H, ArH), 7.74–7.78 (m, 2H, ArH), 7.91–7.93
(m, 2H, ArH), 8.00 (d, J ¼ 7.10 Hz, 2H, ArH). 13C NMR, d: 44.3, 123.6, 127.9,
128.2, 132.1, 133.9, 134.1, 134.5, 167.1, 191.1. ESI-MS (m=z): 265. Anal. calc. for
C16H11NO3: C, 72.45; H, 4.18; N, 5.28. Found: C, 72.48; H, 4.17; N, 5.26.
2-(2-Oxo-2-p-tolyl-ethyl)-isoindole-1,3-dione (2b) (C17H13NO3). Yellow
crystals; mp 184–186 ꢀC. IR (KBr) cmꢄ1: 1416.7, 1689.4, 1725.4, 1775.5. 1H
NMR, d: 2.44 (s, 3H, CH3), 5.11 (s, 2H, CH2), 7.26–7.33 (m, 2H, ArH), 7.74–7.79

512
P. GUPTA ET AL.
(m, 2H, ArH), 7.86–7.93 (m, 4H, ArH); 13CNMR, d: 20.8, 43.1, 123.5, 125.7, 128.2,
133.2, 134.1, 134.6, 145.0, 167.9, 187.4. ESI-MS (m=z): 279. Anal. calc. for
C17H13NO3: C, 73.11; H, 4.69; N, 5.02. Found: C, 73.13; H, 4.67; N, 5.06.
2-[2-(4-Methoxyphenyl)-2-oxo-ethyl]-isoindole-1,3-dione(2c)(C17 H13 NO4).
Pale yellow crystals; mp 164–168 ꢀC; IR (KBr) cmꢄ1: 1420.7, 1600.2, 1716.3, 1773.5.
1H NMR, d: 3.90 (s, 3H, OCH3), 5.08 (s, 2H, CH2), 6.97 (d, J ¼ 8.9 Hz, 2H, ArH),
7.76–7.78 (m, 2H, ArH), 7.86–7.93 (m, 2H, ArH), 7.99 (d, J ¼ 8.9 Hz, 2H, ArH). 13
C
NMR, d: 42.9, 54.6, 113.1, 120.3, 125.5, 128.0, 132.7, 133.1, 163.8, 187.2. ESI-MS
(m=z): 295. Anal. calc. for C17H13NO4: C, 69.15; H, 4.44; N, 4.74. Found: C,
69.18; H, 4.47; N, 4.76.
2-[2-(2,5-Dimethyl-phenyl)-2-oxo-ethyl]-isoindole-1,3-dione
(2d)
(C18H15NO3). White crystals, mp 145–147 ꢀC; IR (KBr) cmꢄ1: 1419.7, 1687.4,
1
1716.5, 1769.1, 2927.4, 2960.7, 3030.8. H NMR, d: 2.39 (s, 3H, CH3), 2.46 (s, 3H,
CH3), 5.01 (s, 2H, CH2), 7.15–7.27 (m, 2H, ArH), 7.61 (s, 1H, ArH), 7.72–7.78(m,
2H, ArH), 7.85–7.96 (m, 2H, ArH). 13C NMR, d: 21.1, 21.2, 45.8, 124.7, 130.5,
133.6, 134.6, 135.5, 135.7, 136.9, 137.8, 169.4, 195.6. ESI-MS (m=z): 293. Anal. calc.
for C18H15NO3: C, 73.71; H, 5.15; N, 4.78. Found: C, 73.73; H, 5.17; N, 4.79.
2-[2-(4-Fluoro-phenyl)-2-oxo-ethyl]-isoindole-1,3-dione
(2e)
(C16H10FNO3). White crystals; mp 114–116 ꢀC. IR (KBr) cmꢄ1: 1419.9, 1510.8,
1
1692.9, 1716.2, 1775.5, 2945.4. H NMR, d: 5.04 (s, 2H, CH2), 7.16–7.26 (m, 2H,
ArH), 7.74–7.78 (m, 2H, ArH), 7.87–7.93 (m, 2H, ArH). 8.02–8.09 (m, 2H, ArH).
13C NMR, d: 44.4, 116.3, 116.5, 116.7, 124.0, 131.2, 132.6, 134.6, 168.2, 189.9.
ESI-MS (m=z): 283. Anal. calc. for C16H10FNO3: C, 67.84; H, 3.56; N, 4.94. Found:
C, 67.83; H, 3.57; N, 4.96.
2-(2-Oxo-propyl)-isoindole-1,3-dione (2f) (C11H9NO3). White solid; mp
122–124 ꢀC. IR (KBr) cmꢄ1: 1415.1, 1467.8, 1726.1, 1773.3, 2940.6, 3064.4. 1H
NMR, d: 2.27 (s, 3H, CH3), 4.50 (s, 2H, CH2), 7.72–7.78 (m, 2H, ArH), 7.84–7.90
(m, 2H, ArH); 13C NMR, d: 27.5, 47.7, 123.6, 132.5, 134.2, 168.0, 203.7. ESI-MS
(m=z): 203. Anal. calc. for C11H9NO3: C, 65.02; H, 4.46; N, 6.89. Found: C,
65.03; H, 4.47; N, 6.91.
2-(2-(4-Nitro-phenyl)-2-oxo-ethyl]-isoindole-1,3-dione (2g) (C16H10N2O5).
Pale yellow solid; mp 234–236 ꢀC; IR (neat) cmꢄ1: 1419.7, 1526.0, 1699.4, 1718.2,
1
2337.5, 2361.8, 2965.2. H NMR, d: 5.17 (s, 2H, CH2), 7.78–7.82 (m, 2H, ArH),
7.91–7.96 (m, 2H, ArH), 8.20 (d, J ¼ 8.9 Hz, 2H, ArH), 8.40 (d, J ¼ 8.9 Hz, 2H,
ArH). 13C NMR, d: 44.6, 123.9, 124.4, 129.5, 132.2, 134.7, 138.9, 151.0, 168.1,
190.4. ESI-MS (m=z): 310. Anal. calc. for C16H10N2O5: C, 61.94; H, 3.25; N, 9.03.
Found: C, 61.97; H, 3.24; N, 9.05.
2-(2-Oxo-cyclohexyl)-isoindole-1,3-dione (2h) (C14H13NO3). White solid;
1
mp 165–167 ꢀC; IR (KBr) cmꢄ1: 1466.2, 1612.7, 1717.6, 1765.2, 2952.6. H NMR,
d: 1.80–188 (m, 2H, CH2), 2.04–2.23 (m, 2H, CH2), 2.25–2.28 (m, 2H, CH2),
2.63–2.69 (m, 2H, CH2), 4.80 (dd, J ¼ 6.3 Hz & 12.9 Hz, 1H, CHN), 7.26–7.76 (m,
2H, ArH), 7.81–7.87 (m, 2H, ArH). 13C NMR, d: 25.2, 26.2, 30.9, 41.4, 58.1,
123.9, 132.4, 134.4, 168.3, 203.2. ESI-MS (m=z): 243. Anal. calc. for C14H13NO3:
C, 69.12; H, 5.39; N, 5.76. Found: C, 69.13; H, 5.37; N, 5.73.

PREPARATION OF 1,2-AMINO ALCOHOLS
513
2-(1-Oxo-indan-2-yl)-isoindole-1,3-dione
(2i)
(C17H11NO3). Reddish
brown solid; mp 191 ꢀC; IR (neat) cmꢄ1: 1468.1, 1611.9, 1714.5, 1777.8, 2925.9,
1
3030.2. H NMR, d: 3.41 (dd, J ¼ 5.9 Hz & 16.5 Hz, 1H, CH), 3.61 (dd, J ¼ 8.4 Hz
& 16.6 Hz, 1H, CH), 5.09 (dd, J ¼ 6.0 Hz & 8.4 Hz, 1H, CHN), 7.41–7.52 (m, 2H,
ArH), 7.64–788 (m, 6H, ArH). 13C NMR, d: 32.0, 53.8, 123.7, 124.7, 126.8, 128.2,
132.3, 134.4, 135.8. 151.1, 167.7, 200.2. ESI-MS (m=z): 277. Anal. calc. for
C11H9NO3: C, 73.64; H, 4.00; N, 5.05. Found: C, 73.63; H, 4.03; N, 5.02.
2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-3-oxo-butyric acid ethyl ester
:
(2j) (C14H13NO5). (Keto=enol ¼ 18:82) white solid, mp 94–96 ꢀC; IR (KBr) cmꢄ1
1
1427.3, 1468.7, 1626.7, 1656.1, 1722.1, 1787.9, 2931.3, 2984.7. H NMR, d: 1.16 (t,
J ¼ 7.1 Hz, 3H, CH3), 1.96 (s, 3H, COCH3), 4.19 (q, J ¼ 7.1 Hz, 2H, OCH2),
7.75–7.83 (m, 2H, ArH), 7.88–7.95 (m, 2H, ArH). 13C NMR, d: 14.5, 18.5, 61.8,
97.1, 124.2, 132.2, 134.7, 168.1, 169.8, 177.3. ESI-MS (m=z): 275. Anal. calc. for
C14H13NO5: C, 61.09; H, 4.76; N, 5.09. Found: C, 61.07; H, 4.74; N, 5.08.
2-(1-Methyl-2-oxo-propyl)-isoindole-1,3-dione (2k) (C12H11NO3). Yellow
1
crystals; mp 77–79 ꢀC; IR (KBr) cmꢄ1: 1467.8, 1714.1, 1776.9, 2942.6, 2994.9. H
NMR, d: 1.65 (d, J ¼ 7.3 Hz, CH3), 2.21 (s, 3H, COCH3), 4.82 (q, J ¼ 7.3 Hz, 1H,
CHN), 7.72–7.80 (m, 2H, ArH), 7.84–7.90 (m, 2H, ArH). 13C NMR, d: 14.6, 26.6,
55.1, 123.5, 132.3, 133.5, 134.5, 169.1. ESI-MS (m=z): 217. Anal. calc. for
C12H11NO3: C, 66.35; H, 5.10; N, 6.45. Found: C, 66.33; H, 5.14; N, 6.43.
Hydrogenation of protected amino ketones (2a, 2b, 2c, 2d). Hydrogen
gas was purged thoroughly in a solution of a-phthalimide ketones (1 mmol) and
Pd=C (10%) (catalytic amount) in anhydrous ethanol (10 mL). The final hydrogen
pressure was adjusted to 40–70 psi, and the reaction mixture was shaken at room
temperature. After a certain time the hydrogen pressure was released and the solvent
was removed after filtration to get the product, which was purified through a
silica-gel column.
NaCNBH3 Reduction of Protected Amino Ketones (2a–k)
General method a (NaCNBH3 in MeOH). NaCNBH3(2.0 equivalents) was
added at 0 ꢀC to a solution of a-phthalimido ketones (1 mmol) in methanol
(15 mL). A trace of bromocresol green was also added to monitor the reaction.
The solution immediately turned blue when 3 N HCl in methanol was added
dropwise to restore the yellow color while stirring continued for 60 h at room tem-
perature. The contents were concentrated under reduced pressure, and the residue
was extracted with diethyl ether. The combined extracts were dried over anhydrous
sodium sulfate and concentrated under reduced pressure. The product was purified
on a silica-gel column.
General method b (NaCNBH3 in acetic acid). NaCNBH3(2 mmol) was
added at room temperature to a solution of a-phthalimido ketones in acetic acid
(1 mmol in 15 mL). After the completion of the reaction as indicated by TLC, the
reaction was quenched by saturated NaHCO3 solution and extracted with ethyl acet-
ate. The combined extracts were washed with water, dried over anhydrous sodium

514
P. GUPTA ET AL.
sulfate, and concentrated under reduced pressure. The product was purified on a
silica-gel column.
2-(2-Hydroxy-2-phenyl-ethyl)-isoindole-1,3-dione (3a) (C16H13NO3).
White solid; mp 161–163 ꢀC; IR (KBr) cmꢄ1: 1420.9, 1457.7, 1695.4, 1768.6,
1
2899.6, 3460.8. H NMR, d: 3.88–4.02 (m, 2H, CH2), 5.01 (dd, J ¼ 4.2 Hz, 3.3 Hz,
1H, CH), 7.1–7.3 (m, 5H, ArH), 7.73–7.77 (m, 2H, ArH), 7.84–7.86 (m, 2H,
ArH). 13C NMR, d: 45.8, 72.6, 123.4, 123.5, 125.9, 127.8, 128.5, 128.9, 131.9,
134.0, 134.1, 141.1, 168.8. ESI-MS (m=z): 267. Anal. calc. for C16H13NO3: C,
71.90; H, 4.90; N, 5.24. Found: C, 71.92; H, 4.93; N, 5.25.
2-[2-Hydroxy-2-p-tolyl-ethyl)-isoindole-1,3-dione (3b) (C17H15NO3). Pale
yellow solid; mp 139–141 ꢀC; IR (KBr) cmꢄ1: 1420.5, 1605.7, 1690.1, 1716.4, 1775.7,
1
2920.4, 3476.4. H NMR, d: 2.39 (s, 3H, CH3), 2.85 (brs, 1H, OH), 3.98 (m, 2H,
CH2), 5.05 (m, 1H, CH), 7.02 (d, J ¼ 8 Hz, 2H, ArH), 7.42 (d, J ¼ 8 Hz, 2H, ArH),
7.75–7.82 (m, 2H, ArH), 7.84–7.93 (m, 2H, ArH). 13C NMR, d: 21.2, 45.4, 72.3,
123.3, 125.9, 129.3, 131.9, 134.1, 137.9, 138.2, 168.8. ESI-MS (m=z): 281. Anal. calc.
for C17H15NO3: C, 72.58; H, 5.37; N, 4.98. Found: C, 72.56; H, 5.36; N, 4.99.
2-[2-Hydroxy-2-(4-methoxy-phenyl)-ethyl]-isoindole-1,3-dione
(3c)
(C17H15NO4). White solid; mp 164–166 ꢀC; IR (KBr) cmꢄ1: 1462.6, 1514.1,
1692.0, 2923.7, 3445.2. 1H NMR, d: 2.84 (brs, 1H, OH), 3.83 (s, 3H, OCH3),
3.88–4.10 (m, 2H, CH2), 5.02–5.10 (m, 1H, CH), 6.90–6.95 (m, 2H, ArH),
7.39–7.43 (m, 2H, ArH), 7.74–7.78 (m, 2H, ArH), 7.86–7.96 (m, 2H, ArH). 13C
NMR, d: 45.7, 55.3, 72.1, 114.1, 122.6, 127.2, 131.2, 133.3, 134.2, 159.5, 168.8.
ESI-MS (m=z): 297. Anal. calc. for C17H15NO4: C, 68.68; H, 5.09; N, 4.71. Found:
C, 68.69; H, 5.07; N, 4.72.
2-[2-(2,5-Dimethyl-phenyl)-2-hydroxy-ethyl]-isoindole-1,3-dione
(3d)
(C18H17NO3). White solid; mp 127–129 ꢀC; IR (KBr) cmꢄ1: 1422.8, 1709.3,
1771.9, 2925.5, 3433.5. 1H NMR, d: 2.43 (s, 3H, CH3), 2.49 (s, 3H, CH3),
3.90–3.94 (m, 2H, CH2), 5.21 (dd, J ¼ 3.7 Hz & 7.8 Hz, 1H, CHOH), 7.06–7.08 (m,
2H, ArH), 7.22 (s, 1H, ArH), 7.64–7.80 (m, 2H, ArH), 7.87–7.93 (m, 2H, ArH).
13C NMR, d: 18.7, 21.2, 45.1, 70.1, 123.7, 123.7, 126.1, 128.8, 130.7, 133.6, 134.4,
135.6, 140.2, 169.4. ESI-MS (m=z): 295. Anal. calc. for C18H17NO3: C, 73.20; H,
5.80; N, 4.70. Found: C, 73.23; H, 5.84; N, 4.71.
2-[2-(4-Fluoro-phenyl)-2-hydroxy)-ethyl]-isoindole-1,3-dione
(3e)
(C16H12FNO3). White solid; mp 162–164 ꢀC; IR (KBr) cmꢄ1: 1510.4, 1609.9,
1
1692.4, 1709.4, 2930.7, 3420.3. H NMR, d: 3.03 (brs, 1H, OH), 3.94–3.99 (m, 2H,
CH2), 5.04–5.07 (m, 1H, CH), 7.04 (t, J ¼ 8.7 Hz, 2H, ArH), 7.39–7.46 (m, 2H,
ArH), 7.71–7.76 (m, 2H, ArH), 7.81–7.88 (m, 2H, ArH). 13C NMR, d: 44.6, 71.0,
114.3, 114.7, 119.5, 125.5, 126.5, 129.9, 133.2, 135.0, 165.0. ESI-MS (m=z): 285.
Anal. calc. for C16H12FNO3: C, 67.36; H, 4.24; N, 4.91. Found: C, 67.38; H, 4.22;
N, 4.90.
2-(2-Hydroxy)-propyl-isoindole-1,3-dione (3f) (C11H11NO3). White solid;
mp 89–91 ꢀC; IR (KBr) cmꢄ1: 1424.2, 1611.2, 1718.1, 1767.4, 2928.6, 2964.7,
3422.4, 3484.2. 1H NMR, d: 1.25 (d, J ¼ 6.4 Hz, 3H, CH3), 3.74–3.78 (m, 2H,
CH2), 4.12–4.17 (m, 1H, CHOH), 7.72–7.78 (m, 2H, ArH), 7.83–7.89 (m, 2H,

PREPARATION OF 1,2-AMINO ALCOHOLS
515
ArH). 13C NMR, d: 20.3, 44.9, 65.7, 122.4, 130.5, 132.4, 168.0. ESI-MS (m=z): 205.
Anal. calc. for C11H11NO3: C, 64.38; H, 5.40; N, 6.83. Found: C, 64.38; H, 5.42; N,
6.84.
2-[2-Hydroxy-2-(4-nitro-phenyl)-ethyl]-isoindole-1,3-dione
(3g)
(C16H12N2O5). Pale yellow solid, mp 166–168 ꢀC; IR (KBr) cmꢄ1: 1401.7, 1518.2,
1
1687.4, 1706.6, 2922.7, 3382.0. H NMR, d: 3.86 (dd, J ¼ 4.5 Hz & 14.1 Hz, 1H,
CHN), 4.01 (dd, J ¼ 8.0 Hz & 14.1 Hz, 1H, CHN), 5.16–5.20 (m, 1H, CHOH),
7.67 (d, J ¼ 8.6 Hz, 2H, ArH), 7.72–7.79 (m, 2H, ArH), 7.81–7.88 (m, 2H, ArH),
8.20 (d, J ¼ 8.7 Hz, 2H, ArH). 13C NMR, d: 45.7, 71.1, 123.7, 123.9, 127.4, 132.2,
134.5, 148.1, 150.2, 168.5. ESI-MS (m=z): 312. Anal. calc. for C16H12N2O5: C,
61.54; H, 3.87; N, 8.97. Found: C, 61.53; H, 3.85; N, 8.95.
2-(2-Hydroxy-cyclohexyl)-isoindole-1,3-dione (3h) (C14H15NO3). White
solid; mp 90–92 ꢀC; IR (KBr) cmꢄ1: 1450.8, 1467.3, 1653.1, 1707.1, 1772.1, 2862.3,
1
2937.9, 3447.8. H NMR, d: 1.21–1.42 (m, 4H, CH2’s), 1.68–1.83 (m, 2H, CH2),
2.13–2.24 (m, 2H, CH2), 3.97 (ddd, J ¼ 3.7, 10.1 & 12.4 Hz, CHN), 4.26–4.37 (m,
1H, CHOH), 7.67–7.74 (m, 2H, ArH), 7.78–7.85 (m, 2H, ArH). 13C NMR, d:
24.2, 25.1, 28.6, 34.6, 57.1, 68.6, 122.7, 131.7, 133.8, 169.5. ESI-MS (m=z): 245. Anal.
calc. for C14H15NO3: C, 68.56; H, 6.16; N, 5.71. Found: C, 68.59; H, 6.15; N, 5.73.
2-(1-Hydroxy-indan-2-yl)-isoindole-1,3-dione (3i) (C17H13NO3). Yellow
solid; mp 217–219 ꢀC; IR (KBr) cmꢄ1: 1468.3, 1711.6, 1771.1, 2854.1, 2925.9,
1
3491.4. H NMR, d: 3.12–3.24 (m, 1H, CH2), 3.95–4.08 (m, 1H, CH2), 5.11–5.18
(m, 2H, CHOH & CHN), 7.29–7.31 (m, 3H, ArH), 7.49–7.53 (m, 1H, ArH),
7.72–7.76 (m, 2H, ArH), 7.84–7.88 (m, 2H, ArH). 13C NMR, d: 32.7, 52.9, 76.2,
123.4, 124.9, 125.6, 127.5, 129.4, 131.9, 134.2, 140.2, 142.5, 169.6. ESI-MS (m=z):
279. Anal. calc. for C17H13NO3: C, 73.11; H, 4.69; N, 5.02. Found: C, 73.13; H,
4.65; N, 5.03.
2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-3-hydroxy-butyric acid ethyl
ester (3j) (C14H15NO5). syn-isomer. mp 58–60 ꢀC; IR (KBr) cmꢄ1: 1468.2, 1717.4,
1
1775.14, 2934.8, 2981.9, 3451.2. H NMR, d: 1.21–1.32 (m, 6H, CH3’s), 4.28 (q,
J ¼ 7.1 Hz, 2H, OCH2), 4.65–4.69 (m, 1H, CHOH), 4.99 (d, J ¼ 4.1 Hz, 1H,
CHN), 7.78–7.82 (m, 2H, ArH), 7.89–7.95 (m, 2H, ArH). 13C NMR, d: 14.5, 20.6,
59.7, 62.6, 67.1, 124.3, 130.8, 134.9, 167.7, 168.8. ESI-MS (m=z): 277. Anal. calc.
for C14H15NO5: C, 60.64; H, 5.45; N, 5.05. Found C, 60.63; H, 5.44; N, 5.01.
anti-isomer. oil; IR (KBr) cmꢄ1: 1468.2, 1717.4, 1775.14, 2934.8, 2981.9,
1
3451.2. H NMR, d: 1.21 (t, J ¼ 7.1 Hz, 3H, CH3CH2), 1.28 (d, J ¼ 6.4 Hz, 3H,
CH3CHOH), 4.28 (q, J ¼ 7.1 Hz, 2H, OCH2), 4.51–4.58 (m, 1H, CHOH), 4.71 (d,
J ¼ 6.5 Hz, 1H, CHN), 7.77–7.80 (m, 2H, ArH), 7.88–7.91 (m, 2H, ArH). 13C
NMR, d: 13.7, 19.3, 57.3, 61.9, 66.2, 123.5, 133.2, 134.5, 167.5, 168.5. ESI-MS
(m=z): 277. Anal. calc. for C14H15NO5: C, 60.64; H, 5.45; N, 5.05. Found: C,
60.63; H, 5.44; N, 5.01.
2-(2-Hydroxy-1-methyl-propyl)-isoindole-1,3-dione (3k) (C12H13NO3).
Semisolid; IR (KBr) cmꢄ1: 1467.7, 1614.1, 1707.0, 1773.7, 2935.2, 2977.4, 3446.7.
1H NMR, d: 1.20–1.27 (m, 3H, CH3CHOH), 1.41–1.48 (m, 3H, CH3CHN), 4.14
(m, 2H, CHOH & CHN), 7.28–7.78 (m, 2H, ArH), 7.82–7.87 (m, 2H, ArH). 13C

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P. GUPTA ET AL.
NMR, d: 12.6, 15.9, 53.5, 69.2, 123.4, 133.2, 134.5, 170.5. ESI-MS (m=z): 219. Anal.
calc. for C12H13NO3: C, 65.74; H, 5.98; N, 6.39. Found: C, 65.73; H, 5.95; N, 6.36.
Hydrazinolysis of 2-Phthalimidoalcohols
Hydrazine hydrate (3 eq.) was added to a suspension of 2-phthalimidoalcohols
(1 mmol) in water (5 mL), and the resulting mixture was stirred at 60 ꢀC for 3 h. After
the completion of the reaction as indicated by TLC, the reaction mixture was satu-
rated with NaCl and extracted with ethyl acetate (3 ꢃ 20 mL). The combined extracts
were washed with water, dried over anhydrous sodium sulfate, and concentrated
under reduced pressure to get amino alcohols (4a–l).
2-Amino-1-phenylethanol (4a) (C8H11NO). White solid; mp 56–58 ꢀC; IR
1
(KBr) cmꢄ1: 1061.5, 1402.4, 1579.5, 2868.3, 3030.0, 3358.5. H NMR, d: 2.67 (dd,
J ¼ 12.9, 7.7 Hz, 1H), 2.80 (dd, J ¼ 12.9, 4.0 Hz, 1H), 4.52 (dd, J ¼ 7.7, 4.0 Hz,
1H), 7.13–7.17 (m, 5H); 13C NMR, d: 49.3, 74.3, 125.9, 127.4, 127.5, 128.4, 128.5,
142.8; ESI-MS (m=z): 137. Anal. calc. for C8H11NO C, 70.08; H, 8.08; N, 10.21.
Found: C, 70.15; H, 8.11; N, 10.30.
2-Amino-1-(4-methylphenyl)ethanol (4b) (C9H13NO). Semisolid; IR (KBr)
cmꢄ1: 1071.9, 1405.3, 1459.1, 2854.3, 2955.5, 3362.5; 1H NMR, (CD3OD) d: 2.32 (s,
3H, CH3), 2.75–2.80 (m, 1H, CHHNH2), 2.89–2.92 (m, 1H, CHHNH2), 4.55–4.58
(m, 1H, CHOH), 7.13 (d, J ¼ 7.6 Hz, 2H, ArH), 7.21 (d, J ¼ 7.6 Hz, 2H, ArH); 13C
NMR (CD3OD) d: 20.7, 48.0, 72.9, 124.7, 128.1, 137.3, 139.2; ESI-MS (m=z): 151.
Anal. calc. for C9H13NO: C, 71.49; H, 8.67; N, 9.26. Found: C, 71.45; H, 8.71; N,
9.29.
2-Amino-1-(4-methoxyphenyl)ethanol (4c) (C9H13NO2). White solid; mp
1
70 ꢀC; IR (KBr) cmꢄ1: 1032.6, 1248.2, 1513.5, 2929.0, 3299.2; H NMR, d: 2.73
(dd, J ¼ 12.5, 8.1 Hz, 1H, CHHNH2), 2.87 (dd, J ¼ 12.5, 4.0 Hz, 1H, CHHNH2),
3.79 (s, 3H, OCH3), 6.85 (d, J ¼ 8.4 Hz, 2H, ArH), 7.23 (d, J ¼ 8.4 Hz, 2H, ArH);
13C NMR, d: 49.2, 55.3, 72.7, 113.8, 127.4, 135.1, 159.1; ESI-MS (m=z): 167. Anal.
calc. for C9H13NO2: C, 64.65; H, 7.84; N, 8.38. Found: C, 64.61; H, 7.97, N, 8.44.
2-Amino-1-(2,5-dimethyl-phenyl)ethanol (4d) (C10H15NO). Semi solid; IR
1
(KBr) cmꢄ1: 1404.0, 2845.3, 2920.0, 3412.2. H NMR, d: 2.43 (s, 3H, CH3), 2.49 (s,
3H, CH3), 3.01–3.60 (m, 2H, CH2), 4.60 (dd, 1H, CHOH), 7.06–7.08 (m, 2H, ArH),
7.10 (s, 1H, ArH). 13C NMR, d: 18.4, 23.2, 48.1, 70.1, 127.7, 128.9, 129.1, 132.7,
134.4, 139.5. ESI-MS (m=z): 165. Anal. calc. for C10H15NO: C, 72.69; H, 9.15; N,
8.48. Found: C, 72.67; H, 9.20; N, 8.51.
2-Amino-1-(4-fluorophenyl)ethanol (4e) (C8H10FNO). Semi solid; IR
1
(KBr) cmꢄ1: 1501.5, 1603.6, 2878.0, 2998.8, 3357.1. H NMR, d: 2.76 (dd, J ¼ 7.8,
12.7 Hz, 1H, CHHNH2), 2.98 (dd, J ¼ 3.9, 12.7 Hz, 1H, CHHNH2), 4.61 (dd,
J ¼ 3.9, 7.8 Hz, 1H, CHOH), 7.90–7.16 (m, 2H, ArH), 7.31–7.38 (m, 2H, ArH);
13C NMR, d: 49.5, 73.2, 113.9, 114.3, 127.1, 127.6, 139.9, 163.1; ESI-MS (m=z):
155. Anal. calc. for C8H10FNO: C, 61.92; H, 6.50; N, 9.03. Found: C, 61.87; H,
6.59; N, 9.12.

PREPARATION OF 1,2-AMINO ALCOHOLS
517
1-Amino-2-propanol (4f) (C3H9NO). Clear to light yellow liquid; mp 1.4 ꢀC;
1
IR (KBr) cmꢄ1: 1423.6, 2913.1, 3395.0. H NMR, d: 1.16 (d, J ¼ 6.3 Hz, 3H, CH3).
2.44 (dd, J ¼ 8.1, 12.7 Hz, 1H), 2.65 (dd, J ¼ 2.65, 12.7 Hz, 1H), 2.55–3.65 (m, 1H).
13C NMR, d: 20.8, 54.9, 71.7. ESI-MS (m=z): 75. Anal. calc. for C3H9NO: C,
47.97; H, 12.08; N,18.65. Found: C, 47.88; H, 12.10; N, 18.73.
2-Amino-1-(p-nitrophenyl)ethanol (4g) (C8H10N2O3). Semisolid; IR (KBr)
cmꢄ1: 1398.5, 1510.3, 2901.0, 3250.2, 3360.3. 1H NMR, d: 2.6–2.9 (m, 2H, CH2), 4.7
(t, J ¼ 4.2, CHOH), 7.5–7.6 (d, 2H, ArH), 8.1–8.2 (d, 2H, ArH). 13C NMR, d: 48.8,
72.9, 123.6, 126.6, 147.4, 149.9. ESI-MS (m=z): 182. Anal. calc. for C8H10N2O3: C,
52.74; H, 5.53; N, 15.38. Found: C, 52.82; H, 5.64; N, 15.42.
2-Amino-1-cyclohexanol (4h) (C6H13NO). White solid; mp 87 ꢀC; IR (KBr)
cmꢄ1: 1074.8, 1499.7, 2857.6, 3283.3; 1H NMR, d: 1.23–1.46 (m, 2H, CH2), 1.65–2.12
(m, 6H, CH2’s), 2.38–2.46 (m, 1H, CHNH2), 3.10–3.15 (m, 1H, CHOH); 13C NMR,
d: 24.8, 25.0, 33.9, 34.3, 56.9, 75.6; ESI-MS (m=z): 115. Anal. calc. for C6H13NO: C,
62.37; H, 11.38; N, 12.16. Found: C, 62.26; H, 11.44; N, 12.21.
2-Amino-1-indanol (4i) (C9H11NO). White to off-white crystal; mp
1
160–161 ꢀC; IR (KBr) cmꢄ1: 1070, 1490, 1570, 2400–3400. H NMR, d: 2.60 (dd,
J ¼ 15.3, 8.0 Hz, 1H, CH2), 3.22 (dd, J ¼ 15.3, 8.0 Hz, 1H, CH2), 3.47 (dt, J ¼ 8.0,
6.5 Hz, 1H, CHN,) 4.79 (d, 6.5 Hz, 1H, CHOH), 7.15–7.60 (m, 4H). 13C NMR, d:
38.8, 62.9, 82.2, 123.6,124.7, 126.9, 128.1, 139.5, 143.3. ESI-MS (m=z): 149. Anal.
calc. for C9H11NO: C, 72.46; H, 7.43; N, 9.39. Found: C, 72.40; H, 7.55; N, 9.43.
Ethyl-2-amino-3-hydroxybutanoate (4j) (C6H13NO3). Semisolid; IR (KBr)
cmꢄ1: 1421.0, 1685.4, 2895.2, 2907.0, 3385.6. 1H NMR, d: 1.21-1.32 (m, 6H, CH3’s),
3.90 (m, 1H, CHN), 4.13 (m, 1H, CHOH), 4.21 (q, J ¼ 7.1 Hz, 2H, OCH2). 13C
NMR, d: 14.5, 20.0, 57.7, 61.6, 65.1, 168.7. ESI-MS (m=z): 147. Anal. calc. for
C6H13NO3: C, 48.97; H, 8.90; N, 9.52. Found: C, 48.89; H, 8.99; N, 9.59.
3-Amino-2-butanol (4k) (C4H11NO). Semisolid; IR (KBr) cmꢄ1: 1216, 1458,
1
1609, 2854, 2924, 3396. H NMR, d: 1.09 (d, J ¼ 6.6 Hz, 3H, CH3CHN), 1.12 (d,
J ¼ 6.9 Hz, 3H, CH3CHOH), 3.26 (m, 1H, CHN), 3.7 (m, 1H, CHOH). 13C NMR,
d: 17.6, 18.9, 54.5, 67.8. ESI-MS (m=z): 89. Anal. calc. for C4H11NO: C, 53.90; H,
12.44; N, 15.71. Found: C, 53.88; H, 12.53; N, 15.79.
2-Acetamido-1-(4-fluorophenyl)ethanol (4l) (C10H12FNO2). Semisolid; IR
(KBr) cmꢄ1: 1222.7, 1403.1, 1642.1, 2925.5, 3285.9. 1H NMR, d: 1.97 (s, 3H),
3.24–3.33 (m, 1H), 3.55–3.65 (m, 1H), 4.77–4.82 (dd, J ¼ 7.8, 3.2 Hz, 1H),
6.97–7.06 (m, 2H), 7.26–7.35 (m, 2H); 13C NMR. d: 23.1, 47.6, 73.0, 115.2, 127.4,
137.6, 161.4, 171.7. ESI-MS (m=z): 197. Anal. calc. for C10H12FNO2: C, 60.90; H,
6.13; N, 7.10. Found: C, 60.88; H, 6.22; N, 7.17.
ACKNOWLEDGMENT
One of the authors (A. R.) is thankful to the Council of Scientific and Indus-
trial Research, New Delhi, India, for the award of a junior research fellowship.

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