Conversion of homochiral amines, β-amino alcohols and α-amino acids to their chiral 2-substituted pyrrole derivatives

Article abstract of DOI:10.1039/b008317h

The conversion of the amino group of chiral amines, amino alcohols, amino acids and their esters into chiral 2-substituted pyrrole derivatives with various halogeno enones is described. The conversion works in good yield and without racemization. The synthesis of 2-phenylpyrrole derivatives was possible with amino alcohols but not with amino acids or their esters.

Full text of DOI:10.1039/b008317h

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Conversion of homochiral amines, ꢀ-amino alcohols and ꢁ-amino
acids to their chiral 2-substituted pyrrole derivatives
Ayhan S. Demir,* Idris M. Akhmedov, Özge Sesenogˇlu, Onur Alptürk, Sinem Apaydın,
¸ ¸
˙
1
Zuhal Gerçek and Nezire Ibrahimzade
˙
Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
Received (in Cambridge, UK) 16th October 2000, Accepted 22nd March 2001
First published as an Advance Article on the web 24th April 2001
The conversion of the amino group of chiral amines, amino alcohols, amino acids and their esters into chiral
2-substituted pyrrole derivatives with various halogeno enones is described. The conversion works in good yield
and without racemization. The synthesis of 2-phenylpyrrole derivatives was possible with amino alcohols but not
with amino acids or their esters.
Introduction
Results and discussion
Compounds containing a pyrrole ring can be found in many
naturally occurring compounds and they have found appli-
cations in medicine and agriculture.1 Chiral pyrrole derivatives
of amines and amino acids are important starting materials for
the synthesis of many different biologically active compounds.
Several useful variants of classical methods can be found in the
literature.2 A stereoselective approach to the synthesis of indol-
izidine alkaloids based on the reaction of pyrrole derivatives
of amino acids has been reported.3 C-2 substituted pyrrole
derivatives also provide access to substituted indolizidine
alkaloids as outlined in Scheme 1.
Halogeno enones are valuable intermediates for the construc-
tion of nitrogen heterocycles. Chloro enones 2a–c provide four
carbon units with a carbonyl and halide functionality to form
pyrrole rings with primary amines. According to Scheme 2,
-alanine methyl ester (S)-1a is refluxed with chloro enone 2a in
benzene and water for 5 hours and during this time the reaction
is monitored by TLC. Purification of the crude product
afforded the desired pyrrole derivative (S)-3a in 80% yield as a
colorless oil. The same reaction was also carried out with the
isopropyl and cyclohexyl derivatives of the enone (2b and 2c).
The reaction afforded the corresponding pyrrole derivatives
3b (76%) and 3c (72%). The reaction also works with alanine
under similar conditions to obtain the free acid pyrrole deriv-
ative (S)-3d in 52% yield.
Under the same reaction conditions, valine, valine methyl
ester, aspartic acid methyl ester, tyrosine ethyl ester and phenyl-
glycine are converted to their 2-methyl-, isopropyl- and
cyclohexyl-pyrrole derivatives in 44–82% yields as summarized
in Table 1. Most of the products are solids or semisolids and
their spectroscopic data are fully in agreement with their
structure.
As shown in Table 1, the esters of amino acids give higher
yields than their free acids. Comparable yields are obtained
with different R3-groups and this shows that varying the
substituents on the chloro enone does not have a large influence
on the yield of the products.
Formation of the optically pure pyrrole derivative of -valinol,
(S)-3q, starting from chloro enone 2a with optically pure -
valinol and -valine methyl ester, showed that no racemization
occurred during the formation of (S)-3g (Scheme 3).
The pyrrole derivative of amino acid esters and amino alco-
hols showed excellent separation properties by chiral HPLC
column.6 Comparison of the optical purity of the products with
that of racemic mixtures by chiral HPLC column gave the same
result, which is that no racemization occurs by the formation of
a pyrrole ring from amino acids and their esters.
Scheme 1
The Paal–Knorr synthesis, starting from primary amines and
1,4-dicarbonyl compounds4 and their masked equivalents such
as tetrahydro-2,5-dimethoxyfuran, is often used for the con-
struction of pyrrole rings.3 During the condensation reaction
for the formation of the pyrrole ring with amino acids, partial
racemization often occurs. Therefore, the development of a
flexible and selective method to obtain such compounds is
desirable. As we described in a previous paper, we have designed
a convenient new route to 2-methyl-substituted pyrrole rings
from amines, amino alcohols and amino acids with 5-
chloropent-3-en-2-one prepared from acetyl chloride and allyl
5
chlorides in the presence of AlCl3 (Scheme 2). As part of our
By the same method, amino alcohols 1h,i and amine 1j were
also converted to their 2-substituted derivatives in high yields.
Chloro enones 2a–c are synthesized starting from the corre-
sponding acyl chlorides and allyl chloride in the presence
Scheme 2
1
continued interest in the chemistry of 2-substituted pyrroles, we
have extended this chemistry to the conversion of homochiral
amines, β-amino alcohols and α-amino acids to their chiral
2-methyl-, -isopropyl-, -cyclohexyl-, and -phenyl-substituted
pyrrole derivatives.
of AlCl3. According to the H NMR spectrum of the crude
products, the reaction afforded the chloro enones 2a–c as the
major products. Isomers 4a–c were formed as minor products.7
The crude mixtures were used for pyrrole-ring formation
without further purification.
1162
J. Chem. Soc., Perkin Trans. 1, 2001, 1162–1167
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b008317h

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Table 1 Preparation of 2-substituted pyrrole derivatives
Amine 1
Product 3
Yield
(%)
Scheme 4
R1
R2
R3
In the case of 2-phenyl-substituted pyrrole derivatives,
problems occurred during the synthesis of the corresponding
chloro enone. The reaction of allyl chloride with benzoyl
chloride in the presence of AlCl3 afforded the chloro enone in
very low yield (4–6%, 1H NMR).
For the synthesis of 2-phenyl derivatives of pyrrole, the use
of the dibromo compound 9 was suggested. As shown in
Scheme 5, the reaction of 5 with 6 afforded the alcohol 7 in 75%
yield according to a literature procedure.8 The bromination of
alcohol 7 and subsequent CrO3-mediated oxidation of dibromo
alcohol 8 afforded the desired dibromo compound 9 in 80%
yield.
(S)-1a CH3
(S)-1a
COOCH3
CH3
(CH3)2CH
C6H11
(CH3)2CH
CH3
C6H11
CH3
(CH3)2CH
CH3
(CH3)2CH
CH3
(CH3)2CH
C6H11
(S)-3a
(S)-3b
(S)-3c
(S)-3d
(S)-3e
(S)-3f
(S)-3g
(S)-3h
(S)-3i
(S)-3j
(S)-3k
(S)-3l
(S)-3m
(S)-3n
(S)-3o
(S)-3p
(S)-3q
(S)-3r
(S)-3r
(S)-3s
(S)-3t
(S)-3u
(S)-3u
(S)-3v
(S)-3v
(S)-3w
(S)-3w
(S)-3x
80
76
72
52
48
56
75
78
80
72
61
44
47
82
77
75
75
76
78
85
78
85
88
81
75
75
76
90
(S)-1a
(S)-1b CH3
(S)-1c (CH3)2CH
(S)-1c
(S)-1d (CH3)2CH
(S)-1d
(S)-1e CH2COOCH3
(S)-1e
(S)-1f C6H5
(S)-1f
(S)-1f
(S)-1g 4-HOC6H4CH2 COOC2H5
(S)-1g
(S)-1g
COOH
COOH
COOCH3
COOCH3
COOH
CH3
(CH3)2CH
C6H11
As illustrated in Scheme 5, the reaction of dibromo com-
pound 9 with valinol, (S)-1h, afforded two different products
after separation of the crude product by column chrom-
atography. The major product was identified as the desired
2-phenylpyrrole derivative (S)-3s (85%). The minor product
was obtained in 10% yield and identified as a cyclopropane
(S)-1h (CH3)2CH
(S)-1h
(R)-1h
(S)-1h
CH2OH
CH3
(CH3)2CH
(CH3)2CH
C6H5
1
derivative 10 using H and 13C NMR spectroscopy. The cyclo-
(R,S)-1i CH3
(S,R)-1i
CH(OH)Ph
CH3
(CH3)2CH
(CH3)2CH
C6H11
C6H11
C6H5
C6H5
CH3
propane ring is assigned as trans. For the formation of 10 we
propose the following mechanism: The enone 11 can be formed
from 9 with Et3N. It is possible that this compound yields furan
derivative 12, which can then form 13 with 11 via the Michael
addition reaction. The intramolecular cyclization reaction of 13
in the presence of Et3N can form 10. This reaction, which is
outlined in Scheme 5, takes 4–6 hours. With interruption of the
reaction after 2 hours it is possible to isolate the products 12
and 13 from the reaction mixture. Both products are identified
spectroscopically. The formation of the pyrrole ring from 9
should work via the formation of enone 11 in the presence of
Et3N. Using a similar reaction norephedrine 1i is also converted
into 2-phenylpyrrole derivatives in good yield (Table 1). In all
reactions, 10 was formed as a minor product. The formation of
10 and the direct formation of a cyclopropane derivative with a
structure similar to that of 10 from dibromo ketones are still
under investigation.
(R,S)-1i
(S,R)-1i
(R,S)-1i
(S,R)-1i
(R,S)-1i
(S)-1j C6H5
CH3
No product formation was observed with 9 with the use of
amino acids and their esters. The reactions afforded an
undefined mixture of products.
Conclusions
In conclusion, we have developed a new synthetic method
for the efficient preparation of 2-substituted pyrroles from
halogeno enones and amines, amino alcohols and amino acids.
The cyclization works without racemization. It was not possible
to synthesize the 2-phenyl-substituted pyrrole derivatives of
amino acids and esters by this method. The synthesis of 2-
phenylpyrrole derivatives works only with amino alcohols. This
reaction also yields a cyclopropane derivative via the formation
of the phenylfuran, Michael additions, and intramolecular
cyclopropanation reaction. Furthermore, this methodology can
be extended to the synthesis of polyfunctionalized pyrroles and
alkaloids.
Scheme 3
Experimental
The isolated yields of the pyrrole products indicated that
both isomers were reacting in the cyclization. For example,
isomer 4a is synthesized by a Grignard reaction starting
from 1,3-dichloropropene (Scheme 4).7e The reaction of 4a with
(S)-1a afforded the pyrrole derivative (S)-3a in 68% yield. We
propose therefore that enone 2a is an essential starting material
for the formation of the pyrrole ring and that chloro enones
4a–c isomerize to 2a–c during the ring formation reaction.
All reagents were of commercial quality and reagent-quality
solvents were used without further purification. Optical
rotations were measured on a Bellingham and Stanley P-20
polarimeter; [α]D-values are given in units of 10Ϫ1 deg cm2 gϪ1
.
IR spectra were determined on a Philips model PU9700
1
spectrometer. H NMR spectra were determined on a Bruker
400 MHz FT spectrometer. GLC analyses were carried out on
an HP 5890 gas chromatograph. Mass spectra were obtained on
J. Chem. Soc., Perkin Trans. 1, 2001, 1162–1167
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Scheme 5
a VGTrio2 spectrometer at an ionization energy of 70 eV.
(c 0.5 in CH3OH) (Found: C, 71.16; H, 8.67; N, 5.73. Calc.
Halogeno enones 2a, 2b, 2c and 4a are synthesized according
for C14H21NO2: C, 71.46; H, 8.99; N, 5.95%); νmax (neat)/cmϪ1
3050–2860, 1730, 1410, 1340, 1213; δH (400 MHz; CDCl3;
Me4Si) 1.18–1.32 (10H, m, CH2), 1.61 (3H, d, J 7.2, CH3), 2.60–
to the literature.7
General procedure for amino acid esters
), 4.72 (1H, q, J 7.2,
2.71 (1H, m, CH), 3.65 (3H, s, OCH3
CHN), 5.76 (1H, d, J 1.5, CH), 6.00 (1H, t, J 3.2, CH), 6.56
(1H, d, J 1.8, CH); δC (100 MHz; CDCl3; Me4Si) 19.3 (q), 26.3
(t), 27.2 (t), 30.2 (t), 33.9 (d), 52.9 (q), 53.8 (d), 104.2 (d), 108.3
(d), 117.3 (d), 134.5 (s), 173.0 (s).
To a stirred solution of amino acid ester (10 mmol) in 5 ml of
water and 10 ml of benzene was added 5 ml of triethylamine at
room temperature. Then chloro enone (2a, 2b, or 2c) (10 mmol)
in 5 ml of benzene was added and the mixture was refluxed for
4–6 hours. After cooling to room temperature, it was diluted
with water and extracted with dichloromethane (3 × 25 ml).
The combined extracts were washed with brine (25 ml), dried
over MgSO4, and concentrated under reduced pressure. Further
purification was performed by flash column chromatography
on silica gel.
(؊)-Methyl (2S)-3-methyl-2-(2-methyl-1H-pyrrol-1-yl)but-
anoate (S)-3g. Obtained according to general procedure, by
using 1.31 g of S-1d and 1.18 g of 2a, as a colorless oil (1.46 g,
75%), Rf 0.58 (1 : 4 EtOAc–hexane); [α]D22 Ϫ50.1 (c 4 in CH3OH)
(Found: C, 67.86; H, 8.61; N, 6.98. Calc. for C11H17NO2: C,
67.66; H, 8.78; N, 7.17%); νmax (neat)/cmϪ1 3050–2850, 1765,
1530, 1470, 1345; δH (400 MHz; CDCl3; Me4Si) 0.78 (3H, d,
J 6.5, CH3), 1.07 (3H, d, J 6.7, CH3), 2.28 (3H, s, CH3), 2.48
(1H, m, CH), 3.75 (3H, s, OCH3), 4.20 (1H, d, J 10.4, CHN),
5.88 (1H, s, CH), 6.12 (1H, m, CH), 6.85 (1H, d, J 2.3, CH); δC
(100 MHz; CDCl3; Me4Si) 12.7 (q), 19.3 (q), 20.1 (q), 32.4 (d),
52.8 (d), 65.4 (q), 107.6 (d), 108.8 (d), 118.9 (d), 130.1 (s), 172.4 (s).
(؊)-Methyl (2S)-2-(2-methyl-1H-pyrrol-1-yl)propanoate (S)-
3a. Obtained according to general procedure, by using 1.03 g of
S-1a and 1.18 g of 2a, as a viscous oil (1.34 g, 80%); Rf 0.64
(1 : 4 EtOAc–hexane); [α]D22 Ϫ48.1 (c 2 in CH3OH) (Found: C,
64.77; H, 7.71; N, 8.18. Calc. for C9H13NO2: C, 64.65; H, 7.84;
N, 8.38%); νmax (neat)/cmϪ1 2995–2850, 1745, 1420, 1295, 1200,
1085; δH (400 MHz; CDCl3; Me4Si) 1.70 (3H, d, J 7.2, CH3),
2.25 (3H, s, CH3), 3.60 (3H, s, OCH3), 4.80 (1H, q, J 7.0, CHN),
5.95 (1H, m, CH), 6.10 (1H, m, CH), 6.75 (1H, m, CH); δC (100
MHz; CDCl3; Me4Si) 12.5 (q), 18.6 (q), 53.2 (q), 54.3 (d), 108.3
(d), 108.6 (d), 118.0 (d), 129.8 (s), 173.3 (s).
(؊)-Methyl (2S)-2-(2-isopropyl-1H-pyrrol-1-yl)-3-methylbut-
anoate (S)-3h. Obtained according to general procedure, by
using 1.31 g of S-1d and 1.46 g of 2b, as a colorless oil (1.74 g,
78%), Rf 0.59 (1 : 4 EtOAc–hexane); [α]D22 Ϫ6.6 (c 0.3 in CHCl3)
(Found: C, 69.78; H, 9.22; N, 6.05. Calc. for C13H21NO2: C,
69.92; H, 9.48; N, 6.27%); νmax (neat)/cmϪ1 2980–2820, 1745,
1475, 1350, 1295; δH (400 MHz; CDCl3; Me4Si) 0.63 (3H, d,
J 6.7, CH3), 0.94 (3H, d, J 6.6, CH3), 1.14 (3H, d, J 6.8, CH3),
1.18 (3H, d, J 6.8, CH3), 2.35 (1H, dqq, J 10.8, 6.6, 6.7, CH),
2.78 (1H, m, CH), 3.63 (3H, s, OCH3), 4.12 (1H, d, J 10.8,
CHN), 5.75 (1H, dd, J 1.6, 0.7, CH), 5.97 (1H, t, J 1.6, CH),
6.68 (1H, dd, J 1.6, 0.7, CH); δC (100 MHz; CDCl3; Me4Si) 19.2
(q), 20.1 (q), 23.4 (q), 24.1 (q), 25.7 (d), 32.6 (d), 52.4 (q), 64.5
(d), 103.5 (d), 108.2 (d), 117.9 (d), 140.1 (s), 171.2 (s).
(؊)-Methyl
(2S)-2-(2-isopropyl-1H-pyrrol-1-yl)propanoate
(S)-3b. Obtained according to general procedure, by using 1.03
g of S-1a and 1.46 g of 2b, as a viscous oil (1.48 g, 76%); Rf 0.66
(1 : 5 EtOAc–hexane); [α]D22 Ϫ15.2 (c 0.7 in CH3OH) (Found: C,
67.51; H, 8.52; N, 6.92. Calc. for C11H17NO2: C, 67.66; H, 8.78;
N, 7.17%); νmax (neat)/cmϪ1 3025–2875, 1750, 1475, 1356, 1340,
1276; δH (400 MHz; CDCl3; Me4Si) 1.06 (3H, d, J 6.8, CH3),
1.15 (3H, d, J 6.8, CH3), 1.60 (3H, d, J 7.1, CH3), 2.73 (1H, m,
CH), 3.62 (3H, s, OCH3), 4.74 (1H, q, J 7.0, CHN), 5.78 (1H, d,
J 1.8, CH), 5.99 (1H, d, J 3.2, CH), 6.56 (1H, d, J 1.8, CH);
δC (100 MHz; CDCl3; Me4Si) 18.5 (q), 19.1 (q), 21.3 (q), 23.9
(d), 52.6 (q), 53.1 (d), 103.8 (d), 108.2 (d), 117.5 (d), 130.1 (s),
172.1 (s).
(؊)-Dimethyl (2S)-2-(2-methyl-1H-pyrrol-1-yl)butanedioate
(S)-3i. Obtained according to general procedure, by using 1.61
g of S-1e and 1.18 g of 2a, as a viscous oil (1.80 g, 80%), Rf
0.45
(1 : 4 EtOAc–hexane); [α]D22 Ϫ48.1 (c 2 in CH3OH) (Found: C,
58.46; H, 6.77; N, 6.43. Calc. for C11H15NO4: C, 58.66; H, 6.71;
N, 6.22%); νmax (neat)/cmϪ1 2990–2850, 1745, 1740, 1570, 1345,
1224; δH (400 MHz; CDCl3; Me4Si) 2.20 (3H, s, CH3), 2.92 (1H,
dd, J 15.7, 6.9, diastereotopic proton of CH2), 3.30 (1H, dd,
(؉)-Methyl (2S)-2-(2-cyclohexyl-1H-pyrrol-1-yl)propanoate
(S)-3c. Obtained according to general procedure, by using 1.03
g of S-1a and 1.86 g of 2c, as a yellow solid (1.6 g, 72%),
mp 118–120 ЊC; Rf 0.25 (1 : 10 diethyl ether–hexane); [α]D22 23.5
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J 15.7, 7.9, diastereotopic proton of CH2), 3.70 (3H, s, OCH3),
3.74 (3H, s, OCH3), 5.18 (1H, t, J 7.4, CHN), 5.90 (1H, s, CH),
6.11 (1H, t, J 3.2, CH), 6.61 (1H, s, CH); δC (100 MHz; CDCl3;
Me4Si) 12.4 (q), 37.7 (t), 52.8 (q), 53.5 (q), 54.9 (d), 108.3 (d),
109.6 (d), 118.5 (d), 130.2 (s), 171.6 (s), 171.8 (s).
General procedure for amino acids
To a stirred solution of amino acid (10 mmol) in 5 ml of water
and 10 ml of benzene at room temperature was added 5 ml of
triethylamine. Then a chloro enone (2a, 2b, 2c) (10 mmol) in 5
ml of benzene was added and the mixture was refluxed for 4–6
hours. After cooling to room temperature, it was diluted with
water and extracted with dichloromethane (3 × 25 ml). The
combined extracts were washed with brine (25 ml), dried over
MgSO4, and concentrated under reduced pressure. Further
purification was performed by flash column chromatography
on silica gel.
(؊)-Dimethyl(2S)-2-(2-isopropyl-1H-pyrrol-1-yl)butanedioate
(S)-3j. Obtained according to general procedure, by using 1.61
g of S-1e and 1.46 g of 2b, as a viscous oil (1.82 g, 72%), Rf 0.5
(1 : 3 EtOAc–hexane); [α]D22 Ϫ17.66 (c 0.1 in CHCl3) (Found: C,
61.28; H, 7.52; N, 5.33. Calc. for C13H19NO4: C, 61.64; H, 7.56;
N, 5.53%); νmax (neat)/cmϪ1 3025–2890, 1740, 1730, 1520, 1346,
1225; δH (400 MHz; CDCl3; Me4Si) 1.18 (3H, d, J 6.8, CH3),
1.21 (3H, d, J 6.8, CH3), 2.70–2.76 (1H, m, diastereotopic
proton of CH2), 2.85–2.92 (1H, m, CH), 3.19–3.25 (1H, m,
diastereotopic proton of CH2), 3.63 (3H, s, OCH3), 3.67 (3H, s,
OCH3), 5.09–5.13 (1H, m, CHN), 5.79 (1H, s, CH), 5.99 (1H,
m, CH), 6.44 (1H, s, CH); δC (100 MHz; CDCl3; Me4Si) 16.1
(q), 23.6 (q), 25.6 (d), 37.9 (t), 52.3 (d), 53.1 (q), 53.9 (q), 104.1
(d), 109.1 (d), 117.4 (d), 140.2 (s), 170.5 (s), 170.6 (s).
(؉)-(2S)-2-(2-Isopropyl-1H-pyrrol-1-yl)propanoic acid (S)-
3d. Obtained according to general procedure, by using 0.89 g of
S-1b and 1.46 g of 2b, as a viscous oil (0.94 g, 52%), Rf 0.38
(1 : 1 : 3 EtOAc–MeOH–hexane); [α]D22 23.5 (c 0.5 in CHCl3)
(Found: C, 66.43; H, 8.11; N, 7.89. Calc. for C10H15NO2: C,
66.27; H, 8.34; N, 7.73%); νmax (neat)/cmϪ1 3335–2860, 1725,
1540, 1285, 1225; δH (400 MHz; CDCl3; Me4Si) 0.91–1.21 (9H,
br d, CH3), 2.85–2.92 (1H, m, CH), 4.33–4.42 (1H, m, CHN),
5.79 (1H, s, CH), 5.99 (1H, m, CH), 6.44 (1H, s, CH); δC (100
MHz; CDCl3; Me4Si) 19.5 (q), 23.2 (q), 23.9 (q), 25.6 (d), 55.1
(d), 102.8 (d), 107.9 (d), 120.2 (d), 140.2 (s), 180.0 (s).
(؊)-Ethyl (2S)-3-(4-hydroxyphenyl)-2-(2-methyl-1H-pyrrol-1-
yl)propanoate (S)-3n. Obtained according to general procedure,
by using 2.09 g of S-1g and 1.18 g of 2a, as a white solid (2.24 g,
82%), mp 128–130 ЊC; Rf 0.52 (1 : 3 EtOAc–hexane); [α]D22
Ϫ37.80 (c 0.6 in CH3OH) (Found: C, 70.11; H, 6.91; N, 5.36.
Calc. for C16H19NO3: C, 70.31; H, 7.01; N, 5.12%); νmax (neat)/
cmϪ1 3460, 3040–2850, 1735, 1580, 1550, 1435, 1285; δH (400
MHz; CDCl3; Me4Si) 1.13 (3H, t, J 3.8, CH3), 1.86 (3H, s, CH3),
2.99 (1H, m, diastereotopic proton of CH2), 3.20 (1H, dd,
diastereotopic proton of CH2), 4.06 (2H, q, J 3.8, CH2), 4.57
(1H, m, CHN), 5.67 (1H, d, J 1.7, CH), 5.97 (1H, t, J 3.1, CH),
6.53 (2H, d, J 8.4, Ar-H), 6.70 (2H, d, J 8.3, Ar-H), 6.72 (1H, br
s, CH); δC (100 MHz; CDCl3; Me4Si) 14.5 (q), 21.4 (q), 39.0 (t),
60.5 (d), 61.9 (t), 96.6 (d), 108.5 (d), 115.8 (d), 117.8 (d), 128.6
(d), 129.2 (s), 130.5 (s), 155.3 (s), 171.8 (s).
(؊)-(2S)-3-Methyl-2-(2-methyl-1H-pyrrol-1-yl)butanoic acid
(S)-3e. Obtained according to general procedure, by using 1.17
g of S-1c and 1.18 g of 2a, as a viscous oil (0.86 g, 48%), Rf 0.43
(1 : 1 : 1 EtOAc–MeOH–hexane); [α]D22 Ϫ22.1 (c 0.5 in CHCl3)
(Found: C, 66.47; H, 8.52; N, 7.91. Calc. for C10H15NO2: C,
66.27; H, 8.34; N, 7.73%); νmax (neat)/cmϪ1 3345, 3030–2880,
1730, 1490, 1385, 1220; δH (400 MHz; CDCl3; Me4Si) 1.24 (6H,
br d, CH3), 2.05 (3H, s, CH3), 2.21 (1H, m, CH), 3.96 (1H, m,
CHN), 5.72 (1H, s, CH), 5.80 (1H, m, CH), 6.60 (1H, s, CH);
δC (100 MHz; CDCl3; Me4Si) 12.2 (q), 18.7 (q), 21.3 (q), 24.6
(d), 59.6 (d), 105.6 (d), 107.4 (d), 117.9 (s), 128.4 (d), 173.0 (s).
(؉)-(2S)-2-(2-Cyclohexyl-1H-pyrrol-1-yl)-3-methylbutanoic
acid (S)-3f. Obtained according to general procedure, by using
1.17 g of S-1c and 1.86 g of 2c, as a colorless solid (1.39 g, 56%),
Rf 0.38 (1 : 2 : 1 EtOAc–hexane–MeOH); mp > 250 ЊC; [α]D22
23.5 (c 0.5 in CH3OH) (Found: C, 72.46; H, 9.11; N, 5.91. Calc.
for C15H23NO2: C, 72.25; H, 9.30; N, 5.62%); νmax (neat)/cmϪ1
3340, 3025–2870, 1730, 1578, 1345, 1213; δH (400 MHz; CDCl3,
Me4Si) 0.68 (3H, d, J 6.7, CH3), 1.03 (3H, d, J 6.5, CH3), 1.16–
1.96 (11H, m, CH ϩ CH2), 2.34–2.39 (1H, m, CH), 4.12 (1H, d,
J 10.6, CHN), 5.76 (1H, d, J 1.9, CH), 6.00 (1H, t, J 3.2, CH),
6.66 (1H, d, J 1.8, CH); δC (100 MHz; CDCl3; Me4Si) 19.2 (q),
20.1 (q), 25.7 (t), 26.6 (t), 27.1 (t), 27.2 (d), 30.1 (d), 55.1 (d),
104.1 (d), 108.6 (d), 117.6 (d), 139.8 (s), 169.5 (s).
(؊)-Ethyl (2S)-3-(4-hydroxyphenyl)-2-(2-isopropyl-1H-pyr-
rol-1-yl)propanoate (S)-3o. Obtained according to general
procedure, by using 2.09 g of S-1g and 1.46 g of 2b, as a viscous
oil (2.32 g, 77%), Rf 0.41 (1 : 3 EtOAc–hexane); [α]D22 Ϫ25.77
(c 0.6 in CHCl3); νmax (neat)/cmϪ1 3550, 3025–2870, 1735, 1590,
1478, 1325, 1272 (Found: C, 71.51; H, 7.51; N, 4.48. Calc. for
C18H23NO3: C, 71.73; H, 7.69; N, 4.65%); δH (400 MHz; CDCl3;
Me4Si) 0.87 (3H, d, J 6.6, CH3), 1.06 (3H, d, J 6.5, CH3), 1.11
(3H, t, J 3.9, CH3), 2.42–2.48 (1H, m, CH), 3.01–3.06 (1H, m,
diastereotopic proton of CH2), 3.19–3.24 (1H, m, diastereo-
topic proton of CH2), 4.06 (2H, q, J 4.0, OCH2), 4.62–4.66 (1H,
m, CHN), 5.71 (1H, m, CH), 6.03 (1H, m, CH), 6.53 (2H, d,
J 8.1, Ar-H), 6.71 (2H, d, J 8.2, Ar-H), 6.75 (1H, m, CH);
δC (100 MHz; CDCl3; Me4Si) 14.4 (q), 23.2 (q), 23.7 (q), 25.5
(d), 39.3 (t), 59.9 (d), 61.9 (t), 103.5 (d), 108.6 (d), 115.8 (d),
117.7 (d), 128.7 (d), 130.6 (s), 140.6 (s), 155.3 (s), 173.0 (s).
(؊)-(2S)-2-(2-Methyl-1H-pyrrol-1-yl)-2-phenylethanoic acid
(S)-3k. Obtained according to general procedure, by using
1.51 g of S-1f and 1.18 g of 2a, as a semisolid (1.31 g, 61%), Rf
0.45 (1 : 1 : 1 EtOAc–MeOH–hexane); [α]D22 Ϫ24.3 (c 0.5
in CHCl3) (Found: C, 72.43; H, 6.21; N, 6.72. Calc. for
C13H13NO2: C, 72.54; H, 6.09; N, 6.51%); νmax (neat)/cmϪ1 3360,
3025–2855, 1740, 1600, 1425, 1356, 1205; δH (400 MHz; CDCl3;
Me4Si) 2.11 (3H, s, CH3), 4.00 (1H, s, CHN), 5.50 (1H, br s,
CH), 5.80 (1H, m, CH), 6.30 (1H, s, CH), 7.00–7.25 (5H, br s,
Ar-H); δC (100 MHz; CDCl3; Me4Si) 8.7 (q), 60.4 (d), 104.3 (d),
106.5 (s), 107.4 (d), 118.7 (d), 126.3 (d), 127.9 (d), 128.2 (d),
136.2 (s), 175.8 (s).
(؉)-Ethyl (2S)-2-(2-cyclohexyl-1H-pyrrol-1-yl)-3-(4-hydroxy-
phenyl)propanoate (S)-3p. Obtained according to general pro-
cedure, by using 2.09 g of S-1g and 1.86 g of 2c, as a white solid
(2.55 g, 75%), mp 145–148 ЊC; Rf 0.52 (1 : 3 EtOAc–hexane);
[α]D22 34.6 (c 0.8 in CH3OH) (Found: C, 73.61; H, 7.66; N, 4.31.
Calc. for C21H27NO3: C, 73.87; H, 7.97; N, 4.10%); νmax (neat)/
cmϪ1 3480, 3030–2860, 1735, 1570, 1470, 1254; δH (400 MHz;
CDCl3; Me4Si) 1.15 (3H, t, J 3.1, CH3), 1.21–1.34 (10H, m,
CH2), 2.30–2.41 (1H, m, CH), 2.99 (1H, m, diastereotopic
proton of CH2), 3.20 (1H, m, diastereotopic proton of CH2),
4.06 (2H, q, J 3.8, CH2), 4.57 (1H, t, J 8.3, CHN), 5.65 (1H, d,
J 1.7, CH), 5.98 (1H, t, J 3.0, CH), 6.53 (2H, d, J 8.4, Ar-H),
6.70 (2H, d, J 8.3, Ar-H), 6.72 (1H, d, J 3.1, CH); δC (100 MHz;
CDCl3; Me4Si) 21.4 (q), 27.3 (t), 28.3 (t), 30.2 (t), 33.9 (d), 39.0
(t), 60.5 (d), 61.9 (t), 96.6 (d), 108.5 (d), 115.8 (d), 117.8 (d),
128.6 (d), 129.2 (s), 130.5 (s), 155.4 (s), 171.8 (s).
(؊)-(2S)-2-(2-Isopropyl-1H-pyrrol-1-yl)-2-phenylethanoic
acid (S)-3l. Obtained according to general procedure, by using
1.51 g of S-1f and 1.46 g of 2b, as a semisolid (1.06 g, 44%),
Rf 0.71 (1 : 1 : 1 EtOAc–MeOH–hexane); [α]D22 Ϫ27.5 (c 0.5
in CHCl3) (Found: C, 74.21; H, 6.89; N, 5.97. Calc. for
C15H17NO2: C, 74.05; H, 7.04; N, 5.76%); νmax (neat)/cmϪ1 3355,
J. Chem. Soc., Perkin Trans. 1, 2001, 1162–1167
1165

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3030–2870, 1745, 1570, 1490, 1465, 1302, 1223; δH (400 MHz;
CDCl3; Me4Si) 1.28 (6H, d, J 6.8, CH3), 3.12–3.25 (1H, m, CH),
5.68 (1H, s, CH), 5.85 (1H, s, CHN), 5.98 (1H, m, CH), 6.42
(1H, s, CH), 7.00–7.25 (5H, m, Ar-H); δC (100 MHz; CDCl3;
Me4Si) 25.2 (q), 25.4 (q), 25.9 (d), 63.0 (d), 107.9 (d), 108.7 (d),
121.3 (d), 127.3 (d), 128.9 (d), 129.9 (d), 134.2 (s), 135.0 (s),
178.0 (s).
CH3), 1.21 (3H, d, J 7.0, CH3), 2.30 (1H, m, CH), 3.67 (2H, m,
CH2), 3.97 (1H, m, CH), 6.15 (1H, t, J 1.8, CH), 6.21 (1H, t,
J 3.2, CH), 6.78 (1H, t, J 1.7, CH), 7.15–7.42 (5H, m, Ar-H);
δC (100 MHz; CDCl3; Me4Si) 22.5 (q), 24.2 (q), 25.8 (d), 54.5
(d), 64.3 (t), 108.5 (d), 108.8 (d), 118.8 (d), 125.8 (s), 127.0 (d),
127.1 (d), 127.5 (d), 128.3 (s).
(؉)-(1R,2S)-2-(2-Methyl-1H-pyrrol-1-yl)-1-phenylpropan-1-
ol (R,S)-3t. Obtained according to general procedure, by using
1.51 g of (R,S)-1i and 1.18 g of 2a, as a white solid (1.67 g,
78%), Rf 0.45 (1 : 3 EtOAc–hexane); mp 55–56 ЊC; [α]D22 52.6
(c 4 in EtOH) (Found: C, 78,32; H, 7.77; N, 6.34. Calc. for
C14H17NO: C, 78.10; H, 7.96; N, 6.51%); νmax (neat)/cmϪ1 3510,
3010–2850, 1560, 1510, 1490, 1325, 1267, 1123; δH (400 MHz;
CDCl3; Me4Si) 1.37 (3H, d, J 6.9, CH3), 2.06 (3H, s, CH3), 2.19
(1H, s, OH), 4.28 (1H, m, CH), 4.82 (1H, d, J 5.2, CH), 5.83
(1H, s, CH), 6.12 (1H, t, J 2.7, CH), 6.80 (1H, s, CH), 7.20–7.40
(5H, m, Ar-H); δC (100 MHz; CDCl3; Me4Si) 12.5 (q), 15.6 (q),
57.6 (d), 77.6 (d), 107.5 (d), 108.2 (d), 117.9 (d), 126.9 (d), 128.9
(d), 129.5 (s), 129.6 (d), 142.5 (s).
(؉)-(2S)-2-(2-Cyclohexyl-1H-pyrrol-1-yl)-2-phenylethanoic
acid (S)-3m. Obtained according to general procedure, by using
1.51 g of S-1f and 1.86 g of 2c, as a semisolid (1.33 g, 47%), Rf
0.71 (1 : 1 : 1 EtOAc–hexane–MeOH); [α]D22 25.8 (c 0.5 in CHCl3)
(Found: C, 76.12; H, 7.53; N, 4.75. Calc. for C18H21NO2: C,
76.29; H, 7.47; N, 4.94%); νmax (neat)/cmϪ1 3365, 3025–2875,
1745, 1610, 1505, 1478, 1223, 1025; δH (400 MHz; CDCl3;
Me4Si) 1.11–1.21 (6H, m, CH2), 1.52–1.54 (4H, m, CH2), 2.20–
2.41 (1H, m, CH), 5.67 (1H, s, CHN), 5.75 (1H, s, CH), 5.98
(1H, m, CH), 6.42 (1H, s, CH), 7.00–7.20 (5H, m, Ar-H);
δC (100 MHz; CDCl3; Me4Si) 26.6 (t), 27.4 (t), 36.9 (t), 37.8 (d),
66.8 (d), 105.6 (d), 108.8 (d), 122.4 (d), 129.7 (d), 130.5 (d),
130.7 (d), 139.3 (s), 140.0 (s), 177.5 (s).
(؉)-(1R,2S)-2-(2-Isopropyl-1H-pyrrol-1-yl)-1-phenylpropan-
1-ol (R,S)-3u and (؊)-(1S,2R)-2-(2-isopropyl-1H-pyrrol-1-yl)-
1-phenylpropan-1-ol (S,R)-3u. Obtained according to general
procedure, by using 1.51 g of (R,S)-1i and (S,R)-1i with 1.46 g
of 2b, as crystals (2.13 g, 88%) and (2.06 g, 85%) respectively;
mp 64–65 ЊC; Rf 0.49 (1 : 3 EtOAc–hexane); [α]D22 21.45 (c 0.3 in
CHCl3) for (R,S)-3u, [α]D22 Ϫ21.15 (c 0.3 in CHCl3) for (S,R)-3u
(Found: C, 79.16; H, 8.58; N, 5.98. Calc. for C16H21NO: C,
78.97; H, 8.70; N, 5.76%); νmax (neat)/cmϪ1 3505, 3020–2880,
1590, 1458, 1324, 1301, 1278, 1078; δH (400 MHz; CDCl3;
Me4Si) 1.06 (3H, d, J 6.8, CH3), 1.11 (3H, d, J 6.8, CH3), 1.49
(3H, d, J 6.8, CH3), 2.05 (1H, br s, OH), 2.58–2.64 (1H, m, CH),
4.26–4.33 (1H, m, CHN), 4.82 (1H, d, J 5.5, CH), 5.81 (1H, d,
J 3.1, CH), 6.12 (1H, dd, J 3.1, CH), 6.82 (1H, d, J 2.3, CH),
7.19–7.36 (5H, m, Ar-H); δC (100 MHz; CDCl3; Me4Si) 15.8 (q),
22.2 (q), 24.6 (q), 25.4 (d), 56.3 (d), 77.6 (d), 102.8 (d), 107.5 (d),
116.6 (d), 125.7 (d), 127.7 (d), 128.3 (d), 139.6 (s), 141.5 (s).
General procedure for amino alcohols
12.5 mmol of amino alcohol, 12.5 mmol of chloro enone (2a,
2b, 2c or bromo ketone 9) and 25 mmol of triethylamine were
refluxed in 20 ml of diethyl ether for 5–7 hours. The mixture
was cooled to room temperature, diluted with water, and
extracted with diethyl ether (3 × 20 ml). The combined extracts
were washed with brine, dried over MgSO4, and concentrated
under reduced pressure. Further purification was performed by
flash column chromatography on silica gel.
(؊)-(2S)-3-Methyl-2-(2-methyl-1H-pyrrol-1-yl)butan-1-ol
(S)-3q. Obtained according to general procedure, by using 1.03
g of S-1h and 1.18 g of 2a, as a colorless oil (1.25 g, 75%), Rf
0.45 (1 : 4 EtOAc–hexane); [α]D22 Ϫ13.2 (c 3 in CH3OH) (Found:
C, 71.96; H, 10.41; N; 8.51. Calc. for C10H17NO: C, 71.81; H,
10.25; N, 8.37%); νmax (neat)/cmϪ1 3470, 2980–2850, 1403, 1358,
1278, 1125; δH (400 MHz; CDCl3; Me4Si) 0.70 (3H, d, J 6.4,
CH3), 1.00 (3H, d, J 6.4, CH3), 1.90 (1H, m, CH), 2.15 (3H, s,
CH3), 3.65 (1H, m, CH), 3.70 (2H, m, OCH2), 5.80 (1H, m,
CH), 6.10 (1H, m, CH), 6.55 (1H, m, CH); δC (100 MHz;
CDCl3; Me4Si) 13.0 (q), 19.5 (q), 20.3 (q), 31.8 (d), 64.7 (d), 65.0
(t), 107.0 (d), 108.8 (d), 116.9 (d), 131.1 (s).
(؉)-(1R,2S)-2-(2-Cyclohexyl-1H-pyrrol-1-yl)-1-phenyl-
propan-1-ol (R,S)-3v and (؊)-(1S,2R)-2-(2-cyclohexyl-1H-
pyrrol-1-yl)-1-phenylpropan-1-ol (S,R)-3v. Obtained according
to general procedure, by using 1.51 g of (R,S)-1i and (S,R)-1i
with 1.86 g of 2c, as viscous oils (2.12 g, 75%) and (2.29 g, 81%)
respectively; Rf 0.6 (1 : 2 EtOAc–hexane); [α]D22 15.62 (c 1.7 in
CHCl3) for (R,S)-3v, [α]D22 Ϫ15.83 (c 1.7 in CHCl3) for (S,R)-3v
(Found: C, 80.71; H, 8.65; N, 5.23. Calc. for C19H25NO: C,
80.52; H, 8.89; N, 4.94%); νmax (neat)/cmϪ1 3495, 3030–2850,
1560, 1523, 1402, 1325, 1208, 1027, 743; δH (400 MHz; CDCl3;
Me4Si) 1.04–1.75 (10H, m, CH2), 1.41 (3H, d, J 6.9, CH3), 1.92
(1H, s, OH), 2.30–2.41 (1H, m, CH), 4.30 (1H, m, CH-N), 4.69
(1H, d, J 5.5, CH), 5.64 (1H, d, J 1.5, CH), 5.98 (1H, t, J 3.1,
CH), 6.66 (1H, d, J 2.5, CH), 7.07–7.21 (5H, m, Ar-H); δC (100
MHz; CDCl3; Me4Si) 16.1 (q), 26.6 (t), 27.3 (t), 27.4 (t), 32.3
(d), 54.5 (d), 80.0 (d), 103.6 (d), 107.9 (d), 116.7 (d), 126.0 (d),
128.0 (d), 128.6 (d), 134.1 (s), 139.3 (s).
(؊)-(2S)-2-(2-Isopropyl-1H-pyrrol-1-yl)-3-methylbutan-1-ol
(S)-3r and (؉)-(2R)-2-(2-isopropyl-1H-pyrrol-1-yl)-3-methyl-
butan-1-ol (R)-3r. Obtained according to general procedure, by
using 1.03 g of S-1h and R-1h with 1.46 g of 2b, as viscous oils
(1.48 g, 76%) and (1.52 g, 78%) respectively, Rf 0.49 (1 : 3
EtOAc–hexane);[α]D22 Ϫ27.54(c0.07inCHCl3)forS-3r, [α]D22 27.5
(c 0.07 in CHCl3) for R-3r (Found: C, 73.96; H, 10.68; N, 6.92.
Calc. for C12H21NO: C, 73.80; H, 10.84; N, 7.17%); νmax (neat)/
cmϪ1 3485, 3015–2880, 1302, 1278, 1025; δH (400 MHz; CDCl3;
Me4Si) 0.63 (3H, d, J 6.7, CH3), 0.97 (3H, d, J 6.6, CH3), 1.16
(3H, d, J 7.3, CH3), 1.20 (3H, d, J 7.3, CH3), 1.45–1.54 (1H, m,
OH), 1.87–1.94 (1H, m, CH), 2.78–2.85 (1H, m, CH), 3.62–3.66
(2H, m, OCH2), 3.76–3.80 (1H, m, CH), 5.77 (1H, d, J 1.6,
CH), 5.99–6.01 (1H, m, CH), 6.47 (1H, s, CH); δC (100 MHz;
CDCl3; Me4Si) 12.5 (q), 18.1 (q), 21.4 (q), 22.2 (q), 23.5 (d), 29.5
(d), 61.4 (d), 62.6 (t), 100.9 (d), 106.4 (d), 113.4 (d), 139.6 (s).
(؉)-(1R,2S)-1-Phenyl-2-(2-phenyl-1H-pyrrol-1-yl)-propan-1-
ol (R,S)-3w and (؊)-(1S,2R)-1-phenyl-2-(2-phenyl-1H-pyrrol-
1-yl)propan-1-ol (S,R)-3w. Obtained according to general
procedure, by using 1.51 g of (R,S)-1i and (S,R)-1i with 3.05 g
of 9, as viscous oils (2.10 g, 76%) and (2.07 g, 75%) respectively,
Rf 0.57 (1 : 2 EtOAc–hexane); [α]D22 6.36 (c 0.072 in CHCl3) for
(R,S)-3w, [α]D22 Ϫ5.4 (c 0.09 in CHCl3) for (S,R)-3w (Found: C,
82.44; H, 6.72; N, 4.78. Calc. for C19H19NO: C, 82.28; H, 6.90;
N, 5.05%); νmax (neat)/cmϪ1 3485, 3020–2860, 1595, 1502, 1489,
1452, 1321, 1208, 749; δH (400 MHz; CDCl3; Me4Si) 1.40 (3H,
d, J 6.8, CH3), 2.11 (1H, br s, OH), 4.37–4.44 (1H, m, CH), 4.53
(1H, d, J 4.7, CH), 5.97 (1H, d, J 3.2, CH), 6.11 (1H, t, J 1.9,
CH), 6.80 (1H, d, J 3.4, CH), 7.03–7.30 (10H, m, Ar-H); δC (100
(؊)-(2S)-3-Methyl-2-(2-phenyl-1H-pyrrol-1-yl)butan-1-ol
(S)-3s. Obtained according to general procedure, by using 1.03
g of S-1h and 3.05 g of 9, as a viscous oil (1.94 g, 85%), Rf 0.53
(1 : 3 EtOAc–hexane); [α]D22 Ϫ49.2 (c 0.3 in CH3OH) (Found: C,
78.36; H, 8.09; N, 6.38. Calc.for C15H19NO: C 78.56; H, 8.35; N,
6.11%); νmax (neat)/cmϪ1 3490, 3025–2880, 1570, 1402, 1356,
1278, 1085; δH (400 MHz; CDCl3; Me4Si) 1.17 (3H, d, J 7.1,
1166
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MHz; CDCl3; Me4Si) 15.3 (q), 57.4 (d), 86.7 (d), 108.7 (d), 109.3
(d), 119.1 (d), 126.0 (s), 127.5 (d), 127.9 (d), 128.6 (d), 128.7 (d),
130.1 (s), 134.1 (d), 134.9 (s), 141.7 (d).
CDCl3; Me4Si) 3.18 (2H, m, CH2), 4.01–4.04 (2H, m, CH2),
4.76–4.83 (1H, m, CH), 7.47–7.99 (5H, m, Ar-H); δC (100 MHz;
CDCl3; Me4Si) 36.9 (d), 44.9 (t), 45.5 (t), 128.5 (d), 129.9 (d),
134.0 (d), 136.5 (s), 196.1 (s).
(؊)-2-Methyl-1[(1S)-1-phenylethyl]-1H-pyrrole
(S)-3x.
Obtained according to general procedure, by using 1.21 g of
S-1j and 1.18 g of 2a, as crystals (1.66 g, 90%), Rf 0.45 (1 : 3
EtOAc–hexane); mp 52 ЊC; [α]D22 Ϫ16.7 (c 1 in CH3OH) (Found:
C, 84.38; H, 8.33; N, 7.56. Calc. for C13H15N: C, 84.28; H, 8.16;
N, 7.56%); νmax (neat)/cmϪ1 3040–2870, 1580, 1425, 1365, 1203,
1102; δH (400 MHz; CDCl3; Me4Si) 1.84 (3H, d, J 7.1, CH3),
2.13 (3H, s, CH3), 5.30 (1H, q, J 7.1, CH), 5.96 (1H, br s, CH),
6.17 (1H, m, CH), 6.83 (1H, br s, CH), 7.00–7.05 (2H, m,
Ar-H), 7.20–7.35 (3H, m, Ar-H); δC (100 MHz; CDCl3; Me4Si)
12.7 (q), 22.9 (q), 55.7 (d), 107.8 (d), 108.1 (d), 118.1 (d), 126.8
(s), 127.1 (d), 128.3 (d), 133.3 (d), 149.5 (s).
Acknowledgements
This research was supported by the Middle East Technical
University (AFP-1999) and the Turkish State Planning Organ-
ization (DPT) (400 MHz NMR instrument).
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H. Lainton, J. W. Huffman, B. R. Martin and D. R. Compton,
Tetrahedron Lett., 1995, 36, 1401; (i) C. Y. De Leon and B. Ganem,
Tetrahedron, 1997, 53, 7731; (j) P. A. Jacobi, L. D. Coults, J. S. Guo
and S. I. Leung, J. Org. Chem., 2000, 65, 205; (k) J. T. Gupton, K. E.
Krumpe, B. C. Burnham, K. A. Dwornik, S. A. Petrich, K. X. Du,
M. A. Bruce, P. Vu, M. Vargas, K. M. Kcerticar, K. N. Hosein,
C. R. Jones and J. A. Sikorski, Tetrahedron, 1998, 54, 5075.
2 T. L. Gilchrist, J. Chem. Soc., Perkin Trans. 1, 1999, 2849.
3 (a) C. W. Jefford, Curr. Org. Chem., 2000, 4, 205; (b) C. W. Jefford,
Q. Tang and A. Zaslona, J. Am. Chem. Soc., 1991, 113, 3513; (c)
F. J. Sardina and H. Rapoport, Chem. Rev., 1996, 96, 1825;
(d) D. H. R. Barton, J. Kervagoret and S. Z. Zard, Tetrahedron,
1990, 46, 7587; (e) N. Ono, H. Kawamura, M. Bougauchi and
K. Maruyama, Tetrahedron, 1990, 46, 7483; ( f ) C. Kashima,
T. Maruyama, K. Harada, S. Hibi and Y. Omote, J. Chem. Res. (S),
1988, 62.
1-Phenylbut-3-en-1-ol 7
To a 100 ml flask charged with Zn (0.12 mol), 25 ml of satur-
ated aq. NH4Cl and 3 ml of THF, was added a mixture of 14.5
g (0.12 mol) of 3-bromopropene and 10 ml (0.10 mol) of benz-
aldehyde dropwise. The temperature of the reaction was kept at
30–40 ЊC for 4 hours. The mixture was stirred for one hour at
room temperature. Finally, it was quenched with 10 ml of 7%
HCl and 5 ml of saturated NH4Cl, and the water layer was
extracted with diethyl ether (3 × 15 ml). The combined extracts
were washed successively with water (2 × 10 ml) and brine
(2 × 10 ml), dried over MgSO4, and concentrated under
reduced pressure. Further purification of the crude product was
achieved by vacuum distillation (bp 81–82 ЊC, 1 mmHg) (12.52
g, 75%), Rf 0.65 (1 : 4 EtOAc–hexane); δH (400 MHz; CDCl3;
Me4Si) 2.45 (2H, t, J 6.7, CH2), 2.77 (1H, s, OH), 4.65 (1H, t,
J 6.7, CH), 5.04–5.13 (2H, m, CH2), 5.68–5.81 (1H, m, CH),
7.19–7.26 (5H, m, Ar-H).
3,4-Dibromo-1-phenylbutan-1-ol 8
4 (a) C. W. Jefford, F. de V. Naide and K. Sienkiewicz, Tetrahedron:
Asymmetry, 1996, 7, 1069; (b) R. Grigg and G. Yoganathan,
Tetrahedron: Asymmetry, 1996, 7, 273; (c) C. W. Bird and G. W. H.
Cheeseman, Comprehensive Heterocyclic Chemistry, ed. A. R.
Katritzky and C. W. Rees, Pergamon Press, Oxford, 1984, vol. 4;
(d) B. Baltazzi and L. I. Kirmen, Chem. Rev., 1963, 63, 511; (e) M. J.
Earle, H. Heaney, Synlett, 1992, 745; ( f ) R. A. Gadzhili, B. M.
Fedoseev, R. A. Necefova and V. R. Caferov, Khim. Geterotsikl.
Soedin, 1990, 1047.
0.059 Mol of Br2 in 10 ml of CCl4 was added dropwise to a
solution of 1-phenylbut-3-en-1-ol 7 (0.067 mol) in 25 ml of
CCl4 at 0 ЊC. After the addition was complete, the mixture was
stirred at room temperature for one hour. Then the mixture
was evaporated and the product obtained was used in the next
step without any further purification (15.43 g, 85%), Rf 0.54
(1 : 4 EtOAc–hexane); δH (400 MHz; CDCl3; Me4Si) 2.23 (2H,
m, CH2), 2.85 (1H, s, OH), 3.83 (2H, m, CH2), 4.53 (1H, m,
CH), 4.86–4.94 (1H, m, CH), 7.24–7.51 (5H, m, Ar-H); δC (100
MHz; CDCl3; Me4Si) 35.8 (t), 46.6 (d), 49.4 (t), 73.4 (d), 128.3
(d), 128.7 (d), 129.2 (s), 129.4 (d).
5 A. S. Demir, I. M. Akhmedov, C. Tanyeli, Z. Gerçek and R. A.
˙
Gadzhili, Tetrahedron: Asymmetry, 1997, 5, 753.
6 Optical purity is determined by chiral HPLC analysis (Chiral pack
AD column, UV detection at 220 nm, 90 : 10 isohexane–propan-
2-ol, flow rate 0.75 ml minϪ1).
7 (a) I. I. Ibragimov, M. M. Guseinov, R. A. Gadzhili, V. G.
Dzhafarov and S. P. Godzhaev, Khim. Geterotsikl. Soedin., 1973,
1434; (b) D. Barbry, C. Faven and A. Ayana, Synth. Commun., 1993,
23, 2647; (c) R. A. Gadzhili, V. M. Fedoseev, R. A. Nadzhafova and
V. G. Dzhafarov, J. Org. Chem. USSR (Engl. Transl.), 1990, 26, 874;
(d) I. I. Ibragimov, E. I. Mamedov, A. T. Ismailov, S. Z. Mekhtieva,
N. N. Mamedov and V. I. Belyaeva, J. Org. Chem. USSR (Engl.
Transl.), 1990, 26, 1981; (e) E. J. Mamedov, A. G. Ismailov, S. I.
Kozhuskov and N. S. Zefirov, J. Org. Chem. USSR (Engl. Transl.),
1992, 28, 260; ( f ) R. A. Gadzhili, V. M. Fedoseev, N. A.
Netkacheva, C. N. Ahhmedov and M. S. Sultanova, J. Org. Chem.
USSR (Engl. Transl.), 1989, 25, 837; (g) O. G. Kulinkovich, I. G.
Tischenka and V. L. Sorokin, J. Org. Chem. USSR (Engl. Transl.),
1985, 21, 1514.
3,4-Dibromo-1-phenylbutan-1-one 9
3,4-Dibromo-1-phenylbutan-1-ol 8 (0.05 mol) was dissolved in
35 ml of acetone in a 200 ml three-necked flask. CrO3 (0.17
mol), 6 ml of concentrated H2SO4, and 10 ml of distilled water
mixture was added dropwise with the temperature kept at
20–25 ЊC. After the addition was complete, the reaction mixture
was stirred for four hours. The layers were separated and the
water layer was extracted with diethyl ether (3 × 15 ml). The
combined extracts were washed successively with water and
brine, dried over MgSO4, and concentrated under reduced
pressure. Crystallization of the crude product in diethyl ether–
hexane afforded ketone 9 as yellow crystals (mp 38–40 ЊC)
(12.31 g, 80%), Rf 0.48 (1 : 4 EtOAc–hexane); δH (400 MHz;
8 (a) X. Coqueret, F. Bourelle and W. J. Chuche, Tetrahedron Lett.,
1983, 34, 5382; (b) C. Petrier and J. L. Luche, J. Org. Chem., 1985,
50, 910.
J. Chem. Soc., Perkin Trans. 1, 2001, 1162–1167
1167