Reaction of alcohols (via the Mitsunobu reaction) and alkyl halides with chiral selone derivatizing agents

Article abstract of DOI:10.1016/S0957-4166(99)00140-8

Coupling of a selone chiral derivatizing agent (CDA) to D,L-alkyl halides gives Se-alkylated adducts in yields ranging from 76-97%. Reaction of D,L-alcohols with the selone CDAs via the Mitsunobu reaction has given rise to Se-alkylated adducts in yields ranging from 82-92%. Examination of the ⁷⁷Se NMR spectra of the resulting diastereomeric adducts indicates that discrimination of remotely disposed chiral centers is possible using this technique.

Full text of DOI:10.1016/S0957-4166(99)00140-8

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1465–1470
Reaction of alcohols (via the Mitsunobu reaction) and alkyl
halides with chiral selone derivatizing agents1
Ruilian Wu,a,† Jerome D. Odom,b R. Bruce Dunlap b and Louis A. Silks III a,∗,‡
aLos Alamos National Laboratory, Bioscience and Biotechnology Group, CST-4 MS, E-529, Los Alamos, NM 87545, USA
bDepartment of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208, USA
Received 23 February 1999; accepted 30 March 1999
Abstract
Coupling of a selone chiral derivatizing agent (CDA) to D,L-alkyl halides gives Se-alkylated adducts in yields
ranging from 76–97%. Reaction of D,L-alcohols with the selone CDAs via the Mitsunobu reaction has given rise
to Se-alkylated adducts in yields ranging from 82–92%. Examination of the 77Se NMR spectra of the resulting
diastereomeric adducts indicates that discrimination of remotely disposed chiral centers is possible using this
technique. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
The development of new chiral derivatizing agents (CDAs) for the determination of the chiral
enrichment of chemical and enzymatic processes is an area that is being actively investigated.2 We
have developed chiral selone CDAs which allow for the determination of enantiomeric excesses (ees)
of carboxylic acids,3 acid chlorides,4 alcohols,5 amines6 and amino acids7 by 77Se NMR spectroscopy.
In addition, the use of these CDAs allows the assessment of the absolute configuration of the chiral center
in some cases.8 In an effort to increase the versatility of this method we have examined the reaction of
alkyl halides and the direct coupling of alcohols via the Mitsunobu reaction to these selone CDAs.9
Usually the ee determination of optically active organohalides is accomplished by measuring the
optical rotation and comparing the value obtained to the literature value. This method gives rise to
accurate determinations; however, it has some known drawbacks.2 Development of a CDA capable of
delivering the same information would be useful.
∗
†
Corresponding author. Fax: 505-665-5052; e-mail: pete-silks@lanl.gov
Current address: CPBD, Inc., 300 Putnam Avenue, Cambridge, Massachusetts, 02139. Tel: (617)-868-2222 (ext. 246); e-mail:
rwu@CPBD.com
‡
Adjunct Associate Professor, Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South
Carolina, 29208.
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00140-8

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2. Results and discussion
Reaction of acyl groups with 1 gives rise to selective N-acylation (Fig. 1). This has been found
for acid chlorides, carbonyl chlorides, carbamoyl chlorides, and DCC activated acids. However, with
softer electrophiles it was expected that alkylation would take a different course. We reported that
reaction of ethyl bromoacetate with 1 afforded the Se-alkylated product.3 The chemoselectivity of the
reaction was confirmed by the observation of a JC–Se=∼140 Hz which is indicative of an sp2 carbon
selenium coupling.10 Based on this result a series of alkyl halides were reacted with 1, giving rise to
the corresponding selenides. Again, observation of JC–Se=∼140 Hz for the alkyl halide adducts studied
to date demonstrates that alkylation had taken place at the selenium atom. In addition, the selenium
chemical shifts of the adducts are within the range reported for selenides.10 As illustrated in Table 1,
for activated systems such as the α-bromo-γ-butyrolactone and the 3-bromocyclohexene, the reaction
proceeds in acetone over a period of 12 h. However, for unactivated systems the alkylation required the
presence of NaI in acetone. After 12 h the reaction was concentrated and the selenide was purified by
flash column chromatography.
Figure 1. Chiral selone 1 structure
The use of the Mitsunobu reaction to effect the coupling of alcohols directly to the selone CDA
was investigated next. There are a few reports of the use of the Mitsunobu reaction to selenides.11
Despite this relatively unknown adaptation of the type of Mitsunobu reaction, we proceeded to evaluate
conditions to effect the direct coupling of alcohols to the selenium atom of these CDAs. Simply mixing
the alcohol, selone, and the triphenylphosphine, followed by the dropwise addition of the diisopropyl
Table 1
Yields and 77Se NMR data of (ꢀ) alkyl halide adducts with (4S,5R)-4-methyl-5-phenyl-oxazolidin-2-
selone

R. Wu et al. / Tetrahedron: Asymmetry 10 (1999) 1465–1470
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azodicarboxylate at ambient temperature gave rise to the adducts in fair to good yield. The yields and
∆δSe values are given in Table 2.
Table 2
Yields and 77Se NMR data of (ꢀ)-alcohol adducts with (4S,5R)-4-methyl-5-phenyl-oxazolidin-2-
selone
1
The sensitivity of the 77Se nucleus (0.07 with respect to H and 2.98 compared to 13C), its natural
abundance (7.5%), and spin (I=1/2) make it an excellent NMR probe. Selenium has the special feature
of possessing a large chemical shift range (∼3400 ppm) and it is extremely sensitive to its electronic
environment. This chemical shift sensitivity has been observed for the mono-deuterated racemic benzyl
alcohol. The NMR analysis of the Mitsunobu coupled product gave ∆δSe=5 Hz. In contrast, attachment
of the alcohol through a carbonyl linker to the selone CDA nitrogen (an adduct possessing an intact
selenocarbonyl) has not given rise to any resolution of the diastereomers by 77Se NMR spectroscopy.
Fig. 2 is the 1D spectrum of the selenide (Table 1, Entry 1) in which the chiral center is 3 atoms removed
from the observed selenium nucleus. The ∆δSe was 19 Hz.
Figure 2. 77Se 1D NMR spectrum of 1-bromo-3-phenylbutane selone adduct
The ability of the selone to undergo selective reaction with halides where the reacting carbon is also
the chiral center has not been evaluated. However, in cases where the chiral center is remotely disposed
from the reaction site, the evaluation of the diastereomeric mixtures via the measurement of the 77Se
NMR spectrum allows for the enantiomeric excess of the parent halide or alcohol to be determined.

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3. Experimental
3.1. General
1
The H, 13C, and 77Se NMR spectra were recorded as [2H]chloroform or [2H]benzene solutions on
Bruker WM-300 or AMX-500 NMR spectrometers. The δH values are expressed in parts per million with
respect to tetramethylsilane at 0.0 ppm; δC values are referenced with respect to internal [2H]chloroform
(δ=77.0 ppm with respect to tetramethylsilane at 0.0 ppm); and δSe values are expressed in parts per
million with respect to a 60% (v/v) solution of (CH3)2Se in [2H]chloroform (0 ppm).12 Positive chemical
shifts denote resonances deshielded with respect to the reference. IR spectra were recorded on a BioRad
FTS-40 spectrometer. Microanalyses were performed on a Perkin–Elmer Series II CHNS/O Analyzer
#2400 (CST-11, Los Alamos National Laboratory). Analytical thin-layer chromatography (TLC) was
carried out on glass plates (silica gel 60, 250 mu thickness) with a UV lamp, I2 staining, and an ethanolic
solution of phosphomolybdic acid. Liquid chromatography separations were carried out on silica gel
(230–400 mesh, Merck).
3-Bromocyclohexene, 1-bromo-2-ethylhexane, α-bromo-γ-butyrolactone, sodium iodide, and diiso-
propyl azodicarboxylate were purchased from Aldrich Chemical Co. and used without purification.
Triphenylphosphine was purchased from Sigma Chemical Co. and used without purification. Acetone
was purchased from Aldrich Chemical Co., as a sure-seal product, and used without purification.
Dichloromethane was distilled from calcium hydride. Triethylamine, and N,N-diisopropylethylamine
were purchased from Aldrich Chemical Co. and distilled from calcium hydride before use. 1-Bromo-
2-methylbutane, and 1-bromo-3-phenylbutane were synthesized from their corresponding alcohols by
standard procedures. Monodeuterated benzyl alcohol was synthesized by reduction of benzaldehyde with
sodium borodeuteride in ethanol. The chiral selones were constructed in two steps from commercially
available amino alcohols.13
3.1.1. General procedure for unactivated alkyl bromides
To a solution of selone (0.128 g, 0.534 mmol) and sodium iodide (1.198 g, 7.99 mmol) in acetone (5.0
mL) was added 1-bromo-2-ethylhexane (0.067 g, 0.330 mmol) followed by N,N-diisopropylethylamine
(0.138 g, 1.068 mmol) dropwise at room temperature. The reaction mixture was stirred overnight.
The solvent was removed under reduced pressure and the residue was purified on silica gel (50% v/v
EtOAc/hexane) to provide 0.113 g (97%) of the product as a colorless oil.
3.1.2. Oxazole, 2-[(3-phenyl)-butan-1-ylseleno]-4,5-dihydro-4-methyl-5-phenyl-,[4S-(4R*,5S*)] (1)
Yield 91%; IR (neat) 3192, 3104, 3082, 3061, 3027, 2970, 2927, 2868, 1606, 1494, 1452, 1377, 1358,
1334, 1291, 1255, 1212, 1110, 1080, 1040, 1029, 955, 934, 913, 879, 762, 748, 725, 699, 639, 540 cm−1;
1H NMR (CDCl3) δ 7.33–7.11 (m, 20H), 5.57 (d, J=9.3 Hz, 1H), 5.56 (d, J=9.3 Hz, 1H), 4.43–4.36 (m,
2H), 2.98–2.76 (m, 6H), 2.10–2.03 (m, 4H), 1.23 (d, J=7.5 Hz, 6H), 0.72 (d, J=6.9 Hz, 6H); 13C NMR
(CDCl3) δ 159.16, 146.02, 136.53, 128.59, 128.46, 128.23, 127.91, 127.03, 126.19, 126.15, 85.43, 65.84,
39.99, 38.69, 25.17, 22.14, 17.71; 77Se NMR (CDCl3) δ 268.66, 268.46. Anal. calcd for C20H23NOSe:
C, 64.51; H, 6.23; N, 3.76. Found: C, 64.44; H, 6.31; N, 3.94.
3.1.3. Oxazole, 2-[(2-methyl)-butan-1-ylseleno]-4,5-dihydro-4-methyl-5-phenyl-,[4S-(4R*,5S*)] (2)
Yield 76%; IR (neat) 3087, 3062, 3028, 2958, 2926, 2872, 1605, 1494, 1454, 1377, 1333, 1289,
1
1256, 1222, 1130, 1105, 1079, 1040, 1029, 958, 934, 875, 749, 698, 639 cm−1; H NMR (CDCl3) δ
7.45–7.23 (m, 5H), 5.68 (d, J=9.5 Hz, 1H), 4.54–4.46 (m, 1H), 3.27–3.18 (m, 1H), 3.12–3.03 (m, 1H),

R. Wu et al. / Tetrahedron: Asymmetry 10 (1999) 1465–1470
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1.83 (sex, J=7.0 Hz, 1H), 1.62–1.49 (m, 1H), 1.38–1.26 (m, 1H), 1.07 (d, J=7.0 Hz, 3H), 0.96 (t, J=7.0
Hz, 3H), 0.83 (d, J=7.0 Hz, 3H); 13C NMR (CDCl3) δ 159.53 (1JC–Se=140.8 Hz), 136.55, 128.19, 127.84,
126.10, 85.44, 65.78, 35.37, 35.31, 34.71 (1JC–Se=55.8 Hz), 29.24, 29.21, 19.42, 17.67, 11.35; 77Se NMR
(CDCl3) δ 233.95, 233.87. Anal. calcd for C15H21NOSe: C, 58.06; H, 6.82; N, 4.51. Found: C, 58.16;
H, 6.88; N, 4.61.
3.1.4. Oxazole, 2-[(2-ethyl)-hex-1-ylseleno]-4,5-dihydro-4-methyl-5-phenyl-,[4S-(4R*,5S*)] (3)
Yield 97%; IR (neat) 3064, 3030, 2959, 2928, 2872, 2858, 1607, 1454, 1378, 1290, 1256, 1110, 1080,
1
1040, 956, 934, 747, 699, 639 cm−1; H NMR (CDCl3) δ 7.31–7.10 (m, 5H), 5.55 (d, J=9.3 Hz, 1H),
4.38 (dq, J=6.9, 9.3 Hz, 1H), 3.17–3.06 (m, 2H), 1.60 (sept, J=6.2 Hz, 1H), 1.38–1.17 (m, 8H), 0.83 (t,
J=7.5 Hz, 6H), 0.70 (d, J=6.9 Hz, 3H); 13C NMR (CDCl3) δ 159.58 (1JC–Se=140.5 Hz), 136.57, 128.17,
127.84, 126.11, 85.45, 65.78, 39.72, 39.70, 33.14, 32.38 (1JC–Se=55.5 Hz), 28.88, 28.85, 26.42, 22.86,
17.66, 13.99, 10.94; 77Se NMR (CDCl3) δ 225.83, 225.10. Anal. calcd for C18H27NOSe: C, 61.35; H,
7.72; N, 3.97. Found: C, 61.23; H, 7.77; N, 4.30.
3.2. General procedure for activated alkyl bromides
To a solution of selone (0.058 g, 0.24 mmol) in acetone (2.0 mL) was added α-bromo-γ-butyrolactone
(0.040 g, 0.24 mmol) dropwise at room temperature. To this was added triethylamine (0.049 g, 0.48
mmol) dropwise at room temperature. The reaction mixture was stirred overnight. The solvent was
removed under reduced pressure and the residue was purified on silica gel (50% v/v EtOAc/hexane)
giving 0.065 g (84%) of the product as a colorless oil.
3.2.1. 2(3H)-Furanone, 3-[(4,5-dihydro-4-methyl-5-phenyl-2-oxazolyl)seleno]dihydro-,[4S-(4R*,5S*)]
(4)
Yield 84%; IR (neat) 3202, 3109, 3087, 3063, 3030, 2974, 2928, 1776, 1611, 1495, 1453, 1375, 1335,
1291, 1259, 1171, 1110, 1080, 1020, 1000, 947, 935, 916, 879, 749, 728, 700, 684, 639 cm−1; 1H NMR
(CDCl3) δ 7.31–7.09 (m, 10H), 5.61 (d, J=9.3 Hz, 1H), 5.59 (d, J=9.3 Hz, 1H), 4.43–4.27 (m, 6H),
4.27–4.20 (m, 2H), 2.87–2.78 (m, 2H), 2.59–2.47 (m, 2H), 0.69 (d, J=6.9 Hz, 3H), 0.68 (d, J=6.9
Hz, 3H); 13C NMR (CDCl3) δ 174.82, 157.18, 135.89, 128.32, 128.10, 126.10, 126.07, 86.20, 67.24,
65.96, 65.90, 36.35, 36.25, 31.36, 31.32, 17.64; 77Se NMR (CDCl3) δ 380.86, 378.76. Anal. calcd for
C14H15NO3Se: C, 51.86; H, 4.66; N, 4.32. Found: C, 51.57; H, 4.79; N, 4.21.
3.2.2. Oxazole, 2-(2-cyclohexen-1-ylseleno)-4,5-dihydro-4-methyl-5-phenyl-,[4S-(4R*,5S*)] (5)
Yield 80%; IR (neat) 3187, 3085, 3060, 3025, 2971, 2925, 2831, 1602, 1494, 1453, 1376, 1290,
1
1252, 1210, 1181, 1107, 1079, 1035, 998, 953, 934, 914, 878, 865, 736, 698 cm−1; H NMR (CDCl3)
δ 7.31–7.10 (m, 10H), 5.86–5.80 (m, 2H), 5.77–5.72 (m, 2H), 5.55 (d, J=9.3 Hz, 2H), 4.43–4.34 (m,
4H), 2.12–2.04 (m, 4H), 2.04–1.97 (m, 4H), 1.81–1.71 (m, 2H), 1.70–1.61 (m, 2H), 0.71 (d, J=6.9 Hz,
3H), 0.70 (d, J=6.9 Hz, 3H); 13C NMR (CDCl3) δ 159.80 (1JC–Se=140.5 Hz), 159.78 (1JC–Se=140.5 Hz),
136.56, 136.52, 130.78, 130.75, 128.19, 127.84, 126.82, 126.12, 85.28, 85.24, 65.80, 41.23 (1JC–Se=55.5
Hz), 41.21 (1JC–Se=55.5 Hz), 30.20, 30.03, 24.85, 19.84, 17.71; 77Se NMR (CDCl3) δ 363.15. (C6D6) δ
360.68, 358.56. Anal. calcd for C16H19NOSe: C, 60.00; H, 5.98; N, 4.37. Found: C, 59.84; H, 6.11; N,
4.30.

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3.3. General procedure for Mitsunobu reactions
To a solution of selone (0.113 g, 0.500 mmol), monodeuterated benzyl alcohol (0.037 g, 0.333 mmol),
and triphenylphosphine (0.131 g, 0.500 mmol) in dichloromethane (5.0 mL) was added diisopropyl
azodicarboxylate (0.106 g, 0.500 mmol) dropwise at room temperature. The mixture was stirred at room
temperature for 2–3 h. The solvent was removed under reduced pressure and the residue was purified on
silica gel with dichloromethane giving 0.973 g (92%) of the product as a colorless oil.
3.3.1. Oxazole, 2-[2-phenyl-1-(2H)ethyl-1-ylseleno]-4,5-dihydro-4-(R)-phenyl (6)
Yield 92%; IR (neat) 3174, 3103, 3082, 3059, 3026, 2961, 2894, 1600, 1582, 1493, 1451, 1333, 1255,
1121, 1076, 1029, 941, 890, 791, 758, 739, 697, 643, 589, 546 cm−1; 1H NMR (CDCl3) δ 7.31–6.95 (m,
20H), 4.89 (d, J=9.3 Hz, 1H), 4.87 (d, J=9.3 Hz, 1H), 4.23 (br s, 1H), 4.20 (br s, 1H), 4.03 (d, J=9.3
Hz, 2H), 3.71 (apparent t, J=7.5 Hz, 2H); 13C NMR (CDCl3) δ 161.51, 141.82, 137.66, 128.99, 128.64,
128.55, 127.62, 127.27, 126.56, 76.17, 70.14, 30.39 (t, J=22.5 Hz); 77Se NMR (CDCl3) δ 344.92, 344.86.
(C6D6) δ 351.47, 351.42. Anal. calcd for C16H14DNOSe: C, 60.57; H, 4.45; N, 4.41. Found: C, 60.19;
H, 4.84; N, 4.39.
Acknowledgements
We gratefully acknowledge financial support from the National Stable Isotopes Resource, NIH
Division of Research Resources (RR 02231) and the grants XL2G and XAB2 of the Los Alamos National
Laboratory Directed Research and Development Fund.
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