Synthesis of optically pure 2-azido-1-arylethanols with isolated enzymes and conversion to triazole-containing β-blocker analogues employing click chemistry

Article abstract of DOI:10.1021/jo8009616

(Chemical Equation Presented) Both antipodes of 2-azido-1-arylethanols were synthesized with excellent optical purity via enzymatic reduction of the corresponding α-azidoacetophenone derivatives catalyzed by a recombinant carbonyl reductase from Candida m

Full text of DOI:10.1021/jo8009616

SCHEME 1. 2-Azido-1-arylethanols as Important
Intermediates
Synthesis of Optically Pure
2-Azido-1-arylethanols with Isolated Enzymes
and Conversion to Triazole-Containing ꢀ-Blocker
Analogues Employing Click Chemistry
Haribabu Ankati, Yan Yang, Dunming Zhu,*
Edward R. Biehl, and Ling Hua*
Department of Chemistry, Southern Methodist UniVersity,
Dallas, Texas 75275
moiety.5 The triazole ring is a potential pharmacophore that has
gained attention over the past few years.6,7 For example, the
1,2,3-triazole moiety has be used as an effective peptide
surrogate in HIV-1 protease inhibitors.8
dzhu@smu.edu; lhua@smu.edu
ReceiVed May 3, 2008
Given the importance of optically active 2-azido-1-aryletha-
nols, various methods have been sought for their preparation
in optically pure form. For example, the azidolysis of optically
pure epoxides9–11 and diol derivatives12 with azide anion led
to the formation of optically active azido alcohols. Resolutions
of racemic 2-azido-1-arylethanols catalyzed by lipases13–15 and
racemic epoxides catalyzed by halohydrin dehalogenase with
azide anion as nucleophile16 have also been utilized to obtain
enantiomerically pure 2-azido-1-arylethanols. Since R-azidoac-
etophenone derivatives are readily available from the azidolysis
of R-haloacetophenes with sodium azide, the enantioselective
reduction of R-azidoacetophenones to chiral 2-azido-1-aryle-
thanols should be an attractive approach. However, only a few
reports have appeared to deal with enantioselective chemical
reduction of R-azidoacetophenones.17–21 Watanabe et al. have
examined the transfer hydrogenation of R-azidoacetophenone
in a study on the asymmetric transfer hydrogenation of
functionalized acetophenones.17 Reddy et al. have reported that
Both antipodes of 2-azido-1-arylethanols were synthesized
with excellent optical purity via enzymatic reduction of the
corresponding R-azidoacetophenone derivatives catalyzed by
a recombinant carbonyl reductase from Candida magnoliae
(CMCR) or an alcohol dehydrogenase from Saccharomyces
cereVisiae (Ymr226c). This provides an effective route to
this class of important compounds in optically pure form.
(S)-2-Azido-1-(p-chlorophenyl)ethanols reacted with alkynes
employing click chemistry to afford high yields of optically
pure triazole-containing ꢀ-adrenergic receptor blocker ana-
logues with potential biological activity.
(5) Su, S.; Giguere, J. R.; Schaus, S. E.; Porco, J. A. Tetrahedron 2004, 60,
8645–8657.
(6) Aufort, M.; Herscovici, J.; Bouhours, P.; Moreau, N.; Girard, C. Bioorg.
Med. Chem. Lett. 2008, 18, 1195–1198.
(7) Zhou, Y.; Zhao, Y.; O’Boyle, K. M.; Murphy, P. V. Bioorg. Med. Chem.
Lett. 2008, 18, 954–958.
(8) Brik, A.; Alexandratos, J.; Lin, Y.-C.; Elder, J. H.; Olson, A. J.; Wlodawer,
A.; Goodsell, D. S.; Wong, C.-H. ChemBioChem 2005, 6, 1167–1169.
(9) Boruwa, J.; Borah, J. C.; Kalita, B.; Barua, N. C. Tetrahedron Lett. 2004,
45, 7355–7358.
Optically active 2-azido-1-arylethanols are precursors of chiral
aziridines and vicinal amino alcohols as shown in Scheme 1.
Chiral aziridines are important building blocks in organic
synthesis1 and key components in bioactive molecules (e.g.,
aziridine-based cysteine protease inhibitors).2–4 Optically pure
ꢀ-amino alcohols are widely used as chiral ligands for asym-
metric catalysis and in the construction of biologically active
compounds such as ꢀ-adrenergic receptor blockers. In addition,
employing click chemistry, i.e., copper(I)-catalyzed azide-alkyne
[3 + 2] cycloaddition, 2-azido-1-arylethanols can be converted
to ꢀ-adrenergic receptor blocker analogues with 1,2,3-triazole
(10) Guy, A.; Dubuffet, T.; Doussot, J.; Godefroy-Falguieres, A. Synlett 1991,
403–4.
(11) Guy, A.; Doussot, J.; Garreau, R.; Godefroy-Falguieres, A. Tetrahedron:
Asymmetry 1992, 3, 247–50.
(12) Cho, B. T.; Kang, S. K.; Shin, S. H. Tetrahedron: Asymmetry 2002,
13, 1209–1217.
(13) Brenelli, E. C. S.; Fernandes, J. L. N. Tetrahedron: Asymmetry 2003,
14, 1255–1259.
(14) Pamies, O.; Baeckvall, J.-E. J. Org. Chem. 2001, 66, 4022–4025.
(15) Kamal, A.; Shaik, A. A.; Sandbhor, M.; Malik, M. S. Tetrahedron:
Asymmetry 2004, 15, 935–939.
(16) Spelberg, J. H. L.; van Hylckama Vlieg, J. E. T.; Tang, L.; Janssen,
D. B.; Kellogg, R. M. Org. Lett. 2001, 3, 41–43.
(17) Watanabe, M.; Murata, K.; Ikariya, T. J. Org. Chem. 2002, 67, 1712–
1715.
(1) Yudin, A., Ed. Aziridines and Epoxides in Organic Synthesis; Wiley:
Chichester, UK, 2006.
(18) Reddy, M. A.; Bhanumathi, N.; Rao, K. R. Chem. Commun. 2001, 1974–
1975.
(2) Mladenovic, M.; Schirmeister, T.; Thiel, S.; Thiel, W.; Engels, B.
ChemMedChem 2007, 2, 120–128.
(19) Yadav, J. S.; Reddy, P. T.; Hashim, S. R. Synlett 2000, 1049–1051.
(20) Rao, A. V. R.; Gurjar, M. K.; Kaiwar, V. Tetrahedron: Asymmetry 1992,
3, 859–62.
(3) Vicik, R.; Helten, H.; Schirmeister, T.; Engels, B. ChemMedChem 2006,
1, 1021–1028.
(4) Lowden, P. A. S. Aziridines and Epoxides in Organic Synthesis; Wiley:
Chichester, UK, 2006; pp 399-442.
(21) Reddy, M. A.; Bhanumathi, N.; Rao, K. R. Chem. Commun. 2001, 1974–
1975.
10.1021/jo8009616 CCC: $40.75
Published on Web 07/16/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6433–6436 6433

SCHEME 2. Enzymatic Reduction of r-Azidoacetophenone
with the D-Glucose Dehydrogenase/D-Glucose NADPH
Regeneration System
the reduction of R-azidoacetophenones with sodium borohydride
in the presence of ꢀ-cyclodextrin gave (S)-2-azido-1-arylethanols
with 4-81% ee.18,21 Yadav, Rao, and their co-workers have
used oxazaborolidine-borane as the reducing agent in the
enantioselective reduction of R-azidoketones.19,20 This scarcity
may be due to the chemoselectivity required over the reduction
of the azido group.
In this context, biocatalytic reduction of R-azidoacetophenone
derivatives has attracted attention. Enantioselective bioreduction
of R-azidoacetophenones to (R)-2-azido-1-arylethanols has been
investigated with whole cell biocatalysts such as baker’s yeast
(Saccharomyces cereVisiae), 22,23 Daucus carota root,24,25 and
Rhodotorula glutinis,26,27 while (S)-2-azido-1-arylethanols have
been obtained with Geotrichum candidum as biocatalyst.27
Stewart et al. have reported an approach to paclitaxel C13 side
chain via Baker’s yeast mediated reduction of methyl 3-azido-
2-oxo-3-phenylpropionate, although its application was limited
by low diastereoselectivity.28 Recently, Edegger et al. have
employed lyophilized cells of E. coli containing an overex-
pressed alcohol dehydrogenase (ADH-‘A’) from Rhodococcus
rubber DSM 44541 as a biocatalyst in the reduction of
R-azidoacetophenone and R-azido-p-hydroxyacetophenone.29
Most of the above biocatalysts follow Prelog’s rule for the
reduction of R-azidoacetophenones, and only one shows anti-
Prelog enantiopreference.
TABLE 1. Screening of Carbonyl Reductases toward the
Reduction of r-Azidoacetophenone
absolute
configuration
entry
enzyma
conversion (%)b
ee (%)c
1
2
3
4
5
6
7
CMCR
SSCR
Ymr226c
Ygl039w
PFADH
GRE2
100
100
100
100
3
>99
>99
>99
27
S
S
R
S
<1
0
7-HSDH
a See the Experimental Section for the sources of these enzymes.
b The conversions were measured by HPLC analysis. c ee values were
measured by chiral HPLC analysis.
The use of isolated enzymes offers several advantages
including the elimination of undesirable enantiomer formation
mediated by contaminating enzymes in the whole cell biocata-
lytic system, the possibility of achieving high substrate load,
easy downstream product separation, and easy handling by
organic chemists without microbiological knowledge. In recent
years, isolated carbonyl reductase enzymes have been demon-
strated to be highly effective catalysts for the enantioselective
reduction of a wide range of ketones.30 Given the advantages
of isolated enzyme catalysts and the importance of optically
pure 2-azido-1-arylethanols, herein we report the synthesis of
both antipodes of 2-azido-1-arylethanols via enantioselective
reduction of R-azido aromatic ketones catalyzed by isolated
carbony reductases. The obtained azido alcohols reacted with
alkynes through click chemistry to give the triazole analogues
of ꢀ-adrenergic receptor blockers, a class of compounds with
potential biological activity.
both antipodes of the corresponding chiral alcohols in
excellent optical purity.31–35 Therefore, we have screened
these isolated enzymes toward the reduction of R-azidoac-
etophenone (1a). R-Azidoacetophenone (1a) was treated with
a catalytic amount of carbonyl reductase and cofactor
NADPH, which was regenerated with D-glucose and D-
glucose dehydrogenase (GDH) systems (Scheme 2), in
potassium phosphate buffer. The reaction mixture was
extracted with methyl tert-butyl ether, and the extract was
subjected to chiral HPLC analysis to determine the conversion
and ee value. The results are summarized in Table 1. It can
be seen from the data that CMCR, SSCR, Ymr226c, and
Ygl039w effectively catalyzed the reduction of R-azidoac-
etophenone (1a) with 100% conversion. The reduction with
CMCR and SSCR gave (S)-2-azido-1-phenylethanol in
essentially optically pure form, while (R)-2-azido-1-phenyle-
thanol was obtained with Ymr226c as the catalyst. For
Ygl039w, the enantioselectivity was poor with 27% ee. Other
enzymes, PFADH, GRE2, and 7-HSDH, showed almost no
activity.
The reductions of R-azidoacetophenone (1a) and other
R-azidoacetophenone derivatives bearing various substituents
on the phenyl ring were carried out with CMCR or Ymr226c
as biocatalyst at about 1 mmol scale. R-Azidoacetophenones
(1a-k) were treated with a catalytic amount of CMCR or
Ymr226c and cofactor NADPH, which was regenerated with
D-glucose and D-glucose dehydrogenase (GDH) systems (Scheme
2), in potassium phosphate buffer. The reaction mixtures were
worked up as described in the Experimental Section. The
products (S)- or (R)-2-azido-1-arylethanols were isolated and
We have recently cloned and overexpressed several car-
bonyl reductase/alcohol dehydrogenase genes from various
sources in E. coli. The recombinant proteins have been
purified and their substrate profiles have been studied. These
isolated enzyme catalysts catalyze the reduction of a series
of ketones, ꢀ-ketonitriles, and R- and ꢀ-ketoesters to furnish
(22) Yadav, J. S.; Thirupathi Reddy, P.; Nanda, S.; Rao, A. B. Tetrahedron:
Asymmetry 2001, 12, 63–67.
(23) Sorrilha, A. E. P. M.; Marques, M.; Joekes, I.; Moran, P. J. S.; Rodrigues,
A. R. Bioorg. Med. Chem. Lett. 1992, 2, 191–6.
(24) Yadav, J. S.; Nanda, S.; Reddy, P. T.; Rao, A. B. J. Org. Chem. 2002,
67, 3900–3903.
(25) Yadav, J. S.; Reddy, P. T.; Nanda, S.; Rao, A. B. Tetrahedron:
Asymmetry 2001, 12, 3381–3385.
(26) Antunes, H.; Fardelone, L. C.; Rodrigues, J. A. R.; Moran, P. J. S.
Tetrahedron: Asymmetry 2004, 15, 2615–2620.
(27) Fardelone, L. C.; Rodrigues, J. A. R.; Moran, P. J. S. J. Mol. Catal. B:
Enzym. 2006, 39, 9–12.
(31) Zhu, D.; Yang, Y.; Hua, L. J. Org. Chem. 2006, 71, 4202–4205.
(32) Zhu, D.; Yang, Y.; Buynak, J. D.; Hua, L. Org. Biomol. Chem. 2006,
4, 2690–2695.
(28) Kayser, M. M.; Mihovilovic, M. D.; Kearns, J.; Feicht, A.; Stewart,
J. D. J. Org. Chem. 1999, 64, 6603–6608.
(29) Edegger, K.; Gruber, C. C.; Poessl, T. M.; Wallner, S. R.; Lavandera,
I.; Faber, K.; Niehaus, F.; Eck, J.; Oehrlein, R.; Hafner, A.; Kroutil, W. Chem.
Commun. 2006, 2402–2404.
(33) Zhu, D.; Ankati, H.; Mukherjee, C.; Yang, Y.; Biehl, E. R.; Hua, L.
Org. Lett. 2007, 9, 2561–2563.
(34) Zhu, D.; Hua, L. J. Org. Chem. 2006, 71, 9484–9486.
(35) Zhu, D.; Malik, H. T.; Hua, L. Tetrahedron: Asymmetry 2006, 17, 3010–
3014.
(30) Moore, J. C.; Pollard, D. J.; Kosjek, B.; Devine, P. N. Acc. Chem. Res.
2007, 40, 1412–1419.
6434 J. Org. Chem. Vol. 73, No. 16, 2008

TABLE 2. Enzymatic Reduction of r-Azidoacetophenones
Catalyzed by Carbonyl Reductases
SCHEME 3. Synthesis of ꢀ-Blocker Analogues Containing
1,2,3-Triazole Moiety
dehydrogenase from Saccharomyces cereVisiae (Ymr226c)
afforded the corresponding (S)- or (R)-2-azido-1-arylethanols
with excellent optical purity. This demonstrated that these
enzymes were valuable biocatalysts for the synthesis of this class
of important compounds in optically pure form. The obtained
2-azido-1-arylethanols reacted with alkynes via copper(I)-
catalyzed [3 + 2] Huisgen’s cycloaddition to give enatiomeri-
cally pure triazole-containing ꢀ-blocker analogues, a type of
compounds with potential biological activity, in high yields.
CMCR
Ymr226c
X
time (h) yield (%) eea (%) time (h) yield (%) eea (%)
1a (H)
1b (4-F)
1c (2,4-F2)
1d (4-Cl)
1e (4-Br)
1f (4-CH3)
1g (4-OCH3)
1h (3-OCH3)
1i (4-NO2)
1j (3-NO2)
1k (4-CN)
24
24
24
24
24
24
24
24
24
24
24
92
93
90
92
88
85
88
95
84
82
80
99 (S)
>99 (S)
>99 (S)
>99 (S)
98 (S)
24
24
24
32
24
96
89
84
82
85
84
87
5b
>99 (R)
>99 (R)
>99 (R)
>99 (R)
>99 (R)
>99 (R)
-
>99 (R)
63 (R)
>99 (R)
-
99 (S)
99 (S) 240
99 (S) 240
99 (S) 216
99 (S) 120
99 (S) 240
19b
10b
85
0
Experimental Section
Typical Procedure for the Enzymatic Reduction of r-Azi-
doacetophenones. A typical procedure for the reduction of R-azi-
doacetophenones was as follows (using R-azidoacetophenone 1a
as an example): Into a solution of carbonyl reductase CMCR (20
U, 1 U was defined as the enzyme converting 1 µmol of NADPH
to NADP+ per minute with ethyl 4-chloro-3-oxobutyrate as
substrate), D-glucose dehydrogenase (5 U), NADPH (5 mg), and
D-glucose (400 mg) in potassium phosphate buffer (100 mM, pH
7.0, 100 mL) was added a solution of R-azidoacetophenone (1a,
170 mg, 1.07 mmol) in DMSO (5 mL). The mixture was stirred at
room temperature with TLC monitoring from time to time. After
complete consumption of substrate, the reaction mixture was
extracted with methyl tert-butyl ether. Removal of solvents gave
the crude product, which was purified by preparative TLC (hexane/
ethyl acetate ) 90/10) to give (S)-2-azido-1-phenylethanol (2a).27
The characterization data are presented in the Supporting Informa-
tion, except for two new compounds.
a The ee value was determined by chiral HPLC analysis. b The yield
was determined by HPLC. The product was not isolated.
characterized by IR and NMR analysis. The ee values were
measured by chiral HPLC analysis. The results are presented
in Table 2.
From Table 2 it can be seen that the carbonyl reductase
(CMCR) efficiently catalyzed the reduction of various R-azi-
doacetophenone derivatives bearing an electron-withdrawing or
electron-donating group on the phenyl ring to furnish the (S)-
enantiomer of the corresponding 2-azido-1-arylethanols in
essentially optically pure form. In some cases, (R)-2-azido-1-
arylethanols were obtained with Ymr226c. The activity of
Ymr226c toward the reduction of these R-azidoacetophenone
derivatives was greatly affected by the substituents on the phenyl
ring. For unsubstituted and para-halo-substituted R-azidoac-
etophenones, the reduction was completed in about 1 day, while
the reaction was much slower for the substrate with 4-methyl,
3- or 4-nitro, and 3- or 4-methoxy groups on the phenyl ring.
No reduction was observed for R-azido-4′-cyanoacetophenone.
The naphthalene analogue was not reduced by both enzymes.
It has be known that copper(I) catalyzed the [3 + 2] Huisgen’s
cycloaddition reaction between azides and terminal alkynes to
form 1,2,3-triazoles.36 (S)-2-Azido-1-(p-chlorophenyl)ethanol
reacted with phenylacetylene or propargyl alcohol under the
action of Cu(I) catalyst, which was in situ generated from the
stable copper(II) sulfate/sodium ascorbate redox system, to
afford (S)-1-(4-chlorophenyl)-2-(4-phenyl-1H-1,2,3-triazol-1-
yl)ethanol (3) and (S)-1-(4-chlorophenyl)-2-(4-(hydroxymethyl)-
1H-1,2,3-triazol-1-yl)ethanol (4) in 90% and 83% yield, re-
spectively (Scheme 3). Since the triazole functional group
showed similar properties as the amide functionality,8 this class
of compounds should be expected to possess potential biological
activity of ꢀ-adrenergic receptor blockers.
(S)-2-Azido-1-(2′,4′-difluorophenyl)ethanol 2c(S). Colorless
liquid, 120 mg, 90% yield (ketone: 130 mg, 0.67 mmol); 1H NMR
(CDCl3) δ (ppm) 2.41 (br, 1H,), 3.44 (dd, J ) 12.5, 7.8 Hz, 1H),
3.53 (dd, J ) 12.5, 3.4 Hz, 1H), 5.16 (dd, J ) 7.8, 3.4 Hz, 1H),
6.81 (m, 1H,), 6.95 (m, 1H), 7.54 (m, 1H); 13C NMR (CDCl3) δ
2
2
(ppm) 57.2, 67.6, 104.2 (t, JC-F ) 25.4 Hz,), 112.1 (dd, JC-F
)
4
2
21.0 Hz, JC-F ) 3.5 Hz), 123.9 (d, JC-F ) 17.3 Hz), 128.9 (dd,
3JC-F ) 9.6 Hz, JC-F ) 5.7 Hz), 160.1 (dd, JC-F ) 246.9 Hz,
3JC-F ) 12.2 Hz), 163.2 (dd, 1JC-F ) 247.9 Hz, 3JC-F ) 12.1 Hz);
IR (cm-1) 3427.4, 2106.7, 1624.6, 1503.1, 1429.2, 1270.3, 1173.7,
3
1
22
1100.1, 964.4, 850.8; [R]D +73.9 (c 0.5, CH3OH). Anal. Calcd
for C8H7F2N3O: C 48.25, H 3.54, N 21.10. Found: C 48.60, H 3.97,
N 20.99.
(S)-2-Azido-1-(4′-cyanophenyl)ethanol 2k(S). Light yellow
1
solid, 81 mg, 80% yield (ketone: 100 mg, 0.54 mmol); H NMR
(CDCl3) δ (ppm) 2.70 (br, 1H), 3.48-3.53 (m, 2H), 4.99-5.03
(m, 1H), 7.57 (d, J ) 8.8 Hz, 2H), 8.23 (d, J ) 8.8 Hz, 2H); 13C
NMR (CDCl3) δ (ppm) 57.8, 72.6, 112.0, 118.5, 126.7, 132.4,
145.7; IR (cm-1) 3422.2, 2230.3, 2103.7, 1642.4, 1260.7, 1079.9,
22
880.2, 815.02; [R]D +139.9 (c 0.17, CH3OH). Anal. Calcd for
C9H8N4O: C 57.45, H 4.29, N 29.76. Found: C 57.63, H 4.57, N
29.44.
Synthesis of ꢀ-Blocker Analogues Containing 1,2,3-Triazole
Moiety. (S)-2-Azido-1-(4′-chlorophenyl)ethanol, 2d(S), was con-
verted to ꢀ-blocker analogues containing 1,2,3-triazole moiety by
following the literature procedures.36 To a suspension of pheny-
lacetylene (204.0 mg, 2.0 mmol) and (S)-2-azido-1-(4′-chlorophe-
nyl)ethanol (395.1 mg, 2.0 mmol) in a 1:1 mixture of water and
tert-butyl alcohol (8 mL) were added sodium ascorbate (0.2 mmol,
In conclusion, enantioselective reductions of R-azidoac-
etophenone derivatives catalyzed by a recombinant carbonyl
reductase from Candida magnoliae (CMCR) or an alcohol
(36) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew.
Chem., Int. Ed. 2002, 41, 2596–2599.
J. Org. Chem. Vol. 73, No. 16, 2008 6435

200 µL of a freshly prepared 1 M solution in water), followed by
coppe (II) sulfate pentahydrate (0.02 mmol, 200 µL of a 0.1 M
solution). The resulting mixture was stirred vigorously at 45 °C
for 5-8 h until TLC showed the disappearance of 2d. The mixture
was cooled to 0 °C and diluted with water (30 mL). White
precipitate formed and was filtered. The solid was washed with
water three times (3 × 20 mL) and dried under vacuum to afford
product.
4.36-4.52 (m, 4H), 4.96 (d, J ) 4.3, 1H), 5.03-5.06 (m, 1H),
7.25 (d, J ) 8.1, 2H), 7.32 (d, J ) 8.2, 2H), 7.69 (s, 1H); 13C
NMR (100 MHz, acetone-d6) δ (ppm) 56.3, 57. 1, 72.1, 123.4,
128.2, 128.7, 133.3, 141.3; IR (cm-1) 3288.2, 3094.18, 2951.3,
2879.4, 1485.9, 1413.9, 1339.9, 1145.4, 1083.1, 1014.3, 825.4,
22
783.4; [R]D
+32.27 (c 1.0, CH3OH). Anal. Calcd for
C11H12ClN3O2: C 52.08, H 4.77, N 16.56. Found: C 51.69, H 4.86,
N 16.27.
(S)-1-(4-Chlorophenyl)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)etha-
nol (3). Colorless crystal, mp 218-219 °C; 341 mg, 90%; 1H NMR
(400 MHz, acetone-d6) δ (ppm) 4.45 (dd, J ) 13.8, 8.0 Hz, 1H),
4.55 (dd, J ) 13.8, 4.0 Hz, 1H), 5.02 (d, J ) 4.40, 1H), 5.11 (m,
1H), 7.17-7.32 (m, 5H), 7.36 (d, J ) 8.36, 2H), 7.75 (d, J ) 8.17,
2H), 8.18 (s, 1H); 13C NMR (100 MHz, acetone-d6) δ (ppm) 57.3,
72.0, 121.9, 125.7, 128.0, 128.3, 128.8, 129.1, 131.9, 133.3, 141.2,
147.0; IR (cm-1) 3413.4, 3134.7, 1631.1, 1483.9, 1224.9, 1081.5,
828.6, 762.7; [R]D +48.93 (c 1.0, acetone). Anal. Calcd for
C16H14ClN3O: C 64.11, H 4.71, N 14.02. Found: C 63.84, H 4.88,
N 14.14.
(S)-1-(4-Chlorophenyl)-2-(4-(hydroxymethyl)-1H-1,2,3-triazol-
1-yl)ethanol (4). White powder, mp 140-141 °C; 422 mg, 83%;
1H NMR (400 MHz, acetone-d6) δ (ppm) 4.05 (t, J ) 5.4, 1H),
Acknowledgment. We thank Southern Methodist University,
DARPA (HR0011-06-1-0032) and the Robert A. Welch Foun-
dation (N-118) for financial support.
Supporting Information Available: The procedure for the
preparation of R-azidoacetophenones, HPLC retention times and
characterization data of 2-azido-1-arylethanols, 1H NMR spectra
of new compounds, and 13C NMR spectra of all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
22
JO8009616
6436 J. Org. Chem. Vol. 73, No. 16, 2008