Preparation of β-fluoro- and ββ-difluoro-histidinols

Article abstract of DOI:10.1016/S0022-1139(03)00096-4

Nucleophilic attack of azide on 2-bromo-3-fluoro-3-(1-trityl-1 H -imidazol-4-yl)-propan-1-ol (1a) in aprotic solvent occurs on the 2-position to give the 2-azido derivative (2a). Reduction of azide and removal of the trityl group produces β-fluorohistidin

Full text of DOI:10.1016/S0022-1139(03)00096-4

Journal of Fluorine Chemistry 123 (2003) 95–99
Preparation of b-fluoro- and b,b-difluoro-histidinols
Bohumil Dolensky, Jayan Narayanan, Kenneth L. Kirk*
Laboratory of Bioorganic Chemistry, National Institute of Diabetes, and Digestive and Kidney Diseases,
National Institutes of Health, DHHS, Bethesda, MD 20892, USA
Received 4 March 2003; received in revised form 1 April 2003; accepted 2 April 2003
This manuscript is dedicated to Professor Eric Banks on the occasion of his 70th birthday
Abstract
Nucleophilic attack of azide on 2-bromo-3-fluoro-3-(1-trityl-1H-imidazol-4-yl)-propan-1-ol (1a) in aprotic solvent occurs on the 2-position
to give the 2-azido derivative (2a). Reduction of azide and removal of the trityl group produces b-fluorohistidinol (6a). Elimination of HBr from
1a followed by ‘‘FBr’’ addition to the resulting double bond gives 2-bromo-3,3-difluoro-3-(1-trityl-1H-imidazol-4-yl)-propan-1-ol (1b).
Nucleophilic attack of azide followed by reduction and removal of the trityl group, as for the preparation of 6a, gives b,b-difluorohistidinol (6b).
Initial attempts, under a variety of conditions, to oxidize the fluorinated histidinol precursors to carboxylic acids have not been successful.
# 2003 Elsevier Science B.V. All rights reserved.
Keywords: ‘‘FBr’’ addition; Imidazole analogues; Histidine biosynthesis; Solvent effects on halogen mobility
1. Introduction
2. Chemistry
The essential amino acid histidine is formed in
microorganisms and plants by a two-step oxidation of 2-
amino-1-(3H-imidazol-4-yl)-propane-1,3-diol (histidinol),
the immediate biosynthetic precursor. Analogues of histi-
dinol thus have attracted interest as potential herbicidal
agents (for example, see [1]). In addition, histidinol has
been shown to have unusual and potentially beneficial proper-
tiesthatrelatetodrugresponse. Forexample, Warringtonetal.
demonstrated that L-histidinol protects normal cells from
antineoplastic drugs while enhancing the toxicity of these
same drugs to cancer cells [2]. L-Histidinol also has been
found to reverse drug resistance [3], and further, has been
shown, on its own, to have antineoplastic activity against
certaintumors[4]. Werecentlyhave developedproceduresfor
the preparation of side-chain fluorinated analogues of biolo-
gically important imidazoles and indoles, including a- and b-
fluorourocanic acid [5,6], b-fluoro- and b,b-difluorohista-
mines [7], and a series of tryptamines [8]. We report herein
the syntheses of b-fluoro- and b,b-difluorohistidinols (6a and
b). These compounds are designed to probe effects of fluorine
substitution on the final side-chain oxidation in histidine
biosynthesis. Their toxicities will be examined as well as
their effects on activities of chemotherapeutic agents.
The starting point for our synthesis (Scheme 1) of
b-fluorohistidinols is racemic (2Sꢀ, 3Rꢀ) propanol 1a, which
we had prepared previously as an intermediate in our
synthesis of b-fluorourocanic acid [6]. Treatment of 1a with
NaN3 in DMF at 110 8C leads to formation of azide 2a
(2Rꢀ,3Rꢀ) in about 30% yield, the result of SN2 substitution.
In addition, E-alkene 3 is formed in similar yield, a result of
anti elimination. This competing elimination reaction repre-
sents no serious problem because 3 is required for the
synthesis of 6b. Trace amounts of compounds 4 also were
observed. We found that changing temperature (80 or
130 8C) or using DMSO instead DMF had almost no
influence on the ratio 2a:3 or on the yields. However, when
the substitution was done in dry methanol the course of the
reaction was dramatically different. In this solvent, the
fluorine atom is substituted instead of bromine, producing
a mixture of the two diastereoisomeric azides 4a and b
with no traces of compounds 2a or 3 being detected. The
poor leaving group ability of fluoride, particularly in
nonprotic solvents, favors SN2 substitution or E2 elimina-
tion of bromide to give 2a and 3. In methanol, apparently
hydrogen bonding is sufficient to lead to facile loss of
fluoride with formation of a stabilized carbonium ion
intermediate, producing the diasteromeric mixture of 4a
and b (for a discussion and references to issues of fluoride
reactivity, see [9]).
* Corresponding author. Tel.: þ1-301-496-2619; fax: þ1-301-402-4182.
E-mail address: kennethk@bdg8.niddk.nih.gov (K.L. Kirk).
0022-1139/$ – see front matter # 2003 Elsevier Science B.V. All rights reserved.
doi:10.1016/S0022-1139(03)00096-4

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B. Dolensky et al. / Journal of Fluorine Chemistry 123 (2003) 95–99
Scheme 1. Substitution of bromine with NaN3. (a) 1a, 110 8C, 29% 2a,
37% 3; (b) 1b, 105 8C, DMSO with H2O, 7 days, 73% 2b and (c) 1a,
methanol, 50 8C, 3 days, 25% 4a, 18% 4b.
Scheme 3. (a) 2a, H2/Pd, 98% 5a; (b) 2b, H2/Pd, 87% 5b; (c) 2a, Boc2O,
H2/Pd, 98% 8; (d) 5a, HCl/MeOH, 95% 6a and (e) 5b, HCl/MeOH, 84% 6b.
Using the usual conditions [10] for the addition of ‘‘FBr,’’
alkene 3 was converted to difluorobromo derivative 1b.
Ketone 7 was found as a byproduct of this reaction
(Scheme 2). Analogous byproducts have been previously
reported in ‘‘FBr’’ additions to fluoroalkenes [11]. In this
report, ketone formation was ascribed to hydrolysis of
originally formed adducts during chromatography on silica
during isolation. However, we observed no formation of
ketone 7 during chromatography of 1b. In light of the fact
that we isolated products from ‘‘HOBr’’ addition as bypro-
ducts of ‘‘FBr’’ addition to vinylimidazole [7], we believe
that origin of ketone 7 lies in ‘‘HOBr’’ addition to alkene 3
followed by spontaneous HF loss.
The bromine present in propanol 1b was replaced with
azide to give 2b using conditions that enhance the reactivity
of b,b-difluorobromides toward nucleophilic displacement
[12]. The azides 2a and b were then reduced by catalytic
hydrogenation to give amines 5a and b. Azide 1b was also
reduced in presence of Boc2O to give 8. A subsequent acidic
detritylation produced fluorohistidinol 6a and difluorohisti-
dinol 6b (Scheme 3).
conditions result in loss of fluorine and decomposition.
We obtained similar results in attempts to oxidize 8. We
are continuing in these efforts, and are also exploring
alternative approaches to the amino acids.
3. Summary
Fluorinated histidinols 6a and b were prepared in good
yields starting from previously prepared bromofluoroimida-
zolylpropanol 1a. Selective displacement of bromine with
azide was a critical step in this sequence. This was achieved
cleanly using dipolar aprotic solvent. However, use of
protic solvent led exclusively to fluoride displacement. This
example of solvent control of chemoselectivity is quite
impressive, and we feel it might be incorporated effectively
into other synthetic strategies. Although we have not yet
been able to prepare histidine derivatives by the approach
presented here, the histidinol derivatives are themselves of
considerable biological interest, and appropriate studies are
underway.
Our intention to use this approach to also prepare fluori-
nated histidines has been thwarted to date. We made several
attempts to oxidize the hydroxymethyl group of 2b to
a carboxylic acid (histidine derivative). In general, we
found that oxidation either does not occur or the reaction
4. Experimental details
The 1H, 19F and 13C NMR spectra were recorded at
frequencies of 300, 282 and 76 MHz, respectively. Chemi-
cal shifts are given in ppm relative to TMS for H and 13
1
C
and to CFCl3 for 19F NMR unless otherwise mentioned.
Melting points were taken in Unimelt capillary melting
point apparatus and were not corrected. High resolu-
tion mass spectra (HRMS) were obtained using FAB
ionization with Xe gas. Elemental analyses were done by
Atlantic Microlab Inc. Silica gel Merck 60 (0.040–
0.063 mm) was used for column chromatography, Unipla-
teTM GF (Analtech) was used for preparative TLC. If not
otherwise indicated, all other reagents and dry solvents
were purchased and used without additional purification or
drying.
Scheme 2. ‘‘FBr’’ addition.

B. Dolensky et al. / Journal of Fluorine Chemistry 123 (2003) 95–99
97
4.1. 2-Bromo-3,3-difluoro-3-(1-trityl-1H-imidazol-4-yl)-
propan-1-ol (1b)
129.57 (6CH), 128.21 (3CH), 128.12 (6CH), 121.18 (d, 6.0,
JCH 192.8 d, C5Imi), 88.67 (d, 173.0, JCH 154.2 d, CHF),
75.75 (Tr), 65.36 (d, 21.7, JCH 142.4 d, CHN3), 60.97 (d, 5.1,
JCH 143.5 t, CH2OH). 19F NMR (CDCl3) d: ꢂ178.8 (dd,
47.0, 12.2). HRMS (FABþ): Calcd. for C25H22FN5O
(MHþ): 428.1887. Found: 428.1880.
A solution of 911 mg (2.37 mmol) of alkene 3 was cooled
to 0 8C and 0.6 ml (3.68 mmol) of Et3Nꢁ3HF was added.
After 30 min 466 mg (2.62 mmol) of NBS was added. The
mixture was stirred at 0 8C for 30 min, then removed from
the cooling bath and allowed to stir overnight at RT. The
reaction mixture was partitioned between brine and CH2Cl2.
The organic layer was separated, dried over MgSO4, eva-
porated to dryness and separated by silica gel column
chromatography using CH2Cl2/Et2O as eluent to give
958 mg (84%) of 1b and 35 mg (3%) of 7. 1H NMR (CDCl3)
d: 7.48 (s, 1H), 7.39–7.31 (m, 9H), 7.16–7.08 (m, 7H), 5.02
(bs, 1H, OH), 4.53 (m, 1H, S J 34.1, CHBr), 4.17 (dd, 1H,
12.9, 4.2), 4.00 (dd, 1H, 12.8, 5.3). 13C NMR (CDCl3) d:
141.54 (3C), 139.24 (C2Imi), 134.00 (dd, 33.7, 31.2, C4Imi),
129.60 (6CH), 128.40 (3CH), 128.24 (6CH), 121.97 (t, 4.5,
C5Imi), 117.94 (dd, 242.0, 241.6, CF2), 76.08 (Tr), 62.05 (t,
3.6, CH2), 54.61 (dd, 30.4, 27.4, CHBr); mp 159.5–160.5 8C
(from cyclohexane). Anal. Calcd. for C25H21BrF2N2O: C,
62.12; H, 4.38; N, 5.80. Found: C, 62.37; H, 4.37; N, 5.92.
HRMS (FABþ): Calcd. for C25H22BrF2N2O (MHþ) doublet:
483.0884, 485.0863. Found: 483.0855, 485.0864.
4.4. 2-Azido-3,3-difluoro-3-(1-trityl-1H-imidazol-4-yl)-
propan-1-ol (2b)
A mixture of 818 mg (1.69 mmol) of 1b, 721 mg
(11.1 mmol) of NaN3, 1.5 ml water and 40 ml of Me2SO
was stirred at 105 8C for 7 days. The mixture was poured
into 400 ml brine and 200 ml of water and the product was
extracted with CH2Cl2. The organic layer was dried over
MgSO4 and evaporated. The residue was subjected to silica
gel column chromatography using petrol ether/Et2O as
1
eluent to afford 551 mg (73%) of 2b. H NMR (CDCl3)
d: 7.45 (q, 1H, 1.2), 7.40–7.31 (m, 9H), 7.15 (q, 1H, 1.5),
7.13–7.07 (m, 6H), 4.65 (br s, 1H), 4.47–4.35 (m, 1H), 3.56–
3.44 (m, 2H). 13C NMR (CDCl3) d: 141.68 (3C), 139.15
(C2imi), 135.20 (t, 31.9, C4imi), 129.64 (6CH), 128.43 (3CH),
128.28(6CH), 120.88(t, 3.8, C5imi), 117.03 (dd, 241.1, 243.1,
CF2), 76.09 (Tr), 73.24 (dd, 27.0, 29.6, CHN3), 50.78 (t, 3.3,
CH2). 19F NMR (CDCl3) d: ꢂ102.1 (dd, 1F, 266.5, 6.5),
ꢂ108.1 (dd, 1F, 266.5, 13.8). M.p. 118–119 8C (from
Et2O). Anal. Calcd. for C25H21F2N5O: C, 67.41; H, 4.75;
N, 15.72. Found: C, 67.42; H, 4.88; N, 15.76. HRMS (FABþ):
Calcd. forC25H22F2N5O (MHþ):446.1792.Found:446.1797.
4.2. 2-Bromo-3-hydroxy-1-(1-trityl-1H-imidazol-4-yl)-
propan-1-one (7)
1H NMR (CDCl3) d: 7.71 (d, 1H, 1.2), 7.50 (d, 1H, 1.2),
7.39–7.33 (m, 9H,), 7.13–7.08 (m, 6H), 5.42 (dd, 1H, 6.9,
4.8), 4.23–4.03 (m, 2H), 3.29 (bs, 1H). 13C NMR (CDCl3) d:
189.36 (CO), 141.33 (3C), 139.57 (C2Imi), 137.94 (C4Imi),
129.59 (6CH), 128.51 (3CH), 128.34 (6CH), 127.72 (C5Imi),
76.45 (Tr), 62.97 (CH2), 47.47 (CHBr); mp 144.5–145.5 8C
(from cyclohexane). Anal. Calcd. for C25H21BrN2O2: C,
65.09; H, 4.59; N, 6.07; Br, 17.32. Found: C, 65.14; H, 4.61;
N, 6.02; Br, 17.21.
4.5. 3-Azido-2-bromo-3-(1-trityl-1H-imidazol-4-yl)-
propan-1-ol (4a)
A mixture of 950 mg (2.04 mmol) of 1a and 686 mg
(10.6 mmol) of NaN3 in 60 ml of dry methanol was stirred
at 50 8C for 17 h. The mixture was evaporated to dryness and
the resulting solid was partitioned between CH2Cl2 and
water. The organic layer was dried over MgSO4, filtered,
and evaporated to give crude product. Silica gel column
chromatography using CH2Cl2/MeOH afforded 252 mg of
4a (25%) and 174 mg (18%) of 4b. 1H NMR (CDCl3) d: 7.48
(d, 1H, 1.2), 7.38–7.32 (m, 9H), 7.18–7.10 (m, 6H), 6.91 (d,
1H, 1.2), 5.00 (d, 1H, 6.0), 4.74 (br s, 1H), 4.46 (q, 1H, 6.0),
4.02–3.98 (m, 2H). 13C NMR (CDCl3) d: 141.83 (3C),
139.05 (dd, JCH 211.4, 7.0, C2Imi), 135.56 (C4Imi), 129.65
(6CH), 128.27 (3CH), 128.17 (6CH), 121.38 (d, JCH 192.5,
C5Imi), 75.74 (Tr), 63.60 (t, JCH 146.7, CH2), 61.75 (d, JCH
143.5, CHN3), 55.85 (d, JCH 153.4, CHBr). HRMS (FABþ):
Calcd. for C25H23BrN5O (MHþ) doublet: 488.1086,
490.1066. Found: 488.1087, 490.1059.
4.3. 2-Azido-3-fluoro-3-(1-trityl-1H-imidazol-4-yl)-
propan-1-ol (2a)
A mixture of 999 mg (2.15 mmol) of 1a [6] and 279 mg of
NaN3 (4.29 mmol) in 30 ml of dry DMF was stirred at
110 8C for 14 h. The mixture was evaporated to dryness
and the resulting solid was partitioned between CH2Cl2 and
water. The organic layer was dried over MgSO4, filtered and
evaporated to give crude product. Silica gel column chro-
matography using CH2Cl2/MeOH afforded 306 mg (37%)
of olefin 3. The physical and spectral properties of 3 were
identical with those reported previously [6]. The desired
azide 2a was obtained as a non-crystalline solid (262 mg,
1
29%). H NMR (CDCl3) d: 7.47 (d, 1H, 1.5), 7.38–7.32
4.6. 3-Azido-2-bromo-3-(1-trityl-1H-imidazol-4-yl)-
propan-1-ol (4b)
(m, 9H), 7.15–7.09 (m, 6H), 7.00 (dd, 1H, 2.2, 1.5), 5.55
(dd, 1H, 46.7, 7.1), 3.96 (m, 1H, S J 32), 3.75 (dd, 2H, 4.4,
0.9), 3.65 (bs, 1H, OH). 13C NMR (CDCl3) d: 141.79 (3C),
139.33 (d, 7.1, JCH 211.4, C2Imi), 135.85 (d, 24.0, C4Imi),
1H NMR (CDCl3) d: 7.48 (d, 1H, 1.5), 7.37–7.31 (m, 9H),
7.17–7.11 (m, 6H), 6.60 (d, 1H, 1.5), 5.48 (bs, 1H, OH), 5.07

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B. Dolensky et al. / Journal of Fluorine Chemistry 123 (2003) 95–99
1
(d, 1H, 4.9), 4.35 (dt, 1H, 6.7, 4.8), 3.96 (dd, 1H, 12.6, 4.5),
(1H, 12.3, 6.9). 13C NMR (CDCl3) d: 141.77 (3C), 139.00
(d, JCH 211.5 C2Imi), 136.31 (C4Imi), 129.60 (6CH), 128.21
(3CH), 128.13 (6CH), 121.03 (d, JCH 192.7 C5Imi),
75.74 (Tr), 63.34 (t, JCH 145.7, CH2), 61.02 (d, JCH
143.1, CHN3), 57.42 (d, JCH 152.4, CHBr). HRMS (FABþ):
Calcd. for C25H23BrN5O doublet: 488.1086, 490.1066.
Found: 488.1070, 490.1070.
(CH2Cl2/Et2O). H NMR (CDCl3) d: 7.43 (s, 1H), 7.37–
7.32 (m, 9H), 7.14–7.08 (m, 7H), 5.17 (br s, 1H), 4.70 (br s,
1H),4.27(m,1H,SJ37),3.61(m,1H,SJ33),3.23(m,1H,SJ
33), 1.43 (s, 9H). 13C NMR (CDCl3) d: 156.51 (CO), 141.69
(3C), 139.11 (C2Imi), 135.27 (t, 31.9, C4Imi), 129.56 (6CH),
128.24 (3CH), 128.14 (6CH), 120.85 (t, 3.9, C5Imi), 117.88 (t,
242.2, CF2), 79.30 (CMe3), 75.87 (Tr), 72.45 (t, 27.4, CH),
40.73(CH2),28.25(3Me).19FNMR(CDCl3)d:ꢂ103.9(d,1F,
265.9), ꢂ107.7 (dd, 1F, 265.9, 13.0). HRMS (FABþ): Calcd.
for C30H32F2N3O3 (MHþ): 520.2412. Found: 520.2429.
4.7. 2-Amino-3-fluoro-3-(1-trityl-1H-imidazol-4-yl)-
propan-1-ol (5a)
4.10. 2-Amino-3-fluoro-3-(1H-imidazol-4-yl)-propan-1-ol
(6a) dihydrochloride
Azide 2a (453 mg, 1.06 mmol) was dissolved in 50 ml of
methanol and 128 mg of catalyst (10% Pd on C) was added.
The atmosphere was changed to hydrogen (balloon) and the
mixture was stirred at room temperature until starting azide
2a was consumed (TLC; 1–3 h). The catalyst was filtered
through a pad of celite and pure amine 5a (419 mg, 98%)
was obtained after evaporation of solvent. 1H NMR (CDCl3)
d: 7.43 (d, 1H, 1.2), 7.36–7.30 (m, 9H), 7.14–7.08 (m, 6H),
6.95 (dd, 1H, 2.7, 1.2), 5.36 (dd, 1H, 47.5, 6.2), 3.79–3.39
(m, 6H). 13C NMR (CDCl3) d: 142.02 (3C), 139.33 (C2imi),
136.63 (d, 23.3, C4imi), 129.68 (6CH), 128.26 (3CH), 128.19
(6CH), 121.49 (d, 6.4), 89.77 (d, 169.0, CHF), 75.68 (Tr),
62.19 (d, 4.4, CH2OH), 55.42 (d, 23.0, CHNH2). 19F NMR
(CDCl3) d: ꢂ103.8 (dd, 1F, 48.0, 13.4). HRMS (FABþ):
Calcd. for C25H25FN3O (MHþ): 402.1903. Found: 402.1982.
To 165 mg (0.41 mmol) of the tritylation histidinol 5a
dissolved in 20 ml of methanol in a 50 ml round bottom flask
and cooled to 0 8C was added 5 ml of 2N aqueous HCl. The
mixture was stirred for 1 h at 0 8C and then overnight at
room temperature. After the solvent MeOH was removed by
rotary evaporation, the aqueous solution was washed with
CH2Cl2. The aqueous layer on concentration by lyophiliza-
tion to afford 87 mg (95%) of the pure product 6a. 1H NMR
(CD3OD) d: 9.12 (s, 1H), 7.96 (dd, 3.3, 1.0, 1H), 6.10 (d, 9.0,
1H), 5.95 (d, 9.0, 1H), 4.16–3.83 (m, 2H), 3.82–3.71 (m,
2H), 3.59–3.51 (m, 2H). 13C NMR (CD3OD) d: 136.50 (JCH
120.4 d, 6.7 d, C2imi), 121.67 (d, 8), 118.66 (d, 26.3), 84.60
(d, 172.0), 72.65 (d, 228.0), 59.44 (d, 5.2). 19F NMR
(CD3OD/TFA) d: ꢂ104.78 (dd, 1F, 48.0, 9.3).
4.8. 2-Amino-3,3-difluoro-3-(1-trityl-1H-imidazol-4-yl)-
propan-1-ol (5b)
4.11. 2-Amino-3,3-difluoro-3-(1H-imidazol-4-yl)-propan-
1-ol (6b) dihydrochloride
Azide 2b (215 mg, 483 mmol) was dissolved in 20 ml of
methanol and 114 mg of catalyst (10% Pd on C) was added.
The atmosphere was changed to hydrogen (balloon) and the
mixture was stirred at room temperature until starting azide 2
disappeared (TLC; 1–3 h). The catalyst was filtered through a
pad of Celite and pure amine 5b (176 mg, 87%) was obtained
afterevaporationofsolvent.1HNMR(CD3OD)d:7.43(s,1H),
7.37–7.27 (m, 9H), 7.13–7.09 (m, 7H), 4.13 (ddt, 1H, 13.0,
9.2, 5.7), 2.94 (d, 2H, 5.7), 2.53 (br s, 2H). 13C NMR (CDCl3)
d: 141.67 (3C), 139.45 (C2imi), 134.60 (t, 31.9, C4imi), 129.59
(6CH), 128.12 (9CH), 121.09 (br s, C5imi), 118.42 (t, 242.2,
CF2), 75.83 (Tr), 70.41 (t, 28.8, CHNH2), 39.94 (br s, CH2).
19F NMR (CDCl3) d: ꢂ103.9 (dd, 1F, 264.0, 9.2), ꢂ107.5
(1F, 264.0, 13.0). HRMS (FABþ): Calcd. for C25H23F2N3O
(MHþ): 420.1809. Found: 420.1893.
To 102 mg (0.240 mmol) of tritylation histidinol 5b dis-
solved in 15 ml of methanol in a 50 ml round bottom flask
and cooled to 0 8C was added 4 ml of 2N aqueous HCl. The
solution was stirred for 1 h at 0 8C and then overnight at
room temperature. After evaporation of MeOH the aqueous
layer was washed with CH2Cl2. The aqueous solution was
lyophilized to produce 51 mg (84%) of the pure product 6b.
1H NMR (CD3OD) d: 9.22 (d, 1H, 1.4), 8.07 (td, 1H, 1.5,
1.4), 4.57 (dddd, 1H, 14.2, 9.6, 6.5, 3.3), 3.36 (dd, 1H, 13.5,
3.3), 3.09 (dd, 1H, 13.5, 9.6). 13C NMR (CD3OD) d: 137.61
(JCH 222.4 d, 6.7 d, C2imi), 127.49 (t, 34.4, JCH 10.5 d, 5.8 d,
C4imi), 121.33 (t, 5.4, JCH 204.8 d, 5.5 d, C5imi), 117.73 (t,
245.9, CF2), 70.17 (dd, 31.6, 27.3, JCH 146.1 d, CHNH2),
40.25 (t, 3.4, JCH 143.6 t, CH2). 19F NMR (CD3OD) d:
ꢂ99.4 (dd, 1F, 275.4, 5.9), ꢂ110.1 (dd, 1F, 275.4, 13.7);
mp 180–187 8C decomp. (from iPrOH). Anal. Calcd. for
C6H11Cl2F2N3O: C, 28.82; H, 4.43; N, 16.80; Cl, 28.35.
Found: C, 28.86; H, 4.44; N, 16.61; Cl, 28.53.
4.9. 2,2-Difluoro-1-hydroxymethyl-2-(1-trityl-1H-
imidazol-4-yl)-ethyl]-carbamic acid tert-butyl ester (8)
To a solution of 212 mg (0.476 mmol) of azide 2b and
0.123 ml (0.575 mmol) of Boc2O dissolved in 6 ml of EtOAc
was added 30 mg of 10% Pd on C. This was stirred in an
atmosphere of H2 (balloon) for 4 h. The catalyst was filtered
througha Celitepad andthefiltratewas evaporatedtodryness.
Pure 8 (243 mg, 98%) was obtained by preparative TLC
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