Z. Li et al. / Tetrahedron Letters 44 (2003) 8143–8147
8145
Table 2. One-pot conversion of alcohols into alkyl chlorides
a
DIC (1 equiv.) Cu(OTf) , rt 1 h
R-OHꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ2ꢀꢀꢀꢀꢀꢀꢁR-Cl
3a (2 equiv.), conditions
Entry
ROH
Solvent
Time (h)
Temp (°C)
Yield (%)b
1
2
3
4
5
6
7
8
8
8
8
THF
Dioxane
THF
THF
THF
THF
Dioxane
THF
THF
THF
3.5
3.5
5 min
4.5
4.5
3.5
3.5
10 min
3.5
10 min
3.5
21.5
10 min
100 (DT)
100 (DT)
160 (mv)
100 (DT)
100 (DT)
100 (DT)
100 (DT)
160 (mv)
100 (DT)
160 (mv)
80 (DT)
85
86
93
64
14
15
16
16
16
17
17
18
18
18
70
68c
73c
74c
9
76 (7)
72 (15)
36 (5)
70 (10)
72 (16)
10
11d
12d
13d
THF
THF
THF
80 (DT)
160 (mv)
a 1 mol% was used for primary alcohols, and 2 mol% was used for secondary alcohols.
b Isolated yield after chromatography. Yields in parentheses refer to elimination product (determined by NMR).
c Less than 5% of elimination product was formed (GC).
d 5 mol% of Cu(OTf)2 was used for the isourea formation.
1,4-dioxane gave identical results (entries 1, 2). When
microwave irradiation was employed, (entry 3), a
slightly better yield was obtained after only 5 min. The
reaction conditions tolerate the presence of ester and
imide functional groups (entries 4 and 5). With sec-
ondary alcohols, the desired alkyl chloride was also
obtained in good yields with minimal difference
between thermal and microwave heating conditions
(entries 6–8; 9–10; and 12–13), except with regard to the
much shorter reaction time for the latter. Secondary
O-alkyl isoureas required a longer microwave irradia-
tion time for the halogenation reaction compared to
primary isoureas, and typically some elimination
product was found in the case of secondary alcohols.
This side-reaction was found to be substrate-dependent.
With 16, only traces of elimination product were
observed, both under thermal as under microwave con-
ditions. However, with 17, about 7% of elimination
products were observed under thermal conditions,
which increased to 15% under microwave irradiation.
With 3b-cholestanol 18 as substrate, a much longer
reaction time was required under thermal conditions
(entries 11, 12), though a reaction time of 10 minutes
was still sufficient under microwave irradiation (entry
13). Interestingly, only the corresponding a-chloride
was obtained, indicating a clean inversion of configura-
tion. We noticed that it is essential that moisture-free
conditions are used. The presence of moisture can be
easily detected as the copper triflate turns blue in the
presence of water.
using CuCl instead of Cu(OTf)2, a similar yield was
obtained (entries 1, 4, 6, 8). When only 1 mol% of CuCl
was used, we could not detect any alkyl chloride
product but when 5 mol% of CuCl was used, GC-analy-
sis revealed the formation of trace amounts of the
corresponding alkyl chloride (ca. 3%).
When DCE and dioxane were compared as solvent
(entries 4 and 5), an identical yield was obtained under
standard reflux conditions, though the reaction
appeared to be finished in a shorter time, though a
higher reaction temperature was used in dioxane. A
benzylic alcohol gave the corresponding bromide in
good yield (entry 8).
A range of functional groups including nitrile, alkyl
bromide, TBDPS–ether, nitro, ester and imide (entries
10–17) were tolerated under the reaction conditions.
Secondary alcohols were also successfully transformed
into the corresponding bromides (entries 18–23), with a
negligible
solvent-dependance.
However,
under
microwave conditions (entries 20, 22), a slightly lower
yield was obtained. The proportion of elimination
product was lower compared to the alkyl chloride
formation, and in the case of 17, no elimination
product was formed at all, as judged by GC analysis
through comparison with an authentic sample. With
3b-cholestanol 18, again only the 3a-isomer was
formed. However, it was disappointing to observe that,
when enantiopure 4-phenyl-2-butanol 16 was used, par-
tial racemisation had occurred, presumably through a
Finkelstein-type bromide exchange reaction.
The results for the conversion of alcohols to alkyl
bromides are shown in Table 3. Isourea formation,
followed by reaction with NBS in refluxing 1,2-
dichloroethane (DCE) gave the corresponding bromide
in good yield (entry 1). When the reaction was con-
ducted in THF using microwave heating, a similar yield
was obtained after a reaction time of only 5 min (entry
2). When the isourea intermediate was synthesised by
The transformation of alcohols into alkyl iodides
proved more difficult than expected, with yields that are
lower compared to the bromination and chlorination
reactions (Table 4, entries 1–4). When 11 was subjected
to the reaction conditions, we found that Finkelstein
reactions complicated the reaction outcome. Apart