Table 1 One-pot conversion of alcohols into the corresponding halides (1 equiv. of DIC used in all cases)
Entry
Alcohol
Catalyst (mol%)
Activator
1 step
2 step
Yield
1
2
3
4
3-Phenylpropanol
3-Phenylpropanol
N-(3-Hydroxypropyl)phthalimide
p-Nitrobenzyl alcohol
CuCl (2%)
CuCl (2%)
CuCl (2%)
CuCl (2%)
AcCl
AcCl
AcCl
AcCl
RT, 16 h
150 °C, 5 min
150 °C, 5 min
150 °C, 5 min
150 °C, 5 min
93%
100%
92%
100 °C, 5 min
100 °C, 5 min
100 °C, 5 min
95%
5
CuCl (1%)
AcCl
RT, 16 h
150 °C, 5 min
82%
6
7
8
3-Phenylpropanol
Cu(OTf)2 (2%)
Cu(OTf)2 (2%)
Cu(OTf)2 (2%)
Cu(OTf)2 (2%)
Cu(OTf)2 (5%)
Cu(OTf)2 (5%)
Cu(OTf)2 (5%)
CuCl (5%)
AcBr
AcBr
AcBr
AcBr
AcCl
AcBr
AcBr
AcBr
AcBr
100 °C, 5 min
100 °C, 5 min
100 °C, 5 min
100 °C, 5 min
100 °C, 5 min
100 °C, 5 min
RT, 16 h
150 °C, 5 min
150 °C, 5 min
150 °C, 5 min
150 °C, 5 min
140 °C, 5 min
120 °C, 5 min
150 °C, 5 min
150 °C, 5 min
120 °C, 5 min
98%
96%
89%
98%
80% (14%)a
95% ( < 3%)a
80% (8%)ab
Complex mixture
88% ( < 3%)ac
6-Chlorohexan-1-ol
N-(3-Hydroxypropyl)phthalimide
p-Nitrobenzyl alcohol
4-Phenylbutan-2-ol
4-Phenylbutan-2-ol
Dihydrocholesterol
9
10
11
12
13
14
Dihydrocholesterol
(R)-4-Phenylbutan-2-ol
RT, 16 h
100 °C, 5 min
Cu(OTf)2 (5%)
a Elimination product (ratio determined by 1H-NMR). b Only the 3-a isomer was observed. c [a]D = +66.2° (CHCl3, c = 0.85). A sample prepared using
Ph3P–CBr4 had [a]D = +64.7° (CHCl3, c = 0.80).
Starting from a secondary alcohol (entry 10), the correspond-
ing chloroalkane was found in good yield, however this was
accompanied by some elimination product.
acetyl chloride to acetic acid and hydrochloric acid, with these
acids as the actual reactants can be ruled out. This is further
demonstrated by the fact that diisopropylurea, which would be
the by-product of the reaction of hydrochloric or acetic acid
with the isourea, is definitely not formed in any significant
amount. Further work is under way in order to confirm the
proposed mechanism.
In conclusion, we have demonstrated that non-protic activa-
tion of isoureas is possible, and has been used to develop a
practical one-pot procedure for the conversion of alcohols into
alkyl halides using readily available reagents. The reaction is
stereoselective, suitable for primary (including propargylic and
benzylic) and secondary alcohols, and acid sensitive groups
survive. The use of microwave irradiation results in reaction
times as short as 5 min per step. The mechanism of this novel
isourea activation method is suggested, but not yet confirmed.
Further work towards the confirmation of the mechanism and to
widen the scope of the reaction is in progress.
We reasoned that for bromination reactions the use of a
different copper catalyst was advisable, as the chloride anion
could cause a Finkelstein-type reaction with the alkyl bromide
produced, which would result in product mixtures. It was found
that copper (II) triflate was an excellent alternative. The use of
this catalyst also gave an additional advantage in that it proved
to be a better catalyst than CuCl: while the microwave-assisted
isourea formation on secondary alcohols catalysed by CuCl
requires long reaction times (20–30 minutes), Cu(OTf)2
catalysed reactions are complete in 5 minutes. It was clear that
the change in catalyst did not influence the second step in a
negative way: high yields were obtained for primary alcohols
(entries 6–9). Acetyl bromide proved to be superior to acetyl
chloride when performing the reaction on secondary alcohols,
giving lower levels of elimination (entries 11–12).
Kaulen has demonstrated that the acylation of secondary
chiral O-alkylisoureas with carboxylic acids proceeds with
inversion of configuration.5 When the isourea of 3b-dihy-
drocholesterol¶ was reacted with acetyl bromide, only the 3a-
bromo diastereoisomer was formed, which proves that an SN2
inversion process is taking place (entry 12). When CuCl was
used instead of Cu(OTf)2 in conjunction with AcBr for the
second step, a complex reaction mixture was obtained consist-
ing of the desired 3a-bromo derivative, as well as the 3a-chloro,
the 3b-bromo and the elimination products (entry 13). This
clearly demonstrates that Finkelstein reaction does take place
with chloride anions originating from the copper catalyst.
Because of the presence of CuCl, there is more than 1 equiv. of
halide ions present in the reaction mixture. As the chloride ions
do react with the activated isourea, there are residual bromide
ions which cause the formation of the 3-b-cholesterol derivative
through Finkelstein reaction with the corresponding 3-a-bromo
derivative. With Cu(OTf)2 as catalyst instead of CuCl, no such
epimerisation was observed.
Similar results were obtained for the bromination of enantio-
pure (R)-4-phenylbutan-2-ol (entry 14). No racemisation was
observed, as evidenced by comparison of the optical rotation
with a sample of (S)-4-phenyl-2-bromobutane, prepared from
(R)-4-phenylbutan-2-ol using Ph3P–CBr4. This gives our
method a clear advantage over the Golding method, where
extensive racemisation was observed even after 30% conver-
sion.
The authors thank Personal Chemistry for the donation of a
Smith SynthesizerTM. The authors acknowledge the supporting
partners of the Southampton Combinatorial Centre of Ex-
cellence for financial support. The funding partners are:
Amersham Health and Amersham Biosciences, AstraZeneca,
GlaxoSmithKline, Eli Lilly, CN Biosciences, Inc., Organon,
Pfizer and Roche. The authors thank Joan Street and Neil Wells
for assistance with NMR and Julie Herniman and John Langley
for assistance with the mass spectrometry.
Notes and references
‡ Typical procedure: the substrate (2.0 mmol), N,NA-diisopropylcarbodii-
mide (2.0 mmol) and catalyst (0.1 mmol) are dissolved in anhydrous THF
(2.0 mL) in a microwave vial. The vial is sealed and heated at 100 °C for 5
min under microwave irradiation. The acetyl halide is added (3.0 mmol) and
the vial is heated at the appropriate temperature for 5 min under microwave
irradiation. The resulting reaction mixture is directly purified by column
chromatography.
§ Performing this step at higher temperatures led to incomplete reactions,
suggesting that the copper catalyst decomposes under these conditions.
¶ Conversion of dihydrocholesterol under microwave irradiation did not
proceed to completion, while performing this step at room temperature
overnight afforded the desired isourea.
1 L. J. Mathias, Synthesis, 1979, 561.
2 S. P. Collingwood, A. P. Davies and B. T. Golding, Tetrahedron Lett.,
1987, 28, 4445.
3 (a) S. Crosignani, P. D. White and B. Linclau, Org. Lett., 2002, 4, 1035;
(b) S. Crosignani, P. D. White and B. Linclau, Org. Lett., 2002, 4,
2961.
4 R. C. Larock, Comprehensive Organic Transformations: a Guide to
Functional Group Preparations, VCH, New York, 1989, p. 353.
5 J. Kaulen, Angew. Chem., Int. Ed., 1987, 26, 773.
The observed inversion of configuration (entries 12, 14) is in
accord with the proposed mechanism (Scheme 1b), which
implies an SN2 substitution in the second step. However so far
the postulated N-acetylurea by-product has not been isolated.
As no alkyl acetates have ever been detected, hydrolysis of the
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