.
take place when pyridine or Hunig’s base was used as a
substitute for triethylamine. Instead, the reaction pro-
duced cyclic carbonate 3.5
Table 2. Chemoselective Chlorination of Aliphatic Primary
Alcohol vs Tertiary Alcohol
Table 1. Optimization Study
a Yield based on product isolated by flash chromatography.
Triphosgene, (Cl3CO)2CdO, is a relatively safe substi-
tute for notoriously toxic phosgene gas. It exists as a stable
nonhygrosopic crystalline material at rt, and its handling
and storage do not demand meticulously anhydrous con-
ditions, thus making it very convenient for typical labora-
tory scale operations.6 This reagent has been used to
achieve various functional group interconversions, parti-
cularly the insertion of the carbonyl moiety.7 The use
of triphosgene in chlorination reactions is also known.
There is ample precedent for the conversion of reactive
(i.e., benzylic, propargylic, and allylic) alcohols to the
corresponding chlorides via triphosgene activation in
pyridine-buffered organic media.8 Chlorination of simple
aliphatic alcohols, however, requires stronger activation,
most notably through the use of a nucleophilic promoter,
such as triphenylphosphine that facilitates triphosgene
decomposition and promotes the ensuing chlorination.9
Due to the unexpected propensity of triphosgene and
triethylamine mixtures to chlorinate diol 1a, we believed
this unexplored reaction warranted further investigation
on its scope and limitations.
a Diols 1a and 1d are racemic. b Yield based on product isolated by
flash chromatography. c Performed under nonanhydrous conditions.
the participating hydroxy group. The activation was per-
formed in dichloromethane at 0 °C, and the mixture was
subsequently warmed to ambient temperature.10 While
these reactions were performed under anhydrous condi-
tions, we found that chlorination under less rigorous
conditions was equally effective (entry 1). As indicated in
entries 2 and 3, the distance between the two hydroxy groups
appeared to have no effect on the chlorination reaction, and
the structural identity of the resulting chloroalcohols 2b and
2c was unambiguously confirmed through X-ray crystallo-
graphy.11 Entries 1ꢀ4 further demonstrate that highly
ionizable tertiary alcohols (1aꢀ1d) are stable, thus under-
scoring the mild nature of the reaction conditions.
As shown in Table 2, exposure of a number of diols
(1aꢀ1g), each bearing a primary and a tertiary alcohol,
to triphosgeneꢀtriethylamine resulted in chemoselective
chlorination at the primary alcohol, and the chloroalcohol
products 2aꢀ2g were obtained in excellent yields. Our
typical chlorination reaction employed 0.5 equiv of tri-
phosgene and 2.5 equiv of triethylamine per equivalent of
To further probe the compatibility of our chlorination
conditions with common functional and protecting
groups, we strategically chose the substrates in Table 3.
Aliphatic alcohols 4a and 4b gave the corresponding alkyl
chlorides in good yields,12 demonstrating tolerance for
alkene and aromatic functionality (entries 1ꢀ2). Likewise,
the highly ionizable epoxide 4c was a suitable substrate.
(5) Burk, R. M.; Roof, M. B. Tetrahedron Lett. 1993, 34, 395–398.
(6) (a) Eckert, H.; Foster, B. Angew. Chem., Int. Ed. Engl. 1987, 26,
894–895. (b) Damle, S. B. Chem. Eng. News 1993, 71, 4. (c) Cotarca, L.
Org. Process Res. Dev. 1999, 3, 377.
(7) Roestamadji, J.; Mobashery, S.; Banerjee, A. Encyclopedia of
Reagents for Organic Synthesis; Wiley: 2006, and references therein.
(8) Goren, Z.; Heeg, M. J.; Mobashery, S. J. Org. Chem. 1991, 56,
7186–7188.
(9) (a) Avdagic, A.; Gelo-Pujic, M.; Sunjic, V. Synthesis 1995, 11,
1427–1431. (b) Portada, T.; Roje, M.; Raza, Z.; Caplar, V.; Zinic, M.;
Sunjic, V. Eur. J. Org. Chem. 2007, 5, 838–856. (c) Wells, A. Synth.
Commun. 1994, 24, 1715–1719.
(10) In typical cases, the starting material was fully consumed within
minutes; however, for generality, our protocol called for an additional
3 h of stirring to ensure completion prior to aqueous workup. See
Supporting Information (SI) for a detailed experimental protocol.
(11) CCDC 879959 (compound 2b) and 879960 (compound 2c)
contain the supplementary crystallographic data for this paper, which
cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge
CB2 1EZ, U.K.; fax: þ44 1223 336033. See SI.
(12) The relatively lower yield was attributed to the high volatility of
the resulting alkyl chloride product.
B
Org. Lett., Vol. XX, No. XX, XXXX