Halogenation through Deoxygenation of Alcohols and Aldehydes

Article abstract of DOI:10.1021/acs.orglett.8b01058

An efficient reagent system, Ph₃P/XCH₂CH₂X (X = Cl, Br, or I), was very effective for the deoxygenative halogenation (including fluorination) of alcohols (including tertiary alcohols) and aldehydes. The easily available 1,2-dihaloethanes were used as key reagents and halogen sources. The use of (EtO)₃P instead of Ph₃P could also realize deoxy-halogenation, allowing for a convenient purification process, as the byproduct (EtO)₃Pa?O could be removed by aqueous washing. The mild reaction conditions, wide substrate scope, and wide availability of 1,2-dihaloethanes make this protocol attractive for the synthesis of halogenated compounds.

Full text of DOI:10.1021/acs.orglett.8b01058

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Halogenation through Deoxygenation of Alcohols and Aldehydes
Jia Chen, Jin-Hong Lin, and Ji-Chang Xiao*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences,
Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: An efficient reagent system, Ph3P/XCH2CH2X (X = Cl, Br, or I), was
very effective for the deoxygenative halogenation (including fluorination) of alcohols
(including tertiary alcohols) and aldehydes. The easily available 1,2-dihaloethanes
were used as key reagents and halogen sources. The use of (EtO)3P instead of Ph3P
could also realize deoxy-halogenation, allowing for a convenient purification process,
as the byproduct (EtO)3PO could be removed by aqueous washing. The mild
reaction conditions, wide substrate scope, and wide availability of 1,2-dihaloethanes make this protocol attractive for the synthesis
of halogenated compounds.
aturally occurring organohalogenated molecules are being
continuously discovered. Over 4700 molecules are now
agent, has proven to be one of the most successful strategies for
halogen incorporation (Figure 1, eq 2).6 However, the
commonly used electrophilic halogen-containing agents,6
including tetrahalomethanes, molecular halogens, and N-halo
compounds, are highly toxic or may result in low functional
group tolerance, owing to their high reactivity. Furthermore,
Wittig-type dihalomethylenation products can sometimes be
obtained as side products during the conversion of
aldehydes.6a,7 Recently, Denton reported an efficient method
for a catalytic Appel reaction, in which a wide substrate scope
was demonstrated.8 To date, the Appel reaction conditions
have been applied well for the halogenation of primary and
secondary alcohols, but not for tertiary alcohols. Although
many deoxy-halogenation approaches have been developed, a
mild and general protocol that can be applied not only to
deoxy-chlorination, -bromination, and -iodination, but also to
deoxy-fluorination has not been developed. Usually, hazardous
agents such as sulfur tetrafluoride (SF4) or diethylaminosulfur
trifluoride (DAST) have to be employed for deoxy-fluorina-
tion.9 Recently, we found that a new reagent system, Ph3P/
XCH2CH2X/nBu4NI (X = Cl, Br, or I), can be used for efficient
and convenient halogenation reactions including fluorination
(Figure 1, eq 3).
N
known, including 30 fluorinated, 2300 chlorinated, 2100
brominated, and 120 iodinated molecules.1 Organohalogenated
compounds are highly valuable intermediates in organic
synthesis and are of increasing importance in pharmaceuticals,2
agrochemicals,3 and functional materials.4 Therefore, significant
efforts have been directed toward the development of mild
approaches for halogen incorporation. A variety of efficient
halogenation strategies have been devised, such as radical,
electrophilic, nucleophilic, and decarboxylative halogenation.5
Because alcohols and aldehydes are inexpensive and easily
available materials, their deoxygenation and subsequent
nucleophilic halogenation is apparently one of the most
straightforward strategies for the incorporation of halogen
atoms. However, efficient protocols for deoxygenative halogen-
ation (including fluorination) are rather scarce.
Traditional deoxy-halogenation methods require the use of
highly acidic agents such as hydrogen halides (HX),
phosphorus halides (PX5, POX3, PX3), and sulfur halides
(SO2X2, SOX2) (Figure 1, eq 1).5b These acidic agents are
corrosive or moisture sensitive, and may lead to rearrangement
or dehydration of alcohols. The Appel reaction, deoxy-
halogenation of alcohols and aldehydes promoted by a trivalent
phosphorus compound and an electrophilic halogen-containing
Our interest in phosphonium chemistry10 led us to discover
that tetraarylphosphonium salts (Ph3P+−Ar I−) can be applied
to the nucleophilic arylation of aldehydes in the presence of
cesium carbonate (Figure 2, eq 1).10b Here, the tetraaryl-
phosphonium salts were prepared in advance from aryl iodide
and triphenylphosphine. Therefore, our initial attempt was to
combine this two-step reaction into a one-pot process, i.e., to
perform the arylation directly with aryl iodide, triphenylphos-
phine, and aldehyde (Figure 2, eq 2). Although various reaction
conditions were screened, the expected arylation product (2a′)
was not obtained. Unexpectedly, a dichlorinated product (2a)
Figure 1. Halogenation through deoxygenation of alcohols and
aldehydes.
Received: April 8, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01058
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Letter
desired products were highly unstable. For deoxy-chlorination
of ketones such as 4′-nitroacetophenone, a dichlorinated
product (ArCCl2CH3) was obtained as a minor product.
Instead, a chlorinated olefin (ArCHClCH2) was observed as
the major product.
The successful deoxy-halogenation of carbonyls encouraged
us to examine the dehydroxy-halogenation of alcohols. After
determining the optimal reaction conditions (see SI), we
investigated the substrate scope for dehydroxy-chlorination,
-bromination, and -iodination of alcohols (Scheme 2). The use
Figure 2. Unexpected chlorination through deoxygenation of an
aldehyde.
was obtained when 1,2-dichloroethane was used as the reaction
solvent.
Scheme 2. Dehydroxy-chlorination, -bromination, and
-iodination of Alcohols
a
The observation of product 2a prompted us to screen the
optimal reaction conditions for the unexpected deoxy-
chlorination of aldehydes. A detailed survey of the conditions
revealed the reaction with ClCH2CH2Cl as the chlorination
agent and reaction solvent proceeded smoothly to give the
desired product in a high yield in the presence of a slight excess
n
of Ph3P and Bu4NI (see Supporting Information (SI)). With
the optimized reaction conditions in hand, we investigated the
substrate scope for deoxy-halogenation of other carbonyls
(Scheme 1). For deoxy-chlorination of aldehydes (2a−2m),
Scheme 1. Deoxy-chlorination and -bromination of
a
Aldehydes
a
Reaction conditions: for X = Cl, alcohol 4 (0.5 mmol), Ph3P (1.2
equiv), and nBu4NI (1.2 equiv) in ClCH2CH2Cl (5 mL) at 120 °C for
0.5 h; for X = Br, alcohol 4 (0.5 mmol), Ph3P (1.2 equiv), and nBu4NI
(1.2 equiv) in BrCH2CH2Br (5 mL) at 60 °C for 2 h; for X = I, alcohol
4 (0.5 mmol) and Ph3P (1.2 equiv) in CH3CN (5 mL) at 60 °C for 2
b
h. All the yields were isolated yields. The reaction was performed on a
a
2 mmol scale (2 mmol of alcohol were used).
Reaction conditions: for X = Cl, substrate 1 (0.5 mmol), Ph3P (1.2
equiv (equiv)) and nBu4NI (1.2 equiv) in ClCH2CH2Cl (5 mL) at 80
°C for 10 h; for X = Br, substrate 1 (0.5 mmol), Ph3P (2 equiv) and
nBu4NI (1 equiv) in BrCH2CH2Br (5 mL) at 60 °C for 10 h. All the
yields were isolated yields except for 2g, which was determined by 1H
NMR.
of ClCH2CH2Cl as the chlorination agent and the reaction
solvent also gave the desired chlorination products in moderate
to high yields in the presence of Ph3P and nBu4NI (5a−5n). In
contrast to deoxy-chlorination of aldehydes, dehydroxy-
chlorination of alcohols occurred much faster (0.5 h versus
10 h), albeit at a higher reaction temperature (120 °C versus 80
°C). Various benzyl alcohols (5a−5i) and alkyl alcohols (5j−
5n) were all suitable for this transformation. Compared with
primary alcohols (5a−5l), a secondary alcohol (5m) and
tertiary alcohol (5n) were converted into the desired products
in slightly lower yields. Dehydroxy-bromination of alcohols by
using BrCH2CH2Br instead of ClCH2CH2Cl also occurred very
well at a lower temperature (6a−6k). A tertiary product (6k)
could also be obtained in moderate yields. The use of DMF or
CH3CN as the reaction solvent allowed for the successful
electron-rich, -neutral, and -deficient aryl aldehydes were all
converted smoothly into the desired products (2a−2l).
Although a high conversion yield was obtained for the
conversion of a substrate containing a strong electron-donating
substituent, the desired product could not be isolated, owing to
its instability (2g). Besides aryl aldehydes, an alkyl aldehyde was
also transformed well (2m). Gratifyingly, the replacement of
ClCH2CH2Cl with BrCH2CH2Br resulted in the deoxy-
bromination of aldehydes (3a−3e). This deoxy-bromination
reaction could be applied to both aryl- and alkyl-aldehydes. The
deoxy-iodination of aldehydes was not fully investigated, as the
B
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deoxy-iodination of alcohols (see the optimization of the
reaction conditions in the SI) with only a slight excess of
ICH2CH2I (1.2 equiv) (7a−7f). In contrast to the above
chlorination and bromination, the iodination proceeded
n
smoothly without the presence of Bu4NI.
Although the iodide anion was present during the
chlorination and bromination, as shown in Scheme 2, no
iodination product was observed, which may be because both
chlorination and bromination were faster than iodination,
owing to the stronger C−X (X = Cl, Br) bond. The successful
iodination prompted us to speculate on the possibility of the
challenging dehydroxy-fluorination of an alcohol when an
external fluoride ion is added to the Ph3P/ICH2CH2I system.
To our delight, a brief survey of the reaction conditions (see SI)
revealed that dehydroxy-fluorination could proceed well when
CsF was used as the fluoride source. With the optimal reaction
conditions in hand, we examined the substrate scope of the
dehydroxy-fluorination of alcohols (Scheme 3). Benzyl alcohols
Figure 3. Proposed mechanism for deoxy-halogenation of aldehydes
and alcohols.
the byproduct (determined by 31P NMR; see SI). The alcohol
could also be activated by salt A to form intermediate E. The
nucleophilic attack of intermediate E by the halide via an SN2
process affords the dehydroxy-halogenation product. For
fluorination, the solvent DMF may attack intermediate A to
produce a Vilsmeier−Haack-type intermediate Me2N+CHI,
which can also activate alcohols and thus allows for dehydroxy-
fluorination.11
Scheme 3. Dehydroxy-fluorination of Alcohols
According to the proposed mechanism, a catalytic amount of
iodide is enough for dehydroxy-chlorination and -bromination,
and ethylene and Ph3PO are produced as byproducts. Indeed,
the presence of 0.2 equiv of iodide led to the chlorination of
aldehyde 1a to give product 2a, albeit in 62% yield (Figure 4).
a
Reaction conditions: alcohol 4 (0.5 mmol), Ph3P (1.5 equiv),
ICH2CH2I (1.5 equiv), and CsF (3 equiv) in DMF (5 mL) at 100 °C
Figure 4. Dehydroxy-chlorination in the presence of a catalytic
amount of Bu4NI.
b
for 2 h. The yields were isolated yields. 2 equiv of 18-crown-6 were
n
c
used, and the reaction temperature was 120 °C. AgF (3 equiv) was
used instead of CsF; the loadings of Ph3P and ICH2CH2I were both
d
decreased to 1.2 equiv. The yield was determined by 19F NMR
However, a 72 h reaction time was required. Furthermore,
owing to the slow chlorination process when using a catalytic
amount of iodide, the quaternization of Ph3P with
ClCH2CH2Cl occurred as a side reaction, resulting in a lower
yield (62% versus 96%, as shown in Scheme 1). Therefore, a
stoichiometric amount of nBu4NI was employed to facilitate the
dehydroxy-chlorination and -bromination reaction.
For the dehydroxy-fluorination, -chlorination, and -bromina-
tion reactions, no iodination product was observed even though
an iodide anion was present. The question arose whether these
products were formed from the substitution of an iodinated
intermediate. If this is the dominant path, retention of
configuration may be observed, owing to the double inversion.
However, the transformation of enantiopure S-4m under the
optimal reaction conditions led to the inversion of config-
uration (Figure 5). The inversion not only indicated that
iodination to give R-7e followed by substitution was not the
spectroscopy.
were quite reactive, and the yields were not affected by the
electronic effects of substituents (8a−8i). Besides benzyl
alcohols, unactivated alcohols could also be smoothly converted
into the desired products (8j−8k). Secondary alcohols
displayed low reactivity under the optimal conditions.
Fortunately, a moderate yield could be obtained by using
AgF instead of CsF (8l). The high volatility of product 8l led to
a decrease in the isolated yield (57%) compared with the yield
determined by 19F NMR.
On the basis of the above results and the experimental
evidence which has to be shown in SI due to length limits, we
propose the plausible reaction mechanism, as shown in Figure
3. For the Ph3P/XCH2CH2X (X = Cl or Br) system,
substitution to provide ICH2CH2X followed by the release of
ethylene produces molecular iodine, which reacts with
triphenylphosphine to afford iodophosphonium salt A. For
the Ph3P/ICH2CH2I system, the halogen bonding drives the
formation of intermediate D, which could be in equilibrium
with salt A. The aldehyde substrate is activated by salt A via
coordination to form complex F, the carbonyl carbon of which
would be easily attacked by a halide anion to give intermediate
G. The further halogenation of intermediate G affords the final
product and releases triphenylphosphine oxide (Ph3PO) as
Figure 5. Inversion of configuration.
C
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Letter
probable path but also supported the SN2 process for
halogenation of intermediate E shown in Figure 3. Apparently,
fluorination, chlorination, and bromination are faster than
iodination, owing to the stronger C−X (X = F, Cl, Br) bond
compared with the C−I bond.
In the above-mentioned reactions, the formation of by-
product Ph3PO could lead to a difficult purification process.
However, the use of (EtO)3P instead of Ph3P could also readily
realize the dehydroxy-halogenation of alcohol (Figure 6). Like
Key Research Program of Frontier Sciences (CAS) (QYZDJ-
SSW-SLH049) for financial support.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01058.
1
Experimental details; references and notes; copies of H,
19F, and 13C NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jchxiao@sioc.ac.cn.
ORCID
Jin-Hong Lin: 0000-0002-7000-9540
Ji-Chang Xiao: 0000-0001-8881-1796
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Basic Research Program of China
(2015CB931903), the National Natural Science Foundation
(21421002, 21472222, 21502214, 21672242), and the Chinese
Academy of Sciences (XDA02020105, XDA02020106), and the
D
DOI: 10.1021/acs.orglett.8b01058
Org. Lett. XXXX, XXX, XXX−XXX