A mild synthesis of vinyl halides and gem-dihalides using triphenyl phosphite-halogen-based reagents

Article abstract of DOI:10.1021/jo061346g

A new application of (PhO)₃P-halogen-based reagents to the synthesis of vinyl halides and gem-dihalides is described. Vinyl halides were prepared in good to excellent yields from enolizable ketones, whereas aldehydes afforded the corresponding gem-dihalides. The halogenation proceeded smoothly under mild conditions.

Full text of DOI:10.1021/jo061346g

Recently, we described the reactivity of amides toward the
halogenating reagent chlorotriphenoxyphosphonium chloride,
i.e., (PhO)3P+ClCl- (henceforth TPPCl2) and proposed a new
and efficient protocol for the mild deacylation of N-monosub-
stituted amides.5a As part of our ongoing studies on the
chemistry and applications of this versatile reagent,5 we wish
to describe here the reactivity of carbonyl compounds such as
ketones and aldehydes toward TPPCl2 and its brominated
analogue TPPBr2, which resulted in a mild synthesis of vinyl
halides and gem-dihalides.
A Mild Synthesis of Vinyl Halides and
gem-Dihalides Using Triphenyl
Phosphite-Halogen-Based Reagents
Alberto Spaggiari, Daniele Vaccari, Paolo Davoli,
Giovanni Torre, and Fabio Prati*
Dipartimento di Chimica, UniVersita` di Modena e Reggio
Emilia, Via Campi 183, 41100 Modena, Italy
By analogy to amides, which are known to form the
corresponding iminochlorides when treated with TPPCl2,5a we
reasoned that such an halogenation on a ketone or aldehyde
carbonyl would also result in a halogen-oxygen exchange to
yield the appropriate vinyl halide (Scheme 1). Encouraging,
though scattered, literature precedents using halogenated phos-
phites6 and phosphines3g,7 hinted at the feasibility of such a
transformation, whose scope and limitations, however, have
never been assessed so far.
prati.fabio@unimore.it
ReceiVed June 29, 2006
To this end, a suitable set of ketones and aldehydes was
subjected to TPPCl2 under standard conditions.5 In a typical
procedure, the carbonyl compound was treated at -20 °C with
a freshly prepared solution of TPPCl2 in either dichloromethane
or chloroform in the presence of triethylamine. After warming
to rt overnight, the reaction mixture was refluxed for 2 h to
achieve complete conversion, and the crude residue was purified
by column chromatography. The results are reported in Table
1. Vinyl chlorides were obtained from enolizable ketones in
excellent yields (Table 1, entries 1-12). If formation of E/Z
isomers was possible, poor stereoselectivity was observed (entry
8); in the case of propiophenone (entry 2), however, nearly
exclusive formation of the thermodynamically favored Z isomer8
occurred. When nonequivalent enolizable positions were present,
A new application of (PhO)3P-halogen-based reagents to
the synthesis of vinyl halides and gem-dihalides is described.
Vinyl halides were prepared in good to excellent yields from
enolizable ketones, whereas aldehydes afforded the corre-
sponding gem-dihalides. The halogenation proceeded smoothly
under mild conditions.
The role and importance of halogenated building blocks in
organic synthesis is long established and undisputed, owing to
the wealth of reactions they can easily undergo. Moreover, the
recent development of new strategic reactions for C-C bond
formation, such as the Suzuki-Miyaura, Stille, or Sonogashira
coupling,1 has resulted in the constant need of readily available
halides as starting materials. Vinyl halides, in particular, are
emerging as versatile substrates in a variety of chemical
transformations,2 and their importance as valuable synthons is
increasing accordingly. Typically, vinyl halides are prepared
from carbonyl compounds by reaction with traditional haloge-
nating reagents such as thionyl chloride or phosphorus halides
under prolonged heating in high-boiling solvents3a-f or by means
of multistep procedures that require the isolation of suitable
intermediates, such as vinyl phosphates3g or hydrazones4 using
the Barton procedure and later modifications. The quest for new
synthetic methods, therefore, is still active, and the development
of milder and straightforward reactions for the preparation of
such halogenated derivatives represents a desirable goal.
(3) For a general review, see: (a) Stanforth, S. P. In ComprehensiVe
Organic Functional Group Transformations II; Katritzky, A. R., Taylor,
R. J. K., Eds.; Elsevier: Oxford, 2005; Vol. 2, p 561. Selected examples:
(b) Burkhard, J.; Janku˚, J.; Vodicˇka, L. Coll. Czech. Chem. Commun. 1988,
53, 110. (c) Kamei, K.; Maeda, N.; Ogino, R.; Koyama, M.; Nakajima, N.;
Tatsuoka, T.; Ohno, T.; Inoue, T. Bioorg. Med. Chem. Lett. 2001, 11, 595.
(d) Eszenyi, Y.; T´ıma´r, T.; Seb_ok, P. Tetrahedron Lett. 1991, 32, 827. (e)
Fry, A. J.; Moore, R. H. J. Org. Chem. 1968, 33, 425. (f) Hurd, C. D.;
Hayao, S. J. Am. Chem. Soc. 1954, 76, 5065. (g) Kamei, K.; Maeda, N.;
Tatsuoka, T. Tetrahedron Lett. 2005, 46, 229.
(4) (a) Barton, D. H. R.; O’Brien, R. E.; Sternhell, S. J. Chem. Soc.
1962, 470. (b) Pross, A.; Sternhell, S. Aust. J. Chem. 1970, 23, 989. (c)
Campbell, J. R.; Pross, A.; Sternhell, S. Aust. J. Chem. 1971, 24, 1425. (d)
Barton, D. H. R.; Bashiardes, G.; Fourrey, J.-L. Tetrahedron 1988, 44, 147.
(e) Barton, D. H. R.; Bashiardes, G.; Fourrey, J.-L. Tetrahedron Lett. 1983,
24, 1605. (f) Furrow, M. E.; Myers, A. G. J. Am. Chem. Soc. 2004, 126,
5436.
(5) (a) Spaggiari, A.; Blaszczak, L. C.; Prati, F. Org. Lett. 2004, 6, 3885.
(b) Spaggiari, A.; Davoli, P.; Blaszczak, L. C., Prati, F. Synlett 2005, 661.
(c) Spaggiari, A.; Blaszczak, L. C.; Prati, F. Ars Pharm. 2005, 46, 167. (d)
Spaggiari, A.; Vaccari, D.; Davoli, P.; Prati, F. Synthesis 2006, 995. (e)
Spaggiari, A.; Prati, F. Phosphorus Sulfur Silicon Relat. Elem. 2006, 181,
1825.
(1) (a) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int.
Ed. 2005, 44, 4442. (b) Espinet, P.; Echavarren, A. M. Angew. Chem., Int.
Ed. 2004, 43, 4704. (c) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron
2002, 58, 9633.
(2) (a) Stanforth, S. P. In ComprehensiVe Organic Functional Group
Transformations II; Katritzky, A. R., Taylor, R. J. K., Eds.; Elsevier:
Oxford, 2005; Vol. 2, p 1025. (b) Dounay, A. B.; Overman, L. E. Chem.
ReV. 2003, 103, 2945. (c) Willis, M. C.; Chauhan, J.; Whittingham, W. G.
Org. Biomol. Chem. 2005, 3, 3094. (d) Durandetti, M.; Pe´richon, J. Synthesis
2004, 3079. (e) Mori, M. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E., Ed.; John Wiley & Sons: Hoboken, NJ,
2002; Vol. 2, p 1213. (f) Blum, J.; Gelman, D.; Baidossi, W.; Shakh, E.;
Rosenfeld, A.; Wassermann, B. C.; Frick, M.; Heymer, B.; Schutte, S.;
Wernik, S.; Schumann, H. J. Org. Chem. 1997, 62, 8681.
(6) (a) Allen, N. E.; Boyd, D. B.; Campbell, J. B.; Deeter, J. B.; Elzey,
T. K.; Foster, B. J.; Hatfield, L. D.; Hobbs, J. N., Jr.; Hornback, W. J.;
Hunden, D. C.; Jones, N. D.; Kinnick, M. D.; Morin, J. M., Jr.; Munroe, J.
E.; Swartzendruber, J. K.; Vogt, D. G. Tetrahedron 1989, 45, 1905. (b)
Hoffmann, R. W.; Bovicelli, P. Synthesis 1990, 657.
(7) (a) Shih, C.; Swenton, J. S. J. Org. Chem. 1982, 47, 2825. (b)
Spangler, L. A.; Swenton, J. S. J. Chem. Soc., Chem. Commun. 1986, 828.
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2001, 37, 52.
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10.1021/jo061346g CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/13/2007
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J. Org. Chem. 2007, 72, 2216-2219

TABLE 1. Synthesis of Vinyl Halides and gem-Dihalides with
TPPX2
SCHEME 1
a regioisomeric mixture of halides was obtained, as in the case
of 2-methylcyclohexanone (entry 11),9 whose halogenation
yielded two regioisomers in ca. 1:1 ratio. Functionalities such
as ester (entry 3), boronate (entry 4), ether (entry 6), double
bond (entry 7), and acetal (entry 16) were left untouched during
the halogenation. When camphor (entry 12) was exposed to
TPPCl2, two constitutional isomeric chloro derivatives were
formed in a 2:1 ratio. In particular, the corresponding vinyl
chloride was obtained as the minor product, whereas the
exomethylene derivative was featured as the major halogenation
product, thus confirming a behavior already described in the
literature with PCl5.10 When a nonenolizable ketone such as
benzophenone was used as the substrate, dichlorodiphenyl-
methane was obtained in 93% yield (entry 13). By contrast,
aldehydes always afforded exclusively gem-dichlorides in
excellent yields (entries 14-16), regardless of the presence of
enolizable protons.
By analogy to the synthesis of vinyl chlorides and gem-
dichlorides described above, the corresponding bromo deriva-
tives were also prepared successfully in comparable yields using
(PhO)3P+BrBr- (TPPBr2) as the reagent (Table 1). Similar
reaction conditions were employed, except for the temperature
at which the halogenating species was generated. According to
literature data,11 and to our own findings as well,5a the TPPX2
reagent may exist under two different species, viz. the halo-
triphenoxyphosphonium halide (PhO)3P+XX- and the dihalo
triphenoxyphosphorane (PhO)3PX2, which bear ionic or covalent
character, respectively, and the former only is active for our
synthetic purposes.12 While TPPCl2 generated at -20 °C
afforded the ionic and the covalent form in ca. 4:1 ratio, as
calculated from 31P NMR spectra,11,12 TPPBr2 at the same
temperature resulted only in a poor 1:3 ratio. However, by
lowering the temperature to -60 °C, the ionic/covalent ratio
improved to ca. 4:1. Accordingly, carbonyl compounds were
reacted at -60 °C with a freshly prepared solution of TPPBr2
in dichloromethane in the presence of triethylamine and left to
warm to rt overnight. After refluxing for 2 h, the reaction
mixture was subjected to chromatographic purification. Eno-
lizable ketones gave vinyl bromides in good to excellent yields
(Table 1, entries 1-12), whereas gem-dibromides were obtained
from aldehydes in good yields (entries 14-16). Comparable
results were observed by using excess of TPPBr2 generated at
0 °C, as reported in the literature for aldehydes.6b Surprisingly,
treatment of benzophenone (entry 13) with TPPBr2 did not
afford the desired dibromodiphenylmethane under any of the
reaction conditions employed. Formation of tetraphenylethyl-
ene13 was observed instead, and traces of the expected gem-
dibromide could be detected only by GC-MS analysis.
a Reaction conditions: ketone or aldehyde (1.0 mmol), (PhO)3P (1.1
mmol), X2 (1.1 mmol), triethylamine (1.2 mmol), dichloromethane or
chloroform (20 mL). b Determined by GC. c GC-MS analysis revealed
formation of gem-dibromide only in traces, while tetraphenylethylene
represented the major reaction product.
(9) Hudrlik, P. F.; Kulkarni, A. K. Tetrahedron 1985, 41, 1179.
(10) (a) Paukstelis, J. V.; Macharia, B. W. J. Org. Chem. 1973, 38, 646.
(b) Fabris, F.; De Martin, A.; De Lucchi, O. Tetrahedron Lett. 1999, 40,
9121.
(11) (a) Michalski, J.; Mikołajczak, J.; Skowron´ska, A. J. Am. Chem.
Soc. 1978, 100, 5386. (b) Michalski, J.; Pakulski, M.; Skowron´ska, A. J.
Org. Chem. 1980, 45, 3122. (c) Gloede, J.; Costisella, B.; Gross, H. Z.
Anorg. Allg. Chem. 1986, 535, 221. (d) Krawczyk, E.; Skowron´ska, A.;
Michalski, J. J. Chem. Soc. Dalton Trans. 2002, 4471.
(12) Hatfield, L. D.; Blaszczak, L. C.; Fisher, J. W. U. S. Patent
4,230,644, 1980.
The formation of vinyl halides from enolizable ketones is
most likely to proceed through a TPPX2-promoted dihalode-
oxobisubstitution14 and can be rationalized as follows (Scheme
2). The well-known strong oxophilicity of the phosphorus atom
must trigger off the rapid formation of a putative oxyphospho-
nium halide species A, which evolves to gem-dihalide B by
J. Org. Chem, Vol. 72, No. 6, 2007 2217

SCHEME 2. Reaction Mechanism
(entry 14) with DBU in refluxing chloroform did yield
quantitatively the corresponding trans-(2-bromovinyl)benzene,
most likely favored by the formation of a more extended
conjugated system.
The peculiar attitude of aldehydes to afford exclusively gem-
dihalides when treated with TPPX2 offers a valuable synthetic
opportunity. gem-Dihalides, in fact, represent important inter-
mediates in many processes used for the preparation of
pharmaceutical, agricultural and fine chemicals,14 and much
synthetic effort has been devoted to their synthesis.14,19 In
particular, gem-dihalides feature as the substrates of choice for
the synthesis of useful alkylidene precursors,20 including me-
tathesis catalysts.21
Halogenation of ketones and aldehydes using halogenated
species of organophosphorus compounds to yield vinyl halides
and gem-dihalides, respectively, is not unprecedented. Examples
3g,7
include (PhO)3PX2,6,22 Ph3P‚X2
and related alkyl-, aryl- or
loss of triphenyl phosphate. The geminal derivative B, in turn,
undergoes base-promoted dehydrohalogenation to afford vinyl
halide C (Scheme 2). Formation of a transient gem-dihalide B
was indeed detected when the reaction was monitored by GC-
MS and was confirmed unambiguously when 4-eptanone (entry
8) was treated with TPPCl2 in the absence of triethylamine. In
fact, analysis of the crude reaction mixture by 1H and 13C NMR
spectroscopy revealed the presence of a conspicuous amount
of an additional compound, along with the expected reaction
product 4-chlorohept-3-ene (as a mixture of E/Z stereoisomers).
By means of HSQC and HMBC experiments, δH and δC values
for the additional product were assigned unambiguously and
were found to match perfectly with those of 4,4-dichloroheptane
prepared independently from 4-heptanone oxime by treatment
with chlorine.15 In particular, the signal at 95 ppm was diagnostic
for the presence of a quaternary carbon bearing two chlorine
atoms. In the case of TPPBr2, the quaternary carbon atom of
the gem-dibromo intermediate (4,4-dibromoheptane) was found
to resonate at 77 ppm, as reported in the literature.16
It is noteworthy that when enolizable aldehydes were used
as the substrate (entries 14-15), the reaction with TPPX2
stopped inevitably to gem-dihalide B, and no vinyl derivative
was isolated, even in the presence of a stronger base such as
DBU under prolonged heating. A similar behavior has been
recently experienced by Furrow and Myers, who were able to
prepare vinyl bromides from ketones in the presence of either
triethylamine or a stronger and more hindered tetramethylguani-
dine base, whereas no vinyl halides were obtained from
aldehydes, which gave exclusively the corresponding geminal
derivative.4f This observation is in line with the fact that primary
gem-dihalides exhibit indeed a remarkable reluctance toward
dehydrohalogenation, and the literature offers only a few
methods to achieve directly this transformation, such as use of
molten salts17 or via flash vacuum pyrolysis over magnesium.18
Surprisingly, however, treatment of 2,2-dibromoethylbenzene
alkylarylphosphite-halogen-based compounds.23 In most
cases, however, aldehydes were used as substrates to afford
gem-dibromides,6b,22,23 whereas ketones have featured only
sporadically.3g,6a,7 Most recently, PPh3‚X2 has been used as the
halogenating species for the synthesis of vinyl halides from
ketones.3g However, such a protocol always required a prelimi-
nary conversion step of the starting ketone into an activated
phosphoenol ester intermediate. By contrast, the TPPX2 protocol
described here allows a direct halogenation of the carbonyl
compound and results in higher yields. For instance, tetralone
(entry 5) was converted into the corresponding vinyl chloride
and bromide in 91% and 96% yield, whereas Kamei and co-
workers reported a 73% and 48% overall yield,3g,24 respectively.
In summary, vinyl halides and gem-dihalides can be prepared
in good to excellent yields from ketones and aldehydes,
respectively, using a straightforward TPPX2-based halogenation.
The method has been applied successfully to a range of
structurally diverse carbonyl compounds and has showed a good
functional group compatibility that further expands the literature
data available from other synthetic applications of this re-
agent.5,6,25 The experimental protocol is mild, simple and high-
yielding, and should be of value for synthetic chemists as an
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R.; Os´ıo Barcina, J.; Garc´ıa Go´mez, C.; Subramanian, L. R. Synthesis 1993,
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36, 1090. (e) Charette, A. B.; Wilb, N. Synlett 2002, 176.
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(22) (a) Desruet, M.-D.; Morin, C.; Ogier, L. Carbohydr. Res. 1997, 301,
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H. J. Org. Chem. 1997, 62, 405. (c) Green, J. O.; Baird, J.-H.; Gibb, B. C.
Org. Lett. 2000, 2, 3845. (d) Dorok, S.; Ziemer, B.; Szeimies, G. Chem.
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(23) (a) Mironov, V. F.; Konovalova, I. V.; Burnaeva, L. M. Zh. Obshch.
Khim. 1995, 65, 401. (b) Mironov, V. F.; Konovalova, I. V. Zh. Obshch.
Khim. 1994, 64, 1350. (c) Mironov, V. F.; Ofitserov, E. N.; Konovalova,
I. V.; Pudovik, A. N. IzV. Akad. Nauk SSSR, Ser. Khim. 1991, (7), 1663.
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Zh. Org. Khim. 1990, 26, 2570. (e) Gloede, J. Z. Chem. 1982, 22, 126.
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(13) (a) Finkelstein, H. Ber. 1910, 43, 1528. (b) Gorvin, J. H. J. Chem.
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F.; Arseneault, M.; Wuest, J. D. Cryst. Growth Des. 2005, 5, 1451.
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2218 J. Org. Chem., Vol. 72, No. 6, 2007

mg, 6.4 mmol) were added to the faint orange solution. The reaction
mixture was stirred for 18 h, while warming to rt, and heated to
reflux for a further 2 h. Purification by column chromatography
yielded 1-bromo-3,4-dihydronaphthalene as a dark orange oil (1.28
g, 96%).
expeditious access to vinyl halides and gem-dihalides from
ketones and aldehydes, respectively.
Experimental Section
Typical Procedure for the Synthesis of Vinyl Chlorides with
TPPCl2. Triphenyl phosphite (1.85 mL, 7.0 mmol) was dissolved
in anhydrous dichloromethane (20 mL) and cooled to -20 °C under
Ar flow. Chlorine was bubbled into the clear colorless solution until
it became bright yellow. The color was discharged by addition of
a few drops of triphenyl phosphite until the solution faded to almost
colorless. Anhydrous triethylamine (1.15 mL, 7.7 mmol) and
tetralone (934 mg, 6.4 mmol) were added. The reaction mixture
was stirred for 18 h while warming to rt. After the mixture was
refluxed for an additional 2 h, the crude material was purified by
column chromatography on silica gel to afford 1-chloro-3,4-
dihydronaphthalene as a yellowish oil (955 mg, 91%).
Typical Procedure for the Synthesis of Vinyl Bromides with
TPPBr2. To a cold solution of triphenyl phosphite (1.85 mL, 7.0
mmol) in anyhdrous dichloromethane (20 mL) maintained at -60
°C under Ar flow, bromine (400 µL, 7.7 mmol) was dropped in.
Anyhdrous triethylamine (1.2 mL, 8.4 mmol) and tetralone (936
Acknowledgment. We are grateful to Ministero
dell’Istruzione, dell’Universita` e della Ricerca Scientifica
(MIUR), for financial support (COFIN 2005) and to Centro
Interdipartimentale Grandi Strumenti (CIGS) at the Universita`
di Modena e Reggio Emilia for MS determinations. Thanks are
due to Stefania Morandi and Claudia Ori for kindly performing
NOESY experiments with E/Z vinyl halides. A.S. thanks
Fondazione Cassa di Risparmio di Modena for a postdoctoral
fellowship.
Supporting Information Available: General considerations,
detailed experimental procedures, and characterization data for all
products, including references to known compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO061346G
J. Org. Chem, Vol. 72, No. 6, 2007 2219