Palladium-catalyzed hydrodehalogenations by fluoride activated polymethylhydrosiloxane

Article abstract of DOI:10.1016/S0040-4039(02)01502-2

A mild, selective, and efficient method for the Pd-catalyzed reduction of aryl bromides and iodides by hypercoordinate polymethylhydrosiloxane (PMHS) is reported. In contrast to related methods, the hydrodehalogenations described herein are amine free and can be carried out in THF with relatively low loads of catalyst. Furthermore, we have evidence to suggest that the reduction of bromostyrene proceeds differently than previously described.

Full text of DOI:10.1016/S0040-4039(02)01502-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7087–7090
Palladium-catalyzed hydrodehalogenations by fluoride activated
polymethylhydrosiloxane
Robert E. Maleczka, Jr.,* Ronald J. Rahaim, Jr. and Robson R. Teixeira
Department of Chemistry, Michigan State University, East Lansing, MI 48824, USA
Received 16 July 2002; accepted 22 July 2002
Abstract—A mild, selective, and efficient method for the Pd-catalyzed reduction of aryl bromides and iodides by hypercoordinate
polymethylhydrosiloxane (PMHS) is reported. In contrast to related methods, the hydrodehalogenations described herein are
amine free and can be carried out in THF with relatively low loads of catalyst. Furthermore, we have evidence to suggest that
the reduction of bromostyrene proceeds differently than previously described. © 2002 Elsevier Science Ltd. All rights reserved.
The formation of arenes from aryl halides represents an
important chemical transformation in organic synthe-
sis.1 Reduction under free radical conditions,1,2 electro-
chemical means,1,3 catalytic hydrogenation,1,4 or metal
catalyzed hydride delivery1,5 are among the common
ways to perform such hydrodehalogenations.
Screening various catalyst, solvent, stoichiometry,
fluoride source, and reaction temperature combinations
revealed that like the original conditions ꢀ6 equiv. of
PMHS worked best (Scheme 1, conditions b). Impor-
tantly though, adding 12 equiv. of KF (aq.) to the
reaction obviated the need for tribenzylamine, allowed
us to reduce the Pd-load from 5 to 1 mol%, and
facilitated the reactions so that they could now be
performed in THF at 70°C or lower (Table 1).9 Fluo-
ride clearly promoted these reductions. Control experi-
ments run in the absence of KF saw yields diminish by
ꢀ80% for the aryl bromides to ꢀ30% for the aryl
iodides.10
In 1986, Pri-Bar and Buchman6 reported that poly-
methylhydrosiloxane (PMHS) in the presence of a
Pd(0) catalyst could effectively reduce aryl, styryl, and
a-keto halides (Scheme 1, conditions a). Milder than
LAH, NaBH4, etc., PMHS is air and moisture stable,
soluble in a number of organic solvents, relatively
non-toxic, and inexpensive.7 Unfortunately, use of this
attractive reductant in hydrodehalogenations also
required the employment of excess tribenzylamine, rela-
tively high boiling and polar solvents (DMSO/MeCN),
elevated temperatures, and fairly high loads (5 mol%)
of (Ph3P)4Pd. As fluoride activation of PMHS is
known,7a,8 we decided to investigate if a combination of
PMHS and fluoride would facilitate aryl halide reduc-
tions and thereby minimize some of the disadvantages
posed by the original protocol.
As compared to the hydrodehalogenations described by
Pri-Bar and Buchman, reduction with PMHS/KF in
THF11 tended to be higher yielding, though they often
took longer to complete. Despite this increased reaction
time, by avoiding the amine and polar high boiling
solvents, reaction monitoring (GC or NMR) as well as
product isolation and purification were made much
easier. Furthermore, it needs to be noted that reduc-
tions under Pri-Bar and Buchman’s conditions at ‘our’
temperatures and times were almost always
incomplete.12
Table 1 details the results of our hydrodehalogenation
experiments. Iodobenzene is efficiently reduced to ben-
zene at room temperature (entry 1). In contrast, com-
plete reduction of bromobenzene required heating to
70°C (entry 2). An iodide can be selectively reduced in
the presence of a bromide and a bromide in the pres-
ence of a chloride (entries 3–4). However, with these
dihalides Pd black tends to precipitate after reduction
of the more facile halide. As illustrated in entries 5–9,
Scheme 1.
Keywords: hydrodehalogenation; reduction; palladium; PMHS.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01502-2

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R. E. Maleczka, Jr. et al. / Tetrahedron Letters 43 (2002) 7087–7090
Table 1. Pd-catalyzed hydrodehalogenations with fluoride activated PMHSa
Entry
Starting material
Temp. (°C)
Time (hours)
Product
% Yieldb
1
2
3
4
5
6
7
8
Iodobenzene
Bromobenzene
Rt
70
Rt
70
70
70
70
70
70
Rt
70
110
110
70
70
70
24
36
26
48
3.5
0.25
48
24
18
24
15
24
72
24
48
24
Benzene
Benzene
90d
100d
100c
90c
66e
80e
79c
99c
92c
90c
89c
Traced
0
1-Bromo-4-iodobenzene
3-Bromochlorobenzene
1-Bromo-4-nitrobenzene
1-Iodo-2,4-dinitrobenzene
4-Bromobenzaldehyde
4%-Bromoacetophenone
Methyl 4-bromobenzoate
2-Bromoacetophenone
2-Bromoacetophenone
Chlorobenzene
Bromobenzene
Chlorobenzene
Nitrobenzene
1,3-Dinitrobenzene
Benzaldehyde
Acetophenone
Methyl benzoate
Acetophenone
Acetophenone
Benzene
9
10
11
12
13
14
15
16
4%-Chloroacetophenone
4-Bromobenzoic acid
a-Bromophenylacetic acid
4-Bromophenol
Acetophenone
Benzoic acid
Phenylacetic acid
Phenol
0
0
17c
a See Ref. 9 for experimental details.
b Yields are an average of two runs.
c As determined by GC (calibration curve).
d As determined by NMR (internal standard).
e Isolated yield.
dehalogenation of bromo arenes bearing nitro, alde-
hyde, ketone, or ester groups takes place smoothly in
good to near quantitative yields. a-Bromo-carbonyl
compounds (entries 10–11) can also be reduced, albeit
with minor side product formation.13
The reduction of b-bromostyrene represents another
apparent departure from reductions with PMHS, Bn3N,
and Pd(0) in DMSO/MeCN. Pri-Bar and Buchman
reported the reduction of b-bromostyrene to styrene in
37% yield (Table 2, entry 8). Under our conditions,
b-bromostyrene was reduced over 24 h at room temper-
ature to PhEt in 92% yield (entry 1). Low yield (24%)
reduction of styrene by Rh-mediated hydrogen transfer
from PMHS has been described.14 However, the
efficiency of entry 1 led us to probe this over reduction
further. Subjecting styrene to our conditions afforded
some PhEt after 24 h at room temperature, but in only
12% yield (entry 3). Heating the reaction at 70°C for 24
h proved more efficient affording PhEt in 72% yield
(entry 4).
Though our protocol holds certain advantages over
Pri-Bar and Buchman’s original procedure, it is not
superior for all substrates. Fluoride activation provides
no advantage with arylchlorides (entries 12–13), as they
are nearly inert under both conditions. Moreover, while
Pri-Bar and Buchman could successfully hydrodehalo-
genate p-bromobenzoic acid and a-bromoacetic acids,
in our system the presence of carboxylic acids or phe-
nols spelled failure (entries 14–16).
Table 2. Reduction of b-bromostyrene, styrene, and control experimentsa
Entry
Starting material
Temp. (°C)
Hours
Product
% Yieldb
1
2
3
4
5
6
7
b-Bromostyrene
Rt
70
Rt
70
Rt
70
Rt
24
22
24
24
24
22
24
PhEt
Styrene
PhEt
PhEt
PhEt
PhEt
PhEt
92c
b-Bromostyrene
42c
Styrene
Styrene
12c,d
72c,d
78d
50/50 Styrene+2-bromoacetophenone
50/50 Styrene+2-bromoacetophenone
Styrene+KBr
43d
12c,d
Under Pri-Bar and Buchman’s conditions
8
9
10
b-Bromostyrene
b-Bromostyrene
Styrene
60
60
60
3
3
3
Styrenee
PhEtf
37e
25d,f
–
No rxnf
a See Ref. 9 for experimental details (entries 1–7).
b Yields are an average of two runs.
c As determined by GC (calibration curve).
d As determined by NMR (internal standard).
e Per Ref. 6.
f Our data.

R. E. Maleczka, Jr. et al. / Tetrahedron Letters 43 (2002) 7087–7090
7089
Acknowledgements
Returning to b-bromostyrene, we looked at its reduc-
tion at 70°C. To our surprise, after 22 h at this tem-
perature a 42% yield of styrene was obtained along
with 48% starting material and only a trace amount
of PhEt (entry 2). Thus, it would appear that b-bro-
mostyrene reduces first to styrene and then on to
PhEt. However, if this were so then why would the
reductions proceed further at room temperature than
at 70°C, especially since the reduction of pure styrene
is much more facile at 70°C than at room tempera-
ture?
We thank the Center for Fundamental Materials
Research (MSU) and the NSF (CHE-9984644) for
generous support, as well as Ms. Andrea M. Pellerito,
Ms. Samantha Dias, Mr. Fontaine J. Sheffey, Mr.
Craig A. Kulesza, Mr. Jason W. Dahl, and Dr.
Joseph S. Ward, III for their assistance.
References
A potential answer to this question may lie in our
observation of a Pd-black precipitate during the 70°C
reduction of b-bromostyrene. Perhaps, some combina-
tion of halide and styrene contributes to an active but
thermally unstable Pd-complex. Thus, reduction of b-
bromostyrene is complete at room temperature, but
stops considerably short of completion at elevated
temperatures. This hypothesis is supported by several
additional experiments. Room temperature reduction
of a 50/50 mixture of styrene and 2-bromoacetophe-
none afforded a 78% yield of PhEt after 24 h (entry
5). In contrast, at 70°C, styrene reduction was
retarded by the presence of 2-bromoacetophenone.
After 22 h, the reaction afforded some PhEt (43%)
along with 52% unreacted styrene and 51% of the
normally easy to reduce 2-bromoacetophenone (entry
6).
1. For reviews, see: (a) Hudlicky, M. In Comprehensive
Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Perga-
mon: Oxford, 1991; Vol. 8, pp. 895–922; (b) Entwistle, I.
D.; Wood, W. W. In Comprehensive Organic Synthesis;
Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991;
Vol. 8, pp. 955–981; (c) Pinder, A. R. Synthesis 1980,
425–452.
2. (a) Studer, A.; Amrein, S. Synthesis 2002, 835–849; (b)
Inoue, K.; Sawada, A.; Shibata, I.; Baba, A. J. Am.
Chem. Soc. 2002, 124, 906–907; (c) Neumann, W. P.
Synthesis 1987, 665–683 and references cited therein.
3. (a) Hudlicky, T.; Claeboe, C. D.; Brammer, L. E., Jr.;
Koroniak, L.; Butora, G.; Ghiviriga, I. J. Org. Chem.
1999, 64, 4909–4913; (b) Bhuvaneswari, N.; Venkatacha-
lam, C. S.; Balasubramanian, K. K. Tetrahedron Lett.
1992, 33, 1499–1502.
4. For representative examples, see: (a) Faucher, N.;
Ambroise, Y.; Cintrat, J.-C.; Doris, E.; Pillon, F.;
Rousseau, B. J. Org. Chem. 2002, 67, 932–934; (b) Kan-
tam, M. L.; Rahman, A.; Bandyopadhyay, T.; Haritha,
Y. Synth. Commun. 1999, 29, 691–696; (c) Marques, C.
A.; Selva, M.; Tundo, P. J. Org. Chem. 1995, 60, 2430–
2435; (d) Zhang, Y.; Liao, S.; Xu, Y. Tetrahedron Lett.
1994, 35, 4599–4602.
5. For representative examples, see: (a) Desmarets, C.;
Kuhl, S.; Schneider, R.; Fort, Y. Organometallics 2002,
21, 1554–1559; (b) Viciu, M. S.; Grasa, G. G.; Nolan, S.
P. Organometallics 2001, 20, 3607–3612; (c) Villemin, D.;
Nechab, B. J. Chem. Res., Synop. 2000, 432–434; (d)
Alonso, F.; Radivoy, G.; Yus, M. Tetrahedron 1999, 55,
4441–4444; (e) Be´nyei, A. C.; Lehel, S.; Joo´, F. J. Mol.
Catal. A: Chem. 1997, 116, 349–354; (f) Wei, B.; Li, S.;
Lee, H. K.; Hor, T. S. H. J. Mol. Catal. A: Chem. 1997,
126, L83–L88; (g) Boukherroub, R.; Chatgilialoglu, C.;
Manuel, G. Organometallics 1996, 15, 1508–1510; (h)
Agrios, K. A.; Srebnik, M. J. Org. Chem. 1993, 58,
6908–6910; (i) Keefer, L. K.; Lunn, G. Chem. Rev. 1989,
89, 459–502; (j) Ram, S.; Ehrenkaufer, R. E. Synthesis
1988, 91–95; (k) Johnstone, R. A. W.; Wilby, A. H.;
Entwistle, I. D. Chem. Rev. 1985, 85, 129–170.
Substituting KBr for 2-bromoacetophenone failed to
promote the reduction of styrene (entry 7); while
adding 1 equiv. of n-Bu4NBr turned the reaction into
an intractable gel after 10 min. Decreasing the
amount of added 2-bromoacetophenone met with a
corresponding decrease in the yield of PhEt. So while
our results indicate that the bromide plays a role in
these reductions, the specifics of this involvement as
well as the mechanism by which the alkene is satu-
rated remain unclear.14b
These results prompted us to repeat15 the reduction of
b-bromostyrene using Pri-Bar and Buchman’s proce-
dure. In our hands, their conditions (60°C, 3 h) also
reduced b-bromostyrene to PhEt (25% yield+38%
unreacted b-bromostyrene), as judged by NMR analy-
sis of the reaction mixture (entry 9).16 No PhEt was
observed when styrene was subjected to these condi-
tions (entry 10), suggesting again an involvement of
the halide in the over reduction.
In summary, the hydrodehalogenation of aryl- and
a-keto-bromides are selectively reduced with KF (aq.),
PMHS, and catalytic (Ph3P)2PdCl2, in THF. This sys-
tem tolerates nitro groups, aldehydes, ketones, and
esters, however, carboxylic acids or phenols are
incompatible. Under these conditions, b-bromostyrene
reduces to PhEt with the bromide playing an impor-
tant but undefined role in the transformation. Addi-
tional synthetic and mechanistic studies will be
presented in due course.
6. Pri-Bar, I.; Buchman, O. J. Org. Chem. 1986, 51, 734–
735.
7. (a) Lawrence, N. J.; Drew, M. D.; Bushell, S. M. J.
Chem. Soc., Perkin Trans. 1 1999, 3381–3391; (b) Lipow-
itz, J.; Bowman, S. A. Aldrichim. Acta 1973, 6, 1–6; (c)
Fieser, M.; Fieser, L. F. Reagents for Organic Synthesis;
Wiley: New York, 1974; Vol. 4, pp. 393–394.
8. (a) Terstiege, I.; Maleczka, R. E., Jr. J. Org. Chem. 1999,
64, 342–343; (b) Chuit, C.; Corriu, R. J. P.; Reye, C.;
Young, J. C. Chem. Rev. 1993, 93, 1371–1448.

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9. General reaction procedure: an oven dried round bottom
11. Substituting DMSO/MeCN for THF proved inefficient.
12. 2-Bromoacetophenone was an exception as its reduction
was complete after 6 h at rt.
13. Byproduct isolation proved difficult, but analysis of crude
reaction mixtures suggests these minor constituents to be
the result of condensation reactions.
14. (a) Blum, J.; Pri-Bar, I.; Alper, H. J. Mol. Catal. 1986, 37,
359–367; (b) For related mechanistic studies, see: Blum, J.;
Bitan, G.; Marx, S.; Vollhardt, K. P. C. J. Mol. Catal. 1991,
66, 313–319.
15. b-Bromostyrene reductions under Pri-Bar and Buchman’s
conditions were repeated four times.
16. Pri-Bar and Buchman assigned their reaction products
by GC analysis. Though we do not know their GC
parameters, retention times for styrene and PhEt on a
30 M×0.32 mm SPB-5 fused silica GC column at 30–
200°C (increased 10°C/min) are similar. Thus, absent
additional analysis PhEt could be easily mis-assigned as
styrene.
flask was charged with 1.0 mmol of aryl halide in 5 mL
THF (0.2 M solution) and 0.01 equiv. of (Ph3P)2PdCl2.
The flask was sealed with a septum and flushed with
nitrogen. While flushing the reaction, 12 equiv. of KF in
2 mL of degassed water were introduced by syringe.
PMHS (6 equiv.) was then injected into the reaction
mixture. If the reaction mixture is heated, a reflux con-
densor is attached to the round bottom and placed in a
preheated oil bath. The reaction was stirred until com-
plete as judged by disappearance of the starting material
(GC analysis). Upon complete reduction, the reaction
mixture was added to a 1 M solution of NaOH. After
stirring overnight to hydrolyze unreacted PMHS, the
mixture was extracted several times with Et2O. The com-
bined organics were dried over MgSO4, concentrated, and
purified by silica gel chromatography.
10. Fluoride free reductions of b-bromostyrene and 2-bro-
moacetophenone saw yields drop by 60 and 40%, respec-
tively.