Stereospecific hydrodehalogenation of alkenyl bromides: A new approach to the synthesis of (E)-alkenes

Article abstract of DOI:10.1039/c4cc00345d

The pair NaBH₄-TMEDA and catalytic PdCl₂(PPh ₃)₂ in THF at room temperature is a mild and efficient system for the hydrodebromination of alkenyl bromides, providing a facile reduction procedure that allows completing the process advantageously, leading from aldehydes to (E)-alkenes. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc00345d

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Stereospecific hydrodehalogenation of alkenyl
bromides: a new approach to the synthesis
of (E)-alkenes†
Cite this: Chem. Commun., 2014,
50, 4069
Received 15th January 2014,
Accepted 17th February 2014
Giorgio Chelucci
DOI: 10.1039/c4cc00345d
www.rsc.org/chemcomm
The pair NaBH4–TMEDA and catalytic PdCl2(PPh3)2 in THF at room
temperature is a mild and efficient system for the hydrodebromination
of alkenyl bromides, providing a facile reduction procedure that
allows completing the process advantageously, leading from aldehydes
to (E)-alkenes.
To prepare geometrically pure 1,2-disubstituted alkenes, metal-
catalyzed cross-coupling reactions between stereodefined 1-bromo-
1-alkenes and a variety of organometallic reagents have proven to be
reliable (5 to 6 and 7 to 8, Scheme 1).1 Consequently, geometrically
pure (Z)- or (E)-alkenyl halides are required. The 1,1-dibromovinyl
functionality 2 is an attractive and versatile bidentate electrophile
for organometallic chemistry, making their metal-catalyzed cross-
couplings with a variety of organometallic reagents (2 to 3,
Scheme 1) facile and selective.2 Moreover, the 1,1-dibromo-1-
alkene moiety is a valuable source of 1-bromoalkenes (2 to 5 or 7,
Scheme 1
Scheme 1). In fact, the palladium-catalysed hydrodehalogenation of at 25 1C afforded the related alkenes stereoselectively, but worked
1,1-dibromoalkenes with Bu3SnH is a well-recognized procedure to well only with alkenyl iodides.5 The second case concerns the
obtain (Z)-vinyl bromides (2 to 5, Scheme 1).2,3 On the other hand, stereospecific hydrodebromination of bromofluoroalkenes with
methodologies for the efficient synthesis of (E)-vinyl bromides HCOOH–n-Bu3N and PdCl2(PPh3)2 in DMF at 35–60 1C.6
from 1,1-dibromo-1-alkenes give satisfactory results only in a few
In this communication we wish to report that the couple
sodium borohydride/N,N,N 0,N 0-tetramethylethylenediamine (NaBH4–
favorable cases (2 to 7, Scheme 1).2,4
Based on this background we cogitated that the successful TMEDA) under palladium catalysis is an efficient and stereospecific
stereospecific hydrodebromination of the (Z)-alkenyl bromide, system for the hydrodebromination of (Z)-1,2-disubstituted-1-
formed after initial trans-selective monosubstitution of the bromo-1-alkenes.
1,1-dibromovinyl group, would offer a simple and convenient
way for converting aldehydes to (E)-1,2-disubstituted alkenes reduction of the model substrate (Z)-1-(2-bromo-2-phenylvinyl)-
(1 - 2 - 3 - 8, Scheme 1). 4-methoxybenzene 1a by using n-Bu3SnH/Pd(PPh3)4 in toluene at
To confirm previous results we initially examined the
The hydrodehalogenation of 1,2-disubstituted-1-halo-1-alkenes 25 1C5 (Table 1). Under these reaction conditions no conversion
to the related alkenes has been pursued using catalyzed5,6 and non- was observed within 48 h. It was also ineffective carry out the
catalyzed approaches.7–9 Two examples of stereoselective catalyzed reaction at 50 1C or use other Pd-catalysts such as Pd(OAc)2–
methods have been described. The system n-Bu3SnH and Pd(PPh3)4 PPh3, Pd2(dba)3–TFP and PdCl2(PPh3)2. On the other hand, when
the reducing system HCOOH–n-Bu3N and PdCl2(PPh3)2 in DMF
at 60 1C was employed,6 total conversion of 1a was obtained after
16 h, affording the product 2a in 66% yield.
This interesting result prompted us to assess other reducing
systems that were effective in the hydrodehalogenation of
halogenated heterocycles (Table 1).10
`
Dipartimento di Agraria, Universita di Sassari, viale Italia 39, I-07100 Sassari,
Italy. E-mail: chelucci@uniss.it; Fax: +39-079-229559; Tel: +39-079-229539
† Electronic supplementary information (ESI) available: General experimental
procedures along with copies of the 1H and 13C NMR spectra of all new
compounds. See DOI: 10.1039/c4cc00345d
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Table 1 Hydrodebromination of (Z)-1-(2-bromo-2-phenylvinyl)-4-methoxy-
benzenea
Table 2 Hydrodebromination of 1,2-diaryl-1-bromo-1-alkenesa
Time Yieldb
Entry Bromo alkene
Product
(h)
(%)
1
20
92
Reducing
agent
Temp. Time Conv. Yieldc
Catalyst
Solvent (1C)
(h)
(2a/1a)b (%)
Pd(PPh3)4
n-Bu3SnH
DMF
60
60
60
48
16
14
48
36
24
20
20
0 : 100
—
2
3
4
5
6
7
10
6
84
67
86
PdCl2(PPh3)2 HCOOH/n-Bu3N DMF
Pd(PPh3)4 HCOONa DMF
PdCl2(PPh3)2 HCOONH4
Pd(PPh3)4 NaOMe
PdCl2(PPh3)2 Et3SiH
Pd(OAc)2/PPh3 NaBH4/TMEDA THF
PdCl2(PPh3)2 NaBH4/TMEDA THF
100 : 0 66
100 : 0 80
33 : 67 nd
100 : 0 33
100 : 0
100 : 0 88
100 : 0 92
MeOH 60
DMF 60
MeCN 60
0
25
25
a
b
c
For experimental details see ESI. Determined by 1H NMR. Isolated
yields.
20
Interestingly, HCOONa and Pd(PPh3)4 in DMF at 60 1C afforded
2a in 80% yield, while HCOONH4–PdCl2(PPh3)2 in MeOH at 60 1C,
NaOMe–Pd(PPh3)4 in DMF at 60 1C, and Et3SiH–PdCl2(PPh3)2 in
MeCN at 60 1C provided unsatisfactory yields. Finally, when 1a was
treated with the couple NaBH4–TMEDA as the hydride source in the
presence of Pd(OAc)2 and PPh3 in THF at room temperature,11 2a
was obtained in 88% yield after 20 h. The proton NMR spectrum of
the crude reaction mixture indicated for 2a a coupling constant of
16.3 Hz due to the trans arrangement of the olefin protons, and
excluded the presence of the corresponding Z-isomer. Gratified by
this result we tried to increase the efficiency of this reducing
procedure by examining other catalysts, Pd(PPh3)4, PdCl2/PPh3,
Pd2(dba)3, Pd2(dba)3–PPh3, Pd2(dba)3–TFP, PdCl2(PPh3)2 and
PdCl2(dppf). Among them PdCl2(PPh3)2 was the best performing
one, increasing the yield of 2a up to 92% (Table 1).
3
13
30
86c
21
30
45
72c
18
20
77
76
8
The scope of the reaction was then explored by using a variety
of (Z)-1,2-disubstituted-1-bromo-1-alkenes. The starting alkenyl
bromides were obtained by C-1 homologation of the related
aldehydes under standard Corey–Fuchs conditions, followed by
stereoselective Suzuki–Miyaura cross-coupling of the initially
formed 1,1-dibromo-1-alkenes,2 with the exception of the bromo
enyne 1p that was prepared by Negishi cross-coupling.2
The reductions were carried out in THF with an excess of
NaBH4 (2.8 equiv.) and TMEDA (3.64 equiv.) in the presence of
PdCl2(PPh3)2 (5.0 mol%) at room temperature (Tables 2 and 3).
In the diaryl alkene series (1a–1k), the hydrodebromination
of the vinyl bromide gave geometrically pure (E)-alkenes in
good yields. Small differences in yields and reaction times were
observed with alkenes having different kinds of substituents in
one (1a–1g) or the other aryl rings (1h–1k). Thus, for instance,
both (Z)-1-(2-bromo-2-phenylvinyl)-3-chlorobenzene 1d and
(Z)-1-(1-bromo-2-phenylvinyl)-3-chlorobenzene 1j afforded the
same reduced product, (E)-1-chloro-3-styrylbenzene 2d, in 86%
(20 h) and 88% yield (24 h), respectively.
9
6
62
10
24
6
88
82
11
a
Reaction conditions: 1-bromoalkene (0.5 mmol), PdCl2(PPh3)2
(0.025 mmol, 5.0 mol%), NaBH4 (1.40 mmol, 2.8 equiv.) and TMEDA
b
c
(1.82 mmol, 3.64 equiv.) in THF (10 mL) at rt. Isolated yields. NaBH4
(0.75 mmol, 1.5 equiv.) and TMEDA (1.0 mmol, 2.0 equiv.).
obtained in only 30% yield, (E)-4-styrylaniline being the main
A particular comment deserves the reduction of the aryl product, formed by consecutive reduction of the bromovinyl
derivatives 1e and 1f, bearing the nitro and methyl ester and nitro groups. Fortunately, by decreasing the amounts of
moieties, respectively. When 1e was hydrogenolyzed under NaBH4 (1.5 equiv.) and TMEDA (2.0 equiv.) and quenching the
the usual reaction conditions, the target product 2e was reaction with aqueous NH4Cl, compound 2e was formed in 86%
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Table 3 Hydrodebromination of 1,2-disubstituted-1-bromo-1-alkenesa
Time Yieldb
Entry Bromo alkene
Product
(h)
(%)
12
24
64
13
14
15
19
24
5
92c
75
60
Scheme 2 Two synthetic approaches to (E)-alkene 2d.
observed.2 However, this predictable event was not detected by
us in the reduction of the bromodienes 1n and 1o, which in
both cases afforded only the (E,E)-diene 2m. On the other hand,
recent studies have shown that cross-coupling reactions of
(Z)-2-bromo-1-en-3-ynes were accompanied by significant, but
partial stereoisomerization,12 while we observed complete
stereoinversion in the reduction of 1p.
In summary, the pair NaBH4–TMEDA and catalytic PdCl2(PPh3)2 in
THF at 25 1C is a mild and efficient system for the hydro-
debromination of alkenyl bromide derivatives. Under these conditions
a variety of (Z)-1,2-disubstituted-1-bromo-1-alkenes are stereo-
specifically converted into the related (E)-alkenes at room
temperature in good yields. Moreover, the reducing system
shows high functional group tolerance, e.g., halogen, ester,
alkyne, alkene, nitro and nitrile substituents.
16
4
88
a
Reaction conditions: 1-bromoalkene (0.5 mmol), PdCl2(PPh3)2
(0.025 mmol, 5.0 mol%), NaBH4 (1.40 mmol, 2.8 equiv.) and TMEDA
(1.82 mmol, 3.64 equiv.) in THF (10 mL) at rt. b Isolated yields. Reaction
c
Importantly, this efficient reduction procedure allows completing
the process advantageously, leading from aldehydes to (E)-alkenes
(aldehydes - 1,1-dibromo-1-alkenes - (E)-1-bromo-1-alkenes -
(E)-alkenes) and providing an alternative way to carry out other
olefination reactions by a judicious selection of the coupling partners
and well-designed starting materials. Thus, for instance, the
(E)-alkene 2d (Scheme 2) is formed in similar yields by
reduction of both 1d and 2j, which were in turn obtained from
3-chlorobenzaldehyde and benzaldehyde, respectively.
carried out at 65 1C.
yield after 13 h. Analogously, the reduction of 1f under these
reaction conditions afforded the alkene 2f in 72% yield.
To further expand the scope of our catalytic system, we
next investigated the hydrodebromination of other kinds of
1,2-disubstituted-1-bromo-1-alkenes (Table 3). Good catalytic
activity at 25 1C was observed in the removal of the vinyl
bromide from compound 1l derived from the aliphatic aldehyde
3-phenylpropanal. On the other hand, the bromide in 1m
originated from the more sterically hindered cyclohexane-
carbaldehyde was unreactive at room temperature, but the
reduction took place at 65 1C within 19 h to give the expected
alkene 2l in excellent yield (92%).
Two types of 1,3-bromodienes were examined bearing the
bromo substituent in the terminal or internal positions of
the conjugate double bonds (1n and 1o, respectively). Both
compounds were hydrodebrominated in good yields (75%
and 60%, respectively). Compound 1n was reduced more
slowly, but afforded a better yield, while 1o afforded opposite
results.
Notes and references
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Finally, the reduction of the 1,3-enyne 1p proceeded
smoothly to afford the cis-alkene 2n as the sole product in
88% yield. Partial or complete stereoinversion at the Br-bearing
CQC bond in Pd-catalyzed cross-coupling reactions of 2-bromo-1,3-
dienes with various types of organozinc reagents has been previously
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