Sterics vs electronics: Revisiting the catalytic regioselective hydrodebromination of 2,3,5-tribromothiophene

Article abstract of DOI:10.1021/acs.organomet.6b00587

The application of sterically hindered palladium catalysts to the regioselective hydrodebromination of 2,3,5-tribromothiophene has been studied in detail, including the effects of catalyst choice, solvent, reaction time, and temperature, as well as the method of NaBH₄ addition and the role of chelating additives to effect NaBH₄ solubility. Ultimately it was determined that the background reaction between NaBH₄ and bromothiophenes is too facile to allow both total conversion and high selectivity. Optimized conditions finally allowed a selectivity of ca. 16:1 with overall conversion of 100%. However, complications of overdebromination under these conditions still limit the yield of the desired 2,3-dibromothiophene to 65%.

Full text of DOI:10.1021/acs.organomet.6b00587

Article
pubs.acs.org/Organometallics
Sterics vs Electronics: Revisiting the Catalytic Regioselective
Hydrodebromination of 2,3,5-Tribromothiophene
Kristine L. Konkol and Seth C. Rasmussen*
Department of Chemistry and Biochemistry, North Dakota State University, NDSU Dept. 2735, P.O. Box 6050, Fargo, North Dakota
58108-6050, United States
S
* Supporting Information
ABSTRACT: The application of sterically hindered palladium catalysts
to the regioselective hydrodebromination of 2,3,5-tribromothiophene has
been studied in detail, including the effects of catalyst choice, solvent,
reaction time, and temperature, as well as the method of NaBH4 addition
and the role of chelating additives to effect NaBH4 solubility. Ultimately it
was determined that the background reaction between NaBH4 and
bromothiophenes is too facile to allow both total conversion and high
selectivity. Optimized conditions finally allowed a selectivity of ca. 16:1
with overall conversion of 100%. However, complications of over-
debromination under these conditions still limit the yield of the desired
2,3-dibromothiophene to 65%.
Scheme 2. Synthesis of Asymmetric Dibromothiophenes
INTRODUCTION
■
Halothiophenes, especially bromothiophenes, are the most
common synthetic precursors for the production of function-
alized thiophenes,1 which in turn have found extensive use as
building blocks for the synthesis of materials,2 natural
products,3 and pharmaceuticals.4 Such bromothiophenes are
typically prepared from direct bromination of thiophene with
Br2 or N-bromosuccinimide (NBS). As illustrated in Scheme 1,
Table 1. Debromination of 2,3,5-Tribromothiophene
Scheme 1. Sequential Bromination of Thiophene
a
a
entry
reagent
5
6
ref
1
2
3
4
BuLi
75
95
18
6
25
3
13, 14
17
NaBH4
MeMgBr
82
92
15
Pd(PPh3)4/NaBH4
17, 18
a
Values given are ratios of products 5 and 6.
the electronic differences between the α- and β-positions5,6 of
the thiophene ring favor the successive formation of 2-
bromothiophene (1),7,8 2,5-dibromothiophene (2),8,9 2,3,5-
tribromothiophene (3),10,11 and 2,3,4,5-tetrabromothiophene
(4).12 While these synthetic steps are relatively straightforward,
the production of bromothiophenes can become complex when
attempting to selectively brominate the less readily accessible β-
positions, which then requires either blocking of the more
reactive α-positions or removing unwanted α-bromides
following polybromination.
This can become even more intricate for the production of
asymmetric dibromothiophenes containing both α- and β-
bromides.13−19 The most simple transformation is the selective
debromination of 3 to give 2,4-dibromothiophene (5) (Scheme
2).13,14,17 This can be accomplished with either butyllithium or
NaBH4 (Table 1, entries 1 and 2) and takes advantage of the
fact that the most reactive bromide is being removed in the
process and thus the electronics drive selectivity.19 Such
electron preference can be overcome via the use of larger
reagents, as has been demonstrated through the use of Grignard
reagents (Table 1, entry 3) to selectively produce 2,3-
dibromothiophene (6).15 In this case, steric hindrance between
the 3-bromo group and the incoming reagent inhibits reaction
at the 2-position and thus debromination at the 5-position is
observed. Due to either cost or difficulties in preparing the
Grignard reagents, however, it is still far more common to use
inexpensive reagents to just remove both α-bromides to give 3-
bromothiophene (7), followed by a single bromination to give
6.16
Received: July 22, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.6b00587
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A significant advance was then reported by Hor and co-
workers beginning in 1996.17,18 In two reports, the authors
presented an approach that combined the use of stoichiometric
NaBH4 with a sterically bulky Pd catalyst, citing both 100%
conversion and high selectivity for 6 over the electronically
favored 5 (ca. 15:1, Table 1, entry 4). As such, these methods
allowed the simple production of 6 without the previously
necessary Grignard reagents, with even higher selectivity.
This approach of utilizing sterically bulky Pd catalysts to
overcome the thiophene electronics was then successfully
applied to regioselective cross-coupling by the Rasmussen
group in 2008.19 Extending the methods of Hor and co-workers
to cross-coupling reactions of 3, the application of the bulky
catalyst Pd(dppf)Cl2 (where dppf = 1,1′-bis(diphenyl-
phosphino)ferrocene) disfavored oxidative addition at the
electronically favored 2-position to allow selective coupling of
a variety of arylzinc chlorides at the 5-position. The observed
selectivity in all cases was ca. 10:1.19
Recent attempts to apply the previous Pd-catalyzed hydro-
debromination methods, however, revealed significant varia-
bility in selectivity. As these observations seemed inconsistent
with the reports of either Hor17,18 or Rasmussen,19 it was
decided that it was worthwhile to revisit methods to utilize
catalyst sterics to overcome electronic selectivity, with the goal
to provide greater understanding concerning the generality of
this approach to controlling selectivity in halothiophenes. As
such, a detailed investigation of the catalytic hydrodebromina-
tion of 3 is presented here, in which the interplay of sterics and
electronics will be discussed in relation to effects on the
observed selectivity. Other experimental conditions that dictate
both selectivity and reactivity will also be presented.
portions” over 1.5 h.18 As such, two methods were investigated,
one in which small powder portions were added to the reaction
five times over the specified 1.5 h (entry 3) and a second case
which utilized a powder addition funnel (entry 4). In both
cases, however, neither the percent conversion nor selectivity
previously reported could be obtained in our hands.
As the previous reports had not used a commercial catalyst
but had synthesized and purified Pd(PPh3)4 in house, the
potential effects of catalyst purity were then investigated. Fresh
Pd(PPh3)4 was synthesized20 and purified via the same
methods reported by Hor and co-workers, after which the
conditions given in entry 4 were repeated with the fresh
catalyst. As can be seen in entry 5, this gave nearly identical
results and thus it was concluded that the catalyst source was
not a significant factor. Finally, the amount of catalyst was
increased to 5 mol %, which did result in the complete
conversion and an increase in selectivity for the production of
6. However, this selectivity is still well below that previously
reported.17,18
The lack of reproducibility here was assumed to be due to an
unintentional lack of detail in the published procedure. The
most likely factor was thought to be the nature and method of
the NaBH4 addition, which had already been shown to affect
both conversion and selectivity in the initial trials (Table 2). As
such, various conditions were investigated concerning the
NaBH4 addition (see Table S1 in the Supporting Information).
While adding the NaBH4 as slow as possible resulted in slight
improvements in selectivity, this was not very practical and any
improvement in selectivity was offset by lower conversion.
Attempting to better understand the effect of NaBH4
addition, we then studied noncatalyzed conditions in order to
determine the extent of any background reaction. As shown in
Table 3, the noncatalyzed debromination of 3 was previously
reported by Hor and co-workers in DMSO.17 In this solvent,
the direct reaction at room temperature is highly facile, with
100% conversion within 4 h when 2 equiv of NaBH4 was
utilized (entry 3). Conversion becomes less efficient with lower
amounts of NaBH4, along with a slight decrease in selectivity.
However, as the previously reported catalytic methods utilized
CH3CN,17,18 it was unclear to what extent the change in solvent
may inhibit this background reaction.
To quantify this effect of solvent choice, noncatalyzed
debromination of 3 in CH3CN was first carried out at room
temperature (Table 3, entry 4). The change to CH3CN gave
almost no reaction at room temperature, with only 3%
conversion after 7 h. Selectivity for the electronically favored
2-position, however, was complete and no reaction was
observed at the 5-position. However, when the reaction was
carried out at the temperature given under the reported
catalytic conditions (i.e., 70 °C), it is essentially complete
within 6 h and shows the expected selectivity for the
electronically favored 2-position (entry 5).
RESULTS AND DISCUSSION
■
As a starting point, efforts were made to replicate the previously
reported reaction conditions as closely as possible. A
complication is that different reaction conditions are reported
between the initial report in 199617 and the more detailed
paper in 1998.18 It is worth noting that although the reaction
conditions changed between these two reports (NaBH4
amount, catalyst amount, reaction time), the stated results
remain essentially identical (Table 2, entries 1 and 2).
Assuming the later conditions to be the more optimized, it
was these conditions that were first investigated. Still, questions
remained concerning the method of the addition of the NaBH4,
with the published procedure stating that it was “added in small
a
Table 2. Comparative Results from Literature Procedures
b
products
NaBH4
entry (mmol)
catalyst
(mol %)
time conversn
(h)
(%)
5
6
7
c
1
2
3
4
5
6
20
30
30
30
30
30
5
1
1
1
24
6
100
100
79
6.1
6
92.5
92
1.4
1
The reactivity of NaBH4 with 3 in hot CH3CN is quite
problematic and explains the difficulty in achieving the high
selectivity previously reported by Hor and co-workers. As
selective debromination at the 5-position only occurs when it is
mediated by the bulky catalyst, conditions would need to
inhibit any background reaction. However, as the background
reaction readily occurs under the conditions utilized, the only
way selectivity could possibly be achieved is if the NaBH4 were
added at a rate in which it was immediately consumed in the
catalytic cycle (Scheme 3) and not allowed to participate in
direct reaction with 3, something which would be highly
d
e
f
6
48
43
9
6
85
40
40
14
52
8
f
g
1
6
88
50
10
20
f
5
6
100
66
a
Constant conditions: 3 (20 mmol), NaBH4, and Pd(PPh3)4 in 100
b
mL of CH3CN and heated at 70 °C. Values given are ratios of
c
d
e
products 5−7. Reference 17. Reference 18. Added in small solid
aliquots. Added via powder addition funnel. Catalyst synthesized
from ref 20.
f
g
B
DOI: 10.1021/acs.organomet.6b00587
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a
Table 3. Noncatalyzed NaBH4 Debromination of 3
b
products
entry
solvent
3:NaBH4
temp (°C)
time (h)
conversn (%)
5
6
7
c
1
DMSO
DMSO
DMSO
CH3CN
CH3CN
THF
1:1
room temp
room temp
room temp
room temp
70
24
6
50
73
100
3
90
93
95
100
95
0
1
8
2
1:1.5
1:2
7
0
c
3
4
2.6
0
2.9
0
4
5
6
7
1:1.5
1:1.5
1:1.5
1:1.5
7
6
99
0
5
0
room temp
66
6
0
0
THF
6
2
100
0
0
a
b
c
Constant conditions: 3 (5 mmol) and NaBH4 in 100 mL of solvent. Values given are ratios of products 5−7. Reference 17.
Scheme 3. Catalytic Cycle and Competing Background
Reaction for Hydrodebromination of 3
CH3CN and diethyl ether and was thus selected as the primary
solvent.
In addition to the change in solvent, it was decided to move
from Pd(PPh3)4 to Pd(dppf)Cl2. This change was motivated by
the fact that the bulkier dppf ligand was found to give slightly
better steric-mediated selectivity in the Pd-catalyzed cross-
coupling of 319 and thus should provide increased selectivity
here as well. In order to keep the methods as simple as possible,
initial trials utilized a one-pot method in which all reagents
were added collectively at the start (Table 4). These initial
conditions exhibited reasonable selectivity but poor product
conversion, as shown in entry 1.
a
Table 4. Comparative Results from One-Pot Methods
b
products
catalyst
(mol %)
NaBH4:
TMEDA
time
(h)
conversn
(%)
entry
5
6
7
1
2
3
4
5
1
1:0
1:1
1:1
1:1
1:2
7
7
9
11
34
33
30
19
17
29
22
17
81
83
72
78
83
0
0
0
0
0
1
1
24
48
24
2.5
2.5
difficult to control. In addition, the general trend found above is
that slower addition also contributes to lower conversion. For
the majority of the catalytic debrominations reported by Hor
and co-workers,18 this would not be an issue, as the bromide
being removed is in the electronically favored position and thus
the catalyzed and background reactions would give the same
product. In fact, it is only the example of 3 in which this
background reaction would play a role in affecting selectivity.
Unfortunately, the selective debromination of the 5-position of
3 under these conditions does not seem to be practical.
Coming to this disappointing conclusion, alternate con-
ditions where then investigated in an attempt to find practical
methods that would inhibit the background reaction while still
allowing efficient and selective conversion of 3 to 6. As solvent
choice plays a large role in the background reaction, this was
the initial variable considered. The extent of the background
reaction is essentially controlled by the solubility of NaBH4
under the selected conditions. As shown in Table 3, CH3CN
provides low solubility and thus low reactivity at room
temperature but better solubility and high reactivity at higher
temperatures. However, it should be pointed out that NaBH4 is
still not completely soluble in hot CH3CN, which accounts for
its slower reactivity in comparison to DMSO. More polar
solvents such as DMF provide good solubility and fall in
between CH3CN and DMSO in terms of facilitating the
background reaction. At the other end of the scale is diethyl
ether, which showed no solubility or reactivity at either room
temperature or reflux temperatures. The closely related THF,
however, provided an intermediate solubility between that of
a
Constant conditions: 3 (5 mmol), NaBH4 (1.5 equiv), and
Pd(dppf)Cl2 in 100 mL THF at reflux. Values given are ratios of
products 5−7.
b
Assuming that the low conversion was due to limited NaBH4
solubility, it was thought that this could be tuned via the
addition of agents to chelate the sodium cation. This might thus
allow optimization of the NaBH4 solubility such that
conversion is enhanced while still minimizing the background
reaction. The addition of various crown ethers to NaBH4
solutions seemed too successful at solubilizing the sodium
salt, and thus our attention shifted to tetramethylethylenedi-
amine (TMEDA) as a potential additive. The use of TMEDA
as an additive in metal-catalyzed NaBH4 reductions has been
previously reported,21 and its addition to NaBH4 solutions
qualitatively appeared to give a good level of solubility
adjustment.
Reactions in THF with TMEDA did show slightly better
conversion, along with a slight enhancement in selectivity
(Table 4, entry 2). Extending the reaction time (entry 3)
resulted in a substantial increase in conversion, although it was
still lower than desired and was coupled with a reduction in
selectivity. Further increasing the reaction time did not result in
further increases in conversion, but increasing the catalyst
loading to 2.5 mol % did help counteract the lower selectivity
(entry 4).
C
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a
Previous reports have attributed the effect of the TMEDA as
either stabilizing the resting state of the catalyst via
coordination of Pd or assisting in the hydride transfer step by
coordinating the resulting BH3.21 While coordinating the
resting state of the catalyst is possible, the addition of the
bidentate TMEDA ligand would result in an 18-electron Pd
species,22 which would significantly inhibit oxidative addition,
either quenching catalytic activity or negatively affecting the
corresponding kinetics. As such, TMEDA chelation would most
likely necessitate the dissociation of a third PPh3 ligand in order
to maintain catalytic activity. Coordination to boron is also a
possibility, but the fact that these reactions are carried out in a
coordinating solvent makes it much more likely that solvent
coordination satisfies the electron-deficient BH3, particularly as
the solvent is present in molar quantities much higher than that
of the added TMEDA (ca. 80:1). As such, the most likely effect
of the TMEDA is simple coordination to the sodium cation of
NaBH4, thus enhancing the solubility of the salt in THF. This is
supported by both the enhanced THF solubility of TMEDA/
NaBH4 mixtures by visible inspection and the reports of
multiple crystal structures exhibiting the chelation of sodium by
TMEDA.23
With the conditions starting to look promising for the one-
pot methods, efforts moved to investigation of slow addition
methods in order to further optimize the reaction. During the
initial investigations outlined in Table 1, the catalyst and 3 were
combined in solvent and the reducing agent was added in small
portions as a solid while the reaction mixture was stirred under
N2 at an elevated temperature. In this case, however, the
addition of NaBH4 required the removal of a septum, which
both exposed the reaction to O2 and introduced loss of solvent
via escaping vapor at reflux. These issues could be bypassed via
the use of a powder addition funnel, but this was impractical
due to the small quantities of reducing agent involved, unless
the reaction was carried out on a suitably large scale. Likewise,
attempts to add the reducing agent via solution addition funnel
were unsuccessful because of the low solubility of NaBH4 in
almost all solvents, and when NaBH4 was soluble, the
background reaction was predominant (Table 3). Thus, a
reverse approach was taken by limiting the amount of 3 in
solution, rather than trying to control NaBH4. By controlling
the availability of 3 via its slow addition to the reaction mixture,
it should be possible to maintain a concentration near the
catalyst concentration, thus limiting transformation via the
background reaction. Therefore, reactant 3 in 50 mL of THF
was added dropwise to the hot reaction mixture consisting of
the remaining components dissolved in another 50 mL (total
solvent thus still 100 mL).
Table 5. Effect of Slow Addition of Tribromothiophene
b
products
add time total time conversn
entry precatalyst
(h)
(h)
(%)
5
6
7
1
2
3
4
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
2
20
19
6
100
100
100
69
5
31
34
65
63
76
64
56
31
27
15
3
10
4
1.5
1.5
1.5
4
10
9
c
5
6
71
a
Constant conditions: 3 (5 mmol), NaBH4 (1.5 equiv), TMEDA (3
equiv), and catalyst (2.5 mol %) in 100 mL THF at reflux. Optimized
conditions are given in boldface. Values given are ratios of products
b
c
5−7. Only 1 equiv of NaBH4 used.
be worth the associated cost in terms of reduced reaction rate.
To test this possibility, these high conversion conditions were
repeated with Pd(PPh3)4. As shown in entry 3 of Table 5, a
substantial increase in reaction rate was observed, with the total
reaction time reduced by half. In addition, the problem of
overdebromination was also significantly reduced and selective
debromination of the 5-position over the more reactive 2-
position was quite high (16:1).
In final hopes to further limit overdebromination and
increase the isolated yield of 2,3-dibromothiophene 6, the
reaction time was limited to only 4 h (entry 4). Unfortunately,
this negatively affected conversion to a greater extent than
reducing overdebromination, thus confirming that these
conditions required the full 6 h to run to completion. Attempts
to reduce the NaBH4 to 1 equiv (entry 5) had a greater effect in
limiting overdebromination but also negatively affected total
conversion. This final result was consistent with the initial
studies of the background reaction under optimal conditions
(Table 3), which revealed that an excess of NaBH4 was
necessary to reach complete conversion.
As neither of the final two modifications successfully
increased the isolation of 6, the maximum yield observed
under the final optimized conditions provided here was limited
to only 65% (Table 5, entry 3). This is not to say that
additional gains are impossible via further tuning of the reaction
conditions. For example, the moderate investigation of solvent
choice described above could be expanded to include mixed
solvent systems, which could allow more fine-tuning of the
NaBH4 solubility and contributions from the background
reaction under the reaction conditions applied. However, at this
point, such gains would be expected to be relatively minor.
Although the yield provided by the optimized conditions
here is not as high as was hoped and is substantially lower than
that originally reported by Hor and co-workers,17,18 the
conditions still provide better selectivity than is possible via
noncatalytic sterically controlled methods such as the use of
Grignard reagents (Table 1). In addition, the methods reported
here result in the production of very low amounts of
dibromothiophene 5, which allows the ultimate purification of
the desired isomer 6. These two isomers are difficult to separate
from one another, as they elute similarly on silica gel and
exhibit very similar boiling points (210−212 °C for 5;27 218.6−
219.6 °C for 628). Under the optimized conditions given here,
the primary byproduct is the monobromo product 7, which is
considerably easier to remove from the desired product.
As can be seen in Table 5, the slow addition of reactant 3 to
NaBH4 resulted in significantly large increases in conversion
such that complete consumption of 3 had occurred within 19−
20 h (entries 1 and 2). Unfortunately, this quite positive
advance in conversion was coupled with significant amounts of
overdebromination, such that ca. 60% of the recovered product
was the doubly debrominated product 3-bromothiophene (7).
At this point, the previous decision to move from Pd(PPh3)4
to the bulkier Pd(dppf)Cl2 was then called into question.
Although this original decision was due to the enhanced steric-
mediated selectivity previously observed for Pd(dppf)Cl2,19 it
was realized that the enhanced sterics most likely contributed to
a reduction in reaction rate. For example, it is known that
increasing ligand sterics negatively affects the rate of oxidation
addition.24−26 Thus, any benefits in reaction selectivity may not
D
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3-Bromothiophene (7). 1H NMR: δ 7.28 (dd, J = 3.1, 5.1 Hz, 1H),
7.22 (dd, J = 1.4, 3.1 Hz, 1H), 7.01 (dd, J = 1.4, 5.1 Hz, 1H). 13C
NMR: δ 130.0, 126.7, 122.8, 110.2. NMR spectral data agree well with
previously reported values.10,18
CONCLUSION
■
The results reported here reconfirm previous reports17−19,29
that reactivity at the more electronically favored 2-postion of
2,3,5-tribromothiophene can be overcome through the use of
sterically bulky catalysts to give selective reaction at the less
hindered 5-postion. However, this can only really be successful in
the absence of any significant background reaction. As such,
attempts to apply this methodology to the hydrodebromination
of haloheterocycles are limited by the very facile noncatalyzed
background reaction when NaBH4 is used as the hydrogen
source. As shown in the results here, attempts to restrict the
background reaction generally results in low conversion, while
conditions that enhance conversion tend to make the
background reaction more favorable. The final optimized
conditions reported here do the best to balance these factors
yet still suffer from significant overdebromination that lowers
the yield of the desired product. As such, the extremely high
levels of selectivity previously reported by Hor and co-
workers17,18 are just not practical via the use of NaBH4. It is
possible that this was also suspected by Hor and co-workers, as
later efforts shifted to the use of alcohols as the hydrogen
source for such hydrodebrominations.30 It should be pointed
out that, of the 30 different examples of “selective” catalytic
hydrodehalogenation of bromothiophenes and related ana-
logues reported by the groups of Hor and Chelucci,17,18,21 the
example studied in this current report is the only case in which
the catalyzed process and the background reaction would be
expected to give different products. As a result, it is perhaps not
surprising that this complicating issue with the facile back-
ground reaction has been previously overlooked.
General Reaction Conditions for Slow Addition of Tribro-
mothiophene. NaBH4 (7.5 mmol), TMEDA (15 mmol), and
catalyst (2.5 mol %) were placed in a flask equipped with a condenser
and an addition funnel that was then evacuated and back-filled three
times with N2, followed by the addition of THF (50 mL). The
addition funnel was then charged with 3 (5.0 mmol) in 50 mL of THF.
The reaction mixture was heated to reflux with stirring and the
solution of 3 added dropwise over the specified time period. Heating
was continued for the allotted time, after which the reaction mixture
was cooled to room temperature and the solvent removed via rotary
evaporation. An aliquot of the crude product was then dissolved in
1
CDCl3 and analyzed by H NMR to determine product distribution.
Optimized Reaction Conditions. NaBH4 (7.5 mmol), TMEDA
(15 mmol), and catalyst (2.5 mol %) were placed in a flask equipped
with a condenser and an addition funnel. The flask was then evacuated
and back-filled three times with N2, followed by the addition of THF
(50 mL). The addition funnel was then charged with 3 (5.0 mmol) in
50 mL of THF. The reaction mixture was heated to reflux with stirring
and the solution of 3 added dropwise over 1.5 h. Heating was
continued for 4.5 h, after which the reaction mixture was cooled to
room temperature and poured into H2O. This mixture was then
extracted with diethyl ether, washed with H2O, and dried over MgSO4,
and the solvent was removed via rotary evaporation. The crude
material was then purified by silica gel chromatography (hexanes) to
give product 6 as a pale oil (60−65% yield).
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.6b00587.
EXPERIMENTAL SECTION
■
Details of attempts to reproduce literature data, details of
studies on background reactions, and sample NMR
spectra used in analysis of product distribution (PDF)
Unless otherwise specified, all reactions were carried out under an N2
atmosphere with reagent grade materials. Diethyl ether and THF were
distilled from sodium/benzophenone prior to use. Acetonitrile was
dried over calcium hydride and distilled prior to use. Sodium
borohydride was stored in a desiccator and used within 1 year of
purchase. Palladium catalysts were purchased from Sigma-Aldrich, and
Pd(PPh3)4 was stored at −5 °C in the absence of light. 2,3,5-
Tribromothiophene (3)11 was synthesized using literature procedures
AUTHOR INFORMATION
■
Corresponding Author
*E-mail for S.C.R.: seth.rasmussen@ndsu.edu.
1
and purified by distillation. H NMR spectra were measured on a 400
MHz Varian spectrometer in CDCl3 unless otherwise stated. Percent
conversions and product distributions were determined through
integration of NMR peaks. All NMR data were referenced to residual
solvent peaks, and peak multiplicities are reported as follows: s =
singlet, d = doublet, dd = doublet of doublets.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
General One-Pot Reaction Conditions. Tribromothiophene 3
(5.0 mmol), NaBH4 (7.5 mmol), TMEDA, and Pd(dppf)Cl2 were
placed in a flask equipped with a condenser. The flask was then
evacuated and back-filled three times with N2, followed by the addition
of THF (100 mL). The reaction mixture was heated to reflux with
stirring, and heating was continued for the allotted time. The reaction
mixture was then cooled to room temperature and the solvent
removed via rotary evaporation. An aliquot of the crude product was
then dissolved in CDCl3 and analyzed by 1H NMR to determine
product distribution.
The authors wish to thank Merck Chemicals Ltd. and North
Dakota State University for support of this research.
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