Directed metalation and regioselective functionalization of 3-bromofuran and related heterocycles with NaHMDS

Article abstract of DOI:10.1016/j.tetlet.2011.10.158

A mild and regioselective functionalization protocol for 3-bromofuran and analogs has been developed. Selective metalation and functionalization of C2 can be achieved as a result of the directing effect of the adjacent electron-withdrawing bromo group. In addition, the C5 position can also be selectively functionalized by blocking the C2 position via silylation or by simply controlling the reaction temperature. These functionalized compounds bearing a C3 bromo substituent may be further elaborated by utilizing a Suzuki-Miyaura cross-coupling procedure.

Full text of DOI:10.1016/j.tetlet.2011.10.158

Tetrahedron Letters 53 (2012) 166–169
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Directed metalation and regioselective functionalization of 3-bromofuran
and related heterocycles with NaHMDS
⇑
Hang Zhao , John W. Dankwardt, Stefan G. Koenig, Surendra P. Singh
Chemical Process Research and Development, Sunovion Pharmaceuticals Inc., 84 Waterford Drive, Marlborough, MA 01752, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild and regioselective functionalization protocol for 3-bromofuran and analogs has been developed.
Selective metalation and functionalization of C2 can be achieved as a result of the directing effect of the
adjacent electron-withdrawing bromo group. In addition, the C5 position can also be selectively function-
alized by blocking the C2 position via silylation or by simply controlling the reaction temperature. These
functionalized compounds bearing a C3 bromo substituent may be further elaborated by utilizing a
Suzuki–Miyaura cross-coupling procedure.
Received 5 October 2011
Revised 25 October 2011
Accepted 31 October 2011
Available online 7 November 2011
Keywords:
Metalation
Ó 2011 Elsevier Ltd. All rights reserved.
Heterocycles
3-Bromofuran
Regioselective functionalization
Cross-coupling
Heterocycles, such as furans, thiophenes, benzofurans and ben-
zothiophenes are important constituents of molecules of interest in
the pharmaceutical,1 agricultural,2 and electronics industry.3 As a
result, controlled manipulation of these heterocycles has attracted
considerable interest within the synthetic community. One of the
most useful strategies for the functionalization of these important
heterocycles employs directed metalation protocol using
bases such as n-BuLi or LDA.4 In addition; Knochel has recently
reported conditions using microwave irradiation for the metalation
of 3-bromobenzofuran and 3-bromobenzothiophene with
TMP2ZnÁ2MgCl2Á2LiCl or TMPZnClÁLiCl, respectively, as an effective
method toward C2 functionalization of these heterocyles.5
Interest in the C2-formylation of 3-bromofuran is of synthetic
value because the resulting aldehyde holds promise for further
elaboration and incorporation into more complex molecular tar-
gets. The best known literature method for the formylation of 3-
bromofuran with LDA gave 3-bromofurfuraldehyde in moderate
yield.6 This protocol was deemed less useful in a scale-up scenario
due to the application of a strong base and the poor impurity pro-
file of the isolated product.
impurities at À20 or 0 °C. Reaction with LiHMDS proceeded to
65% conversion at rt, however only a 48% yield of the aldehyde 2
was obtained after purification (entry 3). This particular base was
studied in other solvents, such as n-hexane, MTBE, and toluene (en-
Table 1
Reaction optimization for the formylation of 3-bromofuran with DMFa
O
Base
DMF
O
CHO
Br
Br
1
2
Entry
Base
Solvent
T (°C)
Conversion (%)
1
2
3
4
5
6
7
8
9
LDA
LDA
THF
THF
THF
n-Hexane
MTBE
Toluene
THF
2-Me-THF
THF
2-Me-THF
THF
2-Me-THF
À20–0
0
50
25
LiHMDS
LiHMDS
LiHMDS
LiHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
KHMDS
KHMDS
0 to rt
0 to rt
0 to rt
0 to rt
0 to rt
0 to rt
0
65 (48b)
<10
<10
<10
>95c
In order to develop a more practical method, a study was initi-
ated to evaluate milder bases for the metalation (LiHMDS, NaHMDS
and KHMDS, Table 1) with the hope of finding a scalable procedure
with a cleaner reaction profile. As a control experiment, the
metalation with LDA, followed by treatment of DMF, resulted in
partial conversion including the formation of several unidentified
>95c
>95 (84)b,e
>95 (85)b,e
>95d
10
11
12
0
0 to rt
0 to rt
>95d
a
b
c
3 mmol 1, 1.2 equiv base and 1.2 equiv DMF were used.
Isolated yield.
With ꢀ20% impurities from LC/MS.
d
e
⇑
With ꢀ40% impurities from LC/MS.
Corresponding author. Tel.: +1 508 357 7420; fax: +1 508 357 7808.
E-mail address: hang.zhao@sunovion.com (H. Zhao).
Order of addition does not affect the outcome (yield and purity) in this case.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.158

H. Zhao et al. / Tetrahedron Letters 53 (2012) 166–169
167
Table 2
All previously reported functionalization reactions of 3-bro-
mofuran, including the aforementioned formylation, utilized direct
metalation approaches with LDA or n-BuLi.6,7 Evaluation of the
scope of our methodology on 3-bromofuran with various electro-
philes was undertaken (Table 3). To our delight, the reaction at
0 °C proceeded smoothly with most electrophiles to give only the
corresponding C2 substituted products (2a, 6a, 7a, and 8a) in good
to excellent yield with none of the C5 isomer detected. Interest-
ingly, two regioisomeric products (9a and 9b) were obtained when
a very sterically hindered ketone was used as the electrophile (en-
try 5). The electron-withdrawing bromo substituent greatly en-
hances the acidity at C2, which leads to preferential reaction at
this site.8 For most electrophiles, increasing the steric bulk did
not affect the reaction rate and only formed the desired C2 func-
tionalized product. However, with the extremely hindered electro-
phile t-Bu2CO, the reaction was much slower even at ambient
temperature and two regioisomeric products (9a and 9b) were pro-
duced as a 3:1 mixture.
Next we extended the protocol to 3-bromothiophene (Table 4).
Traditionally, functionalization of 3-bromothiophene is straight-
forward and gives products in higher yield. However, in most cases
LDA and lower temperatures were generally the most utilized con-
ditions.9 Employing the NaHMDS-mediated functionalization of 3-
bromothiophene at 0 °C, afforded products 10, 11, 12, and 13 with
excellent yields. Also, with this substrate, reaction at C5 was also
observed and appears to correlate with the steric nature of the
electrophile. In the ketone series, from Ph2CO to t-Bu2CO, the prod-
uct distribution indicated that the bulkier electrophile preferred to
react at the less hindered C5 position. Thus, in the reaction with t-
Bu2CO as electrophile, only C5 substituted product 14b was ob-
tained after 15 h at rt.
Investigations into the effect of reaction temperature on the
product regioselectivity were carried out for 3-bromothiophene 3
with DMF and t-BuCOPh (Table 4, entries 1–3 and 6–8). A signifi-
cant temperature effect was observed which manifested itself with
increased C5 substitution with increasing temperature. In both
cases, the C2 substituted product predominated at À20 °C, with
the ratios of 10a:10b and 13a:13b at 34:1 and 10:1, respectively.
Surprisingly, when the reaction was carried out at rt the product
distribution reversed itself, and the major product was the C5 func-
tionalized product. Notably, these results indicated that the regi-
oselectivity could be controlled simply by altering the reaction
temperature. We decided to probe the reversibility of the reaction.
To this end, the isolated C2 substituted product 13a was treated
with NaHMDS in THF at rt. Under thermodynamic conditions,
13a was completely converted to the C5 isomer 13b. However,
when 13b was treated with NaHMDS in THF at rt, then cooled to
Deprotonation of 3-bromofuran under either kinetic or thermodynamic conditionsa
O
O
E
Base
E+
Br
Br
4 E=D
5 E=TMS
1
Entry
1
Base
LDA
T °C
Time (min)
Pdt
Pdt/s.m.b
À78
10
30
4
1/0
1/0
60
1/0
180
30
60
1/0
2
3
NaHMDS
NaHMDS
0
0
4
5
<1/10
<1/10
1/1
30
60
1/1
180
1/1
a
Reaction was conducted on 3 mmol substrate with 1.2 equiv base, then quen-
ched with 5.0 equiv electrophile (D2O or TMSCl). After 1 h, the reaction was
quenched with 3 mL NH4Cl (sat.) aqueous solution and 3 mL water.
b
The ratio of product and starting material in the crude organic layer was
determined by 1H NMR spectroscopy.
tries 4–6). This solvent study indicated THF as the best medium.
When NaHMDS was explored in both THF and 2-Me-THF, the best
results were generated at 0 °C. Remarkably, with this variant both
the conversion (>95%) and isolated yield (84%) were far superior
to other bases. Although 2-Me-THF was a preferred solvent in terms
of work-up and ease of scale-up, THF was selected for this study
because of the commercial availability of NaHMDS in THF solution
and the sufficiently high yields obtained under these conditions.
The formylation of 3-bromofuran with NaHMDS and DMF in THF
was optimized with this system and these conditions were adopted
as our standard metalation protocol for the functionalization of
3-bromofuran and related analogs.
Interestingly, the reaction of 3-bromofuran and NaHMDS with a
compatible electrophile provided a reaction mixture with nearly
100% conversion and correspondingly high yields (Table 1, entries
9 and 10). However, under similar metalation conditions, when a
more reactive electrophile was used for trapping, incomplete con-
version was observed (Table 2, entries 2 and 3). These results could
be rationalized by considering an equilibrium between 1 and
metalated species. Thus, quenching this mixture with a reactive
electrophile such as D2O resulted in less than 10% conversion
whereas in the case of a less reactive electrophile such as DMF
the complete conversion was achieved. Quenching the anion with
TMSCl allowed only 50% conversion to be attained due to compet-
itive silylation with the base. In contrast, with a stronger base such
as LDA, complete metalation occurred with quantitative formation
of the deuterated product 4.
Table 4
Functionalization of 3-bromothiophene
S
S
S
E
E
NaHMDS
E+
Table 3
+
Functionalization of 3-bromofuran
Br
Br
Br
O
a
O
3
b
O
E
E
NaHMDS
E+
+
Entry
Electrophile
E
T °C
Yield
a/b
Br
Br
Br
a
1
2
3
4
5
6
7
8
9a
DMF
DMF
DMF
PhCON(OMe)Me
Ph2CO
t-BuCOPh
t-BuCOPh
t-BuCOPh
t-Bu2CO
CHO
CHO
CHO
PhCO
À20
0
rt
0
0
10 (88%)
10 (77%)
10 (64%)
11 (94%)
12 (93%)
13 (96%)
13 (92%)
13 (95%)
14 (69%)
34/1
12/1
1/5
3/1
7/1
10/1
4/1
0/1
1
b
Entry
Electrophile
DMF
E
T °C
Yield
a/b
1
CHO
PhCO
0
0
0
0
rt
2 (84%)
6 (83%)
7 (84%)
8 (88%)
9 (67%)
1/0
1/0
1/0
1/0
3/1
Ph2COH
2
3
PhCON(OMe)Me
Ph2CO
t-BuC(OH)Ph
t-BuC(OH)Ph
t-BuC(OH)Ph
t-Bu2COH
À20
Ph2COH
t-BuC(OH)Ph
t-Bu2COH
0
4
t-BuCOPh
t-Bu2CO
rt
rt
5a
0/1
a
a
An 87% yield based on reacted starting material. The reaction was carried out at
rt for 15 h.
a 90% yield based on reacted starting material. The reaction was carried out at rt
for 15 h.

168
H. Zhao et al. / Tetrahedron Letters 53 (2012) 166–169
Table 5
R
Functionalization of 3-bromobenzofuran and 3-bromobenzothiophene
1) NaHMDS, 0 ºC
2) ZnBr2, 0 C to rt
S
S
º
X
X
E
NaHMDS
E+
3) 4-IC6H4OMe
or PhI
Br
Br
Br
Pd(PPh3)4
28 R = OMe 88%
Br
16
29 R = H
15 X = O
16 X = S
S
Entry
S.m.
Electrophiles
E
Yield
4-MeSO2C6H4B(OH)2
PdCl2(dppf)-CH2Cl2
Cs2CO3, DMF, 60 ºC
59%
1
2
3
4
15
15
15
15
15
16
16
16
16
DMF
PhCON(OMe)Me
Ph2CO
t-BuCOPh
t-Bu2CO
DMF
PhCON(OMe)Me
Ph2CO
t-BuCOPh
CHO
PhCO
Ph2COH
t-BuC(OH)Ph
t-Bu2COH
CHO
PhCO
Ph2COH
17 (61%)
18 (86%)
19 (60%)
20 (78%)
21 (59%)
22 (88%)
23 (81%)
24 (92%)
25 (75%)
29
SO2Me
5a
6b
7
30
Scheme 1. Application of the metalation-cross-coupling protocol toward the
synthesis of bisfunctionalized heterocycles.
8
9
t-BuC(OH)Ph
a
a 76% yield based on reacted starting material.
LiHMDS was used instead of NaHMDS.
b
One of the features that made this advanced metalation proto-
col so appealing is that the C3 bromo substituent remains a poten-
tial site for further functionalization. In order to broaden the
synthetic potential of our current metalation reaction, we decided
to explore a Negishi/Suzuki–Miyaura double cross-coupling strat-
egy (see Scheme 1) to prepare the corresponding diarylated het-
erocycle 30.13 Under this scenario, the organosodium species
originally formed from metalation of the bromoheterocycle would
be converted to the corresponding zinc halide intermediate for use
in a palladium-catalyzed cross-coupling prior to a second coupling
at the remaining aryl halide site. This strategy requires selectivity
of the more reactive iodoarene coupling partner over the C3 bromo
substituent on the parent heterocycle.
In an initial experiment, 3-bromobenzothiophene was metalat-
ed at C2 via the standard conditions with NaHMDS and subse-
quently converted to the corresponding organozinc species by
treatment with ZnBr2. Gratifyingly, the Negishi cross-coupling
was achieved by the reaction of 4-iodoanisole or iodobenzene in
the presence of 5 mol % Pd(PPh3)4 to afford 28 and 29, respectively,
in high yield. A second cross-coupling with 29 utilizing the Suzuki–
Miyaura protocol was performed with the boronic acid coupling
partner providing the diarylbenzothiophene 30 in a 59% yield.14
Thus, the weaving of our metalation procedure into a two-step
protocol utilizing a sequential Negishi/Suzuki–Miyaura cross-cou-
pling protocol resulted in a concise and efficient synthesis of 30,
further demonstrating the utility of our methodology.
Table 6
Selective formylation on five-position of 3-bromofuran and 3-bromothiophene
X
X
a
R1
Br
X
b OHC
R2
Br
Br
1 X = O
3 X = S
Entry
1b
S.m.
NaHMDS
Electrophiles
R2
Yield(%)
75
3
a) 1.1 equiv
b) 1.5 equiv
a) 1.1 equiv
b) 1.5 equiv
a) 3.2 equiv
b) 0.7 equiv
a) 1.2 equiv TESCl
b) 1.4 equiv DMF
a) 1.2 equiv TMSCl
b) 1.4 equiv DMF
a) 1.5 equiv TIPSCl
b) 3.0 equiv DMF
TES 26
H 10b
2b
3a
3
1
50
67
TIPS 27
a
Silylation conducted at rt for 23 h, then warmed to 40 °C after charging with
DMF.
b
Silylation at 0 °C for 2 h and formylation at 0 °C for 1 h.
0 °C and stirred at this temperature for 6 h, no trace of 13a was
observed.
Application of the standard metalation conditions to 3-bro-
mobenzofuran10 and 3-bromobenzothiophene11 is illustrated in
Table 5. Here, where there was only one position for deprotonation
and functionalization, the reactions provided good to excellent
yields for most cases. The only incomplete reaction was observed
with t-Bu2CO, resulting in a 59% yield of alcohol 21 (Table 5, entry 5).
In addition to the results shown in Tables 3 and 4, we were
interested in developing a more general regioselective functional-
ization method for C5. Taking advantage of the pKa differential
between C2 and C5, we chose to employ a strategy in which the
C2 position was initially blocked with a silyl group, followed by
further functionalization of the C5 position with an electrophile
of choice.9(h), 12 The results of the one-pot procedure were shown
in Table 6. The corresponding aldehydes 26 and 10b were obtained
in good yield (entries 1 and 2). In the case of 10b, unsilylated prod-
uct was isolated due to liability of the TMS protecting group during
acidic work-up. For 3-bromofuran, where the pKa of the C5 C–H
bond is closer to that of the base, the metalation–formylation pro-
cedure had to be carried out at an elevated temperature (40 °C) for
24 h to drive the reaction to completion. As a result, TIPSCl was
used to protect the C2 position due to the partial reactivity of
TMSCl and TESCl with NaHMDS. Application of these conditions
resulted in a 67% yield of 27.
In conclusion, we have demonstrated an efficient and mild
method for regioselective functionalization of 3-bromofuran and
analogs using NaHMDS as a base at mild temperatures. This meth-
od accommodates a variety of synthetically useful electrophiles
and is more amenable to scale-up than existing procedures using
LDA or n-BuLi. Furthermore, this protocol illustrated its practical
benefits in an extended application to molecular targets.
Acknowledgments
We would also like to thank Professor Erick M. Carreira (ETH,
Zürich), Professor Mark Lautens (University of Toronto) and Profes-
sor Peter Wipf (University of Pittsburgh) for helpful discussions.
We would also like to thank Hal Butler and Yu Lan (Sunovion Phar-
maceuticals Inc.) for developing HPLC methods.
Supplementary data
Supplementary data (experimental and spectroscopic data)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2011.10.158.

H. Zhao et al. / Tetrahedron Letters 53 (2012) 166–169
169
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