A closer look at the bromine-lithium exchange with tert-butyllithium in an aryl sulfonamide synthesis

Article abstract of DOI:10.1021/ol4010454

A practical protocol for the one-pot synthesis of various aryl sulfonamides, notably of pyridine-core-substituted 7-azaindolyl sulfonamides, is described. A key step is the well-known bromine-lithium exchange reaction of an aryl bromide with tert-butyllithium (t-BuLi). Differing from the common practice to use 2 or more equiv of organolithium, the exact amount of t-BuLi needed for a sufficient exchange reaction is determined for each aryl bromide in a GC-MS-assisted experiment.

Full text of DOI:10.1021/ol4010454

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
A Closer Look at the BromineÀLithium
Exchange with tert-Butyllithium in an Aryl
Sulfonamide Synthesis
,†
Christopher Waldmann,* Otmar Schober, Gunter Haufe, and Klaus Kopka
†
‡
†,§
€
Department of Nuclear Medicine, University Hospital Mu€nster, Albert-Schweitzer-
Campus 1, Building A1, D-48149 Mu€nster, Germany, and Organic Chemistry Institute,
University of Mu€nster, Corrensstrasse 40, D-48149 Mu€nster, Germany
c.waldmann@uni-muenster.de
Received April 15, 2013
ABSTRACT
A practical protocol for the one-pot synthesis of various aryl sulfonamides, notably of pyridine-core-substituted 7-azaindolyl sulfonamides, is
described. A key step is the well-known bromineÀlithium exchange reaction of an aryl bromide with tert-butyllithium (t-BuLi). Differing from the
common practice to use 2 or more equiv of organolithium, the exact amount of t-BuLi needed for a sufficient exchange reaction is determined for
each aryl bromide in a GCÀMS-assisted experiment.
Arene and heteroarene sulfonamides are of major
importance in pharmaceuticals, agrochemicals, and other
applications.1 The most straightforward laboratory syn-
thesis involves the reaction of arylsulfonyl chlorides with
amines. Within the frame of our ongoing studies of isatin
sulfonamides as selective inhibitors of caspases-3 and -7,2
we were interested in the formation of pyridine-core
substituted 7-azaindolyl sulfonamides. The 7-azaindole
moiety has attracted considerable attention over the past
decades due to its promising potential and proven usefulness
in pharmaceuticals3 as well as its application in coordination
chemistry4 and physicochemical investigations.5 The chem-
istry of 7-azaindoles has been reviewed recently.6 Notably,
most transformations to date involve the pyrrolo moiety of
7-azaindole, and only few examples of derivatization at the
pyridine core were described in literature.7
In an initial attempt to prepare 7-azaindolyl sulfonyl
chlorides as precursors for the corresponding sulfon-
amides, we adapted a reaction sequence starting with N-
triisopropylsilyl (N-TIPS) protected 5-bromo-7-azaindole
(1) (Table 1).8 A bromineÀlithium exchange reaction was
carried out by using 2.0 equiv t-BuLi at À80 °C in tetra-
hydrofuran (THF). The resulting aryllithium was reacted
† University Hospital M€unster.
‡ University of M€unster.
§ Present address: Radiopharmaceutical Chemistry, German Cancer
Research Center (dkfz), Heidelberg, Germany.
(1) (a) Carta, F.; Scozzafava, A.; Supuran, C. T. Expert. Opin. Ther.
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(5) For a recent example, see: Yu, X.; Yamazaki, S.; Taketsugu, T.
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(2) (a) Limpachayaporn, P.; Schafers, M.; Schober, O.; Kopka, K.;
Haufe, G. Bioorg. Med. Chem. 2013, 21, 2025. (b) Podichetty, A. K.;
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Wagner, S.; Schroer, S.; Faust, A.; Schafers, M.; Schober, O.; Kopka,
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r
10.1021/ol4010454
XXXX American Chemical Society

with gaseous SO2 to yield an arylsulfinate, which subse-
quently was oxidized to the desired sulfonyl chloride (2)
with N-chlorosuccinimide (NCS) at room temperature in
dichloromethane (DCM) (entry 1). In repeating experi-
ments, the product yields varied considerably, and differ-
ent numbers and amounts of side products were formed,
e.g., due to difficult dosing of SO2, even when the same
reaction conditions were applied. The search for an alter-
nativeSO2 sourceled us touse the known 1,4-diazabicyclo-
[2.2.2]octane (DABCO)Àbis(sulfur dioxide) (DABSO)
(entry 2).9 The advantages of this bench-stable colorless
solid are its excellent usability and a fully controllable
dosing of SO2 equivalents. This enhanced synthetic proce-
dure made it more feasible, but the reproducibility of
product yield was still unsatisfying. It is known that an
excess of t-BuLi in solution can lead to complications in
product isolation if an electrophile is added.10 To avoid
any residual t-BuLi, we therefore used only 1.0 equiv for
the bromineÀlithium exchange reaction (entry 3). To our
surprise, the starting material was fully converted, the
yields were slightly increased, and much better reproduci-
bility of the reaction was achieved.
Scheme 1. BromineÀLithium Exchange Reaction with 2 equiv
of t-BuLi
prevented from reacting with either the newly formed
organolithium or another t-BuLi in a putative Wurtz-type
coupling. For these reasons, as far as we know, 2 equiv of
t-BuLi was applied in almost all published syntheses
exploiting an bromineÀlithium exchange reaction.7e,8,15
As a result, it has not been investigated so far whether less
than 2 equiv of t-BuLi might be sufficient for the inter-
conversion with various aryl bromides and if Wurtz-type
coupling products are actually formed in those cases.
The bromineÀlithium exchange rates of various aryl
bromides with varying molar equivalents of t-BuLi were
determined using a gas chromatographyÀmass spectro-
metry (GCÀMS) assisted protonation assay. Therefore,
the aryl bromides were reacted with 1 or 2 equiv of t-BuLi,
respectively, and then protonated by addition of methanol.
The relative conversion percentages were determined
via GCÀMS by integrating the peak areas of unreacted
aryl bromides (Ar-Br) and aromatics (Ar-H) (Table 2).
Initially, we investigated several N-protected 7-azaindoles
(entries 1 to 4). All of them underwent bromineÀlithium
exchange with 1.0 equiv of t-BuLi with conversion rates
>95%. Wurtz-type couplings were not detected between
t-BuBr and the corresponding aryllithium compounds or
between t-BuBr and t-BuLi under these conditions. To
further ensure that the generated t-BuBr did not interfere
with the reaction, we treated compound 1 with 1.0 equiv of
t-BuLi at À80 °C in THF and then stirred the reaction
mixture for 24 h at room temperature. After addition of
methanol, the only product found by analysis with
GCÀMS and NMR spectroscopy was Ar-H. Therefore,
t-BuBr seems to not undergo any further reaction which
would compromise the outcome of the experiments. To
expand the scope to other compound classes, brominated
derivatives of pyridine 6, benzene 7, and pyrrole 8 (Table 2,
entries 5À7) were tested. None of these aryl bromides
underwent a complete bromineÀlithium exchange with
1.0 equiv of t-BuLi. We therefore repeated the experiments
by increasing the amount of t-BuLi in 0.2 equiv steps
until conversions >95% were detected. In the case of
the N-unprotected 7-azaindole derivative 9 an acidic pro-
ton had to be removed by sodium hydride prior to the
Table 1. Formation of 7-Azaindolyl Sulfonyl Chlorides
entry
SO2 source
t-BuLi (equiv)
% yield
a
1
2
3
SO2(g)
2.0
2.0
1.0
27À52b
25À56b
56À58c
DABSO
DABSO
a Inserted into the reaction mixture via syringe over 10 min. b Re-
peated three times. c Repeated two times.
The use of t-BuLi in the lithiumÀhalogen exchange
reaction has attracted considerable attention since the
pioneering works by the groups of Corey and Seebach.11,12
Since then its applicability and mechanistical details have
been further investigated.13 The reaction is a fast and
reversible process leading to an equilibrium mixture favor-
ing the more stable organolithium species.14 Irreversibility
can be achieved by using 2 equiv of t-BuLi. The first
equivalent is used for the exchange, and the second reacts
with the produced t-BuBr to form isobutene, isobutane,
and lithium bromide (Scheme 1).12 In addition, t-BuBr is
(8) Mader, M. M.; Shih, C.; Considine, E.; De Dios, A.; Grossman,
C. S.; Hipskind, P. A.; Lin, H.-S.; Lobb, K. L.; Lopez, B.; Lopez, J. E.;
Martin Cabrejas, L. M; Richett, M. E.; White, W. T.; Cheung, Y.-Y.;
Huang, Z.; Reilly, J. E.; Dinn, S. R. Bioorg. Med. Chem. Lett. 2005, 15, 617.
(15) For recent examples, see: (a) Bailey, W. F.; Luderer, M. R.;
Jordan, K. P. J. Org. Chem. 2006, 71, 2825. (b) Woolard, F. X.; Paetsch,
J.; Ellman, J. A. J. Org. Chem. 1997, 62, 6102. (c) Hamze, A.; Giraud, A.;
Messaoudi, S.; Provot, O.; Peyrat, J.-F.; Bignon, J.; Liu, J.-M.; Wdzieczak-
Bakala, J.; Thoret, S.; Dubois, J.; Brion, J.-D.; Alami, M. ChemMedChem
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(9) Woolven, H.; Gonzalez-Rodrıguez, C.; Marco, I.; Thompson,
´
A. L.; Willis, M. C. Org. Lett. 2011, 13, 4876.
(10) Baily, W. F.; Punzalan, E. R. J. Org. Chem. 1990, 55, 5404.
(11) Corey, E. J.; Beames, D. J. J. Am. Chem. Soc. 1972, 94, 7210.
(12) Seebach, D.; Neumann, H. Chem. Ber. 1974, 107, 847.
(13) Seyferth, D. Organometallics 2006, 25, 2.
(14) Applequist, D. E.; O Brien, D. F. J. Am. Chem. Soc. 1963, 85,
743.
€
2009, 4, 1912. (d) Tietze, L. F.; Dufert, M. A.; Hungerland, T.; Oum, K.;
Lenzer, T. Chem.;Eur. J. 2011, 17, 8452. (e) Wynne, J. H.; Stalick, W. M.
J. Org. Chem. 2003, 68, 4845. (f) Amat, M.; Hadida, S.; Sathyanarayana, S.;
Bosch, J. Org. Synth. 1997, 74, 248.
B
Org. Lett., Vol. XX, No. XX, XXXX

bromineÀlithium exchange (Table 2, entry 8).16 These
results show that the use of 2 equiv of t-BuLi is not
mandatory for complete conversions in bromineÀlithium
exchange reactions.
Piperidine turned out to provide high yields and was used
as model amine in all cases. To facilitate the coupling
reaction, piperidine was deprotonated with an equal
€
amount of Hunig’s base prior to addition. Application of
the modified bromineÀlithium exchange conditions
worked well in the reaction sequence delivering the aryl
sulfonamides 10 to 16 in fair to good overall yields.
Compared to the classical approach using 2 equiv of t-
BuLi, the reproducibility of the reaction sequence was even
improved. Additionally, no Wurtz-type coupling products
and few other side products due to excess t-BuLi were
detected by NMR or GCÀMS of the crude product
mixture. In the case of compound 17, we were not able
to isolate the pure product in any attempt but could detect
it by mass spectrometry and NMR spectroscopy.
Table 2. GCÀMS-Assisted Protonation Assay
Scheme 2. Aryl Sulfonamide Formation Using the Determined
Equivalents of t-BuLi for the BromineÀlithium Exchangea
a Percentage of peak areas of aryl-H compounds and unreacted aryl
bromides determined with GCÀMS. b Reaction conditions: aryl bro-
mides (1 equiv, 0.5 mmol), t-BuLi (1À2 equiv), 5 mL of THF, À80 °C,
10 min, MeOH (0.3 mL), À75 °C. c Reaction conditions: NaH (1.4 equiv,
0.7 mmol), substrate 9 (1 equiv, 0.5 mmol), 7 mL of THF, 0 °C, 30 min,
t-BuLi (1À2 equiv), À80 °C, 10 min, AcOH (0.3 mL), À75 °C.
a Isolated yields. b Reaction conditions: aryl bromides (1 equiv,
0.5 mmol), t-BuLi (1À1.6 equiv), 5 mL of THF, À80 °C, 10 min,
DABSO (1 equiv, 0.5 mmol), À75 °C to rt. NCS (1.2 equiv, 0.6 mmol),
(1 equiv, 0.5 mmol), rt, 10 min. c Reaction conditions: NaH (1.4 equiv,
0.7 mmol), substrate 9 (1 equiv, 0.5 mmol), 7 mL of THF, 0 °C, 30 min,
t-BuLi (1.8 equiv), À80 °C, 10 min, DABSO (1 equiv, 0.5 mmol), À75 °C
to rt, NCS (1.2 equiv, 0.6 mmol), 10 mL of DCM, rt, 10 min, piperidine
€
10 mL of DCM, rt, 10 min, piperidine (1 equiv, 0.5 mmol), Hunig’s base
With optimal conditions for the bromineÀlithium ex-
change reaction in hand, we next explored application in
the synthesis of aryl sulfonamides. We found that a four-
step, one-pot synthesis sequence is the most practical
and most rapid way to obtain the desired sulfonamides
(Scheme 2). In contrast to our initial plan, the sulfonyl
chlorides were reacted in situ with a desired amine.
€
(1 equiv, 0.5 mmol), Hunig’s base (1 equiv, 0.5 mmol), rt, 10 min, water
(20 mL). d Pure product could not be isolated.
In conclusion, this paper describes a facile and reliable
one-pot synthesis of pyridine-core substituted 7-azaindolyl
as well as other (hetero)aryl sulfonamides. The included
bromineÀlithium exchange reactions are improved when
(16) Moyer, M. P.; Shiurba, J. F.; Rapoport, H. J. Org. Chem. 1986,
51, 5106.
Org. Lett., Vol. XX, No. XX, XXXX
C

less than 2 equiv of t-BuLi is used. The exact molar amount
of t-BuLi needed was determined in a GCÀMS assisted
protonation assay for every distinct aryl bromide. Our
findings significantly improve the classical protocol using
2 equiv of t-BuLi in terms of reproducibility and atom
efficiency.
Collaborative Research Centre (SFB) 656 “Molecular
Cardiovascular Imaging”, projects A3 and B1.
Supporting Information Available. Experimental, spec-
troscopic, and GCÀMS data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. These investigations were supported
by the Deutsche Forschungsgemeinschaft (DFG) and
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX