Conjugate addition of sodium methanesulfinate to vinyl pyridines and diazines for the synthesis of aliphatic sulfones

Article abstract of DOI:10.1016/j.tetlet.2009.02.037

A convenient method to introduce a sulfone group to pyridines and diazines is described. This efficient method involves the conjugate addition of sodium methanesulfinate to vinyl heterocycles. This process tolerates a wide variety of functional groups and

Full text of DOI:10.1016/j.tetlet.2009.02.037

Tetrahedron Letters 50 (2009) 1928–1933
Contents lists available at ScienceDirect
Tetrahedron Letters
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Conjugate addition of sodium methanesulfinate to vinyl pyridines
and diazines for the synthesis of aliphatic sulfones
*
Gregory M. Schaaf , Sabuj Mukherjee, Alex G. Waterson
GlaxoSmithKline, Oncology Research & Development, Five Moore Drive, Research Triangle Park, NC 27709-3398, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient method to introduce a sulfone group to pyridines and diazines is described. This efficient
method involves the conjugate addition of sodium methanesulfinate to vinyl heterocycles. This process
tolerates a wide variety of functional groups and is performed in the presence of acetic or trifluoroacetic
acid. A one-pot, two-step synthesis of sulfones starting from the corresponding heteroaryl halide is also
described.
Received 21 October 2008
Revised 4 February 2009
Accepted 5 February 2009
Available online 10 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Sulfone
Sodium methanesulfonate
Conjugate addition
Medicinal chemistry
Sulfone-containing molecules are prevalent throughout medic-
inal chemistry. The sulfone moiety has the ability to affect many
physicochemical properties as a consequence of its electron-with-
drawing character.1 It has found use in its ability to attenuate the
basicity of amines as well as affect the pKa of hydrogen bond do-
nors. The dipolar aprotic nature of the sulfone makes it a hydrogen
bond acceptor while its non-charged nature may help increase cel-
lular penetration.2 The sulfone group is isoelectronic to a phos-
phate2 and is an isostere to a carbonyl. Sulfones are the terminal
oxidation state for sulfides and sulfoxides and thus may have re-
duced metabolic liabilities.3
Aryl sulfones can be found in many marketed drugs, such as the
triptan RelpaxÒ used to treat migraines.4 There are also several
prominent examples of aliphatic sulfones, such as the nitrogen-
linked ethyl methyl sulfone in the kinase inhibitor TykerbÒ, which
is indicated for ErbB2 (HER2) positive breast cancer.5 A carbon-
linked ethyl methyl sulfone may be another way to introduce this
important functionality to drug-like molecules (Fig. 1).
propanoic acids 4.9 A wide variety of other Michael acceptors have
been explored as well.
As part of a medicinal chemistry effort to synthesize kinase
inhibitors containing small aliphatic side chains, we wanted to
incorporate an alkyl sulfone into molecules of interest. It was
thought that sodium methanesulfinate could be nucleophilic en-
ough to undergo conjugate addition to heterocyclic vinyl sub-
strates, specifically vinyl pyridines and diazines, to provide
aliphatic sulfones (5). These vinyl substrates can be easily synthe-
sized from the corresponding halide by a variety of methods. This
two-step sequence would be a substantial improvement over tra-
ditional methods described above.
Initial development focused on 2-vinyl pyridine as the substrate
for conjugate addition (Table 1). The use of five equivalents of
O
O
N
S
Relpax® (eletriptan)
Carbon-linked sulfones are synthesized by several methods
(Scheme 1). Synthesis of alkyl halide 2 followed by displacement
with sodium methanesulfinate8 or sodium methyl sulfide followed
by oxidation6 provides the desired product. A similar reaction se-
quence beginning with halomethylketones can also be used,7 add-
ing an additional reduction step.
N
H
O
S
O
O
F
Additionally, aryl sulfinic acids have been shown to participate
in 1,4-addition reactions. These sulfinic acids (3), prepared from
the corresponding chlorosulfinates, react with acrylic acid to form
HN
N
Cl
HN
Tykerb® (lapatinib)
N
O
* Corresponding author. Tel.: +1 919 357 2991.
E-mail address: gms4b@hotmail.com (G.M. Schaaf).
Figure 1. Marketed drugs containing sulfones.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.037

G. M. Schaaf et al. / Tetrahedron Letters 50 (2009) 1928–1933
1929
O
NaSMe
or
O
X
O
O
Ar
OH
O
O
2
O
O
O
S
S
Ar
S
Ar
Me
Na
R
OH
1
4
3
cross
coupling
R = aryl or aliphatic
X = halogen
HAR
HAR
X
HAR = hetroaryl (pyridine
or diazine)
O
O
S
HAR
Me
5
Scheme 1. Strategies for sulfone synthesis.
Table 1
Reaction of 2-vinyl pyridine with sodium methanesulfinate
vided the sulfone in only 30 minutes in refluxing EtOH. Reducing
the equivalents of TFA to one and decreasing the temperature to
room temperature still provided the product in excellent yield in
only 4 h (entry 12). Several Lewis acids, including FeCl3, AlCl3,
and TiCl4, were surveyed with DCM as the solvent. Using BF3ÁEt2O
(entry 13) provided the most promising results and suggests that
Lewis acids could be used as an alternative to protic acids.
O
O
S
O
O
Na
S
(5 eq)
N
N
6
7
Next, we included pyridines and diazines of various substitution
patterns (Table 2). Substrates containing an assortment of functional
groups were included. Acetic acid and TFA were chosen since they of-
fer complementary profiles. Flexibility in the equivalents and
strengths of these acids balanced with the choice of temperature
and time offer a range of conditions to satisfy substrate compatibility.
The basicity of the nitrogen of the heterocycle must be taken
into consideration. Only substrates with a pKa greater than ꢀ5
should be significantly protonated by HOAc and participate in
the reaction. These substrates generally include pyridine and other
electron-rich pyridines. Trifluoroacetic acid is strong enough to
protonate less basic substrates, such as pyridines with electron-
withdrawing groups and most substituted diazines. Additionally,
an appreciable amount of TFA is likely consumed neutralizing so-
dium methanesulfinate to form methanesulfinic acid. Thus, for less
basic substrates it is necessary to add TFA (8 equiv) in excess of the
amount of sodium methanesulfinate (5 equiv) to assure free acid in
the reaction mixture.
While several of the vinyl pyridines are commercially available,
most substrates were synthesized from the corresponding halide
and Molander’s vinyltrifluoroborate.12 The location of the vinyl
group on the substrate is critical. Exposure of the 4-vinyl pyridine
to acetic acid and sodium methanesulfinate (entry 1) provided the
product in excellent yield. As expected, 3-vinyl pyridines, even ba-
sic ones such as 8b, failed to render any product. Consequently, dif-
ferentiation between two vinyl groups is possible. Prepared from
the 2,3-dibromopyridine, divinyl pyridine 8c reacts only at the vi-
nyl group on the 2-position to provide 9c exclusively. In the pres-
ence of TFA, a wide range of electron-poor and electron-rich vinyl
pyridines are converted to the ethyl methyl sulfone (entries 4–7)
with less basic nitropyridine 8g requiring TFA for conversion. Inter-
estingly, the Boc group of aminopyridine 8h remains intact under
TFA conditions to cleanly provide the sulfone. Pyridyls 8i and 8j
which contain substituted vinyl groups achieved only moderate
success. Both 2-vinyl quinoline and quinoxaline (entries 11 and
12) failed to undergo conversion using acetic acid, but were con-
verted in high yield in the presence of TFA. Interestingly, 2-vinyl-
pyrazine 8m was converted to the sulfone in the presence of
HOAc even though it is only weakly basic.13 The reaction pro-
ceeded in excellent yield for a variety of 2-vinyl pyrimidines (en-
tries 14–16), including the scaffold for a kinase inhibitor (8q).14
Entry
Acids
Eq. acid
Time (h)
Temp (°C)
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
H3BO4
HCl
100
5
1
0.5
10
5
5
5
10
5
5
2
2.5
20
24
6
24
24
24
24
8
60
60
60
60
rt
60
55
35
60
60
60
rt
EtOH
EtOH
EtOH
EtOH
EtOH
Toluene
THF
DCM
EtOH
EtOH
EtOH
EtOH
DCM
88
88
91
45
79
57
29
85
85
85
89
85
77
TFA
TFA
BF3ÁEt2O
0.5
4
24
1
2
À78 to rt
sodium methanesulfinate was standard throughout the experi-
ments.10 In entry 1, a large excess of acetic acid in ethanol11
(ꢀ1:1 HOAc/EtOH) affects this conversion at 60 °C in only 2 h.
Decreasing the amount of HOAc to 5 equiv (entry 2) had little effect
on the outcome of the reaction, providing the sulfone product in
excellent yield in 2.5 h. The reaction time is extended to 20 h if
only 1 equiv of acetic acid is used. This reaction can also be carried
out at room temperature (entry 5) but requires extended reaction
times and additional acid. Exposure to substoichiometric amounts
of HOAc resulted in incomplete conversion (entry 4) and recovered
starting material. In the absence of acid no reaction occurred (data
not shown).
Several additional solvents were explored using 5 equiv of
HOAc. Toluene as a solvent (entry 6) provided the product in mod-
est yield. Low conversion was observed with tetrahydrofuran as
the solvent. However, dichloromethane (entry 8) proved to be an
attractive aprotic alternative to EtOH, providing 7 in 85% yield, al-
beit with an extended reaction time.
We explored additional acids. Exposure of the reactants to
H3BO4 (entry 9) in EtOH at reflux provided 7 in excellent yield
but with higher loading (10 equiv). Hydrochloric acid (entry 10)
worked well, though it required longer reaction time compared
to HOAc. Gratifyingly, trifluoroacetic acid (TFA) substantially in-
creased the efficiency and versatility of the process, especially
compared to HOAc. Substituting 5 equiv of TFA for the acid pro-

1930
G. M. Schaaf et al. / Tetrahedron Letters 50 (2009) 1928–1933
Table 2
Reaction of substituted vinyl pyridines and diazines with sodium methanesulfinate
O
O
O
O
(5 eq)
S
S
Na
R
R
acid (5-8 eq)
EtOH, 60oC
8
9
a
Entry
1
Vinyl 8
Sulfone 9
pKa
Acid
Timeb (h)
Yieldc (%)
O
O
S
Me
5.0
6.3
HOAc
6
91
N
N
8a
9a
O
O
S
Me
2
3
TFA
HOAc
20
20
NR
NR
O
N
O
N
8b
9b
O
O
S
Me
4.6
TFA
HOAc
4
6
79
83
N
N
9c
8c
O
O
O
S
O
Me
4
5
6
7
6.3
8.7
2.9
1.6
TFA
TFA
TFA
4
20
2
78
62
86
N
N
N
8d
8e
9d
O
O
S
Me
H2N
N
H2N
9e
O
O
S
Me
O
N
O
N
O
8f
O
9f
O
O
S
Me
N
TFA
HOAc
6
20
65
NR
O2N
N
O2N
8g
9g
O
O
O
O
S
S
Me
O
O
N
N
O
N
H
8
4.6
TFA
HOAc
2
20
94
NR
N
N
O
N
H
8h
9h
O
O
Me
O
N
H
9
4.8
TFA
20
50
O
N
H
8i
9i

G. M. Schaaf et al. / Tetrahedron Letters 50 (2009) 1928–1933
1931
Table 2. (continued)
a
Entry
Vinyl 8
Sulfone 9
pKa
Acid
TFA
Timeb (h)
Yieldc (%)
O
O
O
S
Me
O
O
N
10
4.8
20
37
O
N
H
N
S
N
H
9j
8j
O
O
O
Me
N
11
12
4.9
0.7
TFA
HOAc
20
20
88
NR
N
N
8k
9k
9l
O
N
S
N
Me
N
TFA
HOAc
6
20
91
NR
8l
O
O
N
S
N
Me
13
14
0.7
5.4
HOAc
TFA
5
6
79
51
N
N
8m
9m
O
O
H2N
N
H2N
N
S
Me
N
N
8n
9n
O
O
O
N
O
N
S
Me
15d
2.5
0.7
TFA
TFA
6
2
81
87
N
N
N
8o
9o
O
O
N
S
Me
N
16
N
8p
9p
O
O
H2N
N
H2N
N
S
Me
N
N
17
6.2
TFA
2
70
O
O
O
O
8q
9q
O
O
S
Me
N
N
18e
1.0
TFA
2
62
N
N
O
O
8r
9r
a
ACD labs.
b
c
If incomplete after 20 h, the reaction was quenched and isolated. Typically, unreacted starting material was recovered.
Avg isolated yields of two runs.
Use of 2,2,2-trifluoroethanol prevents displacement of the OMe group.
2 equiv of sodium methanesulfinate.
d
e

1932
G. M. Schaaf et al. / Tetrahedron Letters 50 (2009) 1928–1933
Table 3
One-pot conversion of substituted heteroaryl halides to sulfones
-
i)
F
F
B
PdCl2(dppf) (0.1 eq)
Et3N (2 eq) n-PrOH
100oC µw
F K+
O
O
(2.2 eq)
halide
S
R
R
ii)
O
O
TFA or HOAc (10 eq)
60oC
S
10
11
Na
(5 eq)
Entry
1a
Halide 10
Sulfone 11
Time (h)
Yield (%)
71
F
F
O
O
O
O
Cl
S
S
8
N
N
N
10a
11a
11b
N
Br
N
2a
2
2
62
66
N
10b
Cl
O
O
N
S
3a
O
N
O
O
O
10c
9f
O
O
S
Br
N
O
4b
2
68
O
O
N
H
O
N
N
H
10d
11d
a
TFA was used.
HOAc was used.
b
Due to low MW and volatility, there were several substrates
guide the choice of a strong or weak acid. Additionally, a one-pot
method directly converts halo pyrimidines and diazines to sulf-
ones, eliminating the need to isolate vinyl intermediates. This con-
venient procedure allows for the rapid generation of sulfone-
containing compounds.
which we could not easily prepare or isolate, such as 3-fluoro-2-vi-
nyl pyridine. Since both the coupling and addition reactions take
place in similar alcoholic solvents (EtOH and n-PrOH), we consid-
ered a one-pot method15 where the vinyl compound is not isolated
following the Suzuki reaction. This simplified procedure eliminates
the isolation of volatile vinyl intermediates for low MW substrates
as well as providing a convenient procedure for complex hetero-
aryl chlorides (Table 3).
Accordingly, we subjected fluoropyridine 10a to the usual Suzu-
ki conditions. Upon completion, the vinyl intermediate was di-
rectly treated with sodium methanesulfinate and acid16 to
provide sulfone 11a in excellent yield. Another low MW com-
pound, pyrimidine 10b, was also converted to the corresponding
sulfone in good yield. For ester 10c, the yield of the one-pot se-
quence (66%) compares favorably to the combined yields of the
sequential two-step process (72%), and eliminates purification of
the vinyl intermediate. This transformation also worked well for
azaindole 10d, a common scaffold for many medicinal chemistry
efforts.14
Acknowledgments
Sabuj Mukherjee (University of Texas at Arlington) carried out
this work as a participant in the Summer Talent Identification Pro-
gram at GlaxoSmithKline—Thanks to Professor Carl J. Lovely for the
opportunity to pursue this internship.
References and notes
1. Morgenthaler, M.; Schweizer, E.; Hoffmann-Röder, A.; Benini, F.; Martin, R.
E.; Jaeschke, G.; Wagner, B.; Fischer, H.; Bendels, S.; Zimmerli, D.;
Schneider, J.; Diederich, F.; Kansy, M.; Müller, K. Chem. Med. Chem. 2007,
2, 1100–1115.
2. Huang, Z.; Schneider, C.; Benner, S. A.. In Methods in Molecular Biology; Humana
Press: Totowa, NJ, 1993; Vol. 20. Chapter 15.
3. Parani, G. A.; LaVoie, E. J. Chem. Rev. 1996, 96, 3147–3176.
4. Napier, C.; Stewart, M.; Melrose, H.; Hopkins, B.; McHarg, A.; Wallis, R. Eur. J.
Pharmacol. 1999, 375, 61–74.
5. Petrov, K. G.; Zhang, Y.; Carter, M.; Cockerill, G. S.; Dickerson, S.; Gauthier, C. A.;
Guo, Y.; Mook, R. A.; Rusnak, D. W.; Walker, A. L.; Wood, E. R.; Lackey, K. E.
Bioorg. Med. Chem. Lett. 2006, 16, 4686–4691.
We have found that a wide variety of vinyl pyrimidines and dia-
zines undergo conjugate addition with sodium methanesulfinate
under acidic conditions to provide the corresponding ethyl methyl
sulfones. The basicity of the nitrogen, indicated by its pKa, can

G. M. Schaaf et al. / Tetrahedron Letters 50 (2009) 1928–1933
1933
6. Farbenind, I.G. DE 623883; 1934; FTFVA6; Fortschr. Teerfarbenfabr. Verw. 11. Gipstein, E.; Willson, C. G.; Sachdev, H. S. J. Org. Chem. 1980, 45, 1486–1489.
Industriezweige; DE; Ger.; 22; 1040.
12. Molander, G. A.; Rivero, M. R. Org. Lett. 2002, 4, 107–109.
7. Rumthao, S.; Lee, O.; Sheng, S.; Fu, W.; Mulhern, D. C.; Mesecar, A. D.; Johnson,
M. E. Bioorg. Med. Chem. Lett. 2004, 14, 5165–5170.
13. This may represent a limitation in the software (ACD labs) used to calculate the
pKa’s or incomplete knowledge of the system.
8. Chang, Y.; Ares, J.; Anderson, K.; Sabol, B.; Wallace, R. A.; Faroqui, T.; Uretsky,
N.; Miller, D. D. J. Med. Chem. 1986, 30, 214–218.
9. Dorogov, M. V.; Filimonov, S. I.; Kobylinsky, D. B.; Ivanovsky, S. A.; Korikov, P.
V.; Soloviev, M. Y.; Khahina, M. Y.; Shalygina, E. E.; Kravchenko, D. V.;
Ivachtchenko, A. V. Synthesis 2004, 18, 2999–3004.
10. (a) With 3 equiv of sodium methanesulfinate, the reaction time was extended
to 20 h for the same conditions as shown in entry 2 of Table 1. With 1.5 equiv,
the reaction time was extended to 36 h. (b) Representative procedure: To a
mixture of methyl 6-ethenyl-3-pyridinecarboxylate (80 mg, 0.49 mmol,
1.0 equiv) and sodium methanesulfinate (250 mg, 2.45 mmol, 5.0 equiv) in
EtOH (3.0 mL, 0.16 M) was added TFA (0.18 mL, 2.45 mmol, 5.0 equiv). The
mixture was heated at 60 °C for 2 h. The reaction mixture was quenched with
NaHCO3 (aq) and extracted twice with DCM. The combined organic extracts
were dried over MgSO4, filtered, and concentrated to give 100 mg (84%) of
sulfone 9f as a solid. 1H NMR (400 MHz, DMSO-d6) d ppm 9.00 (d, J = 1.83 Hz,
1H), 8.22 (dd, J = 8.15, 2.29 Hz, 1H), 7.54 (d, J = 8.06 Hz, 1H), 3.86 (s, 3H), 3.52–
3.62 (m, 2H), 3.21–3.29 (m, 2H), 3.00 (s, 3 H).
14. Boyer, S. J. Curr. Top. Med. Chem. 2002, 2, 973.
15. Representative one-pot procedure: To a stirring mixture of ethyl 4-bromo-1H-
pyrrolo[2,3-b]pyridine-2-carboxylate (150 mg, 0.557 mmol, 1.0 equiv), potassium
vinyl trifluoroborate (164 mg, 1.226 mmol, 2.2 equiv), and TEA (0.16 mL,
1.1 mmol, 2.0 equiv) in n-PrOH (5.6 mL, 0.1 M) was added PdCl2(dppf) (41 mg,
0.056 mmol, 0.1 equiv). This reaction mixture was heated under microwave
conditions (optional) for 30 min at 100 °C. The reaction mixture was transferred to
a flask (for convenience) and treated with sodium methanesulfinate (285 mg,
2.79 mmol, 5.0 equiv) and HOAc (0.32 mL, 5.57 mmol, 10 equiv) and stirred at
60 °C for 2 h. The reaction mixture was concentrated to dryness, taken up in DCM,
and absorbed onto silica. The product on silica was subjected to column
chromatography using 10% 2 M NH3 in MeOH/90% DCM solution and DCM as
the solvents. Alternatively, NH4OH in MeOH may be substituted for 2 M NH3 in
MeOH. In some instances it was necessary to perform an aqueous extraction of the
product after column chromatography to remove TEA salts.
16. Ten equivalents of TFA or HOAc was added due to the additional 2 equiv of TEA
used during the Suzuki reaction.