General synthetic strategies towards N-alkyl sulfoximine building blocks for medicinal chemistry and the use of dimethylsulfoximine as a versatile precursor

Article abstract of DOI:10.1016/j.tet.2014.06.120

The sulfoximine group has great potential as a substituent in drug discovery, as evidenced by two new clinical candidates, and can be viewed as an isosteric alternative to the commonly used sulfone. Our aim was to improve the accessibility of this group by synthesising a diverse range of S-alkyl and N-alkyl sulfoximine building blocks with procedures that are applicable on a practical scale (>10 g). In particular, synthesis of the less well exploited N-alkyl sulfoximines and the use of dimethylsulfoximine as a versatile, commercially available precursor is discussed.

Full text of DOI:10.1016/j.tet.2014.06.120

Tetrahedron 70 (2014) 6613e6622
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General synthetic strategies towards N-alkyl sulfoximine building
blocks for medicinal chemistry and the use of dimethylsulfoximine
as a versatile precursor
,
a
b
b
Frederick W. Goldberg a , Jason G. Kettle , Jian Xiong , Daoguang Lin
*
a AstraZeneca, Oncology iMed, Mereside, Alderley Park, Macclesfield SK10 4TG, UK
b WuXi Apptec, #288 FuTe ZhongLu, WaiGaoQiao Free Trade Zone, Shanghai, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The sulfoximine group has great potential as a substituent in drug discovery, as evidenced by two new
clinical candidates, and can be viewed as an isosteric alternative to the commonly used sulfone. Our aim
was to improve the accessibility of this group by synthesising a diverse range of S-alkyl and N-alkyl
sulfoximine building blocks with procedures that are applicable on a practical scale (>10 g). In particular,
synthesis of the less well exploited N-alkyl sulfoximines and the use of dimethylsulfoximine as a ver-
satile, commercially available precursor is discussed.
Received 20 January 2014
Received in revised form 18 June 2014
Accepted 30 June 2014
Available online 3 July 2014
Keywords:
Sulfoximines
Reagents
Ó 2014 Elsevier Ltd. All rights reserved.
Building blocks
Synthesis
Medicinal chemistry
Isosteres
1. Introduction
where methylated sulfoximines such as 3 were equipotent to the
sulfone against the desired target, but with reduced hERG liability7
The sulfone group is commonly used in drug discovery, both as
an aliphatic and an aromatic substituent. One disadvantage with
the sulfone group, however, is that it can introduce poor solubility
due to intermolecular interactions in the solid state.1 The isosteric
sulfoximine group has been less widely used for drug discovery,
although it can provide improved solubility compared to the sul-
fone group.2 The literature on sulfoximines is focussed primarily on
its application in synthetic organic chemistry,3,4 but there are some
reports of its use in drug discovery as has been recently reviewed.5
For example, the sulfoximine group has proven to be useful for the
design of kinase inhibitors, as an alternative to a sulfone as a com-
mon substituent in the solvent channel. Examples of this strategy
include recently disclosed clinical candidates 3(R)-[2-[4-(S-cyclo-
propylsulfonimidoyl)phenylamino]-5-(trifluoromethyl)pyrimidin-
4-yloxy]butan-2(R)-ol 1 (BAY-1000394, Bayer)2 and (3R)-3-methyl-
4-(6-(1-(S-methylsulfonimidoyl)-2,2,3,3-tetradeuterio-cyclo-
propyl)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpho-
line 2 (AZD6738, AstraZeneca),6 as well as a series from Pfizer
(Fig. 1). Interestingly, there are also reported applications of the
sulfoximine group, as well as other sulfur containing functional
groups such as sulfonimidamides, from the agrochemical industry.8
In general, we have observed that sulfoximines are more soluble
than the corresponding sulfones. For NH sulfoximines, this may be
in part due to increased polarity (lower log D), rather than a purely
structural observation. However, it is noteworthy that NMe sul-
foximines are typically isolipophilic to a sulfone, yet also typically
improve solubility. This can be exemplified by a matched triplet of
GPR119 agonists (Fig. 2), where sulfone 4 was found to be in-
soluble.1 The corresponding sulfoximine 5 (R¼NH) had improved
solubility at lower log D, but methyl sulfoximine 6 (R¼NMe) also
had improved solubility despite being isolipophilic to the sulfone.
We have also observed this general trend with an ATR kinase in-
hibitor, sulfone 7,9 where again sulfoximine 8 had improved solu-
bility (at lower log D) as did methyl sulfoximine 9 (at similar log D).
The relative scarcity of sulfoximines in the medicinal chemistry
5
€
literature was recently highlighted by Lucking, where the author
suggested that this was due to a general reluctance of medicinal
chemists to use unfamiliar functional groups when designing bio-
active compounds. We certainly agree with that view, but also
believe that improved access to a diverse range of sulfoximine
* Corresponding author. Tel.: þ44 (0)1625519064; e-mail address: frederick.
goldberg@astrazeneca.com (F.W. Goldberg).
http://dx.doi.org/10.1016/j.tet.2014.06.120
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

6614
F.W. Goldberg et al. / Tetrahedron 70 (2014) 6613e6622
O
N
HO
O
N
F
O NH
S
HN
F
O N
S
F
F
N
HN O
S
N
N
F
NH
F
N
N
N
N
N
H
N
H
BAY-1000394 1
AZD6738 2
3
Fig. 1. Examples of kinase inhibitors that contain the sulfoximine group.
useful S-phenyl sulfoximine building blocks as exemplified in
Scheme 1, by, e.g., amination of 7 with cyanamide/NBS,12 oxidation
of the sulfolimine with m-CPBA and subsequent standard func-
tional group transformations to give 12. This general route was also
applied to synthesise cyclic secondary amines such as 16, again
from the corresponding sulfide 13. However, in this case the cy-
anamide/NBS protocol did not give the desired aminated product,
so instead we used Chloramine-T (TsNCl$Na) to generate N-tosyl-
sulfilimine 14, followed by oxidation to the sulfoximine 15 and
cleavage of the tosyl group as reported by Johnson.11,15 Compounds
like 16 were targeted because of the prevalence of cyclic secondary
amines in the medicinal chemistry literature.
R O
S
O
N
N
N
O
N
O
Ex.
4
R
Aq. solubility (µM)
logD7.4
3.2
O
<0.2
The scope of N-aromatic sulfoximines was then further ex-
panded to aromatic and partially saturated bicyclic structures
(Scheme 2). The chosen route utilised ortho-bromo benzaldehydes
such as 18 with dimethylsulfoximine 19 to generate benzothiazine
20. This could be reduced with Pd/C to the desired aniline 21, then
further reduced with Raney Ni to the saturated analogue 22. This
route was equally applicable to ortho substituted examples such as
23. This route has some precedent in the literature: Harmata has
published on the synthesis of benzothiazines, including the use of
an ortho-bromo benzaldehyde as a starting material with p-tol-
ylsulfoximines,16 but not to our knowledge with dimethylsulfox-
imine. In addition, the direct synthesis of similar saturated rings to
22 and 23 has been reported by Bolm,17 from N-silylated dime-
thylsulfoximines and 1-bromo-2-(bromomethyl)benzene.
When we subsequently attempted to widen our scope to N-
alkylated dimethylsulfoximine building blocks, however, it became
apparent that these were less well precedented. We were in-
terested in these functional groups as we hypothesised they could
potentially act as an isostere of an N-alkyl acetamide or methyl-
sulfonamide group, whilst avoiding the complications of chirality
as the two alkyl groups on the sulfur are both methyl. A concep-
tually simple route to these structures is the use of dime-
thylsulfoximine 19 itself, first reported in 1950,18 as a simple
precursor to such systems as shown in Scheme 3, by using the NH in
alkylations, arylations, reductive aminations or acylation/re-
ductions. Although this strategy is not a common one, Bolm has
reported a similar strategy towards the synthesis of chiral aryl
sulfoximines, using acylation/reductions, alkylations and other di-
verse ways to functionalise the nitrogen of S-aryl sulfoximines.19 In
addition, the key synthetic transformations that were required
(alkylation,20 arylation,21 acylation,22e24 and reductive amina-
tion25) all had some degree of precedent with dimethylsulfoximine.
This strategy proved to be successful in generating a diverse
range of building blocks, as exemplified in Schemes 4e6. Dime-
thylsulfoximine 19 was prepared in two steps from Chloramine-T as
detailed in experimental Section 4.3.4. Where the sulfoximine was
to be attached to a reactive electrophile, such as bromide 24, a mild
alkylation was successful, using either K2CO3 or NaHCO3 as base
(Scheme 4). Ester 25 could be converted to the desired aldehyde 26,
demonstrating the stability of the sulfoximine group to strong re-
ducing reagents (LiAlH4). Due to the excellent stability of the
5
NH
7
5
2.5
6
NMe
3.3
R O
S
N
N
N
O
N
H
H2N
N
Ex.
7
R
Aq. solubility (µM)
logD7.4
O
5
1.9
1.0
1.8
8
NH
145
9
NMe >1000
Fig. 2. Aqueous solubility at pH 7.4 and log D7.4 of sulfone, sulfoximine and methyl
sulfoximine matched triplets of GPR119 agonists (4e6) and ATR inhibitors (7e9).
containing building blocks and more published simple, scalable
synthetic procedures would encourage usage of this potentially
valuable functional group. For such building blocks to be useful
they should contain commonly used functional groups for coupling
to a project scaffold (amine, acid, boronic acid or boronate ester,
aldehyde, alkyl/aryl halide or aniline) and be accessible on practical
scale (>10 g).
2. Results and discussion
The synthesis of sulfoximines from amination of a sulfide and
subsequent oxidation is well described in the literature, and a va-
riety of protocols to effect the key amination step have been
reported.10e14 The reverse sequence (oxidation of a sulfide followed
by amination) is also widely reported, and can also be considered
a general and useful route for synthesising sulfoximines, but for the
specific steps described in this article we found it to be less reliable.
The amination/oxidation route allowed us to synthesise a range of

F.W. Goldberg et al. / Tetrahedron 70 (2014) 6613e6622
6615
O N
S
O NH
S
S
iv
i-ii
iii
NC
HO2C
vi-viii
NC
10
11
12
Cbz
N
H
H
N
Cbz
N
v
N
S
S
HN O
15
S
N O
S
N
14
Tos
13
16
Scheme 1. Example sulfoximine building blocks that were synthesised from the corresponding sulfides. Reagents and conditions: (i) NH2CN, t-BuOK, NBS, MeOH then m-CPBA,
K2CO3, EtOH, 53%; (ii) TFAA, DCM then K2CO3, MeOH, 85%; (iii) (CHO)n, HCO2H then aq NaOH, EtOH, 23%; (iv) Chloramine-T, TBAB, DCM, 73%; (v) NaOCl, TBAB, DCM, EtOAc then Na/
naphthalene, DME, 61%; (vi) Boc2O, MeOH, 87%; (vii) MeI, K2CO3, THF, 51%; (viii) HCl, MeOH, 95%.
O2N
Br
O2N
O
Br
O2N
N
O
i, ii
iii
S
S
+
O
CO2H
NH
19
17
18
20
NH2
iv
O
v
O
N
N
H2N
H2N
O
N
S
S
S
21
22
23
Scheme 2. Synthesis of aromatic and partially saturated bicyclic sulfoximines. Reagents and conditions: (i) BH3$SMe2, NEt3, THF, 62%; (ii) MnO2, DCM, 83%; (iii) Pd2(dba)3,
Xantphos, Cs2CO3, 1,4-dioxane, 52%; (iv) Pd/C, H2, MeOH, 91%; (v) Raney Ni, H2, DCM, 90%.
a useful route for benzylic sulfoximines such as 38 and 39, where
Reduction
the reductive amination was done on the 3- or 4-cyano benzalde-
hyde followed by Raney Ni reduction of the nitrile to the desired
amine.
Aryl
S
R
S
N
O
N
O
As an alternative to reductive amination, a two-step acylation/
reduction protocol was used for targets where the acid chloride was
commercially available, using a borane reduction of an acyl sul-
foximine as suggested by Bolm.19 Thus dimethylsulfoximine 19
couples with the acid chloride derived from previously reported26
acid 40 to afford 41, which could be reduced to 42 and depro-
tected to the desired piperidine 43 (Scheme 6). This route was also
followed for the analogous pyrrolidine 44. Where the aldehyde/
acid chloride starting materials were not available, arylation fol-
lowed by reduction also proved to be a successful strategy. Thus
bromide 45 could be coupled with dimethylsulfoximine to afford
46, which was activated by benzylation to give 47 and reduced to
afford the desired 3-substituted piperidine 48.
Arylation
Reductive
amination
R
Alkylation
O
S
S
R'
N
O
S
Aryl
N
O
NH 19
Acylation
Reduction
O
S
S
R
N
O
R
N
O
Scheme 3. Proposed use of dimethylsulfoximine 19 to synthesise N-alkyl sulfoximines.
3. Conclusion
In summary, dimethylsulfoximine has been utilised as a versa-
tile starting material to synthesise a variety of S- and N-alkyl sul-
foximines. Although S-alkyl sulfoximines are well precedented in
the medicinal chemistry literature, this work has expanded the
scope of interesting, structurally novel S-alkyl building blocks. N-
alkyl sulfoximines, by contrast, have not thus far had the same
degree of interest in medicinal chemistry, neither are they so
thoroughly discussed in the synthetic literature, although the
routes to synthesise them are known. We report herein the syn-
thesis of a diverse range of novel N-alkyl sulfoximine building
blocks on practical (>10 g) scale, using dimethylsulfoximine as
a versatile starting material that we hope will further enhance the
usage of the sulfoximine group by medicinal chemists.
sulfoximine group, a wide range of functionalities was accessible
using this alkylation route, including benzylic compounds such as
27e30 and also amino acid/diamine derived building blocks 33 and
34.
However, for less reactive electrophiles, where the key alkyl-
ation step does not work well, reductive amination or an acylation/
reduction or arylation/reduction sequence (Scheme 5) was
employed. For example, piperidone 35 could be coupled to 19 with
NaBH(OAc)3 to provide the desired N-alkyl sulfoximine 36 directly,
followed by reductive cleavage of the Cbz group to provide the
desired piperidine building block 37. Due to the good commercial
availability of benzaldehyde starting materials, this was also

6616
F.W. Goldberg et al. / Tetrahedron 70 (2014) 6613e6622
S
O
S
Br
S
N
O
i
ii, iii
N
O
S
+
MeO2C
NH
19
MeO2C
24
25
26
O
S
S
N
O
N
O
S
N
O
N
O
27
(57%)
28
(46%)
29
(58%)
30
(58%)
CO2H
NH2
NH2
Cl
O
S
S
HO
S
N
O
N
H2N
S
N
O
N
O
O
O
NH2
B
31
(56%)
32
(44%)
33
(99%)
34
(50%)
O
Scheme 4. N-Alkyl sulfoximine building blocks synthesised from dimethylsulfoximine via alkylation. For compounds 27e34 the yield of the key alkylation step of dime-
thylsulfoximine with an alkyl halide is shown in parentheses. Reagents and conditions: (i) NaHCO3, MeCN, 85%; (ii) LiAlH4, THF, 91%; (iii) MnO2, DCM, 74%.
O
S
O
N
O
N
O
i
ii
S
S
+
CbzN
CbzN
HN
NH
35
36
NH2
37
19
S
O
N
S
O
N
39
38
NH2
(54%, 3 steps)
(84%, 2 steps)
Scheme 5. N-Alkyl sulfoximine building blocks synthesised from 19 via reductive amination. For compounds 38 and 39 the yield of the key reductive amination step of dime-
thylsulfoximine with a benzaldehyde is shown in parentheses. Reagents and conditions: (i) NaBH(OAc)3, DCE, 39%; (ii) Pd(OH)2/C, H2, MeOH, then HCl, MeOH 100%.
O
O
ii
iii
i
S
S
S
N
O
N
O
OH
N
O
CbzN
HN
CbzN
CbzN
40
41
42
43
N
S O
N
H
44
N
O
N
O
S
Br
O
N
O
S
vi
iv
v
S
N+
S
N
+
N
N
N
H
46
47
48
45
Ph
Scheme 6. N-Alkyl sulfoximine building blocks synthesised from dimethylsulfoximine via acylation or arylation, followed by reduction. Reagents and conditions: (i) (COCl)2, NEt3,
DMF, DCM, then 19, NEt3, DCM, 98% overall; (ii) BH3$SMe2, THF, 76%; (iii) Pd(OH)2/C, H2, MeOH, 99%; (iv) Pd2(dba)3, Xantphos, Cs2CO3, 1,4-dioxane, 92%; (v) BnBr, MeCN, 57%; (vi)
NaBH4, MeOH, then Pd(OH)2/C, H2, MeOH, 64% overall.
4. Experimental section
4.1. General methods
(flash) chromatography was performed on either 74e165 mm silica
gel. 1H NMR spectra were recorded at 300, 400 or 700 MHz as in-
dicated. The following abbreviations were used to explain multi-
plicities: s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet,
br¼broad, dd¼doublet of doublets, dt¼doublet of triplets. 13C NMR
spectra were recorded at 75, 100 or 175 MHz as indicated. All
chemical shifts were calibrated using residual non-deuterated
Reactions were performed under nitrogen and with dry glass-
ware unless otherwise stated. Reagents were used as supplied by
commercial vendors without further purification or drying. Column

F.W. Goldberg et al. / Tetrahedron 70 (2014) 6613e6622
6617
solvent as an internal reference and are reported in parts per mil-
lion relative to trimethylsilane. LCMS were taken on a quadrupole
Mass Spectrometer on a Shimadzu LCMS 2010 or Agilent 6110/
1956/1946, operating in ESþ or ESꢀ ionisation mode. High-
resolution mass spectra were recorded for all final compounds,
on a Thermo Fisher LTQ-FT Mass Spectrometer fitted with an
electrospray (ESI) ion source. All final compounds were assessed as
being >95% pure by LCMS and/or NMR, and to be the correct mass
(within 3 ppm) by HRMS. Where the correct mass was not ob-
served, due to extensive fragmentation, an EI fragmentation pat-
tern was generated and analysed for consistency with the proposed
structure, as detailed in Supplementary data for compounds 15 and
16.
dimethylsulfonimidoyl)benzonitrile in EtOH (100 mL), and the re-
action mixture was stirred at 60 ꢂC for 6 h. The reaction mixture
was allowed to cool to rt, then was partially evaporated. The mix-
ture was acidified to pH 3.0 by addition of 1 N aq HCl. The pre-
cipitated solid was collected and washed with acetone to afford the
title compound 12 (13.0 g, 23%) as a white solid, mp 145 ꢂC (dec);
nmax (Nujol) 1716, 1404, 1223, 1153, 1103, 1091 cmꢀ1
; dH (400 MHz,
CD3OD) 8.39 (2H, d, J 8.8 Hz), 8.22 (2H, d, J 8.8 Hz), 3.90 (3H, s), 2.80
(3H, s), CO2H not observed; dC (175 MHz, DMSO) 165.9, 137.7, 136.5,
130.6, 129.2, 41.2, 27.3; m/z MHþ¼214; HRMS (ESꢀ) for C9H10NO3S
[MꢀH]: calcd 212.0387, found 212.0388.
4.2.4. Benzyl 1-(p-tolylsulfonylimino)-1,4-thiazinane-4-carboxylate
14. Chloramine-T trihydrate (178.2 g, 0.633 mol, now commer-
4.2. Synthesis of sulfoximines from amination/oxidation of
cially
available
but
we
prepared
it
from
4-
the corresponding sulfide (Scheme 1, compounds 12, 15 and
16)
methylbenzenesulfonamide, as reported in patent ref. PL171789)
and TBAB (20 g, 0.062 mol) was added to benzyl thiomorpholine-4-
carboxylate (150 g, 0.632 mol, prepared from thiomorpholine in
a similar manner to that reported in patent ref. WO1996005193) in
DCM (2 L). The reaction mixture was stirred for 12 h at rt, then was
filtered and the filtrate was evaporated to afford the title compound
14 (187.5 g, 73%) as a pale yellow solid; dH (400 MHz, CDCl3)
7.82e7.77 (2H, m), 7.39e7.23 (7H, m), 5.13 (2H, s), 4.40e3.90 (4H,
m), 2.90e2.70 (4H, m), 2.39 (3H, s); m/z MHþ¼423.
4.2.1. [(4-Cyanophenyl)-methyl-oxo-l
6-sulfanylidene]cyanami-
de. NBS (122.6 g, 0.689 mol) was added to 4-
methylsulfanylbenzonitrile 10 (70 g, 0.469 mol), t-BuOK (63.2 g,
0.563 mol) and cyanamide (25.6 g, 0.609 mol) in MeOH (1.5 L), and
the reaction mixture was stirred at rt overnight, then was evapo-
rated. The resulting residue was taken up in DCM (500 mL) and
water (300 mL), extracted with DCM (3ꢁ300 mL), and the com-
bined organic layers were washed with brine (2ꢁ400 mL) and dried
over Na2SO4, then evaporated to afford crude (E)-[(4-cyanophenyl)-
4.2.5. 1-Imino-1,4-thiazinane 1-oxide 15. TBAB (41.9 g, 0.13 mol)
and aq NaOCl (1.5 L, 6% w/w) were added to benzyl 1-(p-tol-
methyl-
l
4-sulfanylidene]cyanamide that was used without further
ylsulfonylimino)-1,4-thiazinane-4-carboxylate
14
(100
g,
purification; dH (400 MHz, CDCl3) 7.92e7.86 (4H, m), 3.03 (3H, s).
m-CPBA (122.1 g, 0.708 mol) was added to the crude (E)-[(4-
0.246 mol) in DCM (500 mL) and EtOAc (500 mL). The reaction
mixture was stirred for 5 h at rt, then was partially evaporated. The
resulting residue was collected by filtration and dried in vacuo to
give crude benzyl 1-oxo-1-(p-tolylsulfonylimino)-1,4-thiazinane-4-
carboxylate. Na/naphthalene (1 N, 960 mL, 0.96 mol) was added
dropwise to the crude benzyl 1-oxo-1-(p-tolylsulfonylimino)-1,4-
thiazinane-4-carboxylate in DME (1.5 L) at 0 ꢂC over 2 h, and the
reaction mixture was stirred at 0 ꢂC for 1 h. The reaction mixture
was allowed to warm to rt, then was quenched with 3 N aq HCl
(200 mL). The mixture was washed with DCM (3ꢁ200 mL) (product
stays in aq layer), and the aq layer was evaporated. The residue was
dissolved in water (250 mL) and made alkaline with satd
aq NaHCO3, and the resulting mixture was filtered and the filtrate
was evaporated to afford the title compound (20.2 g, 61%) as
a white solid, mp 178 ꢂC (dec); nmax (Nujol) 1694, 1556, 1422, 1269,
cyanophenyl)-methyl-l
4-sulfanylidene]cyanamide and K2CO3
(131.1 g, 0.949 mol) in EtOH (1 L) at 0 ꢂC, and the reaction mixture
was allowed to warm to rt and stirred at rt overnight. The reaction
mixture was taken up in DCM (600 mL) and water (800 mL),
extracted with DCM (3ꢁ500 mL), and the combined organic layers
were washed with satd brine (2ꢁ500 mL), dried over Na2SO4 and
evaporated. The resulting crude product was purified by flash
chromatography, eluting with 25e50% EtOAc in petroleum ether, to
afford the title compound (51.2 g, 53%) as a pale yellow solid; dH
(400 MHz, CDCl3) 8.11e8.08 (2H, d, J 8.4 Hz), 7.95e7.93 (2H, d, J
8.4 Hz), 3.25 (3H, s); m/z MHþ¼206.
4.2.2. 4-(Methylsulfonimidoyl)benzonitrile 11. Trifluoroacetic anhy-
dride (300 mL) was added dropwise to [(4-cyanophenyl)-methyl-
1247, 1201, 1142, 1110 cmꢀ1
; dH (400 MHz, DMSO) 4.15 (2H, br s),
oxo-
l
6-sulfanylidene]cyanamide (51.2 g, 0.249 mol) in DCM
4.40e3.90 (4H, m), 3.72e3.36 (4H, m); m/z MHþ¼135; HRMS (EIþ)
for [MꢀNH3]: calcd 117.0248, found 117.0254. The fragmentation
pattern for compound 15 was analysed to check consistency with
the proposed structure, see Supplementary data.
(200 mL) at 0 ꢂC, and the reaction mixture was allowed to warm to
rt and stirred at rt overnight. The reaction mixture was evaporated
to give crude N-[(4-cyanophenyl)-methyl-oxo-l
6-sulfanylidene]-
2,2,2-trifluoro-acetamide that was used in the subsequent step
without purification. K2CO3 (60 g, 0.434 mmol) was added to a so-
4.2.6. tert-Butyl
1-imino-1-oxo-1,4-thiazinane-4-carboxylate. Di-
lution of crude N-[(4-cyanophenyl)-methyl-oxo-
l
6-sulfanylidene]-
tert-butyl dicarbonate (87.9 g, 0.403 mol) was added dropwise to 1-
imino-1,4-thiazinane 1-oxide 15 (50 g, 0.373 mol) in MeOH (1.5 L)
at 0 ꢂC, then the reaction mixture was stirred for 5 h at rt and
evaporated. Aq HCl (0.5 M, 200 mL) was added to the residue, and
the mixture was extracted three times with EtOAc (500 mL). The
combined organic layers were washed with satd brine (3ꢁ250 mL),
dried over Na2SO4, filtered and evaporated to afford the title
compound (75.8 g, 87%) as a white solid; dH (400 MHz, CDCl3)
3.94e3.80 (4H, m), 3.02 (4H, m), 2.60 (1H, br s), 1.46 (9H, s); m/z
MHþ¼235.
2,2,2-trifluoro-acetamide in MeOH (300 mL), and the reaction
mixture was stirred at rt for 3 h. The reaction mixture was filtered
and the filtrate was evaporated, then purified by flash chromatog-
raphy, eluting with 33% EtOAc in petroleum ether, to afford the title
compound 11 (38.2 g, 85%) as a pale yellow solid; dH (400 MHz,
DMSO) 8.09 (4H, s), 4.55 (1H, s), 3.13 (3H, s); m/z MHþ¼181.
4.2.3. 4-(N,S-dimethylsulfonimidoyl)benzoic acid 12. 4-(Methyl-
sulfonimidoyl)benzonitrile 11 (47.5 g, 0.264 mol) and para-
formaldehyde (30 g) in formic acid (300 mL) was heated at reflux
overnight. The reaction mixture was allowed to cool to rt, evapo-
rated, and taken up in DCM (500 mL) and satd brine (500 mL). The
organic layer was dried over Na2SO4, filtered and evaporated to
4.2.7. tert-Butyl 1-methylimino-1-oxo-1,4-thiazinane-4-
carboxylate. MeI (54.5 g, 0.384 mol) was added to tert-butyl 1-
imino-1-oxo-1,4-thiazinane-4-carboxylate (75 g, 0.32 mol) and
K2CO3 (88.4 g, 0.64 mol) in THF (2 L), and the reaction mixture was
stirred for 12 h at rt, then was filtered and the filtrate was
afford crude 4-(N,S-dimethylsulfonimidoyl)benzonitrile.
2
N
aq NaOH (100 mL) was added to a solution of crude 4-(N,S-

6618
F.W. Goldberg et al. / Tetrahedron 70 (2014) 6613e6622
evaporated. The resulting residue was purified by recrystallisation
with EtOAc to afford the title compound (40.9 g, 51%) as a white
solid; dH (400 MHz, CDCl3) 7.75e7.72 (2H, m), 3.95 (2H, m),
3.06e3.02 (4H, m), 2.71 (3H, s), 1.43 (9H, s); m/z MHþ¼249.
residue was dissolved in water (1 L) and made alkaline with satd
aq NaHCO3. The mixture was filtered and the filtrate was evapo-
rated to afford the title compound 19 (37.1 g, 82%) as a white solid;
dH (400 MHz, CDCl3) 3.08 (6H, s); m/z MHþ¼94.
4.2.8. 1-Methylimino-1,4-thiazinane 1-oxide hydrochloride 16. HCl
(4 M) in MeOH (200 mL, 0.8 mol) was added to tert-butyl 1-
4.3.5. 4-Methyl-8-nitro-4l
6-thia-5-azabicyclo[4.4.0]deca-
1(6),2,4,7,9-pentaene 4-oxide 20. Xantphos (27.3 g, 47.2 mmol),
Pd2(dba)3 (21.7 g, 23.7 mmol) and Cs2CO3 (231 g, 709.0 mmol) were
added to 2-bromo-4-nitro-benzaldehyde 18 (110 g, 478 mmol) and
dimethylsulfoximine 19 (44.1 g, 473 mmol) in 1,4-dioxane (1.3 L) at
rt, and the reaction mixture was heated at reflux for 3 h. The
mixture was allowed to cool to rt, filtered, and the filtrate was
evaporated. The residue was purified by flash chromatography,
eluting with 17e50% EtOAc in petroleum ether, to afford the title
compound 20 (55.5 g, 52%) as a yellow solid; dH (400 MHz, DMSO)
7.99 (1H, d, J 10.0 Hz), 7.79e7.69 (3H, m), 7.35 (1H, d, J 10.0 Hz), 3.59
(3H, s); m/z MHþ¼225.
methylimino-1-oxo-1,4-thiazinane-4-carboxylate
(40.1
g,
0.161 mol) in MeOH (200 mL) and the reaction mixture was stirred
for 5 h at rt, then was evaporated to afford the title compound 16
(28.3 g, 95%) as a white solid, mp 157 ꢂC (dec); nmax (Nujol) 1636,
1540, 1330, 1285, 1228, 1078, 1060, 1014 cmꢀ1
; dH (400 MHz,
CD3OD) 4.57e4.52 (2H, m), 4.42e4.38 (2H, m), 4.00e3.94 (2H, m),
3.88e3.83 (2H, m), 3.05 (3H, s), NHþ2 not observed; dC (175 MHz,
DMSO) 45.3, 41.9, 26.5; m/z MHþ¼149. HRMS (EIþ) for
[MꢀCH3NH2]: calcd 117.0248, found 117.0258. The fragmentation
pattern for compound 16 was analysed to check consistency with
the proposed structure, see Supplementary data.
4.3.6. 4-Methyl-4-oxo-4
pentaen-8-amine hydrochloride 21. 4-Methyl-8-nitro-4
l
6-thia-5-azabicyclo[4.4.0]deca-1(6),2,4,7,9-
6-thia-5-
4.3. Synthesis of bicyclic sulfoximines (Scheme 2, compounds
22 and 23)
l
azabicyclo[4.4.0]deca-1(6),2,4,7,9-pentaene 4-oxide 20 (24.6 g,
110 mmol) and 10% Pd/C (5 g) in MeOH (1 L) were reacted under
hydrogen (40 psi) at 50 ꢂC overnight. The reaction mixture was
filtered and the filtrate was evaporated. HCl (4 M) in MeOH (50 mL)
was added to the residue, and the mixture was evaporated to afford
the title compound 21 (23.1 g, 91%) as a tan solid; dH (300 MHz,
D2O) 7.77 (1H, d, J 10.0 Hz), 7.48 (1H, d, J 8.2 Hz), 7.00 (1H, s),
6.95e6.90 (2H, m), 3.46 (3H, s), NHþ3 not observed; m/z MHþ¼195.
4.3.1. (2-Bromo-4-nitro-phenyl)methanol. Triethylamine (94.3 g,
0.932 mol) and 10 N BH3$SMe2 in DMS (281 mL, 2.81 mol) were
added to 2-bromo-4-nitro-benzoic acid 17 (230 g, 0.935 mol,
sourced commercially) in THF (1.5 L) at 0 ꢂC, then the reaction
mixture was heated at reflux for 3 h. The reaction mixture was
allowed to cool to rt, then slowly quenched with water (100 mL)
and acidified with concd aq HCl to pH¼1, heated at reflux for
30 min, then allowed to cool to rt. The mixture was extracted three
times with DCM (3ꢁ500 mL), and the combined organic layers
were evaporated and purified by flash chromatography, eluting
with 17e33% EtOAc in petroleum ether, to afford the title com-
pound (135.1 g, 62%) as a yellow solid; dH (400 MHz, CDCl3) 8.39
(1H, d, J 2.0 Hz), 8.20 (1H, dd, J 8.8, 2.0 Hz), 7.75 (1H, d, J 8.8 Hz), 4.83
(2H, s), 2.56 (1H, br s); m/z MHþ¼232, 234.
4.3.7. 4-Methyl-4-oxo-4l
6-thia-5-azabicyclo[4.4.0]deca-1(6),4,7,9-
tetraen-8-amine hydrochloride 22. The parent aniline of compound
21 was generated by repeating the procedure in Section 4.3.6,
without the HCl step. The resulting 4-methyl-4-oxo-4
azabicyclo[4.4.0]deca-1(6),2,4,7,9-pentaen-8-amine (20.5
l
6-thia-5-
g,
0.106 mol) was combined with Raney Ni (5 g) and MeOH (1 L) and
the reaction mixture was heated at 50 ꢂC under H2 (50 psi) over-
night. The reaction mixture was filtered and the filtrate was evap-
orated. HCl (4 M) in MeOH (100 mL) was added to the residue, and
the mixture was evaporated to afford the title compound 22 (22.3 g,
90%) as a white solid, mp 175e180 ꢂC (dec); nmax (Nujol) 1621, 151,
4.3.2. 2-Bromo-4-nitro-benzaldehyde 18. MnO2 (508 g, 5.84 mol)
was added to (2-bromo-4-nitro-phenyl)methanol (135.1 g,
0.582 mol) in DCM (1 L) and the reaction mixture was stirred
overnight at rt. The mixture was filtered and the filtrate was
evaporated to afford the title compound 18 (110.8 g, 83%) as a yel-
low solid; dH (400 MHz, CDCl3) 10.43 (1H, s), 8.54e8.53 (1H, d, J
2.0 Hz), 8.29e8.26 (1H, dd, J 8.8, 2.0 Hz), 8.09e8.07 (1H, d, J 8.8 Hz);
m/z MHþ¼230, 232.
1254,1161,1031 cmꢀ1
; dH (300 MHz, D2O) 7.11 (1H, d, J 11.2 Hz), 6.77
(1H, d, J 11.2 Hz), 6.66 (1H, s), 3.57e3.52 (1H, m), 3.40e3.36 (1H, m),
3.33 (3H, s), 3.20e3.12 (2H, m), NHþ3 not observed; m/z MHþ¼197;
HRMS (ESþ) for C9H13N2OS (MHþ): calcd 197.0749, found 197.0746.
4.3.8. 4-Methyl-4-oxo-4l
6-thia-5-azabicyclo[4.4.0]deca-1(10),4,6,8-
4.3.3. N-[Dimethyl(oxo)-
l
6-sulfanylidene]-4-methyl-benzenesulfona-
tetraen-7-amine hydrochloride 23. Prepared in a similar manner to
compound 22 (see Sections 4.3.1e4.3.5), in five steps from 2-
chloro-3-nitro-benzoic acid to afford the title compound as a tan
solid, mp 196e198 ꢂC (dec); nmax (Nujol) 1626, 1561, 1493, 1337,
mide. Copper(II) chloride dihydrate (20 g, 0.117 mol) was added to
Chloramine-T trihydrate (180 g, 0.639 mol, now commercially
available but we prepared it from 4-methylbenzenesulfonamide as
reported in patent ref. PL171789) in DMSO (800 mL) and the re-
action mixture was heated at reflux for 4 h. The reaction mixture
was cooled to rt and dissolved in water (3 L) and satd aq Na2EDTA
(1 L). The resulting precipitate was collected by filtration to afford
the title compound (141.1 g, 90%) as a white solid; dH (400 MHz,
DMSO) 7.75 (2H, d, J 8 Hz), 7.33 (2H, d, J 8 Hz), 3.42 (6H, s), 2.35 (3H,
s); m/z MHþ¼248.
1307, 1290, 1230, 1204, 1167, 1132, 1086, 1072, 1019 cmꢀ1
; dH
(300 MHz, DMSO) 9.79 (3H, br s), 7.25 (1H, d, J 7.8 Hz), 7.21 (1H, d, J
7.8 Hz), 6.79 (1H, t, J 7.8 Hz), 3.58e3.40 (2H, m), 3.45 (3H, s),
3.42e3.05 (2H, m); dC (175 MHz, DMSO) 139.1, 128.3, 122.3, 122.2,
122.0, 118.6, 43.0, 41.8, 22.6; m/z MHþ¼197; HRMS (ESþ) for
C9H13N2OS (MHþ): calcd 197.0749, found 197.0746.
4.4. Sulfoximines synthesised by alkylation of dime-
thylsulfoximine (Scheme 4, compounds 26e34)
4.3.4. Imino-dimethyl-oxo-
thylsulfoximine) 19. A solution of Na/naphthalene (1 N, 1.96 L,
1.96 mol) was added dropwise to N-[dimethyl(oxo)-
6-sulfanyli-
l
6-sulfane (IUPAC name for dime-
l
4.4.1. General method for alkylation: methyl 4-[[[dimethyl(oxo)-l6
-
dene]-4-methyl-benzenesulfonamide (120 g, 0.485 mol) in DME
(1.5 L) at 0 ꢂC over 2 h, and the reaction mixture was stirred at 0 ꢂC
for 1 h, then allowed to warm to rt and quenched with 3 N aq HCl
(600 mL). The mixture was washed with DCM (3ꢁ300 mL), the
organic layer was discarded, and the aq layer was evaporated. The
sulfanylidene]amino]methyl]benzoate 25. Methyl 4-(bromomethyl)
benzoate (40.1 g, 0.175 mol) and NaHCO3 (22 g, 0.262 mol) were
added to dimethylsulfoximine 19 (16.2 g, 0.174 mol) in MeCN
(500 mL) and the reaction mixture was heated at reflux for 10 h,
then cooled to rt and filtered. The filtrate was evaporated and the

F.W. Goldberg et al. / Tetrahedron 70 (2014) 6613e6622
6619
residue was purified by flash chromatography, eluting with 10e20%
EtOAc in petroleum ether, to afford the title compound 25 (35.6 g,
85%) as a white solid; dH (400 MHz, CDCl3) 8.00 (2H, d, J 8.4 Hz), 7.47
(2H, d, J 8.4 Hz), 4.36 (2H, s), 3.91 (3H, s), 3.09 (6H, s); m/z
MHþ¼242.
43.3, one aliphatic peak missing, assumed to be under DMSO peak;
m/z MHþ¼232; HRMS (ESþ) for C10H15ClNOS (MHþ): calcd
232.0563, found 232.0561.
4.4.8. 2-[[[Dimethyl(oxo)-l
6-sulfanylidene]amino]methyl]benzoni-
trile. Prepared in a similar manner to Section 4.4.1 from 2-(bro-
momethyl)benzonitrile in 58% yield to afford the title compound as
a white solid; dH (400 MHz, CDCl3) 7.59e7.41 (3H, m), 7.26e7.23
(1H, m), 4.37 (2H, s), 3.04 (6H, s); m/z MHþ¼209.
4.4.2. [4-[[[Dimethyl(oxo)-
methanol. LiAlH4 (8.6 g, 0.227 mol) was added portionwise to methyl
4-[[[dimethyl(oxo)- 25
6-sulfanylidene]amino]methyl]benzoate
l
6-sulfanylidene]amino]methyl]phenyl]
l
(35 g, 0.145mol) inTHF (600 mL)at 0 ꢂC, and thereaction mixturewas
stirred for 3 h at0 ꢂC, then allowed towarm to rt. The reaction mixture
was quenched with water (20 mL) and 2.5 M aq NaOH (10 mL). The
mixture was filtered and the filtrate was evaporated to afford the title
compound(28.0g,91%)asawhitesolid;dH (400MHz, CDCl3)7.35(2H,
d, J 8.4 Hz), 7.27 (2H, d, J 8.4 Hz), 4.63 (2H, s), 4.27 (2H, s), 2.99 (6H, s),
OH not observed; m/z MHþ¼214.
4.4.9. 2-[[[Dimethyl(oxo)-
acid 29. Prepared in a similar manner to Section 4.2.3, from
aq NaOH hydrolysis of 2-[[[dimethyl(oxo)-
6-sulfanylidene]amino]
l
6-sulfanylidene]amino]methyl]benzoic
l
methyl]benzonitrile in 92% yield to afford the title compound as
a white solid, mp 106e109 ꢂC; nmax (Nujol) 1556, 1307, 1273, 1249,
1197, 1115, 1024 cmꢀ1
; dH (400 MHz, DMSO) 8.25e8.23 (2H, d, J
7.2 Hz), 7.99e7.91 (1H, t, J 7.2 Hz), 7.76 (1H, t, J 7.2 Hz), 5.11 (2H, s),
3.64 (6H, s), CO2H not observed; dC (100 MHz, DMSO) 171.4, 140.9,
136.2, 128.7, 128.6, 127.5, 125.2, 44.5, 41.2; m/z MHþ¼228; HRMS
(ESþ) for C10H14NO3S (MHþ): calcd 228.0694, found 228.0692.
4.4.3. 4-[[[Dimethyl(oxo)-
hyde 26. MnO2 (113.1 g, 1.3 mol) was added to [4-[[[dimethyl(oxo)-
6-sulfanylidene]amino]methyl]phenyl]methanol (28 g, 0.131 mol)
l
6-sulfanylidene]amino]methyl]benzalde-
l
in DCM (500 mL), and the reaction mixture was stirred at rt for 8 h.
The reaction mixture was filtered and the filtrate was evaporated to
afford the title compound 26 (20.5 g, 74%) as a white solid, mp
72e74 ꢂC; nmax (Nujol) 1693, 1604, 1577, 1305, 1215, 1195, 1115,
4.4.10. [2-[[[Dimethyl(oxo)-
methanamine hydrochloride 30. Raney Ni (9 g) was added to 2-
[[[dimethyl(oxo)-
6-sulfanylidene]amino]methyl]benzonitrile
l
6-sulfanylidene]amino]methyl]phenyl]
l
1016 cmꢀ1
;
dH (400 MHz, CDCl3) 9.98 (1H, s), 7.84 (2H, d, J 8.0 Hz),
(23.1 g, 0.111 mol, see Section 4.4.8) in 300 mL 4 N MeOH/NH3 and
reacted under hydrogen (15 psi) for 2 h. The mixture was filtered,
and the filtrate was evaporated. The residue was treated with
250 mL 4 N HCl in EtOAc and evaporated to afford the title com-
pound 30 (24.5 g, 89%) as a white solid, mp 164 ꢂC (dec); nmax
7.56 (2H, d, J 8.0 Hz), 4.36 (2H, s), 3.05 (6H, s); dC (100 MHz, CDCl3)
192.1, 148.6, 135.2, 130.0, 128.0, 46.7, 42.4; m/z MHþ¼212; HRMS
(ESþ) for C10H14NO2S (MHþ): calcd 212.0745, found 212.0743.
4.4.4. Dimethyl-[(3-nitrophenyl)methylimino]-oxo-
l
6-sulfane. Pre-
(Nujol) 1604, 1524, 1341, 1276, 1243, 1088, 1063, 1050 cmꢀ1
; dH
pared in a similar manner to Section 4.4.1 from 1-(bromomethyl)-
3-nitro-benzene (42 g, 0.194 mol) to afford the title compound
(25.4 g, 57%) as a white solid; dH (400 MHz, CDCl3) 8.24 (1H, s),
8.06e8.03 (1H, m), 7.69 (1H, d, J 8.0 Hz), 7.45 (1H, t, J 8.0 Hz), 4.34
(2H, s), 3.06 (6H, s); m/z MHþ¼229.
(400 MHz, DMSO) 8.70 (3H, br s), 7.55e7.50 (2H, m), 7.37 (2H, m),
4.57 (2H, s), 4.11 (2H, s), 3.91 (6H, s); dC (100 MHz, D2O) 133.0, 131.3,
130.4, 130.0, 129.9, 129.6, 42.1, 39.9, 39.5; m/z MHþ¼213; HRMS
(ESþ) for C10H17N2OS (MHþ): calcd 213.1062, found 213.1058.
4.4.11. (4-Bromophenyl)methylimino-dimethyl-oxo-l
6-sulfane. 1-
4.4.5. 3-[[[Dimethyl(oxo)-
l
6-sulfanylidene]amino]methyl]aniline hy-
Bromo-4-(bromomethyl)benzene (84.4 g, 0.322 mol), dime-
thylsulfoximine 19 (29.2 g, 0.313 mol), K2CO3 (66.7 g, 0.483 mol) in
MeCN (600 mL) was heated at reflux overnight, then allowed to
cool to rt and filtered. The filtrate was evaporated and purified by
flash chromatography, eluting with 2e50% EtOAc in petroleum
ether, to afford the title compound (45.8 g, 56%) as a tan solid; dH
(400 MHz, CDCl3) 7.36 (2H, d, J 8.4 Hz), 7.19 (2H, d, J 8.4 Hz), 4.16
(2H, s), 2.94 (6H, s); m/z MHþ¼262, 264.
drochloride 27. Dimethyl-[(3-nitrophenyl)methylimino]-oxo-l6
-
sulfane (25 g, 0.110 mol) and 10% Pd/C (6 g) in MeOH (600 mL) were
reacted under hydrogen (30 psi) at rt overnight. The mixture was
filtered through Celite and the filtrate was acidified with 100 mL
4 N HCl in MeOH and evaporated to afford the title compound 27
(25.1 g, 97%) as a tan solid, mp 159e161 ꢂC (dec); nmax (Nujol) 1598,
1568, 1530, 1493, 1417, 1335, 1315, 1258, 1222, 1058 cmꢀ1
; dH
(400 MHz, DMSO) 10.67 (3H, br s), 7.48e7.45 (3H, m), 7.35e7.32
(1H, m), 4.56 (2H, s), 3.90 (6H, s); dC (100 MHz, D2O) 137.4, 130.9,
130.4,128.8,123.2,122.6, 43.9, 39.6; m/z MHþ¼199; HRMS (ESþ) for
C9H15N2OS (MHþ): calcd 199.0905; found, 199.0904.
4.4.12. Dimethyl-oxo-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)phenyl]methylimino]-
l
6-sulfane
31. (4-Bromophenyl)methyl-
imino-dimethyl-oxo-
l
6-sulfane (40 g, 0.160 mol), potassium ace-
tate (22.1 g, 0.225 mol), Pd(dppf)Cl2 (11.1 g, 0.015 mol),
bis(pinacolato)diboron (42 g, 0.165 mol) in 1,4-dioxane (800 mL)
was heated at reflux overnight, then was allowed to cool to rt and
taken up in EtOAc (500 mL) and water (200 mL). The organic layer
was isolated, dried over Na2SO4, filtered, evaporated and purified
by flash chromatography, eluting with 2e50% EtOAc in petroleum
ether, to afford the title compound 31 (27.3 g, 55%) as a white solid,
mp 89e93 ꢂC. nmax (Nujol) 1609, 1514, 1396, 1322, 1309, 1267, 1214,
4.4.6. [3-[[[Dimethyl(oxo)-l
6-sulfanylidene]amino]methyl]phenyl]
methanol. Prepared in a similar manner to Sections 4.4.1 and 4.4.2,
with an alkylation between dimethylsulfoximine and methyl 3-
(bromomethyl)benzoate (46% yield) and subsequent LiAlH4 re-
duction (77% yield) to afford the title compound as a white solid; dH
(400 MHz, CDCl3) 7.34e7.19 (4H, m), 4.59 (2H, d, J 5.6 Hz), 4.24 (2H,
s), 2.96 (6H, s), 2.84 (1H, t, J 5.6 Hz); m/z MHþ¼214.
1190, 1170, 1144, 1086, 1016 cmꢀ1
; dH (400 MHz, CDCl3) 7.69 (2H, d, J
4.4.7. [3-(Chloromethyl)phenyl]methylimino-dimethyl-oxo-
fane 28. Thionyl chloride (12.7 g, 0.107 mol) was added to [3-
[[[dimethyl(oxo)-
6-sulfanylidene]amino]methyl]phenyl]metha-
l
6-sul-
8.0 Hz), 7.31 (2H, d, J 8.0 Hz), 4.24 (2H, s), 2.90 (6H, s), 1.26 (12H, s);
dC (100 MHz, CDCl3) 144.6, 134.9, 126.9, 83.7, 47.0, 42.7, 24.9, the
aromatic carbon attached to boron was not observed; m/z
MHþ¼310; HRMS (ESþ) for C15H25BNO3S (MHþ): calcd 310.1648,
found 310.1647.
l
nol (19.1 g, 0.0895 mol) in DCM (600 mL) and the reaction mixture
was stirred at rt for 3 h, then was evaporated to afford the title
compound (20.1 g, 97%) as a tan solid, mp 122 ꢂC (dec); nmax (Nujol)
1489, 1338,1319, 1269, 1249, 1226, 1058 cmꢀ1
;
dH (400 MHz, DMSO)
4.4.13. Dimethyl-[(2-nitrophenyl)methylimino]-oxo-l
6-sulfane. Pre-
7.50 (1H, s), 7.42e7.38 (3H, m), 4.76 (2H, s), 4.51 (2H, s), 3.88 (6H, s);
dC (175 MHz, DMSO) 137.9, 136.9, 128.9, 128.3, 128.3, 128.0, 46.0,
pared in a similar manner to Section 4.4.1 from 1-(bromomethyl)-
2-nitro-benzene in 44% yield to afford the title compound as

6620
F.W. Goldberg et al. / Tetrahedron 70 (2014) 6613e6622
a yellow solid; dH (400 MHz, CDCl3) 7.97e7.95 (1H, d, J 8.2 Hz),
7.88e7.86 (1H, d, J 7.6 Hz), 7.62e7.58 (1H, t, J 8.2 Hz), 7.40e7.37 (1H,
t, J 7.6 Hz), 4.62 (2H, s), 3.08 (6H, s); m/z MHþ¼229.
42.2; m/z MHþ¼152; HRMS (ESþ) for C4H10NO3S (MHþ): calcd
152.0381, found 152.0379.
4.5. Sulfoximines synthesised by reductive amination of di-
methylsulfoximine with a benzaldehyde (Scheme 5, com-
pounds 37e39)
4.4.14. 2-[[[Dimethyl(oxo)-
hydrochloride 32. Dimethyl-[(2-nitrophenyl)methylimino]-oxo-l6
l
6-sulfanylidene]amino]methyl]aniline
-
sulfane (25 g, 110 mmol) and Raney Ni (2.5 g) in MeOH (250 mL)
were stirred under hydrogen (35 psi) at rt for 4 h. The reaction
mixture was filtered, the filtrate was acidified with 100 mL 4 M HCl
in MeOH, and the mixture was evaporated to afford the title com-
pound 32 (24.6 g, 95%) as a white solid, mp 150 ꢂC (dec); nmax
(Nujol) 1626, 1590, 1572, 1532, 1314, 1291, 1248, 1224, 1175, 1123,
4.5.1. Benzyl 4-[[dimethyl(oxo)-l
6-sulfanylidene]amino]piperidine-1-
carboxylate 36. Benzyl 4-oxopiperidine-1-carboxylate 35 (150 g,
0.643mol), dimethylsulfoximine19 (30g,0.322mol)andNaBH(OAc)3
(270 g, 1.27 mol) in DCE (1.5 L) were stirred at 35 ꢂC overnight. The
reaction mixture was filtered and the filtrate was concentrated, the
residue was dissolved inwater, adjusted to pH¼9e10 with 2 N aq HCl,
and extracted with DCM (500 mL). The organic layer was evaporated
and the residue was purified by flash chromatography, eluting with
12.5% MeOH/DCM, to afford the title compound 36 (39.2 g, 39%) as
a yellow oil; dH (400 MHz, CDCl3) 7.37e7.28 (5H, m), 5.13 (2H, s),
4.11e3.97 (2H, m), 3.42e3.39 (1H, m), 3.06e3.00 (8H, m), 1.81e1.77
(2H, m), 1.55e1.51 (2H, m); m/z MHþ¼311.
1090, 1064, 1037 cmꢀ1
; dH (700 MHz, DMSO) 7.61 (1H, d, J 7.6 Hz),
7.49 (1H, d, J 7.6 Hz), 7.43 (1H, td, J 7.6, 1.2 Hz), 7.4 (1H, t, J 7.6 Hz),
4.82 (2H, s), 3.94 (6H, s), NHþ3 not observed; dC (175 MHz, DMSO)
132.0, 129.9, 129.3, 129.2, 127.1, 123.3, 40.2, 40.1; m/z MHþ¼199;
HRMS (ESþ) for C9H15N2OS (MHþ): calcd 199.0905, found 199.0902.
4.4.15. 2-[[Dimethyl(oxo)-l
6-sulfanylidene]amino]acetoni-
trile. Prepared in a similar manner to Section 4.4.1 from 2-
bromoacetonitrile in 99% yield to afford the title compound as
a colourless oil; dH (400 MHz, CDCl3) 3.93 (s, 2H), 3.04 (s, 6H); m/z
MHþ¼133.
4.5.2. Dimethyl-oxo-(4-piperidylimino)-
l
6-sulfane
hydrochloride
37. Benzyl 4-[[dimethyl(oxo)-
l
6-sulfanylidene]amino]piperidine-
1-carboxylate 36 (39 g, 0.126 mol) and 10% Pd(OH)2/C (8 g) in
MeOH (0.7 L) was stirred at 40 ꢂC under H2 (40 psi) for 4 h. The
reaction mixture was filtered, the filtrate was evaporated and the
residue was dissolved in 4 M HCl in MeOH (100 mL, 0.4 mol), then
evaporated to afford the title compound 37 (27.1 g, 100%) as a white
solid, mp 195 ꢂC (dec); nmax (Nujol) 2171, 1592, 1343, 1334, 1313,
4.4.16. tert-Butyl
ethyl]carbamate. 2-[[Dimethyl(oxo)-
N-[2-[[dimethyl(oxo)-
6-sulfanylidene]amino]ace-
l
6-sulfanylidene]amino]
l
tonitrile (25 g, 0.189 mol) and Raney Ni (30 g) in MeOH (500 mL)
and ammonia (30 mL) were stirred under H2 (50 psi) at rt over-
night. The reaction mixture was filtered and the filtrate was evap-
orated to afford the crude amine 33. The crude was then Boc
protected to facilitate purification; the crude was combined with
K2CO3 (40 g) in MeOH (800 mL), and Boc2O (100 mL) was added.
The reaction mixture was stirred overnight at rt. The reaction
mixture was filtered and the filtrate was evaporated, and purified
by flash chromatography, eluting with 3e20% EtOAc in petroleum
ether, to afford the title compound (33.9 g, 76%) as a colourless oil;
dH (400 MHz, CDCl3) 5.10 (1H, br s), 3.24e3.19 (2H, m), 3.17e3.14
(2H, m), 3.01 (6H, s), 1.42 (9H, s); m/z MHþ¼237.
1288, 1237, 1175, 1133, 1075, 1047, 1016 cmꢀ1
; dH (300 MHz, D2O)
3.96e3.89 (1H, m), 3.66 (6H, s), 3.38 (2H, d, J 17.6 Hz), 3.02e2.98
(2H, m), 2.15 (2H, d, J 13.8 Hz), 1.84e1.75 (2H, m), NHþ2 not ob-
served; dC (100 MHz, D2O) 48.0, 42.7, 40.0, 30.0; m/z MHþ¼177;
HRMS (ESþ) for C7H17N2OS (MHþ): calcd 177.1062, found 177.1059.
4.5.3. [4-[[[Dimethyl(oxo)-l
6-sulfanylidene]amino]methyl]phenyl]
methanamine hydrochloride 38. 4-Formylbenzonitrile (22.2 g,
169 mmol) was added to dimethylsulfoximine 19 (15.7 g,
169 mmol) in DCE (500 mL) and the reaction mixture was stirred at
rt for 30 min. NaBH(OAc)3 (71.6 g, 338 mmol) was added, the re-
action mixture was stirred at rt for 12 h, then was washed twice
with satd aq NaHCO3 (2ꢁ400 mL) and with satd brine (500 mL).
The organic layer was isolated, dried over MgSO4, filtered and pu-
rified by flash chromatography, eluting with EtOAc, to afford crude
4.4.17. 2-[[Dimethyl(oxo)-
l
6-sulfanylidene]amino]ethanamine
hy-
drochloride 33. HCl (4 M) in EtOAc (200 mL, 0.8 mol) was added to
tert-butyl N-[2-[[dimethyl(oxo)-
l
6-sulfanylidene]amino]ethyl]car-
bamate (33 g, 0.140 mol) in EtOAc (200 mL) at 0 ꢂC. The reaction
mixture was stirred overnight at rt, then evaporated to afford the
title compound 33 (23.1 g, 96%) as a white solid, mp 144 ꢂC (dec);
nmax (Nujol) 1597, 1490, 1401, 1332, 1313, 1285, 1235, 1162, 1072,
4-[[[dimethyl(oxo)-l
6-sulfanylidene]amino]methyl]benzonitrile as
a white solid; m/z MHþ¼209. Raney Ni (23 g) and the crude 4-
[[[dimethyl(oxo)-l
6-sulfanylidene]amino]methyl]benzonitrile in
1024 cmꢀ1
;
dH (400 MHz, MeOD) 3.89 (6H, s), 3.70e3.68 (2H, t, J
4 N MeOH/NH3 (2 L) was stirred under H2 at rt for 3 h. The reaction
mixture was filtered, evaporated, and dissolved in 4 M HCl in MeOH
(200 mL) and stirred for 1 h, then evaporated. The residue was
washed with EtOAc (3ꢁ50 mL) and dried in vacuo to afford the title
compound 38 (30.1 g, 84%) as a white solid, mp>280 ꢂC (dec); nmax
(Nujol) 2048, 1614, 1516, 1404, 1335, 1314, 1268, 1235, 1081,
6.0 Hz), 3.23e3.21 (2H, t, J 6.0 Hz), NHþ3 not observed; dC (100 MHz,
MeOD) 40.4, 40.3, 39.8; m/z MHþ¼137; HRMS (ESþ) for C4H13N2OS
(MHþ): calcd 137.0749, found 137.0745.
4.4.18. Benzyl 2-[[dimethyl(oxo)-l
6-sulfanylidene]amino]acetate. -
Prepared in a similar manner to Section 4.4.1 from benzyl 2-
bromoacetate in 50% yield to afford the title compound as a col-
ourless oil; dH (400 MHz, CDCl3) 7.32e7.21 (5H, m), 5.16 (2H, s), 3.92
(2H, s), 3.05 (6H, s); m/z MHþ¼242.
1047 cmꢀ1
; dH (700 MHz, DMSO) 8.67 (3H, br s), 7.54 (2H, d, J
8.1 Hz), 7.49 (2H, d, J 8.1 Hz), 4.52 (2H, s), 4.00 (2H, q, J 5.5 Hz), 3.89
(6H, s); dC (175 MHz, DMSO) 136.7, 133.6, 129.1, 128.1, 43.3, 41.8,
39.3; m/z MHþ¼213; HRMS (ESþ) for C10H17N2OS (MHþ): calcd
213.1062, found 213.1060.
4.4.19. 2-[[Dimethyl(oxo)-
34. Benzyl 2-[[dimethyl(oxo)-
l
6-sulfanylidene]amino]acetic
acid
l
6-sulfanylidene]amino]acetate
4.5.4. tert-Butyl
N-[[3-[[[dimethyl(oxo)-l
6-sulfanylidene]amino]
(32 g, 0.133 mol) and 10% Pd(OH)2/C (6 g) in MeOH (600 mL)
were shaken under hydrogen (40 psi) at rt overnight. The re-
action mixture was filtered through Celite and the filtrate was
evaporated to afford the title compound 34 (20.1 g, 100%) as
methyl]phenyl]methyl]carbamate. 3-Formylbenzonitrile (19.7 g,
150 mmol) was added to dimethylsulfoximine 19 (14 g, 150 mmol)
in DCE (500 mL) and the reaction mixture was stirred at rt for
30 min. NaBH(OAc)3 (63.6 g, 300 mmol) was added and the reaction
mixture was stirred at rt overnight, then was quenched with water
(200 mL) and extracted with DCM (2ꢁ300 mL). The combined or-
ganic layers were dried over Na2SO4, then filtered and evaporated
ꢂ
a white solid, mp 140 C (dec); nmax (Nujol) 1712, 1330, 1313,
1271, 1202, 1153, 1030 cmꢀ1
;
dH (400 MHz, DMSO) 3.62 (2H, s),
3.00 (6H, s), CO2H not observed; dC (100 MHz, DMSO) 173.8, 44.9,

F.W. Goldberg et al. / Tetrahedron 70 (2014) 6613e6622
6621
to afford crude 3-[[[dimethyl(oxo)-
l
6-sulfanylidene]amino]methyl]
a colourless oil; dH (300 MHz, CDCl3) 7.34e7.25 (5H, m), 5.10 (2H, s),
4.16 (1H, br s), 2.97 (6H, s), 2.90 (2H, m), 2.80e2.65 (2H, m),
1.78e1.76 (3H, m), 1.69e1.50 (1H, m), 1.20e1.10 (2H, m); m/z
MHþ¼325.
benzonitrile (18.8 g) that was used without purification; dH
(400 MHz, CDCl3) 7.73 (1H, s), 7.62e7.60 (1H, d, J¼8.0 Hz), 7.53e7.51
(1H, d, J¼7.6 Hz), 7.43e7.40 (1H, t, J¼7.6 Hz), 4.31 (2H, s), 3.07 (6H,
s); m/z MHþ¼209. The crude material was combined with Raney Ni
(18 g) and 4 N MeOH/NH3 (1 L), then was stirred under a balloon of
H2 at rt for 2 h. The reaction mixture was filtered through Celite and
evaporated to afford the crude amine compound 39; m/z MHþ¼213.
The crude title compound was taken up in DCM (500 mL) and
triethylamine (22 g, 217 mmol), and di-tert-butyl dicarbonate
(35.5 g, 163 mmol) was added. The reaction mixture was stirred at
rt overnight, then was washed with water (500 mL), Aq HCl (1 N,
500 mL) and satd brine (500 mL). The organic layer was evaporated
and purified by flash chromatography, eluting with 10e50% EtOAc
in petroleum ether, to afford the title compound (25.3 g, 54%) as
a white solid; dH (400 MHz, DMSO) 7.23e7.20 (3H, m), 7.08 (1H, s),
4.77 (1H, br s), 4.24e4.23 (2H, m), 4.21 (2H, s), 2.94 (6H, s), 1.39 (9H,
s); m/z MHþ¼313.
4.6.3. Dimethyl-oxo-(4-piperidylmethylimino)-
ride 43. Benzyl 4-[[[dimethyl(oxo)-
6-sulfanylidene]amino]
l
6-sulfane hydrochlo-
l
methyl]piperidine-1-carboxylate 42 (42 g, 0.129 mol) and 10%
Pd(OH)2/C (8 g) in MeOH (1 L) was shaken at 40 ꢂC under H2 (40 psi)
overnight. The reaction mixture was filtered, and the filtrated was
evaporated, then was taken up in MeOH (200 mL). HCl (4 N) in
MeOH (50 mL, 0.2 mol) was added, the reaction mixture was stirred
for 30 min, then evaporated to afford the title compound 43 (29.1 g,
99%) as a white solid, mp 164e166 ꢂC (dec); nmax (Nujol) 2174, 1587,
1344, 1325, 1250, 1234, 1214, 1167, 1129, 1044 cmꢀ1
; dH (400 MHz,
DMSO) 9.22 (1H, br s), 9.01 (1H, br s), 3.75 (6H, s), 3.37e3.34 (2H,
m), 3.14e3.09 (2H, m), 2.83e2.74 (2H, m), 1.89e1.85 (2H, m),
1.80e1.75 (1H, m), 1.42e1.31 (2H, m); dC (100 MHz, D2O) 45.9, 43.7,
39.6, 33.7, 25.8; m/z MHþ¼191; HRMS (ESþ) for C8H19N2OS (MHþ):
calcd 191.1218; found 191.1215.
4.5.5. [3-[[[Dimethyl(oxo)-
methanamine hydrochloride 39. HCl (4 N) in EtOAc (500 mL) was
added dropwise to tert-butyl N-[[3-[[[dimethyl(oxo)-
6-sulfanyli-
l
6-sulfanylidene]amino]methyl]phenyl]
l
4.6.4. Benzyl 3-[[dimethyl(oxo)-l
6-sulfanylidene]carbamoyl]pyrroli-
dene]amino]methyl]phenyl]methyl]carbamate (42.8 g, 137 mmol)
in ethyl acetate (200 mL) at 0 ꢂC. The reaction mixture was stirred at
rt for 2 h, then was evaporated, co-evaporated with MeOH (150 mL)
and dried in vacuo to afford the title compound 39 (34.1 g, 100%) as
an off-white solid, mp 161 ꢂC (dec); nmax (Nujol) 1613, 1243, 1222,
dine-1-carboxylate. DMF (10 mL) and oxalyl chloride (60.95 g,
480 mmol) were added to 1-benzyloxycarbonylpyrrolidine-3-
carboxylic acid (114 g, 457 mmol, synthesised according to
Ref. 27) in DCM (1.2 L) at rt, and the reaction mixture was stirred
at rt for 3 h. Dimethylsulfoximine 19 (46.9 g, 503 mmol) and
triethylamine (101.8 g, 1006 mmol) in DCM (250 mL) were added
and the reaction mixture was stirred at rt for 18 h, then was
washed with water (500 mL) and with satd brine (500 mL). The
organic layer was dried over Na2SO4, filtered, evaporated and
purified by flash chromatography, eluting with 33e50% EtOAc in
petroleum ether, to afford the title compound (91.3 g, 62%) as
a yellow oil; dH (400 MHz, CDCl3) 7.37e7.26 (5H, m), 5.13 (2H, s),
3.68e3.60 (2H, m), 3.57e3.52 (1H, m), 3.46e3.37 (1H, m), 3.26
(3H, s), 3.26 (3H, s), 3.06 (1H, m), 2.20e2.08 (2H, m); m/z
MHþ¼325.
1047 cmꢀ1
; dH (700 MHz, DMSO) 8.75 (3H, br s), 7.70 (1H, s), 7.48
(1H, d, J 7.3 Hz), 7.44e7.40 (2H, m), 4.53 (2H, s), 4.01 (2H, q, J 5.7 Hz),
3.94 (6H, s); dC (175 MHz, DMSO) 136.9, 134.4, 128.7, 128.3, 128.2,
127.7, 43.1, 42.0, 39.2; m/z MHþ¼213; HRMS (ESþ) for C10H17N2OS
MHþ: calcd 213.1062, found 213.1059.
4.6. N-Alkyl sulfoximines synthesised by arylation/acylation
of dimethylsulfoximine and subsequent reduction (Scheme 6,
compounds 43, 44 and 48)
4.6.1. Benzyl 4-[[dimethyl(oxo)-l
6-sulfanylidene]carbamoyl]piperi-
dine-1-carboxylate 41. Oxalyl chloride (25.3 g, 0.2 mol) was added
to 1-benzyloxycarbonylpiperidine-4-carboxylic acid 40 (50 g,
0.19 mol, prepared according to Ref. 26) and DMF (0.5 mL) in DCM
(300 mL) at 0 ꢂC. The reaction mixture was allowed to warm to rt
and stirred for 5 h. Triethylamine (40 mL) was added, the reaction
mixture was cooled to 0 ꢂC, dimethylsulfoximine 19 (19 g,
0.204 mol) in DCM (100 mL) was added, and the reaction mixture
was allowed to warm to rt and stirred overnight, then was washed
with satd brine (80 mL). The organic layer was evaporated and
purified by flash chromatography, eluting with EtOAc, to afford the
title compound 41 (63.1 g, 98%) as a white solid; dH (400 MHz,
CDCl3) 7.35e7.26 (5H, m), 5.11 (2H, s), 4.12e4.10 (2H, m), 3.24 (6H,
s), 2.92e2.82 (2H, m), 2.44e2.39 (1H, m), 1.94e1.87 (2H, m),
1.68e1.56 (2H, m); m/z MHþ¼339.
4.6.5. Benzyl
methyl]pyrrolidine-1-carboxylate. Prepared in a similar manner to
Section 4.6.2, by borane reduction of benzyl 3-[[dimethyl(oxo)-l6
(3R)-3-[[[dimethyl(oxo)-l
6-sulfanylidene]amino]
-
sulfanylidene]carbamoyl]pyrrolidine-1-carboxylate to afford the ra-
cemate (80.6 g, 99% yield) as a yellow oil. The racemate was separated
by chiral SFC (Column Chiralpak AD-H 150ꢁ4.6 mm I.D. 3
mm, mobile
phase methanol with 0.05% DEA in CO2 from 5% to 40%, flow rate
2.5 mL/min, wavelength 220 nm, retention time 6.56min for R isomer
and6.87minforSisomer)toaffordtheSisomer(32.3g,40%)andtheR
isomer title compound (31 g, 38%); dH (400 MHz, CDCl3) 7.39e7.28
(5H, m), 5.13 (2H, s), 3.61e3.47 (2H, m), 3.44e3.34 (1H, m), 3.22e3.13
(1H, m), 3.10e3.03 (2H, m), 2.99 (3H, s), 2.98 (3H, s), 2.44e2.34 (1H,
m), 2.06e1.95 (1H, m), 1.78e1.67 (1H, m); m/z MHþ¼311.
4.6.6. Dimethyl-oxo-[[(3R)-pyrrolidin-3-yl]methylimino]-l
6-sulfane
4.6.2. Benzyl 4-[[[dimethyl(oxo)-
peridine-1-carboxylate 42. BH3$Me2S (10 N) in DMS (56 mL,
560 mmol) was added to benzyl 4-[[dimethyl(oxo)-
6-sulfanyli-
l
6-sulfanylidene]amino]methyl]pi-
hydrochloride 44. Prepared in a similar manner to Section 4.6.3, by
Pd(OH)2/H2 reduction of benzyl (3R)-3-[[[dimethyl(oxo)-
nylidene]amino]methyl]pyrrolidine-1-carboxylate (31
l
6-sulfa-
g,
l
dene]carbamoyl]piperidine-1-carboxylate 41 (63 g, 186 mmol) in
THF at 0 ꢂC, and the reaction mixture was stirred at rt overnight,
then was quenched with water (200 mL). The mixture was partially
evaporated, then acidified with 12 N aq HCl solution (w150 mL) to
pH¼2, and then heated at reflux for 1 h. After cooling to rt, the
mixture was washed with EtOAc (3ꢁ150 mL) (discard organic
layer), and the aq layer was made alkaline with 5 N aq NaOH
(w150 mL) to pH¼9, then was extracted with EtOAc (3ꢁ750 mL).
The combined organic layers were dried over Na2SO4, filtered and
evaporated to afford the title compound 42 (45.7 g, 76%) as
99.9 mmol) and formation of the hydrochloride salt to afford the
title compound 44 (20.1 g, 95%) as a white solid, mp 160 ꢂC (dec);
nmax (Nujol) 1599, 1321, 1238, 1066, 1044 cmꢀ1
; dH (700 MHz,
DMSO) 9.71 (1H, br s), 9.62 (1H, br s), 3.89 (3H, s), 3.88 (3H, s),
3.43e3.37 (2H, m), 3.31e3.21 (2H, m), 3.14e3.10 (1H, m), 2.98e2.94
(1H, m), 2.59e2.54 (1H, m), 2.11e2.06 (1H, m),1.75e1.70 (1H, m); dC
(175 MHz, DMSO) 47.2, 43.9, 42.4, 39.1, 39.0, 37.6, 27.5; m/z
MHþ¼177; ee¼99.1% according to chiral SFC on the CBz protected
title compound (column Chiralpak AD-H 150x4.6 mm I.D. 3 mm,
mobile phase methanol with 0.05% DEA in CO2 from 5% to 40%, flow

6622
F.W. Goldberg et al. / Tetrahedron 70 (2014) 6613e6622
rate: 2.5 mL/min, wavelength 220 nm, retention time 6.48 min);
HRMS (ESþ) for C7H17N2OS (MHþ): calcd 177.1062, found 177.1059.
analytical support, and Philip MacFaul for physical chemistry
support.
4.6.7. Dimethyl-oxo-(3-pyridylimino)-
l
6-sulfane
46. 3-
Supplementary data
Bromopyridine 45 (30 g, 0.189 mol), dimethylsulfoximine 19
(18 g, 0.193 mol), Pd2(dba)3 (9 g, 9.8 mmol), Xantphos (11.25 g,
19.4 mmol) and Cs2CO3 (93 g, 0.285 mol) in 1,4-dioxane (300 mL)
were combined and heated at reflux for 4 h. The reaction mixture
was allowed to cool to rt, was filtered and the filtrate was evapo-
rated. The residue was taken up in 2 N aq HCl (500 mL), and was
washed with EtOAc (600 mL), then the aq layer was made alkaline
with 5 N aq NaOH solution (w400 mL) to pH¼10, then extracted
twice with 10% MeOH in DCM (1000 mL). The combined organic
layers were dried over Na2SO4, filtered and evaporated to afford the
title compound 46 (29.6 g, 92%) as a yellow solid; dH (400 MHz,
CDCl3) 8.30e8.29 (1H, m), 8.16e8.14 (1H, m), 7.34 (1H, s), 7.11e7.06
(1H, m), 3.11 (6H, s); m/z MHþ¼171.
These data include MS fragmentation pattern of compounds 15
and 16. Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.tet.2014.06.120.
References and notes
1. Scott, J. S.; Birch, A. M.; Brocklehurst, K. J.; Broo, A.; Brown, H. S.; Butlin, R. J.;
Clarke, D. S.; Davidsson, O.; Ertan, A.; Goldberg, K.; Groombridge, S. D.; Hudson,
J. A.; Laber, D.; Leach, A. G.; MacFaul, P. A.; McKerrecher, D.; Pickup, A.; Scho-
field, P.; Svensson, P. H.; Sorme, P.; Teague, J. J. Med. Chem. 2012, 55, 5361e5379.
2. Lucking, U.; Jautelat, R.; Kruger, M.; Brumby, T.; Lienau, P.; Schafer, M.; Briem,
H.; Schulze, J.; Hillisch, A.; Reichel, A.; Wengner, A. M.; Siemeister, G. Chem-
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3. Reggelin, M.; Zur, C. Synthesis 2000, 1e64.
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4.6.8. (1-Benzylpyridin-1-ium-3-yl)imino-dimethyl-oxo-
bromide 47. Benzyl bromide (33.5 g, 0.196 mol) was added to di-
methyl-oxo-(3-pyridylimino)-
6-sulfane 46 (33.5 g, 0.197 mol) in
MeCN (160 mL), and the reaction mixture was heated at reflux
overnight, then was allowed to cool to rt, and the resulting solid
was collected by filtration to afford the title compound 47 (37.9 g,
57%) as a yellow solid; dH (400 MHz, DMSO) 8.64e8.63 (2H, m),
8.03e8.01 (1H, m), 7.90e7.86 (1H, m), 7.54e7.52 (2H, m), 7.45e7.40
(3H, m), 5.75 (2H, s), 3.44 (6H, s); m/z MHþ¼261.
l
6-sulfane
6. Jones, C. D.; Blades, K.; Foote, K. M.; Guichard, S. M.; Jewsbury, P. J.; McGuire, T.;
Nissink, J. W.; Odedra, R.; Tam, K.; Thommes, P.; Turner, P.; Wilkinson, G.;
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l
4.6.9. Dimethyl-oxo-(3-piperidylimino)-
48. Sodium borohydride (8.52 g, 0.225 mol) was added to (1-
benzylpyridin-1-ium-3-yl)imino-dimethyl-oxo-
6-sulfane bromide
l
6-sulfane
hydrochloride
9. Charrier, J.; Durrant, S.; Kay, D.; Knegtel, R.; MacCormick, S.; Mortimore, M.;
O’Donnell, M.; Pinder, J.; Rutherford, A.; Virani, A. N.; Young, S.; Reaper, P. M.
WO2010071837A1, 2010.
l
47 (37.9 g, 0.111 mol) in MeOH (500 mL) at 0 ꢂC, and the reaction
mixture was stirred for 30 min, then evaporated. The residue was
taken up in water (400 mL) and EtOAc (800 mL), and the organic
layer was isolated and evaporated to afford crude (1-benzyl-3,6-
10. Johnson, C. R.; Janiga, E. R. J. Am. Chem. Soc. 1973, 95, 7692e7700.
11. Johnson, C. R.; Mori, K.; Nakanishi, A. J. Org. Chem. 1979, 44, 2065e2067.
~
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10660e10670.
14. Pandey, A.; Bolm, C. Synthesis 2010, 2922e2925.
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17. Pandey, A. G.; McGrath, M. J.; Mancheno, O. G.; Bolm, C. Synthesis 2011,
3827e3838.
18. Bentley, H. R.; Whitehead, J. K. J. Chem. Soc. 1950, 2081e2082.
19. Bolm, C.; Hackenberger, C. P. R.; Simic, O.; Verrucci, M.; Muller, D.; Bienewald, F.
Synthesis 2002, 879e887.
dihydro-2H-pyridin-5-yl)imino-dimethyl-oxo-
l
6-sulfane.
This
crude was combined with 10% Pd(OH)2/C (18 g) and MeOH (1 L) and
the reaction mixture was shaken at 60 ꢂC under H2 (50 psi) for 2
days. The reaction mixture was filtered and the filtrate was added to
4 N HCl in MeOH (50 mL) and evaporated to afford the title com-
pound 48 (15.1 g, 64% yield) as a white solid, mp 164 ꢂC (dec); nmax
(Nujol) 1590, 1343, 1317, 1293, 1223, 1138, 1099, 1068, 1045,
20. Furukawa, N.; Takahashi, F.; Yoshimura, T.; Morita, H.; Oae, S. J. Chem. Soc.,
1011 cmꢀ1
; dH (400 MHz, D2O) 4.01e3.75 (1H, m), 3.64 (6H, s),
Perkin Trans. 2 1981, 432e437.
21. Eis, K.; Prien, O.; Luecking, U.; Guenther, J.; Zopf, D.; Brohm, D.; Voehringer, V.;
Woltering, E.; Beck, H.; Lobell, M.; Li, V. M.; Greschat, S. WO2008141843A1,
2008.
22. Siu, T.; Yudin, A. K. Org. Lett. 2002, 4, 1839e1842.
23. Yadav, M. R.; Rit, R. K.; Sahoo, A. K. Chem.dEur. J. 2012, 18, 5541e5545 S5541/
1eS5541/164.
3.50e3.40 (1H, m), 3.30e3.24 (1H, m), 2.93e2.90 (2H, m), 2.25e1.91
(2H, m), 1.82e1.52 (2H, m), NHþ2 not observed; dC (100 MHz, D2O)
47.8, 47.0, 43.2, 40.0, 39.9, 29.6, 20.4; m/z MHþ¼177. HRMS (ESþ) for
C7H17N2OS (MHþ): calcd 177.1062; found 177.1058.
24. Luecking, U.; Siemeister, G.; Jautelat, R. WO2008025556A1, 2008.
25. Schmidbaur, H.; Kammel, G. Chem. Ber. 1971, 104, 3234e3240.
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P. Tetrahedron 1997, 53, 10983e10992.
Acknowledgements
The authors would like to Jamie Scott for providing advice
and discussion, Howard Beeley and Paul Davey for providing
27. Winkler, M.; Meischler, D.; Klempier, N. Adv. Synth. Catal. 2007, 349, 1475e1480.