Synthesis of sulfoximines and sulfilimines with aryl and pyrazolylmethyl substituents

Article abstract of DOI:10.1002/adsc.200900729

Sulfoximines bearing pyrazolylmethyl and aryl substituents, which are relevant to the crop protection industry, and their corresponding sulfilimine intermediates, have been prepared from sulfide precursors by either iron-catalyzed nitrogen transfer reacti

Full text of DOI:10.1002/adsc.200900729

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DOI: 10.1002/adsc.200900729
Synthesis of Sulfoximines and Sulfilimines with Aryl and
Pyrazolylmethyl Substituents
Olga Garcꢀa MancheÇo,a,b Jonathan Dallimore,c Andrew Plant,c
and Carsten Bolma,*
a
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52056 Aachen, Germany
Fax : (+49)-241-809-2391; phone: (+49)-241-809-4675; e-mail: Carsten.Bolm@oc.rwth-aachen.de
New address: Westfꢁlische Wilhelms-Universitꢁt Mꢂnster, Institute of Organic Chemistry, Corrensstr. 40, 48149 Mꢂnster,
b
Germany
c
Syngenta, Jealottꢃs Hill International Research Centre, Bracknell, Berkshire RG42 6EY, United Kingdom
Received: October 21, 2009; Published online: February 5, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900729.
Abstract: Sulfoximines bearing pyrazolylmethyl and
aryl substituents, which are relevant to the crop
protection industry, and their corresponding sulfil-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
Figure 1) are of particular interest to the crop protec-
tion industry.[3]
Herein, we report the development of two synthetic
approaches towards sulfoximines with such substitu-
tion patterns.
transfer reactions or metal-free imination proce-
dures. Whereas the former approach leads to N-
nosyl-substituted products, the latter affords N-
cyano derivatives.
Initially, two routes were envisaged for the prepara-
tion of aryl pyrazolylmethyl sulfoximines 2 and 3
(Scheme 1): firstly, a straightforward iron-catalyzed
imination of sulfoxides 1 which was recently devel-
oped within our laboratories [route A, to give 2 (X=
SO2R)][6–8] and, secondly, a metal-free approach em-
ploying an NBS-mediated sulfur imination of sulfides
4 with cyanogen amine followed by oxidation of the
resulting aryl pyrazolylmethyl sulfilimines 5 [route B,
to give 3 (X=CN)].[9,10]
Keywords: heterocycles; imination; iron catalysis;
metal-free conditions; sulfoximines
For both approaches sulfides 4 were the key inter-
Sulfoximines have been widely used as building mediates. Their synthesis began with condensation of
blocks for the synthesis of chiral ligands[1] and pseu- methylhydrazine (6) with a range of b-keto esters 7a–
dopeptides,[2] and they are of increasing interest due
to their potential as bioactive molecules.[3,4] Although
a number of synthetic approaches for the preparation
of sulfoximines have been described,[5] the synthesis
of derivatives with heteroaryl and, in particular, aryl-
methyl substituents remains highly challenging. Sulf-
ACHTUNGTRENNUNG
Scheme 1. Approaches towards aryl pyrazolylmethyl sulfox-
ACHTUNGTRENiNUNG mines 2 and 3.
Figure 1. Examples of sulfoximines in crop protection.
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Scheme 3. Imination of aryl pyrazolylmethyl sulfoxides 1a
and 1b under catalysis with FeACTHNURTGNENG(U OTf)2.
iron-catalyzed sulfur iminations, a reaction sequence
starting with imination of sulfides 4 was considered.
Subsequent oxidation of the resulting sulfilimines 11
would then provide sulfoximines 2.
Taking into account the previous observations, the
imination of methoxy-substituited sulfide 4b was ex-
pected to be most challenging and thus, this substrate
was chosen for a brief catalyst optimization study
Scheme 2. Synthesis of aryl pyrazolylmethyl sulfides 4.
d (Scheme 2). Subsequent Vilsmeier–Haack chloro- (Table 1, entries 1–3). Pleasingly, imination with
[12]
[6c]
formylation led to aldehydes 8a–d. Reduction led to either Fe
G
or Fe
G
gave the desired
the corresponding hydroxymethylpyrazoles 9a–d. Al- sulfilimine 11b, in moderate yield after only 0.5 h (51
ternatively, treatment of aldehyde 8a with a solution and 71% yields, respectively) albeit with small
of KOH in methanol at elevated temperature gave amounts of by-product 10. Use of less active catalysts
[6a]
the 5-methoxy derivative 9e following reduction.[11] such as Fe
G
led to longer reactions times
Sulfides 4 were finally obtained by treatment of 9a–e (16 h), resulting in poorer yields and greater quanti-
with various aromatic and heteroaromatic disulfides ties of 10.
in the presence of an excess of (n-Bu)3P in pyridine at
ambient temperature (in yields ranging from 57 to
92%).
As in the sulfoxide imination, changing the 5-meth-
AHCTUNGTRENNUNG
to a more efficient transformation, and sulfilimine 11a
Previous studies within our laboratories identified was obtained from sulfide 4a in 92% yield (Scheme 4,
Fe(OTf)2 as a highly efficient catalyst, when used in Table 1, entry 4). Formation of the corresponding sul-
ACHTUNGTRENNUNG
conjunction with PhI=NNs, for sulfur imination reac- fonamide was not observed. A methoxy substituent in
tions.[6c] Application of this methodology to the direct the ortho position of the aryl group inhibited the
synthesis of the aryl pyrazolylmethyl sulfoximines 2 iron-catalyzed imination as revealed by the attempted
from sulfoxides 1 (prepared by oxidation of sulfides 4 conversion of sulfide 4c, which led only to the decom-
with m-CPBA) was initially investigated (route A, position of starting material (Table 1, entry 5). In con-
Scheme 1). Indeed, when the established imination trast, when the methoxy group was located in the
conditions [15 mol% FeACHTNUGRTENUNG(OTf)2, 0.5 h] were applied to para position of the phenyl ring, as in sulfide 4d, the
compound 1a, the imination proceeded well, affording corresponding sulfilimine 11d was obtained in 54%
exclusively the corresponding sulfoximine 2a in 67% yield (Table 1, entry 6).
yield. However, in the case of sulfoxide 1b, the de-
Unfortunately, a brief investigation into the oxida-
sired product 2b was not formed, instead sulfonamide tion of sulfilimines 11 with peracids did not yield the
10, resulting from substitution at the activated methyl- desired sulfoximines. Thus, subsequent efforts were
ene, was obtained in 40% yield (Scheme 3). We sus- focused on route B (Scheme 1) taking into account
pected that the electron-donating methoxy substituent that heterocyclic sulfoximines bearing a cyano group
at the 5 position of pyrazole 1b was responsible for at the sulfoximine nitrogen are of particular biological
this undesired reaction path.
relevance to the crop protection industry. As a
Since our previous studies revealed that sulfides method for the synthesis of N-cyano sulfilimines 5,
were more reactive than sulfoxides with respect to the recently introduced metal-free sulfide imination
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Synthesis of Sulfoximines and Sulfilimines
Table 1. Iron-catalyzed iminations of sulfides 4a–d to give the corresponding sulfilimines 11a–d.[a]
Entry
4
Fe(L)n
T [h]
Expected Product
Yield of 11 [%][b]
Yield of 10 [%][b]
1
2
3
Fe
Fe
Fe
U
0.5
0.5
16
71
51
7
8
17
59
4b
4
5
4a
4c
Fe
Fe
U
0.5
0.5
92
[c]
–
6
4d
Fe
(OTf)2
0.5
54
[a]
Reaction conditions: Sulfide 4 (1 equiv.), iron salt (15 mol%), PhI=NNs (1.3 equiv.) and 4 ꢆ MS in MeCN (0.1M) at
room temperature.
After column chromatography.
[b]
[c]
Decomposition of the starting material and formation of a complex reaction mixture.
with cyanogen amine mediated by NBS was consider- served, presumably due to the reduced nucleophilicity
ed.[9a] A slight variation of this protocol, employing of sulfur in these sulfides (Table 2, entries 8 and 9).
preformed NCNHNa in methanol at room tempera- The metal-free imination with PhIACHTNUTGRNEUNG(OAc)2 and
ture, was successful and various sulfilimines with N- NCNH2 was also evaluated, but did not represent a
cyano substituents were prepared accordingly. Al- valuable alternative, with product yields generally
though this protocol failed to give the desired product being lower (58–76%; Table 2, entries 1, 3, and 4, re-
with 5-methoxypyrazolyl derivative 4b (Table 2, sults given in parentheses) compared to those ob-
entry 2), it worked well with substrates bearing a tained using the standard NBS/NCNHNa protocol.
chloro group at that position (entries 1, 3–7).
Next, the oxidation of the N-cyano sulfilimines 5 to
Using the NBS/NCNHNa method 5-chloropyrazol- the corresponding sulfoximines 3 was studied. Sulfili-
yl derivatives 4a, c–g with a variety of substituents at mine 5a was chosen as a model substrate and various
the 3-position of the pyrazole ring and/or various aryl oxidation systems were assessed. Notably, H2O2/
groups at the sulfur could efficiently be iminated AcOH (at 08C) and Oxoneꢅ/wet-Al2O3/CH2Cl2 (at
under metal-free conditions. Generally, the yields of 608C) led to decomposition of the sulfilimine. En-
the resulting N-cyano sulfilimines 5 were high (82– couragingly, use of m-CPBA/NaHCO3 in EtOH at
93%). In the cases of 4h and 4i no reaction was ob- room temperature provided the desired sulfoximine,
albeit in 40% yield due to partial conversion of the
starting material. Furthermore, when the oxidation
was performed with KMnO4 in wet acetone,[13] a clean
reaction occurred that afforded sulfoximine 3a in
good yield (Table 3, entries 1 and 2). Similarly, sulfil-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
(58–98%, entries 3–7) under the same conditions.
Although with the preparation of sulfoximines 3
the inital goal of the study was reached, attempts to
Scheme 4. Iron-catalyzed iminations of sulfides 4.
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Table 2. NBS-mediated iminations of sulfides 4 to give N-cyano sulfilimines 5.[a]
Entry
1
R1
R2
Cl
Ar
Ph
5
Yield [%][b]
83 (58)[c]
Me
[d]
2
3
Me
Me
MeO
Cl
Ph
–
2-MeOC6H4
93 (76)[c]
86 (68)[c]
4
Me
Cl
4-MeOC6H4
5
6
CF3
Ph
Cl
Cl
Ph
Ph
85[e]
83[e]
7
8
4-MeOC6H4
Cl
Ph
82[e]
[f]
Me
Me
Cl
Cl
2-Pyr[g]
–
[f]
9
2-Bzth[g]
–
[a]
Reaction conditions: Sulfide 4 (1 equiv.), NBS (1.5 equiv.) and NCNHNa (1.4 equiv.) in methanol (0.1M) at room temper-
ature.
[b]
[c]
[d]
[e]
After column chromatography.
Yields obtained upon imination with PhI
Decomposition occurred.
ACHTUGNRTEN(NUGN OAc)2 (1.2 equiv.) and NCNH2 (2.0 equiv.) in acetonitrile at room temperature.
Purification after 5 min reaction time. With prolonged reaction times partial or total decomposition of the product was
observed.
[f]
No reaction was observed and the corresponding sulfides could be recovered in 80–90% yield.
Pyr=pyrimidine, Bzth=benzothiazole.
[g]
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Synthesis of Sulfoximines and Sulfilimines
Table 3. Oxidation of N-cyano sulfilimines 5 to give sulfoximines 3.[a]
Entry
5
R1
Ar
3
Yield [%][b]
1
5a
5a
5c
5d
5e
5f
5g
Me
Me
Me
Me
CF3
Ph
4-MeOC6H4
Ph
Ph
3a
3a
3c
3d
3e
3f
3g
77
64
65
98
71
84
58
2[c]
3
2-MeOC6H4
4-MeOC6H4
Ph
Ph
Ph
4
5
6
7
[a]
Reaction conditions: Sulfilimine 5, KMnO4 (2 equiv.) in acetone (0.1M) at 508C in a sealed tube.
After column chromatography.
Reaction at 608C.
[b]
[c]
cleave the N-cyano group were initiated in order to
expand the product scope further. Treatment of sulf-
ACHTUNGTRENNUNGoximine 3a with TFAA followed by methanolysis
(K2CO3/MeOH)[9a] was unsuccessful, leading to rapid
decomposition of the starting material. The direct hy-
drolysis of the cyano group under aqueous acidic con-
ditions[14] was first explored using N-cyanomethyl
phenyl sulfoximine 12 as
(Scheme 5). Upon treatment of 12 with 1 N aqueous
HCl in dioxane at 1208C in a sealed tube, the NH-
a
model substrate
Figure 2. Products obtained in attempted hydrolyses of sul-
foximines 3.
sulfoxACHTUNGTRENNUNGimine 13 was obtained in 85% yield. When the
reaction was carried out in MeOH, the corresponding
In conclusion, starting from the corresponding sulf-
urea-type product 14 was isolated as the major prod- oxides and sulfides, aryl pyrazolylmethyl-substituted
uct (83%). Both longer reaction times in MeOH and sulfoximines and sulfilimines have been prepared.
post-treatment of 14 (16–18 h) with 1 N aqueous HCl Either iron-catalyzed or NBS-mediated nitrogen
in dioxane led to the NH-sulfoximine 13.
transfer reactions were applied to achieve the re-
On the basis of these results, the hydrolysis of the quired sulfur iminations. Smooth oxidation of the
N-cyano group of aryl pyrazolylmethyl sulfoximines 3 readily synthesized N-cyano sulfilimines with KMnO4
at 1008C in a 1:1 mixture of 1 N aqueous HCl and di- in acetone provided the corresponding sulfoximines in
oxane was attempted. However, instead of the expect- good yields. An exceptionally high dependence of the
À
ed N C-bond cleavage, two alternate reaction path- reactivity and stability of the aryl pyrazolylmethyl de-
ways were observed. Thus, 3-methyl pyrazolylmethyl rivatives on the substitution pattern at the pyrazole
sulfoximines 3a, c, d led to the corresponding sulfones ring and the aryl group at sulfur was observed. Thus,
15a, c, d in 68–79% yields,[15] and alcohols 9b–d were some standard reactions within sulfoximine chemistry,
obtained as the major products from 3-substituted de- such as the transformation of the N-cyano sulfox-
rivatives 3e–g (Figure 2).
ACHTUNGTRENiNGNU mines into their corresponding NH-derivatives under
acidic hydrolysis conditions provided unexpected
products.[16]
Experimental Section
General Procedure for the Fe
Imination Reaction[6a–c]
ACHTUNGRTEN(NUNG OTf)2-Catalyzed Sulfur
A
mixture of 1 or 4 (0.20 mmol), FeACHTUGNRTEN(NUGN OTf)2 (11 mg,
Scheme 5. Cleavage of the N-cyano group under aqueous
acidic conditions.
0.03 mmol), 4 ꢆ MS (0.4 gmmolÀ1), and PhI=NNs (105 mg,
0.26 mmol) in CH3CN (2 mL) was stirred at room tempera-
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ture for 10–60 min. Once the starting material was con-
sumed (monitored by TLC), the reaction mixture was con-
centrated to half its volume under reduced pressure. The
residue was purified by flash column chromatography.
Chromatography: gradient of ethyl acetate/pentane 1:1 to
ethyl acetate; mp 128–1298C; H NMR (300 MHz, CDCl3):
1
d=7.75–7.67 (m, 3H), 7.58–7.50 (m, 2H), 4.44 and 4.33 (AB
system, J=14.8 Hz, 2H), 3.64 (s, 3H), 1.93 (s, 3H);
13C NMR (75 MHz, CDCl3): d=149.2 (C), 135.6 (CH), 133.5
(C), 130.0 (CH), 129.6 (C), 129.3 (CH), 111.9 (CN), 101.3
(C), 53.6 (CH2), 36.4 (CH3), 12.2 (CH3); MS (EI): m/z (rela-
tive intensity)=310 [M+ (37Cl), 0.3], 308 [M+ (35Cl), 1], 145
[33], 143 [100], 125 [8]; anal. calcd. for C13H13ClN4OS: C
50.57, H 4.24, N 18.14; found: C 50.56, H 4.21, N 18.24.
N-(4-Nitrobenzenesulfonyl)
(5-chloro-1,3-dimethyl-1H-
pyrazol-4-yl)methyl phenyl sulfoximine (2a): Following the
general method, the imination reaction of sulfoxide 1a
(54 mg, 0.20 mmol) with PhI=NNs in the presence of
FeACHTUNGTRENNUNG(OTf)2 gave 2a as a white solid; yield: 63 mg (67%).
Chromatography: gradient of ethyl acetate/pentane 1:2 to
1
1:1; mp 120–1218C (decomp.); H NMR (300 MHz, CDCl3):
General Procedure for the Hydrolysis with HCl[14]
d=8.23 (d, J=8.9 Hz, 2H), 8.10 (d, J=8.9 Hz, 2H), 7.70 (d,
J=8.0 Hz, 2H), 7.65 (t, J=8.0 Hz, 1H), 7.48 (t, J=8.0 Hz,
2H), 4.82 and 4.36 (AB system, J=14.8 Hz, 2H), 3.61 (s,
3H), 1.90 (s, 3H); 13C NMR (75 MHz, CDCl3): d=149.7
(C), 149.3 (C), 149.2 (2C), 135.0 (CH), 134.8 (C), 129.6
(CH), 128.9 (CH), 128.1 (CH), 124.0 (CH), 101.9 (C), 55.3
(CH2), 36.4 (CH3), 12.2 (CH3); MS (EI): m/z (relative inten-
sity)=343 [(MÀPhÀSO)+, 3], 282 [(MÀNs)+, 1], 186 [3],
143 [100]; HR-MS (ESI+): m/z=491.0202, calcd. for
C18H17ClN4O5S2·Na: 491.0221.
To a stirred solution of sulfoximine 3 or 12 (0.3 mmol) in
1,4-dioxane or MeOH (1.5 mL) at room temperature, was
added 1 N HCl (1.5 mL). The mixture was heated to 1008C
or 1208C in a sealed tube and allowed to react until the
starting material was consumed (monitored by TLC). The
mixture was extracted with CH2Cl2, and the combined or-
ganic layers were dried over anhydrous MgSO4, filtered and
evaporated. The residue was purified by flash column chro-
matography.
N-Aminoformyl methyl phenyl sulfoximine (14): Follow-
ing the general procedure, the reaction of sulfoximine 12
(180 mg, 1.0 mmol) with 1 N aqueous HCl in MeOH at
1208C gave 14 as a white solid; yield: 164 mg (83%). Chro-
matography: ethyl acetate; mp 194–1958C; 1H NMR
(400 MHz, CD3OD): d=7.97 (br d, J=7.5 Hz, 2H), 7.69 (tt,
J=7.5, 1.4 Hz, 1H), 7.62 (br t, J=7.5 Hz, 2H), 4.83 (s, 3H),
3.30 (s, 2H); 13C NMR (100 MHz, CD3OD): d=163.4 (C=
O), 139.5 (C), 133.2 (CH), 129.1 (CH), 127.1 (CH), 43.4
(CH3); MS (EI): m/z (relative intensity)=199 [(M+H)+, 6],
183 [100], 182 [27], 77 [24]; HR-MS (EI): m/z=183.0232,
calcd. for C8H10N2O2S-CH3 (C7H7N2O2S): 183.0228.
General Procedure for the Imination of Sulfides with
NBS/NCNHNa[9a]
To
a solution of sulfide 4 (1.0 mmol) and NCNHNa
(105 mg, ca. 85%, 1.4 mmol) in MeOH (8 mL) at room tem-
perature, was added NBS (267 mg, 1.5 mmol). Once the
starting material was consumed (monitored by TLC), the re-
action mixture was concentrated under reduced pressure, sa-
turated aqueous Na2S2O3 was added and the mixture ex-
tracted with CH2Cl2. The organic layer was dried over anhy-
drous MgSO4, filtered and evaporated. The residue was pu-
rified by flash column chromatography.
N-Cyano (5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)methyl
phenyl sulfilimine (5a): Following the imination method, the
reaction of sulfide 4a (253 mg, 1.0 mmol) with NCNHNa
and NBS gave 5a as a white solid; yield: 244 mg (83%).
Chromatography: gradient of ethyl acetate/pentane 1:1 to
ethyl acetate; mp 116–1178C (decomp.); 1H NMR
(400 MHz, CDCl3): d=7.61–7.54 (m, 3H), 7.51–7.45 (m,
2H), 4.24 and 4.07 (AB system, J=13.5 Hz, 2H), 3.68 (s,
3H), 1.91 (s, 3H); 13C NMR (100 MHz, CDCl3): d=148.7
(C), 133.8 (C), 133.3 (CH), 130.0 (CH), 129.0 (C), 126.6
(CH), 120.9 (C), 102.9 (C), 49.4 (CH2), 36.5 (CH3), 12.3
(CH3); MS (EI): m/z (relative intensity)=294 [M+ (37Cl),
0.2], 292 [M+ (35Cl), 0.5], 145 [34], 143 [100], 109 [12]; HR-
MS (ESI+): m/z=315.0429, calcd. for C13H13ClN4S·Na:
315.0442; anal. calcd. for C13H13ClN4S·1/3H2O: C 52.26, H
4.61, N 18.75; found: C 52.02, H 4.55, N 18.60.
(5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)methyl
phenyl
sulfone (15a): Following the general procedure, the reaction
of sulfoximine 3a (100 mg, 0.32 mmol) with 1 N aqueous
HCl in 1,4-dioxane at 1008C in a sealed tube gave 15a as a
white solid; yield: 64 mg (70%). Chromatography: ethyl ace-
tate/pentane 1:1; mp 129–1308C; 1H NMR (400 MHz,
CDCl3): d=7.67 (br d, J=7.5 Hz, 2H), 7.58 (br t, J=7.5 Hz,
1H), 7.44 (br t, J=7.5 Hz, 2H), 4.06 (s, 2H), 3.65 (s, 3H),
1.94 (s, 3H); 13C NMR (100 MHz, CDCl3): d=148.6 (C),
137.9 (C), 133.9 (CH + C), 129.1 (CH), 128.7 (CH), 103.8
(C), 52.3 (CH2), 36.3 (CH3), 12.3 (CH3); MS (EI): m/z (rela-
tive intensity)=286 [M+ (37Cl), 0.3], 284 [M+ (35Cl), 1], 145
[33], 143 [100]; HR-MS (ESI+): m/z=285.0464, calcd. for
C12H13ClN2O2S·H (C12H14ClN2O2S): 285.0459; anal. calcd.
for C12H13ClN2O2S: C 50.61, H 4.60, N 9.84; found: C 50.84,
H 4.64, N 9.66.
[13]
General Procedure for the Oxidation with KMnO4
To a mixture of sulfilimine 5 (0.5 mmol) and KMnO4
(158 mg, 1.0 mmol) in acetone (5 mL) was heated at 508C in
a sealed tube. Once the starting material was consumed
(monitored by TLC), the solvent was removed under re-
duced pressure and the resulting residue purified by flash
column chromatography.
Acknowledgements
This work was supported by the Fonds der Chemischen In-
dustrie and Syngenta. We are grateful to Syngenta for a post-
doctoral fellowship to O.G.M., and to Dr. I. Atodiresei for
help in collecting the analytical data.
N-Cyano (5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)methyl
phenyl sulfoximine (3a): Following the general procedure,
the reaction of sulfilimine 5a (147 mg, 0.5 mmol) with
KMnO4 gave 3a as a white solid; yield: 119 mg (77%).
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Synthesis of Sulfoximines and Sulfilimines
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Adv. Synth. Catal. 2010, 352, 309 – 316