Development of a Continuous Flow Sulfoxide Imidation Protocol Using Azide Sources under Superacidic Conditions

Article abstract of DOI:10.1021/acs.oprd.5b00217

The development of a continuous flow sulfoxide imidation protocol for a pharmaceutically relevant target molecule is described. Sulfoxide imidation is a key step in the preparation of certain ATR kinase inhibitors. Reactions with NaN₃ or TMSN₃ and concentrated sulfuric acid under literature conditions provided low conversions and poor selectivities. In contrast, reactions employing fuming sulfuric acid afforded the target sulfoximine with a selectivity of ～90% after a reaction time of only 10-15 min at 50 °C. The imidation reaction using TMSN₃ as reagent was successfully performed in a flow reactor utilizing CH₂Cl₂/H₂SO₄ biphasic conditions. The mixture was subsequently quenched in-line with H₂O. Phase separation, neutralization, and re-extraction with an organic solvent furnished the product in excellent purity and good yields, albeit with loss of chirality.

Full text of DOI:10.1021/acs.oprd.5b00217

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Technical Note
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Development of a Continuous Flow Sulfoxide Imidation Protocol
Using Azide Sources under Superacidic Conditions
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Bernhard Gutmann,† Petteri Elsner,‡ Anne O'KearneyꢀMcMullan,§ William Goundry,§
Dominique M. Roberge,*,‡ and C. Oliver Kappe*,†
† Institute of Chemistry, University of Graz, Heinrichstrasse 28, Aꢀ8010 Graz, Austria
‡ Microreactor Technology, Lonza AG, CHꢀ3930 Visp, Switzerland
§ AstraZeneca, Silk Road Business Park, Macclesfield SK10 2NA, United Kingdom
____________________
* Corresponding authors. Eꢀmail: dominique.roberge@lonza.com, oliver.kappe@uniꢀgraz.at
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Graphical contents entry:
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O
H2O
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TMSN3
N
O
N
0 °C
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O-
S+
N
50 °C
N
Cl
O-
S+
N
HN
fuming
H2SO4
N
Cl
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Abstract: The development of a continuous flow sulfoxide imidation protocol for a
pharmaceutically relevant target molecule is described. Sulfoxide imidation is a keyꢀstep in
the preparation of certain ATR kinase inhibitors. Reactions with NaN3 or TMSN3 and
concentrated sulfuric acid under literature conditions provided slow reactions and poor
selectivities. In contrast, reactions employing fuming sulfuric acid afforded the target
sulfoximine with a selectivity of ~90% after a reaction time of only 10 to 15 min at 50 °C.
The imidation reaction using TMSN3 as reagent was successfully performed in a flow reactor
utilizing CH2Cl2/H2SO4 biphasic conditions. The mixture was subsequently quenched inꢀline
with H2O. Phase separation, neutralization and reꢀextraction with an organic solvent furnished
the product in excellent purity and good yields, albeit with loss of chirality.
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Keywords: azide; continuous flow; sulfoximines, superacid
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INTRODUCTION
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Research on the chemistry and properties of sulfoximines was triggered by the identification
of methionine sulfoximine as the agent responsible for the toxicity of wheat flour treated with
nitrogen trichloride (agene).1,2 Nitrogen trichloride was used until the late 1940s for the
bleaching of flour (agene process) when it was discovered that diets rich in agenized flour
cause severe neurological disorders. Whitehead and Bentley accomplished the imidation of
methionine sulfoxide with hydrazoic acid (HN3) in the presence of concentrated sulfuric acid
and demonstrated that the product is identical with the toxic factor isolated from ageneꢀtreated
proteins.2 This was the first deliberate synthesis of a sulfoximine functionality and the interest
in sulfoximine chemistry has increased steadily since then.3ꢀ6 Sulfoximines contain an
amphoteric nitrogen and, with two nonꢀidentical carbon substituents on the sulfur atom, a
configurationally stable asymmetric sulfur moiety. Thus, the use of sulfoximines in
asymmetric synthesis as reagents, chiral auxiliaries or as chiral ligands has attracted
significant attention in recent years.4 Furthermore, a number of compounds containing a
sulfoximine structure have been explored in medical studies and several sulfoximines have
recently entered clinical trials.6 AstraZeneca is currently exploring sulfonylꢀmorpholinoꢀ
pyrimidines as inhibitors of kinases of the phosphatidylinositol 3ꢀkinase (PI3 K) family. In
particular, morpholinoꢀpyrimidines with a sulfoximine moiety have been investigated as
ataxia telangiectasia and Rad3ꢀrelated (ATR) protein kinase inhibitors (compounds 3 in
Scheme 1).7 Even though there is currently no clinical precedent for agents targeting ATR,
inhibition of ATR was proposed as a potentially effective approach to future cancer therapy.8
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Scheme 1. Preparation of Sulfoximine 2 by the HN3 Method
The shortest route for the synthesis of sulfoximines is given by a direct transfer of nitrogen
onto the corresponding sulfoxides.3,9 A variety of nitrene precursors are suitable for this
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transformation,
including
Oꢀsulfonylhydroxylamine
derivatives,
such
as
Oꢀ
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mesitylsulfonylhydroxylamine (MSH), or iminoiodane reagents, such as PhI=NR (R = tosyl,
trifluoroacetyl, etc.) in the presence of metals such as copper, rhodium, silver or iron.9 These
reagents allow the preparation of Nꢀprotected sulfoximines, and the reactions often can be
accomplished without racemization of a stereogenic sulfoxide and with retention of the
configuration upon imidation.9 However, subsequent deꢀprotection to produce the
synthetically attractive free sulfoximines can be difficult and is often accompanied by a
significant loss of material.10 The reaction of sulfoxides with HN3, as demonstrated in the
seminal work of Whitehead and Bentley in 1951, provides free sulfoximines directly and is
clearly more atom economic (HN3 method).2 This reaction is usually performed with sodium
azide and sulfuric acid in CHCl3 as solvent.2,3,11ꢀ13 The method is exceedingly successful for
the production of sulfoximines from sulfoxides if both carbon substituents are either methyl or
aryl. In contrast, reactions with sulfoxides with more labile substituents, such as nonꢀprimary
alkyl or benzyl groups, usually lead to heterolysis of the C–S bond under the strongly acidic
and polar conditions.3 Only a few successful transformations of benzylic sulfoxides to the
corresponding free sulfoximines by this method have been reported and the yields are often
modest.5b,12 Furthermore, reactions involving azides are generally associated with severe
safety concerns due to the toxicity and explosiveness of these reagents. In particular,
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hydrazoic acid is an exceedingly explosive and toxic compound
.
Despite their interesting chemical properties, their high chemical stability, profound
hydrogenꢀbond acceptor/donor capability, and appealing physicochemical properties,
sulfoximines are still severely underrepresented in organic synthesis as well as medicinal
chemistry. It was speculated that the severe hazards associated with most current syntheses
and the general inapplicability of these reactions for largeꢀscale production has deterred
chemists from a comprehensive exploitation of this valuable compound class.6 A continuous
flow procedure for the imidation of sulfoxides has the strong potential to significantly
increase the safety of these syntheses and make these compounds more accessible.14 Herein
we describe the development of a continuous flow protocol for the direct synthesis of
compound 2, the keyꢀintermediate in the synthesis of ATR kinase inhibitors of type 3, from
the sulfoxide 1 via the HN3 method under superacidic conditions (Scheme 1).
RESULTS AND DISCUSSION
Batch Experiments Employing NaN3 and H2SO4 in Polar Solvents. Initial optimization
experiments were performed with 0.2 mmol of the sulfoxide 1 in standard 1.5 mL HPLC
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vials. Since homogeneous reaction mixtures are highly preferable for continuous flow
processing, initial batch reactions were performed with aqueous solutions of NaN3 and water
miscible coꢀsolvents, such as MeCN, MeOH, dioxane, AcOH and NMP. For these reactions,
0.2 mmol of the substrate were weighted into 1.5 mL HPLC vials. The vials were equipped
with a stir bar and 0.4 mL of the respective solvent was added. 52 µL of a 4.4 M solution of
aqueous NaN3 (1.1 equiv) and 55 µL of conc H2SO4 (5 equivalents) were then added to the
reaction solution. The vials were closed and placed on a hot plate at 50 °C. Gaillard et al.
reported a reaction time of around 4 h for the sulfoximidation of methyl phenyl sulfoxide at a
reaction temperature of 50 °C using CHCl3 as solvent.11 However, sulfoxide 1 was fully
consumed after a reaction time of only 90 min (the first sample for HPLC analysis was taken
after 90 min). Methanethiol was formed in these reactions and the reaction mixtures quickly
developed a highly disagreeable odor. LCꢀMS analysis of the reaction mixture suggested that
the products formed in these reactions were exclusively derived from a Pummererꢀtype
rearrangement and no desired sulfoximine was produced. Similarly, reactions in the absence
of H2O in AcOH as solvent with various amounts of sulfuric acid provided exclusively
decomposition products (Table S1 in the Supporting Information).
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Batch Experiments Employing TMSN3 and Lewis Acids. Since the Pummerer
rearrangement is probably favored by highly polar reaction conditions, we performed
experiments using TMSN3 as reagent and various Lewis acids as catalysts in toluene as an
unpolar solvent. BF3ꢁOEt2, Yb(OTf)3, Cu(OTf)2 and ZnBr2 were investigated as catalysts (20
mol%). No reaction was observed under these conditions after a reaction time of 1 h at 50 °C.
A reaction with TMSN3 in MeOH as solvent (TMSN3 quickly hydrolyzes in MeOH to release
HN3), gave an unꢀidentified side product in a slow reaction (38% after 5 h at 50 °C). Again,
no desired product was formed in any of these reactions.
Batch Experiments Employing Concentrated H2SO4 in CHCl3 as Solvent. By far the most
common solvent for sulfoxide imidation reactions with HN3 is chloroform. Thus, further
reactions were performed in chloroform under the reaction conditions reported by Pandya et
al.12 In their publication the preparation of a benzylic sulfoximine in 65% yield was described.
The authors mixed the benzylic sulfoxide with NaN3 in CHCl3 as solvent at room
temperature. H2SO4 was then slowly added at a temperature of ꢀ20 to ꢀ25 °C under an Ar
atmosphere. The reaction mixture was then further stirred at room temperature for 12 h and
finally at 45 to 50 °C for 3 additional hours.
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Sulfuric acid is not soluble in CHCl3 and forms a separate, immiscible phase. In
contrast, sulfoxide 1 is soluble in CHCl3, but it is protonated by H2SO4 and slowly extracted
from the CHCl3 phase into the sulfuric acid phase. From the H2SO4 phase, the substrate partly
precipitates as a sticky precipitate. In fact, after stirring the reaction mixture for some time at
room temperature, analysis of the supernatant CHCl3 phase gave an essentially “empty”
HPLC trace, indicating that all of the starting material was either extracted into the H2SO4
phase or precipitated from the mixture. Following the protocol of Pandya et al., reactions with
a reaction time of 14 h at room temperature gave a conversion of 19% in the presence of 3
equivalents of NaN3. The selectivity for the product was ~53% for this reaction according to
HPLC analysis at 215 nm (Table 1; for further results see Table S2 in the Supporting
Information). Comparable results were obtained when the reagents were mixed directly at
room temperature and the subsequent experiments were performed at a reaction temperature
of 50 °C (both with NaN3 and TMSN3 as reagent). Interestingly, the decomposition of the
substrate in the absence of NaN3 was faster than the actual imidation reaction in the presence
of the azide (entry 2 and 4 in Table 1).
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Table 1. Reaction of 1 with NaN3/H2SO4 in CHCl3 at Room Temperaturea
azide
(equiv)
NaN3 (3)
ꢀ
NaN3 (3)
ꢀ
temp time conv
[°C] [h] [%] [%]
2
1
2b
rt
rt
14
14
1
19
60
30
89
10
0
3c
50
50
16
0
4b,c
1
a HPLC peak area at 215 nm. Conditions: sulfoxide 1 and NaN3 in CHCl3 were mixed with
H2SO4 (6 equivalents) at ꢀ20 °C and the mixture was then further heated at room temperature
b
(rt). An additional broad signal was apparent in the HPLC (for details see the Supporting
Information). c Substrate and reagent were mixed at room temperature.
Batch Experiments Employing Fuming H2SO4 in CHCl3 as Solvent. During our
investigations we observed that the selectivity of the reaction decreased when an older bottle
of concentrated sulfuric acid was used (Table S3 in the Supporting Information). We
hypothesized that the lower selectivity for reactions with an older sample of H2SO4 compared
to reactions with fresh H2SO4 is caused by a higher water content. Further experiments were
therefore performed with fuming H2SO4 (20% SO3 content). With fuming H2SO4, the reaction
worked extraordinarily well and product selectivities of up to 87% were attained after reaction
times of only ~30 min at 50 °C (see Table S4 in the Supporting Information). Unfortunately,
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the reaction formed a large amount of a sticky precipitate which deposited on the vessel wall
as well as on the stirꢀbar and rendered stirring difficult (Figure 1).
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Again, the reaction proceeded equally well using TMSN3 as reagent. Less precipitate was
formed with TMSN3 as reagent. In fact, essentially homogenous solutions were obtained in
solvents such as THF or anhydrous DME. However, no desired product was formed in these
solvents (see Table S4 in the Supporting Information).
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Figure 1. Reaction mixture after a reaction on a 0.4 mmol scale (3 equivalents of NaN3, 6
equivalents of fuming H2SO4).
Batch Experiments Employing other Bronsted Acids in CHCl3 as Solvent. For reactions
with different acids, sodium azide (3 equivalents) and the acid (6 equivalents) were mixed in
CHCl3 as solvent and the starting material was then added at room temperature (0.2 mmol).
The vessel was closed and heated to the desired temperature on a hot plate (Table 2). A large
amount of precipitate was formed with sulfuric acid. With the other acids, the reaction
mixture contained far less precipitate (probably the sodium salt of the respective acids). Only
using fuming H2SO4 the product was formed with good selectivity. Interestingly, even though
the pKa of MeSO3H and H2SO4 is very similar, no desired product was formed with this acid
(entry 2 in Table 2).
Using TMSN3 as reagent the reaction mixtures were essentially homogenous with all
tested acids except of H2SO4. However, reactions with none of these acids provided any
product. Instead, the main products formed in these transformations were again derived from
Pummererꢀtype rearrangements. The reaction with CF3SO3H led to a surprisingly slow
reaction considering its low pKa (entry 10 in Table 3).
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Table 2. Reaction of 1 with NaN3 or TMSN3 and Various Acids in CHCl3 at 50 °Ca
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azide
acid
pKa time conv
[min] [%] [%]
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1
2
3
4
5
6
7
8
9
NaN3
NaN3
NaN3
TFA
MeSO3H
H2SO4 (conc)
H2SO4 (fuming)
AcOH
TFA
MeSO3H
H2SO4 (conc)
H2SO4 (fuming)
CF3SO3H
ꢀ0.3
ꢀ2.6
ꢀ3
60
60
60
20
40
40
40
40
40
40
40
7
84
16
98
2
0
0
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NaN3
ꢀ3
75
0
0
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
4.8
ꢀ0.3
ꢀ2.6
ꢀ3
ꢀ3
ꢀ14
ꢀ
14
79
32
100
0
0
10
91
0
10
11
BF3ꢁOEt2
71
0
a
HPLC peak area at 215 nm. Conditions: sulfoxide 1 (0.2 mmol), NaN3 or TMSN3 (3
equivalents) and acid (6 equivalents) in CHCl3 were mixed at room temperature. The mixture
was then further heated to 50 °C.
The results presented above suggest that the sulfoximidation of 1 proceeds entirely in the
+
H2SO4 phase. Hydrazoic acid is partly protonated in concentrated H2SO4 to form a H2N3
species. Olah and coꢀworkers investigated the structure and properties of the aminodiazonium
ion, H2N3 , prepared by protonation of hydrazoic acid in superacids in detail.15,16 The
+
aminodiazonium ion is fairly unstable and decomposes rather quickly under liberation of N2.
+
Importantly, H2N3 is a strong electrophile and was shown to have the capacity to react with
aromatic compounds in an electrophilic amination.15,16
An aminodiazonium ion also might be the actual reagent for the sulfoximidation of
sulfoxides (see Figure S1 in the Supporting Information). However, product was formed only
in the presence of sulfuric acid and only the reaction with fuming sulfuric acid proceeded fast
and cleanly (Table 2). Thus, an alternative mechanism where the azide is activated by
intermediate formation of azido sulfonic acid or azido polysulfonic acid might be operating.17
Indeed, the reaction of alkali azides with gaseous SO3 was reported to give crystalline
products of the composition MN3·x SO3. Upon storage under concentrated sulfuric acid, the
azido polysulfonic acid forms a compound with the formula MS2O6N3 (M = Na, K).18
Reactions in Strong Acids as Solvent. Further reactions were performed in neat concentrated
H2SO4 as solvent. With NaN3 as reagent, the mixture is not homogenous, presumably because
of the formation of insoluble NaHSO4. On the other hand, the substrate slowly dissolves in a
mixture of H2SO4/TMSN3 to give homogenous reaction solutions. Reactions in concentrated
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H2SO4 as solvent provided far better results than reactions with concentrated sulfuric acid as
reagent using CHCl3 as solvent. Indeed, a product selectivity of 82% was obtained after a
reaction time of 40 min at 50 °C with a ~1.5 M solution of the substrate in conc H2SO4 (entry
3 in Table 3). However, as shown in Table 3, the selectivity decreases with increasing
amounts of conc sulfuric acid. Reactions in fuming sulfuric acid gave mostly decomposition
while reactions in CF3SO3H or MeSO3H gave no or only slow conversion (see Table S5 in the
Supporting Information).
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Table 3. Reaction of 1 with Different Azide Sources in H2SO4 (conc) as Solvent at a
Reaction Temperature of 50 °C (40 min Reaction Time)a
azide
H2SO4 conv
2
(µL)
262
524
131
262
524
[%] [%]
1
2
3
4
5
NaN3
NaN3
TMSN3
TMSN3
TMSN3
87
93
91
78
75
59
10
82
43
8
a HPLC peak area at 215 nm. Conditions: azide (3 equivs) in H2SO4 (conc) were mixed with
sulfoxide 1 (0.2 mmol) at room temperature. The mixture was then further heated to 50 °C.
Since the sulfoxide 1 dissolves slowly in concentrated sulfuric acid at room temperature (~20
min in an ultrasonic bath for ~1.5 M solutions), a continuous flow reaction with sulfoxide 1
dissolved in sulfuric acid in one feed and neat TMSN3 in a second feed appeared feasible.
However, preliminary experiments suggested that 1 slowly decomposes in conc H2SO4,
rendering this approach impractical (see Table S6 in the Supporting Information).
Reactions under Biphasic CHCl3/H2SO4 Conditions. As sulfoxide 1 decomposes in neat
sulfuric acid, a flow process under biphasic conditions was envisaged. Since the
sulfoximidation reaction proceeds entirely in the sulfuric acid phase, the sole purpose of the
inert organic phase for continuous flow reactions is to carry the reagents into the reactor
(Scheme 2). To simulate such a process in batch, we dissolved the starting material and
TMSN3 in CHCl3 and this mixture was then added in one shot to a well stirred solution of
fuming sulfuric acid. Two separated, homogeneous phases were obtained with ~14
equivalents of H2SO4 at 50 °C (i.e. 150 µL sulfuric acid, 0.2 mmol substrate in 500 µL of
CHCl3). The typical white, sticky precipitate was formed with lower amounts of H2SO4.
Separate analysis of the CHCl3 and the H2SO4 phase revealed that the sulfuric acid phase
contains the basic sulfoximine product 2, while the CHCl3 phase contains most of the side
products. As anticipated, the reaction worked equally well using CH2Cl2 as solvent. Again,
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the reaction was considerably faster and significantly cleaner with fuming sulfuric acid
compared to reactions with conc sulfuric acid. Indeed >99% conversion was obtained with
fuming sulfuric acid after a reaction time of only 10 min at 50 °C (Table S7 in the Supporting
Information).
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After a reaction on a 0.4 mmol scale (116 mg of sulfoxide 1), the mixture was diluted
with CHCl3/H2O and the phases were separated. The sulfuric acid phase was neutralized with
3 M NaOH and the free sulfoximine was finally extracted into CHCl3. This procedure
provided the desired product with excellent purity (99% according HPLC at 215 nm) in 89%
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1
yield as a clear oil which solidified to a white solid upon standing (see Figure S3 for the Hꢀ
NMR). Caution: the quench of fuming sulfuric acid with H2O is extremely exothermic and
must be done very carefully, even on this small scale, to maintain the temperature at an
acceptable value.
Flow Reactions. A flow reactor was assembled consisting of four syringe pumps (Syrris
Asia), a 10 mL tube reactor in a water bath (PFA, 1/8’’ o.d.; 1/16’’ i.d.; 5 m length), a 2 mL
tubing in an ice bath (PFA, 1/8’’ o.d.; 1/16’’ i.d.; 1 m length) and an adjustable back pressure
regulator (Vapourtec). All supply lines, fittings, Tꢀ and Xꢀpieces were made of
fluoropolymers (H2SO4 is not compatible with PEEK).
For the initial trials, the reaction mixture (feed A, 2 mmol substrate, 3 equivalents of
TMSN3 in 5 mL CH2Cl2) was pumped into the reactor at a flow rate of 750 µL/min, while
fuming sulfuric acid was pumped into the flow reactor at a flow rate of 250 µL/min. For the
inꢀline quench and extraction, feed C and feed D carried H2O and CH2Cl2 at flow rates of 3
and 1.5 mL/min, respectively. The back pressure was adjusted to 3 bar. Distinct
CH2Cl2/H2SO4 segments were formed at the entrance of the coil reactor. The sulfuric acid
phase became yellow as the segments moved through the reactor and large amounts of gas
were formed (N2). The gas pushed the reaction mixture out of the reactor and the residence
time was thus significantly shorter than the calculated 10 min. The reaction under these
conditions gave a conversion of 95% with a selectivity for the product comparable to that
obtained under batch conditions (~85%). Importantly, the temperature of the cross mixer and
the subsequent tubing, in which the highly exothermic quench of fuming H2SO4 was
performed, did not increase above about room temperature.
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Scheme 2. Flow Set-up for Reactions under Biphasic CH2Cl2/H2SO4 Conditions
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Subsequent reactions were performed at a back pressure of 7 bar. Furthermore the CH2Cl2
extraction feed (Feed D) was removed (see Figure S1 in the Supporting Information). Even at
a back pressure of 7 bar, the residence time was only 7 min due to the formation of large
amounts of gases and the reaction did not give complete conversion. To increase the residence
time, the flow rate was finally reduced to 375 µL/min for feed A (~0.12 mmol/min substrate)
and 125 µL for feed B. This gave a residence time of 14 min at a back pressure of 7 bar. A
reaction on a 4 mmol scale (1.16 g of sulfoxide 1) confirmed that the reaction provides full
conversion with a similar product selectivity as that obtained under batch conditions
(complete conversion, 87% selectivity). However, the selectivity in the “postꢀsteadyꢀstate”
stream decreased appreciably (see Table S8 in the Supporting Information). The middle
fractions were combined, the organic phase was separated, and the aqueous phase again
extracted with CH2Cl2. The aqueous phase was brought to pH >7 with 5 N NaOH and reꢀ
extracted with CH2Cl2. Drying of the organic phase and thorough evaporation of the solvent
provided 855 mg of an offꢀwhite powder (70%). The purity of the isolated product was 96%
according to HPLC (see Figure S2 in the Supporting Information).
To get “steadyꢀstate yields”, 3.48 g of sulfoxide 1 (12 mmol) and 4.8 mL of TMSN3
(36 mmol) were added into a graduated cylinder and filled with CH2Cl2 to 37.5 mL. The
reaction mixture was introduced into the flow reactor under the conditions described above.
The effluent mixture was directed to waste. After 20 min on stream, the processed mixture
was collected in a separatory funnel. The mixture was collected for 80 min in total and finally
workedꢀup as described above to provide 2.2 g of a white powder (77%) in a HPLC purity of
90%. In total, ca 6.4 g of sulfoxide 1 and 9 g of TMSN3 were processed in the flow reactor.
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Chiral analysis of the samples produced under continuous flow conditions revealed
that the chirality of (R)ꢀ1 had not been retained. It is well known that sulfoxides racemize
under strongly acidic conditions (for further details see the Supporting Information).19,20
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CONCLUSION
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In conclusion we have developed a continuous flow protocol for the imidation of a sulfoxide
under superacidic conditions. Reactions with concentrated sulfuric acid under literature
conditions gave a slow reaction and poor selectivity (10% product after 14 h at room
temperature). In contrast, reactions with fuming sulfuric acid afforded the sulfoximine with a
selectivity of ~90% after a reaction time of only 10 to 15 min at 50 °C. The imidation reaction
with TMSN3 as reagent was successfully performed in a flow reactor under biphasic
conditions. Dichloromethane was used to carry substrate and TMSN3 into the flow reactor.
The solution was then combined with fuming sulfuric acid at 50 °C. The substrate 1 is
protonated and extracted from the CH2Cl2 phase into the sulfuric acid phase, where it is
converted to the corresponding sulfoximine. The mixture was subsequently quenched inꢀline
with H2O. The organic phase contained mostly sideꢀproducts, whereas the aqueous phase
contained the protonated product. Phase separation, neutralization of the aqueous phase and
reꢀextraction with an organic solvent provided the product in excellent purity and good yields,
albeit with loss of chirality.
Interest in sulfoximine chemistry has increased steadily since their discovery in the
early 1950s,1,2 and first pharmaceuticals containing the sulfoximine moiety now enter Phase I
clinical trials.6 Nevertheless, sulfoximines are still severely underrepresented in organic
synthesis as well as medicinal chemistry. With the emergence of new, efficient, atomꢀ
economic and safe synthetic protocols for the synthesis of sulfoximines, these compounds are
expected to become increasingly appreciated and to play a significant role in the repertoire of
synthetic and medicinal chemists.
EXPERIMENTAL SECTION
1
General Remarks. H NMR spectra were recorded on a Bruker 300 MHz instrument.
Chemical shifts (δ
) are expressed in ppm downfield from TMS as internal standard. 13C NMR
spectra were recorded on the same instrument at 75 MHz. The letters s, d, t, q, and m are used
to indicate singlet, doublet, triplet, quadruplet, and multiplet, respectively. Analytical HPLCꢀ
UV (Shimadzu LC20) analysis was carried out on a C18 reversedꢀphase (RP) analytical
column (150 × 4.6 mm, particle size 5 ꢂm) at 37 °C using a mobile phase A
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(water/acetonitrile 90:10 (v/v) + 0.1 % TFA) and B (MeCN + 0.1 % TFA) at a flow rate of 1.5
mL/min. The following gradient was applied: linear increase from solution 5% B to 80 % B in
15 min. Lowꢀresolution mass spectra were obtained on a Shimadzu LCMSꢀQP2020
instrument using electrospray ionization (ESI) in positive or negative mode. All chemicals
were purchased from commercial sources and were used without further purification.
Caution: Sodium azide and TMSN3 release hydrazoic acid (HN3) in acidic media. Hydrazoic
acid is a volatile, highly toxic and explosive compound. Fuming sulfuric acid is capable of
causing very severe burns and reacts violently with water. Reactions with these reagents
should not be undertaken without proper safety precautions put in place.
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Batch Experiments. Sulfoxide 1 (116 mg; 0.4 mmol) and either NaN3 or TMSN3 (3
equivalents) were mixed in 1 mL of CHCl3 in a 5 mL Pyrex screw cap reaction vial equipped
with a magnetic stir bar. 300 µL of fuming sulfuric acid (20% SO3) were added to this
mixture under stirring at room temperature. The vessel was sealed with a PTFE seal and a
screw cap and placed on a hot plate at 50 °C. After 30 min the reaction vessel was removed
from the hot plate and cooled to room temperature. The reaction mixture was quenched with
H2O and extracted with CHCl3. The aqueous phase was neutralized with 5 M NaOH and
extracted again with CHCl3. Drying with MgSO4 and evaporation of the solvent provided 109
mg of the product 2 as a clear liquid which solidified to a white solid upon standing (89%).
((2ꢀChloroꢀ6ꢀ((R)ꢀ3ꢀmethylmorpholino)pyrimidinꢀ4ꢀyl)methyl)(imino)(methyl)ꢀλ6ꢀsulfanone
1
2: H NMR (300 MHz, CDCl3) δ 6.51 (s, 1H), 4.31 (br s, 1H), 4.26 (s, 2H), 4.04 (br s, 1H),
4.00 (dd,
3.53 (td,
J
= 11.5, 3.7 Hz, 1H), 3.78 (d,
J
= 11.6 Hz, 1H), 3.68 (dd,
J = 11.7, 3.0 Hz, 1H),
J
= 11.9, 2.9 Hz, 1H), 3.30 (td,
J = 12.9, 3.7 Hz, 1H), 3.11 (s, 3H), 2.89 (s, 1H), 1.33
(d,
J
= 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 162.86, 160.74, 158.89, 102.64, 70.63,
66.48, 64.90, 47.60, 42.62, 39.46, 14.01.m/z MS (pos. ESI): m/z = 305 and 307 (M+H+).
Flow Experiments. 3.48 g of sulfoxide 1 (12 mmol) and 4.8 mL of TMSN3 (36 mmol) were
added to a graduated cylinder and filled with CH2Cl2 to 37.5 mL (feed solution A). For the
flow reactions feed A first carried CH2Cl2, feed B carried water and the quench feed C carried
H2O (see Scheme 2). The flow rates for feed A, feed B and feed C were 375, 125 and 1500
µL/min. When a reaction was started, feed B was switched from water to concentrated
sulfuric acid. After concentrated sulfuric acid was pumped through the reactor for ~30 min,
the feed was switched to fuming sulfuric acid. This procedure avoided the direct contact of
fuming sulfuric acid with water. After pumping fuming H2SO4 for ~10 to 15 min, feed A was
switched from CH2Cl2 to the reagent solution. After the reagent solution was finished feed A
was switched back to pure CH2Cl2. The effluent mixture was directed to waste. 20 min after
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feed A was switched from CH2Cl2 to the reagent solution, the processed mixture was
collected in a separatory funnel. The mixture was collected for 80 min in total. The phases
were separated and the CH2Cl2 phase was discarded. The H2O phase was again extracted with
CH2Cl2, neutralized with 5 M NaOH and extracted with CH2Cl2. Drying with MgSO4 and
evaporation of the solvent provided 2.2 g of the product 2 as a a white powder (77%) in a
HPLC purity of 90%.
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ACKNOWLEDGEMENT
We acknowledge funding by NAWI Graz and the Christian Doppler Research Foundation
(CDG). We are grateful to Emma J. Williams and Jerome Dubiez (AstraZeneca, Macclesfield,
United Kingdom) for valuable comments.
Supporting Information
Further optimization data, detailed description of the continuous flow setꢀup, 1HꢀNMR of
product. This material is available free of charge via the Internet at http://pubs.acs.org.
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