Boric acid mediated N-acylation of sulfoximines

Article abstract of DOI:10.1055/s-0030-1259328

The N-acylation of a sulfoximine with carboxylic acids was accomplished with boric acid and several boronic acids. Aliphatic acids give fair yields of products while acids related to phenylacetic and phenoxyacetic acids perform much better. Aromatic acids are ineffective in this process. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1259328

LETTER
361
Boric Acid Mediated N-Acylation of Sulfoximines
Sulfoximine
A
cyla
s
tion winkumar Garimallaprabhakaran, Michael Harmata*
Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211, USA
Fax +1(573)8822754; E-mail: harmatam@missouri.edu
Received 4 November 2010
However, it was interesting to note that the using 0.6
equivalent of boric acid afforded the product in reasonable
yield and 0.8 equivalent of boric acid led to an excellent
yield of 3 (Table 1, entries 4 and 5). The mechanistic basis
for the jump in yield with amounts of boric acid greater
than 0.4 equivalent has not yet been investigated. Lower-
ing the temperature of the reaction led as expected to low-
er yields (Table 1, entry 6), while raising the temperature
had essentially no effect (Table 1, entry 7). When 0.8
equivalent of boric acid was used, higher temperatures
again had no effect on yield; the same was true for extend-
ed reaction times (Table 1, entries 8 and 9).
Abstract: The N-acylation of a sulfoximine with carboxylic acids
was accomplished with boric acid and several boronic acids. Ali-
phatic acids give fair yields of products while acids related to phe-
nylacetic and phenoxyacetic acids perform much better. Aromatic
acids are ineffective in this process.
Key words: sulfoximine, boric acid, boronic acid, amidation, acy-
lation
Our group is involved in understanding and exploring the
chemical properties of sulfoximines1 and their deriva-
tives, primarily in the context of the generation and study
of 2,1-benzothiazines2 containing this functional group,
but also more generally. We recently became interested in
the N-acylation of sulfoximines. While the N-acylation of
sulfoximines with acyl chlorides and active esters is
known,3 we became interested in a process that would
lead directly from carboxylic acids to the desired prod-
ucts, hopefully through a catalytic procedure that was
simple, inexpensive and environmentally friendly. We
were intrigued by reports of the N-acylation of amines us-
ing boric acid4 and various boronic acids5 and wondered
whether NH sulfoximines were sufficiently nucleophilic
to participate in such reactions. This letter reports our ac-
complishments in this area.
Table 1 Optimization of the Boric Acid Mediated Acylation of 1a
O
NH
S
OPh
O
B(OH)3, solvent
temp, time
N
S
Ph
Me
+
OPh
Ph
Me
HO
O
1
2
3
O
Entry B(OH)3 Solvent
Temp (°C) Time (h) Yield (%)
1
2
3
4
5
6
7
8
9
0.1
0.2
0.4
0.6
0.8
0.6
0.6
0.8
0.8
toluene
toluene
toluene
toluene
toluene
toluene
reflux
reflux
reflux
reflux
reflux
60
20
24
24
24
24
24
24
24
48
8
10
15
52
NH
80
Ph
S
O
1
Me
<10b
48
p-chlorotoluene reflux
Figure 1
xylene
reflux
reflux
76
toluene
79
Our starting material for the study of this process was S-
methyl-S-phenylsulfoximine (1), a material readily acces-
sible in both racemic and enantiomerically pure forms.6
To optimize the process, we studied the reaction of 1
(Figure 1) with phenoxyacetic acid (2). Catalyst, acid and
sulfoximine were heated together with concomitant azeo-
tropic removal of water. The results are shown in Table 1.
We used Tang’s work4d as a guide and thus began exam-
ining the reaction in refluxing toluene. Perhaps due to the
relatively low nucleophilicity of the nitrogen atom in 1,
we found that small amounts of boric acid were not effec-
tive in producing good yields of 3 (Table 1, entries 1–3).
a Reactions were run at concentrations of 0.32–0.34 M.
b Yield was based on analysis of a 1H NMR of the crude material.
With these initial results in hand we decided to study the
scope of this methodology. Various carboxylic acids were
thus reacted with racemic 1 under our best reaction condi-
tions (Table 1, entry 5). The results are summarized in
Table 2. Certain substituted acetic acids work very well
under the optimized conditions to yield the corresponding
N-acylated sulfoximines in high yield (Table 2, entries 1
and 2). The same is generally true of aryl acetic acids
(Table 2, entries 3–5). However, aromatic acids such as
benzoic acid did not undergo reaction at all. Not surpris-
ingly, unsaturated acids also failed, as did a-hydroxy ac-
ids such as mandelic acid, which probably formed
SYNLETT 2011, No. 3, pp 0361–0364
x
x.
x
x.
2
0
1
1
Advanced online publication: 19.01.2011
DOI: 10.1055/s-0030-1259328; Art ID: S08610ST
© Georg Thieme Verlag Stuttgart · New York

362
A. Garimallaprabhakaran, M. Harmata
LETTER
Table 2 Synthesis of N-Acylsulfoximines (continued)
heterocyclic boron species that are unreactive. While
chloroacetic and propionic acid gave reasonable yields of
N-acylated sulfoximines (Table 2, entries 6 and 7), the
yields of the N-acylated sulfoximine product derived from
longer chain acids or secondary and tertiary acids was
only fair to good and about 20–30% lower than those af-
forded by the best carboxylic acid participants in this
reaction (Table 2, entries 8–11).
O
B(OH)3 (0.8 equiv)
N
S
R
RCO2H
1, toluene, reflux
24 h, 0.34 M
Ph
Me
O
Entry Acid
Product
Yield (%)
48
O
O
Table 2 Synthesis of N-Acylsulfoximines
( )8
Me
N
S
8
O
( )
HO
Ph
8
B(OH)3 (0.8 equiv)
O
N
S
R
16
RCO2H
1, toluene, reflux
24 h, 0.34 M
17
Ph
Me
O
O
HO2C
N
S
Entry Acid
Product
Yield (%)
80
9
10
11
54
40
44
Ph
Me
O
O
18
OPh
O-2-Naph
Ph
O
19
N
S
1
2
3
4
5
6
7
OPh
O
Ph
Me
HO
HO2C
O
2
N
S
3
Ph
Me
O
20
O
O
21
N
S
85
75
69a
70
63
64
O-2-Naph
O
Ph
Me
HO
4
O
N
S
Ad
Me
CO2H
5
Ph
O
O
22
O
O
23
N
S
Ph
Ph
a The diastereomeric ratio (1:0.9) was determined by 1H NMR.
Ph
Me
HO
6
O
7
The mechanism for the acylation process presumably par-
allels that which has been proposed for the corresponding
amines. Boric acid forms an active acylating agent with
the carboxylic acid, which reacts with 1 to produce the
products observed (Scheme 1).7 However, the strange re-
lationship between yield and the amount of catalyst used
(Table 1) suggests that there may be other complications
of which we are not currently fully aware.
O
Ph
N
S
HO
Et
Ph
Me
Et
O
8
9
O
O
Ph
Ph
N
S
HO
Ph
Ph
Me
H
O
+
O
B–
H
O
Ph
O
O
+
B(OH)3
10
R
OH
11
R
OH
OH
O
O
O
O
Cl
N
S
N
R
1
Cl
HO
Ph
Me
Ph
S
Me
12
O
O
13
Scheme 1 Possible mechanism for the boric acid catalyzed acylati-
on of sulfoximine 1
O
N
S
HO
Ph
Me
Nevertheless, the process works reasonably well with cer-
tain acids. However, we were concerned by the need for
large amounts of boric acid in the process and we decided
to preliminarily explore the use of certain boronic acids as
catalysts.
14
O
15
Synlett 2011, No. 3, 361–364 © Thieme Stuttgart · New York

LETTER
Sulfoximine Acylation
363
Huang, C.; Chen, Y.; Zheng, P.; Gao, X.; Ying, W. Synlett
2008, 2051. (d) Harmata, M.; Rayanil, K.-O.; Gomes, M.
G.; Zheng, P.; Calkins, N. L.; Kim, S.-Y.; Fan, Y.; Bumbu,
V.; Lee, D. R.; Wacharasindhu, S.; Hong, X. Org. Lett. 2005,
7, 143. (e) Harmata, M.; Hong, X. Org. Lett. 2005, 7, 3581.
(f) Harmata, M.; Hong, X. J. Am. Chem. Soc. 2003, 125,
5754. (g) Harmata, M.; Pavri, N. Angew. Chem. Int. Ed.
1999, 38, 2419. (h) Harmata, M.; Claassen, R. J. III
Tetrahedron Lett. 1991, 32, 6497. (i) Harmata, M.
Thus, the reaction of 10 with 1 was examined under con-
ditions that give rather poor yields when boric acid was
used a catalyst as illustrated in Table 3 (entry 1). Phenyl-
boronic acid offered no improvement at the same catalyst
loading, but both 24 and 25 gave 11 in much improved
yield, with 25 functioning as the best catalyst at that (still
rather high) loading.5a Given that no dramatic improve-
ment was observed, we decided not to pursue this line of
investigation further.
Tetrahedron Lett. 1989, 30, 437.
(3) (a) Hwang, K. J.; Logusch, E. W. Tetrahedron Lett. 1987,
28, 4149. (b) Bolm, C.; Hackenberger, C. P. R.; Simic, O.;
Verrucci, M.; Müller, D.; Bienewald, F. Synthesis 2002,
879. (c) Bolm, C.; Müller, D.; Dalhoff, C.; Hackenberger,
C. P. R.; Weinhold, E. Bioorg. Med. Chem. Lett. 2003, 13,
3207. (d) Hackenberger, C. P. R.; Raabe, G.; Bolm, C.
Chem. Eur. J. 2004, 10, 2942. (e) Cho, G. Y.; Okamura, H.;
Bolm, C. J. Org. Chem. 2005, 70, 2346.
Table 3 Catalyst Variation is the Acylation of 1
O
O
NH
cat. (0.4 equiv)
Ph
Ph
N
S
Ph
S
O
1
Me
+
toluene, 0.32 M
115 °C, 24 h
HO
Ph
Me
Ph
Ph
10
O
11
(4) (a) Barajas, J. G. H.; Mendez, L. Y. V.; Kouznetsov, V. V.;
Stashenko, E. E. Synthesis 2008, 377. (b) Maki, T.;
Ishihara, K.; Yamamoto, H. Tetrahedron 2007, 63, 8645.
(c) Arnold, K.; Davies, B.; Giles, R. L.; Grosjean, C.; Smith,
G. E.; Whiting, A. Adv. Synth. Catal. 2006, 348, 813.
(d) Tang, P. Org. Synth. 2005, 81, 262. (e) Latta, R.;
Springsteen, G.; Wang, B. Synthesis 2001, 1611.
(5) (a) Zoubi, R. M.; Marion, O.; Hall, D. G. Angew. Chem. Int.
Ed. 2008, 47, 2876. (b) Ishihara, K.; Ohara, S.; Yamamoto,
H. Org. Synth. 2003, 79, 176.
(6) Brandt, J.; Gais, H.-J. Tetrahedron: Asymmetry 1997, 8, 909.
(7) Marcelli, T. Angew. Chem. Int. Ed. 2010, 49, 6840.
(8) Typical Procedure: A flame-dried, 50-mL single-neck
round-bottomed flask was equipped with a Dean–Stark trap
topped with a reflux condenser fitted with nitrogen inlet, and
a Teflon-coated magnetic stirring bar. The reaction vessel
was charged with racemic 1 (1 g, 6.45 mmol), carboxylic
acid (7.09 mmol, 1.1 equiv), boric acid (310 mg, 0.8 equiv,
5.12 mmol) and toluene (20 mL, 0.32 M). The apparatus
(save the condenser) was wrapped in aluminum foil to
prevent heat loss. The reaction mixture was heated at reflux
for 24 h, and H2O (ca. 0.1 mL) was collected in the Dean–
Stark trap. The remaining volume of toluene in the flask
was ca. 10 mL, corresponding to approximately 0.645 M
concentration of the reactants. The mixture was allowed to
cool at ambient temperature and worked up in one of two
ways.
Entry
Catalyst
Yield (%)
1
2
B(OH)3
15
13
PhB(OH)2
B(OH)2
3
4
35
45
N
24
25
B(OH)2
I
In conclusion, we have demonstrated that boric acid is ca-
pable of mediating the N-acylation of a sulfoximine in
good to high yield.8 Catalyst loading and activity are still
issues to be resolved, but the method is effective and can
be used in a mild process for selective N-acylation of sulf-
oximines.9,10
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
The reaction mass was dissolved in EtOAc (50 mL) and
washed with sat. NaHCO3 (3 × 50 mL) solution to remove
any unreacted carboxylic acid and boric acid present. The
collected organic layer was washed once with 3 N HCl (50
mL), followed by brine (50 mL). The organic layers were
collected, dried with MgSO4 and filtered and the solvent was
removed under vacuum. The crude product was pure in
many cases and did not need further purification.
In an alternative workup, the reaction mass was dissolved in
EtOAc (50 mL) and washed with brine (50 mL) and the
organic layer was dried with MgSO4 and filtered and the
solvent was removed under vacuum. The crude product was
purified by flash column chromatography using 20–40%
EtOAc–hexanes mixtures to afford pure product.
Acknowledgment
The authors thank the donors to the Harmata Research Fund
(Merck) and the National Science Foundation for support. Thanks
to Dr. Charles. L. Barnes for providing the X-ray crystallography
data. Thanks to Professor Dennis G. Hall (Alberta) for a gift of com-
pound 25.
References and Notes
(1) (a) Worch, C.; Mayer, A. C.; Bolm, C. Synthesis and Use of
Chiral Sulfoximines, In Organosulfur Chemistry in
(9) Data for selected compounds: Compound 3: crystalline
white solid; Rf 0.48 (40% EtOAc–hexanes); mp 94.5–98 °C;
yield: 80%. IR (KBr): 3313, 3056, 2943, 2916, 1667, 1488,
1205, 981, 830, 744 cm–1. 1H NMR (500 MHz, CDCl3): d =
7.86 (d, J = 7.5 Hz, 2 H), 7.66 (t, J = 7.5 Hz, 1 H), 7.54 (t,
J = 7.5 Hz, 2 H), 7.30 (t, J = 7.5 Hz, 2 H), 6.98–6.93 (m, 3
H), 4.67 (s, 2 H), 3.38 (s, 3 H). 13C NMR (125 MHz, CDCl3):
d = 177.3, 158.2, 138.2, 133.9, 129.6, 129.3, 127.0, 121.1,
Asymmetric Synthesis; Toru, T.; Bolm, C., Eds.; Wiley-
VCH: Weinheim, 2008, 209–229. (b) Okamura, H.; Bolm,
C. Chem. Lett. 2004, 33, 482. (c) Harmata, M. Chemtracts
2003, 16, 660. (d) Reggelin, M.; Zur, C. Synthesis 2000, 1.
(2) (a) Harmata, M.; Rayanil, K.-O.; Espejo, V. R.; Barnes, C.
L. J. Org. Chem. 2009, 74, 3214. (b) Harmata, M.; Cai, Z.;
Chen, Y. J. Org. Chem. 2009, 74, 5559. (c) Harmata, M.;
Synlett 2011, No. 3, 361–364 © Thieme Stuttgart · New York

364
A. Garimallaprabhakaran, M. Harmata
LETTER
140.0, 139.9, 138.5, 133.6, 129.4, 128.87, 128.86, 128.2,
114.6, 68.9, 44.0. HRMS: m/z [M + Na+] calcd for
C15H15NO3S: 312.0664; found: 312.0655. Compound 7:
white solid; Rf 0.48 (40% EtOAc–hexanes); mp 82.5–84 °C;
yield: 75%. IR (KBr): 3059, 3017, 2924, 1634, 1445, 1209,
974, 837, 743 cm–1. 1H NMR (500 MHz, CDCl3): d = 7.83
(d, J = 7.5 Hz, 2 H), 7.63 (t, J = 7.5 Hz, 1 H), 7.54 (t, J = 7.5
Hz, 2 H), 7.29–7.33 (m, 4 H), 7.23 (m, 1 H), 3.70 (s, 2 H),
3.28 (s, 3 H). 13C NMR (125 MHz, CDCl3): d = 180.2, 138.6,
135.8, 133.6, 129.5, 129.4, 128.2, 128.2, 127.0, 126.5, 57.8,
57.6, 47.0, 46.6. HRMS: m/z [M + Na+] calcd for
C15H15NO2S: 296.0716; found: 296.0713. Compound 11:
fluffy white solid; Rf 0.45 (40% EtOAc–hexanes); mp 131–
133 °C; yield: 70%. IR (KBr): 3026, 3037, 2926, 1649,
1445, 1165, 973, 837, 744 cm–1. 1H NMR (500 MHz,
CDCl3): d = 7.76 (d, J = 7.5 Hz, 2 H), 7.63 (t, J = 7.5 Hz, 1
H), 7.54 (t, J = 7.5 Hz, 2 H), 7.29–7.33 (m, 10 H), 5.12 (s, 1
H), 3.27 (s, 3 H). 13C NMR (125 MHz, CDCl3): d = 180.2,
127.0, 61.3, 43.9. HRMS: m/z [M + Na+] calcd for
C21H19NO2S: 372.1029; found: 372.1019. Compound 15:
white solid; Rf 0.38 (40% EtOAc–hexanes); mp 59–60.5 °C;
yield: 64%. IR (KBr): 3060, 3024, 2964, 2931, 1626, 1437,
1354, 1200, 979, 832, 743 cm–1. 1H NMR (500 MHz,
CDCl3): d = 7.97 (d, J = 7.5 Hz, 2 H), 7.68 (t, J = 7.5 Hz, 1
H), 7.58 (t, J = 7.5 Hz, 2 H), 3.34 (s, 3 H), 2.43 (q, J = 7.5
Hz, 2 H), 1.14 (t, J = 7.5 Hz, 3 H). 13C NMR (125 MHz,
CDCl3): d = 183.5, 138.9, 133.6, 129.5, 127.0, 44.1, 32.7,
9.6. HRMS: m/z [M + Na+] calcd for C10H13NO2S: 234.0559;
found: 234.0560.
(10) Crystallographic data for 3 (CCDC 794098), 5 (CCDC
794100), 13 (CDDC 794099) and 19 (CCDC 794097) may
be obtained from the Cambridge Crystallographic Data
Centre (www.ccdc.cam.ac.uk/data_request/cif or by E-mail
to data_request@ccdc.cam.ac.uk).
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