Parallel synthesis of structurally diverse aminobenzimidazole tethered sultams and benzothiazepinones

Article abstract of DOI:10.1016/j.tetlet.2012.09.135

A solid-phase methodology to construct aminobenzimidazole tethered sultams and benzothiazepinones from commercial amino acids, amines, carboxylic acids, and sulfonyl chlorides is described. Coupling of Fmoc-Cys(Trt)-OH to resin-bound aminobenzimidazole scaffold provided an essential precursor for the construction of a variety of seven membered benzofused cyclic sulfonamides and thiazepinones via palladium catalyzed Buchwald-Hartwig type intramolecular cyclization.

Full text of DOI:10.1016/j.tetlet.2012.09.135

Tetrahedron Letters 53 (2012) 6897–6900
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Parallel synthesis of structurally diverse aminobenzimidazole tethered sultams
and benzothiazepinones
Sureshbabu Dadiboyena a, Adel Nefzi a,b,
⇑
a Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA
b Florida Atlantic University, Boca Raton, FL 33431, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A solid-phase methodology to construct aminobenzimidazole tethered sultams and benzothiazepinones
from commercial amino acids, amines, carboxylic acids, and sulfonyl chlorides is described. Coupling of
Fmoc-Cys(Trt)-OH to resin-bound aminobenzimidazole scaffold provided an essential precursor for the
construction of a variety of seven membered benzofused cyclic sulfonamides and thiazepinones via pal-
ladium catalyzed Buchwald–Hartwig type intramolecular cyclization.
Received 18 September 2012
Revised 26 September 2012
Accepted 30 September 2012
Available online 17 October 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Solid-phase synthesis
Aminobenzimidazoles
Sultams
Cyclic sulfonamides
Benthiazepinones
Intramolecular cyclization
Heterocycles
Introduction
Our retrosynthetic rationale for the synthesis of aminobenzimidaz-
ole derived cyclic sulfonamides is illustrated in Scheme 1. We envi-
Solid phase organic synthesis (SPOS) is a valuable tool for the
expedited parallel synthesis of structurally diverse compounds of
drug discovery interest.1–7 Continuing with our long standing
interest in the development of heterocyclic libraries utilizing re-
sin-bound peptidyl-,5–7 and heterocyclic scaffolds7–9 as starting
materials, we describe an efficient methodology for the parallel
synthesis of structurally diverse aminobenzimidazole tethered sul-
tams and benzothiazepinones. Sultams or cyclic sulfonamides are
useful structural motifs in heterocyclic synthesis,4 applied as chiral
auxiliaries in asymmetric synthesis,10 and are actively sought in
the areas of antimalarial,11 antiviral,12 anticancer,13 antimicro-
bial,14 and antileukemic research.15,16 Likewise, aminobenzimidaz-
ole is a recurring template in the design and for the development of
combinatorial libraries of drugs and drug-like molecules.17,18
We previously reported the application of resin-bound amino-
benzimidazoles as a template for the synthesis of a variety of fused
and/or tethered heterocyclic compounds such as tetracyclic benz-
imidazoles,8b triazino-benzimidazoles,8c branched thiohydantoin
benzimidazolinethiones,9 and aminobenzimidazole tethered hyd-
antoins, thiohydantoins,19 and thiazoles.20 In this Letter, we extend
the application of this practical methodology toward the synthesis
of aminobenzimidazole tethered sultams and benzothiazepinones.
sioned the construction of benzofused cyclic sulfonamides 1 from
the resin-bound free amine 2 via palladium catalyzed cyclization.21
The parallel synthesis of the desired sulfonamides was pursued
using the tea-bag approach, wherein the resin is packed within
sealed polypropylene mesh packets.22 The synthesis of diversified
resin-bound aminobenzimidazoles 3 via nucleophilic substitution
of 4-fluoro-3-nitrobenzoic acid was carried out according to the lit-
erature precendents.8b,c,9,19,20 The resin-bound aminobenzimidaz-
ole was later coupled to Fmoc-Cys(Trt)-OH 4 in the presence of
PyBOP. Following Fmoc deprotection, the generated free amine
219,20 was treated with 2-bromoarylsulfonyl chlorides to furnish
the intermediate sulfonamides which, upon trityl group deprotec-
tion generated a thiol 5. The treatment of resin-bound sulfona-
mides in the presence of Cs2CO3 and palladium led the following
intramolecular cyclization in a Buchwald–Hartwig fashion to the
resin-bound sultams 6.7,23,24 Additional third position of diversity
(R3) was introduced by the treatment of sultams with several aryl
and alkyl halides 7 (Scheme 2). Following cleavage of the resin
with anhydrous HF, the desired cyclic sultams 125 were isolated
in reasonable yields (Table 1).
On the basis of this result, we decided to extend the application
of this protocol toward the synthesis of benzothiazepinones
(Scheme 3) 8. The reaction of the cysteine coupled to resin-bound
aminobenzimidazole 2 with substituted 2-chlorobenzoic acids in
the presence of DIC/HOBT, followed by cleavage of the trityl group
⇑
Corresponding author. Tel.: +1 (772) 345 4739; fax: +1 (772) 345 3649.
E-mail address: anefzi@tpims.org (A. Nefzi).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.135

6898
S. Dadiboyena, A. Nefzi / Tetrahedron Letters 53 (2012) 6897–6900
TrtS
O
O
O
S
S
O
O
N
N
N
N
N
N
H
N
H2N
Buchwald-Hartwig type cyclization
NH2
NH NH2
NH
1
H
N
R3
R2
N
R1
O
O
2
3
R1
R1
Scheme 1. Retrosynthetic illustration of aminobenzimidazole tethered sultams.
TrtS
TrtS
HS
O
O
Fmoc
OH
O
O
Br
S
O
N
H
N
N
N
N
c,d
N
H
N
N
N
H
4
a,b
O
N
H
NH2
NH
NH2
NH
HN
R2
O
O
R1
R1
3
2
R1
5
O
S
S
O
N
H2N
NH
N
R3
R2
N
R1
O
O
f, g
O
S
S
O
NH
7
N
N
e
N
H
HN
R2
O
O
O
S
R1
g
R1
N
O
6
R2
R
3 = H
H2N
NH HN
S
O
N
O
1
Scheme 2. (a) PyBOP (8 equiv, 0.5 M anhyd. DMF), HOBt (8 equiv), DIEA (8 equiv), 12 h, rt; (b) 20% piperidine/DMF, 15 min (2Â), rt; (c) DIEA (10 equiv), R2SO2Cl (10 equiv)
12 h, rt; (d) 6% TFA/DCM (1% TIPS), 15 min (2Â); (e) Cs2CO3 (10 equiv), Pd(PPh3)4 (0.2 equiv), ( )-BINAP (0.4 equiv), anhydrous DMF, 100 °C, 16 h; (f) R3I, DIEA (8 equiv, in
0.2 M DMF); (g) HF, anisole (99:5), 0 °C, 90 min.
Table 1
O
S
S
O
N
N
H2N
NH
1
N
R3
R2
O
O
R1
Entry
Ri
R2
R3
Mass calcd./found
Yielda (%)
1a
1b
1c
1d
1e
1f
19
1h
1i
Cyclopentyl
n-Butyl
i-Butyl
Cyclohexanemethyl
3-(trifluoromethyl)benzyl
Cyclopentyl
n-Butyl
i-Butyl
Cyclohexanemethyl
3-(trifluoromethyl)benzyl
i-Butyl
i-Butyl
n-Butyl
n-Butyl
3-(trifluoromethyl)benzyl
3-(trifluoromethyl)benzyl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
485.6/486.4 (MH+)
473.5/474.3 (MH+)
473.5/474.4 (MH+)
513.6/514.5 (MH+)
575.6/576.5 (MH+)
553.6/554.5 (MH+)
541.5/542.4 (MH+)
541.5/542.4 (MH+)
581.6/582.4 (MH+)
643.6/644.4 (MH+)
593.7/594.5 (MH+)
661.7/662.5 (MH+)
563.7/564.6 (MH+)
631.7/632.5 (MH+)
603.6/604.5 (MH+)
671.6/672.5 (MH+)
44
47
53
42
56
22
24
18
25
15
16
18
32
36
23
12
H
CF3
CF3
CF3
CF3
CF3
H
CF3
H
CF3
H
1j
1k
11
1m
1n
1o
1p
4-OMe-Bn
4-OMe-Bn
Bn
Bn
Et
CF3
Et
Isolated yields of aminobenzimidazole tethered sultams: The products were run on a Vydac column, gradients 5–95% formic acid in ACN in 7 min.
a
The yields are based on the weight of purified products and are relative to the initial loading of the resin.
generated the intermediate thiol which under Buchwald–Hartwig
type conditions proceeded smoothly to yield the resin-bound
thiazepinones 10. Finally, the desired benzothiazepinones 8 were
obtained in moderate yields after cleavage of the resin using anhy-
drous HF (Scheme 3).26 The results are summarized in Table 2. All
these above synthesized products were confirmed by LC-MS and
NMR spectroscopy. The incorporated heterocyclic core in the final
products, is a useful pharmacophore prevalent in many bioactive
compounds endowed with an array of pharmacological
properties.27,28
Conclusions
In conclusion, we have developed a multistep solid-phase
strategy for the parallel synthesis of aminobenzimidazole tethered
sultams and benzothiazepinones via palladium-catalyzed

S. Dadiboyena, A. Nefzi / Tetrahedron Letters 53 (2012) 6897–6900
6899
TrtS
HS
O
O
O
O
Cl
O
N
N
R2
N
H
a,b
d
N
N
+
OH
NH NH2
c
N
H
NH
HN
R2
Cl
R1
O
2
R1
9
O
S
O
S
O
O
N
N
N
H
H2N
NH HN
NH
HN
R2
R2
N
R1
N
O
O
10
8
R1
Scheme 3. Reagents and conditions: (a) DIC (8 equiv, 0.5 M anhyd. DMF), HOBt (8 equiv), 8 h, rt; (b) 6% TFA/DCM (1% TIPS), 15 min (2Â); (c) Cs2CO3 (10 equiv), Pd(PPh3)4
(0.2 equiv), ( )-BINAP (0.4 equiv), anhydrous DMF, 100 °C, 16 h; (d) HF, anisole (99:5), 0 °C, 90 min.
Table 2
13. Scozzafava, A.; Owa, T.; Mastrolorenzo, A.; Supuran, C. T. Curr. Med. Chem. 2003,
10, 925.
14. Zia-ur-Rehman, M.; Choudary, J. A.; Ahmad, S.; Siddiqui, H. L. Chem. Pharm. Bull.
2006, 54, 1175.
15. Silvestri, R.; Marfe, G.; Artico, M.; La Regina, G.; Lavecchia, A.; Novellino, E.;
Morgante, M.; Di Stefano, C.; Catalano, G.; Filomeni, G.; Abruzzese, E.; Ciriolo,
M. R.; Russo, M. A.; Amadori, S.; Cirilli, R.; LaTorre, F.; Sinibaldi Salimei, P. J.
Med. Chem. 2006, 49, 5840.
16. Lebegue, N.; Gallet, S.; Flouquet, N.; Carato, P.; Pfeiffer, B.; Renard, P.; Leonce,
S.; Pierre, A.; Chavatte, P.; Berthelot, P. J. Med. Chem. 2005, 48, 7363.
17. (a) Franzen, R. G. J. Comb. Chem. 2000, 2, 195; (b) Krchnak, V.; Holladay, M. W.
Chem. Rev. 2002, 102.
18. (a) Yu, Y.; Nefzi, A.; Ostresh, M. J.; Houghten, R. A. In Innnovations and
Perspectives in Solid Phase Synthesis and Combinatorial Libraries; Epton, R., Ed.;
Mayflower Worldwide Ltd: London UK, 2004; (b) Nefzi, A.; Ostresh, J. M.; Yu,
Y.; Houghten, R. A. J. Org. Chem. 2004, 69, 3603; (c) Nefzi, A.; Ostresh, J. M.;
Houghten, R. A. Chem. Rev. 1997, 97, 449.
19. Dadiboyena, S.; Nefzi, A. Tetrahedron Lett. 2011, 52, 7030.
20. Dadiboyena, S.; Nefzi, A. Synthesis 2012, 44, 215.
21. (a) Reddy, C. V.; Kingston, J. V.; Verkade, J. G. J. Org. Chem. 2008, 73, 3047; (b)
Dehli, J. R.; Legros, J.; Bolm, C. Chem. Commun. 2005, 973; (c) Hill, L. L.; Moore, L.
R.; Huang, R.; Craciun, R.; Vincent, A. J.; Dixon, D. A.; Chou, J.; Woltermann, C. J.;
Shaughnessy, K. H. J. Org. Chem. 2006, 71, 5117.
O
S
O
N
N
H2N
NH
8
HN
R2
O
R1
Entry
R2
Mass Calcd./Found
Yielda (%)
8a
8b
8c
8d
8e
8f
8g
8h
8i
Cyclopentyl
n-Butyl
H
H
H
H
449.6/452.0 (MH+)
437.5/440.0 (MH+)
437.6/440.1 (MH+)
477.6/480.0 (MH+)
539.6/542.0 (MH+)
484.2/486.0 (MH+)
472.1/474.0 (MH+)
472.2/474.0 (MH+)
512.1/514.0 (MH+)
574.2/576.0 (MH+)
32
43
60
51
53
16
38
11
18
34
i-Butyl
Cyclohexanemethyl
3-(trifluoromethyl)benzyl
Cyclopentyl
H
CI
CI
CI
CI
CI
n-Butyl
i-Butyl
Cyclohexanemethyl
3-(trifluoromethyl)benzyl
8j
Isolated yields of aminobenzimidazole tethered thiazepinones. The products were
run on a Vydac column, gradients 5 to 95% formic acid in ACN in 7 min.
a
22. Houghten, R. A. Proc. Natl. Acad. Sci. U.S.A. 1985, 82, 5131.
23. Liu, L.; Stelmach, J. E.; Natarajan, S. R.; Chen, M.-H.; Singh, S. B.; Schwartz, C. D.;
Fitzgerald, C. E.; O’Keefe, S. J.; Zaller, D. M.; Schmatz, D. M.; Doherty, J. B. Bioorg.
Med. Chem. Lett. 2003, 13, 3979.
The yields are based on the weight of purified products and are relative to the
initial loading of the resin.
24. Kaldor, S. W.; Kalish, V. J.; Davies, J. F., II; Shetty, B. V.; Fritz, J. E.; Appelt, K.;
Burgess, J. A.; Campanale, K. M.; Chirgadze, N. Y.; Clawson, D. K.; Dressman, B.
A.; Hatch, S. D.; Khalil, D. A.; Kosa, M. B.; Lubbehusen, P. P.; Muesing, M. A.;
Patick, A. K.; Reich, S. H.; Su, K. S.; Tatlock, J. H. J. Med. Chem. 1997, 40, 3979.
25. General Procedure for the Solid-Phase Synthesis of Aminobenzimidazole tethered
Sultams: p-Methylbenzhydrylamine (MBHA) resin (100 mg, 1.10 meq/g, 100–
200 mesh) was sealed inside a polypropylene mesh packet. Polypropylene
bottles were used for all the reactions. Fmoc-Amino acid (Fmoc-Cys(Trt)-OH)
Buchwald–Hartwig type coupling/cyclization.25,26 This methodol-
ogy provided a convenient pathway for the assembly of two useful
seven-membered heterocyclic units and also the construction of
C–S bond formation reactions.
Acknowledgments
coupled resin bound aminobenzimidazoles were synthesized according to a
20,21
previous literature.
Following Fmoc deprotection with a solution of 20%
piperidine in DMF and washings, the dried resin-bound free amine 2 was
treated with corresponding benzenesulfonyl chlorides (10 equiv, 0.2 M in
anhydrous DCM) and DIEA (10 equiv). The resulting resin was stirred at room
temperature (8 h), and the resin was washed with DMF (2Â), MeOH (2Â), and
DCM (2Â). Deprotection of the Trityl group with 6% TFA/DCM (1% TIPS) for
15 min (3Â), the resin 5 was washed with DCM (2Â). The palladium-catalyzed
cyclization was performed under anhydrous conditions. The resin-bound
sulfonamides were treated with Cs2CO3 (10 equiv, 0.2 M in anhyd. DMF),
Pd(PPh3)4 (0.2 equiv), and ( )-BINAP (0.4 equiv), and the whole reaction
mixture was heated at 100 °C for 14 h. The resin was then washed with DMF
(2Â), DCM (2Â), and methanol (2Â). Diverse alkyl halides were tethered to the
resin-bound sultams in the presence of DIEA in DMF at room temperature for
36 h and the resulting resin was washed with DMF (3Â) and DCM (3Â). The
resin was cleaved with HF/anisole for 90 min at 0 °C, and the final sultams 1
were obtained following extraction with 95% AcOH in H2O and lyophilization
as a white powder. The aminobenzimidazole tethered sultams 1 were purified
by preparative reverse-phase HPLC and the products were characterized by
LC–MS (ESI) conditions. NMR data for entry 1b: 1H NMR (DMSO-d6): 0.91 (t,
J = 8 Hz, 3H), 1.25–1.35 (m, 2H), 1.69–1.77 (m, 2H), 3.02–3.06 (m, 1H), 3.56–
3.61 (m, 1H), 4.21 (t, J = 8 Hz, 1H), 4.48 (dt, J = 8 Hz, 12 Hz, 1H), 7.51–7.58 (m,
4H), 7.60–7.65 (m, 3H), 7.67–7.70 (m, 1H), 7.80 (d, J = 8 Hz, 1H), 7.94–7.97 (m,
2H), 8.01 (m, 1H); LC–MS m/z data Calcd. for C21H23N5O4S2(MH+): 473.57.
Found: 474.3; NMR data for entry 1g: 1H NMR (DMSO-d6): 0.84 (t, J = 8 Hz, 2H),
0.93 (t, J = 8 Hz, 2H), 1.17–1.24 (m, 1H), 1.31–1.36 (m, 1H), 1.58–1.63 (m, 2H),
3.92–4.01 (m, 1H), 4.08–4.12 (m, 1H), 6.51 (s, 2H), 7.28 (d, J = 8 Hz, 1H), 7.46 (d,
J = 8 Hz, 1H), 7.58 (d, J = 8 Hz, 1H), 7.68 (d, J = 8 Hz, 1H), 7.81 (d, J = 8 Hz, 1H),
7.87 (d, J = 8 Hz, 1H), 7.99 (d, J = 16 Hz, 2H), 8.13–8.14 (m, 2H); LC–MS m/z data
Calcd. for C22H22F3N5O4S2(MH+): 541.57. Found: 542.4; NMR data for entry 1l:
1H NMR (DMSO-d6): 0.87 (d, J = 8 Hz, 3H), 0.83 (d, J = 8 Hz, 4H), 0.92–0.96 (m,
1H), 2.03 (s, 4H), 2.51 (m, 5H), 3.88 (dd, J = 8 Hz, 12 Hz, 1H), 3.96 (dd, J = 8 Hz,
The authors would like to thank the State of Florida Funding,
NIH (1R03DA025850-01A1, Nefzi; 5P41GM081261-03, Hough-
ten; 3P41GM079590-03S1) for providing generous financial
support.
Reference and notes
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Luque, P.; Albericio, F.; Alvarez, M. J. Comb. Chem. 2009, 11, 175.
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K.-H.; Kurth, M. J. J. Org. Chem. 2000, 65, 3520.
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A.; Houghten, R. A.; Yu, Y. Tetrahedron Lett. 2011, 52, 1456.
5. Nefzi, A.; Marcello, G.; Truong, L.; Rattan, S.; Ostresh, J. M.; Houghten, R. A. J.
Comb. Chem. 2002, 4, 175.
6. Nefzi, A.; Ostresh, J. M.; Yu, J.; Houghten, R. A. J. Org. Chem. 2004, 69, 3603.
7. Nefzi, A.; Arutyunyan, S.; Fenwick, J. E. J. Org. Chem. 2010, 75, 7939.
8. (a) Derbel, S.; Ghedira, K.; Nefzi, A. Tetrahedron Lett. 2010, 51, 3607; (b) Hoesl,
C. E.; Nefzi, A.; Houghten, R. A. J. Comb. Chem. 2004, 6, 220; (c) Hoesl, C. E.;
Nefzi, A.; Houghten, R. A. Tetrahedron Lett. 2003, 44, 3705.
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Chem. Lett. 2006, 16, 4115.
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Montis, A.; La Colla, P. Antiviral Chem. Chemother. 1998, 9, 127.

6900
S. Dadiboyena, A. Nefzi / Tetrahedron Letters 53 (2012) 6897–6900
16 Hz, 1H), 6.51 (s, 1H), 7.33 (br s, 1H), 7.59 (d, J = 8 Hz, 1H), 7.70 (d, J = 8 Hz,
NMR data for entry 8b: 1H NMR (DMSO-d6): 0.81 (t, J = 8Hz, 3H), 1.21–1.28 (m,
2H), 1.64–1.72 (m, 2H), 4.17 (t, J = 8Hz, 2H), 6.05 (br s, 1H), 6.41 (br s, 1H), 6.59
(br s, 1H), 7.31 (m, 1H), 7.49–7.62 (m, 6H), 7.72 (d, J = 8Hz, 1H), 7.81 (d, J = 8Hz,
1H), 8.00-8.02 (m, 2H); LC–MS m/z data Calcd. for C22H23N5O3S(MH+): 437.51.
Found: 440.0; NMR data for entry 8i: 1H NMR (DMSO-d6): 0.90–1.05 (m, 6H),
1.45 (d, J = 12Hz, 2H), 1.55–1.56 (m, 4H), 1.79–1.84 (m, 1H), 2,03 (s, 1H), 3.98
(d, J = 8Hz, 2H), 6.00 (s, 1H), 6.36 (s, 1H), 7.30 (br s, 1H), 7.54–7.60 (m, 2H),
7.73–7.81 (m, 3H), 7.95 (br s, 1H), 8.02 (s, 1H); LC-MS m/z data Calcd. for
1H), 7.81 (d, J = 8 Hz, 1H), 7.00 (d, J = 8 Hz, 1H), 7.97–8.01 (m, 2H), 8.15 (br s,
2H); LC–MS m/z data Calcd. for C30H30FN5O2S2(MH+): 661.71. Found: 662.5;
NMR data for entry 1m: 1H NMR (DMSO-d6): 0.88 (d, J = 8 Hz, 3H), 1.25–1.30 (m,
2H), 1.67–1.72 (m, 2H), 2.97–3.03 (m, 1H), 3.50 (d, J = 8 Hz, 1H), 4.19 (t,
J = 8 Hz, 1H), 4.42 (t, J = 8 Hz, 1H), 5.42 (d, J = 4 Hz, 1H), 7.26–7.35 (m, 8H),
7.46–7.54 (m, 3H), 7.63–7.71 (m, 3H), 7.86–7.96 (m, 1H), 7.99–8.03 (m, 2H);
LC–MS m/z data Calcd. for C28H29N5O4S2(MH+): 563.70. Found: 564.6.
26. General Procedure for the Synthesis of Aminobenzimidazole tethered
C
25H26ClN5O3S(MH+): 512.02. Found: 514.0.
benzothiazepinones: The resin-bound free amine
2
was coupled with
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substituted 2-chlorobenzoic acids using DIC (8 equiv, 0.2M in DMF) and
HOBt (8 equiv) conditions for 8 h, and the resulting resin bound amides were
washed with DMF (2x) and DCM (2Â). The trityl group was cleaved with 6%
TFA/DCM (1% TIPS) for 15 min (3Â), and the resin 9 was washed with DCM
(2Â) and dried overnight. The palladium-catalyzed cyclization was performed
under anhydrous conditions. The resin-bound intermediate amides 9 were
treated with Cs2CO3 (10 equiv, 0.2 M in anhyd. DMF), Pd(PPh3)4 (0.2 equiv),
and ( )-BINAP (0.4 equiv), and the whole reaction mixture was heated at
100 °C for 10 h. The resin was then washed with DMF (2Â), DCM (2Â), and
methanol (2Â). The resin was cleaved with HF/anisole for 90 min at 0 °C, and
the desired benzothiazepinones 8 were obtained following extraction with 95%
AcOH in H2O and lyophilization as a white powder. The aminobenzimidazole
tethered benzothiazepinones 8 were purified by preparative reverse-phase
HPLC and the products were characterized by LC–MS under ESI conditions.