PhIO/Bu4NI mediated oxidative cyclization of amidoalkylation adducts for the synthesis of N-benzoyl aziridines and oxazolines

Article abstract of DOI:10.1016/j.tetlet.2009.11.069

An efficient oxidative cyclization of amidoalkylation adducts of activated methylene compounds with the combination of iodosobenzene and a catalytic amount of tetrabutylammonium iodide under neutral conditions is reported. The reaction affords N-benzoyl aziridines or oxazolines in moderate to excellent yields.

Full text of DOI:10.1016/j.tetlet.2009.11.069

Tetrahedron Letters 51 (2010) 453–456
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Tetrahedron Letters
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PhIO/Bu4NI mediated oxidative cyclization of amidoalkylation adducts
for the synthesis of N-benzoyl aziridines and oxazolines
a
a
b,
Renhua Fan a, , Hua Wang , Yang Ye , Jianhong Gan
*
*
a Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
b College of Food Science, Shanghai Fisheries University, 334 Jungong Road, Shanghai 200090, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient oxidative cyclization of amidoalkylation adducts of activated methylene compounds with the
combination of iodosobenzene and a catalytic amount of tetrabutylammonium iodide under neutral con-
ditions is reported. The reaction affords N-benzoyl aziridines or oxazolines in moderate to excellent
yields.
Received 21 August 2009
Revised 14 November 2009
Accepted 17 November 2009
Available online 20 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Dedicated to Professor Lixin Dai on the
occasion of his 85th birthday
Among heterocycles, aziridines and oxazolines have attracted a
lot of interest.1,2 As the core structures, they are frequently found
in a variety of biologically active natural molecules and pharma-
ceuticals. Meanwhile, they are widely used as synthetic intermedi-
ates, ligands, or chiral pools in organic synthesis. Consequently, it
is desirable to search for new efficient methods for the construc-
tion of aziridine and oxazoline derivatives. In the past decades,
amidoalkylations have been developed as a valuable alternative
to the Mannich reaction, and significant advances have been
2 equiv of Bu4NI in THF at room temperature to afford N-benzoyl
aziridine 2a in 78% yield (Scheme 3). As one of the byproducts,
oxazoline 3a was isolated in 4% yield.
Further investigation revealed that the best ratio among sub-
strate, PhIO, and Bu4NI was 1:1.5:0.5, in which the yield of 2a
increased to 88% (Table 1, entry 4). The reaction still proceeded
smoothly when 0.1 equiv of Bu4NI was used (Table 1, entry 5). Con-
trol experiment showed that no aziridine was formed in the
absence of Bu4NI (Table 1, entry 6). The oxidative cyclization could
be carried out in various organic solvents except in methanol
(Table 1, entries 7–11). When the reaction was carried out in an
air-open system with water as the solvent, N-benzoyl aziridine
2a was obtained in 64% yield (Table 1, entry 12).
made.3,4
a-Amidoalkylation of activated methylene compounds
provides ready access to b-amino dicarbonyl compounds,5 which
are proposed to be ready to undergo a [1, 3] or [1, 5] oxidative
cyclization to generate N-acyl aziridines or oxazolines, which are
normally required to be prepared from the corresponding amino
alcohols (Scheme 1).6
Compared with the normally used N-sulfonyl aziridines, N-ben-
zoyl aziridines showed a better reactivity in the enantioselective
As part of a program aimed at developing synthetic application
of hypervalent iodine compounds,7 some of our recent efforts have
been addressed in the iodine(III)-induced oxidative cyclizations of
Michael adducts for the construction of functionalized cyclopro-
panes7e and oxetanes.7a In the current study, we have sought to
further extend the utility of this process by exploring the oxidative
O
E1
E2
HN
R1
R2
C
H2
+
X
(X = OH, OR, OCOR, Halogen, NHCOR, NR2)
amidoalkylation
cyclization of
a-amidoalkylation adducts of activated methylene
compounds, which were prepared with N-(
a-benzotriazolyl-alky-
O
R2
E1
E2
l)amides, developed by the Katritzky group, as the amidoalkylation
reagents under the literature conditions (Scheme 2).5
[1, 3] oxidative cyclization
O
N
The a-amidoalkylation adducts of diethyl malonate 1a were uti-
R2
R1
HN
R1
lized as the model substrate to search for suitable reaction condi-
tions. The preliminary survey indicated that the oxidative
cyclization of 1a occurred in the presence of 2 equiv of PhIO and
R2
H
E1
[1, 5] oxidative cyclization
E2
N
O
E1
E2
R1
Scheme 1. Oxidative cyclization of amidoalkylation adducts.
* Corresponding authors. Tel. +86 21 6564 3462; fax: +86 216 510 2412 (R.F).
E-mail address: rhfan@fudan.edu.cn (R. Fan).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.069

454
R. Fan et al. / Tetrahedron Letters 51 (2010) 453–456
Table 2
O
N
O
Oxidative cyclization of amidoalkylation adducts of malonatesa
E1
E2
HN
R
N
HN
R
O
C
H2
+
Ar
O
R2
COOR3
H
R2
(2 equiv) AlCl3, CH2Cl2, reflux
or
(0.2 equiv) SmI3 , THF, r.t.
E1
Ar
HN
R1
N
(1.5 equiv) PhIO, (0.5 equiv) Bu4NI
THF, r. t.
E2
1a-x
52-92% yield
H
N
COOR3
R1
COOR3
COOR3
2
1
Scheme 2.
a
-Amidoalkylation of activated methylene compounds.
Entry
R1
R2
R3
2b (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
CF3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH3
2a (88)
2b (82)
2c (80)
2d (93)
2e (75)
2f (91)
2g (87)
2h (52)
2i (50)
2j (70)
2kc
Ph
O
O
Ph
o-BrC6H4
o-ClC6H4
2,4-di-ClC6H3
p-FC6H4
m-NO2C6H4
p-NO2C6H4
p-CH3C6H4
o-BnOC6H4
m-BnOC6H4
p-BnOC6H4
p-CH3OC6H4
1-Naphthyl
C6H5
(2 equiv) PhIO
(2 equiv) Bu4NI
N
+
O
HN
Ph
Ph
N
COOEt
COOEt
COOEt
COOEt
THF, r.t.
Ph
CH(COOEt)2
Ph
3a (4%)
1a
2a (78%)
Scheme 3.
2lc
ring-opening reactions to afford useful optically active amines.8
Motivated by the synthetic potential of the possible method, the
scope of this reaction was then investigated under optimized con-
ditions. In most of the cases, the reaction was completed in 10 min.
An electronic substrate effect was observed. Compounds with an
electron-withdrawing substituent were better substrates than
those with an electron-donating substituent, and their reactions
afforded the corresponding N-benzoyl aziridines in good to excel-
lent yields. For example, the reaction of p-CH3-substituted sub-
strate afforded N-benzoyl aziridine 2h in 52% yield (Table 2,
entry 8), while the reaction of p-F- or p-NO2-substituted substrate
afforded the corresponding product 2e or 2g in 75% or 87% yield,
respectively (Table 2, entries 5 and 7). The position of the elec-
tron-donating substituent also had an effect on the reaction. While
moderate yields were obtained from the reactions of o- or m-BnO-
substituted compound 1i or 1j, the reaction of p-BnO-substituted
substrate 1k was complex, and the expected product was not sta-
ble enough to be purified, albeit the formation of aziridine was de-
tected by 1H NMR spectroscopy of the crude product (Table 2,
2m (85)
2n (46)
2o (0)
2p (0)
2q (0)
2y (53)d
C6H5
C6H5
C6H5
CH3CH2CH2
C(CH3)3
CH2CH3
CH2CH3
CH2CH3
CH3
C6H5
a
The reactions were performed with substrate 1 (0.3 mmol), PhIO (0.45 mmol)
and Bu4NI (0.15 mmol) in anhydrous THF (1 mL) at room temperature.
b
Isolated yields.
The formation of aziridine was detected by the 1H NMR of the crude product.
c
d
Oxazoline 3y was isolated in 27% yield.
Table 3
Oxidative cyclization of amidoalkylation adducts of active methylene compoundsa
O
Ph
O
Ph
E1
E2
HN
R1
Ph
(1.5 equiv) PhIO, (0.5 equiv) Bu4NI
THF, r.t.
N
O
E1
E2
+
N
H
E1
R1
R1
E2
entries 9–11). With respect to the
a-amidoalkylation adducts of
3
2
1
other malonates, reaction of the dimethyl derivative 1n gave rise
to product 2n in a moderate yield, while no reaction occurred with
the sterically hindered di-tertbutyl malonate derivative as the sub-
Entry
R1
E1
E2
2b (%)
3b (%)
1
2
3
4
5
6
7
8
p-ClC6H4
p-ClC6H4
p-ClC6H4
C6H5
o-BrC6H4
p-NO2C6H4
p-CH3C6H4
CH3CH2CH2
CH3CO
CH3CO
CH3CO
CH3CO
CH3CO
CH3CO
CH3CO
CH3CO
COOCH2CH3
COOCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
2r (41)c
2s (45)e
2t (12)
2u (12)
2v (19)
2w (14)
2x (13)
2z (8)
3r (33)d
3s (40)f
3t (60)
3u (62)
3v (50)
3w (52)
3x (78)
3z (42)
Table 1
Evaluation of reaction conditionsa
O
O
Ph
HN
Ph
Ph
PhIO, Bu4NI
conditions
N
COOEt
COOEt
CH(COOEt)2
Ph
a
The reactions were performed with substrate 1 (0.3 mmol), PhIO (0.45 mmol)
and Bu4NI (0.15 mmol) in anhydrous THF (1 mL) at room temperature.
1a
2a
b
Isolated yields.
Entry
PhIO (equiv)
Bu4NI (equiv)
Solvent
2ab (%)
c
The diastereoselectivity ratio of 2r: cis/trans = 55:45 (determined by HPLC).
The diastereoselectivity ratio of 3r:cis/trans = 50:50.
The diastereoselectivity ratio of 2s:cis/trans = 60:40.
The diastereoselectivity ratio of 3s:cis/trans = 50:50.
d
1
2
3
4
5
6
7
8
9
2
2
1.5
1
THF
THF
THF
THF
THF
THF
EtOAc
CH3CN
CHCl3
CH2Cl2
MeOH
H2O
78
87
86
88
80
0
70
66
72
70
Trace
64
e
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
f
0.5
0.1
0
0.5
0.5
0.5
0.5
0.5
0.5
Ph
O
Ph
(1.5 equiv) PhIO
(0.5 equiv) Bu4NI
10
11
12
N
O
N
COCH3
COCH3
X
COCH3
COCH3
Ph
THF, r.t.
Ph
a
The reactions were performed with 1a (0.3 mmol), PhIO and Bu4NI (as noted) in
2u
3u
solvent (1 mL) at room temperature.
b
Isolated yields.
Scheme 4.

R. Fan et al. / Tetrahedron Letters 51 (2010) 453–456
455
O
O
Ph
Bu4NI
ONBu4
H
E
Bu4NI
I
O
Ph
N
E
OH
I
Ph
I
I
N
E
E
Ph
n
O
- H2O
- PhI
R
Ph
R
HN
Ph
CHE2
2
A
R
1
Ph
E
O
Ph
N
H
N
O
R
I
OH
Ph
E1
E2
- H2O
- PhI
E
R
3
Scheme 5. Plausible reaction pathway.
McCoull, W.; Davis, F. A. Synthesis 2000, 1347; (g) Dodd, R. H. Molecules 2000, 5,
293; (h) Atkinson, R. S. Tetrahedron 1999, 55, 1519; (i) Stamm, H. J. Prakt. Chem.
1999, 4, 319; (j) Jacobsen, E. N.. In Comprehensive Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 2, p
607; (k) Osborn, H. M. I.; Sweeney, J. Tetrahedron: Asymmetry 1997, 8, 1693;
(l)Comprehensive Heterocyclic Chemistry II; Pearson, W. H., Lian, B. W.,
Bergmeier, S. C., Padwa, A., Eds.; Pergamon: Oxford, 1996; Vol. 1A, p 1; (m)
Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599.
strate (Table 2, entries 14 and 15). When the benzoyl group on the
nitrogen was replaced by an acetyl or trifluoroacetyl group, no oxi-
dative cyclization was observed (Table 2, entries 16 and 17).
When diethyl 2-(1-benzamidobutyl)malonate (Table 2, entry
18) and
a-amidoalkylation adducts of ethyl- or methyl-acetoace-
tate (Table 3, entries 1 and 2) were employed as the substrates, be-
sides the expected N-benzoyl aziridines, the reactions also afforded
the corresponding oxazolines. Further investigation revealed that
the corresponding oxazolines were obtained as the major products
in the cases of 2,4-pentanedione derivatives (Table 3, entries 3–8).
A different electronic substrate effect was observed in the forma-
tion of oxazolines. Reactions of the electron-rich substrates
showed a better selectivity for the formation of oxazolines than
those of the electron-poor substrates.
N-benzoyl aziridine 2u or oxazoline 3u could not be converted
into each other when they were treated with PhIO and Bu4NI under
the optimized reaction conditions (Scheme 4). A plausible reaction
pathway for the PhIO/Bu4NI mediated oxidative cyclization of ami-
doalkylation adducts of activated methylene compounds is out-
lined in Scheme 5. Polymeric iodosobenzene is depolymerized
with Bu4NI to generate a higher reactive iodine(III) species,9 which
reacts with the substrate 1 to form an intermediate A and regener-
ate Bu4NI via a ligand-exchange reaction. After a [1, 3] or [1, 5]
intramolecular nucleophilic displacement by the nitrogen or oxy-
gen atom, the reaction affords the corresponding N-benzoyl aziri-
dine or oxazoline accompanied by the reductive elimination of PhI.
In conclusion, we report here an efficient oxidative cyclization of
amidoalkylation adducts of activated methylene compounds with
the combination of iodosobenzene and a catalytic amount of Bu4NI
under neutral conditions.10 The reaction affords N-benzoyl aziri-
dines or oxazolines in moderate to excellent yields. The scope and
synthetic application are ongoing and will be reported in due course.
2. For selected reviews, see: (a) Nicolaou, K. C.; Liazos, D. E.; Kim, D. W.; Schlawe,
D.; De Noronha, R. G.; Longbottom, D. A.; Rodriguez, M.; Bucci, M.; Cirino, G. J.
Am. Chem. Soc. 2006, 128, 4460; (b) Pirrung, M. C.; Tumey, L. N.; McClerren, A.
L.; Ratz, C. R. H. J. Am. Chem. Soc. 2003, 125, 1575; (c) Bergeron, R. J.; Xin, M. G.;
Weimar, W. R.; Smith, R. E.; Wiegand, J. J. Med. Chem. 2001, 44, 2469; (d) Clark,
D.; Travis, D. A. Bioorg. Med. Chem. 2001, 9, 2857; (e) Onishi, H. R.; Pelak, B. A.;
Gerckens, L. S.; Silver, L. L.; Kahan, F. M.; Chen, M. H.; Patchett, A. A.; Galloway,
S. M.; Hyland, S. A.; Anderson, M. S.; Raetz, C. R. H. Science 1996, 274, 980; (f)
Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835; (g) Davidson, B. S.
Chem. Rev. 1993, 93, 1771; (h) Bergeron, R. J. Chem. Rev. 1984, 84, 587; (i)
Meyers, A. I.; Mihelich, E. D. Angew. Chem., Int. Ed. Engl. 1976, 15, 270.
3. For selected reviews, see: (a) Zaugg, H. E. Synthesis 1984, 85, 181; (b)
Tramontini, M. Synthesis 1973, 703; (c) Zaugg, H. E. Synthesis 1970, 49; (d)
Zaugg, H. E.; Martin, W. B. Org. React. 1966, 14, 52.
4. For selected reviews, see: (a) Katritzky, A. R.; Rachwal, S.; Hitchings, G. J.
Tetrahedron 1991, 47, 2683; (b) Katritzky, A. R.; Yang, Z.; Cundy, D. J. Aldrichim.
Acta 1994, 27, 31; (c) Katritzky, A. R.; Lan, X. Chem. Soc. Rev. 1994, 363; (d)
Katritzky, A. R.; Lan, X.; Fan, W. Q. Synthesis 1994, 445; (e) Katritzky, A. R.; Lan,
X.; Yang, J. Z.; Denisko, O. V. Chem. Rev. 1998, 98, 409.
5. (a) Katritzky, A. R.; Pernak, J.; Fan, W. Q.;Saczewski, F. J. Org. Chem. 1991, 56, 4439;
(b) Wang, X.; Mao, H.; Yu, Y.; Zhu, X.; Zhu, C. Synth. Commun. 2007, 37, 3751.
6. (a) Witte, M. D.; Horst, D.; Wiertz, E. J. H. J.; Van der Marel, G. A.; Overkleeft, H.
S. J. Org. Chem. 2009, 74, 605; (b) Métro, T.-X.; Pardo, D. G.; Cossy, J. J. Org. Chem.
2008, 73, 707; (c) Crosignani, S.; Swinnen, D. J. Comb. Chem. 2005, 7, 688; (d)
Crosignani, S.; Young, A. C.; Linclau, B. Tetrahedron Lett. 2004, 45, 9611; (e)
Gorunova, O. N.; Keuseman, K. J.; Goebel, B. M.; Kataeva, N. A.; Churakov, A. V.;
Kuzmina, L. G.; Dunina, V. V.; Smoliakov, I. P. J. Organomet. Chem. 2004, 689,
2382; (f) Aggarwal, V. K.; Vasse, J.-L. Org. Lett. 2003, 5, 3987.
7. (a) Ye, Y.; Zheng, C.; Fan, R. Org. Lett. 2009, 11, 3156; (b) Fan, R.; Li, W.; Pu, D.;
Zhang, L. Org. Lett. 2009, 11, 1425; (c) Fan, R.; Ye, Y. Adv. Synth. Catal. 2008, 350,
1526; (d) Fan, R.; Li, W.; Ye, Y.; Wang, L. Adv. Synth. Catal. 2008, 350, 1531; (e)
Fan, R.; Ye, Y.; Li, W.; Wang, L. Adv. Synth. Catal. 2008, 350, 2488; (f) Fan, R.; Li,
W.; Wang, B. Org. Biomol. Chem. 2008, 6, 4615; (g) Fan, R.; Pu, D.; Gan, J.; Wang,
B. Tetrahedron Lett. 2008, 49, 4925; (h) Fan, R.; Pu, D.; Wen, F. J. Org. Chem. 2007,
72, 8994.
8. (a) Rowland, E. B.; Rowland, G. B.; Rivera-Otero, E.; Antilla, L. C. J. Am. Chem. Soc.
2007, 129, 12084; (b) Mita, T.; Fukuda, N.; Roca, F. X.; Kanai, M.; Shibasaki, M.
Org. Lett. 2007, 9, 259; (c) Fukuta, Y.; Mita, T.; Fukuda, N.; Kanai, M.; Shibasaki,
M. J. Am. Chem. Soc. 2006, 128, 6312; (d) Yudin, A. K. Aziridines and Epoxides in
Organic Synthesis; Wiley-VCH: Weinheim, 2006; (e) Mita, T.; Fujimori, I.; Wada,
R.; Wen, J.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 11252; (f) Li, Z.;
Fernández, M.; Jacobsen, E. N. Org. Lett. 1999, 1, 1611.
Acknowledgments
Financial support from the National Natural Science Foundation
of China (20702006), the Shanghai Rising-Star program
(07QA14007), and the Fudan University is gratefully acknowledged.
9. (a) Moriarty, R. M.; Vaid, R. K. Synthesis 1990, 431; (b) Stang, P. J.; Zhdankin, V.
V. Chem. Rev. 1996, 96, 1123; (c) Zhdankin, V. V.; Stang, P. J. In Chemistry of
Hypervalent Compounds; Akiba, K., Ed.; VCH: New York, 1999; p 327; (d)
Grushin, V. V. Chem. Soc. Rev. 2000, 29, 315; (e) Zhdankin, V. V.; Stang, P. J.
Chem. Rev. 2002, 102, 2523; (f) Stang, P. J. J. Org. Chem. 2003, 68, 2997; (g)
Moriarty, R. M. J. Org. Chem. 2005, 70, 2893; (h) Zhdankin, V. V.; Stang, P. J.
Chem. Rev. 2008, 108, 5299.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.11.069.
10. General experimental procedure and spectroscopic data:
A solution of a-
References and notes
amidoalkylation adduct 1 (0.3 mmol) in anhydrous THF was treated with
PhIO (99 mg, 0.45 mmol) and Bu4NI (55 mg, 0.15 mmol). The resulted mixture
was stirred at 25 oC. After the substrate disappeared (determined by TLC), the
mixture was concentrated and directly purified by flash column
chromatography (10–20% ethyl acetate in hexane) to provide the
1. For selected reviews, see: (a) Hou, X. L.; Wu, J.; Fan, R.; Ding, C. H.; Luo, Z. B.;
Dai, L. X. Synlett 2006, 181; (b) Hu, X. E. Tetrahedron 2004, 60, 2701; (c) Muller,
P.; Fruit, C. Chem. Rev. 2003, 103, 2905; (d) Sweeney, J. B. Chem. Soc. Rev. 2002,
31, 247; (e) Zwanenburg, B.; ten Holte, P. Top. Curr. Chem. 2001, 216, 93; (f)
corresponding N-benzoyl aziridine
2 or oxazoline 3. Diethyl 1-benzoyl-3-

456
R. Fan et al. / Tetrahedron Letters 51 (2010) 453–456
phenylaziridine-2,2-dicarboxylate 2a: yellow oil; 1H NMR (400 MHz, CDCl3) d
dihydrooxazole-5,5-diyl)diethanone 3t: yellow oil; 1H NMR (400 MHz, CDCl3) d
7.43–7.58 (m, 7 H), 7.37 (t, J = 7.5 Hz, 2H), 6.69 (s, 1H), 2.24 (s, 6H); 13C NMR
(100 MHz, CDCl3) d 190.6, 172.6, 156.8, 135.8, 135.2, 133.5, 132.4, 129.2, 128.7,
128.4, 127.5, 120.1, 93.7, 28.1, 13.2; IR (KBr) 3056, 2931, 2855, 1665, 1400,
8.18 (d, J = 7.0 Hz, 2 H), 7.55 (t, J = 7.2 Hz, 1 H), 7.43–7.48 (m, 4 H), 7.34–7.41
(m, 3H), 4.49 (s, 1 H), 3.89–4.12 (m, 4 H), 1.00 (t, J = 6.9 Hz, 3 H), 0.82 (t,
J = 6.9 Hz, 3 H); 13C NMR (100 MHz, CDCl3) d 174.8, 164.1, 163.6, 133.1, 132.4,
132.2, 128.9, 128.8, 128.5, 128.4, 127.1, 62.8, 61.8, 54.5, 49.0, 13.5; IR (KBr)
3058, 2989, 2932, 1742, 1688, 1449, 1411, 1263 cmꢀ1; HRMS m/z calcd for
C21H22NO5 ([M+H]+): 368.1498, found 368.1511. 1,10-(2,4-diphenyl-4,5-
1269 cmꢀ1
;
HRMS m/z calcd for C19H17ClNO3 ([M+H]+): 342.0897, found
342.0906.