Simple and efficient access to N-tosyl β-amino ketones and their conversion into 2,4-disubstituted azetidines

Article abstract of DOI:10.1021/jo901982n

(Chemical Equation Presented) Treatment of N-tosylaldimines with acetophenone at room temperature in the presence of BF₃· OEt₂ as a catalyst furnished the corresponding N-tosyl β-amino ketones in high yields (77-86%) within 6-9 h. Su

Full text of DOI:10.1021/jo901982n

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carbonyl compounds, and various methods have been deve-
Simple and Efficient Access to N-Tosyl β-Amino
Ketones and Their Conversion into 2,4-Disubstituted
Azetidines†
loped on the basis of these reactions for preparation of these
compounds.5 However, many of these methods suffer
from different drawbacks such as application of expensive
catalysts, longer reaction times, use of toxic reagents, and
harsh reaction conditions. Here we report an easy access
to N-tosyl β-amino ketones and also their conversion into
2,4-disubstituted N-tosylazetidines.
Biswanath Das,* Penagaluri Balasubramanyam,
Boyapati Veeranjaneyulu, and Gandolla Chinna Reddy
Organic Chemistry Division-1, Indian Institute of
Chemical Technology, Hyderabad 500 007, India
In continuation of our work6 on the development of useful
synthetic methodologies using N-tosylaldimines, we have
observed that these compounds, when treated with aceto-
biswanathdas@yahoo.com
phenone in the presence of BF3 OEt2, afforded the corre-
3
Received September 15, 2009
sponding N-tosyl β-amino ketones at room temperature
(Scheme 1). The previous methods for preparation of these
SCHEME 1. Synthesis of N-Tosyl β-Amino Ketones from
N-Tosylaldimines
compounds are limited.7 Moreover, N-tosylaldimines were
not directly converted previously into N-tosyl β-amino
ketones by treatment with enolizable ketones.
Initially, the reaction of N-tosylbenzaldimine (1a, R1 = Ph)
with acetophenone was carried out by the use of various
catalysts (Table 1).
Treatment of N-tosylaldimines with acetophenone at room
temperature in the presence of BF3 OEt2 as a catalyst
3
furnished the corresponding N-tosyl β-amino ketones in
high yields (77-86%) within 6-9 h. Subsequent reduction
and cyclization of these compounds afforded 2,4-disubsti-
tuted N-tosylazetidines, comprising a three-step, high-
yielding synthesis starting from aldimines.
Considering the reaction time and yield, BF3 OEt2 was
3
found to be the most effective catalyst for this conversion.
Subsequently, a series of N-tosyl β-amino ketones were
prepared (Table 2) using this catalyst following the above
procedure (Scheme 1). Many of these products are new
compounds.7 The N-tosylaldimines were derived8 from
aromatic, heteroaromatic, and aliphatic aldehydes. The
aromatic aldehydes contained electron-donating as well as
electron-withdrawing groups. The products were formed in
high yields (77-86%) within 6-9 h. Different functional
groups such as halogen, ether, carbonyl, and nitro remained
unchanged. The N-tosyl group of the products can easily be
deprotected to genarate β-amino ketones.9 The free amine
group can be utilized to prepare various analogues of the
compounds.
β-Amino carbonyl compounds possess various important
biological properties including hypoglycemic, antiketogenic,
and antifungal activities.1 They are also useful synthetic
intermediates for various valuable pharmaceuticals and
bioactive natural products,2 Taxol, a highly potent antitu-
mor agent, contains a β-amino acid in its side chain.3
β-Amino carbonyl compounds can also be converted into
γ-amino alcohols which are structural units in various
natural nucleoside antibiotics.4 The Mannich-type reactions
involving aldehydes, amines (or directly imines), and enoliz-
able ketones are widely applied for constructing β-amino
In some recent reports, the synthesis of N-tosyl β-amino
carbonyl compounds has been described, but interestingly, in
any of these reports the preparation of 1,3-diaryl analogues has
† Studies on Novel Synthetic Methodologies. 194.
(1) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991.
(2) (a) Arend, M.; Westerman, B.; Risch, N. Angew. Chem., Int. Ed. 1998,
37, 1044. (b) Kobayashi, S.; Ishitani, S. Chem. Rev. 1999, 99, 1069. (c) Evans,
G. B.; Furneaux, R. H.; Tyler, P. C.; Schramm, V. L. Org. Lett. 2003, 5, 3639.
(d) Joshi, N. S.; Whitaker, L. R.; Francis, M. B. J. Am. Chem. Soc. 2004, 126,
15942.
(6) Das, B.; Balasubramanyam, P.; Krishnaiah, M.; Veeranjaneyulu, B.;
Chinna Reddy, G. J. Org. Chem. 2009, 74, 4393.
(3) (a) Wani, M. S.; Taylor, H. L.; Wall, M. E.; Coggon, P.; McPhail,
A.-T. J. Am. Chem. Soc. 1971, 93, 2325.
(4) (a) Kobinaka, K.; Uramoto, M.; Nishii, M.; Kusakabe, H.; Nakamura,
G.; Isono, K. Agric. Biol. Chem. 1980, 44, 1709.
(7) (a) Miura, K.; Tamaki, K.; Nakagawa, T.; Hosomi, A. Angew. Chem.,
Int. Ed. 2000, 39, 1958. (b) Pandey, M. K.; Bisai, A.; Pandey, A.; Singh, V. K.
Tetrahedron Lett. 2005, 46, 5039. (c) Zhao, C.-H.; Liu, L.; Wang, D.; Chen,
Y.-J. Eur. J. Org. Chem. 2006, 2977.
(5) (a) Kobayashi, S.; Ishitani, H. Chem. Commun. 1995, 1379. (b)
Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 1997, 119, 7135.
(c) List, B. J. Am. Chem. Soc. 2000, 122, 9336. (d) Coardova, A. Acc. Chem.
Res. 2004, 37, 102. (e) Ollevier, T.; Nadeau, E. J. Org. Chem. 2004, 69, 9292.
(f) Yang, Y.-Y.; Shou, W.-G.; Wang, Y.-G. Tetrahedron 2006, 62, 10079. (g)
Wang, R.; Li, B.; Huang, T.; Shi, L.; Lu, X. Tetrahedron 2007, 48, 2071.
(8) (a) Jennings, W. B.; Lovely, C. J. Tetrahedron 1991, 47, 5561. (b) Love,
B. E.; Raje, P. S.; Williams, T. C. III. Synlett 1994, 493. (c) Chemla, F.;
Hebbe, B.; Normant, J.-F. Synthesis 2000, 75.
(9) (a) Bajwa, J. S.; Chen, G. P.; Prasad, K.; Repic, O.; Blacklock, T. J.
Tetrahedron Lett. 2006, 47, 6425. (b) Nandi, P.; Redko, M. Y.; Petersen, K.;
Dye, J. L.; Lefenfeld, M.; Vogt, P. F.; Jackson, J. E. Org. Lett. 2008, 10, 5441.
DOI: 10.1021/jo901982n
r
Published on Web 11/13/2009
J. Org. Chem. 2009, 74, 9505–9508 9505
2009 American Chemical Society

Das et al.
JOCNote
TABLE 1. Evaluation of the Catalytic Activity of Different Catalysts
TABLE 2. Synthesis of N-Tosyl β-Amino Ketones by the Reaction
of Various N-Tosylaldimines and Acetophenone in the Presence of BF3 OEt2
for the Preparation of N-Tosyl β-Amino Ketonesa
a
3
aReaction conditions: N-tosylaldimine (1.0 mmol), acetophenone
(1.2 mmol), catalyst (25 mol %), CH2Cl2 (3 mL), rt, N2 atmosphere.
bIsolated yield. cNo reaction.
not been mentioned.10 The ring-opening of N-tosylaziridines
with 2-lithiodithianes followed by hydrolytic desulfurization
afforded the protected β-amino ketones in varient yields.10a
However, the azridine derived from phenylglycine was un-
reactive. The reductive cleavage of the C(2)-N bond of
N-tosyl-2-benzoylaziridines using Mg in methanol was also
unsuccessful to produce the corresponding N-tosyl β-amino
ketones.10d The reduction of these aziridine derivatives by
SmI2 was not mentioned, though other 2-acylaziridines
were reported to be reduced at 0 °C.10b,c N-Tosyl β-amino
carbonyl compounds have also been prepared by aza-
Micheal addition of P-TsNH2 to enones in the presence
of different Lewis acids, but the conversion times were high
and yields of some products were unsatisfactory.10e,f
A CAN-mediated oxidative cleavage of N-tosyl 4-aryl-
3,4-dihydroxypiperidines to β-amino carbonyl compounds
has also recently been developed,10g but the conversion was
conducted under reflux and N-formyl β-amino ketones
were the major products. The products contained no
aryl/alkyl substrates at the β-position.
N-Tosyl β-amino ketones have subsequently been con-
verted into N-tosylazetidines. Azetidines are four-mem-
bered nitrogen-containing heterocyclic compounds, and
they possess various important biological properties.11
They exhibit significant anti-influenza virus A activity
aReaction conditions: N-tosylaldimine (1.0 mmol), acetophenone
(1.2 mmol), BF3 OEt2 (0.25 mmol), CH2Cl2 (3 mL), rt, N2 atmosphere.
(10) (a) Howson, W.; Osborn, H. M. I.; Sweeney, J. J. Chem. Soc., Perkin
Trans. 1 1995, 2439. (b) Molander, G. A.; Stengel, P. J. Tetrahedron 1997, 53,
8887. (c) Molander, G. A.; Stengel, P. J. J. Org. Chem. 1995, 60, 6660. (d)
Pak, C. S.; Kim, T. H.; Ha, S. J. J. Org. Chem. 1998, 63, 10006. (e) Lee,
A. S.-Y.; Wang, S.-H.; Chang, Y.-T.; Chu, S.-F. Synlett 2003, 2359. (f) Lin,
Y.-D.; Kao, J.-Q.; Chen, C.-T. Org. Lett. 2007, 9, 5195. (g) Chang, M.-Y.;
Lin, C.-Y.; Pai, C.-L. Tetrahedron Lett. 2006, 47, 2565.
3
bIsolated yield.
and anti-HIV and anti-HSV-1 and HSV-2 properties.12
The azetidine moiety has also been found in some natural
(11) (a) Bannon, A. W.; Decker, M. W.; Holladay, M. W.; Curzon, P.;
Donnelly-Roberts, D.; Puttfarcken, P. S.; Bitner, R. S.; Diaz, A.; Dickenson,
A. H.; Porsolt, R. D.; Williams, M.; Arneric, S. P. Science 1998, 279, 77. (b)
Cheng, Q.; Kiyota, H.; Yamaguchi, M.; Horiguchi, T.; Oritani, T. Bioorg.
Med. Chem. Lett. 2003, 13, 1075. (c) Singh, S.; Crossley, G.; Ghosal, S.;
Lefievre, Y.; Pennington, M. W. Tetrahedron Lett. 2005, 46, 1419. (d) Brandi,
A.; Cicchi, S.; Cordero, F. M. Chem. Rev. 2008, 108, 3988.
(12) (a) Nishiyama, S.; Kikuchi, Y.; Kurata, H.; Yamamura, S.; Izawa,
T.; Nagahata, T.; Ikeda, R.; Kato, K. Bioorg. Med. Chem. Lett. 1995, 5, 2273.
(b) Zoidis, G.; Fytas, C.; Papanastasiou, I.; Foscolos, G. B.; Fytas, G.;
Padalko, E.; Clercq, E. D.; Naesens, L.; Neyts, J.; Kolocouris, N. Bioorg.
Med. Chem. 2006, 14, 3341.
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Das et al.
JOCNote
SCHEME 2. Synthesis of a 2,4-Disubstituted N-Tosylazetidine
from an N-Tosylaldimine
N-Tosyl β-amino ketone 3a were reduced first with
NaBH4 in MeOH at room temperature to form the corres-
ponding N-tosyl γ-amino alcohols 4a and 4b in excellent
yields with a diastereomeric ratio of 76:24. The reduction
was completed within 1 h, and the diastereomers were
separated by column chromatography. The major amino
alcohol 4a was then treated15a,b with TsCl/KOH under
reflux for 45 min to produce 2,4-diaryl-N-tosylazetidine 5a
in three steps (overall yield 64%) (Table 3). Following a
similar method (Scheme 2), β-amino ketones 3g and
3i were converted into the corresponding N-tosylazeti-
dines 5b (overall yield 57%) and 5c (overall yield 61%),
respectively. Thus, the synthesis of these azetidines
was accomplished in three high-yielding steps starting
from N-tosylaldimines. The structures of azetidines were
deduced from the mode of their synthesis (Scheme 2) as
well as spectral [IR, 1H and 13C NMR, ESIMS and
HRMS(ESI)] data.
TABLE 3. Synthesis of 2,4-Disubstituted N-Tosylazetidines from
N-Tosylaldimines
In conclusion, we have developed a simple, mild, and
efficient method for synthesis of N-tosyl β-amino ketones
and also converted these compounds into the corresponding
2,4-disubstituted N-tosylazetidines. These amino ketones
and azetidines can be utilized for bioevaluation as well as
for preparation of various nitrogen-containing molecules of
biological importance.
Experimental Section
General Experimental Procedure for Synthesis of N-Tosyl
β-Amino Ketones. To a solution of N-tosylaldimine (1.0 mmol)
in CH2Cl2 (3 mL) was added acetophenone (1.1 mmol) under N2
atmosphere, and BF3 OEt2 (0.25 mmol) was added to this
3
mixture. The mixture was stirred at room temperature, and
the reaction was monitored by TLC. After completion, the
reaction mixture was washed with cold water (2 ꢀ 5 mL) and
subsequently extracted with CH2Cl2 (3 ꢀ 5 mL). The extract was
dried and concentrated. The residue was subjected to column
chromatography (silica gel, hexane-EtOAc) to obtain pure
N-tosyl β-amino ketone.
4-Methyl-N-(3-oxo-1,3-diphenylpropyl)benzenesulfonamide (3a).
IR: 3336, 1677, 1593, 1444, 1328 cm-1 1H NMR (200 MHz,
.
CDCl3): δ 7.81 (2H, d, J = 8.0 Hz), 7.62 (2H, d, J = 8.0 Hz), 7.55
(1H, t, J = 8.0 Hz), 7.40 (2H, t, J = 8.0 Hz), 7.24 - 7.10 (7H, m),
5.86 (1H, brs), 4.89 (1H, m), 3.59 (1H, dd, J = 17.0, 5.0 Hz), 3.42
(1H, dd, J = 17.0, 6.0 Hz), 2.36 (3H, s). 13C NMR (50 MHz,
CDCl3): δ 198.0, 143.7, 140.0, 137.2, 136.4, 133.7, 129.9,
129.2, 128.6, 127.5, 127.3, 126.4, 126.2, 54.8, 40.9, 20.6. HRMS
(ESI): m/z calcd for C22H21NO3SNa (M þ Na)þ 402.1139, found
402.1127.
General Experimental Procedure for Synthesis of N-Tosylaze-
tidines. N-Tosyl β-amino ketones were reduced with NaBH4
in MeOH at room temperature for 1 h following the usual
procedure to form N-tosyl γ-amino alcohols. These com-
pounds were subsequently utilized for the preparation of
N-tosylazetidines.
aOverall yield starting from N-tosylaldimines, after column chroma-
tographic purification.
bioactive molecules.13 In addition, ring-opening reactions
of azetidines have been utilized to construct various nitro-
gen-containing compounds.14 However, the methods for
the preparation of 2,4-disubstituted N-tosyl azetidines are
limited.15 We have observed that the prepared N-tosyl β-
amino ketones can conveniently be converted into 2,4-
disubstituted azetidines by reduction followed by cycliza-
tion (Scheme 2).
To a suspension of powdered KOH (3.1 mmol) in dry THF
(10 mL) was added TsCl (1.2 mmol). To this mixture was added
an N-tosyl γ-amino alcohol (1.1 mmol) dropwise at room
temperature. The mixture was refluxed for 45 min when the
reaction was completed. Cold water (10 mL) was added to the
mixture, and it was extracted with EtOAc (3 ꢀ 10 mL). The
extract was washed with brine (3 ꢀ 10 mL) and water (3 ꢀ
10 mL), dried over anhydrous Na2SO4, and concentrated under
reduced preassure. The crude product was subjected to column
chromatography (silica gel, hexane-EtOAc) to obtain pure
2,4-disubstituted N-tosylazetidine.
(13) (a) Fouden, L. Biochem. J. 1956, 64, 323. (b) Isono, K.; Asahi, K.;
Suzuki, S. J. Am. Chem. Soc. 1969, 91, 7490.
(14) (a) Akiyama, T.; Daidouji, K.; Fuchibe, K. Org. Lett. 2003, 5, 3691.
(b) Vanecko, J. A.; West, F. G. Org. Lett. 2005, 7, 2949. (c) Van Brabandt,
W.; Landeghem, R. V.; De Kimpe, N. Org. Lett. 2006, 8, 1105.
(15) (a) Powell, B. F.; Reichenthal, J.; Overberger, G. G.; Anselme, J.-P.
J. Hetero. Chem. 1980, 17, 219. (b) Ghorai, M. K.; Das, K.; Kumar, A.
Tetrahedron Lett. 2007, 48, 2471. (c) De Kimpe, N. In Comprehensive Hetero-
cyclic Chemistry II; Padwa, A., Ed.; Elsevier: Oxford, 1996, Vol. 1B, pp
507-589. (d) Davis, D. E.; Storr, R. C. In Comprehensive Heterocyclic
Chemistry; Lwowski, W., Ed.; Pergamon: Oxford, 1984; Vol. 7, pp 237-284.
J. Org. Chem. Vol. 74, No. 24, 2009 9507

Das et al.
JOCNote
2,4-Diphenyl-1-tosylazetidine (5a). IR: 1600, 1455, 1341, 1156
cm-1. 1H NMR (200 MHz, CDCl3): δ 7.61 (2H, d, J = 8.0 Hz),
7.48 (2H, d, J = 8.0 Hz), 7.40 - 7.22 (10H, m), 4.92 (2H, t, J =
7.0 Hz), 2.81 (1H, m), 2.41 (3H, s), 2.13 (1H, m). 13C NMR (50
MHz, CDCl3): δ 144.9, 141.2, 129.5, 128.6, 128.5, 127.5, 126.4,
62.1, 35.7, 21.0. HRMS (ESI): m/z calcd for C22H21NO2SNa
(M þ Na)þ 386.1190, found 386.1200.
Acknowledgment. We thank CSIR and UGC, New Delhi
for financial assistance.
Supporting Information Available: Experimental proce-
dure, spectral data and spectra [1H and 13C NMR and HRMS-
(ESI)] of the products 3a-l and 5a-c. This material is available
free of charge via the Internet at http://pubs.acs.org.
9508 J. Org. Chem. Vol. 74, No. 24, 2009