Functional desymmetrization of 1,3-dioximes for the obtention of 1,2,3-hetero trisubstituted carbocycles

Article abstract of DOI:10.1016/j.tetlet.2010.02.048

Carbocylic 1,3-dioximes react with acyl chlorides giving systems that may, upon heating, suffer [3,3]-sigmatropic rearrangements in high yields in only one of the oximes esters, yielding 1,3-dinitrogen-2-oxygen trisubstituted carbocycles. Use of more reac

Full text of DOI:10.1016/j.tetlet.2010.02.048

Tetrahedron Letters 51 (2010) 2029–2031
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Functional desymmetrization of 1,3-dioximes for the obtention
of 1,2,3-hetero trisubstituted carbocycles
Valdemar B. C. Figueira a, Arantxa G. Esqué a, Ravi Varala a, Concepción González-Bello b,
a,
Sundaresan Prabhakar a, , Ana M. Lobo
*
*
a Chemistry Department, REQUIMTE/CQFB, and SINTOR-UNINOVA, Faculty of Sciences & Technology, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal
b Departamento de Química Orgánica, Facultad de Química, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Carbocylic 1,3-dioximes react with acyl chlorides giving systems that may, upon heating, suffer [3,3]-sig-
matropic rearrangements in high yields in only one of the oximes esters, yielding 1,3-dinitrogen-2-oxy-
gen trisubstituted carbocycles. Use of more reactive electrophiles, such as p-toluenesulfonyl chloride and
diethyl chlorophosphate, introduces the halogen at position 2, while cleaving the N–O bond of just one of
the oxime functions.
Received 11 January 2010
Revised 4 February 2010
Accepted 8 February 2010
Available online 12 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Oximes
Sigmatropic rearrangements
Carbocycles
Amines
Esters
1,2,3-Hetero trisubstituted carbocycles are important structural
features found in a variety of products of practical importance.
Examples are manifold and can bear the 1,2,3-trihydroxy motif, as
in the key biosynthetic precursor shikimic acid, or include other het-
eroatoms, such as nitrogen, as in the1,2-diamino-3-hydroxy present
in the anti-flu drug TamifluÒ.1 The size of the cycle can also vary, and
the 1,2,3-trisubstituted motif can be found embedded in, for exam-
ple, 5-membered rings, part of more complex structures.2,3
further heating at 110 °C for 22 h in toluene a smooth [3,3]-sig-
matropic rearrangement afforded the tribenzoyl 3a in 75% yield
[Scheme 2(a)].9
Compound 3a now displays the 3 contiguous heteroatoms N, O
and N, and still retains one oxime function for further transforma-
We disclose in this work a method to generate precursors of
the densely functionalized system of 1,3-diamino-2-hydroxy car-
bocycles by functional desymmetrization of simple symmetrical
cyclic 1,3-dioximes 1 (Scheme 1). These are simple compounds
which can be easily generated from the corresponding 1,3-dicar-
bonyl compounds by reaction with hydroxylamine.4 In basic
media, the anionic species derived from 1, that is, 1A, 1B, and
1C, are amenable to react with electrophiles. Species 1C, in par-
ticular, is a key for the desymmetrization reaction, since it con-
tains one of the oxime functions as the tautomeric ene-
hydroxylamine, ideally suited for further transformation.5–7 For
example, cyclohexan-1,3-dioxime (1a)8 (1 equiv), when reacted
at 0 °C to rt in the presence of a base (3 equiv), such as Et3N,
DABCO or Hunig’s, and a suitable electrophile such as Cl(CO)Ph
(3 equiv), gave rise after work-up to compound 2a which pre-
sented the diagnostic olefinic proton (d 6.63) in position 2. Upon
* Corresponding authors. Tel.: +351 212948387; fax: +351 212948550 (A.M.L.).
E-mail address: aml@fct.unl.pt (A.M. Lobo).
Scheme 1. 1,3-Dioximes as precursors of 1,3-diamino-2-hydroxy carbocycles.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.048

2030
V. B. C. Figueira et al. / Tetrahedron Letters 51 (2010) 2029–2031
Scheme 2. Reactions of 1,3-dioximes 1 and (a) benzoyl chloride, (b) p-toluenesulfonyl chloride, (c) diethyl chlorophosphate.
Table 1
Functional desymmetrization of 1,3-dioximes via [3,3]-sigmatropic rearrangement of their acyl derivatives
Entry
1,3-Dioxime
Electrophile
Temp (°C)
Solvent/time (h)
Productsa
Yieldb (%)
1
2
3
4
5
6
1a
1a
1b
1b
1c
1c
PhC(O)Cl
CH3C(O)Cl
PhC(O)Cl
CH3C(O)Cl
PhC(O)Cl
CH3C(O)Cl
110
110
110
110
110
110
Toluene/22
Toluene/15
Toluene/26
Toluene/22
Toluene/54
Toluene/42
3a
3b
3c
3d
3e
3f
75
95
85
92
60
98
a
All the products characterized by NMR, IR, and mass spectrometry.
Yield refers to pure products after chromatography and/or crystallization.
b
Figure 1. X-ray analysis of 6b (left) and packing in the unit cell (right).

V. B. C. Figueira et al. / Tetrahedron Letters 51 (2010) 2029–2031
2031
Table 2
Functional desymmetrization of 1,3-dioximes derivatives using strong electrophiles
Entry
1,3-Dioxime
Electrophile
Temp (°C)
Solvent/time (h)
Productsa
Yieldb (%)
1
2
3
4
5
6
1a
1a
1b
1b
1c
1c
p-CH3C6H4SO2Cl
(EtO)2P(O)Cl
p-CH3C6H4SO2Cl
(EtO)2P(O)Cl
p-CH3C6H4SO2Cl
(EtO)2P(O)Cl
0 to rt
0 to rt
0 to rt
0 to rt
0 to rt
0 to rt
THF/12
THF/6.5
THF/12
THF/5
THF/12
THF/6
6a
7a
6b
7b
6c
7c
98
60
74
70
73
81
a
All the products characterized by NMR, IR, and mass spectrometry.
Yield refers to pure products after chromatography and/or crystallization.
b
tion. Other 1,3-dioximes, such as the substituted 1b,10 (Table 1, en-
tries 3 and 4) as well as five-membered ring oximes, such as 1c,11
(entries 5 and 6) reacted in a similar fashion.
With more reactive electrophiles, such as p-toluenesulfonyl
chloride, reaction with 1b gave instead compound 6b most proba-
bly via the intermediates 4b and 5b [Scheme 2(b)]. Introduction of
the halogen at position 2 occurs now with simultaneous cleavage
of the N–O bond of one the oximes derivatives.
The X-ray structure of 6b, shown in the Figure 1, confirms the
structure attributed and reveals an interesting crystal packing with
strong interactions among the aromatic rings (p–p) as well as in be-
tween thesulfonyl group of one moleculeand the amino groupof an-
other, leading to a ladder-type structure.12 Other similar results 7a–
c, obtained with ClP(O)(OEt)2, are collected in Table 2 (entries 2, 4
and 6) [cf. Scheme 2(c)]. In conclusion the yields of the compounds
obtained range from good to excellent and the ease of the reaction
makes it suitable for application to a wide variety of carbocycles,
intermediates in the synthesis of more complex materials.
4. Part of this work was presented in the XXI National Meeting of the Portuguese
Chemical Society, Oporto, June 2008.
5. Dannenberg, H.; Meyer, E. Chem. Ber. 1969, 102, 2384–2391; Bhatt, M. V.; Rao,
C. G.; Rengaraju, S. Chem. Commun. 1976, 103a; Bhatt, M. V.; Reddy, G. S.
Tetrahedron Lett. 1980, 21, 2359–2360; Reddy, G. S.; Bhatt, M. V. Indian J. Chem.
Sect. B: Org. Chem. 1980, 19, 213–215.
6. Reis, L. V.; Lobo, A. M.; Prabhakar, S.; Duarte, M. P. Eur. J. Org. Chem. 2003, 190–
208.
7. Reis, L. V.; Lobo, A. M.; Prabhakar, S. Tetrahedron Lett. 1994, 35, 2747–2750.
8. Heilbron, H.; Bunburry, L. W.. In Dictionary of Organic Compounds; Eyre &
Spottiswood: New York, 1953; Vol. 2.
9. Experimental procedure: Table 1, entry 1—to a solution of dioxime 1a (142 mg,
1 equiv) in dry distilled THF, under inert atmosphere, was added at rt with
stirring i-Pr2NEt (3 equiv). The mixture was then cooled in an ice-bath and
benzoyl chloride (3 equiv) carefully added. The reaction was allowed to reach
room temperature and showed the full consumption of the starting dioxime
after 2 h. The amine salt was removed by filtration and the resulting solution
was evaporated under vacuum, the residue of 2a redissolved in CH2Cl2, washed
with brine, dried and heated in toluene t 110 °C for 22 h to afford after work-up
and purification by preparative TLC (SiO2, CH2Cl2/n-hexane, 1:1)
crystalline solid (yield 75%) of 3a: mp 164–165 °C (CH2Cl2:n-hexane); IR (KBr)
: 3419, 3067, 1750, 1689, 1645, 1599 cmÀ1 1H NMR (400 MHz, CDCl3) dH:
a white
t
;
1.99 (2H, m), 2.92 (2H, t, J = 6.4 Hz), 3.26 (2H, t, J = 6.0 Hz), 7.39–7.68 (9H, m,
ArH), 7.71 (2H, d, J = 7.3 Hz), 8.02 (2H, d, J = 7.2 Hz), 8.11 (1H, br s), 8.24 (2H, d,
J = 8.4 Hz, ArH) ppm; 13C NMR (CDCl3) selected dC: 163.23, 164.42, 165.04 ppm.
Calcd C27H22N2O5: C, 71.35; H, 4.88; N, 6.16. Found: C, 71.29; H, 4.97; N, 6.10.
Table 2, entry 4—to a solution of dioxime 1b (170 mg, 1 equiv) in dry destilled
THF (5 ml), under inert atmosphere, was added at rt with stirring i-Pr2NEt
(3 equiv). The mixture was then cooled in an ice-bath and diethyl
chlorophosphate (3 equiv) carefully added. The reaction was allowed to reach
room temperature and showed the full consumption of the starting dioxime
after 5 h. The amine salt was removed by filtration and the resulting solution
was evaporated under vacuum, the residue dissolved in CH2Cl2, washed with
brine, dried and the product purified by preparative TLC (SiO2, AcOEt) to give a
Acknowledgments
We thank the Foundation for Science and Technology (Lisbon,
Portugal) for partial financial support and for research fellowships
(to V.B.C.F. and R.V.). The bilateral Portugal–Spain Cooperation
Agreement—AI/E-59/06—is also thanked for financing the stay in
the Portuguese Laboratory of A.G.E. It is a pleasure to record
our gratitude to Ms. Luz Fernandes and Ms. Carla Rodrigues of
REQUIMTE Analytical Services Laboratories for, respectively, mass
spectra and elemental analyses.
clear light-yellow oil (214 mg, yield 70%) of 7b: IR (KBr)
m
: 3326, 3208, 2961,
1633, 1600, 1557, 1470, 1386, 1367, 1258, 1165, 1034 cmÀ1
;
1H NMR
(400 MHz, CDCl3) dH: 1.04 (6H, s), 1.36 (6H, t, J = 7.0 Hz), 2.21 (2H, s), 2.59
(2H, s), 4.21–4.29 (4H, m), 4.56 (2H, br s) ppm; 13C NMR (CDCl3) dC: 14.21 (2C),
19.70, 27.41, 27,56, 37.12, 46.51, 59.84 (2C), 124.65, 129.8, 166.75 ppm; 31P
NMR (CDCl3) dP: À0.137 ppm; EI–MS m/z: 324 (8) [M]+), 289 (3), 188 (3), 174
(14), 172 (48), 137 (53), 116 (62), 99 (100). Calcd. C12H22ClN2O4P: C, 44.38; H,
6.83; N, 8.63. Found: C, 44.56; H, 6.69; N, 8.39. Table 2, entry 3—a similar
protocol but using instead p-toluenesulfonyl chloride afforded after 12 h a
white crystalline solid (yield 74%) of 6b: mp 148–150 °C (CH2Cl2/n-hexane); IR
References and notes
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Schultze, L. M.; Yu, R. H.; Zhang, L. J. Org. Chem. 1998, 63, 4545–4550;
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(KBr)
m
: 3472, 3371, 3203, 2960, 1633, 1595, 1469, 1359, 1278, 1190, 1176,
1122 cmÀ1
;
1H NMR (400 MHz, CDCl3) dH: 0.99 (6H, s), 2.16 (2H, s), 2.42 (3H, s),
2.51 (2H, s), 4.64 (2H, br s), 7.31 (2H, d, J = 8.2 Hz), 7.91 (2H, J = 8.2 Hz). Calcd.
C15H19ClN2O3: C, 52.55; H, 5.59; N, 8.17. Found: C, 52.67; H, 5.39; N, 8.32.
All new compounds gave correct microanalyses and/or HRMS. Spectral data for
selected compounds: dH (CDCl3), 7a: 1.38 (6H, t, J = 7.12 Hz), 2.24 (2H, t,
J = 6.3 Hz), 2.51 (2H, t, J = 6.9 Hz), 2.76 (2H, quint, J = 6.4 Hz), 4.19–4.25 (4H, m),
4.68 (2H, br s); 6a: 1.75–1.81 (2H, quint, J = 6.3 Hz), 2.31–2.35 (2H, t, J = 6.2 Hz),
2.43 (3H, s), 2.68–2.71 (2H, t, J = 6.5 Hz), 7.32 (2H, d, J = 8.1 Hz), 7.93 (2H, d,
J = 8.2 Hz); 8.02 (2H, d, J = 7.2 Hz), 8.11 (1H, br s), 8.24 (2H, d, J = 8.4 Hz); 3b:
1.92 (2H, m), 2.14 (3H, s), 2.16 (3H, s), 2.27 (3H, s), 2.51 (2H, t, J = 6.3 Hz), 2.72
(2H, t, J = 5.8 Hz) 8.05 (1H, br s); 3f: 2.12 (3H, s), 2.16 (3H, s), 2.29 (3H, s), 3.10
(2H, m), 3.52 (2H, m), 8.90 (1H, br s).
2. Li, S.-W.; Batey, R. A. Chem. Commun. 2007, 3759–3761. and references cited
therein.
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Katritzsky, A. R., Meth-Cohn, O., Rees, C. W., Eds.; Oxford: Pergamon, 1995; Vol. 3,
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Compd 2005, 41, 722–729.
11. Aldrich’s reagents catalogue 2007.
12. CCDC 756960 contains the crystallographic data which can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, by emailing data_request
@ccdc.cam.ac.uk, or by contacting CCDC, UK; fax: +44 1223 336033.