Stereoselective denitrohydrogenation reactions of 4-alkyl-5-glyco-4-nitrocyclohex-1-enes

Article abstract of DOI:10.1016/S0957-4166(01)00304-4

The denitrohydrogenation of chiral 4-alkyl-5-glyco-4-nitrocyclohex-1-enes (1 and 3) with tri-n-butyltin hydride and azobisisobutironitrile proceeded in a completely stereoselective way. In each case, the hydrogen atom provided by tri-n-butyltin hydride adds to a free radical intermediate in a trans mode to the adjacent, sterically demanding, sugar side-chain. Attempts to perform denitroalkylation reactions of 1a, 3a or 8 with electron-deficient alkenes yielded only denitrohydrogenated products.

Full text of DOI:10.1016/S0957-4166(01)00304-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1673–1675
Stereoselective denitrohydrogenation reactions of
4-alkyl-5-glyco-4-nitrocyclohex-1-enes
M. V. Gil,a E. Roma´n,a,* J. A. Serrano,a M. B. Hursthouseb and M. E. Lightb,*
aDepartamento de Qu´ımica Orga´nica, Facultad de Ciencias, Universidad de Extremadura, 06071 Badajoz, Spain
bDepartment of Chemistry, University of Southampton, Southampton SO17 1BJ, UK
Received 13 June 2001; accepted 29 June 2001
Abstract—The denitrohydrogenation of chiral 4-alkyl-5-glyco-4-nitrocyclohex-1-enes (1 and 3) with tri-n-butyltin hydride and
azobisisobutironitrile proceeded in a completely stereoselective way. In each case, the hydrogen atom provided by tri-n-butyltin
hydride adds to a free radical intermediate in a trans mode to the adjacent, sterically demanding, sugar side-chain. Attempts to
perform denitroalkylation reactions of 1a, 3a or 8 with electron-deficient alkenes yielded only denitrohydrogenated products.
© 2001 Elsevier Science Ltd. All rights reserved.
The replacement of a nitro group by hydrogen consti-
tutes a useful process in synthetic organic chemistry.
This type of reaction was first reported in 1978 by
Kornblum et al.1 who utilized tertiary nitro compounds
and the sodium salt of methanethiol as a denitrating
agent. Since them, many other reagents have been
discovered,2 the most extensively used being tri-n-
butyltin hydride (TBTH) in the presence of a radical
initiator as benzoyl peroxide3 or azobis(isobutyryl-
nitrile) (AIBN);4 this metal hydride has been shown to
effect selective and clean denitrohydrogenation of ter-
tiary and even some secondary nitro compounds with-
out affecting other functional groups. Furthermore, as
these reactions with TBTH are known to proceed
through alkyl free radical intermediates, tertiary and
secondary nitro compounds can also be used as ade-
quate substrates for intra- or intermolecular radical
CꢀC bond-forming reactions.5
cyclohexenes 1a, 3b, 3c and 3d (Scheme 1) in which a
sugar side-chain, that is adjacent to the nitro function-
ality, works as the stereodifferentiating element. The
configuration at C(4) and C(5) of these starting com-
pounds is a consequence of their provenance from
either
D
-galacto- or
D-manno-1-nitroalkenes, that
yielded the above cited nitrocyclohexenes through
cycloaddition with 2,3-dimethylbuta-1,3-diene, followed
by Michael reaction of the resulting Diels–Alder adduct
with methyl acrylate, acrylonitrile or methyl vinyl
ketone.10 Attempts at radical denitroalkylations
between these substrates and olefins are also described.
Nevertheless, given the importance and potential appli-
cations of the denitration reaction, surprisingly few
reports have been focused on studying the stereochemi-
cal outcome;6 to our knowledge, apart from the works
of Sinou7 and Barco,8 in which stereoselective denitro-
hydrogenations were effected, this problem has only
been treated in radical cyclizations of certain nitroalk-
anes.5a,5c,5d,9 Herein, we report our preliminary findings
in the denitrohydrogenation reactions of tertiary nitro-
* Corresponding authors. E-mail: roman@unex.es
Scheme 1.
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00304-4

1674
M. V. Gil et al. / Tetrahedron: Asymmetry 12 (2001) 1673–1675
detected, the reactions yielded non-crystallizable oils,
that had to be purified by column chromatography on
silica gel. In addition to the expected 4b (40%), 4c
(65%) and 4d (54% yield), we found fractions that
contained mixtures of partially deacetylated com-
pounds,13,14 which probably arise through silica gel
promoted catalytic processes.
Treatment of 1,2,3,4,5-penta-O-acetyl-1-C-[(4R,5S)-
1,2-dimethyl-4-(2-methoxycarbonylethyl)-4-nitrocyclo-
hex-1-en-5-yl]-
-galacto-pentitol 1a10 with 2 equivalent
D
of TBTH in refluxing benzene (2 h.) in the presence of
AIBN (0.5 equivalent) led, after evaporation of the
solvent and crystallization (MeOH) of the resulting oil,
to 1,2,3,4,5-penta-O-acetyl-1-C-[(4S,5S)-1,2-dimethyl-
4 - (2 - methoxycarbonylethyl)cyclohex - 1 - en - 5 - yl] - D-
galacto-pentitol 2a.
The opposite configurations at C(4) and C(5) for 2a
and 4b were deduced from data of their respective
aldehyde derivatives 2g and 4g, which showed spectral
identity and nearly equal and opposite values for their
optical rotations.15 These aldehydes were prepared by a
two-step sequence, in which treatment of pure pentaac-
etates 2a or 4b (or their denitrohydrogenation reaction
mixtures) with sodium methoxide afforded pentitols 2e
(67%) and 4f (64%); then, oxidative cleavage of their
deacetylated sugar side-chains with sodium metaperio-
date yielded quantitatively aldehydes 2g and 4g. Based
on the proposed pathway for denitrohydrogenation
showed in Scheme 2, and also taking into account the
1
The H NMR spectrum of the crude mixture at the end
of the reaction time indicated a single denitrohydro-
genated product, thus the process was completely
stereoselective. The structure of the new compound 2a
is supported by elemental analysis and spectroscopic
1
data (IR, H and 13C NMR);11 the absolute configura-
tion at C(4) being unambiguously established by X-ray
single crystal structure analysis.12 The result of this (see
Fig. 1), showed that both chains on the cyclohexene
ring, i.e. the sugar side-chain at C(5) (C(1%)ꢀC(5%)) and
the other at C(4) (C(1¦)ꢀC(4¦)) adopt roughly planar,
zig–zag conformations. The torsion angles C(1¦)ꢀ
C(4)ꢀC(5)ꢀC(1%)=66.9° and C(4)HꢀC(4)ꢀC(5)ꢀC(5)H=
64.6° indicate a cis-relationship between substituents at
C(4) and C(5).
1
close resemblance of H and 13C NMR spectra between
compounds 4b, 4c and 4d, we propose that they must
present identical configurations at their stereogenic cen-
ters, C(4) and C(5).
As pointed out above, the free radical intermediates
arising in denitrohydrogenation reactions could partici-
pate in CꢀC bond-forming processes when they are
treated with electron-deficient alkenes. For example,
Dupuis et al.5b reported on the reaction of nitro sugar
6 and a large excess of acrylonitrile in the presence of
TBTH/AIBN, yielding product 7 in 55% yield (Scheme
3).
Figure 1. ORTEP view of compound 2a.
Scheme 3.
Since a free radical intermediate 5 (Scheme 2) would be
involved in denitration of 1a, it is noteworthy that only
one of the possible stereoisomeric products was formed.
This completely stereoselective process could be ration-
alized by supposing that the hydrogen atom, provided
by tri-n-butyltin hydride, adds to the less-hindered face
of 5; i.e. the opposite to that occupied by the sterically
demanding sugar side-chain.
By using the same methodology, we reacted tertiary
nitro compounds 1a and 3b (and even the secondary 8)
with either methyl acrylate or acrylonitrile; however, we
found that only the respective denitrohydrogenated
compounds 2a (55%), 4b (38%) and 9 (27% isolated
yield) were formed, with any evidence of hypothetical
4,4-dialkyl-5-glycocyclohexenes, as for example 10.
This result, that indicates severe steric crowding in the
radical intermediate 5, could support the complete
stereoselection observed in the denitrohydrogenation
reaction.
Scheme 2.
In order to check our above results, we carried out
reactions starting from 3b, 3c and 3d, and using the
same conditions described for the preparation of 2a.
Although in each one of the respective reaction mix-
tures only one denitrohydrogenated product was

M. V. Gil et al. / Tetrahedron: Asymmetry 12 (2001) 1673–1675
1675
Acknowledgements
11.7, H-5%), 3.78 (dd, 1H, J4%,5¦ 7.3, H-5¦), 3.63 (s, 3H,
COOCH3), 2.3–2.1 (m, 2H, H-2¦a, H-2¦b), 2.11 (s, 3H,
OCOCH3), 2.09 (s, 6H, 2×OCOCH3), 2.08 (s, 3H,
OCOCH3), 2.00 (s, 3H, OCOCH3), 1.94 (m, 1H, J5,6a
10.0, H-6a), 1.9–1.45 (m, 4H, H-1¦a, H-1¦b, H-3a, H-6b),
1.72 (m, 1H, H-5), 1.56 (s, 6H, CH3-1, CH3-2), 1.48 (m,
1H, H-3b), 1.37 (m, 1H, H-4); 13C NMR (100 MHz,
CDCl3, ppm): 174.3 (C-3¦), 170.5, 170.4, 170.3, 170.0
(OCOCH3), 123.8, 123.2 (C-1, C-2), 71.0 (C-1%), 68.2
(C-2%, C-3%), 68.1 (C-4%), 62.7 (C-5%), 38.4 (C-5), 35.5 (C-6),
32.5 (C-3, C-2¦), 31.7 (C-4), 30.1 (C-1¦), 21.0, 20.9, 20.8,
20.7 (OCOCH3), 19.3, 18.9 (CH3-1, CH3-2). Anal. calcd
for C27H40O12: C, 58.26; H, 7.24. Found: C, 58.28; H,
7.21%. All the other new compounds were fully charac-
terized by spectroscopic means (1H, 13C NMR, IR) and
analytical or HRMS data.
This work was supported by the Spanish Ministerio de
Educacio´n y Cultura (CICYT, PB98-0997) and the
Junta de Extremadura-Fondo Social Europeo through
grant IPR98A066. We also thank the Junta de
Extremadura for a fellowship to M. V. Gil.
References
1. Kornblum, N.; Carlson, S. C.; Smith, R. G. J. Am.
Chem. Soc. 1978, 100, 290; Ibid. 1979, 101, 647.
2. (a) KOH in ethylene glycol: Krasuska, A. L.; Pitrowska,
H.; Urbanski, T. Tetrahedron Lett. 1979, 1243; (b) 1-Ben-
zyl-1,4-dihydronicotinamide: Ono, N.; Tamura, R.; Kaji,
A. J. Am. Chem. Soc. 1980, 102, 2851; Ibid. 1983, 105,
4017; (c) Lithium aluminium hydride: Rosini, G.; Ballini,
R. Synthesis 1983, 137; (d) Sodium hydrogentelluride:
Suzuki, H.; Takaota, K.; Osuka, A. Bull. Chem. Soc. Jpn.
1985, 58, 1067; (e) Hydride transfer in the presence of a
palladium(0) complex: Ono, N.; Hamamoto, I.;
Kamimura, A.; Kaji, A. J. Org. Chem. 1986, 51, 3734; (f)
Enzymes: Blehert, D. S.; Knoke, K. L.; Fox, B. G.;
Chambliss, G. H. J. Bacteriol. 1997, 179, 6912; (g)
Na2S2O4–Et3SiH in HMPA–H2O: Kamimura, A.;
Kurata, K.; Ono, N. Tetrahedron Lett. 1989, 30, 4819.
3. Tanner, D. D.; Blackburn, E. V.; D´ıaz, G. E. J. Am.
Chem. Soc. 1981, 103, 1557.
12. A single crystal of 2a, crystallizing from methanol by
slow evaporation of the solvent, with approximate size of
0.30×0.20×0.10 mm was employed. The compound crys-
tallized in the monoclinic space group P2 with a=
,
A,
5.8425(5),
b=18.5242(18),
c=13.2751(7)
3
,
i=90.885(4)°, V=1436.6(2) A , Z=2, Dc=1.280 Mg/
m3, v=0.101 mm. The intensities were measured on an
Enraf Nonius Kappa CCD area detector diffractometer
(ƒ and ꢀ scans to fill the Ewald sphere). A total of 8586
reflections were collected in the range q 3.07–75° utilizing
,
Mo Ka radiation (u=0.71073 A), and of these 4544 were
independent (Rint=0.0726). The structure was solved by
direct methods with SHELXS-86 (Sheldrick, G. M. Acta
Crystallogr. 1990, A46, 467) and refined by full matrix
least squares using SHELXL-97 (Sheldrick, G. M. Pro-
gram for Crystal Structure Refinement; University of
Go¨ttingen: Germany, 1997). X-Ray crystallographic data
have been deposited with the Cambridge Crystallographic
Data Centre (CCDC 165154), which are available free of
charge from the Director, Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK.
13. From the reaction mixture of 3b, the C(4%) deacetylated
product (5% yield) was isolated in addition to 4b. This
showed C(4%)H at 3.69 ppm, coupled with OH (D2O
exchangeable signal, 3.33 ppm).
4. Ono, N.; Miyake, H.; Tamura, R.; Kaji, A. Tetrahedron
Lett. 1981, 22, 1705.
5. (a) Ono, N.; Miyake, H.; Kamimura, A.; Hamamoto, I.;
Tamura, R.; Kaji, A. Tetrahedron 1985, 41, 4013; (b)
Dupuis, J.; Giese, B.; Hartung, J.; Leising, M. J. Am.
Chem. Soc. 1985, 107, 4332; (c) Chen, Y. J.; Chang, W.
H. J. Org. Chem. 1996, 61, 2536; (d) Grossman, R. B.;
Rasne, R. M.; Patrick, B. O. J. Org. Chem. 1999, 64,
7173.
6. For a general review concerning stereoselection with rad-
ical systems, see: Curran, D. P.; Porter, N. A.; Giese, B.
Stereochemistry of Radical Reactions; VCH: Weinheim,
1996.
7. Brakta, M.; Lhoste, P.; Sinou, D.; Banoub, J. Carbohydr.
Res. 1990, 203, 148.
8. Barco, A.; Benetti, S.; De Risi, C.; Pollini, G. P.; Romag-
noli, R.; Spalluto, G.; Zanirato, V. Tetrahedron 1994, 50,
2583.
14. Probably due to partial deacetylation, the yields of 4b
and 4d were only moderate. In fact, when the crude
denitrohydrogenation mixture from 3b was treated with
sodium metaperiodate, deacetylated derivative 4f was iso-
lated in 64% yield.
15. Compound 2g: [h]D=−3.0 (c 2.0, CHCl3); 4g: [h]D=+3.0
(c 2.0, CHCl3). These enantiomeric compounds were oils,
showing the following spectroscopic data: IR (film, cm−1):
9. (a) Chen, Y. J.; Lin, W. Y. Tetrahedron Lett. 1992, 33,
1749; (b) Chen, Y. J.; Lin, W. Y. Tetrahedron 1993, 49,
10263; (c) Chen, Y. J.; Chen, Ch. M.; Lin, W. Y.
Tetrahedron Lett. 1993, 34, 2961.
1
2900, 2840, 2820, 2700, 1700, 1190, 1150; H NMR (400
MHz, CDCl3, ppm): 9.72 (d, 1H, J5,CHO 1.2, CHO), 3.67
(s, 3H, H-4¦), 2.54 (m, 1H, J4,5=J5,6a=J5,6b 4.0, H-5),
2.38 (m, 2H, H-2¦a, H-2¦b), 2.21 (m, 2H, H-6a, H-6b),
2.13 (d, 1H, J3a,4 5.2, H-3a), 2.06 (m, 1H, H-4), 1.90 (dd,
1H, J3a,3b 16.6, J3b,4 7.3, H-3a), 1.70 (m, 2H, H-1¦a,
H-1¦b), 1.65 and 1.61 (each s, each 3H, CH3-1, CH3-2);
13C NMR (100 MHz, CDCl3, ppm): 205.0 (CHO), 173.7
(C-3¦), 124.7, 123.4 (C-1, C-2), 51.5, 49.5 (C-4¦, C-5),
33.9 (C-4), 35.2, 32.0, 30.2 (C-3, C-6, C-1¦, C-2¦), 19.0,
18.8 (CH3-1, CH3-2).
10. Areces, P.; Gil, M. V.; Higes, F. J.; Roma´n, E.; Serrano,
J. A. Tetrahedron Lett. 1998, 39, 8557.
11. Analytical data for the representative compound 2a:
white solid; yield (unoptimized) 57%; mp 128–130°C; Rf
0.64 (hexane:EtOAc, 1:1); [h]D=+69.5 (c 0.51; CHCl3);
IR (KBr, cm−1): 2980, 2920, 2840, 1730, 1630, 1210, 1020;
1H NMR (400 MHz, CDCl3, ppm): 5.33 (d, 1H, J2%,3% 9.6,
H-2%), 5.16 (m, 1H, H-4%), 5.13 (dd, 1H, J3%,4% 1.6, H-3%),
5.06 (d, 1H, J1%,5 9.2, H-1%), 4.32 (dd, 1H, J4%,5% 4.4, J5%,5¦
.