An efficient reduction protocol for the synthesis of β-hydroxycarbamates from β-nitro alcohols in one pot: a facile synthesis of (-)-β-conhydrine

Article abstract of DOI:10.1016/j.tetlet.2008.08.113

An efficient and practical one-pot protocol for the reduction of β-nitro alcohols to their corresponding N-(tert-butoxycarbonyl) amino alcohols using Zn-NH₄Cl in aqueous methanol is described. Other reducible groups such as ketones and isolated double bonds remained intact. This methodology allows a short synthesis of (-)-β-conhydrine to be achieved.

Full text of DOI:10.1016/j.tetlet.2008.08.113

Tetrahedron Letters 49 (2008) 6508–6511
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient reduction protocol for the synthesis of b-hydroxycarbamates
from b-nitro alcohols in one pot: a facile synthesis of (ꢀ)-b-conhydrine
*
Partha Pratim Saikia, Gakul Baishya, Abhishek Goswami, Nabin C. Barua
Natural Products Chemistry Division, North East Institute of Science and Technology, Jorhat 785 006, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and practical one-pot protocol for the reduction of b-nitro alcohols to their corresponding
N-(tert-butoxycarbonyl) amino alcohols using Zn–NH4Cl in aqueous methanol is described. Other
reducible groups such as ketones and isolated double bonds remained intact. This methodology allows
a short synthesis of (ꢀ)-b-conhydrine to be achieved.
Received 25 July 2008
Revised 26 August 2008
Accepted 29 August 2008
Available online 3 September 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
b-Nitro alcohols
b-Hydroxy amine
b-Hydroxycarbamates
Zn–NH4Cl (aq)
b-Conhydrine
b-Amino alcohols are useful intermediates in the elaboration of
pharmacologically important products and are also widely used in
the preparation of chiral auxilaries.1 They are also found as impor-
NH
NH
OH
tant partial structures of many bioactive compounds such as
a/b-
OH
adrenergic agonists or antagonists,2 HIV protease inhibitors3 and
antifungal or antibacterial peptides.4 The presence of this moiety
and the stereochemistry of the hydroxyl as well as the amino group
play a vital role in the biological activity of the parent compound.
Moreover, a number of their amide derivatives, isolated from bac-
terial cultures display significant activity against aminopepti-
dases.5 A straightforward method for the synthesis of b-amino
alcohols involves reduction of 2-nitroalcohols, which are prepared
by condensing aliphatic nitro compounds with a carbonyl com-
pound.6 Reduction of aromatic nitro compounds to aryl amines
can be effected using various reagents.7 However, procedures for
reduction of aliphatic nitro compounds to their corresponding
amines are rare.8 The most commonly used methods for reduction
of nitro aliphatics involve catalytic hydrogenation processes and
therefore are not applicable to substrates containing double bonds.
The use of Zn–NH4Cl (aq) for reduction of aromatic nitro com-
pounds to their corresponding aryl amines has been reported in
the literature, but the scope of this method was not fully explored
with aliphatic nitro compounds, especially 2-nitroalcohols, which
are known to be susceptible to retro-Henry cleavage.9 In continua-
(–)-β-conhydrine
(+)-β-conhydrine
Figure 1.
tion of our interest in the synthesis of biologically active natural
products using aliphatic nitro compounds,10 and our ongoing
efforts to synthesize the alkaloid (ꢀ)-b-conhydrine (Fig. 1), we
needed a method to reduce 2-nitroalcohol 7a (Table 1) to its b-
hydroxy carbamate without affecting the double bond. Our initial
attempts to reduce the nitro group in 4-nitro-6-hepten-3-ol (7a)
14
with NaBH4/10% Pd–C,11 NaBH4–Ni2B,12 LAH,13 LAH–AlCl3 and
Sn/HCl15 did not give the desired product and suffered from the
drawbacks of complete reduction of both the nitro bond and the
double bond and/or decomposition. We argued that Zn–NH4Cl
(aq) might be the system of choice in this case, as catalytic hydro-
genation is not a part of the reduction process with this reagent. As
expected, when the substrates listed in Table 1 (entries 1–11) were
treated with Zn–NH4Cl (aq) at 0 °C, the reaction proceeded
smoothly to give the corresponding 2-amino alcohol in almost
quantitative yield (Scheme 1). To our satisfaction, the isolated dou-
ble bond (entries 3, 7 and 11) remained unaffected under these
reaction conditions. We also observed that when Boc2O was added
* Corresponding author.
E-mail address: ncbarua12@rediffmail.com (N. C. Barua).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.113

P. P. Saikia et al. / Tetrahedron Letters 49 (2008) 6508–6511
6509
Table 1
Reduction of 2-nitro alcohols to 2-hydroxy carbamates in one-pot using Zn–NH4Cl(aq)/Boc2O in methanol
Entry
Substratea
Product
2-Amino alcohol
2-Hydroxy carbamateb
(Yield)c
83
OH
NO2
OH
OH
1
NH2
NHBoc
Cl
Cl
Cl
1b
1a
1c
OH
OH
OH
NO2
OH
NHBoc
NH2
OH
2
3
89
78
2b
2a
2c
OH
NH2
NO2
NHBoc
O
O
O
3c
3a
3b
OH
OH
OH
4
84
NO2
4a
NH2
4b
NHBoc
4c
OH
OH
OH
5
6
82
83
6
6
6
NO2
NH2
NHBoc
5c
5a
5b
OH
OH
OH
NH2
NO2
NHBoc
6c
6a
6b
OH
OH
OH
7
8
76
86
NO2
7a
NH2
7b
NHBoc
7c
OH
OH
OH
NH2
NHBoc
NO2
8a
8b
9b
8c
OH
NO2
OH
OH
NHBoc
NH2
9
79
73
9a
9c
Ph OH
NHBoc
Ph OH
NO2
Ph OH
NH2
10
10a
10b
10c
O
O
O
O2N
H2N
BocHN
11
78
11c
11a
11b
a
b-Nitroalcohols 1a–7a were prepared by condensing the appropriate nitroalkane with the appropriate aldehyde in the presence of a base. Compounds 8a–10a were
prepared from 2-nitrocyclohexane following literature procedures, and compound 11 was prepared by Michael addition of nitromethane to carvone. All the products were
characterized by spectroscopic methods before use.
b
Products were characterized by IR, NMR and MS.
Yield refers to the isolated yield of the carbamate.
c
to the crude reaction mixtures, the corresponding b-hydroxycarba-
mates were formed in excellent yields in one-pot.
In a further experiment, carvone was treated with Zn–NH4Cl
(aq) and it was observed that the conjugated double bond of carv-

6510
P. P. Saikia et al. / Tetrahedron Letters 49 (2008) 6508–6511
pyridine in 90% yield. In order to install the piperidine ring system
NHBoc
R3
NO2
NH2
R2
R1
R2
R1
R2
R1
present in the target molecule, compound 12 was subjected to allyl-
ation with allyl bromide and NaH in DMF at room temperature to
give the diallyl compound 13 in 78% yield. Compound 13 was then
treated with 10 mol % of Grubbs’ second generation catalyst fol-
lowing a reported method21 to give the expected cyclic enamine
which was further hydrolysed using K2CO3 in methanol to furnish
the corresponding alcohol 14 in 75% yield over two steps. Finally,
the cyclic enamine 14 was subjected to Pd-C catalyzed hydrogena-
tion followed by Boc deprotection to afford (ꢀ)-b-conhydrine. The
physical and spectral properties of our synthetic material closely
matched with the literature data. Similarly, the synthesis of the
other isomer, (+)-b-conhydrine can be achieved simply by chang-
ing the ligand in the asymmetric Henry reaction step.
In conclusion, an efficient synthesis of (ꢀ)-b-conhydrine has
been achieved in 21% overall yield using an asymmetric Henry
reaction and our new method for reduction of b-nitro alcohols to
their b-hydroxy carbamates as the key steps. To the best of our
knowledge, this is the first asymmetric synthesis of (ꢀ)-b-conhy-
drine using Shibasaki’s asymmetric Henry reaction as the source
of chirality. The synthetic strategy described has significant poten-
tial for further extension to the synthesis of (+)-b-conhydrine.
General procedure for the one-pot reduction of 2-nitro alcohols to
2-hydroxy carbamates: To a stirred solution of the 2-nitro alcohol
(1 mmol) in methanol and saturated ammonium chloride solution
(4 mL, 1:1) was added zinc dust (10 mmol) portionwise over
15 min while maintaining the temperature at 0 °C. After 10 min,
(Boc)2O (1.2 mmol) was added and the reaction mixture was
allowed to warm to room temperature. After completion of the
reaction (TLC), the reaction mixture was filtered through Celite,
the methanol was distilled off under vacuo and the aqueous resi-
due was extracted with diethyl ether (3 ꢁ 15 mL). The combined
organic phases were dried (Na2SO4) and concentrated. The crude
product was purified by column chromatography over silica gel.
Spectral data of selected compounds: Compound 3c: 1H (300 MHz,
CDCl3): 7.43–7.26 (m, 2H), 6.92–6.89 (m, 2H), 6.11–5.98 (m, 1H),
5.38 (dd, 2H, J = 18.0, 9.0 Hz), 5.02–5.00 (m, 1H), 4.52 (d, 2H,
J = 6.0 Hz), 3.71–3.66 (m, 1H), 3.62–3.61 (m, 1H), 1.45 (s, 9H); 13C
(75 MHz, CDCl3): d 153.5, 132.8, 126.9, 125.5, 114.4, 78.2, 74.6,
(Boc)2O
73-89%
Zn/NH4Cl
aq MeOH
R3
R3
OH
OH
OH
R1= alkyl, R2= H,alkyl, aryl, R3 = H, alkyl
Scheme 1.
one was reduced under these reaction conditions without affecting
the isolated double bond which reveals that this reagent works in a
single electron transfer (SET) fashion.
We next focused our attention on the synthesis of (ꢀ)-b-conhy-
drine, which is a natural alkaloid having a 2-(1-hydroxyalkyl)
piperidine unit and was isolated from the seeds and leaves of the
poisonous plant Conium maculatum L.16 Various methods docu-
mented in the literature17 for the synthesis of (ꢀ)-b-conhydrine
are based mainly on either auxiliary-supported or chiral pool ap-
proaches. In formulating a synthetic route to (ꢀ)-b-conhydrine,
we envisaged that the piperidine ring unit could be obtained from
ring-closing metathesis of the dialkene 13 followed by catalytic
hydrogenation. The key intermediate amino alcohol 7c can be
traced back to 4-nitro-1-butene. We contemplated that the stereo-
chemistry at the C-3 and C-4 positions of b-conhydrine could be
secured via Shibasaki’s asymmetric Henry reaction18 (Scheme 2).
The synthesis was initiated employing Shibasaki’s asymmetric
Henry reaction of 4-nitro-1-butene19 with propionaldehyde in
the presence of La-(R)-BINOL catalyst at ꢀ50 °C in THF to afford
the key intermediate 7a in 74% yield and 91% ee20 (Scheme 3).
Treatment of 2-nitroalcohol 7a with Zn–NH4Cl (aq)/Boc2O gave
the corresponding b-hydroxy carbamate 7c in 76% yield, which
was then protected as the acetate 12 with acetic anhydride and
Shibasaki
NH
NBoc
RCM
OH
m
3392, 1698, 1632 cmꢀ1; MS (ESI)
13
68.5, 37.4, 27.9; IR (CHCl3):
OAc
m/z: 293.1 (M+); Compound 4c: 1H (300 MHz, CDCl3): 4.82–4.79
(m, 1H), 3.49–3.47 (m, 1H), 3.3 (br s, 1H), 2.7 (br s, 1H), 1.44 (m,
2H), 1.37 (s, 9H), 1.01 (d, 3H, J = 9.0 Hz), 0.89 (t, 3H, J = 4.5 Hz);
13C (75 MHz, CDCl3): d 155.9, 79.0, 75.5, 49.5, 28.0, 26.06, 18.03,
NHBoc
9.1; IR (CHCl3):
m
3440, 2977, 1690 cmꢀ1; MS (ESI) m/z: 203.1
NO2
4-nitro-1-butene
(M+); Compound 5c: 1H (300 MHz, CDCl3): 4.90–4.85 (m, 1H),
3.6–3.5 (m, 1H), 1.42 (s, 9H), 1.26–1.18 (m, 16H), 1.06 (d, 3H,
J = 6.0 Hz), 0.85 (t, 3H, J = 6.0 Hz); 13C (75 MHz, CDCl3): d 155.9,
79.0, 74.4, 50.1, 33.8, 33.1, 31.5, 29.2, 28.0, 27.4, 25.7, 22.3, 13.7;
OH
7c
Scheme 2. Retrosynthetic analysis of (ꢀ)-b-conhydrine.
NHBoc
NO2
b
76%
a
NO2
74%
OR
OH
7c R = H
7a
c
90%
12 R = Ac
NBoc
NBoc
e
NH
f
d
75%
over two steps
73%
over two steps
78%
OAc
OH
OH
β)-conhydrine
13
14
(–)-(
Scheme 3. Reagents and conditions: (a) propionaldehyde, La-(R)-BINOL, THF, ꢀ50 °C, 60 h; (b) Zn–NH4Cl/MeOH, (Boc)2O, 0 °C–rt, 2 h; (c) Ac2O, pyridine, rt, 2 h; (d) NaH, allyl
bromide, DMF, 0 °C–rt; (e) (i) Grubbs’ catalyst, CH2Cl2, rt, 10 h; (ii) K2CO3, MeOH; (f) (i) H2, 10% Pd–C, MeOH, 1 atm (ii) TFA, rt.

P. P. Saikia et al. / Tetrahedron Letters 49 (2008) 6508–6511
6511
IR (CHCl3):
m
3440, 2976, 1687 cmꢀ1; MS (ESI) m/z: 301.2 (M+);
References and notes
Compound 9c: 1H (300 MHz, CDCl3): 4.5 (br s, 1H), 3.49–3.36 (m,
1H), 1.77–1.70 (m, 2H), 1.66–1.62 (m, 2H), 1.45 (s, 9H), 1.18–
1.17 (m, 4H), 1.11 (s, 3H); 13C (75 MHz, CDCl3): d 156.1, 79.7,
1. (a) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835–875; (b)
Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
Eds., 1st ed.; Springer: Berlin, 1999; (c) Catalytic Asymmetric Synthesis, 2nd ed.;
Ojima, I., Ed.; Wiley-VCH: New York, 2000.
2. (a) Bloom, J. D.; Dutia, M. D.; Johnson, B. D.; Wilssner, A.; Burns, M. G.; Largis, E.
E.; Dolan, J. A.; Claus, T. H. J. Med. Chem. 1992, 35, 3081–3084; (b) Howe Rao, B.
S.; Holloway, B. R.; Stribling, D. J. Med. Chem. 1992, 35, 1751–1759.
3. Askin, D.; Wallace, M. A.; Vacca, J. P.; Reamer, R. A.; Volante, R. P.; Shinkai, I. J.
Org. Chem. 1992, 57, 2771–2773.
75.1, 54.1, 30.0, 28.0, 24.4, 22.7, 22.5, 19.3; IR (CHCl3):
m 3343,
2932, 1686 cmꢀ1; MS (ESI) m/z: 229.1 (M+); Compound 7a: ½a 2D0
ꢂ
ꢀ6.6 (c 0.6, CHCl3); 1H (300 MHz, CDCl3): 5.75–5.71 (m, 1H), 5.21
(dd, 2H, J = 9.0, 3.0 Hz), 4.53–4.50 (m, 1H), 3.85–3.81 (m, 1H),
2.62–2.57 (m, 2H), 1.60–1.49 (m, 2H), 0.97 (t, 3H, J = 7.5 Hz); 13C
(75 MHz, CDCl3): d 136.7, 124.2, 96.6, 78.2, 39.5, 31.3, 10.8; IR
4. Ohfune, Y. Acc. Chem. Res. 1992, 25, 360–366.
5. (a) Umezaw, K.; Ikeda, Y.; Uehihata, Y.; Naganaw, H.; Kondo, S. J. Org. Chem.
2000, 65, 459–463; (b) Babine, R. L.; Bender, S. E. Chem. Rev. 1997, 97, 1359–
1472.
6. Ballini, R.; Bosica, G.; Forconi, P. Tetrahedron 1996, 52, 1677–1684 and
references cited therein.
7. Zhang, Y.; Ma, K.; Wang, H.; Sun, X.; Jiang, J.; Wang, J.; Li, R.; Ma, J. Catal. Lett.
2008 and references cited therein.
8. Ankner, T.; Hilmersson, G. Tetrahedron Lett. 2007, 48, 5707–5710.
9. (a) Saikia, A. K.; Hazarika, M. J.; Barua, N. C.; Bezbarua, M. S.; Sharma, R. P.;
Ghosh, A. C. Synthesis 1996, 981–985; (b) Bezbarua, M. S.; Saikia, A. K.; Barua, N.
C.; Kalita, D. Synthesis 1996, 1289–1290.
10. (a) Kalita, D.; Khan, A. T.; Barua, N. C.; Bez, G. Tetrahedron 1999, 55, 5177–5184;
(b) Kalita, B.; Barua, N. C.; Bezbarua, M. S.; Bez, G. Synlett 2001, 1411–1414; (c)
Borah, J. C.; Gogoi, S.; Boruwa, J.; Kalita, B.; Barua, N. C. Tetrahedron Lett. 2004,
45, 3689–3691; (d) Gogoi, N.; Boruwa, J.; Barua, N. C. Tetrahedron Lett. 2005, 46,
7581–7582; (e) Boruwa, J.; Barua, N. C. Tetrahedron 2006, 62, 1193–1198; (f)
Gogoi, N.; Boruwa, J.; Barua, N. C. Eur. J. Org. Chem. 2006, 1722–1725.
11. Ballini, R.; Petrini, M.; Rosini, G. Synthesis 1987, 713–714.
12. Osby, J.; Ganem, B. Tetrahedron Lett. 1985, 26, 6413–6416.
13. Nakagawa, M.; Kodato, S.; Nakayama, K.; Hino, T. Tetrahedron Lett. 1987, 28,
6281–6284.
(CHCl3):
m
3420, 2924, 1637, 1551 cmꢀ1; MS (ESI) m/z: 159.0
(M+); Compound 7c: ½a 2D0
ꢂ
ꢀ24.1 (c 0.8, CHCl3); 1H (300 MHz,
CDCl3): 5.72–5.70 (m, 1H), 5.19–5.16 (m, 2H), 3.17–3.14 (m, 1H),
3.02–2.99 (m, 1H), 2.57–2.51 (m, 2H), 1.58–1.46 (m, 2H), 1.38 (s,
9H), 0.94 (t, 3H, J = 4.8 Hz); 13C (75 MHz, CDCl3): d 134.1, 122.8,
85.5, 77.5, 36.5, 30.5, 27.3, 10.9; IR (CHCl3):
m 3396, 2929, 1743,
1641 cmꢀ1; MS (ESI) m/z: 229.2 (M+); Compound 12: ½a 2D0
ꢀ7.6 (c
ꢂ
0.7, CHCl3); 1H (300 MHz, CDCl3): 5.71–5.69 (m, 1H), 5.20 (dd,
2H, J = 8.5, 3.0 Hz), 4.68 (m, 1H), 3.24–3.23 (m, 1H), 2.56–2.53
(m, 2H), 1.82 (s, 3H), 1.66–1.61 (m, 2H), 1.36 (s, 9H), 0.97 (t, 3H,
J = 7.5 Hz); 13C (75 MHz, CDCl3): d 169.6, 159.2, 130.2, 119.8,
88.6, 72.9, 46.3, 33.7, 29.9, 21.0, 20.4, 11.6; IR (CHCl3):
m 3428,
1689, 1642, 1219 cmꢀ1; MS (ESI) m/z: 294.1 (M++ Na); Compound
13: ½a 2D0
ꢂ
ꢀ6.5 (c 0.4, CHCl3); 1H (300 MHz, CDCl3): 5.63–5.47 (m,
2H), 5.10–5.05 (m, 4H), 4.30–4.21 (m, 1H), 3.11–3.09 (m, 1H),
2.55–2.43 (m, 4H), 1.85 (s, 3H), 1.64–1.62 (m, 2H), 1.43 (s, 9H),
1.05 (t, 3H, J = 9.0 Hz); 13C (75 MHz, CDCl3): d 168.5, 158.7, 131.7,
125.5, 118.6, 87.9, 71.8, 45.9, 38.3, 29.0, 20.9, 19.4, 12.2, 7.5; IR
14. Fieser, L. F.; Fieser, M. In Reagents for Organic Synthesis; Wiley: New York, 1967;
Vol. 1, p 1179.
15. Smith, M. B. Oxidation. In Organic Synthesis, 2nd ed; McGraw-Hill: New York,
2002; pp 258–263.
(CHCl3):
m
3403, 1702, 1638, 772 cmꢀ1; MS (ESI) m/z: 311.1 (M+);
16. Wertheim, T. Liebigs Ann. Chem. 1856, 100, 328–330.
Compound 14: ½a 2D0
ꢂ
ꢀ28.5 (c 0.4, CHCl3); 1H (300 MHz, CDCl3):
17. (a) Comins, L. D.; Williams, A. L. Tetrahedron Lett. 2000, 41, 2839–2842; (b)
Agami, C.; Couty, F.; Rabasso, N. Tetrahedron 2001, 57, 5393–5401; (c) Agami,
C.; Couty, F.; Rabasso, N. Tetrahedron Lett. 2000, 41, 4113–4116; (d) Pandey, S.
K.; Kumar, P. Tetrahedron Lett. 2005, 46, 4091–4093.
18. (a) Sasai, H.; Suzuki, T.; Arai, T.; Shibasaki, M. J. Am. Chem. Soc. 1992, 114, 4418–
4420; (b) Sasai, H.; Suzuki, T.; Itoh, N.; Shibasaki, M. Tetrahedron Lett. 1993, 34,
851–854.
5.22–5.17 (m, 1H), 4.98–4.91 (m, 1H), 3.83–3.80 (m, 2H),
3.64–3.61 (m, 1H), 3.53–3.49 (m, 1H), 2.45–2.43 (m, 2H), 1.54–
1.51 (m, 2H), 1.37 (s, 9H), 0.87 (t, 3H, J = 7.5 Hz); 13C (75 MHz,
CDCl3): d 155.5, 129.7, 121.2, 75.2, 69.1, 52.3, 42.5, 28.8, 21.5,
18.7, 7.2; IR (CHCl3):
m
3403, 1687, 1634 cmꢀ1; MS (ESI) m/z:
19. Witucki, E. F.; Rowley, G. L.; Warner, M.; Frankel, M. B. J. Org. Chem. 1972, 37,
152–154.
264.1 (M++Na).
20. The enantiomeric excess (ee) was measured by HPLC analysis that was carried
out using a Waters 510 HPLC system. A Chiracel OD packed in a SS column of
4.6 mm i.d. ꢁ 250 m was used. Isocratic elution was applied with a mobile
phase consisting of n-hexane 90% and isopropanol 10% at a flow rate of 0.8 mL/
min and a pressure of 125 psi. UV detection at 243 nm.
21. For recent review on ring closing metathesis see: (a) Fürstner, A. Angew. Chem.,
Int. Ed. 2000, 39, 3031–3043; (b) Prunet, J. Angew. Chem., Int. Ed. 2003, 42,
2826–2830.
Acknowledgements
The authors thank the Director, NEIST, Jorhat for providing facil-
ities to carry out this work. P.P.S. and A.G. also thank CSIR and UGC
New Delhi, respectively, for the award of fellowships.