A convenient and simple procedure for the preparation of nitrate esters from alcohols employing LiNO3/(CF3CO)2O

Article abstract of DOI:10.1016/j.tetlet.2005.07.065

Alcohols in small peptides, monosaccharides and steroids (12 examples) are conveniently transformed to their corresponding nitrate esters upon treatment with an acetonitrile solution of LiNO₃ and trifluoroacetic anhydride. The in situ formed mi

Full text of DOI:10.1016/j.tetlet.2005.07.065

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6205–6207
A convenient and simple procedure for the preparation of
nitrate esters from alcohols employing LiNO3/(CF3CO)2O
Adina Gavrila, Lisbeth Andersen and Troels Skrydstrup*
Department of Chemistry, University of Aarhus, Langelandsgade 140, 8000 Aarhus C, Denmark
Received 15 June 2005;revised 1 July 2005;accepted 14 July 2005
Abstract—Alcohols in small peptides, monosaccharides and steroids (12 examples) are conveniently transformed to their corre-
sponding nitrate esters upon treatment with an acetonitrile solution of LiNO3 and trifluoroacetic anhydride. The in situ formed
mixed anhydride (CF3COONO2) is proposed to be the reactive nitration reagent.
Ó 2005 Published by Elsevier Ltd.
Subjection of nitrate esters to either photolysis or tri-
butyltin hydride–AIBN represents a viable source of
alkoxy radicals. Depending on the substrates, such reac-
tive radicals have successfully been exploited for syn-
thetically useful fragmentations,1–8 as well as hydrogen
atom abstractions.9 For example, Easton and co-work-
ers have demonstrated that nitrate esters of b-hydroxy-
a-amino acid derivatives react with tributyltin hydride
to afford alkoxy radicals, which can readily undergo
b-scission, providing a convenient route for the regio-
controlled production of a-carbon-centred amino acid
radicals.10,11
One of the more common methods for the conversion of
alcohols to nitrate esters requires treatment of an alco-
hol with a reactive mixed anhydride (acetyl nitrate) in
either acetic anhydride or acetic acid.15–17 As this nitra-
tion species is formed in situ from fuming nitric acid and
acetic anhydride, we explored the possibility of generat-
ing a more reactive mixed anhydride under less harsh
conditions starting from a nitrate salt and trifluoroacetic
anhydride (Scheme 1). The results of this study are de-
picted in Table 1 with the serine containing dipeptide 1.
Attempts were first made by simply mixing equimolar
amounts of dried lithium nitrate with trifluoroacetic
anhydride in various solvents. In all cases, the two
reagents were stirred together for 30 min at 20 °C and
Our interest in the generation of glycyl radicals via the
samarium diiodide promoted reduction of functional-
ized peptides12–14 prompted us to examine the use of
such nitrate esters of b-hydroxy-a-amino acid deriva-
tives. However, concerned about the compatibility and
reproducibility of the conditions for known nitration
reactions of alcohols (fuming nitric acid,15–17 mixtures
of nitric and sulfuric acid,15,17 boron trifluoride
hydrate–potassium nitrate18), we set out to develop a
more convenient one-step synthesis of nitrate esters
from alcohols.19 In this report, we demonstrate that
the combination of LiNO3/(CF3CO)2O/Na2CO3 in ace-
tonitrile provides a viable means for carrying out such
transformations under mild conditions.
OH
R1
R2
Ac2O + HONO2
(CF3CO)2O + MetONO2
O
O
NO2
??
NO2
F3C
O
H3C
O
ONO2
R2
R1
Keywords: Nitrate esters;Alcohols;Peptides;Carbohydrates;Steroids.
*
Corresponding author. Tel.: +45 8942 3932;fax: +45 8619 6199;
e-mail: ts@chem.au.dk
Scheme 1.
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.07.065

6206
A.Gavrila et al./ Tetrahedron Letters 46 (2005) 6205–6207
Table 1. Nitration studies with the dipeptide 1
OH
OMe
OR
OMe
O
O
CbzHN
CbzHN
Ph
N
N
see conditions
in table
H
H
O
O
Ph
1
2
R = NO2
3 R = COCF3
Entry
Nitration reagent
Solvent
Temperature (°C)
Yield of nitrate ester 2a (%)
Yield of trifluoroacetate 3 (%)
1
2
3
4
5
6
7
8
9
LiNO3/TFAA
LiNO3/TFAA
LiNO3/TFAA
LiNO3/TFAA Na2CO3
LiNO3/TFAA Na2CO3
NaNO3/TFAA Na2CO3
Mg(NO3)2/TFAA Na2CO3
Al(NO3)3/TFAA Na2CO3
LiNO3/Ac2O
CH2Cl2
THF
0
0
0
0
20
0
0
0
0
—
—
70
91
80
—
—
—
—
93
—
20
3
15
—
—
—
—
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Ac2O
a Isolated yields after recrystallization from EtOAc/pentane.
Table 2. Formation of nitrate esters with LiNO3/(CF3CO)2O/Na2CO3
in acetonitrile
then cooled to 0 °C prior to the addition of 1 (0.5 equiv).
Use of dichloromethane furnished almost exclusively the
corresponding trifluoroacetate 3 after a reaction time of
5 h (entry 1), which is explained by the lack of formation
of the mixed anhydride due to the insolubility of the lith-
ium nitrate. However, in both THF and acetonitrile, a
clear solution was obtained after stirring the two
reagents for approx 30 min. Whereas with THF as the
solvent, multiple products were formed upon addition
of the dipeptide (entry 2), in acetonitrile the desired
nitrate 2 could be isolated as the major product in
70% yield after recrystallization (entry 3). Nevertheless,
Entry Yield of nitrate Nitrate ester
estera (%)
O2NO
O
H
N
1
2
3
4
5
6
70
87
50
63
80
63
CbzHN
OMe
O
Ph
Ph
O
H
N
CbzHN
OMe
1
the H NMR spectrum of the crude reaction mixture
O
O
ONO2
revealed the presence of the trifluoroacetate 3 (entry 3)
with a ratio of 2:3 equal to 3.5:1. Performing the same
reaction in the presence of sodium carbonate in order
to neutralize the trifluoroacetic acid generated during
the reaction, improved the ratio of 2:3 considerably
and provided the nitrate ester in 91% yield (entry
4).20,21 Increasing the reaction temperature led to a de-
crease in the ratio (entry 5). As indicated in entries 6–
8, use of other nitrate sources proved ineffective for ni-
trate ester formation. Likewise, treatment of the alcohol
1 with LiNO3 in acetic anhydride also did not provide
any yield of the nitrate ester 2 (entry 9).
BocHN
O2NO
N
H
CO2Me
Ph
O
H
N
CbzHN
N
H
ONO2
CO2Me
CO2Me
O
O
O
Ph
O
H
N
With the identification of appropriate reaction condi-
tions for the alcohol to nitrate ester transformation,
we investigated the suitability of this approach to a vari-
ety of other alcohols as illustrated in Table 2.20 As indi-
cated, hydroxyl groups present in peptides (entries 1–5),
monosaccharides (entries 6–9) and steroids (entries
10 and 11) were conveniently converted to the nitrate
esters in acceptable to good yields upon subjection to
the LiNO3/(CF3CO)2O/Na2CO3 combination in aceto-
nitrile. The derivatized peptides, carbohydrates and
steroids were all purified by recrystallization as chroma-
tography led to reduced yields of some of the nitrate
esters particularly with the peptide substrates due to
their ability to undergo facile b-elimination. A double
nitration of the tert-butyl ester of deoxycholic acid was
CbzHN
N
H
ONO2
O
O
O
ONO2
O
O
O
O
7
59
ONO2
O
O

A.Gavrila et al./ Tetrahedron Letters 46 (2005) 6205–6207
6207
Table 2 (continued)
4. Lopez, J. C.;Alonso, R.;Fraser-Reid, B. J.Am.Chem.
Soc. 1989, 111, 6471–6473.
5. Yeung, W. A.;Alonso, R.;Vite, G. D.;Fraser-Reid, B. J.
Carbohydr.Chem. 1989, 3, 413–427.
Entry Yield of nitrate Nitrate ester
estera (%)
6. Begley, M. J.;Fletcher, R. J.;Murphy, J. A.;Sherburn, M.
O
O
O
O2NO
S. J.Chem.Soc,. Chem.Commun.
1993, 1723–1725.
7. Hussain, N.;Morgan, D. O.;White, C. R.;Murphy, J. A.
8
89
80
82
O
Tetrahedron Lett. 1994, 35, 5069–5072.
O
´
´
8. Francisco, C. G.;Leo n, E. I.;Martı n, A.;Moreno, P.;
´
´
Rodrıgez, M. S.;Sua rez, E. J.Org.Chem. 2001, 66, 6967–
O
O
6976.
O
9. Robins, M. J.;Guo, Z.;Samano, M. C.;Wnuk, S. F.
Am.Chem.Soc. 1999, 121, 1425–1433.
10. Easton, C. J.;Ivory, A. J.;Smith, C. A. J.Chem.Soc,.
Perkin Trans.2 1997, 503–507.
J.
O
9
O
O2NO
11. Headlam, H. A.;Mortimer, A.;Easton, C. J.;Davies, M.
J. Chem.Res.Toxicol. 2000, 13, 1087–1095.
12. Ricci, M.;Madariaga, L.;Skrydstrup, T. Angew.Chem,.
Int.Ed. 2000, 39, 242–245.
13. Ricci, M.;Blakskjær, P.;Skrydstrup, T. J.Am.Chem.Soc.
2000, 122, 12413–12421.
14. Blakskjær, P.;Gavrila, A.;Andersen, L.;Skrydstrup, T.
Tetrahedron Lett. 2004, 45, 9091–9094.
15. Boschan, R.;Merrow, R. T.;van Dolah, R. W. Chem.
Rev. 1955, 55, 485–510.
16. Campbell, R. D.;Behr, F. E. J.Org.Chem. 1973, 38,
1183–1186.
H
H
H
10
H
H
H
O2NO
O2NO
CO2tBu
H
H
11
65b
O2NO
H
17. Coombes, R. G. In Comprehensive Organic Chemistry:
The Synthesis and Reactions of Organic Compounds;
Barton, D. H. R., Ollis, W. D., Eds.;Pergamon Press:
Oxford, 1979;Vol. 2, pp 360–363.
a Isolated yield after recrystallization.
b 4 equiv of the nitration reagents used.
18. Olah, G. A.;Wang, Q.;Li, X.;Surya Prakash, G. K.
Synthesis 1993, 207–208.
also possible providing the corresponding dinitrate
diester in 65% yield (entry 11).
19. Other two-step procedures are also known such as alcohol
to sulfonate transformation followed by substitution with
a nitrate salt (Ref. 3), or generation of a chloroformate
followed by treatment with silver nitrate (Ref. 18).
20. General procedure for the nitration of alcohols: Trifluoro-
acetic anhydride (2.0 mmol) was added to a solution of
LiNO3 (2.0 mmol) in dry acetonitrile (5 mL) at 20 °C. The
mixture was stirred until complete dissolvation of LiNO3
(approx 30 min) and the solution was then cooled to 0 °C.
Sodium carbonate (2.0 mmol) and the alcohol (1.0 mmol)
were then added and the reaction mixture was stirred for
5–7 h. The reaction mixture was poured into an ice-cold
solution of saturated NaHCO3. Extraction with CH2Cl2
followed by drying and evaporation under reduced
pressure afforded the nitrate ester, which was purified by
recrystallization from EtOAc/hexane. Column chroma-
tography with the same solvent system led to reduced
yields for the peptide nitrates.
In conclusion, we have developed an alternative
approach for the nitration of alcohols under mild condi-
tions via a mixed anhydride generated from LiNO3/
(CF3CO)2O. Further work is in progress to test the com-
pabtibility of this approach with longer peptides, as well
as cyclic peptides and to examine the ability of these
nitrates to undergo reduction upon subjection to samar-
ium diiodide. This work will be reported in due course.
Acknowledgements
Generous financial support from the Danish Natural
Science Research Council, The Marie Curie Training
Program and the University of Aarhus, is gratefully
acknowledged.
21. Data for compound 2: 1H NMR (CDCl3, 400 MHz): d
(ppm) 7.38–7.15 (m, 10H), 6.77 (br s, 1H), 5.24 (br s, 1H),
5.10 (d, 1H, J = 10.0 Hz), 5.07 (d, 1H, J = 9.0 Hz), 4.83
(m, 1H), 4.76 (br d, 1H, J = 11.3 Hz), 4.69 (dd, 1H,
J = 11.3, 3.9 Hz), 4.49 (m, 1H), 3.76 (s, 3H), 3.13 (dd, 1H,
J = 14.0, 6.8 Hz), 3.07 (dd, 1H, J = 13.7, 6.6 Hz). 13C
NMR (CDCl3, 125 MHz): d (ppm) 171.4, 168.4, 156.2,
136.2, 136.0, 129.4, 129.2 (2C), 129.1, 129.0, 128.7, 128.5,
128.3, 127.4, 71.1, 67.5, 56.2, 53.4, 50.8, 38.2. ES-HRMS
C21H23N3O8 [M+Na+]: Calculated: 468.1383, found:
468.1391.
References and notes
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2047–2048.
2. Binkley, R. W.;Koholic, D. J. J.Carbohydr.Chem. 1984,
3, 85–106.
3. Tam, T. F.;Fraser-Reid, B. J.Chem.So,c. Chem.
Commun. 1984, 1122–1123.