Observations on the reaction of nitronate anions with oxalyl chloride: A new method for the preparation of geminal chloronitroso compounds

Article abstract of DOI:10.1016/j.tetlet.2010.11.031

A simple method for the preparation of geminal chloronitroso compounds from secondary nitro compounds via their derived nitronate anions is presented.

Full text of DOI:10.1016/j.tetlet.2010.11.031

Tetrahedron Letters 52 (2011) 2097–2099
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Observations on the reaction of nitronate anions with oxalyl chloride:
a new method for the preparation of geminal chloronitroso compounds
⇑
Rafael Bou-Moreno, Sandra Luengo-Arratta, William B. Motherwell
Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 23 November 2010
A simple method for the preparation of geminal chloronitroso compounds from secondary nitro com-
pounds via their derived nitronate anions is presented.
Ó 2010 Elsevier Ltd. All rights reserved.
Dedicated with respect, affection and
gratitude to Professor Harry Wasserman, a
creative scientist, a scholar and a gentleman
on the occasion of his 90th birthday
Keywords:
Chloronitroso
Hetero Diels–Alder
Oxalyl chloride
Nitronate anion
The use of the rich and extensive chemistry of the highly reac-
tive nitroso group has burgeoned in recent years. This is a direct
consequence of its wide ranging reactivity, as illustrated; inter alia,
by its behaviour as a radicophile,1 an ambident electrophile for
both amination2 and oxyamination3 and especially of course as a
partner in pericyclic processes such as the Alder—ene4 and hetero
Diels–Alder reactions.5 To some extent, however, the selection of a
particular nitroso compound for a given reaction is always a com-
promise between reactivity and stability with methods ranging, for
example, from the in situ generation of highly reactive acyl nitroso
intermediates6 to the selection of much more stable aryl nitroso
as, for example, in competitive chloronium ion formation from
an olefinic oxime.13
In light of the above situation, we were therefore, intrigued by
the possible existence of the alternative strategy outlined in
Scheme 1, whereby the simple reaction of a nitronate anion (1)
with oxalyl chloride would proceed via O-acylation (2) followed
by chloride anion capture to give 3 and subsequent breakdown
to the desired geminal chloronitroso compound 4. Precedent for
the initial O-acylation step comes from a seminal study by Zefirov
on the [2,3] sigmatropic rearrangement of acyloxy nitronic acids.14
We now report the results of our preliminary study of this
transformation.
compounds.7 Within this framework, geminally functionalised
chloronitroso compounds, as with their
-acetoxy congeners,8
a-
a
In the first instance, several early experiments provided
valuable insight into the necessary requirements for successful
implementation of this mechanistic pathway. Thus, as shown in
Scheme 2, even though it was possible to reproduce the simple
are of particular value, since liberation of the free amino group
by subsequent hydrolytic cleavage becomes possible. This protocol
has been demonstrated in such useful reactions as electrophilic
amination using the Oppolzer sultam,9 in an elegant chiral variant
of the hetero ene reaction by Vasella,10 and especially by construc-
tion of the valuable 3,6-dihydro-1,2-oxazine unit through nitroso
Diels–Alder cycloaddition.5 Methods for the preparation or in situ
ene reaction of a-methyl styrene with 1-chloro-1-nitrosocyclohex-
ane15 (6) prepared from the oxime by standard electrophilic chlo-
rination, an attempted in situ reaction from nitrocyclohexane (9)
led to the isolation of oxime (5) and cyclohexanone (10), without
any evidence for the desired nitrone (8) or its hydrochloride salt
7. It was significant to note however, that the bright blue colour
of the geminal nitroso compound was observed during this reac-
tion and indeed was also noted both in the absence of the alkene
and also with 2-nitropropane.
generation of an
a-chloronitroso compound invariably involve
treatment of an oxime with an electrophilic halogen source such
as chlorine11 or tert-butyl hypochlorite.12 However, such oxidising
reagents are often incompatible with more sensitive functionality
A possible explanation for the apparent instability of the gemi-
nal chloronitroso compound under the reaction conditions and the
subsequent isolation of the oxime is shown in Scheme 3.
⇑
Corresponding author. Tel.: +44 (0) 2076797533; fax: +44 (0) 2076797524.
E-mail address: w.b.motherwell@ucl.ac.uk (W.B. Motherwell).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.031

2098
R. Bou-Moreno et al. / Tetrahedron Letters 52 (2011) 2097–2099
Cl
O
O
O
O
O
R
O
R
N
R
N
Cl
+
Cl
O
N
O
R1
R2
O
N
O
R1
R2
Cl
R
M
O
6
11
M
Cl
1
2
SET
O
N
R
R
R
NO2
12
O
Cl
R
Cl
-CO2
-CO
R1
O
N
R1
O
N
O
-Cl-
M
Ph
R2
O
R2
Cl
Cl
R
+
+MCl
R
NO2
R
R
Ph
N
O
R
N
4
3
X
R
O
Scheme 1.
14
12
H atom
Ph
SET
abstraction
O
N
OH
OH
N
R
R
R
R
N
Work up
Cl
Cl
N
O
N
OH
NO2
+
Ph
i
ii
R
R
5
Ph
5
6
7
Scheme 3.
-HCl
O
N
Table 1
Optimisation conditions
Ph
Entry
Base
Solvent (yield of (16)%)
Et2O
THF
Toluene
8
53%
iii
iv
ii
NO2
OH
O
N
1
2
3
4
5
6
LDA
23
35
41
—
60
82
4
37
23
—
51
56
21
3
16
—
66
85
LiHMDS
nBuLi
+
NaH
KOtBu
KOtBu/nBuLi
9
5
22%
10
36%
Scheme 2. Reagents and conditions: (i) t-BuOCl (1.2 equiv), K2CO3 (5.0 equiv),
CH2Cl2, 0 °C, 1 h. (ii) -Methylstyrene, rt, 2 d. (iii) t-BuOK (1.0 equiv), Et2O, 0 °C, 1 h.
a
(iv) Oxalyl chloride (1.0 equiv, 0 °C), 1 h.
iv
i, ii, iii
Cl
O
N
O
NO2
Cl
N
Thus, if single electron transfer (SET) between the product
a-
chloronitroso compound (6) and nitronate anion (11) was to occur,
the expulsion of chloride from the resultant radical anion (12)
would be especially favoured in terms of generating a low energy
iminoxyl radical (13 M 14) which can then undergo either hydro-
15
v
gen atom abstraction from a-methyl styrene or a second electron
transfer from nitronate anion followed by protic workup to give
the observed oxime (5).
Cl
O
NH2
16
A logical consequence of the above hypothesis is that the con-
tact time between the nitronate anion and the product chloronitr-
oso compound should be minimised, and an experimental protocol
involving a rapid single addition of oxalyl chloride to nitronate was
accordingly adopted. We also noted parenthetically that, as in the
conversion of acids to acid chlorides, the addition of a catalytic
amount of dimethylformamide can also be beneficial if required.
The second practical factor which surfaced in preliminary
screening experiments related to efficient generation of a reactive
nitronate anion, especially since separate isolation of a nitronate
salt is not advisable.16 In this respect, a selection of bases and sol-
vent systems were tested (Table 1) using the reaction sequence
shown in Scheme 4, which involved generation of 2-chloro-2-nitr-
osopropane (15) from 2-nitropropane followed by hetero Diels–Al-
der trapping with 1,3-cyclohexadiene and hydrolysis to give the
known bicyclic adduct (16).17
Scheme 4. Reagents and conditions: (i) base (1.0 equiv), Et2O, 0 °C. (ii) Oxalyl
chloride (5.0 equiv). (iii) Filtration. (iv) Cyclohexadiene (3.0 equiv). (v) MeOH, aq
HCl.
Whilst examination of the results in Table 1 indicated, as ex-
pected, that O-acylation is favoured by the selection of a charge
separated potassium nitronate, the overall superiority of Schlos-
ser’s base (entry 6) for the deprotonation serves as a cogent remin-
der that nitronate anion formation is a slow process subject to
general base catalysis with a linear free energy relationship ob-
served between the acidity of the nitroalkane and the rate of ioni-
sation (2-nitropropane pKa = 7.74) and a similar relationship also
noted between the strength of the base and the rate of ionisation.
For 2-nitropropane at room temperature the ratio [Me2C@NO2H]/
[Me2CHNO2] is 3 Â 10À3 18
.
By comparison, lithium nitronates

R. Bou-Moreno et al. / Tetrahedron Letters 52 (2011) 2097–2099
2099
proved to be inferior whilst efforts to prepare the sodium nitronate
salt using sodium hydride, either with or without imidazole as a
catalyst, were unsuccessful.
In summary, the above results exemplify a direct simple and
practical method for the preparation of geminal chloronitroso
compounds from secondary nitro compounds via their derived
nitronate anions. Furthermore, in contrast to traditional methods,
the present protocol obviates the necessity of using an electrophilic
chlorinating reagent and hence provides an alternative non-oxida-
tive strategy for this useful functionalised unit.
Whilst the above study indicates that the generation of 2-
chloro-2-nitrosopropane proceeds in at least 85% yield, the vast
majority of [4+2] cycloadditions in the literature have relied on
the use of less volatile 1-chloro-1-nitrosocyclohexane as a reagent.
Under otherwise identical conditions the selection of nitrocyclo-
hexane furnished adduct (16) in 55% yield. In the first instance,
as shown in Scheme 5, it was therefore, of interest to demonstrate
that the above method could be used to prepare and, albeit at the
expense of efficiency, isolate (6) as a deep blue liquid.
Acknowledgements
The authors would like to thank Dr. Abil E. Aliev for his collab-
oration on the NMR study.
Given that 2-nitropropane is a much cheaper and more atom
economical reagent than 1-nitrocyclohexane and that the resultant
geminal chloronitroso compound is less sterically congested than
its cyclohexyl congener, we have also carried out a brief compara-
tive study of standard Diels–Alder reactions involving simple cyclic
dienes which have been shown to be, inter alia, useful precursors
for highly functionalised cyclopentanoids,8a inositols19 and tropane
alkaloids.20
For straightforward comparative purposes the yields of the iso-
lated adducts shown are based on the diene and involve the use of
only 1.5 M equivalents of the nitro compound, even though many
of the literature protocols employ an excess of the chloronitroso
reagent in order to achieve higher conversion (Table 2). Compari-
son of the reactions involving cyclopentadiene with those of cyclo-
heptadiene indicates that the selection of the smaller nitroso
reagent may be beneficial in more hindered situations. For the case
of cyclohepta-3,5-diene-1-ol the comparable yields with either
chloronitroso reagent may arise as a consequence of hydrogen
bonding from the hydroxyl to the nitroso group which can then
facilitate delivery of the reagent.8a This idea is also supported by
the observed diastereoselectivity of 88:12 in favour of the isomer
shown as determined by a careful NOE NMR study. Overall, how-
ever, in situ generation from 2-nitropropane is generally
recommended.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.11.031.
References and notes
1. For a review of spin traps see Janzen, E. G. Acc. Chem. Res. 1971, 4, 31–40.
2. (a) Yamamoto, H.; Kawasaki, M. Bull. Chem. Soc. Jpn. 2007, 80, 595–607; (b)
Yamamoto, Y.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 4128–4129.
3. (a) Guo, H.-M.; Cheng, L.; Cun, L.-F.; Gong, L.-Z.; Miac, A.-G.; Jiang, Y.-Z. Chem.
Commun. 2006, 429–431; (b) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji, M.
Tetrahedron Lett. 2003, 44, 8293–8296.
4. Adam, W.; Krebs, O. Chem. Rev. 2003, 103, 4131–4146.
5. (a) Gouverneur, V.; McCarthy, S. J.; Mineur, C.; Belotti, D.; Dive, G.; Ghosez, L.
Tetrahedron 1998, 54, 10537–10554; (b) Vogt, P. F.; Miller, M. J. Tetrahedron
1998, 54, 1317–1348; (c) Streith, J.; Defoin, A. Synthesis 1994, 1107–1117; (d)
Waldmann, H. Synthesis 1994, 535–551; (e) Weinreb, S. M. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon Press:
New York, 1991; Vol. 5, pp 401–512; (f) Weinreb, S. M.; Staib, R. R. Tetrahedron
1982, 38, 3087–3128; (g) Kirby, G. W. Chem. Soc. Rev. 1977, 6, 1–24.
6. (a) Pulacchini, S.; Sibbons, K. F.; Shastri, K.; Motevalli, M.; Watkinson, M.; Wan,
H.; Whiting, A.; Lightfoot, A. P. Dalton Trans. 2003, 2043–2052; (b) Flower, K. R.;
Lightfoot, A. P.; Wan, H.; Whiting, A. J. Chem. Soc., Perkin Trans. 1 2002, 2058–
2064; (c) Iwasa, S.; Fakhruddin, A.; Tsukamoto, Y.; Kameyama, M.; Nishiyama,
H. Tetrahedron Lett. 2002, 43, 6159–6161; (d) Iwasa, S.; Tajima, K.; Tsushima, S.;
Nishiyama, H. Tetrahedron Lett. 2001, 42, 5897–5899; (e) Flower, K. R.;
Lightfoot, A. P.; Wan, H.; Whiting, A. Chem. Commun. 2001, 1812–1813; (f)
Jenkins, N. E.; Ware, R. W., Jr.; Atkinson, R. N.; King, S. B. Synth. Commun. 2000,
30, 947–953; (g) Martin, S. F.; Hartmann, M.; Josey, J. A. Tetrahedron Lett. 1992,
33, 3583–3586; (h) Kirby, G. W.; Sweeny, J. G. J. Chem. Soc., Chem. Commun.
1973, 704–705.
O
NO2
Cl
N
i, ii
7. Streith, J.; Defoin, A. Synlett 1996, 189–200.
28%
8. (a) Calvet, G.; Guillot, R.; Blanchard, N.; Kouklovsky, C. Org. Biomol. Chem. 2005,
3, 4395–4401; (b) Calvet, G.; Dussaussois, M.; Blanchard, N.; Kouklovsky, C.
Org. Lett. 2004, 6, 2449–2451.
9. Oppolzer, W.; Tamura, O. Tetrahedron Lett. 1990, 31, 991–994.
10. (a) Braun, H.; Felber, H.; Krebe, G.; Ritter, A.; Schmidtchen, F. P.; Schneider, A.
Tetrahedron 1991, 47, 3313–3328; (b) Krebe, G.; Vasella, A.; Felber, H.; Ritter,
A.; Ascherl, B. Recl. Trav. Chim. Pays-Bas 1986, 105, 295–298.
9
6
Scheme 5. Reagents and conditions: (i) Et2O, 0 °C, n-BuLi, KOtBu, 30 min. (ii) Oxalyl
chloride (2.5 equiv), 15 min.
11. (a) Tordeux, M.; Boumizane, K.; Wakselman, C. J. Fluorine Chem. 1995, 70, 207–
214; (b) Oxenrider, B. C.; Rogic, M. M. J. Org. Chem. 1982, 47, 2629–2633; (c)
Sakai, I.; Kawabe, N.; Ohno, M. Bull. Chem. Soc. Jpn. 1979, 52, 3381–3383; (d)
Schenk, C.; De Boer, T. J. Recl. Trav. Chim. Pays-Bas 1979, 98, 18–21; (e) Müller,
E.; Fries, D.; Metzger, H. Chem. Ber. 1954, 88, 1449–1460.
Table 2
Synthesis of bicyclic adducts
12. (a) Archibald, T. G.; Garver, L. G.; Baum, K.; Cohen, M. C. J. Org. Chem. 1989, 54,
2869–2873; (b) Lee, G. A. Synthesis 1982, 6, 508–509; (c) Labaziewicz, H. L.;
Riddel, F. G. J. Chem. Soc., Perkin Trans. 1 1979, 2926–2929; (d) Barnes, M. W.;
Patterson, J. M. J. Org. Chem. 1976, 41, 733–735; (e) Dieckmann, H.; Lüttke, W.
Angew. Chem., Int. Ed. Engl. 1968, 7, 387–388.
Diene
Isolated cycloaduct
Yield % from
Lit. Ref.
15
6
13. (a) Dondas, H. A.; Grigg, R.; Hadjisoteriou, M.; Markandu, J.; Kennewell, P.;
Thornton-Pett, M. Tetrahedron 2001, 57, 1119–1128; (b) Baran, P. S.; Burns, N.
Z. J. Am. Chem. Soc. 2006, 128, 3908–3909.
14. Daineko, V. I.; Proskurnina, M. V.; Skornyakov, Y. V.; Trofimov, B. A.; Zefirov, N.
S. Russ. J. Org. Chem. 2002, 38, 1431–1433.
O
N
Boc
38
40
34
8a
20
15. Schenk, C.; De Boer, T. J. Tetrahedron 1979, 35, 147–153.
O
NH2
Cl
16
50
16. Kornblum, N.; Wade, P. A. J. Org. Chem. 1973, 38, 1418–1420.
17. (a) Defoin, A.; Joubert, M.; Heuchel, J.-M.; Strehler, C.; Streith, J. Synthesis 2000,
1719–1726; (b) Kesler, E. J. Heterocycl. Chem. 1980, 17, 1113.
18. For a detailed discussion of deprotonation and tautomerisation see Nielsen, A.
T. In The Chemistry of the Nitro and Nitroso Group; Fever, H., Ed.; Interscience:
New York, 1969; p 349.
19. Kresze, G.; Dittel, W. Justus Liebigs Ann. Chem. 1981, 610–611.
20. (a) Iida, H.; Watanabe, Y.; Kibayashi, C. J. Org. Chem. 1985, 50, 1818–1825; (b)
Iida, H.; Watanabe, Y.; Kibayashi, C. Tetrahedron Lett. 1984, 25, 5091–5094.
OH
OH
H
52
—
O
Cl
NH2
Reagents and conditions: diene (1.0 equiv), chloronitroso compound (15) or (6)
(1.5 equiv) from stock solution in MeOH.