Complex intermediates in the NO insertion reactions into lithium amides

Article abstract of DOI:10.1002/poc.1069

Nitric oxide (NO) is known to produce the carcinogenetic nitrosamines but it has also been recently reported, both as a regulator of many important physiological functions and as a possible pharmaceutical delivery system. The present paper describes the N

Full text of DOI:10.1002/poc.1069

JOURNAL OF PHYSICAL ORGANIC CHEMISTRY
J. Phys. Org. Chem. 2006; 19: 748–751
Published online 29 November 2006 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/poc.1069
Complex intermediates in the NO insertion reactions
into lithium amidesy
*
´
Alvaro Vazquez and N. Sbarbati Nudelman
´
´
Departamento de Quımica Organica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pab. II, P 3 Ciudad Universitaria
(1428), Buenos Aires, Argentina
Received 15 December 2005; accepted 2 March 2006
ABSTRACT: Nitric oxide (NO) is known to produce the carcinogenetic nitrosamines but it has also been recently
reported, both as a regulator of many important physiological functions and as a possible pharmaceutical delivery
system. The present paper describes the NO insertion into N—Li bond of lithium amides, to afford very good to almost
quantitative yields of N-nitrosamines. A study of the reaction intermediate suggested a further advantage of this
synthetic methodology, widening its scope to its use in tandem reactions. Thus, in situ addition of an organolithium
—
reagent into the N O bond leads to an almost quantitative conversion into the corresponding hydrazone. This
—
compound could further add a second equivalent of the same (or another) organolithium affording substituted
hydrazines. The hydrazines thus prepared have a potential chiral carbon, by running the reaction in the presence of a
chiral auxiliary, enantiomeric excess could be obtained. By reducing the compound with Raney Ni, the scope of this
methology could be enlarged for the potential preparation of chiral primary amines, project that is currently under
progress. Copyright # 2006 John Wiley & Sons, Ltd.
KEYWORDS: nitrosamines; lithium amides; NO insertion; tandem reactions; hydrazones
INTRODUCTION
reported a preliminary synthetic procedure based on
the NO insertion into N—Li bond of lithium amides, that
afforded an almost quantitative yield of di-cyclohexylni-
trosamine.8 In the present paper, we describe further
research on the subject looking for reaction intermediates
that could be used in tandem reactions.
The synthetic strategies, known as ‘tandem,’ ‘domino,’
or ‘cascade reactions’ combine several transformations,
often incorporating added components.9 Avery important
advantage of these synthetic procedures is the minimiz-
ation of waste, since several bonds could be formed in
one sequence without isolating the intermediates or
changing the reaction conditions,10 the amounts of
solvents, reagents, adsorbents and energy is dramatically
decreased, compared with stepwise reactions.11 The
design of tandem reactions involving organometallic
compounds combines the mentioned advantages with the
versatility of organometallic reagents, we have recently
published two reviews related to tandem reactions
involving organolithium intermediates.12
Nitrosation of amines and of DNA by nitrosamines is
a well known carcinogenetic effect;1,2 a recent study
investigated nitric oxide (NO)-mediated nitrosation of 2-
amino-3,8-dimethylimidazo-4,5-f]quinoxaline and the
influence of dietary (hemin) and inflammatory [NO,
myeloperoxidase, and H2O2] components on nitrosation.3
Nevertheless, a new and unexpected role of nitric oxide
(NO) has been recently reported, both as a regulator
of many important physiological functions in vivo and as
a possible pharmaceutical delivery system.4,5 In spite of
the increased interest in nitrosamines, there are few
reported procedures for their synthesis with good
yields;6,7 a recent approach describes a combined
solid/solution-phase methodology that enables the effi-
cient synthesis of some individual nitrosamines as well as
mixture-based nitrosamines libraries.4 We recently
´
*Correspondence to: N. S. Nudelman, Departamento de Quımica
Organica, Facultad de Ciencias Exactas y Naturales, Universidad de
´
Buenos Aires, Pab. II, P 3 Ciudad Universitaria (1428), Buenos Aires.
Argentina.
E-mail: nudelman@qo.fcen.uba.ar
Contract/grant sponsor: University of Buenos Aires; Contract/grant
number: EX213-UBA.
RESULTS AND DISCUSSION
Contract/grant sponsor: CONICET (National Scientific Research
Council, Argentine); Contract/grant number: PID 6019.
ySelected article presented at the Eighth Latin American Conference
on Physical Organic Chemistry (CLAFQ0-8), 9–14 October 2005,
Florianopolis, Brazil.
Reaction of lithium amides with NO
This reaction constitutes a very convenient metho-
dology for the synthesis of alkyl N-nitrosamines, 3, from
Copyright # 2006 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2006; 19: 748–751

COMPLEX INTERMEDIATES IN THE NO INSERTION REACTIONS INTO LITHIUM AMIDES
749
amines, 1, by nitrosation of lithium amides, 2,
[Eqn (1)].
This observation led us to develop a new methodology
for the tandem preparation of substituted hydrazones, 4,
and hydrazines, 5 in very good to excellent yields. Thus,
starting from 1a, transforming it into 2a and carrying out
the reaction with NO in the presence of 2 equivalents of
BuLi, and almost quantitative conversion of 1a into 4a,
was obtained without isolation of the corresponding 3a. If
the reaction is carried out in a great excess of BuLi (3–4
equivalents) a 70% of the corresponding hydrazine, 5a,
(R3 ¼ CH(CH2)2CH3) was obtained.
n-BuLi
1
O
1
1
NO
R
R
R
NH
NLi
N
N
2
2
o
2
R
R
0 C
R
1
2
3
a: R1 = R2 = c-(C6H11)
b: R1 = i-C3H7 ; R2 = c-(C6H11)
The methodology is quite general: by carrying out the
reaction in the presence of second equivalent of BuLi,
and, without isolating the intermediate adding n-C5H11Li
the corresponding 5 (R3 ¼ C5H11) is obtained in good
yield (ca. 70%). It is worth mentioning that 5 exhibits an
asymmetric C atom; therefore, by carrying out the
addition of the second organolithium reagent in the
presence of a chiral auxiliary, enantioselective formation
of 5 could be obtained. Examination of the scope of this
step is under progress.
(1)
The NO insertion into the N—Li bond described
herewith, afforded almost a quantitative yield of N-
nitrosodicyclohexylamine, 3a, and near 80% yield of N-
nitrosoisopropylcyclohexylamine, 3b. The reaction can
be carried out under mild conditions: in THF at low
temperature (ꢀ78 or 08C) and atmospheric pressure, (ca.
1013 bar) giving only one product. It was initially carried
out using a cylinder of NO,8 but due to the present
difficulties for importing NO, it was desirable to try
methods for the preparation of NO at atmospheric
pressures, and test the methodology under these
conditions. Optimization of the NO preparation as
described in the experimental section, afforded almost
the same yields of 3a and 3b stated above.
It is known, that lithium dialkylamides exhibit large
structural varieties and this fact has generated a persistent
debate about the relative reactivity of different aggrega-
tion states.13 An enormous body of structural investi-
gations, mostly crystallographic14 and spectroscopic,15
has been accumulated in the last years. Concomitantly
with the experimental investigations many detailed
computational studies of aggregates of lithium dialkyla-
mides have been carried out by using ab initio and/or
semiempirical methods16–18 with variable degrees of
accuracy, according to the size and nature of the systems
examined. On the other hand, we have recently
demonstrated that lithium amides formed from cyclic
amines (such as piperidine) formed mixed aggregates
with the precursors amine,19 while lithium amides formed
from open dialkyl amines forms homodimers.20 Never-
theless, for the sake of simplicity, in Eqn (1), and the
following equations, 2 is written as monomer.
Reaction intermediate
It was of interest to make some contribution toward the
understanding of the mechanism of the insertion reaction
of NO into the N—Li bond. Therefore, a 13C NMR
examination of the reaction mixture of the lithium
dicyclohexylamide with NO in THF was carried out under
the conditions that led to the complete conversion to 3a.
Table 1 gathers the significant signals for the dicyclohex-
ylamine, 1a, the lithium dicyclohexylamide, 2a, the N-
nitrosamine 3a and the reaction mixture.
It can be observed that the reaction mixture shows
distinctive signals. The 13C NMR of the reaction mixture at
t ¼ 0, at 08C, shows the signals for 2a, while at t ¼ 60 min
Table 1. 13C NMR of the dicyclohexylamine 1a, lithium
dicyclohexylamide 2a, N-nitrosamine 3a, and the reaction
mixture
Compound
C1
C2
C3
C4
1a
2a
53.2
62.3
34.9
40.1
26.8
27.6
25.4
27.6
3a
Reaction
mixture
60.10/54.61 35.42/30.16 26.9/26.7 26.4/26.35
58.4
35.1
29.8
26.6
To get good yields of N-nitrosamines, the preparation
of the lithium dialkylamide has to be carried out with a
slight excess of the corresponding amine; if BuLi is in
excess addition to the double bond of 3, could occur under
the reaction conditions, as shown by Eqn (2).
R3
N
R1
R3Li
R1
R2
O
R1
R2
CH(CH2)2CH3
H
CH(CH2)2CH3
n-BuLi
N
N
N
N
N
R2
ð2Þ
3
4
5
Copyright # 2006 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2006; 19: 748–751

´
A. VAZQUEZ AND N. S. NUDELMAN
750
no signals for 1a, nor 3a were observed, some 2a remained
unreacted and the new signals shown in Table 1 appeared.
As it is well known, NO is paramagnetic, nevertheless the
13C NMR shows sharp signals. We believe that a dimeric
form of the nitrosamine lithiated precursor might be
involved; nevertheless further insight into the mechanism of
this useful reaction is needed.
several days, refluxed and distilled over sodium, they were
then kept under nitrogen in sealed ampoules, which were
opened immediately prior to use. n-Butyllithium was
prepared as previously described.23 Several methods were
tested to generate NO; the best results were obtained by
the reported method using ferrous sulfate and sodium
nitrite solutions.24
R3
H
R3
H
H2N
R3Li
Raney - Ni / H2
R1
R2
C(CH2)2CH3
H
ð3Þ
4
N
N
C(CH2)2CH3
SAM
S-5
S-6
It has been recently reported a convenient methodology
for the synthesis of chiral primary amines starting from
hydrazones, producing hydrazines in the presence of a
chiral inductor (SAM/RAM procedure).21 Hydrazines 5
obtained from amines according to the methodologies
shown by Eqns (1)–(3), prepared in the presence of a
chiral auxiliary, could then be reduced by Raney Ni,
affording new chiral primary amines. Therefore, the
herewith-described methodology could be enlarged to a
tandem sequence for the enantioselective preparation of
chiral primary amines [Eqn (3)]. Examination of this step
is under progress.
Preparation of lithium dialkylamides
Cooled (08C) n-BuLi (5 mL, 0.8 M in hexane) was
syringed into a non-air stopper capped tube under
nitrogen atmosphere, and freshly distilled dicyclohex-
ylamine (7.4 mmol) was added. The precipitate lithium
dicyclohexylamide was centrifugated, the supernatant
removed, and the white crystals were washed thrice with
5 mL of hexane followed by centrifugation each time.
The resulting solid was dried under vacuum at room
temperature. Atmospheric pressure was restored by
flushing with dry, oxygen-free nitrogen. Lithium iso-
propylcyclohexylamide was prepared in a similar way
but, since it is soluble in hexane, the solvent was distilled
at reduced pressure until the total volume left was nearly
1.5–2 times the volume of the added amine. The resulting
syrup was dissolved in THF and used immediately. Both
lithium amides were titrated as previously described.25
EXPERIMENTAL SECTION
General comments
CAUTION: NO is dangerous; use of an efficient hood
and protecting shield is essential. N-nitrosamines are
carcinogenic; they have to be handled and disposed
with special care avoiding skin contact. All reactions
involving organolithium reagents were carried out by
standard techniques for the manipulation of air- and
water-sensitive compounds.22 The GLC analyses were
carried out on a 5890 Series II Plus Hewlett-Packard
(using a HP-5 column) gas chromatograph, at 60–2508C
programmed temperature. Mass spectra were recorded on
Reaction between lithium
dialkylamides and NO
Typical reaction conditions are described for lithiumdi-
cyclohexylamide. A 100 mL round-bottomed flask con-
taining a teflon-coated stirring bar and capped with a no-
air stopper was evacuated and filled with dry nitrogen
alternatively several times, and then nitric oxide was
added at ca. 1013 mbar. After that the flask was put into an
ice-water bath, and a solution of lithium dicyclohex-
ylamide (1 mmol) in anhydrous THF (4 mL) was added at
once under vigorous magnetic stirring, that was kept for
3 h. The initial colorless solution turned to orange at the
beginning of the reaction and this color stayed along
the reaction. The reaction was worked up by treating the
reaction mixture with 0.2 mL of distilled methanol.
Excess NO was removed and distilling the THF under
reduced pressure afforded slightly orange crystals of N-
nitrosodicyclohexylamine, in an almost quantitative
1
a BG Trio-2 spectrometer. H- and 13C-NMR spectra
were recorded in a Brucker 200 MHz.
Solvents and reagents
Distilled THF was refluxed over sodium benzophenone
ketyl until a dark blue solution was obtained and then
distilled immediately before use under dry oxygen-free
nitrogen. Hexane was treated in a similar way.
Commercial dicyclohexylamine and isopropylcyclohex-
ylamine were separately left over sodium strings for
Copyright # 2006 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2006; 19: 748–751

COMPLEX INTERMEDIATES IN THE NO INSERTION REACTIONS INTO LITHIUM AMIDES
751
yield. Crystallization from ethanol–water rendered white
crystals, m.p. 104.5–105.58C. The N-nitrosoisopropylcy-
clohexylamine was obtained in a similar way. Both
nitrosamines were fully characterized by mass spectrom-
110 (11.4), 98 (23.2), 83 (36.6), 69 (28.3), 56 (42.9), 55
(75.88).
1
etry, H- and 13C-NMR spectroscopy.
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For the preparation of N-i-propylcyclohexyl-hydrazo-
butanone, the methodology described for the preparation
of lithium amides was used but using 15 mL of Bu Li
(0.8 M in hexane) instead of 5 mL. The rest of the
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resulting lithium i-propylcyclohexylamide with NO.
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N-i-propylcyclohexylnitrosamine with Bu Li.
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105.58C. H-NMR (CDCl3) (ppm): 1.60 (m, 20H), 3.73
(m, 1H), 4.84 (m, 1H). 13C-NMR (CDCl3) (ppm): 26.36,
26.41, 26.66, 26.90, 30.16, 35.42, 54.61, 60.10. MS m/e
(rel. int.): 210 (6.96), 129 (7.28), 98 (12.83), 83 (100.00),
67 (12.72), 55 (61.74), 41 (42.17).
N-cyclohexy-i-propylnitrosamine, 3b. 1H-NMR (CDCl3)
(ppm): 1.16 (d), 1.51 (d), 1.6 (m), 3.75 (m, 2H), 4.23 (m,
1H), 4.80 (m, 1H), 5.05 (m, 2H). 13C-NMR (CDCl3)
(ppm): 19.05, 23.77, 25.18, 25.32, 25.48, 25.97, 29.20,
34.10, 44.72, 50.85, 52.70, 58.47.
N-cyclohexy-i-propyl-butylhydrazone, 4b. 1H-NMR
(CDCl3) (ppm): 0.94 (t, 3H), 1.07 (d, 6H), 1.47 (m,
12 H), 2.20 (m, 2H); 3.07 (m, 1H), 3.58 (m, 1H), 6.88
(t, 1H). 13C-NMR (CDCl3) (ppm): 13.80, 20.29, 20.80,
26.11, 30.86, 31.02, 35.20, 47.70, 56.89, 141.01. MS m/e
(rel.int.): 211 (38.21), 196 (60.85), 168 (83.96), 126
(56.13), 114.00 (100.00), 99 (11.91), 86 (16.16), 84
(20.40), 71 (26.06), 56 (68.40), 42 (70.75).
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Copyright # 2006 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2006; 19: 748–751