The synthesis of alkyl aryl nitriles from N-(1-arylalkylidene)-cyanomethyl amines: Some mechanistic conclusions

Article abstract of DOI:10.1039/a905563k

A mechanistic investigation of the rearrangement of N-(1-arylalkylidene)cyanomethylamines [1, ArC(=NCH₂CN)R; R = alkyl, aryl] to alkyl aryl nitriles [2, ArCH(R)CN] in refluxing DMF in the presence of a base is reported. Under these conditions, p-phenyl substituted N-(1-arylethylidene)cyanomethylamines (Ar = p-BrC₆H₄, p-ClC₆H₄, p-CH₃C₆H₄ and p-CH₃OC₆H₄; R = CH₃) follow the Hammett linear free-energy relationship, with a large positive p value (1.86), implying that electron-withdrawing substituents enhance the reaction rate by an initial deprotonation step. However, C-alkylated imines [Ph₂C=NCH(R′)CN; R′ = Me, n-Bu] do not yield the corresponding nitriles [Ph₂C(R′)CN], indicating the need for both methylene protons in order for the reaction to begin. Different mechanistic pathways are then discussed. A base-catalysed imine double bond isomerisation, considered plausible, is excluded, since N-alkylformimidoyl cyanides [ArCH(N=CHCN)R] interconvert quantitatively to imines 1 prior to the formation of nitriles 2. The photochemical activation of the reaction is also ruled out. The results of isotope labelling experiments, using ¹³C- and ¹⁵N-labelled N-(1-phenylethylidene)cyanomethylamines [PhC(=NCH₂-¹³CN)CH₃ and PhC(=¹⁵NCH₂CN)CH₃] are consistent with a mechanism based upon an intramolecular nucleophilic substitution reaction, since the cyano groups of the products 2 appear to come in preference from the methyleneiminic fragment (=NCH₂-) of the reagents. The mechanism is proposed to proceed via an intermediate three-membered nitrogen heterocycle, generated by a nucleophilic intramolecular attack, which eliminates cyanide to afford the product nitrile.

Full text of DOI:10.1039/a905563k

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The synthesis of alkyl aryl nitriles from N-(1-arylalkylidene)-
cyanomethyl amines: some mechanistic conclusions
Alvise Perosa, Maurizio Selva* and Pietro Tundo
Dipartimento di Scienze Ambientali, Università Ca’ Foscari, Dorsoduro 2137 – 30123 Venezia,
Italy. E-mail: selva@unive.it
Received (in Cambridge, UK) 9th July 1999, Accepted 26th August 1999
A mechanistic investigation of the rearrangement of N-(1-arylalkylidene)cyanomethylamines [1, ArC(᎐NCH CN)R;
᎐
2
R = alkyl, aryl] to alkyl aryl nitriles [2, ArCH(R)CN] in refluxing DMF in the presence of a base is reported.
Under these conditions, p-phenyl substituted N-(1-arylethylidene)cyanomethylamines (Ar = p-BrC6H4, p-ClC6H4,
p-CH3C6H4 and p-CH3OC6H4; R = CH3) follow the Hammett linear free-energy relationship, with a large positive
ρ value (1.86), implying that electron-withdrawing substituents enhance the reaction rate by an initial deprotonation
step. However, C-alkylated imines [Ph C᎐NCH(RЈ)CN; RЈ = Me, n-Bu] do not yield the corresponding nitriles
᎐
2
[Ph2C(RЈ)CN], indicating the need for both methylene protons in order for the reaction to begin.
Different mechanistic pathways are then discussed. A base-catalysed imine double bond isomerisation, considered
plausible, is excluded, since N-alkylformimidoyl cyanides [ArCH(N᎐CHCN)R] interconvert quantitatively to imines
᎐
1 prior to the formation of nitriles 2. The photochemical activation of the reaction is also ruled out. The results of
isotope labelling experiments, using 13C- and 15N-labelled N-(1-phenylethylidene)cyanomethylamines [PhC(᎐NCH -
᎐
2
13CN)CH and PhC(᎐15NCH CN)CH ] are consistent with a mechanism based upon an intramolecular nucleophilic
᎐
3
2
3
substitution reaction, since the cyano groups of the products 2 appear to come in preference from the methylene-
iminic fragment (᎐NCH –) of the reagents.
᎐
2
The mechanism is proposed to proceed via an intermediate three-membered nitrogen heterocycle, generated by a
nucleophilic intramolecular attack, which eliminates cyanide to afford the product nitrile.
reaction under photochemical activation (UV radiation: 500 W
lamp). However, the influence of the specific reaction condi-
tions was beyond the scope of the present study.
The novelty of such a transformation prompted us to under-
take a mechanistic study of the reaction 1→2. This paper
reports some conclusive results of the investigation.
Introduction
Alkyl aryl nitriles [ArCH(R)CN, 2] are widely used intermedi-
ates for the syntheses of a number of carboxylic acids or
amines.1 A well-known example of their pharmaceutical
relevance is the class of 2-arylpropionitriles [ArCH(CH3)CN]
which are intermediates for the preparation of hydratropic
acids (2-arylpropionic acids), important non-steroidal anal-
gesics such as Naproxen, Ibuprofen and Ketoprofen.2
We recently reported that nitriles 2 could be synthesised by
a new two-step one-carbon homologation, starting from the
corresponding ketone (ArCOR), via an intermediate N-(1-
arylalkylidene)cyanomethylamine (1, Scheme 1).3
Results
(i) Hammett free-energy relationship
Different
p-substituted
N-(1-arylethylidene)cyanomethyl
amines [aryl = p-XC6H4; X = Br (1a), Cl (1b), H (1c), CH3O
(1d), CH3 (1e)] were synthesised and reacted under the condi-
tions of Scheme 1 (K2CO3 in refluxing DMF):3 solutions of
1a–e (0.12 M) in 10 mL DMF were heated at reflux (153 ЊC),
under nitrogen, in the presence of a 1.5 molar excess of K2CO3
[eqn. (1)].
Scheme 1 A two-step homologation of alkyl aryl ketones to nitriles.
The alkyl aryl ketones were condensed with the hydro-
chloride salt of aminoacetonitrile to yield derivatives 1 [reac-
tion (a)].4 The resulting imines rearranged to nitriles 2 when
heated in refluxing DMF, in the presence of a base [K2CO3;
reaction (b)], through a loss of HCN (see the Results and Dis-
cussion sections). The reaction (b) proceeded only at relatively
high temperature (T ≥ 150 ЊC) and although it turned out to be
feasible both for alkyl aryl and diaryl ketones, the conditions
appeared to be quite stringent. For example, both organic (i.e.
Et3N, Bu3N, DMAP) and inorganic (i.e. KF) bases, in the pres-
ence of different solvents such as polyethylene glycols, aromatic
hydrocarbons, acetonitrile, THF, etc., were ineffective. Also,
radical pathways were excluded: although photoactivation was
reported for other imines and nitriles,5 compounds 1 yielded no
The reactions were followed by GLC and showed that the
related concentration versus time plots fitted well the first-order
rate law expression ln (C0/C) = kt (C0 and C = substrate concen-
trations at t = 0 and at a later time t, respectively).
As an example, by applying the integrated form of the first-
order kinetic equation to the disappearance curve of N-(1-
phenylethylidene)cyanomethyl amine 1c,6 the resulting plot of
ln (C0/C) against time gave a straight line (r > 0.99), whose
slope was the rate constant kobs of substrate disappearance
(Fig. 1; kobs = 8.1 × 10Ϫ2 minϪ1).
J. Chem. Soc., Perkin Trans. 2, 1999, 2485–2492
This journal is © The Royal Society of Chemistry 1999
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a
Table 1 The reaction of XC6H4C(᎐NCH2CN)CH3 in DMF solvent, in the presence of K2CO3
᎐
kobs b/10Ϫ2 minϪ1
σp
Product
Yield (%) by GCd
c
Entry
Substrate (X)
1
2
3
4
5
1a (p-Br)
1b (p-Cl)
1c (H)
1d (p-CH3)
1e (p-CH3O)
25.0
20.2
8.1
4.0
2.6
0.26
0.24
0
Ϫ0.14
Ϫ0.28
p-BrC6H4CH(CH3)CN 2a
p-ClC6H4CH(CH3)CN 2b
PhCH(CH3)CN 2c
p-CH3C6H4CH(CH3)CN 2d
p-CH3OC6H4CH(CH3)CN 2e
64
47
41
38
41
a All reactions were carried out in refluxing DMF (153 ЊC) and using a 1.5 molar excess of the base. b First-order rate constants for the disappearance
d
of the substrate. c Hammett σ constants for p-phenyl substituents; from ref. 7. Yields are referred to the internal standards used: n-tetradecane
(entries 1,3,4), n-hexadecane (entry 2) and n-dodecane (entry 5).
CH Ph and Ph CH–N᎐CHPh.7 No rearrangement to 2-phenyl-
᎐
2
2
propionitrile was observed.
On the other hand, the double bond isomers of imines 1,
N-alkylformimidoyl cyanides [RRЈCH–N᎐CHCN; 4] behaved
᎐
differently. Compounds 4 [RRЈCH–N᎐CHCN; 4c: R = Me,
᎐
RЈ = Ph; 4f: R = RЈ = Ph; 4g: R = Et, RЈ = Me] were synthesised
by oxidising the appropriate amine [RRЈCHNHCH2CN] with
aqueous NaOCl, in a one-pot N-chlorination–hydrodechlorin-
ation sequence.‡ The procedure afforded compound 4g as a
pure product, while, in the cases of 4f and 4c, a mixture of
Fig. 1 Plot of ln C0/C against time for imine 1c.
isomers was obtained (Scheme 2): 4c and PhC(᎐NCH CN)CH
᎐
2
3
1c (44:1 ratio), and 4f and Ph C᎐NCH CN 1f (4:10 ratio).
᎐
2
2
Scheme 2 Synthesis of N-alkylformimidoyl cyanides 4.
Fig. 2 Hammett plot for compounds 1a–1e.
Under the same conditions as for 1c, the first-order rate
constants were evaluated for the disappearance of all imines
1a–e. Table 1 reports the results.
Both imines 4c and 4g were reacted under the conditions of
Scheme 1. Initially, they underwent a rapid and quantitative
isomerisation to the corresponding imines 1 [PhC(᎐NCH CN)-
᎐
2
The reaction fitted the Hammett relationship equation, log
(k/k0) = σρ [where k and k0 are the rate constants for the
p-phenyl substituted (1a–b, d–e) and the unsubstituted imines
1c, respectively, and σp constants are from ref. 7], giving a
positive ρ value of 1.86. Fig. 2 shows the results.
CH 1c and CH CH C(᎐NCH CN)CH 1g, respectively]. While
᎐
3
3
2
2
3
the further reaction of 1g afforded a mixture of high boiling
compounds with no 2-methylbutanonitrile (the expected
product according to Scheme 1), 1c underwent the previously
observed rearrangement, after a 15 min induction time, afford-
ing 2c (Fig. 3 and Scheme 3).
The imine 1g was also synthesised independently,4 and
reacted under the same conditions to afford the same high boil-
ing products observed in the case of 4g. The 4:6 mixture of 4f
and 1f was not reacted.
(ii) Isomerisation of the iminic double bond under basic
conditions
To investigate how deprotonation and, possibly, isomerisation
of ketimines could take place under the condition of Scheme 1,
N-(1-phenylethylidene)benzylamine [3; PhC(᎐NCH Ph)CH ]
᎐
2
3
was subjected to the same reaction conditions as for derivatives
1a–e,3 and a 40:60 mixture of isomers 3 and 3a† was obtained
at equilibrium after 7.5 h [eqn. (2)], a result analogous to the
‡ The syntheses of compounds 4 is reported in the literature as a two
step preparation:8 (i) the treatment of secondary amines with Ca(OCl)2,
to isolate the corresponding N-chloro adduct, and (ii) the successive
reaction of the chlorinated intermediate with a base to afford a single
product, or mixture of isomers, depending on the substrate. In this
work, the reported imines 4 were synthesized in one pot using a novel
procedure, by treating cyanomethyleneamines directly with a com-
mercial aqueous solution of NaOCl (10–13% available chlorine).20
reported base-catalysed interconversion between Ph C᎐N–
᎐
2
† 3a was identified by comparison with an authentic sample prepared
by condensing α-methylbenzylamine with benzaldehyde.
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2-phenylproprionitrile standards (entries 3,4, respectively). We
assumed the same response for *2c and 2c*, which have equal
molecular masses, with respect to the standards.
(v) Titration of the cyanide released by the reaction 1→2
Titration by AgNO3 of the aqueous extracts of the reaction of
compound Ph C᎐NCH CN 1f, under the conditions of Scheme
᎐
2
2
1, yielded a molar amount of cyanide (51%) corresponding to
the isolated molar yield of diphenylacetonitrile 2f (48%).
Discussion
(i)–(iii) Hammett free-energy relationship, isomerisation of the
iminic double bond, and reactions with n-BuLi
Fig. 3 Reaction of 4c under the rearrangement conditions of eqn. (1).
The investigation of the mechanism of the transformation 1→2
was first addressed by considering the effect of a series of para-
substituents on the aryl ring of 1. The trend of first-order rate
constants kobs for the disappearance of imines 1a–e (Table 1)
clearly shows that electron-withdrawing p-phenyl substituents
enhance the reaction rate, while electron-donating ones
decrease it with an overall variation (from p-Br to p-CH3O) by a
factor of 10. Also, the positive ρ value (1.86) obtained from the
Hammett equation (Fig. 2) can be associated with a developing
negative charge in a transition state more stabilised by electron-
withdrawing substituents.10–12 If this is the case, the negative
charge may develop initially by proton abstraction by the base
on the methylene carbon; an hypothesis which seems further
verified by both the equilibrium of eqn. (2) (whose establish-
ment implies proton abstraction–migration from a methylene to
an imine carbon), and the reaction of 1f with n-BuLi which
yields an anion capable of affording diphenylacetonitrile upon
reflux in a DMF solution. In both cases, the initial occurrence
Scheme 3 Isomerization of N-alkylformimidoyl cyanides.
(iii) Reaction of 1f with n-BuLi
Imine 1f was treated with n-BuLi in THF at Ϫ90 ЊC. The
brown–red coloured solution was then heated at the reflux tem-
perature of THF (67 ЊC): no reaction was observed. However,
when THF was distilled off and replaced with DMF, and the
solution refluxed at 150 ЊC, the usual clean rearrangement to
nitrile Ph2CH(CN) 2f was observed. If, instead of replacing the
solvent, the solution was quenched with either n-bromobutane
¯
of a species such as PhC(᎐NCHR)RЈ (3: R = Ph, RЈ = Me; 1f:
᎐
R = CN, RЈ = Ph) seems more than reasonable.
Moreover, the proton shift of eqn. (2) suggests that the
double bond isomers of imines 1, namely N-alkylformimidoyl
cyanides 4 [formed in analogy to eqn. (2)], should also be
expected to afford nitriles 2.
However, the study of the reactivity of imines 4 proves that
any mechanistic hypothesis based upon an initial isomerisation
of 1 to 4 must be excluded. Under the conditions of Scheme 1,
compounds 4c and 4g (c: R = Ph, RЈ = Me; g: R = Et, RЈ = Me)
first undergo complete isomerisation to the corresponding
imines 1. Then, while 1c gives the usual clean rearrangement to
2-phenylpropionitrile, the dialkyl compound 1g furnishes only
high boiling products with none of the expected nitrile (Scheme
3 and Fig. 3).
Further indirect evidence can be inferred by the preparation
of the imines 4: while the dialkyl imine 4g and the alkylaryl
imine 4c are obtained as single products, the attempt to syn-
thesise the diaryl derivative 4f gives a mixture of 4f/1f in a 4:10
ratio. In the alkaline environment (NaOCl aq.), 1f clearly repre-
sents the more stable highly conjugated structure.
or methyl iodide, it yielded the two alkylated imines Ph C᎐
᎐
2
NCH(n-Bu)CN 5a and Ph C᎐NCH(CH )CN 5b, respectively.
᎐
2
3
Both 5a and 5b were subjected to the conditions of Scheme 1:
only a mixture of products was detected, with no Ph2C(n-Bu)-
CN or Ph2C(CH3)CN among them.
(iv) Isotope labelling experiments
A series of reactions was conducted using isotope labelled
substrates. 13C- and 15N-labelled N-(1-phenylethylidene)cyano-
methylamines [PhC(᎐NCH 13CN)CH : *1c, and PhC(᎐15NCH -
᎐
᎐
2
3
2
CN)CH3: 1c*, respectively] were synthesised independently,
by condensing acetophenone with NH2CH213CNؒH2SO4 (13C,
99%) and 15NH2CH2CNؒH2SO4 (15N, 99%).4 §
The imines *1c and 1c* were then reacted under the condi-
tions of eqn. (1), and the outcome was monitored by GC/MS.
In order to quantitatively evaluate the labelled isotopic enrich-
ment of the resulting nitriles [PhCH(CH3)13CN: *2c and
PhCH(CH3)C15N: 2c*], two reference compounds were pre-
pared: labelled (13C, 99%) and unlabelled 2-phenylpropionitriles
were synthesised by nucleophilic substitution with Na13CN
(13C, 99%) and NaCN, on 1-chloro-1-phenylethane [PhCH-
(CH3)Cl], according to reported conditions.9 The isotope
distribution in the products of the rearrangement reactions
conducted using the isotope enriched substrates is reported in
Table 2.
However, the formation of nitriles 2 requires both protons at
the methylene position: in fact, alkylated imines 5a and 5b
[Ph C(᎐NCHRCN); R = n-Bu, Me] do not undergo the desired
᎐
2
rearrangement, and yield a mixture of products.
(iv–v) Isotope labelling experiments, and titration of the cyanide
released by the reaction 1→2
The most significant mass peaks [Mϩ ϩ 1, Mϩ, Mϩ Ϫ 1,
(Mϩ ϩ 1) Ϫ CH3, Mϩ Ϫ CH3 and (Mϩ Ϫ 1) Ϫ CH3] are shown
for both compounds *2c and 2c* (entries 1,2), and for the
A different approach to the mechanistic investigation was
aimed at establishing which part of the iminomethylenenitrile
moiety (᎐NCH –CN) of the reacting imines 1 is incorporated as
᎐
2
the cyano functionality in nitriles 2.
As was noted earlier, N-(1-phenylethylidene)benzylamine 3
does not rearrange to 2-phenylpropionitrile, which means that
§ The structure of the imines *1c and 1c* was confirmed by comparison
of their mass spectra with that of the unlabelled compound 1c. The
identification peaks of *1c and 1c* (Mϩ = 158, Mϩ ϩ 1 = 159 and
M
ϩ Ϫ CH3 = 144) were shifted by one mass unit with respect to 1c,
the cyano fragment (᎐NCH –CN) of the iminomethylene
᎐
2
moiety of compounds 1a–e is necessary for the reaction to
while their relative intensity was unchanged (see Experimental).
J. Chem. Soc., Perkin Trans. 2, 1999, 2485–2492
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Table 2 Isotopic enrichment of 2-phenylpropionitrile produced from different source compoundsa
Identifying mass peaks (%, relative intensity)
Isotopic
enrichment Source
(%)
(Mϩ ϩ 1) Ϫ
ϩ Ϫ 1 CH3
(Mϩ Ϫ 1) Ϫ
CH3
Entry product
M
ϩ ϩ 1 Mϩ
M
M
ϩ Ϫ CH3
compound
1
2
3
PhCH(CH3)13CN *2c 133 (1)
PhCH(CH3)C15N 2c* 133 (3)
132 (17) 131 (27) 118 (5)
132 (37) 131 (34) 118 (6)
117 (65)
117 (100)
117 (100)
116 (100)
116 (83)
116 (Ϫ)
(13C, 32)b
(15N, 57)b
(13C, 99)
Ph(᎐NCH213CN)CH3
᎐
Ph(᎐15NCH2CN)CH3
᎐
PhCH(CH3)13CN
(standard)
133 (3)
132 (4)
133 (1)
132 (37) 131 (4)
118 (8)
PhCH(CH3)Cl
c
4
5
PhCH(CH3)CN
(standard)
131 (38) 130 (4)
117 (10)
116 (100)
117 (30)
115 (Ϫ)
PhCH(CH3)Cl
PhCH(CH3)13CN
132 (10) 131 (33) 118 (2)
116 (100)
(13C, 15)b
Ph(᎐NCH2CN)CH3
᎐
a Entries 1,2: products of the reactions of the imines *1c and 1c* carried out in refluxing DMF solutions in the presence of K2CO3, according to
conditions of eqn. (1). Entries 3,4: products synthesised from PhCH(CH3)Cl and Na13CN (13C, 99%; entry 3) or NaCN (entry 4). Entry 5: product
obtained from the reaction of Ph(᎐NCH2CN)CH3 in the presence of an equimolar amount of Na13CN (13C, 99%), under the conditions of eqn. (1).
᎐
b Evaluated from mass spectra of labelled and unlabelled 2-phenylpropionitrile standards [PhCH(CH3)13CN and PhCH(CH3)CN] reported in entries
3 and 4, respectively. c Natural abundance of 13C.
proceed. Moreover, the CNϪ molar amount released by the
reaction 1→2 was shown to be equal to the molar yield of
products 2: that is, the overall rearrangement proceeds via the
loss of HCN.
These facts lead us to believe that cyanide may act as a leav-
ing group along the reaction pathway. If this is the case, the
cyano functionality of nitriles 2 may perhaps derive from
the iminomethylene fragment (᎐NCH –CN) of the reacting
imines 1.
᎐
2
In our opinion, this exchange determines the degree of
scrambling. The apparent contradiction of the lower enrich-
ment observed by adding labelled cyanide to the reaction of 1c
(13C, 15%), compared with the reaction of *1c without added
labelled cyanide [eqn. (3): 13C, 32%] might be accounted for by a
solvent cage effect, which favours attack of 13CNϪ on 2c with
respect to its diffusion [eqn. (3)]. Thus, exchange becomes pre-
ferred with respect to the case where 13CNϪ is added to the
reaction mixture.
In this sense, further evidence is provided by the fact that
C-alkylated imines 5a,b do not rearrange to the respective
nitriles, suggesting that the =NCH2– is likely incorporated in
nitriles 2 through an intramolecular mechanism.
To study these aspects in detail, labelled imines PhC-
(᎐NCH 13CN)CH (*1c) and PhC(᎐15NCH CN)CH (1c*) were
᎐
᎐
2
3
2
3
prepared and reacted under the usual conditions. The outcome
of the reaction was monitored by GC/MS.
From the data in Table 2, isotopic enrichments of 32 and 57%
can be calculated for the two obtained products *2c [PhCH-
(CH3)13CN] and 2c* [PhCH(CH3)C15N], respectively (entries
1,2). These results indicate that the cyano functionality of
nitriles 2 derives from both the cyano [CN, (A)] and the
Mechanistic pattern
The conclusions drawn from (i) the Hammett equation applied
to p-phenyl substituted imines 1, (ii) the study of the reactivity
of N-alkylformimidoyl cyanides 4, and (iii) the reaction of
imines 1 with n-BuLi and their subsequent alkylation, strongly
suggest that the initial rate-determining step of the mechanism
is deprotonation at the methylene carbon to yield 1Ϫ, while a
double bond isomerisation can be excluded.
In addition, the reaction is dramatically sensitive to the struc-
ture of imines 1. Under the same reaction conditions, similar
compounds such as PhC(᎐NCH Ph)CH do not give either
PhCH(R)CN or PhCH(CH3)Ph. This observation, together
with the recovery of cyanide from the reaction mixture,
strengthens the hypothesis that the cyano group of imines 1
behaves as a leaving group which is not found later in the
product nitrile, unless by a CN exchange on the final nitrile 2.
The tests carried out on isotopically labelled imines 1 suggest
that the reaction proceeds through a mechanism mainly based
upon an intramolecular process: in particular, the iminomethyl-
iminomethylene [᎐NCH –, (B)] fragments of the reagents.
᎐
2
However, a definite regioselectivity is observed: the values of
the isotopic enrichments for *2c and 2c* (32 and 57%, respect-
ively) indicate that the cyano group originates mainly from the
iminomethylene part (B) of the reagent, in a 2:1 ratio with
respect to portion (A). Since it is hardly imaginable that frag-
ment B can be lost from the substrate (and successively re-
introduced in the product), this behaviour suggests that the
reaction has to proceed mainly via an intramolecular process.
However, the labelled minor product coming from A does not
exclude an intermolecular reaction involving a labelled cyanide
fragment previously eliminated from the substrate.
᎐
2
3
A crossover experiment was therefore carried out in order to
elucidate whether the reaction proceeds through an intra- or an
intermolecular process. In particular, the unlabelled imine 1c
[PhC(᎐NCH CN)CH ] was reacted according to the conditions
ene fragment (᎐NCH –) of the reagent is the primary source of
᎐
᎐
2
3
2
of eqn. (1) (refluxing DMF, 1.5 molar excess of K2CO3) in the
presence of an equimolar amount of Na13CN (13C, 99%). Entry
5 of Table 2 reports the mass peak abundances of the obtained
2-phenylpropionitrile, which corresponds to a labelled isotopic
enrichment of 15%. Although the occurrence of the crossover
reaction shows that an intermolecular process operates, the low
isotopic enrichment (15%) of the product also indicates that the
intermolecular reaction occurs only to a low extent.
In order to explain formation of *2c, we propose that the
13CNϪ generated from the reaction of *1c [eqn. (3)] can undergo
exchange with the ϪCN of 2c. This kind of isotopic crossover is
documented for acetonitrile, which undergoes nitrile exchange
with labelled cyanide.13
cyano groups into the product 2.
In our view, these combined observations justify a general
mechanistic hypothesis, which involves an intramolecular
nucleophilic attack by the carbanion 1Ϫ on the imine carbon to
form an azirine ring system (Scheme 4).
The analogous spiro(2H-azirine-2,9Ј-fluorene) intermediate
was previously isolated in the reaction of 9-(azidomethylene)-
fluorene, and further reacted to yield a mixture of 9-cyano- and
9-isocyanofluorene.14
The formation of the aziridine 6 is the common starting
point for the two following different pathways.
Route “a”. The aziridine 6 deprotonates on the nitrogen, to
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second route lies in the degree of symmetry of intermediate 8:
this would provide a complete scrambling of the isotopes, and
therefore does not account for the iminomethylene fragment as
the preferential source of the cyano group, according to the
isotope labelling studies.
The two suggested pathways for the rearrangement also
rationalise the fact that alkylated imines 5a and 5b do not
undergo the rearrangement. Neither the intermediate aziridine
6 nor the azirine of route “a”, nor the intermediate 6bϪ of route
“b” would be able to rearrange to the nitrile because of the
missing proton on the heterocycle.
At this stage it is not possible to choose one mechanism vs.
another, though our preference goes to path “a” of Scheme 4,
which better justifies the observed degree of isotopic scram-
bling. Additional work is therefore in progress, aimed at the
synthesis and study of the reactivity of the postulated azirine
and aziridine intermediates.
The moderate yields (40–65%) of nitriles 2, which are
reported in Table 1, may perhaps be explained based on the
previous considerations. An initial anionic species, such as the
proposed one, may undergo intermolecular reactions, leading
to the formation of uncharacterisable tars, which are observed
as by-products of our reaction (except for minor amounts, ≤5%,
of the corresponding ketones, ArCOR). Also N-alkylimino-
acetonitriles (R–N᎐CHCN) have been claimed to form oligo-
᎐
mers by an anionic mechanism under mildly alkaline conditions
at room temperature.15
Therefore, the starting CN content present in reagent 1 is
distributed in two portions: it either ends up as cyanide when
the intramolecular rearrangement occurs and 2 is formed (as
observed by titration) or it may form organic polymers via an
intermolecular process.
Conclusions
The reported experimental evidence sketches out a working
hypothesis toward the final determination of the reaction path-
way, through the mechanism of Scheme 4. Future work will fill
in the reaction steps by independently synthesising some of the
proposed intermediates, and subjecting them to the reaction
conditions of Scheme 1.
The significance of the studied transformation lies in its syn-
thetic applicability, and in its mechanistic relevance. More
importantly, the reaction is unprecedented, and it opens an
unexplored area of investigation which hopefully will allow
expansion of its scope, by using functional groups other than
CN.
Experimental
General
Scheme 4 Hypotheses for the mechanisms of the base catalysed
rearrangement of imines 1 to nitriles 2.
All compounds were ACS grade and used without further puri-
fication. Melting points are uncorrected. 1H NMR spectra were
recorded at 400 MHz on a Varian Unity Spectrometer, using
CDCl3 as solvent and TMS as the internal standard. GC anal-
yses were performed using a 30 m DB5 capillary column. GC-
MS analyses were carried out using an HP mass detector at
70 eV coupled to a gas chromatograph fitted with a 30 m DB5
capillary column. The fitting curves of experimental data were
obtained using the Microcal Origin software.
yield anion 6aϪ, which expels cyanide to form the azirine 7 (the
CN group here behaves somewhat like in the benzoin conden-
sation: it favours deprotonation of 6 and then acts as a leaving
group), which isomerises by protonation–reprotonation and
yields nitrile 2. This pathway requires that 100% of the final CN
derives from the iminomethylene fragment of the starting
imine. The observed label scrambling must therefore take place
in a second step, as proposed earlier [eqn. (3)].
In addition, 2H-azirines have been proposed as intermediates
also in the conversion of vinyl azides to nitriles.14
Preparation of N-(1-arylethylidene)cyanomethyl amines (1a–e)
and labelled N-(1-phenylethylidene)cyanomethyl amines (*1c,
1c*)
Route “b”. The aziridine 6 deprotonates on the carbon, to
yield anion 6bϪ, which by successive rearrangements forms
the intermediate 8. This intermediate offers, by prototropy, a
pathway for both the cyano and iminomethylene functions to
contribute to the retained and expelled cyano groups in the
product. Finally, intermediate 9 may expel CNϪ and provide 10,
which rearranges to the product 2. The major drawback of this
N-(1-Arylethylidene)cyanomethyl amines 1a–e were prepared
by the condensation of the corresponding ketones (p-XC6H4-
COCH3; X = Br, Cl, H, CH3O and CH3, respectively) with
NH2CH2CNؒHCl according to a procedure previously reported
by us.4 Likewise, labelled N-(1-phenylethylidene)cyanomethyl
J. Chem. Soc., Perkin Trans. 2, 1999, 2485–2492
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amines [*1c: PhC(᎐NCH 13CN)CH ; 1c*: PhC(᎐15NCH CN)-
ments; they confirm the position of labelled isotope 15N. In fact,
for both compounds 1c and *1c, the same fragments appear
shifted by one mass unit at m/z 116 and 103, respectively.
᎐
᎐
2
3
2
CH3] were prepared using NH2CH213CNؒH2SO4 (13C, 99%) and
15NH2CH2CNؒH2SO4 (15N, 99%), respectively, as the iminating
agents of acetophenone. In turn, the labelled aminoacetonitrile
salts were synthesised by using 13NaCN (13C, 99%) or 15NH4Cl
(15N, 99%), according to reported procedures.16 Both the imines
*1c and 1c* were not isolated; they were directly reacted to yield
the corresponding nitriles *2c and 2c*, respectively.
Preparation of N-[1-(ethyl)ethylidene]cyanomethyl amine 1g.
According to the above reported procedure,4 the dialkyl imine
1g (1.15 g, 10.5 mmol; 75%) was obtained as a dense yellow
liquid by condensing methyl ethyl ketone (1.0 g, 13.9 mmol)
with NH2CH2CNؒHCl. 1H NMR (CDCl3) δ: 1.09 (t, 3H, CH3,
J 7.32), 1.90 (s, 3H, CH3), 2.33 (q, 2H, CH2, J 7.32), 4.15 (s, 1H,
CH2CN). Mass spectrum (70 eV) m/z (relative intensity): 11
(Mϩ, 110), 95 (14), 81 (100), 70 (14), 68 (22), 67 (11), 54 (60).
The product turned to a brown colour on standing.
N-[1-(p-Bromophenyl)ethylidene]cyanomethyl amine 1a.
Starting from 6.0 g of p-bromoacetophenone, 3.7 g of 1a was
obtained (96% pure by GC; 52% yield); mp 96–98 ЊC. The
product was recrystallised from n-pentane–diethyl ether (95:5
v/v). 1H NMR (CDCl3) δ: 2.29 (s, 3H, CH3), 4.38 (s, 2H, CH2),
7.54 (dd, 2H, Ar; J 8.8 Hz, JЈ 2.0 Hz), 7.70 (dd, 2H, Ar; J 8.8
Hz, JЈ 2.0 Hz). Mass spectrum (70 eV) m/z (relative intensity):
238 (29), 237 (Mϩ, 40), 236 (29), 235 (39), 223 (96), 221 (100),
183 (55), 181 (54), 157 (18), 102 (41), 75 (22), 76 (17).
General procedure for the transformation of imines 1a–e into the
corresponding nitriles 2a–e
A DMF (10 mL) solution of the substrate (0.13 M; 10 mL)
containing the internal standard (0.3 molar with respect to 1;
n-tetradecane for 1a,c,d, n-hexadecane for 1b, and n-dodecane
for 1e, respectively) and K2CO3 (in 1.5 molar excess with respect
to the reactant 1) was loaded in a three-necked, round-
bottomed flask fitted with a silicone septum for sampling, a
refluxing condenser capped with a stopcock, and another stop-
cock. The mixture was degassed by vacuum/N2 cycles and
nitrogen was admitted from a rubber reservoir and maintained
throughout the reaction. Then, the mixture was heated under
stirring at the reflux temperature (153 ЊC); after a few minutes
the solution becomes a characteristic dark brown–red colour.
The reaction course was followed by GC. ATTENTION! The
reaction mixture contains cyanide, great care must be used for
all further operations.
N-[1-(p-Chlorophenyl)ethylidene]cyanomethyl amine 1b.
Starting from 5.0 g of p-chloroacetophenone, 4.4 g of 1b was
obtained (99% pure by GC; 71% yield); mp 60–64 ЊC. The
product was recrystallised from n-pentane–diethyl ether (95:5
v/v). 1H NMR (CDCl3) δ: 2.29 (s, 3H, CH3), 4.38 (s, 2H, CH2),
7.38 (d, 2H, Ar; J 8.8 Hz), 7.77 (d, 2H, Ar; J 8.8 Hz). Mass
spectrum (70 eV) m/z (relative intensity): 194 (9), 193 (15), 192
(Mϩ, 28), 191 (38), 180 (4), 179 (34), 178 (11), 177 (100), 152 (8),
150 (11), 139 (18), 137 (55), 102 (12), 75 (12).
N-(1-Phenylethylidene)cyanomethyl amine 1c. Full data are in
ref. 4.
Under the same conditions, the imine 1c [PhC(᎐NCH CN)-
᎐
2
N-[1-(p-Methoxyphenyl)ethylidene]cyanomethyl amine 1d.
Starting from 5.0 g of p-methoxyacetophenone, 5.0 g of 1d was
obtained (98% pure by GC; 80% yield); mp 46–47.5 ЊC. The
product was recrystallised from n-hexane–CHCl3 (95:5 v/v).
1H NMR (CDCl3) δ: 2.29 (s, 3H, CH3), 3.85 (s, 3H, OCH3), 4.38
(s, 2H, CH2), 6.91 (dd, 2H, Ar; J 9.2, JЈ 2.0 Hz), 7.8 (dd, 2H, Ar;
J 9.2, JЈ 2.0 Hz). Mass spectrum (70 eV) m/z (relative intensity):
189 (6), 188 (Mϩ, 50), 187 (31), 174 (8), 173 (68), 134 (10), 133
(100), 103 (8), 90 (8), 80 (9), 77 (7), 55 (8).
CH3] was also reacted in the presence of an equimolar amount
of Na13CN (13C, 99%).
Compounds 2a–e were not isolated: their characterisation
was through GC/MS analysis by comparison with authentic
samples.2c,3
The reactions of labelled imines *1c and 1c*. As above
described, solutions of the crude imines *1c and 1c* in DMF
were obtained by condensing acetophenone with NH2CH2-
13CNؒH2SO4 (13C, 99%) and 15NH2CH2CNؒH2SO4 (15N, 99%),
respectively. According to the same procedure used for com-
pounds 1a–e, the solutions of *1c and 1c* were then added to
K2CO3 (1.5 molar excess with respect to the reacting imine),
and heated under stirring at the reflux temperature.
N-[1-(p-Methylphenyl)ethylidene]cyanomethyl amine 1e.
Starting from 5.0 g of p-methylacetophenone, 3.5 g of 1e was
obtained (98% pure by GC; 55% yield); mp 29–31 ЊC. The
1
product was recrystallised from n-hexane. H NMR (CDCl3)
δ: 2.29 (s, 3H, CH3), 2.38 (s, 3H, CH3), 4.38 (s, 2H, CH2), 7.47
(d, 2H, Ar), 7.71 (d, 2H, Ar). Mass spectrum (70 eV) m/z
(relative intensity): 172 (Mϩ, 17), 171 (20), 158 (11), 157 (100),
130 (16), 117 (58), 116 (24), 91 (12), 89 (12), 77 (6), 65 (12). The
product decomposes on standing.
The labelled 2-phenylpropionitriles (*2c and 2c*) were not
isolated and they were characterized by GC/MS as described in
Table 2.
Preparation of N-alkylformimidoyl cyanides (4c,f,g)
13C-labelled N-(1-phenylethylidene)cyanomethyl amine *1c,
PhC(᎐NCH 13CN)CH3. Under the conditions reported in ref. 4,
N-Alkylformimidoyl cyanides 4c,f,g were prepared by a new
method20 devised as a modification of reported N-chlorination
and dehydrochlorination procedures.8 Accordingly, the appro-
priate amines RRЈCHNHCH2CN (R = Ph, RЈ = CH3; R = Et,
RЈ = CH3)8,17 were added dropwise to a vigorously stirred
aqueous solution of NaOCl (1.5 M; 10–13% available chlorine;
1.2 molar equiv. with respect to the amine), providing that the
reaction temperature was kept below 10 ЊC. Then, the mixture
was allowed to warm to room temperature, stirred for 1 h, and
extracted with diethyl ether (3 × 25 mL). The combined organic
layers were dried over Na2SO4, and, after filtration, the diethyl
ether was carefully removed by rotary evaporation. Compound
4g was further purified by distillation.
᎐
2
acetophenone (0.25 g) was reacted with NH2CH213CNؒH2SO4
(13C, 99%; 0.51 g), affording *1c in 88% yield (by GC). The
product *1c was not isolated. The structure was confirmed by
GC/MS. Mass spectrum (70 eV) m/z (relative intensity): 159
(Mϩ, 17), 158 (43), 145 (9), 144 (100), 117 (8), 116 (22), 103 (31),
82 (8), 77 (16), 76 (8), 51 (12).
15N-labelled N-(1-phenylethylidene)cyanomethyl amine 1c*,
PhC(᎐15NCH CN)CH . Under the conditions reported in ref. 4,
᎐
2
3
acetophenone (0.25 g) was reacted with 15NH2CH2CNؒH2SO4
(15N, 99%; 0.51 g), affording 1c* in 83% yield (by GC). The
product 1c* was not isolated. The structure was confirmed by
GC/MS. Mass spectrum (70 eV) m/z (relative intensity): 159
(Mϩ, 22), 158 (52), 145 (10), 144 (100), 118 (6), 117 (23), 104
(31), 82 (9), 77 (13), 51 (9). The peaks 117 and 104 of com-
pound 1c* represent the (PhC᎐15NCH)ϩ and (PhC᎐15N)ϩ frag-
In the case of the solid amine Ph2CHNHCH2CN (0.5 g), the
reaction was run dissolving the amine in dioxane (4 mL). When
used neat, no reaction took place at all.
N-sec-Butylformimidoyl cyanide 4g. Starting from N-sec-
᎐
᎐
2490
J. Chem. Soc., Perkin Trans. 2, 1999, 2485–2492

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butylaminoacetonitrile (5.0 g, 44.6 mmol),17 a mixture of 4g
and starting amine was obtained in a 95:5 ratio, respectively
(2.68 g; bp 66–69 ЊC, 20 mmHg). 4g, E isomer: 1H NMR
(CDCl3) δ: 0.81 (t, 3H, CH3, J 7.2 Hz), 1.22 (d, 3H, CH3, J 7.2
Hz), 1.60 (quintet, 2H, CH2, J 7.2 Hz), 3.26 (q, 1H, CH, J 7.2
product (Ph2CHCN, 2f) was purified by column chromato-
graphy: 48% yield (0.13 g, 0.65 mmol).
The molar ratio CNϪ/2f was 1.1.
Reaction of 1f with n-BuLi
Hz), 7.35 (s, 1H, N᎐CH); traces (≤5%) of the Z isomer were
᎐
Ph C᎐NCH CN 1f (0.50 g, 2.3 mmol) dissolved in 15 mL of
᎐
2
2
also detected. Mass spectrum (70 eV) m/z (relative intensity): 95
(Mϩ Ϫ CH3, 18), 82 (16), 81 (100), 68 (13), 57 (22), 54 (44). The
product rapidly decomposed on standing.
anhydrous THF was treated with 0.95 mL of n-BuLi (2.5 M in
hexanes; 2.4 mmol) at –90 ЊC, under N2. The solution turned
brown.
N-(ꢀ-Methyl)benzylformimidoyl cyanide 4c. Starting from
Procedure A. The solution was warmed slowly to room tem-
perature, THF was distilled off under vacuum and replaced
with an equal amount of anhydrous DMF, and brought to the
reflux temperature. The reaction was followed by GC: 2f was
the sole product, identified by GC/MS by comparison with
a known sample.
N-(α-methyl)benzylaminoacetonitrile (1.0 g, 6.3 mmol),18
a
mixture of 4c, starting amine and 1c was obtained in an 88:10:2
ratio, respectively (0.65 g; not distilled). 4c, E isomer: 1H NMR
(CDCl3) δ: 1.59 (d, 3H, CH3, J 6.6 Hz), 4.59 (q, 1H, CH, J 6.6
Hz), 7.29–7.39 (m, Ph and N᎐CH); traces of the Z isomer were
᎐
also detected. Mass spectrum (70 eV) m/z (relative intensity):
158 (Mϩ, 6), 116 (20), 106 (10), 105 (100), 103 (12), 79 (12), 77
(21), 51 (9). The initially pale yellow liquid turned to brown in
24 h, even when stored at ϩ4 ЊC.
The reaction of Ph2CHNHCH2CN gave a mixture of 1f
(60%), 4f (25%) and N-(α-methyl)benzylaminoacetonitrile
(15%). Products were not separated. 4f: mass spectrum (70 eV)
m/z (relative intensity): 220 (Mϩ, 7), 168 (15), 167 (100), 166
(12), 165 (34), 152 (19), 116 (8), 89 (7), 77 (7), 51 (5).
Procedure B. The solution was warmed to room temperature
and quenched with 1.0 equiv. of either n-BuBr or MeI. The
mixture was cooled to 0 ЊC, treated with water, washed with
half saturated brine (3 × 20 mL), the organic layer was dried
over Na2SO4, filtered and the solvent removed by rotary evap-
oration. The products 5a and 5b were obtained as yellow oils,
and were characterised by GC-MS and 1H NMR.
1
5a. Yield = 90%. H NMR (CDCl3) δ: 7.16–7.86 (m, 10H,
Spectroscopic data of the secondary amines
aromatic), 4.22 (t, 1H, J 6.6 Hz, CH), 2.08–1.76 (m, 2H), 1.52–
1.20 (m, 4H), 0.89 (t, 3H, J 7.5 Hz); mass spectrum (70 eV) m/z
(relative intensity): 276 (Mϩ, 34), 275 (92), 233 (12), 222 (12),
220 (24), 219 (80), 209 (18), 208 (100), 194 (11), 165 (37), 117
(10), 116 (93), 104 (34), 103 (13), 89 (14), 77 (32).
N-sec-Butylaminoacetonitrile.17 Starting from 10 g (137
mmol) of sec-butylamine, 9.95 g was obtained (65%; bp 38 ЊC,
0.3 mmHg; 95% pure by GC). 1H NMR (CDCl3) δ: 0.91 (t, 3H,
CH3, J 7.2 Hz), 1.05 (d, 3H, CH3, J 6.6 Hz), 1.28 (br s, 1H,
NH), 1.35 (dq, 1H, CH2, J 7.2 Hz), 1.47 (dq, 1H, CH2, J 7.2
Hz), 2.81 (sextet, 1H, CH, J 6.6 Hz), 3.66 (dd, 2H, CH2CN,
J 8.2 Hz); mass spectrum (70 eV) m/z (relative intensity): 158
(Mϩ, 6), 116 (20), 106 (10), 105 (100), 103 (12), 79 (12), 77 (21),
51 (9); IR (CCl4): ν/cmϪ1 2243 (CN), 3357 (NH).
5b. Yield = 92%. Mass spectrum (70 eV) m/z (relative inten-
sity): 234 (Mϩ, 62), 233 (74), 219 (12), 207 (25), 180 (48), 166
(23), 165 (37), 157 (20), 156 (12), 116 (100), 104 (78), 103 (14),
77 (71).
N-(ꢀ-Methyl)benzylaminoacetonitrile.18 Starting from 5 g
(41.3 mmol) of (α-methyl)benzylamine, 2.5 g was obtained
(38%; bp 86–88 ЊC, 0.2 mmHg). H NMR (CDCl3) δ: 1.41 (d,
3H, CH3, J 7.8 Hz), 2.4 (br s, 1H, NH), 3.42 (dd, 2H, CH2CN,
J 17 Hz), 4.09 (q, 1H, CH, J 7.8 Hz), 7.28–7.38 (m, 5H, Ph);
mass spectrum (70 eV) m/z (relative intensity): 158 (Mϩ, 6), 116
(20), 106 (10), 105 (100), 103 (12), 79 (12), 77 (21), 51 (9); IR
(CCl4): ν/cmϪ1 2235 (CN), 3334 (NH).
Acknowledgements
The authors wish to thank a Referee for suggesting a plausible
mechanism for the rearrangement discussed in this paper (route
“b” of Scheme 4).
This work was supported by MURST (Ministero
dell’Università e della Ricerca Scientifica e Tecnologica), and
by INCA (Consorzio Interuniversitario “la Chimica per
l’Ambiente”).
1
N-Benzhydrylaminoacetonitrile. Starting from 3 g (16.4
mmol) of benzhydrylamine, 2.4 g was obtained (65%; mp 73–
74.5 ЊC). The product was crystallised from n-hexane–diethyl
ether (2:1 v/v). 1H NMR (CDCl3) δ: 2.00 (br s, 1H, NH), 3.58
(s, 2H, CH2CN), 5.10 (s, 1H, CH), 7.25–7.55 (m, 10H, 2Ph);
mass spectrum (70 eV) m/z (relative intensity): 222 (Mϩ, 19),
168 (12), 167 (70), 166 (13), 165 (39), 152 (21), 146 (11), 145
(100), 144 (19), 104 (39), 77 (17), 67 (24), 51 (11); IR (KBr):
ν/cmϪ1 2243 (CN), 3342 (NH).
References
1 R. C. Larock, in Comprehensive Organic Transformations: A Guide
to Functional Group Preparations, VCH, Weinheim, 1989.
2 (a) A. Kleemann and J. Engel, in Pharmazeutische Wirkstoffe,
Synthesen, Patente, Anwendeungen, George Thieme Verlag, Stuttgart,
New York, 1987; (b) J. P. Rieu, A. Boucherle, H. Cousse and G.
Mouzin, Tetrahedron, 1986, 42, 4095; (c) M. Selva, C. A. Marques
and P. Tundo, J. Chem. Soc., Perkin Trans. 1, 1994, 1323.
3 M. Selva, A. Bomben and P. Tundo, Synth. Commun., 1999, 29,
1561.
4 M. Selva, C. A. Marques and P. Tundo, Synth. Commun., 1995, 25,
369.
5 (a) J. H. Boyer, J. Dunn and J. Kooi, J. Chem. Soc., Perkin Trans. 1,
1975, 1743; (b) J. P. Ferris, R. S. Narang, T. A. Newton and
V. R. Rao, J. Org. Chem., 1979, 44, 1273.
6 G. Pannetier and P. Souchay, in Chemical Kinetics, Elsevier, Barking
(UK), 1967.
7 C. K. Ingold and C. L. Wilson, J. Chem. Soc., 1933, 1493.
8 (a) J. H. Boyer and J. Kooi, J. Am. Chem. Soc., 1976, 98, 1099;
(b) J. R. Lindsay Smith, L. C. McKeer and J. Taylor, Org. Synth.,
1989, 67, 222.
9 Nissan Chemical Industries, Ltd., Jpn. Kokai Tokkyo Koho, JP 59
46,257 (15 Mar 1984); Chem. Abstr., 1984, 101, 90603e.
10 J. March, in Advanced Organic Chemistry, 3rd edn., J. Wiley & Sons,
New York, 1985, p. 244.
Titration of the cyanide released by the reaction 1→2
The particular case of Ph C᎐NCH CN 1f was considered. 1f
᎐
2
2
(0.30 g, 1.4 mmol) was reacted under the conditions of Scheme
1, and once the reaction was completed, the DMF solvent (10
mL) was distilled off under vacuum. To the solid brown residue
was added ultrapure water (40 mL, produced by a Millipore
Milli-Q-plus system). The mixture was then extracted with
diethyl ether (3 × 20 mL). The aqueous phase was titrated by
aq. AgNO3 (0.01 M volumetric standard) using established pro-
cedures:19 the concentration of the resulting cyanide solution
was 1.8 × 10Ϫ2 M (0.72 mmol of CNϪ in 40 mL).
The combined organic layers were dried over Na2SO4 and
filtered. After removal of the solvent by rotary evaporation, the
J. Chem. Soc., Perkin Trans. 2, 1999, 2485–2492
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View Article Online
17 J. Corse, J. T. Bryant and H. A. Shonle, J. Am. Chem. Soc., 1946,
11 H. Maskill, in The Physical Basis of Organic Chemistry, Oxford
University Press, Oxford, 1989.
68, 1905.
12 K. Bowden, N. B. Chapman and J. Shorter, Can. J. Chem., 1964, 42,
18 T. Okawara and K. Harada, J. Org. Chem., 1972, 37, 3286.
19 A. Vogel, in A Textbook of Quantitative Inorganic Analysis, 3rd edn.,
Longman, London, 1961, 272.
1979.
13 M. Jay, W. J. Layton and G. A. Digenis, Tetrahedron Lett., 1980, 21,
2621.
14 W. Bauer and K. Hafner, Angew. Chem., Int. Ed. Engl., 1969, 8, 772.
15 J. P. Ferris, D. B. Donner and W. Lotz, J. Am. Chem. Soc., 1972, 94,
6968.
20 A. Perosa, M. Selva and P. Tundo, Tetrahedron Lett., 1999, in the
press.
16 (a) W. K. Anslow and H. King, J. Chem. Soc., 1929, 2465; (b)
R. Adams and W. D. Langley, Org. Synth., 1941, Coll. Vol. I, 355.
Paper 9/05563K
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