A mild synthesis of nitriles by von Braun degradation of amides using triphenyl phosphite-halogen-based reagents

Article abstract of DOI:10.1055/s-2007-1072591

A mild procedure for the synthesis of aromatic and aliphatic nitriles is disclosed. In the presence of bromotriphenoxyphosphonium bromide (TPPBr ₂), N-alkyl and N,N-dialkyl amides undergo von Braun degradation to nitriles in good to excellent yields under the mildest conditions ever reported. The reaction proceeds via formation of an iminoyl bromide intermediate at -60°C, which subsequently dealkylate upon refluxing in chloroform or even at room temperature. In the case of N-tert-butyl, N-α-phenylethyl and N-benzhydryl amides, chlorotriphenoxyphosphonium chloride (TPPCl₂) generated at -30°C was also effective. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-1072591

LETTER
1317
A Mild Synthesis of Nitriles by von Braun Degradation of Amides Using
Triphenyl Phosphite–Halogen-Based Reagents
Mild von Braun
D
a
egradation t
n
o Nitriles iele Vaccari, Paolo Davoli, Alberto Spaggiari, Fabio Prati*
Dipartimento di Chimica, Università di Modena e Reggio Emilia, via Campi 183, 41100 Modena, Italy
Fax +39(059)373543; E-mail: prati.fabio@unimore.it
Received 26 October 2007
could be extended and the reaction would gain a renewed
appeal for the preparation of nitriles.
Abstract: A mild procedure for the synthesis of aromatic and ali-
phatic nitriles is disclosed. In the presence of bromotriphenoxy-
phosphonium bromide (TPPBr2), N-alkyl and N,N-dialkyl amides
undergo von Braun degradation to nitriles in good to excellent
yields under the mildest conditions ever reported. The reaction pro-
ceeds via formation of an iminoyl bromide intermediate at –60 °C,
which subsequently dealkylate upon refluxing in chloroform or
even at room temperature. In the case of N-tert-butyl, N-a-phenyl-
ethyl and N-benzhydryl amides, chlorotriphenoxyphosphonium
chloride (TPPCl2) generated at –30 °C was also effective.
Recently, we have exploited halotriphenoxyphosphonium
halides, viz. (PhO)3P+X X– (henceforth TPPX2, where
X = Cl or Br), for the activation of a variety of amides into
the corresponding iminoyl halides; this has resulted in the
development of exceedingly mild protocols for the deacy-
lation of secondary amides,9a,b for the synthesis of nitro-
gen-containing heterocycles such as b-carbolines9c and
pyrroles,9d and also for the dehydration of primary amides
into nitriles.9e
Key words: amide degradation, halotriphenoxyphosphonium ha-
lides, imidoyl halides, nitriles, triphenyl phosphite
By close analogy, we envisaged that the remarkable halo-
genating potential of TPPX2 could be exploited also in the
framework of a von Braun degradation which is well
known to proceed via an imidoyl halide intermediate.6b,10
In this paper, therefore, we wish to describe a general
method which embodies a von Braun degradation under
very mild conditions to convert secondary and tertiary
alkyl amides into aromatic and aliphatic nitriles.
Since the first nitrile synthesis reported by Wöhler and
von Liebig as early as 1832,1 a great deal of research has
been devoted to the development of efficient and straight-
forward processes for the preparation of organic cya-
nides.2 Nitriles, in fact, play an important role in organic
synthesis as useful substrates for a variety of transforma-
tions, and their relevance has increased accordingly along
the years.3 Most recently, nitriles have even featured as
partners in alkyne metathesis.4
To this end, a suitable set of aromatic and aliphatic N-
alkyl and N,N-dialkyl amides were synthesized from p-
toluic acid or 10-undecenoic acid and the appropriate
amine following standard literature procedures,11 and sub-
jected to TPPX2 under typical conditions (Equation 1).12
In particular, amides 1a–x were treated at –60 °C with a
freshly prepared solution of TPPBr2 in chloroform in the
presence of triethylamine; in the case of tertiary amides,
triethylamine was not included. After warming to room
temperature, the reaction mixture was gently refluxed
overnight to achieve complete conversion, when neces-
sary, and the crude residue was purified by column chro-
matography.13 When TPPCl2 was used, the starting
temperature could be raised to –30 °C.14 The results are
summarized in Table 1.
Dealkylation of secondary and tertiary benzamides upon
heating in the presence of halogenating reagents is tradi-
tionally referred to as the von Braun degradation. Namely,
when N-alkyl and N,N-dialkyl amides are treated with in-
organic phosphorus halides or thionyl chloride, decompo-
sition into a nitrile and alkyl halide(s) occurs.5,6 The
reaction requires harsh conditions (typically 90–150 °C)
and, in addition, the resulting products need to be isolated
by distillation from the crude reaction mixture, owing to
the formation of otherwise intractable phosphoric tars and
byproducts. Because of these drawbacks, the von Braun
degradation has found relatively little use for the prepara-
tion of nitriles sensu stricto, and applications have mainly
focused on the alkyl halide product(s) instead, especially
for structure elucidation purposes in the alkaloid field.7
Although slight modifications have been proposed,8 the
reaction conditions still remain quite aggressive, and have
limited the usage of this process for synthetic applica-
tions. Clearly, if milder reaction conditions were avail-
O
O
TPPBr2
R1
R1
or
R
N
R
N
R1
R
N
CHCl3
–60 °C to r.t.,
then reflux
H
Equation 1 Synthesis of aromatic and aliphatic nitriles by von
able, the synthetic scope of the von Braun degradation Braun degradation of secondary and tertiary amides using TPPBr2
SYNLETT 2008, No. 9, pp 1317–1320
x
x.
x
x.
2
0
0
7
Advanced online publication: 16.04.2008
DOI: 10.1055/s-2007-1072591; Art ID: G35007ST
© Georg Thieme Verlag Stuttgart · New York

1318
D. Vaccari et al.
LETTER
Table 1 TPPX2-Promoted von Braun Degradation of Secondary
Table 1 TPPX2-Promoted von Braun Degradation of Secondary
and Tertiary Amidesa (continued)
and Tertiary Amidesa
Entry
1
Substrate
Yield (%)
53
Entry
Substrate
Yield (%)
O
O
O
O
12
52
N
N
H
Ph
Ph
Ph
H
1l
1a
Ph
O
13
14
91
N
H
N
2
3
4
5
6
7
8
9
40
H
1m
1b
O
55d
N
Ph
Ph
Ph
N
80
H
1n
1o
1p
O
O
1c
O
N
H
15
16
92
96b (87)b
N
H
MeO
1d
O
96b
N
H
N
68
MeO
H
1e
O
O
B
O
17
60
O
N
Ph
N
Ph
Ph
Ph
Ph
97 (0)
96b,c (90)
94b (99)b
70d (0)
H
H
1q
O
1f
O
S
18
19
62
67
N
Ph
N
H
H
S
1r
O
1g
O
Ph
N
H
Ph
Ph
Ph
N
H
1s
O
1h
O
20
21
22
70b
70b
88b
N
H
N
Ph
1t
O
1i
O
N
H
10
11
48d
61
N
N
1u
1v
1j
O
O
N
H
Ph
N
H
1k
Synlett 2008, No. 9, 1317–1320 © Thieme Stuttgart · New York

LETTER
Mild von Braun Degradation to Nitriles
1319
Table 1 TPPX2-Promoted von Braun Degradation of Secondary
amides. Yet again, use of the a-phenylethyl group as the
alkyl substituent at nitrogen allowed to omit the refluxing
step and resulted in comparable yields to those of the cor-
responding N-benzyl analogues (compare entry 15 with
16, and 19 with 20). In the case of e-lactam 1x (entry 24),
treatment with TPPBr2 failed to give the expected w-bro-
monitrile, even after prolonged refluxing.
and Tertiary Amidesa (continued)
Entry
23
Substrate
Yield (%)
49b
H
N
O
MeO
The mechanism of the von Braun degradation has been
long since clarified.6,10 The reaction is well known to pro-
ceed through activation of the amide into an imidoyl ha-
lide intermediate, which sometimes has also been
isolated.6b,10 Subsequent dealkylation is reported to occur
through nucleophilic displacement at the adjacent N-alkyl
carbon atom by means of halide ions to afford the desired
nitrile and the corresponding alkyl halide. Such a dis-
placement may well occur directly onto the imidoyl halide
itself, or on the corresponding nitrilium ion.10 For N,N-di-
alkyl amides the dealkylation step is further repeated, and
two molecules of alkyl halide are eventually produced.
1w
NH
24
0e
O
1x
a Reaction conditions: amide (1.0 mmol), (PhO)3P (1.2 mmol), Br2
(1.2 mmol), Et3N (1.3 mmol), CHCl3 (20 mL), –60 °C to r.t., then re-
flux for 16 h (unless otherwise noted). Yields in brackets refer to
TPPCl2-mediated reactions: –30 °C to r.t., then reflux for 16 h (unless
otherwise noted).
b Without reflux.
c Optically pure amide 1g was used; in addition to tolunitrile, (R)-1-
phenylethyl bromide with 25% optical purity was also isolated.15
d Without addition of Et3N.
The experimental data for our own set of secondary and
tertiary amides agree well with such a reaction pathway
and mechanism. Use of TPPX2 as the halogenating re-
agent brings about imidoyl halide formation, along with
triphenyl phosphate (TPPO) as byproduct (Scheme 1), as
previously described.9 When secondary amides are em-
ployed, concomitant release of hydrogen halide also oc-
curs (Scheme 1), thereby requiring preventive addition of
triethylamine to the reaction mixture in order to maintain
neutrality.
e Unreacted e-caprolactam was recovered.
p-Toluamides 1a–j were all converted by TPPBr2 into tol-
unitrile in moderate to quantitative yields (Table 1, entries
1–10). In the case of secondary amides 1a–h (entries 1–8),
excellent yields were obtained for a-substituted N-alkyl
groups such as isopropyl (1c), tert-butyl (1d), benzyl (1f),
a-phenylethyl (1g), and benzhydryl (1h). Most remark-
ably, dealkylation of secondary amides 1d,g,h (entries 4,
7, and 8) proceeded smoothly at room temperature with-
out any reflux. Reaction of N-methyl, N-decyl and N-allyl
amides 1a,b,e afforded tolunitrile in only moderate yields
(entries 1,2, and 5). On the other hand, tertiary amides 1i,j
(entries 9 and 10) gave lower yields than the correspond-
ing secondary amides, despite the choice of alkyl substit-
uents that had well performed for the latter such as the
isopropyl and the benzyl group. When TPPCl2 was em-
ployed, comparable results were obtained for amides
1d,g,h, even though yields were generally slightly higher
with TPPBr2. However, for benzyl amides 1f and 1i the re-
action with TPPCl2 failed.
gentle
reflux
O
X
TPPX2
R1
(A)
R
N
R1
R
R
N
H
R
R
N
R1
X
TPPO
HX
gentle
reflux
O
X
TPPX2
TPPO
R1
(B)
R
N
R1
N
R1
N
R1
2 R1
X
Scheme 1 TPPX2-mediated von Braun degradation of secondary
(A) and tertiary amides (B)
In the case of 10-undecenoyl amides (Table 1, entries 11–
14), benzhydryl amide 1m was converted into 10-un-
decenenitrile in excellent yield (entry 13), whereas N-tert-
butyl, N-benzhydryl, and N,N-dibenzyl amides (1k,l,n)
gave only moderate yields (entries 11, 12, and 14).
As far as the dealkylation of the iminoyl halide is con-
cerned, the greater the ease with which the adjacent N-
alkyl carbon atom can host a positive charge, the more
likely the dealkylation is to proceed via SN1-type mecha-
nism, and the milder the reaction conditions. This is in-
deed the case for tert-butyl, a-phenylethyl and benzhydryl
amides such as, for instance, 1d,g,h. In fact, complete
conversion into the corresponding nitrile was achieved at
room temperature without the need to reflux. The mono-
molecular mechanism is further corroborated by the par-
tial racemization which has been observed for the
degradation of optically pure N-a-phenylethyl amide 1g
into tolunitrile, resulting also in the isolation of (R)-phen-
ylethyl bromide with only 25% optical purity.15 For N-
alkyl carbon atoms of secondary, allylic or benzylic na-
ture, as in the case of 1c,e,f, competition between SN1- and
On the basis of these results, a further set of N-benzyl and
N-a-phenylethyl secondary amides was prepared to test
substrate and functional group compatibility of the
TPPBr2-promoted von Braun degradation. Aromatic and
aliphatic N-benzyl, N-a-phenylethyl or N-tert-butyl
amides 1o–w were synthesized from the parent carboxylic
acid by reaction of the corresponding acyl chloride with
benzylamine, a-phenylethylamine or tert-butylamine, and
subjected to the action of TPPBr2 under standard condi-
tions.13 Nitriles were obtained in moderate to excellent
yields (Table 1, entries 15–23), especially for aromatic
Synlett 2008, No. 9, 1317–1320 © Thieme Stuttgart · New York

1320
D. Vaccari et al.
LETTER
(4) Geyer, A. M.; Gdula, R. L.; Wiedner, E. S.; Johnson, M. J.
A. J. Am. Chem. Soc. 2007, 129, 3800.
(5) von Braun, J. Ber. Dtsch. Chem. Ges. 1904, 37, 3210.
(6) (a) Leonard, N. J.; Nommensen, E. W. J. Am. Chem. Soc.
1949, 71, 2808. (b) Vaughan, W. R.; Carlson, R. D. J. Am.
Chem. Soc. 1962, 84, 769.
SN2-like mechanism may occur; although yields range to
moderate to excellent, complete conversion is accom-
plished only after heating to reflux. In contrast, yields are
lower when the reaction is bound to proceed through bi-
molecular mechanism, viz. for amides 1a,b.
(7) For instance, see: (a) Prelog, V.; Zalan, E. Helv. Chim. Acta
1944, 27, 535. (b) Götz, M.; Bögri, T.; Gray, A. H.
Tetrahedron Lett. 1961, 2, 707. (c) Sallay, I.; Ayres, R. H.
Tetrahedron 1963, 19, 1397. (d) Fodor, G.; Bauerschmidt,
E.; Cymerman, C. J. Can. J. Chem. 1969, 47, 4393.
(e) Butruille, D.; Fodor, G.; Saunderson Huber, C.;
Letourneau, F. Tetrahedron 1971, 27, 2055.
(8) (a) Fodor, G.; Ryan, J. J.; Letourneau, F. J. Am. Chem. Soc.
1969, 91, 7768. (b) Blum, J.; Fisher, A. Tetrahedron Lett.
1970, 23, 1963. (c) Dennis, W. E. J. Org. Chem. 1970, 35,
3253. (d) Perni, B. R.; Gribble, G. W. Org. Prep. Proced.
Int. 1983, 15, 297.
(9) (a) Spaggiari, A.; Blaszczak, L. C.; Prati, F. Org. Lett. 2004,
6, 3885. (b) Spaggiari, A.; Blaszczak, L. C.; Prati, F. Ars.
Pharm. 2005, 46, 167. (c) Spaggiari, A.; Davoli, P.;
Blaszczak, L. C.; Prati, F. Synlett 2005, 661. (d) Spaggiari,
A.; Vaccari, D.; Davoli, P.; Prati, F. Synthesis 2006, 995.
(e) Vaccari, D.; Davoli, P.; Bucciarelli, M.; Spaggiari, A.;
Prati, F. Lett. Org. Chem. 2007, 4, 319.
For amides where the SN1 mechanism is operative,
TPPBr2 can be replaced by TPPCl2 as the halogenating re-
agent with similar results (see Table 1, entries 4, 7, and 8).
When compared to TPPBr2, however, the efficiency of
TPPCl2 decreases as long as the bimolecular mechanism
tends to prevail, i.e., benzhydryl > a-phenylethyl > ben-
zyl. In fact, whilst degradation of benzhydryl amide 1h
occurred quantitatively at room temperature, a-phenyleth-
yl amide 1g required heating to reflux, whereas benzyl
amides 1f,i failed to give any tolunitrile when treated with
TPPCl2, even after prolonged heating at reflux.
The failure of e-caprolactam (1x) to undergo TPPBr2-me-
diated von Braun degradation is worthy of note, and sug-
gests that this protocol is restricted to acyclic amides.
Further, it corroborates the involvement of a nitrilium ion
intermediate, whose formation is not permitted in cyclic
amides for geometric constraints.
(10) (a) Phillips, B. A.; Fodor, G.; Gal, J.; Letourneau, F.; Ryan,
J. J. Tetrahedron 1973, 29, 3309. (b) Fodor, G.; Nagubandi,
S. Tetrahedron 1980, 36, 1279.
In summary, a variety of aromatic and aliphatic nitriles
were prepared from alkyl-substituted secondary and ter-
tiary acyclic amides by von Braun degradation using
TPPBr2 as the halogenating species. The dealkylation was
carried out under the mildest conditions ever reported in
the literature and afforded nitriles in good to excellent
yields. This application further demonstrates the synthetic
versatility of triphenyl phosphite–halogen-based reagents
in functional-group transformations and should be of val-
ue as a mild and expeditious access to nitriles from acyclic
alkyl amides.
(11) All compounds were characterized by 1H NMR and EI-MS
analysis. For new compounds, 13C NMR and elemental
analysis were also performed.
(12) Spaggiari, A.; Vaccari, D.; Davoli, P.; Torre, G.; Prati, F.
J. Org. Chem. 2007, 72, 2216.
(13) TPPBr2-Promoted von Braun Degradation; General
Procedure
Bromine (0.31 mL, 6.0 mmol) was added to a solution of
triphenyl phosphite (1.57 mL, 6.0 mmol) in anhyd CHCl3
(20 mL) maintained at –60 °C under argon flow. After
addition of dry Et3N (0.9 mL, 6.5 mmol), the amide (5.0
mmol) was added to the pale orange clear solution (for
tertiary amides, however, Et3N was not used). After leaving
to warm to r.t. over a period of 3–4 h, the reaction mixture
was gently heated to reflux for 16 h, except when TLC
analysis already showed complete disappearance of the
starting amide (see Table 1). The solvent was then
evaporated under reduced pressure and the resulting nitrile
was purified by column chromatography on silica gel.
(14) TPPX2 is generated by reacting triphenyl phosphite with an
equimolecular amount of Cl2 or Br2 at low temperature, viz.
from –30 °C to –20 °C for chlorine or from –60 °C to –50 °C
for bromine. Under such conditions, the predominant
species is the halotriphenoxyphosphonium halide
(PhO)3P+X X–, which is active for our synthetic scope. When
generated at higher temperatures, increasing amounts of the
synthetically inactive covalent species dihalo triphen-
oxyphosphorane (PhO)3PX2 are also formed.9a,12
(15) (a) Reaction of optically pure (S)-a-phenylethyl amide 1g,
[a]D +54.1 (c 1.3, acetone); lit.15b [a]D +57.0 afforded
tolunitrile along with (R)-phenylethyl bromide, [a]D +28.4 (c
2.1, CHCl3); lit.15c [a]D +111.5. (b) Nerdel, F.; Goetz, H.;
Wendenburg, J. Liebigs Ann. Chem. 1959, 627, 106.
(c) Lau, K. S. Y.; Wong, P. K.; Stille, J. K. J. Am. Chem. Soc.
1976, 98, 5832.
Acknowledgment
Financial support (COFIN) from the Ministero dell’Università e
della Ricerca Scientifica (MiUR) was greatly appreciated. A.S.
thanks Fondazione Cassa di Risparmio di Modena for a postdocto-
ral fellowship.
References and Notes
(1) Wöhler, F.; von Liebig, J. Justus Liebigs Ann. Chem. 1832,
3, 267.
(2) (a) Mowry, D. T. Chem. Rev. 1948, 42, 189. (b) Sandler, S.
R.; Karo, W. Organic Functional Group Preparations In
Organic Chemistry, 2nd ed., Vol. 12-I; Wasserman, H. H.;
Blomquist, A. T., Eds.; Academic Press: San Diego, 1983,
Chapt. 17, 549–584. (c) Subramanian, L. R. In Science of
Synthesis, Vol. 19; Thieme: Stuttgart, 2004, 79.
(3) (a) The Chemistry of the Cyano Group; Rappoport, Z., Ed.;
Wiley-Interscience: New York, 1970. (b) Larock, R. C.
Comprehensive Organic Transformations, 2nd ed.; Wiley-
VCH: New York, 1999.
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