Domino reaction of lithiated allenes with nitriles

Article abstract of DOI:10.1039/a803040e

Addition of nitriles to dilithiated allenes results in a unique domino cyclization which involves the so far highest number of nitrile molecules added to an organolithium reagent to form unambiguously characterized oligomers.

Full text of DOI:10.1039/a803040e

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Domino reaction of lithiated allenes with nitriles†
a
b
c
Peter Langer,* ‡ Manfred Döring and Dietmar Seyferth
a
Institut für Organische Chemie der Georg-August-Universität Göttingen, Tammannstrasse 2, 37077 Göttingen, Germany
Institut für Anorganische und Analytische Chemie der Universität Jena, August-Bebel-Strasse 2, 07743 Jena, Germany
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
b
c
Addition of nitriles to dilithiated allenes results in a unique
reaction of the allene with three and four nitriles, respectively,
had been formed. The yield of 4 was significantly improved by
use of 4.5 equiv. of the nitrile. Yellow-coloured imidazole 3 and
colourless 5-imidazol-5-yl-1,4-dihydropyrimidine 4 were iso-
lated in 12 and 51% yield, respectively.§ Similar results were
obtained when 10 equiv. of PhCN were employed. Reaction of
dilithioallene 2 with pivalonitrile afforded as the sole isolated
product the colourless imidazole 5 (66%). The imine group was
hydrolyzed during aqueous work-up to generate an a,b-
unsaturated keto group. Reaction of 2 with p-tolunitrile gave the
orange coloured imidazole 6 (28%).
domino cyclization which involves the so far highest number
of nitrile molecules added to an organolithium reagent to
form unambiguously characterized oligomers.
The development of domino reactions is of ongoing interest in
1
organic synthesis. Interestingly, although the base-catalyzed
polymerization of nitriles has been followed for a long time and
the mixtures obtained were among the first organic polymers,
only a few structurally unambiguously characterized oligomers
derived from multiple addition reactions of nitriles have been
reported so far. In contrast, the palladium-catalyzed oligomer-
ization of six isonitrile molecules has recently been reported.2
Addition of 2 equiv. of a nitrile to an organometallic reagent has
been achieved by reaction of 2,3-bis-lithiated methylbutadiene
Formation of the sterically crowded imidazoles 3–6 can be
rationalized by the mechanism shown in Scheme 2. The
R
3a
N
with PhCN, by 1,4-addition of nitriles to (butadiene)zircono-
cene3 and by base-induced oligomerization of glycoloni-
trile.3d Very recently, a domino reaction initiated by addition of
R
C
N
–N
•
b,c
Ph
Ph
R
(3 equiv.)
2
THF, 0 °C
4a
a Grignard reagent to a tris-nitrile has been reported. Herein
we report the addition of up to 4 equiv. of a nitrile to dilithiated
allenes, a process which we believe includes a novel type of
rearrangement reaction.5
R
–N
Li+
2
R
R
I
Ph
–N
Ph
N
N
1,1-Diphenyl-3,3-dilithioallene 2 was generated in one pot by
Ph
N
treatment of the TBDMS enol ether 1 with an excess of LDA in
THF, a reaction recently developed by us.6 This process
presumably proceeds via a mechanism involving initial lithia-
tion of the allyl system of the silyl enol ether, elimination of
lithium silanolate and lithiation of the 1,1-diphenylallene
formed (Scheme 1). The elimination could either occur directly
–
R
C
N
Ph
Li
R
R
N
R
Li
III
Li+
Li+
–
II
+R
C
N
R
(
path A) or proceed via a O?C silyl migration/Peterson
R
elimination sequence (path B).
N
Ph
N
–
N
–N
Reaction of lithiated allenes with nitriles was expected to
result in formation of allenylimines. Selected examples of these
compounds have recently been prepared in moderate yields by
Ph
N
+R
(
C
N
1 equiv.)
Ph
–N
R
Ph
R
–R
C
N
7
reaction of allenic aldehydes with amines. Reaction of 2 with
–N
2 Li+
R
R
2 Li+
R
2
.2 equiv. of PhCN resulted in a complex reaction mixture from
R
V
which two products, 3 (9%) and 4 (14%) (Scheme 2), were
isolated by column chromatography in low yields. Much to our
surprise, FAB-MS suggested that products derived from
IV
H2O
–N
R
Ph Ph
N
R
OTBDMS
N
–
Li
Li
Ph HN
N
R
Ph
Ph
3
.3 equiv. LDA
Ph
CH3
•
R
N
R
THF, 0 °C
Ph
Ph
2
Li+
VI
1
2
LDA
X
R
(slow)
LDA
fast)
(
H2O
3
R = Ph, X = NH, 12%
R
OTBDMS
CH2–
–
LiOTBDMS
Ph
Ph
H
H
HN
R
t
Ph Ph
N
(fast)
5 R = Bu , X = O, 66%
Ph
•
N
R
Li+
path A
6
R = 4-MeC6H4, X = NH, 28%
Ph
O–
Li+
R
N
H
Ph
TBDMS
path B
Peterson
reaction
Ph
Scheme 1
4
R = Ph, 51%
Scheme 2
Chem. Commun., 1998
1927

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open-chained oligonitrile.9 This striking difference to the
reaction of the allene dianion 2 suggests that the addition of the
imine anion to the nitrile is a reversible process which becomes
irreversible when the amidine anion generated can undergo a
consecutive reaction to form a more stable intermediate (such as
IV and VI in Scheme 2).¶ It is noteworthy that the number of
nitrile molecules added to the dianion does not depend on the
number of equivalents of the nitrile employed in the reaction.
Therefore, there is some relationship between the reaction
reported and self-assembly processes.
3
.3 equiv. LDA
OTBDMS
Ph
Li
Ph
Li
THF, 0 °C
•
Ph
Ph
7
Ph
8
N
Ph
–N
Ph
C N
Ph
(
3 equiv.)
•
8
Ph
2 Li+
Ph
N–
I
Ph
Ph
P. L. thanks Professor A. de Meijere for his support. Financial
support from the Fonds der Chemischen Industrie e. V. (award
of a fellowship to P. L.) is gratefully acknowledged.
Ph –N
Ph –N
N
N
+
Ph
C
N
Ph
Li+
Ph
(
1 equiv.)
Ph
Ph
Notes and References
N–
Ph
– Ph
C
N
Ph
N
–N
Li+
† Regioselective reactions of ambident dianions, Part 5. For Part 4, see ref.
5(d).
2
2
II
Ph
‡
§
1
E-mail: planger@uni-goettingen.de
Preparation of imidazole 4. To a THF solution (40 ml) of silyl enol ether
III
(1.80 g, 5.6 mmol) was added a THF solution of LDA which was prepared
n
in hexane) to a THF solution (20 ml) of Pri
H2O
by addition of Bu Li (1.6
M
2
NH
Ph
(3.3 equiv.) at 0 °C. The solution was stirred at 20 °C for 6 h during which
time the color of the solution became deep red. A THF solution (10 ml) of
PhCN (2.58 ml, 4.5 equiv.) was added at 0 °C by syringe. After stirring for
10 h at 20 °C, water (20 ml) was added to the deep purple solution and the
HN
N
Ph
N
Ph
Ph
N
N
+
Ph
colour changed to yellow. The reaction mixture was extracted (Et
= 1:1) and the combined organic layers were dried (MgSO ), filtered and
the solvent was removed in vacuo to give imidazole 4 (1.73 g, 51%) after
purification by column chromatography (silica gel, Et O–light petroleum =
2
O–THF
Ph
N
N
4
Ph
Ph
H
9
(15%)
Ph
2
2
1
6
d
1
1
1
:1) as a colorless solid, mp 146–150 °C; d
H 8
([ H ]THF, 200 MHz)
1
0 (13%)
.75–8.20 (m, 30 H, Ar), 8.75 (br, 1 H, NH), 10.68 (br, 1 H, NH);
([ H ]THF, 50 MHz) 107.20 (C, CPh ), 125.27, 125.76, 125.87, 126.06,
C 8 2
26.26, 127.12, 127.30, 127.50, 128.02, 128.08, 128.17, 128.30, 128.68,
28.90, 129.21, 129.76 129.92, 130.86 (CH, Ph), 132.15, 132.19, 136.43,
2
), 145.67, 148.50, 148.78 (C,
); nmax(KBr)/cm 3495 (br), 3395 (br),
3060 (m), 3029 (m), 2923 (w), 1640 (s), 1598 (m), 1578 (m), 1524 (s), 1496
2
Scheme 3
terminal carbon atom of the allene dianion 2 initially reacts with
two molecules of the nitrile. Presumably, the negative charge
will mainly be localized at the nitrogen atoms. A third nitrile
molecule is attacked (intermediate I) and the amidine anion thus
formed attacks the terminal allene carbon atom to give
intermediate II which contains a five-membered ring and a
vinyl carbanion function. An aromatic imidazole anion (inter-
mediate III) is generated next by elimination of 1 equiv. of the
nitrile. The vinyl carbanion subsequently reacts with the nitrile
to give intermediate IV. The fourth nitrile molecule is attacked
by the imine anion of intermediate IV to generate an amidine
anion (intermediate V). The amidine anion attacks the terminal
allene carbon atom bearing the phenyl groups to give a
dihydropyrimidine anion (intermediate VI). Aqueous work-up
furnishes heterocycles 4 and 3 derived from intermediates VI
and IV, respectively.
Reaction of PhCN with the dianion of 1,3-diphenyl-
,3-dilithioallene 8 (formed in situ by reaction of silyl enol ether
with 3.3 equiv. of LDA) afforded after hydrolytic work-up a
mixture of 2,4,6-triphenyltriazine 9 (formed by trimerization
of the nitrile) and imidazole 10 (a 1:4 product). The formation
of 10 can be explained by a reaction sequence similar to that
leading to oligonitrile 4 (Scheme 3). This reaction seems to
involve migration of a phenyl rather than a phenylimino
group.
36.73, 137.37, 138.19 (C, Ph, §CCPh
21
C§CN), 150.65, 150.78 (C, CN
2
(m), 1446 (m), 1395 (s), 1370 (m), 1178 (m), 1072 (m), 1028 (m), 697 (s);
+
m/z (FAB) 605 (100%, M +1); Calc. for C43
32 4
H N : C, 85.41; H, 5.33; N,
9
¶
.26. Found.: C, 85.17; H, 5.61; N, 9.62%.
The reactions cited in refs. 3(a)–(d) involve only a single addition of each
nucleophilic center to a nitrile molecule since the imine anions formed are
intramolecularly trapped to form stable dianionic systems. In contrast, in
ref. 4, a second nitrile group is attacked by the initially formed imine anion.
Thus, in the third step of the reaction, a stable anion could be formed.
1 For reviews on domino reactions, see: L. F. Tietze and U. Beifuss, Angew.
Chem., 1993, 105, 137; Angew. Chem., Int. Ed. Engl., 1993, 32, 131; A.
de Meijere and F. E. Meyer, Angew. Chem., 1994, 106, 2473; Angew.
Chem., Int. Ed. Engl., 1994, 33, 2379.
2
T. Tanase, T. Ohizumi, K. Kobayashi and Y. Yamamoto, J. Chem. Soc.,
Chem. Commun., 1992, 707.
3
(a) R. B. Bates, B. Gordon III, P. C. Keller and J. V. Rund, J. Org. Chem.,
1
7
1
980, 45, 168; (b) G. Erker, M. Berlekamp, L. Lopez, M. Grehl, B.
Schönecker and R. Krieg, Synthesis, 1994, 212; (c) M. Riedel and G.
Erker, Synthesis, 1994, 1039; (d) G. Arrhenius, K. K. Baldridge, S.
Richards-Gross and J. S. Siegel, J. Org. Chem., 1997, 62, 5522.
4 (a) S. Mathé and A. Rassat, Tetrahedron Lett., 1998, 39, 383; (b) see also:
L. N. Cherkasov and K. V. Balyan, Zh. Org. Khim., 1965, 1, 1811.
8
5
For domino reactions of dilithio compounds from our laboratory, see: (a)
P. Langer, M. Döring, H. Görls and R. Beckert, Liebigs Ann./Receuil,
1
997, 2553; (b) P. Langer and M. Döring, Synlett, 1998, 396; (c) P.
It is noteworthy that all carbon atoms of the allene system are
involved sequentially in the reaction leading to cyclic oligoni-
trile 4. The intramolecular attack of the amidine anion on the
terminal (rather than on the central) allene carbon atom and the
subsequent rearrangement reaction (I?IV, Scheme 2) are
surprising. However, this process can be explained by the
stability of the aromatic imidazole anion formed. Steric
hindrance seems to be the reason that no addition of a fourth
nitrile molecule takes place for 5 and 6. Interestingly, treatment
of the dianion of 2-methylbenzimidazole or of amide derived
dianions with 4.5 equiv. of PhCN resulted in addition of only 1
equiv. of the nitrile to the dianion rather than in formation of an
Langer and M. Döring, Synlett, 1998, 399; (d) P. Langer, J. Wuckelt, M.
Döring and R. Beckert, Eur. J. Org. Chem., 1998, 1467.
D. Seyferth, P. Langer and M. Döring, Organometallics, 1995, 14,
4457.
7 M. S. Sigman and B. E. Eaton, Tetrahedron Lett., 1993, 34, 5367.
8 Triazines have been previously obtained by base induced cyclotrimeriza-
tion of aryl nitriles: see C. Grundmann, in Methoden Org. Chem.
6
(Houben-Weyl), 4th edn., Thieme, Stuttgart, New York, 1985, vol. E512,
1
544.
9
For open-chained oligonitriles see M. Buhmann, M. H. Möller, U.
Rodewald and E.-U. Würthwein, Chem. Ber., 1993, 126, 2467.
Received in Cambridge, UK, 23rd April 1998; 8/03040E
1928
Chem. Commun., 1998