Titanium-mediated [4 + 1] assembly of 1,3-dienes and nitriles: Formation of 3-cyclopentenyl amines and cyclopentenones

Article abstract of DOI:10.1039/b503643g

In the presence of Ti(OⁱPr)₄ and ⁱPrMgCl, dienes couple with nitriles to afford the title products in good yields. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b503643g

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Titanium-mediated [4 + 1] assembly of 1,3-dienes and nitriles: formation
of 3-cyclopentenyl amines and cyclopentenones
Christophe Laroche, Philippe Bertus* and Jan Szymoniak*
Received (in Cambridge, UK) 11th March 2005, Accepted 3rd May 2005
First published as an Advance Article on the web 24th May 2005
DOI: 10.1039/b503643g
i
In the presence of Ti(OiPr)4 and PrMgCl, dienes couple with
nitriles to afford the title products in good yields.
Transition metal-mediated reactions that allow the construction of
five-membered carbocycles are of significant synthetic interest.1
Whereas the reactions involving [2 + 2 + 1] or [3 + 2] strategies have
attracted much attention,1,2 those involving [4 + 1] strategies are
much less common.3 Of those reactions, very few have used
conjugated dienes as four-carbon components.3a,d–f
Among conjugated diene complexes, those of Group 4
transition metals (M 5 Ti, Zr, Hf) are well documented (Fig. 1).
In particular, diene-zirconocenes and related compounds have
been extensively studied,4 and the metallacyclopentene form
(D3-zirconacyclopentene III in Fig. 1) has been considered to
Scheme 1
reasonably fit the structure of s-cis diene complexes. Therefore,
cyanide (1), isoprene and Ti(OiPr)4, followed by BF3?OEt2, only
insertion reactions into the zirconium–carbon bond in III
cyclopropylamine 3 was obtained (Scheme 2). No trace of the
vinylcyclopropylamine 2 was observed. Obviously, the insertion of
the nitrile into A occurred before the formation of B.11 We then
considered preforming the titanacyclopentene intermediate B
before adding the nitrile (Scheme 2). Thus, Ti(OiPr)4 and isoprene
(2 equiv.) were dissolved in ether, the solution cooled to 278 uC
(MLn 5 ZrCp2) have been carried out, but only open-chain
products were obtained after hydrolysis.5 Furthermore, there have
been reports of the synthetic uses of diisopropoxy titanacyclopen-
tene complexes of type III. Two recent papers have reported some
reactions of III (MLn 5 Ti(OiPr)2), through the insertion of
aldehydes, ketones, esters and nitriles.6 The open-chain products
were also formed in these reactions. By using 1,3-dienes, the
titanium-mediated de Meijere synthesis of tertiary cyclopropyla-
mines from amides7 was extended to 2-alkenyl substituted
derivatives.8 To our knowledge, no conversion of metallacyclo-
pentenes (M 5 Zr, Ti) of type III (derived from 1,3-dienes) to
5-membered carbocycles is known.
i
and PrMgCl (2 equiv.) added dropwise. The temperature was
allowed to slowly increase to room temperature within ca. 2–3 h,
and during this period a nitrile was added (step ii). The reaction
was completed by the addition of BF3?OEt2 at room temperature.
We noticed that the course of the reaction strongly depended on
the temperature at which the latter addition occurred. When
adding the nitrile 1 at 260 uC, only 3 (derived from the complex A)
was formed. When adding 1 at higher temperatures, within the
range of 250 to 230 uC, mixtures of the cyclopropylamine 3 and
the unexpected cyclopentenyl amine 4 were formed (3 : 4 5 95 : 5,
45 : 55 and 20 : 80 for 250, 240 and 230 uC respectively).
In this paper we report the first example of a titanium-mediated
reaction that allows the formation of 5-membered carbocyclic
derivatives from 1,3-dienes and a one-carbon component.
As part of our work on the titanium-mediated synthesis of
cyclopropylamines from nitriles,9 we studied the feasibility of
preparing cyclopropylamines bearing a 2-alkenyl moiety. In
keeping with this aim we applied a ligand exchange procedure
with the initial titanacyclopropane complex A and isoprene
i
(Scheme 1).10 When PrMgCl was added to a solution of benzyl
Fig. 1 Conjugated diene forms I, II and III.
*philippe.bertus@univ-reims.fr (Philippe Bertus)
jan.szymoniak@univ-reims.fr (Jan Szymoniak)
Scheme 2
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Interestingly, increasing the addition temperature to 220 uC led to
the exclusive formation of 4. Addition of 1 at higher temperatures
(0 uC to rt) decreased the yield of 4. The exclusive formation of 4
similarly took place in the absence of an additional Lewis acid, the
yield of 4 being the same with or without BF3?OEt2. These results
clearly indicate that ligand exchange occurs partially (250 to
230 uC) or completely (220 uC) in the reaction conditions. The
relative instability of the intermediate complex B could explain the
decrease of the yield at temperatures higher than 0 uC.
The spontaneous elimination in the hydrolytic workup conditions
afforded the cyclopentenone derivatives 6a–d in good yields. Both
aromatic and aliphatic nitriles were successfully employed for
this transformation. Finally, the same procedure could be applied
with esters. Thus, the reaction of myrcene with ethyl acetate
afforded 3-(4-methyl-3-pentenyl)-1-methyl-3-cyclopenten-1-ol in
59% yield.13
In conclusion, we have reported the first example of a titanium-
mediated reaction of 1,3-dienes with one-carbon components,
leading to cyclopentene derivatives. The simplicity of the procedure
as well as the readily available reagents and starting materials are
noteworthy. Further studies on titanium-mediated [4 + 1] assembly
reactions are currently underway.
The reaction pathway depicted in Scheme 2 opens the way for
the assembly of 5-membered carbocyclic rings through titanium-
mediated [4 + 1] addition reactions. When applying the optimised
conditions below, the reaction of nitriles with 1,3-dienes proceeded
smoothly to afford the corresponding 3-cyclopentenyl amines in
good yields. Table 1 summarises the results employing different
Christophe Laroche, Philippe Bertus* and Jan Szymoniak*
UMR 6519 - Re´actions Se´lectives et Applications, CNRS - Universite´ de
Reims Champagne-Ardenne, BP 1039, 51687 REIMS Cedex 2, France.
E-mail: philippe.bertus@univ-reims.fr; jan.szymoniak@univ-reims.fr;
Fax: +33 326 913 166; Tel: +33 326 913 244
i
nitriles and dienes, together with PrMgCl and Ti(OiPr)4. Both
aliphatic and aromatic nitriles coupled with isoprene (entries 1–3
and 4, 5 respectively). The reaction even took place with the
sterically hindered 1-adamantanecarbonitrile (entry 3) and an
a,b-unsaturated nitrile (entry 6). A bromine atom can be present in
the substrate and is tolerated by the reaction conditions (entry 5).
The use of other 2-substituted and 2,3-substituted dienes was also
successful (entries 7–9).12
Notes and references
{ Representative procedure, preparation of 3-methyl-1-nonyl-3-cyclopen-
tenylamine (entry 2, Table 1): To a solution of Ti(OiPr)4 (0.33mL,
1.1 mmol) and isoprene (0.2 mL, 2 mmol) in Et2O (5 mL) a solution of
iPrMgCl (1.1 mL, 2 M in Et2O) was added under argon at 278 uC. The
mixture was warmed for ca. 2 h up to 220 uC, during which period the
solution became green. At this temperature, decanenitrile (0.19 mL,
1 mmol) was added. After the resulting dark red mixture was allowed to
warm to rt and stirred for 1 h, 1 N HCl (ca. 3 mL) and ether (ca. 15 mL)
were added. NaOH (10% aq, ca. 10 mL) was added and the mixture was
extracted with ether. The combined ether layers were dried (MgSO4),
filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel (Et2O : Et3N 98 : 2) to
afford 188 mg (84%) of the title product as a colourless oil; IR n/cm21
3355, 2924, 1591, 1466; 1H-NMR (250 MHz; CDCl3) d 0.85 (t, J 5 6.8 Hz,
3H), 1.20–1.35 (m, 18H), 1.70 (s, 3H), 1.97–2.12 (m, 2H), 2.30–2.46 (m,
2H), 5.25 (s, 1H); 13C-NMR (63 MHz; CDCl3) d 14.5, 17.3, 23.1, 25.3,
29.7, 30.0, 30.1, 30.7, 32.3, 43.6, 48.6, 52.5, 61.4, 122.7, 138.8; MS (70 eV)
The reaction with nitriles is not limited to the preparation of
3-cyclopentenyl amines. It also offers a new access to 3-substituted
2-cyclopentenones (Scheme 3). With 2-trimethylsilyloxybutadiene
the reaction took place using the previously established conditions,
leading to the corresponding silyloxycyclopentenyl amines 5a–d.
Table 1 Preparation of 3-cyclopentenylamines{
R1
R2
R3
Yield (%)a,b
?
m/z 223 (M , 15), 208 (13), 194 (6), 154 (48), 124 (84), 96 (100); Analysis
calculated for C15H29N?HCl (%): C, 69.33; H, 11.64; N, 5.39; found C,
69.14; H, 11.69; N, 5.29.
Entry
1
2
3
4
5
6
7
8
9
a
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
Me
CH2Ph
nC9H19
1-Adamantyl
Ph
61
84
79
74
66
45
77
79
63c
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Soc., 1992, 114, 6245–6246 and references therein.
3-BrC6H4
CHLCH–Ph
nC9H19
(CH2)2–CHLCMe2
Ph
Me
nC9H19
nC9H19
All reactions were performed under Ar with 1.1 eq of Ti(OiPr)4,
i
2 equiv. of diene and 2.2 equiv. of PrMgBr unless otherwise stated.
b
c
Isolated yields. Reaction performed with two-fold amount of
reagents.
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51, 109–162; (b) G. Erker, G. Kehr and R. Fro¨hlich, J. Organomet.
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5 In contrast, a number of insertion reactions have been performed
starting from isomeric D2-zirconacyclopentenes, leading to both open-
chain and cyclic final products, see: E. Negishi and S. Huo, in Titanium
Scheme 3
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proved to be inefficient here.
12 1-Substituted dienes did not afford the corresponding 3-cyclopentenyl
amines under the conditions used here.
13 3-Cyclopentenols were prepared from dienes and carboxylic esters by
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