A zinc(II) catalyst system for the conia-ene reaction of alkynyl-aminomalonates applicable to 5-endo-dig reactions

Article abstract of DOI:10.1002/adsc.201100401

The zinc(II)-catalyzed 5-exo-dig (Conia-ene) and 5-endo-dig cyclizations of a range of alkynyl-α-aminomalonates give rise to nitrogen heterocycles with good efficiency. The reaction allows the synthesis of a broad range of synthetically useful building blocks. Copyright

Full text of DOI:10.1002/adsc.201100401

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DOI: 10.1002/adsc.201100401
A Zinc(II) Catalyst System for the Conia-Ene Reaction of
Alkynyl-Aminomalonates Applicable to 5-Endo-Dig Reactions
Wilfried Hessa and Jonathan W. Burtona,*
a
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA,
U.K.
Fax : (+44)-1865-285-002; e-mail: jonathan.burton@chem.ox.ac.uk
Received: May 17, 2011; Revised: July 21, 2011; Published online: November 7, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100401.
Abstract: The zinc(II)-catalyzed 5-exo-dig (Conia-
ene) and 5-endo-dig cyclizations of a range of alk-
ACHTUNGTRENNUNGynyl-a-aminomalonates give rise to nitrogen hetero-
cycles with good efficiency. The reaction allows the
synthesis of a broad range of synthetically useful
building blocks.
they utilized in an efficient synthesis of the 20S pro-
teasome inhibitor salinosporamide A.[5n] Inspired by
this beautiful work, and coupled with our own interest
in the cyclization reactions of alkynyl-a-aminomalo-
nates,[6] we aimed to develop another catalyst system
for the Conia-ene reaction of alkynyl-a-aminomalo-
nates. Herein, we report that zinc(II) chloride[7] and
zinc(II) iodide are effective catalysts for the synthesis
of a range of nitrogen heterocycles by Conia-ene re-
action of alkynyl-a-aminomalonates [1!2 (n=1);
Scheme 1]. Furthermore, these inexpensive zinc(II)
salts are effective catalysts for the 5-endo-dig cycliza-
tion of alkynyl-a-aminomalonates to give pyrrolines
and pyrrolinones [1!3 (n=0); Scheme 1].[8]
Keywords: aminomalonates; Conia-ene reaction; 5-
endo-dig process; 5-exo-dig process; nitrogen het-
erocycles; zinc
The addition of enols and enolates to unactivated al-
Our initial cyclization experiments were conducted
kynes represents an atom-economic method for the using zinc(II) chloride as catalyst in 1,2-dichloro-
formation of carbon-carbon bonds.[1] In this regard ethane (DCE) at 1008C; conditions described by Li
the Conia-ene reaction has been widely used for the and co-workers for the formation of carbocycles by
preparation of cyclopentanes and related carbocy- the Conia-ene reaction.[7] Thus, exposure of diethyl 2-
cles.[2] Recently, the development of numerous transi- [benzyl(but-3-ynyl)amino]malonate 4a to 10 mol%
tion metal-catalyzed variants of the Conia-ene reac- zinc(II) chloride in DCE in a sealed tube at 1008C
tion has overcome many of the shortfalls of the origi- gave the desired exo-methylenepyrrolidine 5a in good
nal thermal reaction and has allowed the use of di- yield (Table 1, entry 1).[9] The scope of this reaction
ACHTUNGTRENNUNG
alkyl malonates as enolate precursors.[3] The synthesis was demonstrated with a range of alkynyl-a-amino-
of heterocycles by the addition of metal enols/eno- malonates 4 which readily underwent cyclization to
lates onto alkynes (including the Conia-ene reaction) give the corresponding pyrrolidines 5 (Table 1).[10,11]
has been far less studied.[1,4,5] Recently, Hatakeyama The terminal alkyne tertiary amine substrates (4a, b,
and co-workers reported a beautiful indiumACTHUNTGRNEUNG(III)-cata- d) were successfully converted into the corresponding
lyzed Conia-ene reaction of alkynylmalonates for the exo-methylenepyrrolidines in 58–86% yield, although
synthesis of nitrogen and oxygen heterocycles which it was necessary to utilise zinc(II) iodide in place of
Scheme 1. Proposed zinc(II)-catalyzed exo- and endo-dig cyclizations.
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Adv. Synth. Catal. 2011, 353, 2966 – 2970

A Zinc(II) Catalyst System for the Conia-Ene Reaction of Alkynyl-Aminomalonates
Table 1. Zinc(II)-catalyzed Conia-ene reaction of alkynyl-a-
aminomalonates.
Table 2. Zinc(II)-catalyzed Conia-ene reaction of alkynyl-a-
amidomalonates.
Entry[a]
R
Product
Yield [%]
(E):(Z)
Entry[a]
R1
R2
Product
Yield [%]
1[b]
2
3
4
5
Me
Et
n-Pr
n-Bu
Ph
a
b
c
d
e
80
51
52
66
25
>48:1
15:1
>100:1
>42:1
>70:1
1
2
Bn
Me
H
PMB
Bn
Bn
Bn
CO2Bn
H
H
H
H
Me
n-Bu
Ph
nBu
a
b
c
d
e
f
76
86
11
58
3[b]
4[c]
5
91[d]
86[d]
85[d]
80[d]
6
7
8
[a]
Reaction conditions: 0.5 mmol 6, 10 mol% zinc(II) chlo-
ride, ClCH2CH2Cl, 1008C, sealed tube 15 h.
ZnI2 was used in place of ZnCl2.
g
h
[b]
[a]
Reaction conditions: 0.5 mmol 4, 10 mol% zinc(II) chlo-
ride, ClCH2CH2Cl, 1008C, sealed tube 15 h.
Only impure product 5c could be isolated; yield estimat-
[b]
[c]
66% (Table 2, entries 2–5). It is noteworthy that no
a,b-unsaturated pyrrolidinones were observed in
these reactions.
The application of this simple catalyst system to the
formation of larger nitrogen heterocycles was briefly
investigated (Scheme 2).[5n,9,11] The piperidines 9 and
1
ed by H NMR.
Substrate 4d and product 5d contained a di-t-butyl a-ami-
nomalonate in place of a diethyl a-aminomalonate, and
zinc(II) iodide was used as the catalyst; an inseparable
4:1 mixture of 5d:4d was isolated – yield is adjusted for
presence of substrate.
[d]
Products isolated as >35:1 mixture of (E):(Z)-diastereo- 11 were formed in excellent yields from the corre-
mers.
under
sponding
alkynyl-amino-/amidomalonates
zinc(II) chloride catalysis. In order to coax the alkyn-
yl-a-aminomalonate 12 into cyclising it was necessary
zinc(II) chloride for the successful cyclization of the to utilise a full equivalent of zinc(II) chloride and to
di-t-butyl a-aminomalonate 4d presumably due to the increase the reaction temperature to 1208C. Under
presence of (Lewis) acid-sensitive functional groups these conditions the azepane 13 was isolated in 52%
such as the t-butyl esters and the 4-methoxybenzyl- yield along with small amounts of substrate 12.[13]
A
Having successfully demonstrated a simple catalyst
tion with substrate 4c giving low yields of the corre- system for the 5-exo-dig cyclization (Conia-ene reac-
sponding pyrrolidine 5c at complete conversion tion) of a-amino-/amidomalonates we sought to de-
(Table 1, entry 3).
velop a catalyst which would promote the more un-
With initial results in hand we investigated the use usual 5-endo-dig cyclisation with related substrates
of internal alkynes as substrates (entries 5–8). The a- (Table 3).[8,11] Not surprisingly, the electronically
aminomalonates 4e–h all underwent cyclization under biased a-amidomalonates 14a and 14b readily under-
zinc(II) chloride catalysis with the corresponding pyr-
rolidines 5e–h being isolated in 80–91% yield with
very high (E):(Z) selectivity. Both N-alkyl- and N-alk-
ACHTUNGTRENNUNG
oxycarbonylaminomalonates[12] were competent sub-
strates for the cyclization (Table 1, entries 5–8).
Application of this zinc-catalyzed Conia-ene reac-
tion to a range of internal alkynyl-a-amidomalonates
was investigated next (Table 2).[5n,11] The cyclization of
the methyl-substituted alkyne 6a under zinc iodide
catalysis gave the corresponding pyrrolidinone 7a in
80% yield with high (E):(Z) selectivity (Table 2,
entry 1);[9] the use of zinc chloride resulted in the
product being isolated with diminished (E):(Z) selec-
tivity. Cyclization of substrates with larger alkyl/aryl
groups on the alkyne gave the corresponding pyrroli-
Scheme 2. Conia-ene reaction for the synthesis of piperi-
dinones with high (E):(Z) selectivity in yields of 25– dines and an azepane.
Adv. Synth. Catal. 2011, 353, 2966 – 2970
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2967

Wilfried Hess and Jonathan W. Burton
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Table 3. Zinc(II)-catalyzed 5-endo-dig cyclization of alkynyl-
a-amino-/amidomalonates.
Entry[a]
1
R1
R2
Et
Y
O
X
Product
Yield [%]
Bn
Cl
I
Cl
I
a
93
92
80
88
83
50[b]
73
72
80
64
89
43
69
Scheme 3. Exo- and endo-dig cyclization of amidomalonate
14h.
2
3
4
Bn
Ph
H
O
b
c
Bn
H2 Cl
I
H2 Cl
I
H2
H2 Cl
I
CO2Bn
H
d
5
6
CO2Me
Bn
H
Et
I
e
f
7
Bn
Ph H2 Cl
I
g
[a]
Reaction conditions: 0.5 mmol 14, 10 mol% zinc(II) salt,
ClCH2CH2Cl, 1008C, sealed tube 15 h.
Product isolated as a mixture with starting material.
[b]
went Michael-type 5-endo-dig cyclisation to give the
corresponding a,b-unsaturated pyrrolidinones in 80–
93% yield under either zinc(II) chloride or zinc(II)
iodide catalysis (Table 3, entries 1 and 2). Somewhat
surprisingly a-aminomalonates (14c–g) were also
viable substrates for this reaction (Table 3, entries 3–
Scheme 4. Proposed mechanism for 5-exo- and 5-endo-dig
cyclization reactions.
7). With terminal (Table 3, entries 3, 4 and 5) and in- coordination of the substrate to zinc(II) promotes
ternal alkynes (Table 3, entries 6 and 7) the products enol formation and alkyne coordination to give inter-
of 5-endo-dig cyclisation were formed exclusively in mediate 17.[4] When n=1, the alkyne complex 17a
good to excellent yields. The use of zinc(II) iodide could reasonably undergo syn-seletive cyclisation to
gives slightly higher product yields than zinc(II) chlo- give the alkenyl zincate 18 which gives the 5-exo-dig
ride; however, the reaction is generally slower which product 19 on protodemetallation. Alternatively,
can lead to incomplete conversion (Table 3, entry 3). when n=0, the intermediate 17b could undergo car-
With the a-amidomalonate 14h we observed cyclisa- bonyl group decomplexation followed by anti-selec-
tion by both 5-endo-dig and 4-exo-dig modes tive cyclisation to give the zincate 20 which on proto-
(Scheme 3) giving the pyrrolidinone 15h (60%) and demetallation gives 21.
the b-lactam 16 (30%).[11,14] It is not entirely clear why
In summary, we have developed zinc(II)-catalysed
the a-amidomalonate 14h is the sole substrate that 5-exo and 5-endo-dig cyclisations which offer a rapid,
undergoes 4-exo-dig cyclization. It is possible that the mild, economic and efficient route to functionalised
internal alkynes do not undergo 4-exo-dig cyclization pyrrolidines and pyrrolidinones. The products are ob-
due to the developing A1,3-strain[15] between the tained in moderate to excellent yields with very good
alkyne substituents which is not present in the com- diastereoselectivity. The reaction tolerates a variety of
peting 5-endo-dig transition state; the developing functional groups including esters, carbamates,
A1,3-strain would likely be greater with a-amidomalo- amines, and ethers. Piperidines and piperidinones as
nates than with the corresponding a-aminomalonates. well as an azepane may also be synthesised using the
Based on previous work on the zinc(II)[4,5l,p,7] and developed methodology. The new catalyst system
indiumACHTUNGTRENNUNG
(III)[5n] catalysed Conia-ene reaction and allows for the synthesis of a number of nitrogen-con-
recent DFT studies,[4] we postulate a mechanism for taining heterocyclic building blocks for use in a varie-
the 5-exo- and 5-endo dig reactions (Scheme 4). Thus, ty of applications including natural product synthesis.
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Adv. Synth. Catal. 2011, 353, 2966 – 2970

A Zinc(II) Catalyst System for the Conia-Ene Reaction of Alkynyl-Aminomalonates
Bouyssi, N. Monteiro, G. Balme, Tetrahedron Lett.
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Typical Procedure: Cyclisation of 4a to give 5a
The cyclisation of 4a to give 5a is representative, for full ex-
perimental procedures see Supporting Information.
Diethyl 2-[benzyl(but-3-ynyl)amino]malonate 4a (159 mg,
0.5 mmol, 1.0 equiv.) and zinc chloride (7 mg, 0.05 mmol,
10 mol%) were dissolved in DCE (5 mL) and heated in a
sealed tube to 1008C for 15 h. The cooled reaction mixture
was filtered through silica (Et2O) and the solvent was re-
moved. After purification by flash chromatography (PE/
Et2O=5:1) diethyl 1-benzyl-3-methylenepyrrolidine-2,2-di-
carboxylate 5a was obtained as a clear oil; yield: 120.9 mg
(0.38 mmol, 76%); 1H NMR (400 MHz, CDCl3): d=7.43–
7.39 (m, 2H, Har), 7.33–7.29 (m, 2H, Har), 7.27, 7.23 (m, 1H,
Har), 5.40 (t, 1H, J=2.2 Hz, CHH=C), 5.21 (t, 1H, J=
2.2 Hz, CHH=), 4.32 (dq, 2H, J=10.7, 7.1 Hz, OCHH), 4.24
(dq, 2H, J=10.7, 7.1 Hz, OCHH), 3.90 (s, 2H, CH2Ph), 2.84
(t, 2H, J=6.7 Hz, CH2N), 2.58 (tt, 1H, J=6.7, 2.2 Hz,
CH2C=C), 1.31 (t, 6H, J=7.1 Hz, CH3); 13C NMR
(100 MHz, CDCl3): d=169.0 (2ꢁCO), 147.1 (Car), 139.5
(Colef), 128.5 (2ꢁCHar), 128.2 (2ꢁCHar), 126.9 (CHar), 111.0
(CH2-olef), 77.5 [C(CO)2], 61.4 (2ꢁCH2), 54.7 (CH2Ph), 49.0
(CH2N), 31.1 (CH2), 14.2 (2ꢁCH3); IR (film): n=2980 m,
2935 w, 2831 m, 1729 s, 1454 w, 1367 w, 1227 s, 1137 m, 1051
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AHCTUNGTRENNUNG1
s, 903 w, 743 w, 699 cmM w; MS (ESI+): m/z=318 (45,
[M+H]+), 657 (100, [2M+Na]+); HR-MS (ESI): m/z=
318.1703, calcd. for C18H24NO4 ([M+H]+): 318.1700. HMQC
was used for assignment.
Cyclisation of a closely related substrate under indium-
ACHTUNGTRENNUNG(III) catalysis was reported by Hatakeyama and co-work-
ers.[5n]
Acknowledgements
We thank the European Commission (FP7-PEOPLE-2009-
IEF-254038) for financial support. We thank the analytical
sections of our Department for their excellent support.
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COMMUNICATIONS
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[11] The structures of all of the products were confirmed by
extensive NMR studies.
[12] Hatakeyama and co-workers reported sluggish reaction
with an N-alkoxycarbonyl aminomalonate under
indium
[13] Hatakeyama and co-workers reported the formation on
(III) catalysis, see ref.[5n]
ACHTUNGTRENNUNG
an azepane with 15 mol% indium
ACHTUNGERTN(NUNG III) triflate as cata-
lyst, see ref.[5n]
[14] The use of zinc(II) chloride as catalyst also gave a mix-
ture of 15h and 16.
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89, 1841.
[9] Cyclization of a closely related substrate under indium-
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[10] The aminomalonates were readily prepared according
to the method of Chai see: C. L. L. Chai, J. A. Elix,
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Adv. Synth. Catal. 2011, 353, 2966 – 2970