Palladium-catalysed cyclisation of N-alkynyl aminomalonates

Article abstract of DOI:10.1002/chem.201001951

Go around in (hetero)cycles! The palladium-catalysed tandem cyclisation/coupling reaction of alkynyl- and alkenyl-substituted aminomalonates leads to highly functionalised pyrrolidines and piperidines in good yield (see scheme). The reaction allows efficient access to a broad range of synthetically valuable building blocks.

Full text of DOI:10.1002/chem.201001951

COMMUNICATION
DOI: 10.1002/chem.201001951
Palladium-Catalysed Cyclisation of N-Alkynyl Aminomalonates
Wilfried Hess and Jonathan W. Burton*[a]
Pyrrolidines and pyrrolidinones are highly important
structural motifs in organic chemistry. They are present in
many ligands for asymmetric catalysis, as catalysts in the
ever-growing field of organocatalysis,[1] and in a vast number
of natural products.[2] Moreover, pyrrolidines and nitrogen
heterocycles, in general, are exceedingly important motifs in
medicinal chemistry. The pursuit of new and efficient meth-
ods for the synthesis of pyrrolidines and pyrrolidinones,
therefore remains an important goal in modern organic syn-
thesis. We envisaged a novel approach to pyrrolidines by
palladium-catalysed intramolecular cyclisation of aminomal-
onates onto alkynes, which would result in the formation of
Our initial efforts focussed on the cyclisation of N-benzyl-
protected aminomalonate 4[10] to form 5a[11] under palladium
and copper catalysis[4c,h] (Table 1). Thus, exposure of 4 to
5.0 mol% [PdCl2ACHTUNTRGNEUNG(dppf)] (dppf=1,1’-bis(diphenylphosphi-
no)ferrocene), 10.0 mol% CuI and stoichiometric tBuOK in
THF at 608C delivered the desired pyrrolidine 5a in 18%
yield, along with a fully substituted alkene by-product prod-
uct 13g (Table 1, entry 1). Reducing the catalyst loading to
Table 1. Initial screen of conditions.[12]
ꢀ
two C C bonds and a stereodefined alkene in a single step
(1!2!3, Scheme 1);[3] an analogous scheme has been em-
ployed successfully for the cyclisation of 4-alkynyl malonates
and related compounds,[4–6] and a related three-component
reaction for the synthesis of 3-alkylidene pyrrolidines has
been developed by Balme and co-workers.[7] Apart from the
beautiful indium-catalysed Conia-ene reaction for the for-
mation of pyrrolidines and pyrrolidinones reported from
Hatakeyamaꢀs group,[8] the cyclisation of a-aminomalonates
onto alkynes has barely been studied.[9]
Entry[a] Pd
source[l]
PhI
[equiv]
Base
ACHTUNGTRENUN[NG equiv] [h]
t
Yield
Yield
G
5a [%][c] 6 [%]
1[b,c]
2
N
N
1.0
1.0
2.0
–
1.5
1.5
2.0
1.0
1.5
1.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
15
18
0.25 59
0.25 58
–
20
–
3
N
CHTUNGTRENNUNG
4
N
G
15
0.5
–
16
A
)
5[e]
E
6[f]
0.25 16
0.5 45
0.25 71
0.25 72
0.25 76
7[g,h]
8[h]
9[h,i]
10[h,j]
11[h,k]
N
CHTUNGTREN(NGNU xantphos)] 1.5
C
1.5
1.5
1.5
1.5
–
–
–
–
N
R
C
20
–
[a] Reaction conditions: 4 (1.0 equiv), PhI (1.0–2.0 equiv), [PdCl
(2.5 mol%), CuI (5.0 mol%), tBuOK (1.0–2.0 equiv), in THF at ambient
temperature. [b] Reaction conducted at 608C. [c] [PdCl2A(dppf)]
2ACHTUNGTRENNUNG(dppf)]
CHTUNGTRENNUNG
(5.0 mol%) and CuI (10.0 mol%) were used; the product 13g was also
isolated (25%). [d] The product resulting from ethoxydecarbonylation
and alkene isomerisation of 6 was the only isolated compound.[6b] [e] The
Sonogashira product was also isolated (32%). [f] Products resulting from
ethoxydecarbonylation and alkene isomerisation of 6 were also observ-
Scheme 1. Proposed Pd-catalysed cyclisation. (R1 =aryl, vinyl, alkynyl,
allyl).
ed.[6b] [g] [PdCl
2ACHTNUTRGNEUNG(xantphos)] (5.0 mol%) was used and recovered starting
[a] Dr. W. Hess, Dr. J. W. Burton
material was isolated (33%). [h] The malonate was deprotonated sepa-
rately prior to addition to the reaction mixture. [i] NaH was used as the
base. [j] Lithium bis(trimethylsilyl)amide was used as the base. [k] N,O-
Bis(trimethylsilyl)acetamide was used; no conversion was detected by
TLC analysis after 4 h whereas after 20 h the Glaser coupling product
was isolated (22%). [l] dppf=1,1’-bis(diphenylphosphino)ferrocene;
Department of Chemistry, University of Oxford
Chemistry Research Laboratory
12 Mansfield Road, Oxford OX1 3TA (UK)
Fax : (+44)1865-285002
E-mail: jonathan.burton@chem.ox.ac.uk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001951.
dppe=1,2-bis(diphenylphosphino)ethane;
phosphino)-9,9-dimethylxanthene.
xantphos=4,5-bis(diphenyl-
Chem. Eur. J. 2010, 16, 12303 – 12306
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
12303

2.5 mol% Pd and 5.0 mol% Cu with a concomitant reduc-
tion of the reaction temperature to ambient increased the
yield of 5a to 59% with the methylene pyrrolidine 6 being
isolated in 20% yield (Table 1, entry 2). Increasing the
equivalents of iodobenzene or changing the ligands on palla-
dium proved to be detrimental. Adding the deprotonated
malonate to a solution of the catalysts and iodobenzene in
THF resulted in the formation of 5a in much improved
yields with concomitant reduction in the amount of by-prod-
ucts formed (Table 1 entries 7–10). Strong lithium, sodium
and potassium bases were equally effective in the reaction
(Table 1 entries 8–10); however, the use of N,O-bis(trime-
thylsilyl)acetamide[4d] proved ineffective.
With the optimised reaction conditions in hand the scope
of the halide coupling partner was investigated (Table 2).
Electron-deficient as well as electron-rich aryl iodides
(Table 2, entries 1–4) participate in the reaction with the
corresponding pyrrolidines 5b–e being isolated in 68–73%
yield. As expected, an aryl iodide could be selectively cou-
pled in the presence of an aryl bromide (Table 2, entry 5).
Vinyl iodides (Table 2, entries 6 and 7) and iodo alkynes[4c]
(Table 2, entry 8) are also competent coupling partners
giving the desired pyrrolidines in 54–56% yield. The cross-
coupling with allyl bromide[4c,d] was also efficient with no al-
lylation at the malonate carbon being detected (Table 2,
entry 9). However, aryl and vinyl bromides, and allyl acetate
were poor substrates for the reaction (Table 2, entries 10–
12).
Variation within the malonate ester groups and the pro-
tecting group on nitrogen was investigated next (Table 3). A
common side-product was the corresponding exo-methylene
Table 3. Variation of malonate and nitrogen protecting group.[12]
Entry[a]
substrate [R’, R, X][c]
Yield 8 [%], (8:9)
1
2
3
4
7a, Bn, tBu, H2
7b, Me, Et, H2
73 (32:1)
66 (9:1)
58 (3:1)
72 (10:1)
72 (11:1)
42 (3.2:1)
–
7c, PMB, tBu, H2
7d, CO2Me, Et, H2
7e, CO2Bn, Et, H2
7 f, CO2Bn, tBu, H2
7g, H, Et, O
5
6
7[b]
[a] Reaction conditions:
7 (1.0 equiv), PhI (1.5 equiv), [PdCl2ACHTUNGTRENNUNG(dppf)]
(2.5 mol%), CuI (5.0 mol%), NaHMDS (1.0 equiv, 0.6m in toluene), in
THF for 5 min at ambient temperature. [b] Reaction quenched after
25 min. [c] PMB=4-methoxybenzyl.
pyrrolidine 9.[13] The formation of this side-product could be
reduced by employing NaHMDS in place of LiHMDS
(HMDS=hexamethyldisilazide). The diethyl and di-tert-
butyl malonates 7a–c cyclised without incident (Table 3, en-
tries 1–3). Moreover, various substituents on the nitrogen,
including benzyl (entry 1), methyl (entry 2), 4-methoxyben-
zyl (entry 3) and benzyl- and methyloxycarbonyl (entries 4–
6) are all tolerated in the reaction. Attempted cyclisation of
the corresponding amido malonate 7g (Table 3, entry 7) re-
sulted in rapid decomposition of the substrate.
Table 2. Variation of halide coupling partner.[12]
Entry[a]
1
RX[f]
t [min]
Product
Yield [%]
73
5
5b
Slight modification of the experimental procedure allowed
for the synthesis of piperidines (Table 4).[14] Again, both
electron-rich and electron-deficient aryl iodides were com-
petent coupling partners.
2
5
5c
68
3
5
5
5d
5e
70
69
4[b]
5
5
5 f
64
Table 4. Synthesis of piperidines.[12]
6
5
5
5
5g
5h
5i
55
54
56
7[c]
8[c]
9
5
5j
73
20
Entry[a]
RI
Product
11a
Yield [%]
10
1200
5k
11[d]
12[e]
1200
30
5a
5j
–
1
2
70
42
15
11b
[a] Reaction conditions:
4 (1.0 equiv), RX (1.5 equiv), [PdCl2ACHTUNTGNUER(NG dppf)]
(2.5 mol%), CuI (5.0 mol%), LiHMDS (1.0 equiv, 1m in toluene), in
THF at ambient temperature. [b] Product is contaminated with 6 (ap-
proximately 7%); yield adjusted for purity. [c] NaHMDS used in place of
LiHMDS. [d] No conversion was observed. [e] The reaction was
quenched after 30 min and 6 was also isolated (51%). [f] Bn=benzyl.
3
11c
56
[a] Reaction conditions: 10 (1.0 equiv), RI (1.5 equiv), [PdCl2ACHTUNGTRENNUNG(dppf)]
(5.0 mol%), NaHMDS (1.0 equiv, 0.6m in toluene), in THF for 72 h at
608C.
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Chem. Eur. J. 2010, 16, 12303 – 12306

Nitrogen Heterocycles
COMMUNICATION
Table 6. Use of alkenyl aminomalonates.
Having demonstrated the synthesis of trisubstituted alkyli-
dene pyrrolidines and piperidines our efforts turned to the
synthesis of stereodefined fully substituted alkylidene pyrro-
lidines.[4b,15] Using the reaction conditions that were success-
ful for the synthesis of the piperidines,[14] the synthesis of a
wide range of tetrasubstituted alkenes 13 in 62–88% yield
as single diastereomers was achieved (Table 5). As with the
previous substrates electronically diverse aryl iodides were
well-tolerated coupling partners as were vinyl iodides.
Entry[a]
1[b]
RI
Product
Yield [%]
67
15a
2
3
4
15b
15c
15d
66
70
33
Table 5. Synthesis of fully substituted alkenes.[12]
[a] Reaction conditions: 14 (1.0 equiv), R2I (1.5 equiv), [PdCl
2ACHTUNGTRENNUNG(dppf)]
(5.0 mol%), NaHMDS (1.0 equiv, 0.6m in toluene), in THF, 608C, 15 h.
[b] Reaction was conducted at RT for 60 h.
Entry[a]
R1, substrate
Me, 12a
Me, 12a
Me, 12a
Me, 12a
nBu, 12b
nBu, 12b
Ph, 12c
R2I
Product
13a
Yield [%]
1[b]
2[c]
3
88
82
75
62
68
68
83
13b
13c
4[d]
5
13d
13e
6
13 f
7[e]
13g
[a] Reaction conditions: 12 (1.0 equiv), R2I (1.5 equiv), [PdCl
2ACTHNUTRGNE(NUG dppf)]
(5.0 mol%), NaHMDS (1.0 equiv, 0.6m in toluene), in THF, 72 h, 608C.
[b] Reaction complete in 3 h at RT. [c] Reaction complete in 15 h. [d] A
1.0:5.6 mixture of starting material:product was isolated, yield is given
for the amount of product present. [e] Reaction conducted at 608C for
60 h.
Scheme 2. Proposed cyclisation mechanism.
Lastly we conducted preliminary experiments into the
cyclisation of the corresponding olefinic substrate 14.[9b,16–20]
Under the same conditions as used for the internal alkyne
substrates, the alkenyl malonate 14 gave the corresponding
pyrrolidines 15 in 33–70% yield (Table 6). As with the al-
kynyl substrates 4, aryl iodides were better coupling part-
ners for the reaction (Table 6, entries 1–3) than the corre-
sponding alkenyl iodides (Table 6, entry 4).
A plausible mechanism for the reaction, analogous to that
proposed in the all carbon series is given below
(Scheme 2).[19] In the presence of a copper salt the deproton-
ated malonate 16 undergoes cyclisation to give the vinylcop-
per species 17. After oxidative addition of iodobenzene to
the Pd0 catalyst, transmetallation occurs with the vinylcop-
per species giving 18, which on reductive elimination deliv-
ers the product 5a and regenerates the Pd0 catalyst. In the
absence of a copper(I) salt, cyclisation of the anion 16 onto
the alkyne occurs under PdII catalysis to give 18 directly
(dotted arrow).
In summary, we have developed a palladium-catalysed
tandem cyclisation/coupling reaction which offers a rapid,
mild and efficient route to functionalised pyrrolidines, the
products being obtained in moderate to excellent yields as
single diastereomers. The reaction tolerates a variety of
functional groups including: esters, carbamates, amines,
ethers, silyl ethers and aryl bromides; as well as a variety of
malonyl esters. Piperidines may also be synthesised using
the developed methodology. The described methodology
offers a new entry into various pyrrolidine building blocks
for use in numerous synthetic applications including natural
product synthesis.
Experimental Section
See Supporting Information for full experimental details.
Chem. Eur. J. 2010, 16, 12303 – 12306
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www.chemeurj.org
12305

J. W. Burton and W. Hess
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Acknowledgements
Generous financial support by the Deutsche Forschungsgemeinschaft is
gratefully acknowledged. We thank the analytical sections of our Depart-
ment for their excellent support.
Keywords: aminomalonates
·
copper
·
nitrogen
heterocycles · palladium · pyrrolidines
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ꢀ
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ꢀ
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Received: July 9, 2010
Published online: September 13, 2010
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Chem. Eur. J. 2010, 16, 12303 – 12306