Enantioselective [2 + 2 + 2] cycloaddition reaction of isocyanates and allenes catalyzed by nickel

Article abstract of DOI:10.1021/ja105541r

The enantioselective intermolecular [2 + 2 + 2] cycloaddition reaction of two molecules of isocyanate and one molecule of allene is catalyzed by a nickel(0)/(S,S)-i-Pr-FOXAP complex, providing an efficient access to enantiomerically enriched dihydropyrimidine-2,4-diones.

Full text of DOI:10.1021/ja105541r

Published on Web 09/14/2010
Enantioselective [2 + 2 + 2] Cycloaddition Reaction of Isocyanates and
Allenes Catalyzed by Nickel
Tomoya Miura, Masao Morimoto, and Masahiro Murakami*
Department of Synthetic Chemistry and Biological Chemistry, Kyoto UniVersity, Katsura, Kyoto 615-8510, Japan
Received June 24, 2010; E-mail: murakami@sbchem.kyoto-u.ac.jp
Abstract: The enantioselective intermolecular [2 + 2 + 2]
cycloaddition reaction of two molecules of isocyanate and one
molecule of allene is catalyzed by a nickel(0)/(S,S)-i-Pr-FOXAP
complex, providing an efficient access to enantiomerically en-
riched dihydropyrimidine-2,4-diones.
Transition-metal-catalyzed [2 + 2 + 2] cycloaddition reactions
Figure 1. Chiral ligands examined in the optimization studies.
provide a powerful tool for rapid construction of six-membered
ring carbo- and heterocycles.1 Isocyanates are often employed as
Table 1. Ni(0)-Catalyzed Enantioselective [2 + 2 + 2]
the π component due to their unique reactivity as well as availability
from commercial sources.2 Transition metal complexes such as
cobalt(I),3 nickel(0),4 ruthenium(II),5 and rhodium(I)6 can catalyze
the intermolecular [2 + 2 + 2] cycloaddition reaction of one
molecule of isocyanate and two molecules of alkyne, leading to
the formation of 2-pyridones.7 Pyrimidine-2,4-diones were also
synthesized by [2 + 2 + 2] cycloaddition of two molecules of
isocyanate and one molecule of alkyne.6a,8 Rovis and co-workers
developed a regio- and enantioselective rhodium(I)-catalyzed bi-
molecular [(2 + 2) + 2] cycloaddition reaction of ω-alkenyl
isocyanates with alkynes forming bicyclic lactams or vinylogous
amides and applied this strategy to the asymmetric total synthesis
of (+)-lasubine II and (-)-209D.9 Despite numerous studies on
the metal-catalyzed [2 + 2 + 2] cycloaddition reactions, however,
there has been no report on the use of allenes as the coupling partner
of isocyanates.10,11 Herein, we describe the nickel-catalyzed
intermolecular [2 + 2 + 2] cycloaddition reaction of 1 equiv of
allene 1 and 2 equiv of isocyanate 2 to afford the corresponding
dihydropyrimidine-2,4-dione 3 with high levels of enantioselectivity
(eq 1).
Cycloaddition: Screening of Chiral Phosphine Ligandsa
entry
chiral ligand
yield (%)b
rs (3:4)c
ee (%)d
1
2
3
4
5
6
(S,S)-CHIRAPHOS
(S,S)-NORPHOS
(S)-BINAP
(R)-i-Pr-PHOX
(S,S)-i-Pr-FOXAP
(S,S)-Ph-FOXAP
78e
19
5:1
4:1
2:1
16:1
>20:1
>20:1
33
19
5
87
97
67
43e
32
68
66
a All reactions were carried out on a 0.2 mmol scale. b Combined
yield of regioisomers. c Ratio of regioisomers determined by 1H NMR.
d Enantiomeric excess determined by chiral HPLC analysis. e The
product was accompanied with small amounts (∼10%) of unidentified
compounds.
1a and two molecules of isocyanate 2a. We next extended our
ligand survey to chiral phosphine ligands to observe good catalytic
activity with the use of C2-symmetric bisphosphine ligands such
as (S,S)-Chiraphos, (S,S)-Norphos, and (S)-Binap (Figure 1).
However, both the regioselectivity (3aa:4aa) and the enantiose-
lectivity of 3aa were low (Table 1, entries 1-3). The regioselectivity
was significantly improved when unsymmetrical phosphino-oxazo-
line ligands were used (entries 4-6). Among them, (S,S)-i-Pr-
FOXAP13 proved to be the optimal ligand; 3aa was obtained in
68% yield with >20:1 regioselectivity, and its enantioselectivity
was 97% ee (entry 5).14
The results of the reaction with various combinations of
allenes 1 and isocyanates 2 using a nickel(0)/(S,S)-i-Pr-FOXAP
complex are summarized in Table 2. Monosubstituted allenes
1b-d possessing a primary alkyl group readily reacted with 2a
to afford the corresponding products 3ba-da in good yields with
high regio- and enantioselectivities (entries 1-3),15 whereas the
reaction of cyclohexylpropa-1,2-diene (1e) was sluggish to give
the product 3ea only in 26% yield (entry 4).16 Functional groups
such as benzyloxy, siloxy, and alkenyl groups were tolerated in
the alkyl chain under the reaction conditions (entries 5-7). The
Initially, a variety of achiral phosphine ligands were evaluated
using nickel(0) as the transition metal and undeca-1,2-diene (1a)
and tolyl isocyanate (2a) as the model substrates; a mixture of 1a
(1.0 equiv) and 2a (3.0 equiv) in THF was heated at 80 °C in the
presence of a nickel(0) catalyst generated in situ from Ni(cod)2 (10
mol %) and a phosphine ligand (P/Ni ) 4:1). Whereas the use of
monophosphine ligands such as PMe3, PCy3, P(t-Bu)3, and PPh3
resulted in only oligomerization of the allene 1a,12 a cycloaddition
reaction was observed with bisphosphine ligands such as Dppe and
Dppbenz. For example, when Dppe was employed, a mixture of
3aa and 4aa (4:1) was produced in 13% combined yield. The
products 3aa and 4aa are regioisomers, both arising from inter-
molecular [2 + 2 + 2] cycloaddition between one molecule of allene
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15836 J. AM. CHEM. SOC. 2010, 132, 15836–15838
10.1021/ja105541r  2010 American Chemical Society

C O M M U N I C A T I O N S
tions (eq 2).20 Highly stereoselective functionalization of the olefin
could be achieved.
Table 2. Ni(0)-Catalyzed Enantioselective [2 + 2 + 2]
Cycloaddition of 1 (R1CHdCdCH2) and 2 (R2NCO)a
yield
ee
entry
1 (R1)
1b (Hex)
1c (CH2Cy)
1d ((CH2)2Ph)
1e (Cy)
1f ((CH2)4OBn)
1g ((CH2)4OTBS)
1h ((CH2)2CH)CMe2) 2a
1a (Oct)
2 (R2)
2a (Tol)
2a
2a
2a
2a
2a
3
(%)b rs (3:4)c (%)d
1
2
3
4
5
6
7
8
9
3ba 67
3ca 67
3da 65
3ea 26
3fa 61
3ga 60
3ha 64
57
>20:1 96
>20:1 94
>20:1 94
e
e
5:1
>20:1
97
97
>20:1 94
>20:1 99
>20:1 98
>20:1 99
>20:1 98
f
2b (4-Me2N-C6H4) 3ab
2c (4-MeO-C6H4)
2d (Ph)
1a
3ac 65
3ad 70
3ae 73
10 1a
11 1a
12 1a
13 1a
14 1a
15 1a
16 1a
17 1a
e
e
e
e
2e (4-Cl-C6H4)
>20:1
16:1
>20:1
6:1
89
97
94
88
In summary, we have developed a highly enantioselective nickel-
catalyzed [2 + 2 + 2] cycloaddition of two molecules of isocyanate
and one molecule of allene, providing an efficient access to
enantiomerically enriched dihydropyrimidine-2,4-diones. Further
investigation on the reaction mechanism, the substrate scope, and
the utilization of dihydropyrimidine-2,4-diones as chiral building
blocks are underway.
2f (4-MeO2C-C6H4) 3af 76
2g (4-MeCO-C6H4) 3ag 55
2h (4-CF3-C6H4)
2i (3-Me-C6H4)
2j (2-Naphthyl)
2k (Bn)
3ah 79
3ai 65
3aj 82
3ak 12
>20:1 97
>20:1 97
>20:1 94
a The reaction was carried out with 1 (0.2 mmol), 2 (0.6 mmol),
Ni(cod)2 (10 mol %), i-Pr-FOXAP (20 mol %) in THF (1 mL) at 80 °C
for 12 h, unless otherwise noted. b Combined yield of regioisomers.
c Ratio of regioisomers determined by 1H NMR. d Enantiomeric excess
determined by chiral HPLC analysis. e Using 1,4-dioxane (1 mL) at 100
Acknowledgment. This work was supported in part by MEXT
(Grant-in-Aid for Scientific Research on Innovative Areas, No.
22106520). We thank Prof. Susumu Kitagawa, Dr. Satoshi Horike,
and Mr. Tomohiro Fukushima (Kyoto Univ.) for performing an
X-ray analysis.
f
°C. 1H NMR yield using CHBr2CHBr2 as an internal standard.
cycloaddition reaction of 1a with a diverse array of aryl
isocyanates 2b-j proceeded well to give the corresponding
products 3ab-aj in yields ranging from 55 to 82% with
enantioselectivities ranging from 88 to 99% ee (entries 8-16).
Higher regioselectivity was observed with electron-rich aryl
isocyanates than with electron-deficient aryl isocyanates. In the
reaction of benzyl isocyanate (2k) with 1a, large amounts of
isocyanate oligomers were produced together with a small
amount of the cycloadduct 3ak, which was isolated in only 12%
yield (entry 17). Other alkyl isocyanates including hexyl
isocyanate, cyclohexyl isocyanate, and tert-butyl isocyanate all
failed to undergo the cycloaddition reaction.
A plausible mechanism for the production of dihydropyrimidine-
2,4-dione 3 from allene 1 and isocyanate 2 is depicted in Scheme
1.17 Initially, the intermolecular oxidative cyclization of a heteropair
of 1 and 2 occurs on nickel(0) to give five-membered ring
azanickelacyclic intermediate A.18,19 Subsequent insertion of
another molecule of 2 into the nickel-nitrogen bond expands A to
seven-membered ring azanickelacycle B, which is in equilibrium
with zwitterionic π-allylnickel species C. Finally, intramolecular
recombination occurs at the more substituted carbon of the allyl
moiety to afford 3 along with nickel(0).
Supporting Information Available: Experimental procedures,
spectral data for the new compounds, and details of the X-ray analysis.
This material is available free of charge via Internet at http://
pubs.acs.org.
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C O M M U N I C A T I O N S
(15) The absolute configuration of 3ca was determined by an X-ray crystal
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