Copper-catalyzed enantioselective [2.+2] cycloadditions of 2-nitrosopyridine with ketenes

Article abstract of DOI:10.1002/adsc.201000153

Copper(I)-catalyzed [2.+2] cycloadditions of various ketenes with 2-nitrosopyridine to afford synthetically highly valuable l,2-oxazetidine-3-ones are shown to occur with good enantioselectivities. The thermal uncatalyzed process furnishes the unstable regioisomeric oxazetidinone. Density function theory (DFT) calculations give evidence that the reaction occurs via a concerted [2.+2]cycloaddtion pathway.

Full text of DOI:10.1002/adsc.201000153

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DOI: 10.1002/adsc.201000153
Copper-Catalyzed Enantioselective [2+2]Cycloadditions of
2-Nitrosopyridine with Ketenes
Indranil Chatterjee,a,b Chandan Kumar Jana,a Marc Steinmetz,a Stefan Grimme,a,*
and Armido Studera,*
a
Organisch-Chemisches Institut, Westfꢀlische Wilhelms-Universitꢀt, Corrensstrasse 40, 48149 Mꢁnster, Germany
Fax : (+49)-251-833-6523; phone: (+49)-251-833-3291; e-mail: studer@uni-muenster.de
NRW Graduate School of Chemistry, Westfꢀlische Wilhelms-Universitꢀt, Corrensstrasse 40, 48149 Mꢁnster, Germany
b
Received: January 29, 2010; Revised: February 26, 2010; Published online: April 7, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000153.
Abstract: Copper(I)-catalyzed [2+2]cycloadditions
of various ketenes with 2-nitrosopyridine to afford
synthetically highly valuable 1,2-oxazetidine-3-ones
are shown to occur with good enantioselectivities.
The thermal uncatalyzed process furnishes the un-
stable regioisomeric oxazetidinone. Density func-
tion theory (DFT) calculations give evidence that
the reaction occurs via a concerted [2+2]cycloadd-
tion pathway.
Herein, we report the first catalytic enantioselective
[2+2]cycloadditions of 2-nitrosopyridines with vari-
ous ketenes. DFT calculations are presented to sup-
port the suggested mechanism.
Keywords: catalysis; copper; cycloadditions; DFT
calculations; stereoselective synthesis; synthetic
methods
We and others recently reported on Cu-catalyzed
The [2 +4]cycloaddition of nitroso compounds with stereoselective nitroso Diels–Alder reactions of nitro-
dienes, the so-called nitroso-Diels–Alder (NDA) reac- sopyridine derivatives with various dienes.[7,8] Chiral
tion, has been intensively used in organic synthesis.[1] diphosphines were used as ligands. Encouraged by
However, the [2+2]cycloaddition of nitroso deriva- these results we assumed that Cu-diphosphine systems
tives with olefins is not well investigated to date. Stau- might also be able to catalyze [2+2]cycloadditions of
dinger was the first to show that ketenes efficiently nitrosopyridines with ketenes. As test reaction we in-
react with aryl nitroso compounds to provide the two vestigated the cycloaddition of phenyl ethyl ketene
regioisomers 1 and 2 [Eq. (1)].[2] The regioselectivity with 2-nitrosopyridines to give 1,2-oxazetidine-3-ones
of that cycloaddition was later reinvestigated.[3] 1a and 1b [Eq. (2)].
Whereas compounds of type 1 can be isolated, re-
gioisomers 2 further react by CO2 elimination to give
the corresponding imines. Ketenimines[4] and elec-
tron-rich olefins[5] also undergo [2+2]cycloadditions
with nitroso derivatives. To the best of our knowledge,
only a single report on stereoselective cycloadditions
of ketenes with aryl nitroso derivatives has been pub-
lished to date:[6] Fu reported very recently that chiral
Lewis bases are able to catalyze the stereoselective
formation of 1,2-oxazetidine-3-ones 1. Reactions were
supposed to occur via intermediates and hence can
only formally be regarded as [2+2]cycloadditions. 10 mol% of [CuAHCTUNTGRENNUNG
Reactions were conducted in CH2Cl2 by using
(MeCN)4]PF6 in the presence of vari-
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Indranil Chatterjee et al.
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ous phosphines (10 mol%) with 2-nitrosopyridine to
give 1a. The ketene was added by a syringe pump at
À708C for 3.5 h and the reaction mixture was then al-
lowed to warm to À508C and stirring was continued
for 12 h at À508C.
The Cu-free process conducted at room tempera-
ture afforded only traces of the desired product 1a
(Table 1, entry 1). Regioisomer 2a (R1 =Et, R2 =Ph,
Aryl=2-pyridyl) was formed as major product which
partially decomposed to the corresponding imine
upon attempted purification (55% combined yield).
Pleasingly, a reversal of the regiochemistry was
achieved for Cu-catalyzed reactions. In these experi-
ments isomer 2a was formed in <5%.[9] As side reac-
tion ketene dimerization occurred. With PBu3 as
ligand, 1a was isolated in 65% yield (entry 2). Chelat-
ing bisphosphines such as 1,3-bis(diphenylphosphino)- Figure 1. Various ligands tested.
propane (dppp) also provided the desired regioisomer
in an acceptable yield (entry 3). Hence, the stage was
set for enantioselective cycloadditions by using chiral
diphosphines (Figure 1). With (S)-BINAP[10a] a good ner the product was formed with high selectivity (er=
yield was obtained; however, 1a was formed with low 97:3, entry 10). Reducing catalyst loading to 5 mol%
enantioselectivity (entry 4).[11] A slightly better selec- provided a lower yield and slightly lower selectivity
tivity was achieved with Difluorphos[10b] (entry 5). An (entry 11). In toluene, the reaction could not be con-
excellent yield but poor selectivity was noticed with ducted due to the insolubility of 2-nitrosopyridine in
Segphos[10c] (entry 6). Surprisingly, with 6-methyl-2-ni- this solvent and the reaction in THF provided a
trosopyridine as reaction partner, the targeted cyclo- worse result (entry 12). Only traces of 1a were identi-
adduct 1b was formed in only trace amounts (entry 7) fied by TLC by using (R,P)-Walphos-CF3 in the ab-
and Solphos[10d] showed almost no stereoinduction sence of the Cu salt (entry 13). Hence, Lewis base cat-
(entry 8). Best results were achieved with Walphos- alysis by the chiral bisphosphine for formation of 1a
type ligands.[10e] The methyl derivative afforded 1a can be excluded. Under optimized conditions we stud-
with an er of 88:12 (entry 9) and with the CF3-conge- ied the scope and limitations of the cycloaddition
(Table 2).
para-Substitutents at the aryl moiety in the ketene
were tolerated (entries 1 and 2). High selectivities
were achieved for meta-substituted aryl ethyl ketenes
(entries 3–7). However, the ortho-substituted aryl
ethyl ketenes furnished the corresponding cycload-
ducts 1h and 1i with poor enantioselectivities and
moderate yields (entries 6 and 7). A good result was
achieved with b-naphthyl ethyl ketene (entry 8). As
compared to the aryl ethyl ketenes, the smaller aryl
methyl ketenes reacted with slightly lower selectivities
(entries 9 and 10). Similar results were observed in
the reaction with cyclohexyl, n-butyl and 3-methylbu-
tyl phenyl ketenes (entries 11–13). The heteroaryl-
substituted 3-thienyl ethyl ketene also underwent
enantioselective cycloaddition (entry 14).
Table 1. Ligand screening (see Figure 1).
Entry
Ligand
–
Yield of 1a [%]
er
1[a]
2
<2
65
–
–
–
[b]
PBu3
3
Dppp
(S)-Binap
(S)-Difluorphos
(R)-Segphos
(R)-Segphos
(R)-Solphos
52
83
86
97
<2
80
4[b]
5[c]
6
41.5:58.5
24.0:76.0
67.0:33.0
–
51.5:48.5
88.0:12.0
97.0:3.0
91.0:9.0
92.5:7.5
–
7[d]
8
9
N
83
10
11[e]
12[f]
13[g]
U
80
62
35
<2
For assignment of the absolute configurations, 1,2-
oxazetidine-3-one 1a was reduced with LAH to the
[a]
Cu catalyst was not added.
20 mol% of PBu3 were used.
R-Enantiomer formed in excess.
6-Methyl-2-nitrosopyridine was used and 1b was only
identified in traces.
5 mol% catalyst loading.
À
corresponding alcohol. Subsequent Cu-catalyzed N O
[b]
[c]
[d]
bond cleavage provided known diol 3 in a good over-
all yield [Eq. (3)].[12] Comparison of the optical rota-
tion of 3 with the literature value revealed that the S-
isomer was formed as major product in our reaction.
All other compounds were assigned in analogy. This
reaction sequence shows the potential of our method
[e]
[f]
THF as solvent.
With the ligand but in the absence of the Cu salt.
[g]
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Adv. Synth. Catal. 2010, 352, 945 – 948

Copper-Catalyzed Enantioselective [2+2]Cycloadditions of 2-Nitrosopyridine with Ketenes
Table 2. Variation of the ketene.
Entry Aryl
R
Yield [%] er
(product)[a]
AHCTUNGTRENNUNG
1
2
3
4
5
6
7
8
4-MeC6H4
4-ClC6H4
3-MeC6H4
3-MeOC6H4 Et
3-FC6H4
2-MeC6H4
2-FC6H4
b-naphthyl
Ph
3-MeOC6H4 Me
Ph
Ph
Ph
Et
Et
Et
89 (1c)
68 (1d)
83 (1e)
76 (1f)
69 (1g)
55 (1h)
29 (1i)
79 (1j)
81 (1k)
80 (1l)
52 (1m)
70 (1n)
92.5:7.5[b]
95.0:5.0
97.0:3.0
97.5:2.5
97.5:2.5
56.0:44.0
54.5:45.5
95.5:4.5
88.5:11.5
91.5:8.5
93.0:7.0
95.0:5.0
95.0:5.0
93.5:6.5
Et
Et
Et
Et
Me
9
10
11
12
13
14
cyclohexyl
n-Bu
CH2CH
Et
(i-Pr) 53 (1o)
78 (1p)
3-thienyl
[a]
[b]
Isolated yield.
Determined after LAH reduction, see Supporting Infor-
mation.
for the synthesis of chiral 1,2-diols bearing a quater-
nary alcohol moiety.
Figure 2. Computed enthalpies (DH298) (relative to free reac-
tands in kcalmolÀ1) for initial complexes, transition states
and products for the reactions to 1 and 2 (Aryl=2-pyridyl,
R1 =R2 =Me). The dashed arrows indicate the computed
barriers and the preferred pathway is shown in black. The
structures shown represent the transition states.
To get an insight into the mechanism of our reac-
tions we performed DFT calculations on the Cu-free the copper complex for which a strongly reduced bar-
À
À
as well as Cu-mediated process. To reduce the com- rier (for the N CO compared to the O CO attack)
plexity of the system, dimethyl ketene and PMe3 were of only 3.3 kcalmolÀ1 is computed for cycloaddition
chosen for theoretical investigations. We have em- leading to 1.
ployed two different dispersion corrected density
In conclusion, we have presented the first enantio-
functionals that yield qualitatively the same picture selective [2+2]cycloadditions of 2-nitrosopyridine
but want to discuss here only the results from with various ketenes to give 1,2-oxazetidine-3-ones.
the B2PLYP-D/QZVPP//BP86-D/TZVP[13] treatment Reactions were efficiently mediated by Cu(I)/Wal-
shown graphically in Figure 2.
phos-CF3 as catalyst. The uncatalyzed thermal reac-
In all cases the reaction proceeds as expected from tion afforded the regioisomeric oxazetidinones.
a loosely bound reactand complex through a concert- Hence, the catalyst controlled the regio- and the
ed but asynchronous transition state very exothermi- enantioselectivity. Importantly, our reaction allowed
cally to the products. In agreement with the experi- the generation of chiral tertiary carbon centers with
mentally observed regiochemistry, we find in the Cu- high enantioselectivities. The products obtained are
free reaction (upper part in Figure 2) a slightly lower highly valuable compounds for further synthetic ma-
À1
À
barrier (by 1.4 kcalmol ) for the O CO arrangement nipulations. This was documented by the transforma-
leading to 2 as compared to the barrier leading to 1. tion of a 1,2-oxazetidine-3-one to the corresponding
As also observed experimentally, this is reversed with 1,2-diol. Many other interesting reactions with these
Adv. Synth. Catal. 2010, 352, 945 – 948
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947

Indranil Chatterjee et al.
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References
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According to GP1: (R,P)-Walphos (12.9 mg, 0.014 mmol),
[Cu(I)
(CH3CN)4]PF6
(5.17 mg,
0.014 mmol),
CH2Cl2
(2.0 mL), 2-nitrosopyridine (15 mg, 0.14 mmol) in CH2Cl2
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Rf =0.5 (pentane/MTBE, 2:1); [a]2D5: +84.36 (c 0.78, CHCl3);
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˜
FT-IR (film): n=3057, 2979, 2939, 1730, 1651, 1582, 1448,
1
1398, 1263, 976, 930, 882, 731, 699 cmÀ1; H NMR (300 MHz,
CDCl3): d=8.34 (d, J=4.5 Hz, 1H) , 7.65–7.59 (m, 1H),
7.51–7.48 (m, 2H), 7.37–7.28 (m, 3H), 7.20 (d, J=8.2 Hz,
1H), 7.0–6.96 (m, 1H), 2.33–2.17 (m, 2H), 1.03 (t, J=
7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=164.6, 148.9,
148.6, 138.0, 135.4, 128.1, 128.7, 124.8, 120.1, 109.85, 102.5,
29.9, 7.7; HR-MS (ESI): m/z=277.0946, exact mass calculat-
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meric ratio (97:03) was determined by chiral HPLC
(column: Chiralcel IA; solvent: cyclohexane:2-propanol
(99:01); flow: 1.0 mLminÀ1): minor enantiomer tr =
12.206 min, major enantiomer tr =14.359 min.
Supporting Information
Further experimental procedures and compound characteri-
zation data are available as Supporting Information.
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Acknowledgements
We thank the DFG for supporting our work. Solvias AG is
acknowledged for donation of various chiral ligands.
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Adv. Synth. Catal. 2010, 352, 945 – 948