A promising new catalyst family for enantioselective cycloadditions involving allenes and imines: chiral phosphines with transition metal-CH2-P: linkages

Article abstract of DOI:10.1016/j.tetlet.2006.07.005

The racemic rhenium-containing phosphine (η⁵-C₅H₅)Re(NO)(PPh₃)(CH₂PPh₃) (3) catalyzes the [3+2] cycloaddition of H₂C{double bond, long}C{double bond, long}CHCO₂Et and

Full text of DOI:10.1016/j.tetlet.2006.07.005

Tetrahedron Letters 47 (2006) 6335–6337
A promising new catalyst family for enantioselective
cycloadditions involving allenes and imines: chiral
phosphines with transition metal–CH2–P: linkages
Alexander Scherer and J. A. Gladysz*
Institut fu¨r Organische Chemie, Friedrich-Alexander-Universita¨t Erlangen-Nu¨rnberg, Henkestraße 42, 91054 Erlangen, Germany
Received 4 July 2006; accepted 5 July 2006
Available online 25 July 2006
Abstract—The racemic rhenium-containing phosphine (g5-C5H5)Re(NO)(PPh3)(CH2PPh3) (3) catalyzes the [3+2] cycloaddition of
H2C@C@CHCO2Et and N-tosyl imines ArCH@NTs in C6H6 (RT, 1 d, 20 mol %) to give 2-aryl-3-carbethoxy-3-pyrrolines (Ar@p-
C6H4X (X = H, NO2, OMe, Me, Cl, Br), 2-furyl; 95–84% isolated). Similar reactions with enantiopure (S)-3 are conducted in
C6H5Cl at À30 °C (8 d) to maximize enantioselectivities (60–51% ee; 93–90% isolated).
Ó 2006 Elsevier Ltd. All rights reserved.
Phosphorus Lewis bases catalyze numerous types of
organic transformations, usually via the nucleophilic
activation of an educt.1,2 Most of these reactions are
capable of generating new stereocenters. Many chiral
phosphorus Lewis bases are now readily available in
enantiomerically pure form. Hence, much attention is
currently being directed at developing enantioselective
versions of these processes.
species. Appreciable enantioselectivities can furthermore
be achieved.
The [3+2] cycloaddition of the allene ethyl 2,3-buta-
dienoate (1) and N-tosyl imines (2), originally developed
by Lu, was selected as the test reaction.9,10 As shown in
Scheme 1, this process is catalyzed by Ph3P and
(n-Bu)3P, and affords chiral functionalized 3-pyrrolines.
The first step is believed to generate the zwitterion III, to
which the tosyl amine adds to give IV. For initial screen-
ing, the readily available chiral rhenium-containing
phosphine (g5-C5H5)Re(NO)(PPh3)(CH2PPh2) (3)11 was
chosen. This air-stable eighteen-valence-electron species
can be prepared in racemic form in 6 steps and 44%
overall yield from commercial Re2(CO)10, or in enantio-
pure form in 9 steps and 36% overall yield.
We wondered whether it might be possible to catalyze
such transformations with transition-metal-containing
phosphorus Lewis bases of the formulae LnMPR2 or
LnMCH2PR2. Increasing numbers of chiral LnM frag-
ments are easily accessed in enantiomerically pure
form.3 Furthermore, it is now well established that
coordinatively saturated metal fragments enhance the
Lewis basicities and nucleophilicities of directly-bound
donor atoms D: and CH2D: analogs.4–6 This is believed
to originate from the types of orbital interactions
sketched in Figure 1.7 Some involve repulsive interac-
tions between filled orbitals (I, IIa), and others attractive
interactions between filled and vacant orbitals (IIb).
The extensively exploited enhanced nucleophilicities
of allyl silanes arise from interactions between
Si–C r and C@C p or p* orbitals analogous to IIa,b.8
Accordingly, in this communication we report the first
examples of nucleophilic catalysis with LnMCH2PR2
L
L
L
L
L
L
L
L
L
L
P
L
C
L
C
R
P
P
L
L
L
R
I
IIa
(σ orbital /
IIb
(metal d lone pair /
phosphorus lone pair)
(metal d lone
pair / σ* orbital)
phosporus lone pair)
*
Figure 1. Key orbital interactions in coordinatively saturated
Ln MPR2 (I) and LnMCH2PR2 (II) complexes.
Corresponding author. Tel.: +49 9131 85 22540; fax: +49 9131 85
26865; e-mail: gladysz@chemie.uni-erlangen.de
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.005

6336
A. Scherer, J. A. Gladysz / Tetrahedron Letters 47 (2006) 6335–6337
Table 1. Yields and enantioselectivites for cycloadditions (Scheme 1)
catalyzed by racemic 3 and (S)-3 (20 mol %)a
Ts
N
H
R
R
Isolated yield Isolated yield (%), ee (%)
(%), racemic scalemic 4 ((S)-3,
4 (3, benzene, chlorobenzene,
R3P:
(er)b,
Ts
+
CO2Et
R
N
scalemic 4
RT, 1 d)
À20 °C, 8 d)
CO2Et
1
2
4
a, C6H5
94
92
95
94
90
91
90
84
92
90
93
92
90
91
90
91
—
60 (80:20)
51 (76:24)
54 (77:23)
58 (79:21)
58 (79:21)
52 (76:24)
57 (79:22)
56 (78:22)
—
R3P: = Ph3P:,
(n-Bu)3P:
b, p-C6H4NO2
c, p-C6H4OMe
d, p-C6H4Me
e, p-C6H4F
f, p-C6H4Cl
g, p-C6H4Br
h, 2-furyl
Re
H2C
(reference 9)
or this work:
PPh3
PPh2
ON
3 or (S)-3
Ts
N–
i, CH@CHC6H5 61
R
C
a Benzene, RT (racemic 3) or chlorobenzene, À20 °C ((S)-3); see the
Supplementary data for additional details.
b Determined by HPLC.
H
H
C
O
H
δ−
H
δ−
H
OEt
OEt
H
C
O
H
III
+PR3
IV
+PR3
δ−
Next, similar reactions were examined with (S)-3. In
benzene at room temperature, 1 and 2a gave 4a with
an ee value of 26%, as assayed by HPLC. In order to
maximize enantioselectivities, cycloadditions were con-
ducted in the lower-freezing solvent chlorobenzene at
À20 °C. Although longer reaction times were required
(8 d), 4a–h could be isolated in 93–90% yields with ee
values of 60–51%, as summarized in Table 1.
Scheme 1. Phosphine-catalyzed [3+2] cycloadditions of ethyl 2,3-
butadienoate (1) and N-tosyl imines (2).
Benzene solutions of 1 and 2 (1.00:1.20 mol ratio) were
stirred in the presence of 20 mol % of racemic 3. After
24 h, flash chromatography gave the aryl-substituted
cycloadducts 4a–h as analytically pure powders in 95–
84% yields, as summarized in Table 1. Analogous cyclo-
adducts could sometimes be observed with non-aryl
substituents. That with R = C6H5CH@CH (4i) was iso-
lated in 61% yield. However, those with aliphatic groups
(e.g., t-Bu) formed in lower yields, and could not be
further purified.
Complexes with RePR2 linkages are much more nucleo-
philic than their ReCH2PR2 analogs.4,13 Thus, similar
reactions of 1 and 2a were investigated with the phosph-
ido complex (g5-C5H5)Re(NO)(PPh3)(PPh2) (5).13 How-
ever, no 4a was detected. Independent reactions of 1a
and 5 showed the rapid formation of allene oligomers,
as evidenced by mass spectrometry. Hence, such com-
plexes appear too reactive, presumably giving intermedi-
ate zwitterions III that are less discriminating than those
derived from 3.
A
variety of other conditions were investigated.
Comparable yields of 4a (R = C6H5) were obtained in
chlorobenzene (93%), CHCl3 (92%), and CH2Cl2
(90%). However, temperatures above 40 °C also proved
deleterious. NMR spectra of the crude products sug-
gested the presence of a [3+2] cyclodimer of 1 that has
been previously isolated from the independent reaction
of 1 and PPh3 (10 mol %) in benzene.12 Data for 4a–i,
most of which are known compounds,9a are given in
the Supplementary data.
As illustrated in Scheme 2, Kwon has found that the
replacement of 1 in Scheme 1 by the methyl-substituted
allene H2C@C@C(Me)CO2Et (6) leads to tetrahydro-
pyridines 7.9d,14 The mechanism involves an alternative
C@N addition mode to the zwitterion III, followed by
proton transfer from the methyl group to nitrogen.
Indeed, 3 (20 mol %) could also catalyze this transfor-
Ts
CH3
R
N
R3P:
Ts
+
CO2Et
R
N
CO2Et
6
2
7
R3P: = Ph3P:
data: see text
(reference 14)
or this work:
Re
PPh3
PPh2
ON
H2C
3
Scheme 2. Phosphine-catalyzed [4+2] annulations of ethyl 2-methyl-2,3-butadienoate (6) and N-tosyl imines (2).

A. Scherer, J. A. Gladysz / Tetrahedron Letters 47 (2006) 6335–6337
6337
mation in benzene at room temperature. However, the
Supplementary data
yields and purities of the cycloadducts were lower
(R = C6H5, 53%; p-C6H4NO2, 47%; p-C6H4OMe,
63%), and extended reaction times were required (8 d).
The solvents chlorobenzene, CHCl3, and CH2Cl2 did
not give any improvements. Hence, no enantioselective
reactions were attempted.
Supplementary data associated with this article (repre-
sentative procedures, and characterization of 4a–i
(microanalysis, IR, 1H NMR, 13C NMR, mass spec-
trometry)) can be found, in the online version, at
doi:10.1016/j.tetlet.2006.07.005.
To our knowledge, there is only one previous study, by
Marinetti and Jean, involving non-racemic chiral phos-
phorus Lewis base catalysts for the cycloadditions in
Scheme 1. A number of commercially available enantio-
pure diphosphines and monophosphines were
screened.10 The systems that gave the highest ee values
often afforded only modest yields ((S)-BINAP, 45% ee,
13%; (R,R)-Et-FerroTANE, up to 66% ee, 36%; (S)-
Phanephos, 64% ee, 32%). The broad and consistent
activity that characterizes (S)-3 could not be realized.
References and notes
1. Methot, J. L.; Rousch, W. R. Adv. Synth. Catal. 2004, 346,
1035.
2. Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34,
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3. (a) Brunner, H. Angew. Chem., Int. Ed. 1999, 38, 1194;
Angew. Chem. 1999, 111, 1248; (b) Ganter, C. Chem. Soc.
Rev. 2003, 32, 130.
4. Delacroix, O.; Gladysz, J. A. Chem. Commun. 2003, 665,
and earlier references therein.
Importantly, the rather high loadings of 3 and (S)-3 em-
ployed do not reflect any intrinsic problem with catalyst
stability or deactivation. Rather, since side reactions
dominate above room temperature, the loading repre-
sents the only other conveniently-varied parameter for
achieving reasonable rates. NMR spectra show that
appreciable amounts of catalyst remain when cycloaddi-
tions are complete, and the addition of fresh educts gives
further reaction. The poorer performance of 3 in Scheme
2 constitutes another manifestation of the often appre-
ciable sensitivity of phosphine catalyzed processes to
the reaction conditions, exact nature of the adducts
and catalyst, etc.1 In this context, 3 features a number
of diversity elements that can be exploited to optimize
yields and selectivities (e.g., the cyclopentadien- yl ligand,
the rhenium-bound phosphine, substituents on the
spacer carbon or the Lewis basic phosphorus atom that
could furthermore introduce new stereocenters).
5. (a) Giner Planas, J.; Hampel, F.; Gladysz, J. A. Chem.
Eur. J. 2005, 11, 1402; (b) Kromm, K.; Eichenseher, S.;
Prommesberger, M.; Hampel, F.; Gladysz, J. A. Eur. J.
Inorg. Chem. 2005, 298.
6. (a) Fulton, J. R.; Sklenak, S.; Bouwkamp, M. W.;
Bergman, R. G. J. Am. Chem. Soc. 2002, 124, 4722; (b)
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allics 2004, 23, 1656; (d) Rais, D.; Bergman, R. G. Chem.
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7. For other possible contributing factors, see: Holland, P.
L.; Andersen, R. A.; Bergman, R. G. Comments Inorg.
Chem. 1999, 21, 115.
8. Kahn, S. D.; Pau, C. F.; Chamberlin, A. R.; Hehre, W. J.
J. Am. Chem. Soc. 1987, 109, 650.
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Lu, X. Tetrahedron Lett. 1999, 40, 549; (c) Zhao, G.-L.;
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Henry, C. E.; Kwon, O. Tetrahedron 2005, 61, 6276.
10. Jean, L.; Marinetti, A. Tetrahedron Lett. 2006, 47, 2141.
11. (a) Kromm, K.; Zwick, B. D.; Meyer, O.; Hampel, F.;
Gladysz, J. A. Chem. Eur. J. 2001, 7, 2015; (b) Eichense-
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13. Buhro, W. E.; Zwick, B. D.; Georgiou, S.; Hutchinson,
J. P.; Gladysz, J. A. J. Am. Chem. Soc. 1988, 110,
2427.
In summary, 3 and (S)-3 are effective catalysts for the
[3+2] cycloaddition in Scheme 1, and allow significant
enantioselectivities to be achieved. They represent a
promising new direction for transition-metal-containing
Lewis bases or ‘organocatalysts’, nearly all of which
have to date been based upon ferrocene, as exemplified
by the extensive work of Fu.15,16 Future reports will
describe the use of 3 and (S)-3 as catalysts for other
types of organic transformations,17 as well as advanced-
generation catalysts for Schemes 1 and 2.
14. (a) Zhu, Z.-F.; Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003,
125, 4716; (b) Tran, Y. S.; Kwon, O. Org. Lett. 2005, 7,
4289; (c) Zhao, G.-L.; Shi, M. Org. Biomol. Chem. 2005, 3,
3686; (d) Wurz, R. P.; Fu, G. C. J. Am. Chem. Soc. 2005,
127, 12234.
15. Fu, G. Acc. Chem. Res. 2004, 37, 542.
Acknowledgements
16. For a recent report of a non-ferrocene-based system, see:
Nguyen, H. V.; Butler, D. C. D.; Richards, C. J. Org. Lett.
2006, 8, 769.
We thank the Deutsche Forschungsgemeinschaft (DFG,
GL 300/8-1; SPP 1179) for support.
17. Seidel, F.; Gladysz, J. A., in preparation.