Chiral palladium-pincer complex catalyzed asymmetric condensation of sulfonimines and isocyanoacetate

Article abstract of DOI:10.1016/j.tetasy.2008.07.027

The asymmetric condensation of isocyanoacetate and sulfonimines was studied. Chiral BINOL and biphenantrol-based palladium-pincer complexes proved to be efficient catalysts affording 2-imidazoline derivatives with up to 86% ee. The level of enantioselectivity was clearly dependent on the γ-substituents of the BINOL ring. The best results were obtained by using biphenantrol-based pincer-complex catalysts. Some of the complexes induced the selective formation of the anti-diastereomer of the 2-imidazoline. The diastereo- and enantioselectivity showed an interesting solvent dependence as well. It was found that the application of diglyme as a solvent instead of THF leads to preferential formation of the anti product with a slight decrease of the enantioselectivity.

Full text of DOI:10.1016/j.tetasy.2008.07.027

Tetrahedron: Asymmetry 19 (2008) 1867–1870
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Tetrahedron: Asymmetry
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Chiral palladium-pincer complex catalyzed asymmetric condensation
of sulfonimines and isocyanoacetate
*
Juhanes Aydin, Andreas Rydén, Kálmán J. Szabó
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, Stockholm SE-10691, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric condensation of isocyanoacetate and sulfonimines was studied. Chiral BINOL and biphe-
nantrol-based palladium-pincer complexes proved to be efficient catalysts affording 2-imidazoline deriv-
atives with up to 86% ee. The level of enantioselectivity was clearly dependent on the c-substituents of
the BINOL ring. The best results were obtained by using biphenantrol-based pincer-complex catalysts.
Some of the complexes induced the selective formation of the anti-diastereomer of the 2-imidazoline.
The diastereo- and enantioselectivity showed an interesting solvent dependence as well. It was found
that the application of diglyme as a solvent instead of THF leads to preferential formation of the anti prod-
uct with a slight decrease of the enantioselectivity.
Received 24 June 2008
Accepted 25 July 2008
Available online 9 August 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
NTs
NHTs
Ar
1
[ ]cat.
M
+
ð1Þ
ð2Þ
+
Chiral-pincer complexes represent a promising new tool in
asymmetric catalysis.1–8 These species are characterized by strong
metal to ligand bonding and a well-defined stoichiometry, which
allows an efficient fine-tuning of the catalytic properties and
rational ligand design.9–21 In previous studies, we have systemati-
Ar
COOMe
O
MeOOC
N
[Pdpinc]cat.
NC
2
Ar
Ar
base
O
Ar
cally developed
palladium-pincer complexes, in which the substituents were var-
ied at the
-position of the BINOL unit (Fig. 1).9,10 These complexes
could be employed in the asymmetric allylation22–27 of various
imine substrates (Eq. 1). It was found that -substitution of the BI-
a series of BINOL and biphenantrol-based
MeOOC
COOMe
NTs
N
PCP
[
]
c
cat.
+
NC
ð3Þ
N
c
Ar
Ts
NOL units has a high influence on the enantioselectivity of the ally-
lation reaction. For the allylation of sulfonimines, the best results
were achieved using catalyst 1a to afford the corresponding homo-
allylamine with 85% ee. Another important area of application of
palladium-pincer complexes is the aldol reaction of aldehydes with
isocyanides affording oxazoline derivatives (Eq. 2).12–16 The oxazo-
line derivatives obtained in these reactions can be hydrolyzed to
2
3
4
Recently, we have shown that using pincer complex catalysis, a
similar condensation reaction (Eq. 3) can be performed for isocya-
nides 2 and sulfonimines 3 to obtain imidazoline derivatives 4.28
The resulting imidazoline derivatives 4 can be readily hydrolyzed
to
a,b-diaminoacids, which are important bioactive com-
pounds.29,30 Condensation reactions of 2 and 3 affording imidazo-
line derivatives 4 have previously been performed using gold,31–33
ruthenium,34 and copper35 catalysis; however, common
palladium catalysts31 performed poorly. On the other hand, palla-
dium-pincer complex catalysis is very efficient28 and highly selec-
tive compared to simple mono- and bidentate palladium catalysts.
Accordingly, we decided to develop an asymmetric version of the
palladium catalyzed condensation of 2 and 3 using chiral-pincer
complex catalysts 1. In these studies we have investigated the role
of the substituent pattern and chirality of the BINOL/biphenantrol
ligands9 on the stereo- and enantioselectivity of the reactions. The
non-natural
merically pure
a
-aminoacids. The possibility of obtaining enantio-
-aminoacids by this process has stimulated the
a
development of the asymmetric version of this reaction using chi-
ral-pincer complexes.12–16 In these studies, the best results (up to
75% ee) were presented by Nishiyama et al.14 using phebox derived
pincer complexes.
* Corresponding author. Tel.: +46 8 6747485; fax: +46 8 154908.
E-mail address: kalman@organ.su.se (K.J. Szabó).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.07.027

1868
J. Aydin et al. / Tetrahedron: Asymmetry 19 (2008) 1867–1870
O
P
O
P
O
P
O
O
O
O
O
O
O
O
O
Pd
I
Pd
I
P
H
1a
1b
SMe
MeS
SPh
PhS
O
P
O
O
P
O
P
O
O
O
O
O
O
O
O
Pd
I
P
Pd
I
H
SMe
MeS
SPh
SMe
PhS
MeS
1d
1c
O
P
O
P
O
P
O
P
O
O
O
O
O
O
O
O
Pd
I
Pd
I
SMe
MeS
1e
1f
Figure 1. Chiral pincer complexes used as catalysts (5 mol %) in the condensation reactions of 2 and 3.
enantioselective synthesis of the anti-products anti-4 and anti-5 is
particularly interesting, as these species are not accessible by gold-
ferrocenyl complex catalyzed asymmetric condensation of 2 and 3
as reported by Lin et al.32,33
hydrolysis of the imidazoline derivatives 4 obtained, and the ee
was determined for 5. Similarly to the allylation studies (Eq. 1),
the highest ee, 86%, was obtained with biphenantrol complex 1a
(entry 1). This enantiomeric excess is somewhat higher than the
corresponding value (up to 75%) obtained for the pincer complex
catalyzed condensation of 2 with aldehydes.13,14 Furthermore,
the selectivity achieved with 1a is almost as high (88%) as in the
gold-ferrocenyl complex catalyzed reaction by Lin et al.32,33 On
the other hand, the stereoselectivity of the 1a catalyzed process
(dr syn/anti = 1:1) is clearly inferior to the gold catalyzed (dr syn/
anti = 94:6) asymmetric catalysis.
Changing the chirality of the biphenantrol-based catalyst leads
to change of the enatioselectivity of the condensation reaction.
Accordingly, using 1a as catalyst the major enantiomer is (2S,3S)-
4-syn (entry 1); however, when 1b is used under identical reaction
conditions the major enantiomer is (2R,3R)-4-syn (entry 4) with
slightly lower ee (72%). Interestingly, change of the solvent from
2. Results and discussion
The condensation reaction of 2 and 3 is very efficiently cata-
lyzed by complexes 1a–f (Fig. 2, Table 1) using THF and other
ether-based solvents (such as dioxane and diglyme). According to
31P NMR spectroscopy of the final reaction mixtures, the chiral pal-
ladium catalysts remained completely unchanged in the reactions
studied. This suggests that 1a–f can be completely recycled after
the completed catalytic processes. The formed imidazoline prod-
ucts 4 can be readily hydrolyzed to the corresponding
a,b-diami-
noacid derivatives 5. As the partial hydrolysis of 4 can take place
under the HPLC analysis of the products, we performed a complete
H
N
H
N
MeOOC
Ar
MeOOC
O
O
MeOOC
Ar
MeOOC
Ar
N
N
+
+
+
N
N
Ar
NHTs
(2R,3R)- syn
NHTs
(2S,3S)- syn
Ts
Ts
5
COOMe
NTs
5
4
(2S,3S)- syn
- 4
(2R,3R) syn
1
[ ]cat.
+
HCl/THF
NC
Ar
H
H
2
3
MeOOC
N
MeOOC
N
O
O
MeOOC
Ar
N
MeOOC
Ar
N
+
N
N
Ar
Ar
NHTs
NHTs
Ts
Ts
4
4
(2S,3R)- anti
(2R,3S)- anti
5
5
(2R,3S)- anti
(2S,3R)- anti
Figure 2. Direct products (4) of the condensation of 2 and 3 and the corresponding a,b-diaminoacid derivatives 5 obtained by hydrolysis.

J. Aydin et al. / Tetrahedron: Asymmetry 19 (2008) 1867–1870
1869
Table 1
Product distribution in palladium-pincer complex (1) catalyzed condensation of 2 and 3a
Entry
Catalyst
Imine
Product 4
Product 5
Yield 4b
Syn/antic
ee synd
ee antid
H
N
MeOOC
O
MeOOC
N
NTs
1
1a
98
1:1
86 (2S,3S)
28 (2R,3S)
N
Ph
Ph
3a
Ph
NHTs
5a
Ts
4a
2e
3f
4
1b
1b
1b
1b
1c
1d
1e
1f
3a
3a
3a
3a
3a
3a
3a
3a
4a
4a
4a
4a
4a
4a
4a
4a
5a
5a
5a
5a
5a
5a
5a
5a
98
98
98
98
98
98
98
98
1:4
1:1
1:1
1:2.5
1:4
1:2
25 (2R,3R)
73 (2R,3R)
72 (2R,3R)
20 (2S,3S)
37 (2S,3S)
10 (2S,3S)
44 (2R,3R)
14 (2R,3R)
75 (2S,3R)
68 (2S,3R)
18 (2S,3R)
62 (2R,3S)
64 (2R,3S)
46 (2R,3S)
12 (2S,3R)
46 (2S,3R)
5e
6
7
8
9
1:2
1:4
H
N
MeOOC
O
NTs
MeOOC
N
10
1e
98
1:2
35 (2R,3R)
7 (2S,3R)
N
3b
NHTs
5b
Ts
4b
F
F
F
a
Unless stated otherwise, 3a–b (0.2 mmol), 2 (0.2 mmol) and the corresponding catalyst 1a–f (1 mol %) were reacted in THF at 20 °C for 18 h.
b
c
d
e
f
Isolated yield [%].
Diastereomer ratio determined by 1H NMR.
Enatiomeric excess [%].
Diglyme was used as solvent.
Dioxane was used as solvent.
THF to dioxane (entry 3) leads to only minor change of the enanti-
oselectivity of the formation of the syn diastereomer; however, the
ee of the anti-diastereomer is increased to 68% (c.f. entries 3 and 4).
The enantioselectivity for the formation of the anti-isomer can
be further increased to 75% (entry 2), when diglyme is employed
as the solvent instead of THF or dioxane. Gratifyingly, the diastereo-
selectivity (dr syn/anti = 1:4) of the condensation reaction could
also be improved upon by using diglyme as a solvent (c.f. entries
2 and 4). Thus application of 1b as catalyst in diglyme can be con-
sidered as a complement to the gold-ferrocenyl complex catalyzed
reaction, which is syn-selective (dr syn/anti = 94:6).32 Complex 1a
performed similarly to 1b in diglyme by increasing the anti selec-
tivity and the ee of the anti form; however, the extent of the effect
was less pronounced (c.f. entries 1 and 5).
3. Conclusions
Palladium-pincer complexes based on BINOL and biphenantrol-
based ligands 1 are efficient catalyst for the condensation of iso-
cyanoacetate 2 and sulfonimines 3 in up to 86% ee. The reactions
proceed with higher enantioselectivity, when the biphenantrol
1a–b based systems are employed instead of BINOL derivatives.
For BINOL based complexes the selectivity is higher in the presence
of bulky SPh substituents 1c at the
c-position of the BINOL ring
than with SMe substituent 1d–e or with the parent system 1f.
The catalytic condensation reaction shows a tendency for the
selective formation of the anti diastereomer, and thus it may com-
plement the gold-ferrocenyl complex catalyzed method published
by Lin et al.32
The enantioselectivity with BINOL-based pincer complexes 1c–f
proved to be lower than with the biphenantrol analogues (1a–b).
However, in the presence of bulky thioether substituents at the
4. Experimental
c
-position of the BINOL unit, the enantioselectivity is clearly higher
All experiments were conducted under an argon atmosphere
employing standard manifold techniques. The enantiomerically
pure chiral palladium-pincer complexes 1a–f were prepared from
enantiopure BINOL and biphenantrol derivatives using our previ-
ously published9,10 procedures. All solvents used in the reactions
were freshly distilled prior to use. HPLC chromatograms were ob-
tained using an AcquityTM Ultra Performance LC and Daicel Chiracel
OD-H or AD-H columns with the parameters given in the experi-
mental part. For column chromatography, Merck Silica Gel 60
(230–400 mesh) was used.
than with the parent system 1f. Accordingly, using the SPh deriva-
tive 1c (entry 6) the enantioselectivity is higher (64%) than with
the SMe derivatives (entries 7 and 8) 1d or 1e (up to 46%) or with
BINOL derivative (entry 8) 1f (46%). Interestingly, these reactions
are also selective for the formation of the anti-product (dr syn/anti
up to 1:4).
We also performed limited studies with substituted sulfonim-
ine derivatives, such as 3b. The para-fluoro substitution of the sul-
fonimine led to an increase of the reactivity in the condensation
process, but a decrease in the diastereo- and enatioselectivity
when compared to 3a.
4.1. General procedure for the synthesis of 2-imidazoline
derivatives 4a–b and a,b-diaminoacid derivatives 5a–b
As can be seen from the above studies, the enantio- and diaste-
reoselectivity of the coupling reaction are strongly dependent on
the structure of the pincer complex catalysts and also modified
by solvent effects. Our previous mechanistic studies28 indicate that
the stereo- and enantioselectivity of the process are probably
determined in the same reaction step. However, an exact descrip-
tion of the steric and electronic effects determining the selectivity
can only be given on the basis of in depth DFT modeling studies,
which are currently in progress.
A mixture of N-sulfonylimine 3a–b (0.2 mmol), methyl iso-
cyanoacetate 3 (0.02 g, 0.2 mmol), and the corresponding catalyst
1a–f (0.002 mmol, 1 mol %) was stirred in THF (1.0 ml) at 20 °C
for 18 h. After filtration through a thin pad of Celite, the solvent
was removed to yield a syn/anti mixture of 2-imidazoline deriva-
tive 4a–b. The syn/anti ratio was determined from crude 1H NMR

1870
J. Aydin et al. / Tetrahedron: Asymmetry 19 (2008) 1867–1870
spectra. The NMR data obtained for 4a–b are identical with the lit-
erature values.28 For the determination of the ee values, 2-imidaz-
oline derivatives 4a–b were hydrolyzed to 5a–b by stirring a
mixture of water (0.022 g, 1.4 mmol), HCl (37%, 0.004 g,
References
1. The Chemistry of Pincer Compounds; Morales-Morales, D., Jensen, C. M., Eds.;
Elsevier: Amsterdam, 2007.
2. Albrecht, M.; Koten, G. v. Angew. Chem., Int. Ed. 2001, 3750.
3. Dupont, J.; Consorti, C. S.; Spencer, J. Chem. Rev. 2005, 105, 2527.
4. Boom, M. E. v. d.; Milstein, D. Chem. Rev. 2003, 103, 1759.
5. Szabó, K. J. Synlett 2006, 811.
0.11 mmol), THF (1.5 ml), and 2-imidazoline
4 (0.195 mmol)
for 3 h at 20 °C. Thereafter, the crude mixture was purified by
chromatography using CH2Cl2/CHCl3/MeOH (50:50:1) as eluent to
yield 5a–b.
6. Singleton, J. T. Tetrahedron 2003, 59, 1837.
7. Beletskaya, I. P.; Cheprakov, A. V. J. Organomet. Chem. 2004, 689, 4055.
8. Benito-Garagorri, D.; Kirchner, K. Acc. Chem. Res. 2008, 41, 201.
9. Aydin, J.; Kumar, K. S.; Sayah, M. J.; Wallner, O. A.; Szabó, K. J. J. Org. Chem. 2007,
72, 4689.
10. Wallner, O. A.; Olsson, V. J.; Eriksson, L.; Szabó, K. J. Inorg. Chim. Acta 2006, 359,
1767.
4.2. Methyl 2-formylamino-3-[(4-methylphenyl)sulfonyl]-
amino-3-phenylpropanoate 5a
11. Baber, R. A.; Bedford, R. B.; Betham, M.; Blake, M. E.; Coles, S. J.; Haddow, M. F.;
Hurthouse, M. B.; Orpen, A. G.; Pilarski, L. T.; Pringle, P. G.; Wingad, R. L. Chem.
Commun. 2006, 3880.
12. Gorla, F.; Venanzi, L. M. Organometallics 1994, 13, 43.
13. Longmire, J. M.; Zhang, X.; Shang, M. Organometallics 1998, 17, 4374.
14. Motoyama, Y.; Kawakami, H.; Shimozono, K.; Aoki, K.; Nishiyama, H.
Organometallics 2002, 21, 3408.
15. Stark, M. A.; Richards, C. J. Tetrahedron Lett. 1997, 38, 5881.
16. Gosiewska, S.; Veld, M. H. i.; Pater, J. J. M. d.; Bruijnincx, P. C. A.; Lutz, M.; Spek,
A. L.; Koten, G. v.; Gebbink, R. J. M. K. Tetrahedron: Asymmetry 2006, 17, 674.
17. Nishiyama, H.; Shiomi, T.; Tsuchiya, Y.; Matsuda, I. J. Am. Chem. Soc. 2005, 127,
6972.
This compound was obtained by the above general procedure.
The NMR data obtained for 5a are identical with the literature val-
ues.28 The enantiomeric excess of 5a was determined by chiral
phase HPLC (Daicel Chiralcel OJ-H, hexane/iPrOH 85:15, flow rate
1.0 ml/min). The retention times are the following: syn diastereo-
mer tr (2R,3R) = 33 min; tr (2S,3S) = 62 min. anti diastereomer tr
(2S,3R) = 16 min; tr (2R,3S) = 23 min. Specific rotation: ½a D20
¼ þ32
ꢀ
(c 1.1, THF); corresponding to a syn:anti ratio of 1.6:1 for which
the enantiomeric excess was syn 86% and anti 28%. The absolute
configuration of the major product was determined by comparison
of the observed specific rotation to literature data.32
18. Takenaka, K.; Uozumi, Y. Org. Lett. 2004, 6, 1833.
19. Takenaka, K.; Minakawa, M.; Uozumi, Y. J. Am. Chem. Soc. 2005, 127, 12273.
20. Stark, M. A.; Jones, G.; Richards, C. J. Organometallics 2000, 19, 1282.
21. Fossey, J. S.; Richards, C. J. Organometallics 2004, 23, 367.
22. Solin, N.; Kjellgren, J.; Szabó, K. J. Angew. Chem., Int. Ed. 2003, 42, 3656.
23. Solin, N.; Kjellgren, J.; Szabó, K. J. J. Am. Chem. Soc. 2004, 126, 7026.
24. Solin, N.; Wallner, O. A.; Szabó, K. J. Org. Lett. 2005, 7, 689.
25. Gagliardo, M.; Selander, N.; Mehendale, N. C.; Koten, G. v.; Klein-Gebbink, R. J.
M.; Szabó, K. J. Chem. Eur. J. 2008, 14, 4800.
4.3. Methyl-3-(4-fluorophenyl)-2-formylamino-3-[(4-methyl-
phenyl)sulfonyl]amino-propanoate 5b
26. Wallner, O. A.; Szabó, K. J. Chem. Eur. J. 2006, 12, 6976.
27. Wallner, O. A.; Szabó, K. J. Org. Lett. 2004, 6, 1829.
28. Aydin, J.; Kumar, K. S.; Eriksson, L.; Szabó, K. J. Adv. Synth. Catal. 2007, 349,
2585.
29. Viso, A.; Pradilla, R. F. d. l.; Garcia, A.; Flores, A. Chem. Rev. 2005, 105, 3167.
30. Ding, H.; Friestad, G. K. Synthesis 2005, 2815.
31. Hayashi, T.; Kishi, E.; Soloshonok, V. A.; Uozumi, Y. Tetrahedron Lett. 1996, 37,
4969.
32. Zhou, X.-T.; Lin, Y.-R.; Dai, L.-X.; Sun, J.; Xia, L.-J.; Tang, M.-H. J. Org. Chem. 1999,
64, 1331.
This compound was obtained by the above general procedure.
The NMR data obtained for 5b are identical with the literature val-
ues.28 The enantiomeric excess of the syn diastereomer of 5b was
determined by chiral phase HPLC (Daicel Chiralcel AD-H, hexane/
iPrOH 70:30, flow rate 0.7 ml/min). The retention times are the fol-
lowing: syn enantiomers tr (2S,3S) = 26 min; tr (2R,3R) = 30.7 min.
The enantiomeric excess of the anti diastereomer of 5b was deter-
mined by chiral phase HPLC (Daicel Chiralcel OD-H, hexane/iPrOH
70:30, flow rate 1.0 ml/min). The retention times are the following:
anti enantiomers tr (2R,3S) = 32.7 min; tr (2S,3R) = 41.9 min.
33. Zhou, X.-T.; Lin, Y.-R.; Dai, L.-X. Tetrahedron: Asymmetry 1999, 10, 855.
34. Lin, Y.-R.; Zhou, X.-T.; Dai, L.-X.; Sun, J. J. Org. Chem. 1997, 62, 1799.
35. Benito-Garagorri, D.; Bocokic, V.; Kirchner, K. Tetrahedron Lett. 2006, 47, 8641.