New enantiopure NHCs derived from camphor

Article abstract of DOI:10.1039/b911476a

A new class of enantiopure carbene precursors based on cheap camphor has been developed, and a restricted rotation of one N-substituent due to the C-10 methyl group of the camphor skeleton has been found; in situ prepared corresponding carbenes revealed t

Full text of DOI:10.1039/b911476a

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New enantiopure NHCs derived from camphorw
´ ´
Peddiahgari Vasu Govardhana Reddy, Sobia Tabassum, Amelie Blanrue and Rene Wilhelm*
Received (in Cambridge, UK) 11th June 2009, Accepted 3rd August 2009
First published as an Advance Article on the web 18th August 2009
DOI: 10.1039/b911476a
A new class of enantiopure carbene precursors based on cheap
camphor has been developed, and a restricted rotation of one
N-substituent due to the C-10 methyl group of the camphor
skeleton has been found; in situ prepared corresponding carbenes
revealed the same behaviour.
A restricted rotation in salts 5b and 5c was shown to
be present by the 1H-NMR signal of the C(2)–H bond.
Compounds 5b and 5c are shifted upfield to 4.79 and
5.89 ppm, respectively. On the other hand the signals of salts
5a and 7 are at 8.47 and 8.94 ppm. The large upfield shift of the
protons of 5b and 5c is due to the fact that they are in close
proximity to the middle of the arene rings next to the C-10
methyl group of the camphor skeleton. Unfortunately it was
not possible to acquire an X-ray structure of the salts to see the
conformation in the solid state.
NHCs (N-heterocyclic carbenes) have recently emerged as a
new important family of ligands in various applications in
organometallic chemistry and as organocatalysts.1 As the next
step several enantiopure NHC precursors have been prepared
and applied in many transformations.1,2 However, although
camphor is a cheap desirable starting material from the chiral
pool, only a few carbene precursors such as 12a or 22b have
been prepared and successfully used so far as ligands or as
organocatalysts in asymmetric catalysis.
In order to show that the carbenes are formed from the
salts, 5a was treated with KHMDS in toluene for 30 min as an
example. Thereafter, the carbene was trapped by the addition
of CS2 and after 10 min the product 8 was isolated in 37%
yield as a red solid (Scheme 2).
Due to the absence of the C(2)-proton in the corresponding
carbenes, it would be difficult to verify the suggested
conformation of the carbenes by NMR measurements as it
was done for the precursor salts. Hence, it was decided to
support this assumption by using the carbenes as Lewis base
catalysts in a formal [2+2] reaction of ketenes and aldehydes.
This enantioselective reaction5 is a straightforward way to
obtain b-lactones from aldehydes and ketenes (Scheme 3).
Optically active b-lactones are important synthons.6 Recently,
Ye et al.5j applied an enantiopure triazolium salt based carbene
in the [2+2] reaction of electron deficient 2-oxoaldehydes
with alkyl(aryl)ketenes and diarylketenes, while Fu and
Wilson catalyzed the [2+2] reaction of benzaldehydes with
dialkylketenes with an enantiopure planar DMAP ferrocene
derivative.5f
C1 symmetric chiral camphor-based carbene precursors of
type 5 have not been reported so far (Scheme 1). The NCN
unit would be embedded in a rigid bicyclic system being part of
a six and seven-membered ring. Hence, the corresponding
carbene possesses a higher basicity than carbenes with
imidazolium and imidazolinium moieties.3 In addition, the
free rotation of a substituent next to the C-10 methyl group of
the camphor skeleton could be limited due to steric hindrance,
which could provide an asymmetric differentiation in a
catalytic reaction step. The diamine 3 can be prepared readily
via a Schmidt reaction from (+)-camphoric acid,4 a cheap
chiral building block derived from camphor.
In such a reaction with carbenes derived from 5a–c the
following mechanism would be reasonable as shown in
First, the desired carbene precursors 5a–c were prepared as
shown in Scheme 1 via standard transformations from
diamine 3 and MesCH2Cl, benzaldehyde or anthracene-9-
carbaldehyde. In addition, salt 7 was prepared according to
Scheme 1 by applying only 1 equiv. of 2,4,6-trimethyl benzyl
chloride and amine 6 was isolated in 69% yield due to the
larger steric hindrance on one of the amine function in 3.
Institute of Organic Chemistry, Clausthal University of Technology,
Germany. E-mail: rene.wilhelm@tu-clausthal.de;
Fax: +49 5323 722834; Tel: +49 5323 723886
w Electronic supplementary information (ESI) available: Full
experimental procedures, spectra and HPLC runs. See DOI:
10.1039/b911476a
Scheme 1 Preparation of NHC precursors.
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Table 1 Different NHC salts in the [2+2] reaction with benzaldehydea
Entry
Salt
T/1C
Yield (%)
ee (%)
1
2
3
4
5
6
5b
5b
5b
5c
5a
7
ꢁ20
ꢁ40
ꢁ60
ꢁ60
ꢁ60
ꢁ60
72
70
75
69
32
21
51
86
92
73
19
0
Scheme 2 Trapping the carbene with CS2.
a
With ketene 9, benzaldehyde, 10 mol% salt and 8 mol% KHMDS in
toluene.
with a lower ee of 73% (Table 1, Entry 4). The less hindered
salt 5a resulted in a yield of 32% and an ee of 19% (Table 1,
Entry 5). Finally, salt 7 gave, as expected, racemic product in
21% yield (Table 1, Entry 8). In all cases the
(S)-b-lactone was the major enantiomer.
With the optimized conditions in hand, different ketenes
and aldehydes were applied in the reaction with salt 5b as
catalyst precursor as shown in Scheme 3. The results are
summarized in Table 2. The reactions were carried out at
ꢁ78 1C, although it did not have an influence on the result
compared to ꢁ60 1C (Table 2, Entry 1). Different aldehydes
were used with ketene 9 and it was found that electron
deficient and electron rich aldehydes gave up to 91% ee
(Table 2, Entries 2–5). Next, a solution of cyclopentylmethyl
ketene in toluene8 with benzaldehyde gave the product in 99%
yield. Both diastereomers had nearly the same ee of 80%
(Table 2, Entry 6).
Scheme 3 [2+2] Reaction of ketenes with aldehydes.
Scheme 4. The carbene attacks the ketene. Since the ketene is
shielded from one side, the aldehyde can only approach from
the side opposite of the C-10 methyl group of the camphor
skeleton. After the new bond is formed the carbene is released
with the formation of an (S)-b-lactone. It is reasonable to
assume that in intermediate 12 the NCN unit and the enolate
are not in one plane but perpendicular to each other due to
steric hindrance in analogy to the CS2 adduct 8 and other
literature reported analogues.7
First, the reaction of ketene 9 (R1,R2= –(CH2)6–) and
benzaldehyde was chosen in order to screen the different
carbenes and to optimize conditions (Scheme 3). The results
are summarized in Table 1. The carbenes were generated from
the different salts by treating them with KHMDS at ꢁ60 1C
and warming up the solution to rt to give a yellow solution.
Thereafter, the reaction was cooled down to ꢁ20 1C and
benzaldehyde was added followed by the addition of 1.5 equiv.
of ketene.
In one example the reaction was worked up with a 2% aq.
solution of NH4BF4 and the regenerated salt 5b could be
recovered during column chromatography in 81% yield by
changing the mobile phase after the isolation of the product to
a 5% methanol–CH2Cl2 mobile phase.
In summary, a novel class of enantiopure carbene precursors
based on camphoric acid has been prepared. The generated
highly nucleophilic carbenes were able to catalyze a formal
[2+2] reaction of ketenes with aldehydes. In these new
carbenes the small C-10 methyl group is responsible for the
chirality transfer. Good yield and significant ee were achieved,
which was for product 11 (Table 2, Entry 1) an increase of
10% compared to the so far best reported ee in the literature.5f
Current work within the group is exploring these new carbenes
and further analogues as ligands in metal catalyzed reactions.
This work was supported by the DFG. Financial support by
Fonds der Chemischen Industrie is gratefully acknowledged.
P. V. G. R. gratefully acknowledges a fellowship from the
With salt 5b and KHMDS in dry toluene the desired product
was formed in 72% yield and 51% ee (Table 1, Entry 1). By
lowering the temperature it was possible to increase the ee to
92%, while the yield remained the same (Table 1, Entries 2 and
3). The reaction was repeated under the same conditions with
the other salts. Salt 5c gave nearly the same yield as 5b, but
Table 2 Salt 5b with different ketenes and aldehydesa
Entry
Ketene
Aldehyde
Yield (%)
ee (%)
1
2
3
4
–(CH2)6–
–(CH2)6–
–(CH2)6–
–(CH2)6–
–(CH2)6–
C5H9, Me
Ph
76
72
82
73
80
99
92
91
91
80
4-F-C6H4
4-Me-C6H4
2-Me-C6H4
4-Cl-C6H4
Ph
5
81
82, 79
6b
a
b
10 mol% salt 5b and 8 mol% KHMDS at ꢁ78 1C. Ketene
prepared according to ref. 8 as a 0.24 M solution in toluene,
trans : cis ratio 1 : 2.
Scheme 4 Possible mechanism.
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Alexander von Humboldt foundation and S. T. from the
J. M. Lassaletta, J. Am. Chem. Soc., 2004, 126, 13242;
(q) V. Jureık, M. Gilani and R. Wilhelm, Eur. J. Org. Chem.,
´
DAAD/HEC. Dr Drager from the University of Hannover
¨
is acknowledged for HRMS measurements.
2006, 5103; (r) M. Gilani and R. Wilhelm, Tetrahedron: Asymmetry,
2008, 19, 2346; (s) A. O. Larsen, W. Leu, C. N. Oberhuber,
J. E. Campbell and A. H. Hoveyda, J. Am. Chem. Soc., 2004,
126, 11130; (t) P. L. Arnold, A. C. Scarisbriick, A. J. Blake and
C. Wilson, Chem. Commun., 2001, 2340; (u) D. Martin, S. Kehrli,
M. dAugustin, H. Clarvier, M. Mauduit and A. Alexakis, J. Am.
Chem. Soc., 2006, 128, 8416.
Notes and references
1 For recent reviews see: (a) W. A. Herrmann, Angew. Chem., Int. Ed.,
2002, 41, 1290; (b) D. Bourissou, O. Guerret, F. P. Gabbai and
G. Bertrand, Chem. Rev., 2000, 100, 39; (c) M. C. Perry and
3 (a) A. M. Magill, K. J. Cavell and B. F. Yates, J. Am. Chem. Soc.,
2004, 126, 8717; (b) M. Iglesias, D. J. Beetstra, J. C. Knight, L.-L. Ooi,
A. Stasch, S. Coles, L. Male, M. B. Hursthouse, K. J. Cavell,
A. Dervisi and I. A. Falis, Organometallics, 2008, 27, 3279.
4 D. Jaramillo, D. P. Buck, J. G. Collins, R. R. Fenton,
F. H. Stootman, N. J. Wheate and J. R. Aldrich-Wright, Eur. J.
Inorg. Chem., 2006, 839.
5 For examples see: (a) H. Wynberg and E. G. J. Staring, J. Am.
Chem. Soc., 1982, 104, 166; (b) G. S. Cortez, R. L. Tennyson and
D. Romo, J. Am. Chem. Soc., 2001, 123, 7945; (c) S. G. Nelson,
C. Zhu and X. Shen, J. Am. Chem. Soc., 2004, 126, 14; (d) C. Zhu,
X. Shen and S. G. Nelson, J. Am. Chem. Soc., 2004, 126, 5352;
(e) M. A. Calter, O. A. Tretyak and C. Flascheriem, Org. Lett.,
2005, 7, 1809; (f) J. E. Wilson and G. C. Fu, Angew. Chem., Int. Ed.,
2004, 43, 6358; (g) V. Gnanadesikan and E. J. Corey, Org. Lett.,
2006, 8, 4943; (h) D. A. Evans and J. M. Janey, Org. Lett., 2001, 3,
2125; (i) D. Borrmann and R. Wegler, Chem. Ber., 1967, 100, 1575;
(j) L. He, H. Lv, Y.-R. Zhang and S. Ye, J. Org. Chem., 2008, 73,
8101.
K. Burgess, Tetrahedron: Asymmetry, 2003, 14, 951; (d) V. Cesar,
´
S. Bellemin-Laponaz and L. H. Gade, Chem. Soc. Rev., 2004, 33,
619; (e) E. A. B. Kantchev, C. J. O0Brien and M. G. Organ, Angew.
Chem., Int. Ed., 2007, 46, 2768; (f) N-Heterocyclic Carbenes in
Synthesis, ed. S. P. Nolan, Wiley-VCH, Weinheim, 2006. For recent
reviews as organocatalysts see: (g) K. Zeitler, Angew. Chem., Int.
Ed., 2005, 44, 7506; (h) M. Christmann, Angew. Chem., Int. Ed.,
2005, 44, 2632; (i) D. Enders and T. Balensiefer, Acc. Chem. Res.,
2004, 37, 534; (j) N. Marion, S. Diez-Gonzalez and S. P. Nolan,
Angew. Chem., Int. Ed., 2007, 46, 2988; (k) D. Enders, O. Niemeier
and A. Henseler, Chem. Rev., 2007, 107, 5606.
2 For a few examples see: (a) S. Lee and J. F. Hartwig, J. Org. Chem.,
2001, 66, 3402; (b) Y. Li, Z. Feng and S.-L. You, Chem. Commun.,
2008, 2263; (c) D. Baskakov, W. A. Herrmann, E. Herdtweck and
S. D. Hoffmann, Organometallics, 2007, 26, 626; (d) Y. Matsuoka,
Y. Ishida, D. Sasaki and K. Saigo, Chem.–Eur. J., 2008, 14, 9215;
(e) R. L. Knight and F. J. Leeper, J. Chem. Soc., Perkin Trans. 1,
1998, 1891; (f) M. S. Kerr and T. Rovis, Synlett, 2003, 1934;
(g) F. Glorius, R. Altenhoff, R. Goddard and C. Lehmann, Chem.
Commun., 2002, 2704; (h) J. R. Struble, J. Kaeobamrung and
J. W. Bode, Org. Lett., 2008, 10, 957; (i) J. Pesch, K. Harms and
T. Bach, Eur. J. Org. Chem., 2004, 2025; (j) T. J. Seiders,
D. W. Ward and R. H. Grubbs, Org. Lett., 2001, 3, 3225;
(k) Y. Ma, C. Song, C. Ma, Z. Sun, Q. Chai and M. B. Andrus,
6 (a) Y. Wang, R. L. Tennyson and D. Romo, Heterocycles, 2004, 64,
605; (b) C. Schneider, Angew. Chem., Int. Ed., 2002, 41, 744.
7 (a) W. Kirmse, Eur. J. Org. Chem., 2005, 237; (b) J. Nakayama,
J. Synth. Org. Chem., Jpn., 2002, 60, 106; (c) J. Nakayama, Sulfur
Lett., 1993, 15, 239; (d) L. Delaude, Eur. J. Inorg. Chem., 2009,
1681.
Angew. Chem., Int. Ed., 2003, 42, 5871; (l) A. Furstner, M. Alcarazo,
¨
8 A solution of 0.35 M ketene in toluene was prepared by stirring
1 equiv. of 2-cyclopentylpropanoyl chloride and 1 equiv. DABCO in
toluene at 80 1C for 3 h. After cooling down to rt, the ketene was
condensed with the toluene under high vacuum in a Schlenk tube
cooled with liquid nitrogen. The concentration was calculated via
the addition of n-PrNH2 to a solution.
H. Krause and C. W. Lehmann, J. Am. Chem. Soc., 2007, 129,
12676; (m) Y. Matsumoto and K. Tomioka, Tetrahedron Lett.,
2006, 47, 5843; (n) D. Enders and U. Kallfass, Angew. Chem., Int.
Ed., 2002, 41, 1743; (o) Y.-R. Zhang, L. He, X. Wu, P.-L. Shao and
S. Ye, Org. Lett., 2008, 10, 277; (p) M. Alcarazo, S. J. Roseblade,
E. Alonso, R. Fernandez, E. Alvarez, F. J. Lahoz and
´
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5912 | Chem. Commun., 2009, 5910–5912