One-pot synthesis of β-amino acid derivatives via addition of bis(O-silyl) ketene acetals on iminium salts

Article abstract of DOI:10.1016/j.tetlet.2007.09.119

We report here our findings on a new and highly efficient strategy for the synthesis of β-amino acids involving the addition of bis(O-silyl) ketene acetals on Mannich type iminium electrophiles.

Full text of DOI:10.1016/j.tetlet.2007.09.119

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 8277–8280
One-pot synthesis of b-amino acid derivatives via addition of
bis(O-silyl) ketene acetals on iminium salts
a,c
b
a
Roba Moumne, Bernard Denise,b,z Andree Parlier, Solange Lavielle,
´
´
Henri Rudlerb and Philippe Karoyana,*
aUniversite´ Pierre et Marie Curie-Paris 6, FR2769, CNRS, UMR 7613, Case Courrier 45, 4, Place Jussieu, 75252,
Paris Cedex 05, France
bUniversite´ Pierre et Marie Curie-Paris 6, FR2769, CNRS, UMR 7611, Case Courrier 181, 4, Place Jussieu, 75252,
Paris Cedex 05, France
cSenn Chemicals AG, Industriestrasse 12, PO BOX 267, CH-815 Dielsdorf, Switzerland
Received 10 July 2007; revised 18 September 2007; accepted 19 September 2007
Available online 21 September 2007
The authors wish to dedicate this work to the memory of their friend Bernard Denise
Abstract—We report here our findings on a new and highly efficient strategy for the synthesis of b-amino acids involving the addi-
tion of bis(O-silyl) ketene acetals on Mannich type iminium electrophiles.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Knochel and co-workers reported the reaction of
preformed dibenzylidene iminium trifluoroacetate salt,
obtained from the corresponding N,N,N00,N00-tetrabenz-
yl aminal, with organozinc and magnesium derivatives.6
We have recently shown that this reaction can be
extended to zinc-enolates in a Reformatsky type reac-
tion leading to b2-amino acids bearing proteinogenic
amino acids side chains7 (Scheme 1).
The Mannich reaction between a carbonyl compound
and an in situ generated imine is a classical method
for the preparation of b-amino ketones and represents
one of the most important basic reaction types in organ-
ic chemistry.1 It has also been extended to the prepara-
tion of b-amino acids2 and b-lactams by the use of
preformed enol synthetic equivalents.3 However, this
reaction is difficult to apply to the synthesis of com-
pounds bearing no substituent in position 3. This is
mainly due to the difficult access to a stable formyl imine
equivalent. Many reagents were reported in the litera-
ture in order to overcome this limitation, for instance,
the use of precursors such as N,O-acetals or aminals,
which lead to formyl iminium ion by activation with a
strong Lewis acid. However, these unstable reagents
are difficult to prepare and to handle. Plus, their poor
reactivity leads to low yields of aminomethylation.4 Fi-
nally, the protecting groups of these aminomethylating
agents have to be removed under harsh conditions.5
In the reported strategy, zinc-enolates were generated
after nitric oxidation and subsequent esterification of
a-amino acids, and reacted with dibenzylidene iminium
trifluoroacetate, leading after classical deprotection
steps to b2-amino acids. Enantiomerically pure Boc-b2-
homoleucine was obtained in a good overall yield
starting from inexpensive (L)-leucine and using
Oppolzer’s sultam as the chiral auxiliary. However, if
excellent selectivity was obtained in that case, further
(i) Zn
+
(i) Nitric oxidation
(ii) esterifcation
(ii)
CF3CO2
NBn2
-
H N CO H
Br CO R'
2
CO2R'
2
2
Bn N
2
Keywords: b-Amino acids; Bis(O-silyl) ketene acetals; Mannich type
R
R
R
2
iminium electrophiles.
α-amino acids
β -amino acids
*
Corresponding author. Tel.: +33 1 44 27 38 42; fax: +33 1 44 27 71
50; e-mail: karoyan@ccr.jussieu.fr
Scheme 1. b2-Amino acids synthesis by homologation of a-amino
z Deceased November 14th, 2005.
acids.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.119

8278
R. Moumne´ et al. / Tetrahedron Letters 48 (2007) 8277–8280
investigations demonstrated that unsatisfying diastere-
oselectivities were obtained for derivatives bearing side
chains with poor steric hindrance. On a formal point
of view, the homologation route we have developed
could be considered as the aminomethylation of an ester
enolate, as first reported by Evans et al.8 and Oppolzer
et al.9 and then applied by Lelais and Seebach to the
preparation of b2-amino acids.10 However, the ami-
nomethylating reagents used in the previously described
syntheses present severe limitations, which have ham-
pered up-scaling. We hypothesized that the addition of
dibenzylidene iminium trifluoroacetate onto ester eno-
lates might circumvent all these restrictions. However,
all the attempts with ester enolates generated by various
bases have failed. Silyl enol ether derivatives have been
reported as an alternative to ester enolates; they have
been used for example in Mannich type reactions using
preformed or in situ generated methylene iminium
salts.11 In order to get a general methodology, we re-
ported recently that the in situ generated iminium ion
can also be introduced on chiral silyl ketene N,O-ace-
tals12 (Scheme 2).
explore their potential as nucleophiles in aminomethyla-
tion reactions with formyl iminium ion derivatives. If
successful, such a reaction would lead to b2-amino acid
derivatives by a mononucleophilic addition reaction to
iminium salts. Herein, we describe our preliminary
results on the reactivity of bis(O-trimethylsilyl) ketene
acetals toward various iminium electrophiles, results
which led not only to b2-amino acid derivatives, but also
depending on the structure of the starting ketene acetals
to a,b-unsaturated d-amino acid derivatives.
2. Results and discussion
In a preliminary study, we have shown that in the pres-
ence of ethylchloroformate, imine 2 is able to add to
bis(O-trimethylsilyl) ketene acetals, leading to a new
product, obtained in 40% yield as a white solid, mp
130 °C. According to NMR data, its structure is consis-
tent with the disubstituted b-amino acid 3a16 (Scheme
3).
The same behavior was obtained with the monosubsti-
tuted ketene acetal 1b, which led to a 3:1 mixture of dia-
stereomeric acids 3b.
This methodology allowed us to prepare a wide range of
optically pure b2-amino acids bearing alkyl or function-
alized side chains, orthogonally protected for peptide
synthesis. We have shown that the N,N,N00,N00-tetrabenz-
yl aminal can be very easily prepared on a 100 g scale,
isolated and stored as a highly stable crystalline com-
pound. Consequently, it represents a very convenient
precursor for aminomethylating reagent. One possible
improvement of the reported synthesis would be the
reduction of the number of steps, for instance, by reduc-
ing the deprotection procedures. Among silyl enol deriv-
atives, bis(O-silyl) ketene acetals constitute an original
class of nucleophiles, as they can behave as 1,3-carbon,
oxygen dinucleophiles resulting from the successive
cleavage of both oxygen–silicon bonds. Kunz and
co-workers have reported the reaction between bis(O-
silyl) ketene acetals and N-galactosyl-aldimines in the
We assumed that the imine is first activated by the addi-
tion of the ethylcarbonyl group on the nitrogen atom
leading to an iminium ion, which reacts then with the
ketene acetal. Since the crucial intermediate in these
transformations is an iminium salt, the scope of this
methodology was analyzed by reacting various ketene
acetals with different iminium salts. Thus, compounds
4a–c were generated from the corresponding aminals
in the presence of acetyl chloride or trifluoroacetic anhy-
dride. They were reacted with different bis (O-trimethyl-
silyl) ketene acetals after isolation (4a) or in situ
generated in a one-pot procedure (4b and 4c) avoiding
difficult handling of the iminiums and thus leading to
better yields in these cases17 (Scheme 4, Table 1).
presence of zinc chloride leading to disubstituted b2,3
-
amino acid derivatives in high yields and diastereoselec-
tivity.13 However, the addition on non-substituted Schiff
bases, (i.e., formylimine derivatives that would lead to
b2-amino esters) was not reported. Rudler and co-work-
ers have recently shown that the addition of bis (O-tri-
methylsilyl) ketene acetals to pyridines and their
derivatives, in situ activated with ethylchloroformate,
could occur both at the a- and b-carbon atom with re-
spect to the nitrogen atom, that is, on a formal point
of view, at the carbon of an iminium.14 Simultaneously,
the same group and the group of Langer extended this
strategy to other N-heterocyles.15 The ease of prepara-
tion of bis(trimethylsilyl) ketene acetals and their clean
reaction with activated imine electrophiles led us to
Amino acid 5a was obtained in 50% yield by condensing
the isolated iminium salt 4a on ketene acetal 1a. In a
one-pot procedure, compound 6a was obtained as a
white solid in 70% yield. Finally, ketene acetals 1a–e
were reacted with the iminium salt 4c (i.e., dibenzylidene
iminium trifluoroacetate) leading to compounds 7a–e,
obtained as solids or an oil (7d) in good yields. Interest-
ingly, among the iminium salts, 4c led to b2-amino acid
derivatives that could be debenzylated and suitably pro-
tected for peptide synthesis (Scheme 5).
Noticeably, the use of bis(trimethylsilyl) ketene acetals
led to carboxylic acid, avoiding additional deprotection
EtOCOCl
OTMS
OTMS
Ph
CH Cl
TMSOTf
NEt3
2
2
NBn
N
2
CO2H
R
-
N
EtO2C
R
CF3CO2
S*
H
Ph
R
R
Bn N
2
S*
N
R
OTMS
O
1a R= Me
1b R= H
3a 40%
3b 20%
S
O
2
O
O
Scheme 2. Addition of chiral silyl ketene N,O-acetals on in situ
Scheme 3. Reaction of bis(O-trimethylsilyl) ketene acetals with imine
generated iminium salt.
in the presence of ethylchloroformate.

R. Moumne´ et al. / Tetrahedron Letters 48 (2007) 8277–8280
8279
Cl-
N
CO H
2
4a
Me N
2
5a
N
Cl-
CO2H
OTMS
OTMS
4b
N
R
2
6a
R1
Bn
Bn
-
N
CF CO
3
2
4c
1a : R =R = CH
3
1
1
1
1
2
CO2H
R
2
1b : R = H, R = CH
Bn2N
2
3
R
1
1c : R = Ph, R = CH
2
3
7a-e
1d : R = n-Bu, R = CH
2
3
1e : R = CH OPh, R = CH
1
2
2
3
Scheme 4. Reaction of bis(O-trimethylsilyl) ketene acetals with differ-
ent iminium salts.
Table 1. Yields of the reaction of bis(O-trimethylsilyl) ketene acetals
with different iminium salts
Figure 1. Diamond projection of the Z isomer of compound 9.
Ketene acetal
Iminium salt
Product [yield (%)]
1a
1a
1a
1b
1c
1d
1e
4a
4b
4c
4c
4c
4c
4c
5a (50)
6a (70)
7a (98)
7b (60)
7c (85)
7d (75)
7e (90)
The two isomers were partially separated by silicagel
chromatography to give major Z isomer as white crys-
tals suitable for an X-ray crystallographic structure
determination. A Diamond projection of this compound
confirmed the c-addition of the trimethylsilylester eno-
late to iminium salt 4a20 (Fig. 1).
The unsaturated d-aminoacid obtained as its ammonium
chloride salt has a trans geometry between the acid func-
tion and the methyl group. This class of amino acids is a
useful tool for structure–activity relationship studies of
biologically active peptides.21
(i) NH HCO , Pd-C, MeOH-THF
4
2
(ii) Boc O, K CO dioxane-H O
2
2
3,
2
CO2H
R1 R2
CO2H
R1 R2
Bn2N
BocHN
7a-e
8a-e
Scheme 5. Debenzylation and N-Boc protection.
3. Conclusion
step. Debenzylations of compounds 7 were performed
on Pd/C using ammonium formate as the source of
hydrogen. In the case of compound 7e, nitrogen depro-
tection required the addition of sodium hydrogenocar-
bonate to reach the completion of the reaction. It can
be hypothesized that zwitterion formation decreased
the rate of debenzylation because of steric hindrance
generated by internal chelation. The resulting amines
were then N-protected as tert-butyloxycarbonyl carba-
mates 8a–e in good yields for deprotection–protection
steps (65–80%).
In summary, bis(O-trimethylsilyl) ketene acetals repre-
sent a good alternative to enolates for the synthesis of
b2-amino acids using iminium ions as aminomethylating
agents. Indeed, ketene acetals can be (i) easily prepared
and (ii) reacted at room temperature in a one-pot proce-
dure with in situ prepared iminium ions. We are cur-
rently working on an asymmetric synthesis and the
extension of this strategy for the preparation of various
substituted d-aminoacids.
Acknowledgments
The presence of an additional double bond in the ketene
acetal modified the course of the reaction. Indeed, when
the ketene acetal 1f was reacted with the iminium salt 4a,
instead of the corresponding b2-amino acid, the a,b-
unsaturated-d-aminoacid was obtained as a 80:20 mix-
ture of Z:E isomers 9 in a vinylogous Mannich type
reaction18,19 (Scheme 6).
The authors thank Dr. Albert Loffet and Dr. Fabrice
Cornille for their help and Senn Chemicals for financial
support.
References and notes
1. Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int.
Ed. 1998, 37, 1044.
N+Cl-
2. (a) Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem.
Biodiv. 2004, 1, 1111; (b) Cheng, P. R.; Gellman, S. H.;
Degrado, W. F. Chem. Rev. 2001, 101, 3219.
3. Hart, D. J.; Deok-Chang, H. Chem. Rev. 1989, 89, 1447.
4. (a) Hintermann, T.; Seebach, D. Helv. Chim. Acta 1998,
81, 2093; (b) Sebesta, R.; Seebach, D. Helv. Chim. Acta
OSiMe3
OSiMe3
4a
Me2N
CO2H
Me2N
Z : E (80:20)
CO2H
9
1f
Scheme 6. a,b-Unsaturated-d-aminoacids.

8280
R. Moumne´ et al. / Tetrahedron Letters 48 (2007) 8277–8280
2003, 86, 4061; (c) Gademann, K.; Kimmerlin, T.; Hoyer,
or trifluoroacetic anhydride (1.1 equiv) was slowly added
at room temperature to a solution of bis(trimethylsilyl)
ketene acetal (1.05 equiv) and aminal in dichloromethane
(20 mL/mmol). Stirring for 12 h followed by evaporation
of the solvent and flash column chromatography (AcOEt/
EP, 60/40) gave the product. 3-Dimethylamino-2,2-
dimethyl propionic acid 5a: 50% yield (0.20 g); white solid
mp 150 °C; 1H NMR (200 MHz, D2O): d: 3.24 (s, 2H);
2.76 (s, 6H); 1.16 (s, 6H); 13C NMR (50 MHz, CDCl3): d:
179.5; 65.3; 45.5; 41.4; 23.3; MS: calcd for C7H16NO2
[M+H] 146, found 146. 2,2-Dimethyl-3-pyrrolidin-1-yl-
propionic acid 6a: 70% yield (0.44 g); white solid mp
D.; Seebach, D. J. Med. Chem. 2001, 44, 2460; (d)
Seebach, D.; Namoto, K.; Mahajan, Y. R.; Bindscha¨dler,
P. Chem. Biodiv. 2004, 1, 65.
5. (a) N-Chloromethylbenzamide: see Ref. 12; 1(N-benzoyl
aminomethyl)benzotriazole, see: (b) Katritzky, A. R.; Lan,
X.; Fan, W-Q. Synthesis 1994, 445; N-bromomethyl
`
phtalimide, see: (c) Calmes, M.; Escale, F.; Glot, C.;
Rolland, M.; Martinez, J. Eur. J. Org. Chem. 2000, 2459.
6. Millot, N.; Piazza, C.; Avolio, S.; Knochel, P. Synthesis
2000, 7, 941.
´
7. Moumne, R.; Lavielle, S.; Karoyan, Ph. J. Org. Chem.
1
2006, 71, 3332.
185 °C; H NMR (200 MHz, D2O): d: 3.57 (m, 2H); 3.34
8. Evans, D. A.; Urpi, F.; Somers, T. C.; Clark, J. S.;
Bilodeau, M. T. J. Am. Chem. Soc. 1990, 112, 8215.
9. Oppolzer, W.; Moretti, R.; Thomi, S. Tetrahedron Lett.
1989, 30, 5603.
(s, 2H); 3.05 (m, 2H); 1.93 (m, 4H); 1.20 (s, 6H); 13C NMR
(50 MHz, CDCl3): d: 179.7; 63.1; 56.8; 41.7; 23.4; 22.9. 2-
Methyl-2-dibenzylaminomethyl propionic acid 7a: 98% yield
1
(3.5 g); white solid mp 198–200 °C; H NMR (250 MHz,
10. (a) Enantioselective Synthesis of Beta-Amino Acids, 2nd
ed., Juaristi, E., Soloshonok, V. A., Eds.; John Wiley &
Son, 2005; (b) Lelais, G.; Seebach, D. Biopolymers
(Peptides Science) 2004, 76, 206.
11. Danishefsky, S.; Prisbylla, M.; Lipisko, B. Tetrahedron
Lett. 1980, 21, 805.
D2O): d: 7.4 (s, 10H); 4.3 (s, 4H); 3.4 (s, 2H); 1.1 (s, 6H);
13C NMR (62.5 MHz, D2O): d: 179.4; 131.4; 130.1; 129.1;
128.5; 59.4; 40.8; 23.3; HRMS: calcd for C19H23NO2
[M+H] 298.180, found 298.179. 2-Dibenzylaminomethyl-
propionic acid 7b: 60% yield (2.5 g); white solid mp 196–
1
198 °C; H NMR (250 MHz, CD3OD): d: 7.49 (m, 10H);
´
12. (a) Moumne, R.; Denise, B.; Guitot, K.; Rudler, H.;
4.43 (d, 2H, J = 20 Hz); 4.27 (d, 2H, J = 20 Hz); 3.39–3.25
(m, 1H); 3.08 (m, 1H); 2.78 (m, 1H); 1.07 (d, 3H,
J = 10.8 Hz); 13C NMR (62.5 MHz, D2O): d: 177.6;
130.9; 130.08; 129.2; 53.8; 34.8; 14.5. HRMS: calcd for
C18H21NO2 [M+H] 284.163, found 284.164. 2-Phenyl-2-
dibenzyl aminomethyl-propionic acid 7c: 85% yield (3 g);
Lavielle, S.; Karoyan, P. Eur. J. Org. Chem. 2007, 1912;
´
(b) Karoyan, P.; Lavielle, S.; Moumne, R.; Rulder, H.;
Denise, B. French Patent FR2890069, 2007.
13. Kunz, H.; Burgard, A.; Schanzenbach, D. Angew. Chem.,
Int. Ed. 1997, 4, 386.
14. Rudler, H.; Denise, B.; Xu, Y.; Parlier, A.; Vaissermann,
J. Eur. J. Org. Chem. 2005, 17, 3724.
15. Rudler, H.; Denise, B.; Xu, Y.; Vaissermann, J. Tetrahe-
dron Lett. 2005, 46, 3449; Ullah, E.; Rotzoll, S.; Schmidt,
A.; Michalik, D.; Langer, P. Tetrahedron Lett. 2005, 46,
8997; Rotzoll, S.; Ullah, E.; Fischer, C.; Michalik, D.;
Spannenberg, A.; Langer, P. Tetrahedron 2006, 62, 12084.
16. General procedure for the introduction of an imine in the
1
colorless glue; H NMR (400 MHz, CDCl3): d: 7.31–7.13
(m, 15H); 3.59 (m, 2H); 3.25–3.18 (br, 2H); 3.18–3.08 (m,
2H); 1.42 (s, 3H); 13C NMR (100 MHz, CDCl3): d: 177.6;
142.8; 133.7; 129.9; 128.9; 128.5; 128.3; 127.6; 127.4; 127.2;
126.3; 126.1; 61.1; 57.6; 49.4; 25.9. HRMS: calcd for
C24H25NO2 [M+H] 360.195, found 360.195. 2-Dibenzyl
aminomethyl-hexanoic acid 7d: 75% yield (2.5 g); colorless
1
oil; H NMR (400 MHz, CDCl3): d: 7.40–7.28 (m, 10H);
presence of ethyl chloroformate:
A
dichloromethane
3.99 (d, 2H, J = 12 Hz); 3.54 (d, 2H, J = 12 Hz); 2.86 (tr,
1H); 2.67 (m, 1H); 2.64 (m, 1H); 2.52 (m, 1H); 1.85 (m,
1H); 1.27 (m, 5H); 0.88 (t, 3H, J = 6 Hz); 13C NMR
(100 MHz, CDCl3): d: 175.7; 134.6; 129.7; 129.4; 128.8;
128.3; 127.2; 58.1; 55.6; 54.2; 39.6; 29.2; 28.4; 22.7; 13.8.
HRMS: calcd for C21H27NO2 [M+H] 326.211, found
326.211. 2-Phenyl etherhydroxy-2-dibenzylamino methyl-
propionic acid 7e: 90% yield (1.5 g); white solid mp 192–
194 °C; 1H NMR (250 MHz, CD3OD): d: 7.60–7.51 (m,
10H); 7.33–7.27 (m, 2H); 7.14–7.11 (m, 1H); 6.96–6.94 (d,
1H, J = 8 Hz); 6.94–6.93 (d, 1H, J = 4 Hz); 4.70 (m, 4H);
3.30 (AB, 2H, J = 4 Hz); HRMS: calcd for C24H25NO3
[M+H] 376.190, found 376.190.
(2.5 mL/mmol) solution of ethylchloroformate (1.9 equiv)
was slowly added at room temperature to a solution of
bis(trimethylsilyl) ketene acetal (1.05 equiv) and benzyl-
idene-methylamine in dichloromethane (20 mL/mmol).
Stirring for 12 h followed by evaporation of the solvent
and flash column chromatography (AcOEt/EP, 60/40)
gave the product. 3-(Ethoxycarbonyl-methyl-amino)-2,2-
dimethyl-3-phenyl-propionic acid 3a: 40% yield (0.25 g);
solid mp 130 °C; 1H NMR (200 MHz, D2O): d: 11.3 (s,
1H); 7.31 (s, 5H); 5.86 (s, 1H); 4.22 (q, 2H, J = 7.0 Hz);
2.70 (s, 3H); 1.43 (d, 6H, J = 5 Hz); 1.32 (t, 3H, J = 7 Hz);
13C NMR (50 MHz, CDCl3): d: 183.1; 158.3; 129.0; 127.7;
64.2; 62.3; 47.2; 33.4; 33.2; 26.9; 22.7; 15.1; MS: calcd for
C15H22NO4 [M+H] 280, found 280. 3-(Ethoxycarbonyl-
methylamino)-2-methyl-3-phenyl propionic acid 3b: 20%
yield (global) (0.11 g); oil; 1H NMR (200 MHz, D2O):
major product: d: 8.30 (s, 1H); 7.20–7.31 (s, 5H); 5.24 and
5.35 (d, 1H, J = 10 Hz); 4.02 (m, 2H); 3.29 (m, 1H); 2.68
(s, 3H); 1.18 (m, 3H); 1.02 (d, 3H, J = 6 Hz); minor
product: d: 8.30 (s, 1H); 7.20–7.31 (s, 5H); 5.41 and 5.54
(d, 1H, J = 10 Hz); 4.10 (m, 2H); 3.17 (m, 1H); 2.50 and
2.67 (s, 3H); 1.20 (m, 3H); 1.23 (d, 3H, J = 6 Hz); 13C
NMR (50 MHz, CDCl3): d: major product: 177.8; 156.6;
155.8; 137.2; 127.0; 60.8; 60.6; 39.0; 28.3; 20.4; 13.5; minor
product: 177.8; 156.3; 155.4; 137.2; 127.0; 60.7; 58.8; 39.5;
27.6; 26.4; 24.1; 14.6.
18. (a) Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G.
Chem. Rev. 2000, 100, 1929; (b) Martin, S. F. Acc. Chem.
Res. 2002, 35, 895.
19. 5-Dimethylamino-3-methyl-pent-2-enoic acid 9: 30% yield
(global) (0.12 g); white solid mp 135 °C; 1H NMR
(250 MHz, CD3OD): cis compound: d: 5.78 (s, 1H); 3.17
(m, 2H); 2.90 (m, 2H); 2.80 (s, 6H); 1.84 (s, 3H); trans
compound: d: 5.72 (s, 1H); 3.16 (m, 2H); 2.87 (m, 2H);
2.80 (s, 6H); 2.00 (s, 3H); 13C NMR (50 MHz, CDCl3): d:
170.2; 155.4; 118.2; 55.5; 43.1; 35.1; 18.4.
20. CCDC 232958 contains the supplementary crystallo-
graphic data for this paper. The data can be obtained
free of charge from the Cambridge Crystallographic Data
Center via www.ccdc.cam.ac.uk/data.request/cif.
`
17. General procedure for the introduction of iminium salt: A
dichloromethane (4 mL/mmol) solution of acetyl chloride
21. Grison, C.; Coutrot, P.; Geneve, S.; Didierjean, C.;
Marraud, M. J. Org. Chem. 2005, 70, 10753.