Hindered Bronsted bases as Lewis base catalysts

Article abstract of DOI:10.1039/b908899g

KHMDS and KOtBu are well established as strong, hindered, non-nucleophilic Bronsted bases. However, in the present work these bases are applied as highly active Lewis base catalysts for the formal [2+2] cycloaddition of ketenes with aldehydes and imines.

Full text of DOI:10.1039/b908899g

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Hindered Brønsted bases as Lewis base catalysts
Sobia Tabassum, Oksana Sereda, Peddiahgari Vasu Govardhana Reddy and Rene´ Wilhelm*
Received 6th May 2009, Accepted 2nd July 2009
First published as an Advance Article on the web 24th July 2009
DOI: 10.1039/b908899g
KHMDS and KOtBu are well established as strong, hindered, non-nucleophilic Brønsted bases.
However, in the present work these bases are applied as highly active Lewis base catalysts for the formal
[2+2] cycloaddition of ketenes with aldehydes and imines.
Table 1 Staudinger reaction of 1a and 2a catalyzed by 10 mol% of
catalysts at -78 ◦C in THF
Introduction
Alkali metal hexamethyldisilazanes are well known as non-
nucleophilic hindered Brønsted bases and are extensively used
in synthesis.1 HMDS has a pKa of 26 and N,N-diisopropylamine
a pKa of 36 in THF. HOtBu has a pKa of 29.4 in DMSO.2 The
lower pKa of HMDS can be explained by a-silyl stabilization.3
However, a few examples where these bases act as nucleophiles are
also known. Despite its lower basicity and the more pronounced
sterical screening of the nitrogen atom of MHMDS compared to
LDA, more examples4 of the HMDS anion acting as a nucleophile
are known than for LDA.5 Moreover, KOtBu may also act as a
nucleophile.6
The Staudinger cycloaddition7 as well as the formal [2+2]
cycloaddition of aldehydes and ketenes, the Wynberg reaction,8 are
established methods to obtain b-lactams and b-lactones,9 which
are important compounds due to their biological activity and
utility in synthesis.10 The reactions are often promoted by Lewis
base catalysts. These catalysts are normally weak Brønsted bases.
Here we report that the hindered strong base NaH-
MDS/KHMDS is an efficient Lewis base catalyst for the
Staudinger reaction of disubstituted ketenes and imines with a
para-nosyl group.11 In addition hindered Brønsted bases are also
active catalysts for the cycloaddition of ketenes with aldehydes and
reactions were conducted to exclude some possible mechanistic
pathways.
entry
catalyst
T [min]
yield [%]a
trans:cis
1
2b
3b,c
4c
5
6
KHMDS
10 min
5 min
1 h
24 h
<5 min
3 h
85
99
99
0
99
28
0
77
48
20:80
33:66
20:80
—
20:80
20:80
—
28:72
37:63
55:45
50:50
50:50
—
NaHMDS
LiHMDS
HMDS
LDA
NaOTMS
DMAP
Et3N
DABCO
DBU
—
7
8
24 h
1.5 h
20 min
3.5 h
24 h
24 h
24 h
9d
10
11
12
13b
14b
92
17
44
traces
24 h
0
—
a Yields of isolated 3a. b Reaction performed at rt. c Reaction performed in
toluene. d Reaction was stopped by quenching with NH4Cl(aq) at -78 ◦C.
Scheme 1 Staudinger reaction catalyzed by different Lewis bases.
was observed (Table 1, entry 8). This can be attributed to the lower
nucleophilicity of the lithium amides, due to the stronger covalent
bond character between the lithium and nitrogen.
Results and discussion
Several Lewis bases were screened for their nucleophilic capacity
to catalyze the Staudinger cycloaddition of imine 1a with a para-
nosyl group and phenylethyl ketene 2a (Scheme 1). Along with
strong amine bases, alkali metal amides were also tested under
different reaction conditions as shown in Table 1. Due to their
nucleophilic nature, the best results were observed in the cases
when amide catalysts were applied. Furthermore, the character
of the alkali metal had an influence on the reacti◦on. NaHMDS
and KHMDS resulted in total conversion at -78 C in less than
5 min and 10 min respectively (Table 1, entries 1 and 5), however
LiHMDS gave just a moderate yield of 28% in 3 h (Table 1, entry 6).
LDA catalyzed the reaction in a good yield of 77% but the reaction
time increased to 1.5 h, and a decrease in the diastereoselectivity
When toluene was used as a solvent instead of THF only traces
of the product were obtained at -78 ◦C with KHMDS. This can be
mainly explained by the poor solubility of the imines.12 At room
temperature the reaction proceeded in toluene with quantitative
yield, and the diastereomeric ratio of the product was found to be
similar to that obtained at -78 ◦C in THF (Table 1, entry 3). The
reaction performed in THF at room temperature (Table 1, entry 2)
resulted in a decrease in the diastereomeric ratio.
As shown in Scheme 2, it is known that NaHMDS reacts
with aldehydes to form TMS-protected imines with liberation
of NaOTMS. This reaction is much faster with LiHMDS and
can be carried out at -40 ◦C, but it is much slower with
KHMDS.4i Since alkoxides have not so far been used as Lewis
base catalysts in [2+2] cycloadditions, the Staudinger reaction was
repeated with NaOTMS as a potential catalyst (Table 1, entry 9).
The reaction was stopped after 20 min in order to compare
Institute of Organic Chemistry, Clausthal University of Technology, Leib-
nizstr. 6, 38678 Clausthal-Zellerfeld, Germany. E-mail: rene.wilhelm@tu-
clausthal.de; Fax: +49 5323 722834; Tel: +49 5323 723886
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Table 2 Staudinger reaction with different imines 1 and ketenes 2, catalyzed by 10 mol% MHMDS
entry
1
imine
ketene
base
T [min]
yield [%]a
99
3b (trans:cis)
3a (20:80)
1a Ph
2a
NaHMDS
< 5
R1 = Et
R2 = Ph
2
3
4
5
6
7
8
9
1b 2-Cl-C6H4
1c 2-Thiophenyl
1d 1-Naphthyl
1e 2-Naphthyl
1f 4-CH3-C6H4
1g 4-Cl-C6H4
1h 4-CF3-C6H4
1i 4-NC-C6H4
1j 4-F-C6H4
2a
KHMDS
KHMDS
KHMDS
NaHMDS
NaHMDS
NaHMDS
KHMDS
NaHMDS
KHMDS
NaHMDS
NaHMDS
< 3
15
90
99
68
89
98
87
92
99
99
98
88
72
3b (12:88)
3c (43:57)
3d (14:86)
3e (45:55)
3f (33:67)
3g (26:74)
3h (43:57)
3i (36:64)
3j (25:75)
3k (22:78)
3l (30:70)
2a
2a
2a
10
2a
< 10
< 5
10
15
10
120
10
2a
2a
2a
10
11
12
2a
1k 3,4-(MeO)2-C6H3
1a Ph
2a
2b
R1 = Me
R2 =Ph
13
1j 4-F-C6H4
1a Ph
2b
NaHMDS
NaHMDS
10
180
94
99
3m (32:68)
3n
14c
2c
R1 = Ph
R2 = Ph
15c
16
1j 4-F-C6H4
1a Ph
2c
NaHMDS
NaHMDS
180
90
97
48
3o
3p
2d
R1, R2 = -(CH2)6-
a Isolated yields. b Diastereomers were separated by column chromatography. c Reaction performed at -78 ◦C to rt.
but a lower diastereoselectivity. In several cases the formation of
the product was completed in less than 10 min.
Also, different disubstituted ketenes were applied in the reac-
tion. Changing from an ethyl to a methyl substituent in the ketene
gave the desired product in good yield and diastereoselectivity
(Table 2, entry 12). The 1,1¢-diphenylketene 2c had a lower
reactivity and reacted with imines 1a and 1j at room temperature
in 98% yield (Table 2, entries 14 and 15). As an example for an
alkyl-alkyl substituted ketene, imine 1a was reacted with ketene
2d to give the product in 49% yield (Table 2, entry 16). The lower
yields of 3l and 3p can be attributed to the alternative possibility
of oligomerization and dimerization of the ketene. In all cases
the diketone dimers of the corresponding ketenes were observed.13
The possible b-alkenyl-b-lactone dimers were not found.14
Due to the results for the Staudinger cycloaddition, we were
interested to see whether NaHMDS has a catalytic effect in
the formal [2+2] cycloaddition of ketenes and aldehydes. We
focused on the ketene/aldehyde system shown in Scheme 4. Since
there was no solubility issue expected, as for the Staudinger
reaction, and due to the observation that in toluene a higher
diastereomeric ratio was achieved (Table 1, entry 3), it was
decided to carry out the subsequent cycloaddition in toluene.
In analogy to other reports it was found with the presented
catalytic system that aryl-aryl and aryl-alkyl ketenes were
not active enough to react with benzaldehydes.8h,8k Therefore,
Scheme 2 Reaction of aldehydes with NaHMDS.4g
the results with NaHMDS and to eliminate the possibility that
NaOTMS is formed with the ketene in analogy to Scheme 2.
The yield and the diastereoselectivity were lower compared to the
NaHMDS catalyzed reaction, but nevertheless NaOTMS showed
good catalytic activity.
Commonly used tertiary amines were also applied in the
reaction in order to compare their catalytic activity to MHMDS. In
all cases poor yields were obtained under the reaction conditions
(Table 1, entries 10–13). The reactions of tertiary amines with
such highly substituted ketenes are normally performed over
several hours at room temperature or on heating.7f,7t,7u,7v In the
absence of a catalyst no reaction took place (Table 1, entry 14).
An attempt to use a tosyl protected analogue of 1a in the reaction
gave an unidentified mixture of compounds and not the desired
product.
Next, several imines and ketenes were used in the Staudinger
reaction under the optimized conditions (Table 2, Scheme 3). In
general all imines gave the corresponding products in significant
yields and diastereoselectivity with the cis-adduct prevailing.
Exceptions were the imines 1c, 1e and 1h which gave good yields,
Scheme 3 Staudinger reaction with different imines and ketenes.
4010 | Org. Biomol. Chem., 2009, 7, 4009–4016
Scheme 4 Base catalyzed [2+2] reaction with ketene and benzaldehyde.
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Table 4 KHMDS catalyzed Wynberg reaction with ketene 2da
Table 3 Base catalyzed [2+2] reaction with ketene 2e and aldehyde 4aa
entry
base
t [◦C]
time
yield [%]b
trans:cisc
entry
Ar
yield [%]b
product
1
2
3
4
5
6
7
8
9
NaHMDS
KHMDS
LiHMDS
KOtBu
NaOTMS
NaHMDS
KHMDS
KOtBu
-78
1 h
1 h
1 h
5 h
5 h
5 h
5 h
5 h
5 h
5 h
30
36
0
traces
0
99
99
54
98
0
33:67
22:78
—
—
—
50:50
50:50
37:63
50:50
—
1
2
3
4
5
6
7c
4a Ph
59
60
60
56
55
61
49
8b
8c
8d
8e
8f
8g
10
-78
4b 2-Me-C6H4
4c 4-Cl-C6H4
4d 4-Me-C6H4
4e 4-CF3-C6H4
4f 4-F-C6H4
9 PhCOCF3
-78
-78 to -20
-78
-78 to rt
-78 to rt
-78 to rt
-10 to rt
-78 to rt
a Ketene 2d (2 equiv.). b Isolated yield. c -78 ◦C to rt.
NaOTMS
—
10
a Ketene (2 equiv.) in a 0.27 M toluene solution. b Isolated yield.
c Determined by 1H-NMR.
alkyl-alkyl ketenes were used in the reaction. Ketene 2e was
prepared from 2-cyclopentylpropanoylchloride in toluene with 1
equiv. of DABCO. After 3 h at 80 ◦C ketene 2e was vacuum
transferred together with the solvent to give a 0.27 M solution.
First, reactions with NaHMDS or KHMDS as catalysts were
carried out at -78 ◦C for 1 h to give the product in low yields.
With LiHMDS no product was obtained (Table 3, entries 1–3). In
addition, KOtBu was tested as a hindered non-nucleophilic base
◦
to give only traces of product at -20 C. When the reaction was
repeated with KHMDS and NaHMDS and the reaction mixture
was allowed to warm to room temperature, quantitative yields
were obtained. However, the diastereoselectivity decreased. With
KOtBu a yield of 54% was isolated at room temperature. In the
absence of a catalyst no conversion occurred (Table 3, entry 10).
In order to exclude the possibility that NaOTMS is generated
according to Scheme 2, a control reaction with NaOTMS as the
catalyst was performed at -78 ◦C and no conversion was observed.
If NaOTMS is applied as the catalyst between -10 ◦C and room
temperature, product 8a is formed in 98% yield (Table 3, entries
5 and 9). Thus, NaOTMS is less active than NaHMDS. Since
NaHMDS, KHMDS and NaOTMS gave excellent yields, but a
50:50 ratio of diastereomers, when the reaction was warmed up to
room temperature (Table 3, entries 6, 7 and 9) it is not possible
to rule out completely that some NaOTMS was generated from
NaHMDS at room temperature according to Scheme 2. However,
the reaction in Scheme 2 normally proceeds at higher temperatures
than room temperature and in the case of KHMDS even higher
temperatures are needed.4g
Scheme 5 KHMDS catalyzed Wynberg reaction with ketene 2d.
10 mol% NaOTMS at -78 ◦C gave the desired product in 32%
yield after 10 min.
In addition, ketene 2f7e,15 was reacted with benzaldehyde or para-
methylbenzaldehyde. The reactions were complete after 15 min.
For easier handling, the products were directly transformed to
diols 11 with LiAlH4, with an overall yield of 82 and 89%,
respectively (Scheme 6).
Scheme 6 KHMDS catalyzed Wynberg reaction.
In addition, ketene 2d7e,15 was tested in the reaction with
benzaldehyde, beginning with experiments at -78 ◦C or room
temperature in the absence of a catalyst. No conversion into
the product 8b was observed. However, with 10 mol% KHMDS
the less hindered ketene 2d displayed with several aldehydes
(Table 4) a far higher reactivity than ketene 2e. Thus, the
reactions were complete after 10 min to give the desired products
(Scheme 5). Furthermore, it was even possible to apply a,a,a-
trifluoroacetophenone (9) in the reaction with ketene 2d and to
isolate the tetrasubstituted b-lactone 10 in 49% yield (Table 4,
entry 7).
Based on the present results, the mechanism in Scheme 7 can
be proposed for the reaction of aldehydes with ketenes. After the
initial nucleophilic attack of the HMDS anion at the ketene, the
amide enolate 12 is formed, which obviously must allow a 1,3
silyl shift to anion 13. The process would be encouraged by the
oxophilicity of silicon. However, this rearrangement could be slow
or lead to an equilibrating mixture from which 12 is consumed
by the aldehyde. Taking into consideration that the HMDS group
in enolate 12 is far larger than the cyclopentyl ring, the aldehyde
approaches from the side opposite to the HMDS group and the cis
product is formed, which is observed in the majority of examples of
Lewis base catalysed [2+2] cycloadditions of ketenes with imines
or aldehydes.7,8
Prolonged stirring did not result in a higher yield due to
competing dimerization of the ketene to the corresponding
diketone. Electron-richand -deficientaldehydes gave similar yields.
Furthermore, a reaction with ketene 2d, benzaldehyde (4a) and
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General experimental procedure for the Staudinger cycloaddition.
An imine 1 (0.1 mmol) and a ketene 2 (0.25 mmol) were dissolved
in dry THF (1 mL) and cooled down to -78 ◦C. KHMDS
or NaHMDS (0.01 mmol) was added, and the reaction was
monitored by TLC. After total conversion the reaction mixture
was sujected to column chromatography and the products were
eluted with 1:8 ethyl acetate/petrol ether to give the desired
diastereomers mostly as white solids (yields: 48–99%) For yields
and ratios see Tables 1 and 2.
3a: trans-Isomer: white crystals, mp 144 ◦C. 1H NMR
(200 MHz): d = 0.57 (t, J = 7.4 Hz, 3 H), 1.25–1.43 (m, 1 H),
1.64–1.89 (m, 1 H), 5.24 (s, 1 H), 7.21–7.44 (m, 10 H), 8.12 (d, J =
8.9 Hz, 2 H), 8.34 (d, J = 8.98 Hz, 2 H). 13C NMR (50 MHz): d =
8.7, 27.1, 68.1, 69.9, 124.6, 126.2, 127.2, 128.1, 128.9, 129.2, 129.3,
-1
=
133.6, 137.4, 143.9, 151.0, 168.6. IR (KBr) n/cm : 1792 (C O).
MS (ES+): m/z = 459.1 [M + Na]+ Anal. Calcd for C23H20N2O5S:
C, 63.29; H, 4.62; N, 6.42%. Found: C, 6◦3.20; H, 4.67; N, 6.35%.
cis-Isomer: white crystals, mp 144–145 C. 1H NMR (200 MHz):
d = 0.94 (t, J = 7.4 Hz, 3 H), 2.20 (q, J = 7.4 Hz, 2 H), 5.15 (s,
1 H), 6.70–6.76 (m, 2 H), 6.82–6.91 (m, 2 H), 6.94–7.16 (m, 6 H),
7.95 (d, J = 8.9 Hz, 2 H), 8.26 (d, J = 8.9 Hz, 2 H). 13C NMR
(50 MHz): d = 9.3, 32.6, 69.1, 70.3, 124.4, 127.2, 127.4, 128.2,
128.2, 128.3, 128.9, 129.0, 133.7, 134.5, 144.4, 150.8, 167.8. IR
Scheme 7 Proposed mechanism.
Conclusions
-1
+
+
=
In conclusion it has been shown that potassium and sodium
hexamethyldisilazane amides can act as highly active Lewis base
catalysts in the formal [2+2] cycloaddition of ketenes with imines
or aldehydes. The Staudinger cycloaddition was completed in a
short time of 5 to 15 min at -78 ◦C. The useful para-nosyl group
can be removed in high yield under mild conditions.16 The speed
and simplicity of the reported procedure makes it a valuable tool
for preparing libraries of b-lactams and b-lactones. It was also
possible to obtain a tetrasubstituted b-lactone via the Wynberg
reaction. In addition, it was shown that KOtBu and NaOTMS
are also good Lewis base catalysts for these cycloadditions. These
findings may encourage the exploration of tandem reactions with
these bases or the development of chiral analogues.
(KBr) n/cm : 1792 (C O). MS (ES ): m/z = 459.1 [M + Na] .
Anal. Calcd for C23H20N2O5S: C, 63.29; H, 4.62; N, 6.42%. Found:
C, 63.38; H, 4.73; N, 6.28%.
3b: trans-Isomer: white crystals, mp 107 ◦C. 1H NMR
(400 MHz): d = 0.83 (t, J = 8.0 Hz, 3 H), 2.09–2.17 (m, 1 H),
2.24–2.33 (m, 1 H), 5.64 (s, 1 H), 6.70–6.72 (m, 1 H), 6.81–6.84
(m, 1 H), 6.95–6.98 (m, 2 H), 7.03–7.07 (m, 3 H), 7.29–7.23 (m, 2
H), 8.22 (d, J = 8.8 Hz, 2 H), 8.43 (d, J = 8.8 Hz, 2 H). 13C NMR
(100 MHz, CDCl3): d = 9.3, 30.7, 64.7, 71.5, 124.8, 126.9, 128.5,
129.3, 129.4, 129.7, 132.3, 133.1, 134.1, 143.8, 151.2, 168.4. IR
-1
+
+
=
(KBr) n/cm : 1787 (C O). MS (ES ): m/z = 493.1 [M + Na] .
Anal. Calcd for (C23H19ClN2O5S): C, 58.66; H, 4.07; N, 5.95%.
Found: C, 58.45; H, 4.05; N, 5.97%.
◦
1
cis-Isomer: white crystals, mp 107 C. H NMR (200 MHz):
d = 0.59 (t, J = 7.4 Hz, 3 H), 1.70 (q, J = 7.3 Hz, 2 H), 5.56 (s, 1
H), 7.03–7.07 (m, 5 H), 7.34–7.48 (m, 4 H), 8.15 (d, J = 8.8 Hz, 2
H), 8.37 (d, J = 8.8 Hz, 2 H). 13C NMR (50 MHz): d = 8.6, 25.4,
Experimental
General experimental
64.7, 69.5, 124.7, 126.7, 127.9, 128.3, 130.0, 129.2, 132.2, 133.1,
-1
=
All reactions were conducted under an atmosphere of dry nitrogen.
Glassware was dried in an oven or flame-dried under vacuum
prior to use. THF was distilled from sodium benzophenone ketyl.
Toluene was distilled from sodium. Reactions were monitored
by TLC with MERCK Silica gel 60 F254 plates. Flash column
chromatography was performed on silica gel 60 (70–230 mesh
ASTM) from MERCK. Ketenes 27e,8h,15 and imines 112 were prepared
according to literature procedures. Aldehydes 4 were distilled or
sublimed. All other chemicals, were purchased from commercial
sources. Melting points were taken on a Dr. Tottoli apparatus
133.9, 143.6, 151.1, 168.1. IR (KBr) n/cm : 1793 (C O). MS
(ES+): m/z = 493.1 [M + Na]+. Anal. Calcd for (C23H19ClN2O5S):
C, 58.66; H, 4.07; N, 5.95%. Found: C, 58.71; H, 4.09; N, 5.81%.
3c: trans-Isomer: white crystals, mp 116 ◦C. 1H NMR
(200 MHz): d = 0.64 (t, J = 7.6 Hz, 3 H), 1.50–1.68 (m, 1 H),
1.85–2.03 (m, 1 H), 5.53 (s, 1 H), 7.04–7.11 (m, 2 H), 7.24–7.37
(m, 6 H), 8.10 (d, J = 9.0 Hz, 2 H), 8.34 (d, J = 9.2 Hz, 4 H).
13C NMR (50 MHz): d = 8.7, 27.7, 65.8, 68.3, 124.5, 126.2, 126.7,
127.5, 127.9, 128.2, 129.2, 129.2, 136.5, 137.1, 144.0, 168.2. IR
(KBr) n/cm : 1782 (C O). MS (ES ): m/z = 465.0 [M + Na] .
Anal. Calcd for (C21H18N2O5S2): C, 57.00; H, 4.10; N, 6.33%.
Found: C, 56.99; H, 4.10; N, 6.30%.
cis-Isomer: white crystals, mp 124 C. H NMR (200 MHz):
d = 0.97 (t, J = 7.2 Hz, 3 H), 2.25 (q, J = 8.0 Hz, 2 H), 5.49 (s,
1 H), 6.73–6.75 (m, 2 H), 6.97–7.04 (m, 3 H), 7.11–7.18 (m, 3 H),
7.93 (d, J = 9.04 Hz, 2 H), 8.25 (d, J = 9.04 Hz, 2 H). 13C NMR
(50 MHz): d = 9.3, 32.4, 64.9, 70.5, 124.4, 126.4, 127.2, 127.9,
128.5, 128.9, 129.1, 134.5, 137.2, 144.4, 150.8, 167.2. IR (KBr)
-1
+
+
=
¨
from BUCHI and are uncorrected. Infrared spectra were recorded
on a Vector 22 FT-IR from BRUKER. The absorption of solids was
measured by potassium bromide pellets, the absorption of liquids
◦
1
1
by using a thin layer between sodium chloride plates. H-NMR
spectra were taken on an AMX 400 (400 MHz) or an AC 250 P
(200 MHz) from BRUKER in CDCl3 unless otherwise stated. 13C-
NMR spectra were taken on an AMX 400 (100 MHz) or on an AC
250 P (50 MHz) from BRUKER in CDCl3 unless otherwise stated.
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-1
+
+
=
n/cm : 1790 (C O). MS (ES ): m/z = 465.0 [M + Na] . Anal.
Calcd for (C21H18N2O5S2): C, 57.00; H, 4.10; N, 6.33%. Found: C,
57.13; H, 4.15; N, 6.26%.
MS (ES+): m/z = 473 [M + Na]+. Anal. Calcd for (C24H22N2O5S):
C, 63.98; H, 4.92; N, 6.22%. Found: C, 63.99; H, 5.02; N, 6.21%.
3g: trans-Isomer: white crystals, mp = 163 ◦C. 1H NMR
(200 MHz): d = 0.59 (t, J = 7.4 Hz, 3 H), 1.25–1.43 (m, 1 H),
1.62–1.80 (m, 1 H), 5.17 (s, 1 H), 7.16–7.21 (m, 2 H), 7.29–7.35 (m,
5 H), 7.42 (d, J = 8.6 Hz, 2 H), 8.14 (d, J = 9.0 Hz, 2 H), 8.36 (d,
J = 9.0 Hz, 2 H). 13C NMR (50 MHz): d = 8.6, 27.1, 68.0, 69.1,
124.5, 126.0, 128.1, 128.4, 129.0, 129.1, 129.2, 132.2, 135.1, 136.9,
3d: trans-Isomer: white crystals, mp 182 ◦C. 1H NMR
(200 MHz): d = 0.66 (t, J = 7.4 Hz, 3 H), 1.26–1.43 (m, 1 H),
1.58–1.78 (m, 1 H), 5.82 (s, 1 H), 7.05–7.10 (m, 2 H), 7.34–7.38 (m,
3 H), 7.43–7.63 (m, 5 H), 7.87–7.97 (m, 2 H), 8.27 (d, J = 9.0 Hz,
2 H), 8.46 (d, J = 9.0 Hz, 2 H). 13C NMR (50 MHz): d = 8.9, 24.1,
68.5, 68.8, 122.9, 124.8, 125.1, 125.2, 126.5, 126.9, 128.6, 129.5,
129.5, 129.6, 129.7, 130.9, 133.9, 136.6, 144.0, 169.7. IR (KBr)
-1
+
=
143.5, 151.0, 168.2. IR (KBr) n/cm : 1789 (C O). MS (ES ):
m/z = 493.0 [M + Na]+. Anal. Calcd for C23H19ClN2O5S: C 58.66;
H 4.07; N 5.93%. Found: C 58.79; H 3.95; N 5.92%.
-1
+
+
=
n/cm : 1787 (C O). MS (ES ): m/z = 509.2 [M + Na] . Anal.
Calcd for (C27H22N2O5S): C, 66.65; H, 4.56; N, 5.76%. Found: C,
66.77; H, 4.78; N, 5.59%.
cis-Isomer: white crystals, mp = 134 ◦C. 1H NMR (200 MHz):
d = 0.90 (t, J = 7.4 Hz, 3 H), 2.16 (q, J = 7.4 Hz, 2 H), 5.11 (s,
1 H), 6.72 (d, J = 8.4 Hz, 2 H), 6.83–6.87 (m, 2 H), 7.01 (d, J =
8.6 Hz, 2 H), 7.05–7.12 (m, 2 H), 8.02 (d, J = 9.2 Hz, 2 H), 8.33
(d, J = 9.2 Hz, 2 H). 13C NMR (50 MHz): d = 9.1, 32.2, 68.2,
70.3, 124.4, 127.0, 127.6, 128.4, 128.9, 129.2, 132.4, 133.9, 134.8,
◦
1
cis-Isomer: white crystals, mp 186 C. H NMR (200 MHz):
d = 0.97 (t, J = 7.6 Hz, 3 H), 2.26–2.47 (m, 2 H), 6.05 (s, 1 H),
6.69–6.99 (m, 6 H), 7.50–7.69 (m, 4 H), 7.83 (d, J = 7.8 Hz, 1 H),
8.02 (d, J = 8.2 Hz, 1 H), 8.15 (d, J = 9.0 Hz, 2 H), 8.38 (d, J =
9.0 Hz, 2 H). 13C NMR (50 MHz): d = 9.5, 31.2, 64.9, 71.6, 121.7,
124.7, 125.1, 126.1, 126.8, 127.2, 127.6, 128.1, 129.0, 129.3, 129.5,
129.6, 131.3, 133.5, 134.1, 138.3, 144.4, 168.6. IR (KBr) n/cm-1:
1782 (C O). MS (ES ): m/z = 509.2 [M + Na] . Anal. Calcd for
(C27H22N2O5S): C, 66.65; H, 4.56; N, 5.76%. Found: C, 66.58; H,
4.87; N, 5.54%.
-1
+
=
144.1, 150.9, 167.5. IR (KBr) n/cm : 1792 (C O). MS (ES ):
m/z = 493.1 [M + Na]+. Anal. Calcd for C23H19ClN2O5S: C 58.66;
H 4.07; N 5.93%. Found: C 58.80; H 4.09; N 6.05%.
◦
+
+
1
=
3h: trans-Isomer: white crystals, mp = 158–159 C. H NMR
(200 MHz): d = 0.61 (t, J = 7.2 Hz, 3 H), 1.23–1.42 (m, 1 H),
1.60–1.78 (m, 1 H), 5.22 (s, 1 H), 7.16–7.20 (m, 2 H), 7.31–7.37
(m, 3 H), 7.53 (d, J = 8.0 Hz, 2 H), 7.72 (d, J = 8.2 Hz, 2 H),
8.16 (d, J = 9.0 Hz, 2 H), 8.38 (d, J = 9.0 Hz, 2 H). 13C NMR
(50 MHz): d = 8.6, 27.0, 68.2, 69.1, 124.6, 125.9, 126.0, 127.4,
128.3, 129.0, 129.2, 136.7, 137.8, 143.3, 151.0, 168.0. IR (KBr)
n/cm : 1783 (C O). MS (ES ): m/z = 527.0 [M + Na] . Anal.
Calcd for C24H19F3N2O5S: C 57.14; H 3.80; N 5.55%. Found: C
56.98; H 3.85; N 5.40%.
3e: trans-Isomer: white crystals, mp = 155 ◦C. 1H NMR
(400 MHz): d = 0.56 (t, J = 7.2 Hz, 3 H), 1.31–1.40 (m, 1 H),
1.74–1.83 (m, 1 H), 5.42 (s, 1 H), 7.30–7.41 (m, 6 H), 7.54–7.58
(m, 2 H), 7.73–7.77 (m, 2 H), 7.87–7.91 (m, 2 H), 8.13 (d, J =
8.8 Hz, 2 H), 8.34 (d, J = 8.8 Hz, 2 H). 13C NMR (100 MHz): d =
8.6, 27.0, 29.7, 68.2, 69.9, 124.2, 124.4, 126.2, 126.7, 126.9, 127.0,
127.8, 127.9, 128.0, 128.7, 129.0, 129.1, 130.8, 132.9, 133.4, 137.3,
143.9, 150.9, 168.4. IR (KBr) n/cm : 1783 (C O). MS (ES ):
m/z = 508.8 [M + Na]+.. Anal. Calcd for C27H22N2O5S: C 66.65;
H 4.56; N 5.76%. Found: C 66.70; H 4.43; N 5.71%.
-1
+
+
=
cis-Isomer: white crystals, mp = 131 ◦C. 1H NMR (200 MHz):
d = 0.91 (t, J = 7.4 Hz, 3 H), 2.17 (q, J = 7.0 Hz, 2 H), 5.16 (s, 1
H), 6.81–6.81 (m, 2 H), 6.94 (d, J = 8.0 Hz, 2 H), 7.10–7.30 (m, 3
H), 7.30 (d, J = 8.0 Hz, 2 H), 8.37 (d, J = 9.0 Hz, 2 H), 8.35 (d,
J = 9.0 Hz, 2 H). 13C NMR (50 MHz): d = 9.1, 31.9, 68.0, 70.7,
-1
+
=
cis-Isomer: white crystals, mp = 177 ◦C. 1H NMR (200 MHz):
d = 0.99 (t, J = 7.4 Hz, 3 H), 2.17–2.36 (m, 2 H), 5.33 (s, 1 H),
6.51 (d, J = 8.6 Hz, 1 H), 6.89–7.01 (m, 5 H), 7.29 (d, J = 8.6 Hz,
1 H), 7.41–7.50 (m, 3 H), 7.57–7.69 (m, 2 H), 7.86 (d, J = 9.2 Hz,
2 H), 8.12 (d, J = 9.0 Hz, 2 H). 13C NMR (50 MHz): d = 9.2, 32.8,
69.3, 70.0, 124.2, 124.5, 126.6, 126.9, 127.1, 127.3, 127.7, 127.7,
128.2, 128.6, 128.8, 130.9, 132.5, 133.0, 134.3, 144.2, 150.6, 167.6.
IR (KBr) n/cm : 1788 (C O). MS (ES ): m/z = 995.0 [2M +
Na]+. Anal. Calcd for C27H22N2O5S: C 66.65; H 4.56; N 5.76%.
Found: C 66.78; H 4.55; N 5.80%.
124.5, 125.0, 125.1, 125.2, 127.0, 127.7, 128.1, 128.4, 128.9, 133.6,
-1
=
138.0, 143.9, 150.9, 167.4. IR (KBr) n/cm : 1796 (C O). MS
(ES+): m/z = 526.8 [M + Na]+. Anal. Calcd for C24H19F3N2O5S:
C 57.14; H 3.80; N 5.55%. Found: C 56.87; H 3.85; N 5.39%.
3i: trans-Isomer: white crystals, mp = 168 ◦C. 1H NMR
(200 MHz): d = 0.61 (t, J = 7.4 Hz, 3 H), 1.22–1.42 (m, 1 H),
1.56–1.76 (m, 1 H), 5.18 (s, 1 H), 7.12–7.17 (m, 2 H), 7.31–7.37
(m, 3 H), 7.55 (d, J = 8.2 Hz, 2 H), 7.78 (d, J = 8.4 Hz, 2 H),
8.16 (d, J = 9.0 Hz, 2 H), 8.38 (d, J = 9.0 Hz, 2 H). 13C NMR
(50 MHz): d = 8.6, 27.0, 68.4, 69.0, 113.2, 118.0, 124.6, 125.8,
127.7, 128.4, 129.0, 129.3, 132.6, 136.4, 139.1, 143.1, 151.1, 167.8.
-1
+
=
3f: trans-Isomer: white crystals, mp 142 ◦C. 1H NMR
(200 MHz): d = 0.57 (t, J = 7.4 Hz, 3 H), 1.25–1.43 (m, 1 H),
1.59–1.83 (m, 1 H), 2.39 (s, 3 H), 5.21 (s, 1 H), 7.21–7.43 (m, 9 H),
8.12 (d, J = 9.0 Hz, 2 H), 8.35 (d, J = 9.04 Hz, 2 H). 13C NMR
(50 MHz): d = 8.7, 21.4, 27.2, 68.0, 70.0, 124.6, 126.2, 127.2, 128.1,
129.2, 130.5, 137.5, 139.2, 144.0, 151.1, 168.7. IR (KBr) n/cm-1:
1785 (C O). MS (ES ): m/z = 473 [M + Na] . Anal. Calcd for
(C24H22N2O5S): C, 63.98; H, 4.92; N, 6.22%. Found: C, 64.05; H,
5.17; N, 6.02%.
-1
+
=
IR (KBr) n/cm : 1797 (C O). MS (ES ): m/z = 484.09 [M +
Na]+. Anal. Calcd for C24H19N3O5S: C 62.46; H 4.15; N 9.11%.
Found: C 62.61; H 4.19; N 9.15%.
cis-Isomer: white crystals, mp = 103–104 ◦C. 1H NMR
(200 MHz): d = 0.87 (t, J = 7.4 Hz, 3 H), 2.05–2.25 (m, 2 H),
5.13 (s, 1 H), 6.80–6.86 (m, 2 H), 6.99 (d, J = 8.4 Hz, 2 H), 7.04–
7.09 (m, 3 H), 7.37 (d, J = 8.4 Hz, 2 H), 8.13 (d, J = 9.0 Hz, 2
H), 8.41 (d, J = 9.0 Hz, 2 H). 13C NMR (50 MHz): d = 9.1, 31.5,
67.8, 71.1, 112.3, 112.6, 118.0, 124.7, 126.9, 127.9, 128.2, 128.6,
129.0, 131.9, 133.3, 139.5, 143.7, 151.1, 167.2. IR (KBr) n/cm-1:
+
+
=
cis-Isomer: white crystals, mp 147 ◦C. 1H NMR (200 MHz): d =
0.93 (t, J = 8.0 Hz, 3 H), 2.18 (q, J = 7.2 Hz, 2 H), 2.20 (s, 3 H),
5.11 (s, 1 H), 6.60 (d, J = 8.0 Hz, 2 H), 6.78 (d, J = 8.0 Hz, 2 H),
6.85–6.89 (m, 2 H), 7.02–7.09 (m, 3 H), 7.87 (d, J = 9.0 Hz, 2 H),
8.18 (d, J = 9.0 Hz, 2 H). 13C NMR (50 MHz): d = 9.3, 21.2, 32.8,
+
+
=
1786 (C O). MS (ES ): m/z = 484.09 [M + Na] . Anal. Calcd for
C24H19N3O5S: C 62.46; H 4.15; N 9.11%. Found: C 62.45; H 4.19;
N 9.36%.
69.2, 70.0, 124.3, 127.3, 127.4, 128.2, 128.3, 128.9, 129.0, 130.5,
-1
=
134.6, 138.9, 144.4, 150.8, 167.9. IR (KBr) n/cm : 1781 (C O).
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 4009–4016 | 4013
©

View Article Online
3j: trans-Isomer: white crystals, mp = 79 ◦C. 1H NMR
(200 MHz): d = 0.59 (t, J = 7.4 Hz, 3 H), 1.25–1.43 (m, 1 H),
1.63–1.81 (m, 1 H), 5.19 (s, 1 H), 7.09–7.21 (m, 4 H), 7.29–7.39
(m, 5 H), 8.13 (d, J = 9.2 Hz, 2 H), 8.36 (d, J = 9.0 Hz, 2 H).
13C NMR (50 MHz): d = 8.5, 27.0, 68.0, 69.1, 115.7, 116.2, 124.5,
126.0, 128.1, 128.7, 128.9, 129.0, 129.1, 129.3, 129.4, 137.0, 143.6,
m/z = 463.08 [M + Na]+. HRMS Calcd for C22H17FN2O5SNa:
463.0740. Found: 463.0758.
cis-Isomer: white crystals, mp = 139 ◦C. 1H-NMR (200 MHz):
d = 1.77 (s, 3 H), 5.09 (s, 1 H), 6.68–6.79 (m, 4 H), 6.85–6.91 (m,
2 H), 7.04–7.11 (m, 3 H), 8.04 (d, J = 9.0 Hz, 2 H), 8.35 (d, J =
9.0 Hz, 2 H). 13C NMR (50 MHz): d = 24.9, 69.9, 70.2, 115.0,
115.5, 124.5, 126.6, 127.6, 128.5, 128.9, 129.3, 129.5, 129.6, 129.6,
135.4, 143.8, 150.9, 160.2, 165.1, 168.2. IR (KBr) n/cm-1: 1794
-1
+
=
168.3. IR (KBr) n/cm : 1786 (C O). MS (ES ): m/z = 477.0
[M + Na]+.
cis-Isomer: white crystals, mp = 124 ◦C. 1H NMR (200 MHz):
d = 0.91 (t, J = 7.4 Hz, 3 H), 2.16 (q, J = 7.4 Hz, 2 H), 5.13 (s,
1 H), 6.72–6.76 (m, 4 H), 6.82–6.87 (m, 2 H), 7.04–7.11 (m, 3 H),
8.01 (d, J = 9.0 Hz, 2 H), 8.33 (d, J = 9.0 Hz, 2 H). 13C NMR
(50 MHz): d = 9.2, 32.2, 68.2, 70.3, 115.0, 115.4, 124.4, 127.1,
127.5, 128.3, 128.9, 129.6, 129.6, 129.7, 134.1, 144.2, 150.8, 160.2,
(C O). MS (ES ): m/z = 463.1 [M + Na] . HRMS Calcd for
+
+
=
C22H17FN2O5SNa: 463.0740. Found: 463.0741.
3n: white crystals, mp 156 ◦C. 1H NMR (200 MHz): d = 5.86 (s,
1 H), 6.87–7.21 (m, 10 H), 7.28–7.48 (m, 5 H), 8.00 (d, J = 9.0 Hz,
2 H), 8.26 (d, J = 9.0 Hz, 2 H). 13C NMR (50 MHz): d = 69.6,
73.3, 124.4, 126.9, 127.6, 127.8, 128.0, 128.3, 128.4, 129.0, 129.1,
129.2, 133.4, 135.6, 138.7, 143.9, 150.9, 166.7. IR (KBr) n/cm-1:
-1
+
=
165.1, 167.6. IR (KBr) n/cm : 1784 (C O). MS (ES ): m/z =
477.0 [M + Na]+.
1781 (C O). MS (ES ): m/z = 507.0 [M + Na] . Anal. Calcd for
(C27H20N2O5S): C, 66.93; H, 4.16; N, 5.78%. Found: C, 66.97; H,
4.31; N, 5.77%.
+
+
=
◦
1
3k: trans-Isomer: light yellow crystals, mp 143 C. H NMR
(200 MHz): d = 0.59 (t, J = 7.4 Hz, 3 H), 1.26–1.49 (m, 1 H),
1.69–1.87 (m, 1 H), 3.86 (s, 3 H), 3.92 (s, 3 H), 5.16 (s, 1 H), 6.84
(s, 1 H), 6.88–6.89 (m, 2 H), 7.18–7.39 (m, 5 H), 8.13 (d, J =
9.0 Hz, 2 H), 8.35 (d, J = 9.0 Hz, 2 H). 13C NMR (50 MHz): d =
8.7, 27.1, 56.1, 56.2, 68.2, 69.9, 110.2, 111.3, 119.9, 124.6, 125.9,
126.2, 128.1, 129.2, 137.5, 143.9, 149.3, 149.8, 151.1, 168.8. IR
(KBr) n/cm : 1793 (C O). MS (ES ): m/z = 518.8 [M + Na] ,
829.0. Anal. Calcd for (C25H24N2O7S): C, 60.47; H, 4.87; N, 5.64%.
Found: C, 60.41; H, 4.83; N, 5.63%.
cis-Isomer: yellow crystals, mp 146 C. H NMR (200 MHz):
d = 0.94 (t, J = 7.4 Hz, 3 H), 2.18 (q, J = 7.4 Hz, 2 H),
3.21 (s, 3 H), 3.79 (s, 3 H), 5.08 (s, 1 H), 5.82 (s, 1 H), 6.57–
6.59 (m, 2 H), 6.84–6.92 (m, 2 H), 7.06–7.09 (m, 3 H), 7.93
(d, J = 9.0 Hz, 2 H), 8.26 (d, J = 9.0 Hz, 2 H). 13C NMR
(50 MHz): d = 9.3, 32.6, 55.4, 55.9, 69.2, 69.9, 110.3, 110.6, 121.8,
124.3, 125.7, 127.2, 127.5, 128.4, 129.0, 129.2, 134.9, 144.4, 148.5,
149.5, 150.8, 167.9. IR (KBr) n/cm : 1787 (C O). MS (ES ):
m/z = 518.8 [M + Na]+, 829.0. Anal. Calcd for (C25H24N2O7S):
C, 60.47; H, 4.87; N, 5.64%. Found: C, 60.47; H, 4.90;
N, 5.67%.
◦
1
3o: white crystals, mp 121 C. H NMR (200 MHz): d = 5.84
(s, 1 H), 6.75–6.96 (t, 6 H), 7.01–7.09. (m, 3 H), 7.28–7.44 (m, 5
H), 8.04 (d, J = 9.0 Hz, 2 H), 8.30 (d, J = 9.0 Hz, 2 H). 13C NMR
(50 MHz): d = 29.7, 68.8, 115.2, 115.6, 124.4, 126.8, 127.7, 128.3,
128.4, 128.9, 129.1, 129.5, 129.7, 135.2, 138.3, 143.6, 166.5. IR
(KBr) n/cm : 1791 (C O). MS (ES ): m/z = 524.8 [M + Na] .
Anal. Calcd for C27H19FN2O5S: C 64.53; H 3.81; N 5.57%. Found:
C 64.83; H 3.89; N 5.67%.
-1
+
+
-1
+
+
=
=
◦
3p: white crystals, mp 168 ◦C. 1H NMR (200 MHz): d = 1.06–
1.38 (m, 4 H), 1.46–1.66 (m, 6 H), 1.72–2.02 (m, 2 H), 4.85 (s, 1 H),
7.11–7.33 (m, 5 H), 8.12 (d, J = 8.8 Hz, 2 H), 8.38 (d, J = 8.8 Hz,
2 H). 13C NMR (50 MHz): d = 22.8, 23.7, 29.0, 29.1, 30.0, 35.4,
64.3, 70.5, 124.6, 127.1, 128.8, 129.0, 129.2, 134.1, 144.2, 151.0,
1
-1
+
=
171.3. IR (KBr) n/cm : 1787 (C O). MS (ES ): m/z = 437.2
[M + Na]+. Anal. Calcd for (C21H22N2O5S): C, 60.85; H, 5.35; N,
6.76%. Found: C, 60.71; H, 5.47; N, 6.69%.
-1
+
=
Preparation of cyclopentyl methyl ketene 2e. The ketene
was prepared by dehydrochlorination of 2-cyclopentylpropanoyl
chloride (2.73 g, 17 mmol) with DABCO (1.9 g 17 mmol) in
toluene (20 mL) under a nitrogen atmosphere at 80 ◦C. After
3 h the reaction mixture was allowed to cool down to room
temperature and the ketene and toluene were vacuum transferred
into another flask. To quantify the amount of ketene generated
by this procedure, 0.5 mL of yellow ketene solution was quenched
with an excess of n-propylamine. Evaporation of the solvent and
excess amine furnished 2-cyclopentyl-N-propylpropanamide as a
white solid (24.4 mg). The concentration of ketene solution was
0.27 M. 1H NMR (200 MHz) d = 0.88 (t, J = 7.5 Hz, 3 H), 1.00–
1.16 (m, 5 H), 1.43–1.61 (m, 6 H), 1.65–1.82 (m, 2 H), 1.84–1.96
(m, 2 H), 3.07–3.27 (m, 2 H), 5.83 (s, 1 H).
3l: trans-Isomer: white crystals, mp 163 ◦C. 1H NMR
(200 MHz): d = 1.18 (s, 3 H), 5.28 (s, 1 H), 7.20–7.42 (m, 10 H),
8.15 (d, J = 9.0 Hz, 2 H), 8.37 (d, J = 9.0 Hz, 2 H). 13C NMR
(50 MHz): d = 20.0, 64.1, 70.0, 124.6, 125.4, 127.0, 128.2, 129.0,
129.2, 129.3, 129.4, 133.6, 139.6, 144.0, 151.1, 169.1. IR (KBr)
-1
+
+
=
n/cm : 1787 (C O). MS (ES ): m/z = 445.1 [M + Na] . Anal.
Calcd for (C22H18N2O5S): C, 62.55; H, 4.29; N, 6.63%. Found: C,
63.19; H, 4.64; N, 6.63%.
◦
1
cis-Isomer: white crystals, mp 142 C. H NMR (200 MHz):
d = 1.81 (s, 3 H), 5.12 (s, 1 H), 6.71–6.77 (m, 2 H), 6.86–6.93 (m,
2 H), 6.95–7.16 (m, 6 H), 7.98 (d, J = 9.0 Hz, 2 H), 8.29 (d, J =
9.0 Hz, 2 H). 13C NMR (50 MHz): d = 25.4, 66.0, 71.1, 124.5,
126.8, 127.6, 127.9, 128.3, 128.5, 129.0, 129.1, 133.6, 135.8, 144.2,
150.9, 168.5. IR (KBr) n/cm : 1791 (C O). MS (ES ): m/z =
445.1 [M + Na]+. Anal. Calcd for (C22H18N2O5S): C, 62.55; H,
4.29; N, 6.63%. Found: C, 63.14; H, 4.60; N, 6.50%.
-1
+
=
General experimental procedure for Table 3. To a ketene
solution of 2e (0.75 mmol, 2.82 mL toluene) was added ben-
zaldehyde (4a) (30mL, 0.3 mmol) at -78 ◦C followed by the
addition of MHMDS (0.5 M solution in toluene), NaOTMS or
KOtBu (0.03 mmol). After the given times and temperatures in
Table 3, the reaction mixture was subjected directly to column
chromatography on silica gel and the diastereomers were eluted
with a 1:19 diethyl ether–petrol ether mixture to give the desired
compounds as oils. For yields and diastereomeric ratios see Table 3.
3m: trans-Isomer: white crystals, mp = 59 ◦C. 1H NMR
(400 MHz): d = 1.18 (s, 3 H), 5.23 (s, 1 H), 7.11–7.19 (m, 4
H), 7.28–7.35 (m, 5 H), 8.16 (d, J = 8.8 Hz, 2 H), 8.38 (d, J =
8.8 Hz, 2 H). 13C NMR (100 MHz): d = 19.8, 29.7, 64.0, 69.3,
115.9, 116.2, 124.6, 125.2, 128.2, 128.6, 128.7, 129.0, 129.3, 139.1,
-1
+
=
143.6, 151.0, 168.8. IR (KBr) n/cm : 1795 (C O).). MS (ES ):
4014 | Org. Biomol. Chem., 2009, 7, 4009–4016
This journal is
The Royal Society of Chemistry 2009
©

View Article Online
8a: trans-Diastereomer: 1H NMR (200 MHz) d = 0.91 (s,
3 H), 1.26–1.58 (m, 2 H), 1.62–1.78 (m, 4 H), 1.79–2.06 (m, 2
H), 2.21–2.38 (m, 1 H), 5.39 (s, 1 H), 7.22–7.46 (m, 5 H); 13C
NMR (50 MHz) d = 15.5, 25.5, 25.6, 27.8, 28.3, 44.3, 63.3, 79.5,
125.4, 128.3, 128.6, 135.6, 174.5. The spectral data were consistent
with literature values.8h
cis-Diastereomer: 1H NMR (200 MHz) d = 0.89–1.29 (m, 3 H),
1.30–1.53 (m, 5 H), 1.55 (s, 3 H), 1.97–2.08 (m, 1 H), 5.30 (s, 1 H),
7.28–7.44 (m, 5 H); 13C NMR (50 MHz) d = 17.0, 25.6, 25.8,
26.7, 28.2, 39.8, 63.3, 83.7, 126.1, 128.5, 128.6, 135.6, 174.7. The
spectral data were consistent with literature values.8h
129.4, 131.2, 172.2. IR (NaCl) n/cm-1 3055, 2987, 1845, 1422,
1266, 1179, 748.
General experimental procedure for the reaction with ketene 2f.
Ketene 2f (0.6 mmol, 1.62 mL, 0.37 M solution in THF) and
aldehyde 4a or 4d (0.3 mmol) were added at -78 ◦C to toluene
(2 mL) followed by the addition of KHMDS (0.03 mmol, 0.5 M
solution in toluene). The reaction was monitored by TLC. After
15 min the reaction was completed. The reaction was worked up
with sat. NH4Cl(aq) (5 mL) and the aqueous phase was extracted
with CH2Cl2 (3 ¥ 5 mL). The combined organic phases were dried
(Na2CO3) and the solvent removed. The resulting product was
dissolved in THF (5 mL) and LiAlH4 (1.2 mmol) was added. After
1 h stirring the reaction was carefully quenched with 1 M NaOH
(5 mL) and H2O (5 mL). The aqueous solution was extracted with
EtOAc (3 ¥ 5 mL) and the combined phases were dried (Na2SO4)
and the solvent removed. The crude product was purified on silica
gel and the products were eluted with 1:2 diethyl ether–petrol ether
mixture to give the desired compounds as white solids. The spectral
data were consistent with literature values.8h
11a: Ar = Ph, solid, yield 82%. 1H NMR (200 MHz) d = 0.89–
1.29 (m, 3 H), 1.30–1.53 (m, 5 H), 1.55 (s, 3 H), 1.97–2.08 (m, 1 H),
5.30 (s, 1 H), 7.28–7.44 (m, 5 H); 13C NMR (50 MHz) d = 17.0,
25.6, 25.8, 26.7, 28.2, 39.8, 63.3, 83.7, 127.4, 128.4, 137.1, 138.4.
11b: Ar = 4-Me-C6H4-, solid, yield 89%. 1H NMR (200 MHz)
d = 0.81 (s, 3 H), 0.86 (s, 3 H), 2.34 (s, 3 H), 3.15 (s, 2 H), 3.48
(d, J = 10.2 Hz, 1 H), 3.58 (d, J = 10.5 Hz, 1 H), 4.59 (s, 1 H),
7.11–7.59 (m, 4 H). 13C NMR (50 MHz) d = 18.9, 21.7, 22.7, 39.0,
72.0, 82.1, 127.4, 127.5, 128.4, 137.1, 138.4.
General experimental procedure for Table 4. Ketene 2d (93 mg,
0.75 mmol) and an aldehyde 4 or 9 (0.3 mmol) were placed into a
dry Schlenk flask with dry toluene (2 mL) at -78 ◦C. KHMDS
(0.5 M solution in toluene, 0.03 mmol, 10 mol%) was slowly
added. The reaction mixture was stirred for 10 min. The solvent
was removed under reduced pressure giving the crude products
8, which were purified by column chromatography (2/98 diethyl
ether/hexane) to give the desired lactones. For yields see Table 4.
8b: oil; 1H NMR (400 MHz) d = 1.25–1.42 (m, 4 H), 1.55–1.64
(m, 4 H), 1.85–1.90 (m, 2 H), 2.14–2.25 (m, 2 H), 5.30 (s, 1 H),
7.25–7.46 (m, 5 H); 13C-NMR (100 MHz) d = 22.9, 23.8, 29.1,
29.2, 30.4, 35.4, 64.0, 84.2, 125.9, 128.7, 135.5, 175.5. Spectral
data were consistent with literature values.8h
8c: oil, 1H NMR (400 MHz) d = 1.44–1.57 (m, 9 H), 1.74–1.76
(m, 1 H), 1.90–1.94 (m, 1 H), 2.16–2.22 (m, 1 H), 2.30 (s, 3 H),
2.42–2.48 (m, 1 H), 5.40 (s, 1 H), 7.19 (d, J = 8.0 Hz) 7.27–7.35
(m, 2 H), 7.47–7.49 (m, 1 H); 13C NMR (100 MHz) d = 18.4, 22.0,
22.7, 28.4, 28.7, 30.9, 34.9, 62.7, 81.7, 124.4, 125.3, 127.1, 129.2,
128.9, 132.9, 133.1, 174.2. IR (NaCl) n/cm-1 1827, 1458, 1460,
1102, 937.
Acknowledgements
8d: oil, 1H NMR (400 MHz) d = 1.26–1.37 (m, 5 H), 1.60–1.69
(m, 4 H), 1.85–1.90 (m, 1 H), 2.13–2.19 (m, 1 H), 2.27–2.31 (m, 1
H), 5.31 (s, 1 H), 7.30 (d, J = 8.0 Hz, 2 H),7.45 (d, J = 8.0 Hz, 2
H); 13C NMR (100 MHz) d = 22.7, 23.7, 28.98, 29.03, 30.3, 35.2,
64.1, 83.4, 127.2, 128.9, 134.0, 134.4, 175.0. IR (NaCl) n/cm-1
1827, 1460, 1092, 940.
8e: oil, 1H NMR (200 MHz) d = 1.22–1.25 (m, 5 H), 1.50–1.57-
(m, 4 H), 1.70–1.90 (m, 1 H), 1.90–1.94 (m, 1 H), 2.05–2.25 (m,
2 H), 2.30 (s, 3 H), 5.20 (s, 1 H), 7.05–7.18 (m, 4 H); 13C NMR
(50 MHz) d = 21.4, 22.9, 23.8, 29.2, 29.8, 30.3, 35.4, 63.8, 84.3,
125.9, 129.4, 132.5, 138.5, 175.7. IR (NaCl) n/cm-1 1823, 1459,
1260, 1106, 938.
8f: oil, 1H NMR (200 MHz) d = 1.20–1.63 (m, 9 H), 1.84–1.97
(m, 1 H), 2.09–2.37 (m, 2 H), 5.34 (s, 1 H), 7.44 (d, J = 8.0 Hz, 2
H), 7.71 (d, J = 8.0 Hz, 2 H); 13C NMR (50 MHz), d = 22.7, 23.6,
28.9, 29.0, 30.4, 35.3, 64.5, 83.2, 121.2, 125.6, 125.8, 126.1, 130.4,
131.1, 139.5, 174.6. IR (NaCl) n/cm-1 1827, 1512, 1264, 1108, 939.
8g: oil, 1H NMR (200 MHz) d = 1.25–1.45 (m, 4 H), 1.63–1.68
(m, 4 H), 1.82–1.92 (m, 2 H), 2.06–2.32 (m, 2 H), 2.30 (s, 3 H),
5.28 (s, 1 H), 7.07–7.15 (m, 2 H), 7.24–7.31 (m, 2 H); 13C NMR
(50 MHz), d = 22.3, 23.2, 27.8, 28.5, 29.6, 34.8, 63.5, 83.0, 115.2
(d, J = 22 Hz), 127.1 (d, J = 8 Hz), 131.1, 162.2 (d, J = 245 Hz),
174.6. IR (NaCl) n/cm-1 1826, 1512, 1459, 1261, 1109, 939.
10: oil, 1H NMR (200 MHz) d = 1.20–1.91 (m, 10 H), 2.15–2.40
(m, 2 H), 7.24–7.55 (m, 5 H); 13C NMR (50 MHz), d = 22.7, 23.1,
29.3 (q, J = 2.8 Hz), 29.5, 29.7, 34.3, 66.7, 84.7 (q, J = 30.2 Hz),
124.1 (q, J = 281.6 Hz), 125.3 (q, J = 2.2 Hz), 126.5, 128.2, 129.2,
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 Alexander von
Humboldt foundation and S. T. from the DAAD/HEC. Dr
Dra¨ger of the University of Hanover (Germany) is gratefully
acknowledged for HRESI measurements.
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