N-arenesulfonyl-2-aminomethylpyrrolidmes - Novel modular ligands and organocatalysts for asymmetric catalysis

Article abstract of DOI:10.1002/adsc.200404098

A novel series of (S)-N-arenesulfonyl-2-aminomethylpyrrolidines were prepared in high overall yield starting from N-Boc-L-proline. The mono-sulfonyldiamines were evaluated as organocatalysts in the asymmetric α-amination of propanal using diethyl azadicarboxylate (DEAD) as the amine source. The initially formed α-aminated aldehyde was reduced in situ to the corresponding N-aminooxazolidinone, which was obtained in moderate to high yield in up to 87% ee.

Full text of DOI:10.1002/adsc.200404098

COMMUNICATIONS
N-Arenesulfonyl-2-aminomethylpyrrolidines ꢀ Novel Modular
Ligands and Organocatalysts for Asymmetric Catalysis
Nils Dahlin, Anders Bøgevig, Hans Adolfsson*
Department of Organic Chemistry, the Arrhenius Laboratory, Stockholm University, SE-10691 Stockholm, Sweden
Fax: (þ46)-8-154908, e-mail: hansa@organ.su.se
Received: March 26, 2004; Accepted: July 19, 2004
Abstract: A novel series of (S)-N-arenesulfonyl-2-
aminomethylpyrrolidines were prepared in high
overall yield starting from N-Boc-l-proline. The
mono-sulfonyldiamines were evaluated as organoca-
talysts in the asymmetric a-amination of propanal
using diethyl azadicarboxylate (DEAD) as the
amine source. The initially formed a-aminated alde-
hyde was reduced in situ to the corresponding N-
aminooxazolidinone, which was obtained in moder-
ate to high yield in up to 87% ee.
thermore, significantly better solubility properties can
be expected by choosing a proper R group on the sulfon-
yl moiety. In fact, both acidity and solubility can be fine-
tuned by varying the R group and hence a modular cat-
alyst system can be obtained.
Keywords: asymmetric catalysis; diamines; organic
catalysis; pyrrolidines; sulfonamides
In addition, to be potentially useful as an organocata-
lyst the mono-sulfonyl diamine 2 can be expected to
serve as a ligand for transition metal catalysts. Rutheni-
um complexes based on similar mono-sulfonyldiamines,
e.g., TsDPEN (3), have been shown to be powerful and
selective catalysts in asymmetric reduction of ketones
[
4,5]
Asymmetric organocatalysis, using simple enantiomeri- under transfer-hydrogenation conditions.
We have
cally pure amino acid catalysts, has emerged as a power- previously developed dipeptide-like ligands based on
ful tool and alternative to organic processes typically amino acids and amino alcohols for this particular proc-
[6]
catalyzed by either chiral metal complexes or enzymes ess and, based on our results using these catalysts,
and other biocatalysts. In particular, the use of proline along with the successful catalysts developed by Noyori
[
5]
(
1) as the organocatalyst has been highly successful in and co-workers, we envisioned ligand 2 to be of poten-
asymmetric organic transformations involving enamine tial use.
[1,2]
chemistry. Currently there are an extensive number
of reports on reactions catalyzed by proline, and the
common theme in most of the cases is processes showing
high reactivity and stereoselectivity. However, the rath-
er poor solubility of proline in many solvents has result-
ed in the use of sub-stoichiometric amounts of the cata-
lyst, often up to 30 mol %, which effectively reduce the
Herein we present the preparation of a novel class of
turnover number. This drawback has emphasized the pyrrolidines and the preliminary results obtained using
need for further development of novel organocatalysts these compounds in asymmetric catalysis.
[
3]
with better solubility properties. We envisioned the
The preparation of mono-sulfonyl-2-aminopyrroli-
use of mono-N-sulfonyl derivatives of chiral diamines dines was carried out according to the route depicted
[
7]
to be proper alternatives to proline. Such compounds, in Scheme 1. Reduction of N-Boc-protected l-proline
here exemplified by 2, can easily be reached by a few with borane-dimethyl sulfide smoothly generated the
simple transformations starting from proline. Although corresponding (S)-prolinol in 95% yield. Treating the
compound 2 is a diamine, it fulfils all the criteria neces- protected prolinol with tosyl chloride resulted in the for-
sary to work as an organocatalyst in reactions where pro- mation of the sulfonyl ester 6 in high yield. Initially we
line normally is used. The secondary amine allows for a intended to directly transform compound 6 into the de-
reversible formation of the enamine intermediate pres- sired mono-sulfonyl-2-aminomethylpyrrolidine deriva-
ent in proline-catalyzed reactions, and the sulfonyl tive by substituting the tosylate by an appropriate sulfo-
group on the primary amine would effectively increase namide. This substitution was, however, unsuccessful
its acidity to facilitate required proton transfers. Fur- and we obtained no formation of the wanted compound.
Adv. Synth. Catal. 2004, 346, 1101–1105
DOI: 10.1002/adsc.200404098
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1101

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Nils Dahlin et al.
[a]
Table 1. Asymmetric a-amination of aldehydes.
Entry
R
Catalyst
Time
Yield
[%]
ee
[%]
[
b]
[c, d]
[
h]
e
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Et
2a
2b
2c
2d
2e
2a
2a
2a
9
4
9
24
24
23
47
2
58
87 (R)
86 (R)
83 (R)
82 (R)
68 (R)
85 (R)
80 (R)
61 (R)
54
55
70
19
77
88
18
n-C H
i-Pr
5
11
Scheme 1.
[
[
[
[
a]
b]
c]
d]
For reaction conditions, see experimental section.
Yields determined by GLC.
Enantiomeric excess determined by GLC analysis.
In analogy with the l-proline-catalyzed reaction we ob-
tained the same absolute configuration of the major prod-
uct enantiomer, as determined by GLC analysis.
Yield of isolated product.
[
e]
sodium borohydride and the formed N-aminooxazolidi-
none was obtained in 58% yield and 87% ee (entry 1, Ta-
ble 1). Screening the other N-arylsulfonyl-2-aminome-
thylpyrrolidines as catalysts in the same reaction gave
similar results with the only exception being catalyst
Figure 1.
The poor reactivity of tosylate 6 can most likely be 2e which generated the oxazolidinone product in some-
traced to steric hindrance, and we decided to use a less what lower enantioselectivity (entry 5, Table 1). Fur-
hindered nucleophile for the substitution. Displacing thermore, we used catalyst 2a in the reaction between
the tosylate with sodium azide in dry DMSO gave N- other alkyl aldehydes and DEAD. Linear substrates
Boc-(S)-2-azidomethylpyrrolidine (7) in 90% yield. gave yields and selectivity in the same range as obtained
The azide was readily reduced to the mono-protected di- with propanal (entries 6 and 7), whereas the reaction
[
8]
amine 8 using the Staudinger protocol. Compound 8 with a branched substrate resulted in poor yield and low-
served as the common intermediate in the preparation er enantioselectivity (entry 8). Comparing the obtained
of the five mono-sulfonyl-2-aminomethylpyrrolidines results with reactions performed using l-proline as the
presented in Figure 1. Thus, treating diamine 8 with catalyst show that these novel mono-sulfonyldiamines
[11]
the appropriate arenesulfonyl chloride followed by re- are only slightly inferior in inducing asymmetry. On
moval of the carbamate using trifluoroacetic acid gave the other hand, the fact that reasonably high selectivity
compounds 2a–e in good overall yields.
was obtained makes these compounds interesting as po-
With the mono-sulfonyl-2-aminomethylpyrrolidines tential organocatalysts in other asymmetric transforma-
2
a–e in hand, we decided to investigate the catalytic tions, for instance, the analogues a-amination of ke-
[
1c,10c]
properties of these compounds in the a-amination of al- tones.
dehydes using diethyl azadicarboxylate (DEAD) as the
amine source (Scheme 2). This protocol has previously dehydes, we have employed the series of (S)-N-arylsul-
In addition to the enantioselective a-amination of al-
[
9]
been used by Jørgensen and co-workers who showed fonyl-2-aminomethylpyrrolidines as ligands in the
[
1c,10]
that l-proline efficiently catalyzed the reaction.
In ruthenium-catalyzed transfer hydrogenation of aceto-
an initial experiment, propanal was treated with phenone. The reductions were carried out using the fol-
DEAD and catalyst 2a (1 mol %) and the reaction mix- lowing conditions: substrate-ruthenium-ligand-base in a
ture was stirred for 3 h. The reaction was quenched with 100:1:1:3 ratio, with 0.2 M concentration of acetophe-
Scheme 2.
1102
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N-Arenesulfonyl-2-aminomethylpyrrolidines
COMMUNICATIONS
pounds with different electronic and structural proper-
ties. The obtained compounds were employed as orga-
nocatalysts in the asymmetric a-amination of aldehydes
and as ligands for ruthenium in the asymmetric transfer
hydrogenation of prochiral ketones. The best catalytic
results were acquired in the former reaction, where
the isolated N-aminooxazolidinone formed after reduc-
tion of the initial amination product, was obtained in up
to 87% enantioselectivity.
Scheme 3.
Table 2. Asymmetric ruthenium-catalyzed transfer hydroge-
nation of acetophenone.
[a]
[
b]
[c]
Entry Ligand Time [h] Conversion [%]
ee [%]
1
2
3
4
5
2a
2b
2c
2d
2e
4
3
3
4
4
26
12
8
15
18
33 (S)
61 (S)
54 (S)
41 (S)
31 (R)
Experimental Section
[7]
N-Boc-(S)-prolinol
A solution of N-Boc-(S)-proline (4.94 g, 23 mmol) in THF
35 mL) was stirred under nitrogen and cooled to 08C, when
(
[
[
[
a]
For reaction conditions, see experimental section.
Conversion determined by GLC.
Enantiomeric excess determined by GLC analysis.
BH -DMS(4.38 mL, 46 mmol) was carefully added. The reac-
b]
c]
3
tion mixture kept at 08C for an additional 5 h and then left to
warm up overnight. Water (ꢁ80 mL) was carefully added to
quench the reaction. Ethyl acetate (500 mL) was added and
the organic phase was washed with saturated aqueous solutions
of NaCl (80 mL), NaHCO (80 mL), H O (2Â80 mL) and
none in 2-propanol. The pre-catalyst was prepared by
initially drying a mixture of [RuCl (p-cymene)]
3
2
2
2
finally NaCl (80 mL). The organic phase was evaporated under
reduced pressure to yield the crude alcohol, which was purified
by flash chromatography on a silica gel column (eluent:
(
0.5 mol %) and the mono-sulfonyldiamine (1 mol %)
under vacuum for 15 minutes followed by addition of
oxygen-free 2-propanol. The solution was heated to
8
pentane:EtOAc:EtOH, 88:6:6). The yield was 4.37 g
1
08C for 20 minutes and thereafter cooled to room tem-
(
95%). H NMR (400 MHz, CDCl , 258C): d¼1.47 (s, 9H),
3
perature. Acetophenone and sodium hydroxide 1.53 (m, 1H), 1.80 (m, 2H), 2.00 (m, 1H), 3.32 (m, 1H), 3.44
(
3 mol %) were added to the reaction vessel and the (m, 1H), 3.59 (m, 2H), 3.96 (b, 1H), 4.71 (m, 1H).
progress of the reaction was monitored by analyzing
small samples using GLC methods. The results obtained
after 3–4 hours reaction time using the different cata- N-Boc-(S)-2-(4-toluenesulfonyloxy)methylpyrrolidine
lysts are presented in Table 2. The catalytic activity (6)
was rather poor irrespective of the ligand structure,
and the obtained enantioselectivity ranged from 31%
ee up to 61% ee. Prolonging the reaction time did not in-
crease conversion, which suggests that the catalysts were
To an ice-cold solution of N-Boc-(S)-prolinol (4.37 g,
2
1.7 mmol) in pyridine (23 mL) was added 4-toluenesulfonyl
chloride (4.94 g, 25.9 mmol). The reaction mixture was stirred
for 6 h and then diluted with diethyl ether (200 mL). The or-
decomposing during the first period of the reaction. In- ganic phase was washed with 10% HCl (3Â75 mL), NaHCO3
terestingly, in the transfer hydrogenation using the (3Â75 mL) and NaCl (2Â75 mL). The organic phase was
dried over Na SO and the solvent was evaporated under re-
ruthenium catalyst derived from ligand 2e, the opposite
stereoisomer of 2-phenylethanol was obtained as the
major isomer. The reason for this switch in enantioselec-
tivity is presently unknown, but the electronic nature of
the N-arenesulfonyl group in compound 2e is certainly
quite different in comparison to the other ligands used
in this study. This could perhaps influence the stereo-
chemical outcome of the hydride transfer. The poor con-
version and enantioselectivity obtained with these com-
pounds as ligands support the statement by Noyori that
2
4
duced pressure. The crude product was subjected to flash chro-
matography on silica gel (eluent: pentane:EtOAc 3:2). The
yield was 6.47 g (84%). H NMR (400 MHz, CDCl , 608C):
1
3
d¼1.44 (s, 9H), 1.78 (m, 3H), 1.96 (m, 1H), 2.42 (s, 3H), 3.18
(
8
m, 3H), 3.32 (b, 1H), 3.86 (b, 1H), 7.28 (m, 2H), 7.73 (d, J¼
.2 Hz, 2H).
[8b]
N-Boc-(S)-2-azidomethylpyrrolidine (7)
N-Boc-(S)-2-(4-toluenesulfonyloxy)methylpyrrolidine (4.38 g,
12.3 mmol) was dissolved in dry DMSO (130 mL) and sodium
azide (4.81 g, 74.0 mmol) was added. The reaction mixture was
heated to 648C for 19 h, allowed to cool to room temperature
and diluted with diethyl ether (250 mL). The organic phase was
the “presence of an NH terminus in the ligand structure
2
[
4e]
is crucially important” for a successful reduction.
In conclusion, we have successfully prepared a novel
series of modular (S)-N-arylsulfonyl-2-aminomethyl-
pyrrolidines starting from l-proline. The synthetic pro-
tocol is rather straightforward and allows for the intro-
duction of various sulfonyl groups at a late stage in the (2.53 g, 90%), was not further purified and was stored in the re-
synthesis, thereby facilitating the formation of com- frigerator until it was further used. H NMR (400 MHz, CDCl ,
washed with H O (3Â200 mL) and NaCl (100 mL), dried with
2
Na SO and the solvent was evaporated. The crude product
2
4
1
3
Adv. Synth. Catal. 2004, 346, 1101–1105
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1103

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Nils Dahlin et al.
2
1
58C): d¼1.47 s, 9H), 1.86 (m, 4H), 3.37 (m, 4H), 3.80–4.00 (b,
129.2 (2C), 129.0, 128.2, 126.9, 124.6, 124.2, 57.3, 47.1, 46.1,
28.8, 25.6.
H).
[
8b]
N-Boc-(S)-2-aminomethylpyrrolidine (8)
(S)-2-[N-(2,4,6-Triisopropylbenzensulfonyl)amino-
methyl]pyrrolidine (2c)
N-Boc-(S)-2-azidomethylpyrrolidine (0.46 g, 2.0 mmol) was
dissolved in anhydrous THF (17 mL) and triphenylphosphine
Compound 2c was obtained in 55% yield from 8 (two steps).
1
(
1.1 g, 4.1 mmol) followed by H O (0.08 mL, 4.2 mmol) were
H NMR (400 MHz, CDCl , 258C): d¼1.22 (s, 3H), 1.23 (s,
2
3
added. The reaction mixture was heated to reflux until all start-
ing material had been consumed (about 2 h). The organic sol-
vent was then removed under reduced pressure and the re-
maining oil was dissolved in diethyl ether (45 mL). The pH
was adjusted to around 2 with 1 M HCl and vigorous stirring
and the aqueous phase was washed with diethyl ether (2Â
3H), 1.24 (s, 3H), 1.26 (s, 9H), 1.40 (m, 1H), 1.69 (m, 3H),
2.78 (m, 1H), 2.88 (m, 2H), 3.35 (m, 1H), 3.80 (b, 2H), 4.15
1
3
(m, 2H), 7.14 (s, 2H); C NMR (100 MHz, CDCl , 258C):
3
d¼152.5, 150.3, 132.4, 123.7, 57.1, 46.7, 46.2, 34.2, 29.7, 29.1,
25.9, 25.0, 23.6.
2
2
0 mL). The pH of the aqueous phase was adjusted to 13 using
M NaOH, and extracted with CH Cl (6Â20 mL). The organ-
2
2
(
S)-2-(N-Pentametylbenzensulfonylaminomethyl)-
ic phase was dried with Na SO and concentrated under re-
2
4
pyrrolidine (2d)
duced pressure to afford the crude product (0.30 g, 74%). The
1
crude was not further purified. H NMR (400 MHz, CDCl ,
Compound 2d was obtained in 57% yield from 8 (two steps).
3
1
2
1
58C): d¼1.40 (s, 9H), 1.49 (m, 2H), 1.75 (m, 4H), 2.62 (m,
H NMR (400 MHz, CDCl , 258C): d¼1.36 (m, 1H), 1.68 (m,
3
H), 2.77 (b, 1H), 3.26 (m, 2H), 3.75 (m, 2H).
3H), 2.24 (s, 6H), 2.28 (s, 3H), 2.58 (m, 1H), 2.60 (s, 6H), 2.75
(
1
3
m, 1H) 2.88 (m, 2H), 3.29 (m, 1H); C NMR (100 MHz,
CDCl , 258C): d¼139.3, 134.8, 134.3, 126.0, 57.0, 46.9, 46.4,
3
2
9.1, 26.2, 19.0, 17.9, 17.1.
General Preparation of Compounds 2a–e,
Exemplified for the Synthesis of (S)-2-[(N-4-
Toluenesulfonyl)aminomethyl]pyrrolidine (2a)
(
S)-2-(N-Pentafluorobenzensulfonylaminomethyl)-
N-Boc-(S)-2-aminomethylpyrrolidine (0.53 g, 2.62 mmol) was
dissolved in triethylamine (4.6 mL), the solution was cooled to
pyrrolidine (2e)
0
8C and 4-toluenesulfonyl chloride (0.62 g, 3.26 mmol) was
Compound 2e was obtained in 15% yield from 8 (two steps).
1
added. The reaction mixture was stirred for 2 h, diluted with di-
ethyl ether (100 mL) and washed with 10% HCl (40 mL),
NaHCO3 (2Â40 mL) and NaCl (2Â40 mL). The organic
phase was dried with Na SO and purified by flash chromatog-
H NMR (400 MHz, CDCl
3
, 258C): d¼0.85 (m, 1H), 1.69 (m,
2H), 1.97 (m, 1H), 2.99 (t, 1H), 3.34 (d, 1H), 3.60 (m, 1H),
3.90 (m, 2H), 5.77 (b, 1H); C NMR (100 MHz, CDCl ,
1
3
3
258C): d¼146.7, 144.3, 142.4, 132.6, 51.6, 51.5, 48.9, 29.4, 24.5.
2
4
raphy on silica gel (3:1 pentane: EtOAc) to afford the N-Boc-
derivative; yield: 0.48 g (53%).
The N-Boc-derivative (0.48 g, 1.29 mmol) was dissolved in a
:1 mixture of trifluoroacetic acid and dichloromethane
8 mL) and the solution was stirred for 2 h at ambient temper-
ature, at which time the solvent was evaporated under reduced
General Procedure for the a-Amination Exemplified
1
(
for the Formation of (4-Methyl-2-oxooxazolidin-3-
[10]
yl)carbamic Acid Ethyl Ester
pressure. The pH was adjusted to 8 with aqueous NaHCO and
Propanal (0.11 mL, 1.5 mmol) and diethyl azodicarboxylate
(0.16 mL, 1.0 mmol) were suspended in dichloromethane
(2.5 mL). The catalyst 2 (0.01 mmol) was added and the reac-
tion mixture was stirred until the yellow colour disappeared
(3 h) at which time MeOH (2.5 mL) and NaBH4 (50 mg,
1.32 mmol) were added. After 20 min, 0.5 M NaOH (2.5 mL)
was added and the mixture was stirred for 2 h when the organic
solvents were evaporated. The aqueous phase was extracted
with EtOAc and the organic phase was dried with NaSO4.
Evaporation of the solvent yielded the N-aminooxazolidinone.
The enantiomeric excess was determined using GLC using the
following conditions (CP Chirasil DEX CB), oven: 2508C
3
the aqueous phase was extracted with dichloromethane (3Â
20 mL). The combined organic phases were dried with
Na SO and the solvent was evaporated at reduced pressure
2
4
to afford the pure title compound; yield: 0.31 g (90%).
1
H NMR (400 MHz, CDCl , 258C): d¼1.38 (m, 1H), 1.68 (m,
3
3
7
(
H), 2.40 (s, 3H), 2.95 (m, 4H), 3.31 (b, 1H), 4.22 (b, 2H),
13
.27 (d, J¼8.1 Hz, 2H), 7.72 (d, J¼8.2 Hz, 2H); C NMR
100 MHz, CDCl , 258C): d¼143.2, 137.1, 129.8, 127.1, 58.0,
3
4
6.7, 46.1, 28.8, 25.5, 21.6.
3
0 min R : major (1): 15.4 min, minor (2): 15.6 min.
t
(
S)-2-[N-(1-Naphthalenesulfonyl)aminomethyl]-
pyrrolidine (2b)
Compound 2b was obtained in 61% yield from 8 (two steps).
General Procedure for the Catalytic Transfer
Hydrogenation of Acetophenone
1
H NMR (400 MHz, CDCl , 258C): d¼1.25 (m, 1H), 1.59 (m,
3
3
7
1
H), 2.74 (m, 3H), 2.92 (m, 1H), 3.18 (m, 1H), 4.51 (b, 2H),
.48 (m, 3H) 7.90 (m, J¼8.0 Hz, 1H), 8.02 (m, J¼5.2 Hz,
H), 8.21 (m, J¼7.2 Hz, 1H), 8.67 (d, J¼8.5 Hz, 1H);
Compound 2 (0.01 mmol) and [RuCl (p-cymene)] (0.0031 g,
2
2
0.005 mmol) were added to a dried reaction tube and the reac-
tion vessel was put under vacuum for 1 h. The tube was filled
1
3
C NMR (100 MHz, CDCl , 258C): d¼135.0, 134.2, 134.0,
3
1104
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Adv. Synth. Catal. 2004, 346, 1101–1105

N-Arenesulfonyl-2-aminomethylpyrrolidines
COMMUNICATIONS
with N (gas) and 2-PrOH (2.5 mL) was added. The mixture
was heated to 808C for 20 min and then cooled to room temper-
ature. Acetophenone (0.12 mL, 1 mmol) and 3 mol % NaOH
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2
(
0.13 mL of 0.227 M solution in 2-PrOH) were added. Samples
taken at various time-points were passed through a funnel of
silica and washed with ethyl acetate. The solutions were ana-
lyzed by chiral GLC using the following conditions (CP Chira-
sil DEX CB), oven: 1108C 10 min, 808C/min to 2008C, hold
[
5
6
min, Rt: acetophenone: 3.4 min, (R)-1-phenylethanol:
.9 min and (S)-1-phenylethanol: 7.4 min.
Acknowledgements
We would like to thank Dr. A. C o´ rdova for valuable discussions.
This work was supported by the Swedish Research Council and
The Carl Trygger Foundation.
[
6] a) I. M. Pastor, P. Vꢁstilꢁ, H. Adolfsson, Chem. Com-
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[
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4
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