Enantioselective -chlorination of aldehydes with recyclable fluorous (s)-pyrrolidine-thiourea bifunctional organocatalyst

Article abstract of DOI:10.1055/s-0029-1219198

A novel fluorous (S)-pyrrolidine-thiourea bifunctional organocatalyst is prepared. The catalyst shows good activity and enantioselectivity for direct -chlorination of aldehydes using N-chlorosuccinimide (NCS) as the chlorine source. It can be recovered fr

Full text of DOI:10.1055/s-0029-1219198

LETTER
433
Enantioselective a-Chlorination of Aldehydes with Recyclable Fluorous
(S)-Pyrrolidine–Thiourea Bifunctional Organocatalyst
E
a
nantioselective
i
a
-Chl
a
orination
o
n
A
ldehydes g Wang,a,c Chun Cai,*a Dennis P. Curran,b Wei Zhang*c
Chemical Engineering College, Nanjing University of Science & Technology, Nanjing 210094, P. R. of China
Fax +86(25)84315030; E-mail: c.cai@mail.njust.edu.cn
b
c
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Blvd., Boston, MA 02125, USA
Fax +1(617)2876030; E-mail: wei2.zhang@umb.edu
Received 21 October 2009
scope of applications.12,13 To the best of our knowledge,
there is no literature describing the direct asymmetric a-
chlorination of aldehydes with a thiourea-based bifunc-
tional organocatalyst. According to the mechanism of the
Abstract: A novel fluorous (S)-pyrrolidine–thiourea bifunctional
organocatalyst is prepared. The catalyst shows good activity and
enantioselectivity for direct a-chlorination of aldehydes using N-
chlorosuccinimide (NCS) as the chlorine source. It can be recovered
from the reaction mixture by fluorous solid-phase extraction with secondary amine-catalyzed asymmetric reactions and
excellent purity for direct reuse.
fluorous chemistry, we believe that a fluorous bifunction-
al catalyst 1 containing a secondary amine and a thiourea
should be able to activate and facilitate the reaction pro-
cess (Scheme 1). Moreover, the strong electron-with-
drawing effect of the fluorous tag in the para position
enhances the acidity of the NH proton of the thiourea and
Key words: bifunctional organocatalyst, a-chlorination, a-chloro-
aldehyde, N-chlorosuccinimide (NCS), fluorous catalyst, fluorous
solid-phase extraction (F-SPE)
Currently, there is much interest in organocatalysts due to thus provides a stronger hydrogen-bonding interaction
low toxicity, operational simplicity, efficiency, and good with the substrate. The fluorous tag can provide a handle
stereoselectivity compared to traditional metal-based cat- for the catalyst recovery using F-SPE technique. Herein
alysts.1 However, the need for high catalyst loading (up to we wish to report the preparation of a novel recyclable
20 mol%) and difficult to recover the catalyst are still the fluorous (S)-pyrrolidine–thiourea bifunctional organocat-
issues to be addressed. Recyclable organocatalysts such as alyst 1 and its application in direct a-chlorination of alde-
solid-supported catalysts have been developed,2 the activ- hydes using NCS as the chlorine source.
ity may be effected due to the heterogeneous catalysis en-
vironment.
O
C8F17
S
Recently, fluorous organocatalysts3 have emerged as at-
tractive tools in asymmetric reactions and have showed
high enantioselectivity and recyclability in Michael addi-
tion reaction,4 Diels–Alder reaction5 as well as aldol reac-
O
+
+
N
Cl
R
N
N
H
H
H
N
H
O
1
tion.6
Compared
to
recyclable
heterogeneous
S
organocatalysts, the fluorous organocatalysts are soluble
in common reaction solvents, yet they can be easily sepa-
rated and recovered from the reaction mixture by fluorous
solid-phase extraction (F-SPE).7
N
N
C8F17
H
H
N
O
Asymmetric chlorination is an important reaction because
the chlorinated products are versatile synthetic intermedi-
ates in medicinal chemistry and material science.8 Opti-
cally active a-chlorocarbonyls can be easily converted to
various chiral building blocks.9 In 2004, the enantioselec-
tive direct a-chlorination of unbranched aldehydes was
independently reported by Jørgensen group10 and Mac-
Millan group11 utilizing chiral secondary amine catalysts.
Cl
N
R
O
Scheme 1 Plausible transition state of the chlorination reaction ca-
talyzed by catalyst 1
The N-Boc fluorous (S)-pyrrolidine-thiourea catalyst 5
was prepared via the condensation of 4-(perfluorooc-
tyl)aniline (2) with phenyl chlorothioformate (3) followed
by the substitution of phenol by (S)-tert-butyl 2-(amino-
methyl) pyrrolidine-1-carboxylate (4)14 following Berkes-
sel’s method.15 Subsequent removal of the Boc group in
TFA–CH2Cl2 at 25 °C afforded the catalyst 1 as yellow
solid in 55% yield (Scheme 2).
The use of hydrogen-bonding interactions has become a
popular approach in recent years. In particular, thiourea-
based bifunctional organocatalysts have found a broad
SYNLETT 2010, No. 3, pp 0433–0436
1
2.
0
2.
2
0
1
0
Advanced online publication: 18.01.2010
DOI: 10.1055/s-0029-1219198; Art ID: S12209ST
© Georg Thieme Verlag Stuttgart · New York

434
L. Wang et al.
LETTER
C8F17
S
C8F17
S
DIPEA, pyridine
NH2
+
+
N
N
N
H
H
CH2Cl2
58%
Cl
OPh
N
NH2
Boc
Boc
2
3
4
5
C8F17
S
TFA
N
H
N
CH2Cl2
95%
H
N
H
1
Scheme 2 Preparation of fluorous (S)-pyrrolidine–thiourea bifunctional organocatalyst 1
We first carried out a model reaction involving hydrocin- ed. In the absence of catalyst, trace yield was obtained af-
namaldehyde, NCS, and fluorous bifunctional catalyst 1 ter 24 hours. When 5 mol% of catalyst was used, the
to optimize the reaction conditions. As seen from Table 1, reaction was accelerated and afforded the product in 71%
the solvent had a pronounced effect on both yield and ee yield and 85% ee, while 10 mol% of catalyst was found to
(entries 1–5). Excellent yields were obtained when em- be most efficient. Other secondary amine catalysts such as
ploying CH2Cl2, CHCl3, or DCE as a solvent, while the L-proline and L-prolinamide were also utilized for the
best ee (85%) was found in CH2Cl2.
same reaction. Both catalysts promoted the reaction effec-
tively, but lower ee values were obtained (18% and 76%,
respectively). In order to prove whether the thiourea part
in the catalyst can facilitate the reaction, the reaction was
conducted using thiourea as catalyst. The result indicated
that thiourea could promote the reaction to provide the
product in 52% yield after 12 hours (entry 10).
Table 1 Organocatalyst-Promoted a-Chlorination of Hydrocinnam-
aldehyde with NCSa
O
O
catalyst
H
+
NCS
H
Cl
To demonstrate the scope of the reaction, a series of alde-
hydes were used for chlorination reactions. As revealed in
Table 2, all the reactions proceeded efficiently to furnish
the products in excellent yields (91–99%) and good enan-
tioselectivities (85–95% ee). In all cases the reaction was
found to proceed cleanly and no other byproducts, such as
dichlorosubstitued aldehydes, were formed. The products
listed in Table 2 are known compounds and their relative
and absolute configurations were determined by compar-
ison with the literature 1H NMR and 13C NMR data, and
by chiral HPLC or GC analyses.
Entry Catalyst (mol%)
Solvent Time (h) Yield (%)b ee (%)c
1
2
1 (10)
1 (10)
1 (10)
1 (10)
1 (10)
1 (5)
CH2Cl2
CHCl3
DCE
3
3
3
99
99
99
85
78
82
0
3
4
MeOH <1 min 99d
5
THF
3
3
47
71
<5
99
99
52
29
85
0
6
CH2Cl2
Finally, we performed the catalyst-recovery experiment
using 0.5 mmol of aldehyde and 33 mg of catalyst 1
(Scheme 3). After completion of the reaction, the mixture
was concentrated and then loaded onto a FluoroFlash® sil-
ica gel cartridge for F-SPE.17 It was found that the catalyst
could be recovered in high yield (87%) with excellent pu-
rity (99%). The second-round reaction using the recov-
ered catalyst gave similar product yield and ee. Moreover,
the fluorous catalyst is stable and can be stored at room
temperature for months without any sign of decomposi-
tion.
7
–
CH2Cl2 24
8
L-proline (10)
CH2Cl2
3
3
18
76
0
9
L-prolinamide (10) CH2Cl2
thiourea (10)
10
CH2Cl2 12
a Reaction conditions: hydrocinnamaldehyde (0.5 mmol), NCS (0.65
mmol), solvent (1 mL), 25 °C.
b Measured by GC using benzyl methyl ether as internal standard.
c The ee was determined by chiral HPLC after reduction to the corre-
sponding alcohol.
d Acetalization of aldehyde.
O
O
CH2Cl2, 25 °C
+
H
NCS
H
THF was less efficient, affording the product in 29% ee.
To our surprise, acetalization of aldehyde was found to be
very quick (<1 min) when the reaction was conducted in
methanol. This may be due to the in situ formation of HCl
from NCS, which was accelerated by thiourea part of the
Cl
1st: 99% yield, 85% ee
nd: 99% yield, 86% ee
fluorous catalyst 1
F-SPE recovery
2
recovery yield: 87%
purity: 99%
catalyst.16 The effect of catalyst loading was also evaluat- Scheme 3 Catalyst recycling experiment
Synlett 2010, No. 3, 433–436 © Thieme Stuttgart · New York

LETTER
Enantioselective a-Chlorination of Aldehydes
435
Table 2 Enantioselective a-Chlorination: Substrate Scopea
NMR (300 MHz, CD3OD): d = 7.72–7.69 (d, J = 9 Hz, 2 H), 7.57–
7.54 (d, J = 9 Hz, 2 H), 3.68–3.50 (m, 2 H), 3.48–3.41 (m, 1 H),
2.94–2.92 (m, 2 H), 2.00–1.71 (m, 3 H), 1.58–1.46 (m, 1 H). 13C
NMR (75 MHz, CD3OD): d = 182.84, 143.97, 132.37, 128.74,
127.29, 122.35–106.56 (m, CF2,CF3), 62.23, 47.31, 47.15, 30.38,
26.45. 19F NMR (282.4 MHz, CD3OD): d = –80.82 (m, 3 F), –
110.23 (m, 2 F), –121.33 (m, 2 F), –121.83 (m, 6 F), –122.80 (m, 2
F), –126.21 (m, 2 F). ESI-HRMS: m/z calcd for C20H16F17N3S [M +
H]+ : 654.0872; found: 654.0880.
O
O
1 (10 mol%)
R
+
NCS
H
R
CH2Cl2, 25 °C
H
Cl
Entry
R
Time (h)
Yield (%)b
ee (%)c
86
1
2
3
4
5
6
7
8
Et
2
2
2
2
3
3
3
3
99
97
95
92
96
95
91
99
i-Pr
90
Typical Procedure for the a-Chlorination of Hydrocinnamalde-
hyde and Recycling of the Catalyst
n-Pr
t-Bu
87
Fluorous catalyst 1 (32.65 mg, 0.05 mmol, 10 mol%) was added to
a stirred ice-cooled solution of hydrocinnamaldehyde (65.8 mL, 0.5
mmol) in CH2Cl2 (1.0 mL) followed by the addition of NCS (87 mg,
0.65 mmol). The reaction mixture was stirred for 1 h, then warmed
to 25 °C, and stirred until the aldehyde was completely consumed
as determined by GC analysis (ca. 2 h) using benzyl methyl ether as
internal standard. After the completion of the reaction, the mixture
was concentrated and then loaded onto a FluoroFlash® silica gel
cartridge (2 g) for F-SPE. The cartridge was first eluted with THF–
H2O (80:20, 10 mL) for the all the nonfluorous products, then with
THF (5 mL) for the fluorous catalyst. The combined filtrates of
THF–H2O fraction were extracted with hexane, dried over Na2SO4,
and concentrated to afford the pure 2-chloro hydrocinnamaldehyde
in 99% yield. Then the aldehyde was diluted with MeOH (2 mL),
followed by addition of NaBH4 (100 mg, 2.6 mmol) in several por-
tions. The mixture with stirred for 10 min, quenched with H2O and
extracted with EtOAc. The organic layer was separated and dried
over Na2SO4. After evaporating the solvent, the crude product was
95
n-hexyl
n-nonyl
All
92
91
89
Bn
85d
a Reaction conditions: aldehyde (0.5 mmol), NCS (0.65 mmol),
CH2Cl2 (1 mL).
b Measured by GC using benzyl methyl ether as internal standard.
c The ee was determined by chiral GC.
d The ee was determined by chiral HPLC after reduction to the corre-
sponding alcohol.
In summary, a new fluorous (S)-pyrrolidine–thiourea bi-
functional organocatalyst has been developed. The cata-
lyst shows high activity and enantioselectivity in
asymmetric a-chlorination of aldehydes using inexpen-
sive NCS as a chlorination reagent. Also, the catalyst can
be easily recovered by F-SPE with a good yield and high
purity. Application of this catalyst for other asymmetric
reactions are under investigation and will be reported in
due course.
1
purified by flash column with pentane–EtOAc (4:1) as eluent. H
NMR (300 MHz, CDCl3): d = 7.35–7.22 (m, 5 H, Ar), 4.26–4.18
(dm, J = 24 Hz, 1 H, CHCl), 3.84–3.64 (m, 2 H, OCH2), 3.18–3.01
(m, 2 H, PhCH2), 2.21 (t, J = 6.3 Hz, 1 H, OH). 13C NMR (75 MHz,
CDCl3): d = 137.05, 129.26, 128.52, 126.94, 65.81, 64.74, 40.65.
The ee was determined by HPLC on a Daicel Chiralpak OD-H col-
umn with hexane–i-PrOH (98:2) as eluent; tR (min) = 11.38 (minor);
12.18 (major). The fluorous catalyst, in the THF fraction, was easily
recovered by evaporating the solvent.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
General Procedure for the Fluorous (S)-Pyrrolidine–Thiourea
Bifunctional Organocatalyst
Phenyl chlorothioformate (3, 276 mL, 345 mg, 2 mmol) was added
to a solution of 4-(heptadecafluorooctyl)aniline (2, 1.022 g, 2
mmol) and pyridine (178 mL, 174 mg, 2.2 mmol) in CH2Cl2 (10 mL)
at 25 °C. The mixture was stirred for 2 h, then added slowly to a so-
lution of (S)-tert-butyl 2-(aminomethyl) pyrrolidine-1-carboxylate
(4, 400.4 mg, 2 mmol) in CH2Cl2 (2 mL). N,N-Diisopropylethy-
lamine (331 mL, 259 mg, 2 mmol) was then added, and the mixture
was stirred for 30 min. Sat. aq NaHCO3 (20 mL) was added, the
phases were separated, and the aqueous layer was extracted with
CH2Cl2 (3 × 20 mL). The combined organic layers were washed
with brine (20 mL) and dried over Na2SO4. The solvent was re-
moved under reduced pressure, and the residue was purified by
flash chromatography (EtOAc–hexane = 5:1) to give the N-Boc-
derivative 5 as a white amorphous solid (0.873 g, 58%).
Acknowledgment
We thank Nanjing University of Science & Technology, University
of Massachusetts Boston Joseph P. Healey grant and NIH GMS
(1P50GM067082) for financial support.
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LETTER
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