Organocatalytic sequential α-amination/Corey-Chaykovsky reaction of aldehydes: A high yield synthesis of 4-hydroxypyrazolidine derivatives

Article abstract of DOI:10.1021/ol300739b

A tandem reaction of in situ generated α-amino aldehydes with dimethyloxosulfonium methylide under Corey-Chaykovsky reaction conditions proceeds efficiently to give 4-hydroxypyrazolidine derivatives in high yields with excellent enantio- and diastereosele

Full text of DOI:10.1021/ol300739b

ORGANIC
LETTERS
2012
Vol. 14, No. 10
2468–2471
Organocatalytic Sequential r-Amination/
CoreyꢀChaykovsky Reaction of
Aldehydes: A High Yield Synthesis of
4-Hydroxypyrazolidine Derivatives
B. Senthil Kumar, V. Venkataramasubramanian, and Arumugam Sudalai*
Chemical Engineering and Process Development Division, National Chemical
Laboratory, Pashan Road, Pune-411 008, India
a.sudalai@ncl.res.in
Received March 22, 2012
ABSTRACT
A tandem reaction of in situ generated R-amino aldehydes with dimethyloxosulfonium methylide under CoreyꢀChaykovsky reaction conditions
proceeds efficiently to give 4-hydroxypyrazolidine derivatives in high yields with excellent enantio- and diastereoselectivities. This
organocatalytic sequential method provides for the efficient synthesis of anti-1,2-aminoalcohols, structural subunits present in several
bioactive molecules as well.
Pyrazolidines (1), pyrazolines (2), and pyrazoles are an
interesting class of heterocyclic units found in many com-
plex bioactive natural products.1 Among them chiral
hydroxypyrazolidine derivatives represent not only useful
building blocks in the pharmaceutical industry2 but also
powerful intermediates in the preparation of enantiopure
1,3-diamines (3) (Figure 1).3 More importantly, the deri-
vatives of densely functionalized pyrazolidines exhibit a
wide variety of biological acitivities including anticon-
vulsant,4 antidepressant,5 and antitumor6 properties along
with other minor uses (e.g., as brightening agent).7 Gen-
erally, these nitrogen-containing heterocyclic rings are con-
structed by [3 þ 2]-cycloaddition strategies under strongly
acidic (AcOH/H2SO4)8aꢀc as well as thermal conditions
(g150 °C).8dꢀg Their asymmetric versions are reported
employing chiral Zr(OTf)4/BINOL,9 Si-based Lewis acid
derivatives,10 and transition metal (Pd, Ni, Au)-catalyzed
intramolecular annulations.11 However, these methods are
limited because of harsh reaction conditions, complex
(1) (a) Sondhi, S. M.; Dinodia, M.; Singh, J.; Rani, R. Curr. Bioact.
Compd. 2007, 3, 91–108. (b) Elguero, J. In Comprehensive Heterocyclic
Chemistry; Potes, K. T., Ed.; Pergamon: Oxford, 1997; Vol. 5, p 167. (c)
Ellis, J. M.; King, S. B. Tetrahedron Lett. 2002, 43, 5833–5835. (d) Berhr,
L. C.; Fusco, R.; Jarboe, C. H. In Pyrazoles, Pyrazolines, Pyrazolidines,
Indazoles and Condensed Rings; The Chemistry of Heterocyclic Com-
pounds 22; Interscience Publishers: New York, 1967.
(2) (a) Guerra, F. M.; Mish, M. R.; Carreira, E. M. Org. Lett. 2000, 2,
4265–4267. (b) Whitlock, G. A; Carreira, E. M. Helv. Chim. Acta 2000,
83, 2007–2022. (c) Barluenga, J.; Fernandez-Mari, F.; Viado, A. L.;
Aguilar, E.; Olano, B.; Garcia-Granda, S.; Moya-Rubiera, C. Chem.;
Eur. J. 1999, 5, 883–896. (d) Stanovnik, B.; Jelen, B.; Turk, C.; Zlicar,
M.; Svete, J. J. Heterocycl. Chem. 1998, 35, 1187–1204. (e) Mish, M. R.;
Guerra, F. M.; Carreira, E. M. J. Am. Chem. Soc. 1997, 119, 8379–8380.
(f) Lepold, T. P.; Kerr, M. A. Org. Lett. 2009, 11, 4354–4357. (g)
Mederski, W.; Tsaklakidis, C.; Dorsch, D.; Cezanne,B.; Gleitz, J. U.S.
Patent 7,557,102 B2. (h) Chauveau, A.; Martens, T.; Bonin, M.;
Micouin, L.; Husson, H.-P. Synthesis 2002, 1885–1891.
(4) (a) Kornet, M. J.; Garret, R. J. J. Pharm. Sci. 1979, 68, 377–378.
(b) Ozdemir, Z.; Kandilici, H. B.; Gumusel, B.; Calis, U.; Bilgin, A. A.
Eur. J. Med. Chem. 2007, 42, 373–379.
(5) Prasaad, Y. R.; Lakshmana Rao, A.; Prasoona, L.; Murali, K.;
Ravi Kumar, P. Bioorg. Med. Chem. Lett. 2005, 15, 5030–5034.
(6) Brozozowski, Z.; Saczewski, F.; Gdaniec, M. Eur. J. Med. Chem.
2000, 35, 1053–1064.
€
€
(3) (a) Jahn, T.; Konig, G. M.; Wright, A. D.; Worheide, G.; Reitner,
J. Tetrahedron Lett. 1997, 38, 3883–3884. (b) When, P. M.; Du Bois, J. J.
Am. Chem. Soc. 2002, 124, 12950–12951. (c) Morgen, M.; Bretze, S.; Li,
P.; Menche, D. Org. Lett. 2010, 12, 4494–4497. (d) Kammermeier, T.;
Wiegrebe, W. Arch. Pharm. 1995, 328, 409–415. (e) Vickery, K.; Bonin,
A. M.; Fenton, R. R.; O’Mara, S.; Russell, P. J.; Webster, L. K.;
Hambley, T. W. J. Med. Chem. 1993, 36, 3663–3668.
(7) Wang, M.; Zhang, J.; Liu, J.; Xu, C.; Ju, H. J. Lumin. 2002, 99,
79–83.
r
10.1021/ol300739b
Published on Web 05/04/2012
2012 American Chemical Society

procedure for a tandem R-amination/CoreyꢀChaykovsky
reaction of aldehydes 4aꢀk that proceeds to give
4-hydroxypyrazolidine derivatives 6aꢀk in a highly enan-
tio- and diastereoselective manner (Scheme 1).
Scheme 1. In Situ Trapping of R-Amino Aldehydes A with
Dimethyloxosulfonium Methylide
Figure 1. Some bioactive molecules.
chiral pool resources, expensive chiral ligands, and metal
catalysts often involving multistep reaction sequences.
In recent years, proline-catalyzed direct R-amination of
aldehydes has emerged as a reliable method for the en-
antioselective synthesis of R-amino acid derivatives.12 In
this regard, the in situ generated amino aldehyde A was
readily transformed into several functionalized organic
derivatives: e.g., 1,2-aminoalcohols,12a 3,6-dihydropyrida-
zines,13a functionalized β-aminoalcohols,13b and γ-amino-
R,β-unsaturated esters.13c As part of our program directed
toward asymmetric synthesis of bioactive molecules em-
ploying organocatalysts,13c,14 we envisaged that in situ
trapping of amino aldehyde A with Corey’s sulfur ylide
(dimethyloxosulfonium methylide)15,17a under basic condi-
tions should provide the corresponding highly functionalized
terminal amino epoxides 5a. Surprisingly, the reaction
took a different course to furnish the corresponding
4- hydroxypyrazolidine derivatives 6aꢀk in high yields
(Scheme 1). In this communication, we describe a one-pot
As a model substrate, the amination of hydrocinnamal-
dehyde 4a was carried out following the List protocol12a
that produced the corresponding R-amino aldehyde A
in situ. As intermediate A is prone to racemization16 under
basic conditions, several experiments were conducted to
identify the most effective and suitable condition for the
CoreyꢀChaykovsky reaction; the results are presented in
Table 1. First, a solution of dimethyloxosulfonium methy-
lide in DMSO [sulfur ylide (1.5 equiv), prepared in situ
from OdSMe3I/NaH in DMSO]17a was added to inter-
mediate A at 25 °C which gave 6a as a single diastereomer
in 80% yield with 5% ee (low % ee is probably due to
racemization) (entry 1). A dramatic improvement in en-
antioselectivity (75% ee) was however realized by per-
forming the reaction at 10 °C for 2 h. Finally, the
best results could be obtained when the addition of
ylide was conducted at ꢀ5 °C (91% ee with 73% yield).
However, further lowering of the temperature to
(8) (a) Fouchet, B.; Joucla, M.; Hamelin, J. Tetrahedron Lett. 1981,
22, 1333–1336. (b) Shimizu, T.; Hayashi, Y.; Ishikawa, S.; Teramura, K.
Bull. Chem. Soc. Jpn. 1982, 55, 2450–2455. (c) Shimizu, T.; Hayashi, Y.;
Miki, M.; Teramura, K. J. Org. Chem. 1987, 52, 2277–2285. (d) Ibrahim,
Y. A.; Abdou, S. E.; Selim, S. Heterocycles 1982, 19, 819–824. (e)
Badawy, M. A.; El-Bahaie, S. A.; Kadry, A. M.; Ibrahim, Y. A.
Heterocycles 1988, 27, 7–10. (f) Khau, V. V.; Martinelli, M. J. Tetra-
hedron Lett. 1996, 37, 4323–4326. (g) Sun, B.; Adachi, K.; Noguchi, M.
Tetrahedron 1996, 52, 901–914.
(9) (a) Kobayashi, S.; Hirabayashi, R.; Shimizu, H.; Ishitani, H.;
Yamashita, Y. Tetrahedron Lett. 2003, 44, 3351–3354. (b) Kobayashi,
S.; Shimizu, H.; Yamashita, Y.; Ishitani, H.; Kobayashi, J. J. Am. Chem.
Soc. 2002, 124, 13678–13679. (c) Yamashita, Y.; Kobayashi, S. J. Am.
Chem. Soc. 2004, 126, 11279–11282.
(10) (a) Shirakawa, S.; Lombardi, P. J.; Leighton, L. J. J. Am. Chem.
Soc. 2005, 127, 9974–9975. (b) Zamfir, A.; Schenker, S.; Bauer, W.;
Clark, T.; Tsogoeva, S. B. Eur. J. Org. Chem. 2011, 3706–3709.
(c) Zamfir, A.; Tsogoeva, S. B. Synthesis 2011, 1988–1992.
(11) (a) Ma, S.; Jiao, N.; Zheng, Z.; Ma, Z.; Lu, Z.; Ye, L.; Deng, Y.;
Chen, G. Org. Lett. 2004, 6, 2193–2196. (b) Yang, Q.; Jiang, X.; Ma, S.
Chem.;Eur. J. 2007, 13, 9310–9316. (c) LaLonde, R. L.; Wang, Z. J.;
Mba, M.; Lackner, A. D.; Toste, F. D. Angew. Chem., Int. Ed. 2010, 49,
598–601. (d) Suga, H.; Funyu, A.; Kakehi, A. Org. Lett. 2007, 9, 97–100.
(12) (a) List, B. J. Am. Chem. Soc. 2002, 124, 5656–5657. (b) Bogevig,
A.; Juhl, K.; Kumaragurubaran, N.; Zhuang, W.; Jorgensen, K. A.
Angew. Chem., Int. Ed. 2002, 41, 1790–1793. (c) Kumaragurubaran, N.;
Juhl, K.; Zhuang, W.; Bogevig, A.; Jorgensen, K. A. J. Am. Chem. Soc.
2002, 124, 6254–6255. (d) Vogt, H.; Vanderheiden, S.; Brase, S. Chem.
Commun. 2003, 2448–2449.
(16) R-Amino aldehydes are often susceptible to racemization: (a)
Fehrentz, J. A.; Castro, B. Synthesis 1983, 676–678. (b) Rettle, K. E.;
Homnick, C. F.; Ponticello, G. S.; Evans, B. E. J. Org. Chem. 1982, 47,
3016–3018. (c) Lubell, W. D.; Rapoport, H. J. Am. Chem. Soc. 1988, 110,
7447–7455.
(17) General Experimental Procedure: (a) Preparation of sulfur ylide:
0.18 g (7.5 mmol) of NaH (previously washed with petroleum ether to
remove oil) was added to an oven-dried three-necked flask, followed by
the addition of dry DMSO (10 mL) through a septum to it, and the whole
slurry was stirred at 25 °C under a N2 atmosphere. Then trimethylox-
osulfonium iodide (1.67g, 7.5 mmol) was added to the slurry over a
period of 5 min via a solid addition funnel until it became a homogenous
solution. (b) Sequential r-Amination/CoreyꢀChaykovsky Reaction of
Aldehydes: To a cooled solution of azadicarboxylate (5.0 mmol) and
L-proline (10 mol%) in dry CH3CN (20 mL) at 0 °C was added
R-unsubstituted aldehyde (4aꢀk, 5 mmol), and the mixture was stirred
for 3 h at 0 °C. This was followed by the addition of a solution of
dimethyloxosulfonium methylide in DMSO at ꢀ5 °C and allowed to stir
for 2 h at the same temperature. The progress of the reaction can be
monitored by TLC. It was then quenched by the addition of an aq.
NH4Cl solution. The mixture was concentrated in vacuum to remove
acetonitrile and concentrate extracted with diethyl ether (3 ꢁ 40 mL).
The combined organic layers were washed with brine, dried over anhyd.
Na2SO4, and concentrated under reduced pressure to give the crude
products, which were then purified by flash column chromatography
(100ꢀ200 mesh) using petroleum ether and ethyl acetate as eluents to
afford the pure products 6aꢀk.
(13) (a) Oelke, A. J.; Kumarn, S.; Longbottom, D. A.; Ley, S. V.
Synlett 2006, 2548–2552. (b) Chowdari, N. S.; Ramachary, D. B.;
Barbas, C. F., III. Org. Lett. 2003, 5, 1685–1688. (c) Kotkar, S. P.;
Chavan, V. B.; Sudalai, A. Org. Lett. 2007, 9, 1001–1004.
(14) (a) Kotkar, S. P.; Sudalai, A. Tetrahedron Lett. 2006, 47, 6813–
6815. (b) Rawat, V.; Chouthaiwale, P. V.; Chavan, V. B.; Suryavanshi,
G.; Sudalai, A. Tetrahedron Lett. 2010, 51, 6565–6567.
(15) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353–
1364.
Org. Lett., Vol. 14, No. 10, 2012
2469

either ꢀ20 or ꢀ40 °C had a deleterious effect on both
the yield and enantioselectivity.
Table 2. Proline-Catalyzed Asymmetric Tandem R-Amination/
CoreyꢀChaykovsky Reactiona
productsa
Table 1. Proline-Catalyzed R-Amination/CoreyꢀChaykovsky
6aꢀk
Reaction of Hydrocinnamaldehydea
substrates
amine
(R0)
yield
(%)b
ee
(%)c
no.
4aꢀk (R)
1
2
3
4
benzyl (4a)
iPr
iPr
Bn
iPr
73
71
80
74
91
94
90
95
3,4-dimethylbenzyl (4b)
3,4-methylenedioxybenzyl (4c)
2-Br-4,5-methylenedioxybenzyl
(4d)
5
2-CN-4,5-methylenedioxybenzyl
(4e)
iPr
75
75
amine
(R0)
temp
yield of
ee
de
6
naphthalene-1-yl-methyl (4f)
2-NO2-4,5-dimethoxybenzyl (4g)
n-butyl (4h)
iPr
iPr
Bn
Bn
Bn
iPr
70
68
65
66
70
72
90
90
92
91
90
98
no.
1
(°C)
6a (%)b
(%)c
(%)d
7
8
iPr
25
10
ꢀ5
80
75
5
99
99
99
9
4-azidopropyl (4i)
75
10
11
3-benzyloxymethyl (4j)
3-benzyloxypropyl (4k)
73
91
(45)e
52
(79)e
88
ꢀ20
ꢀ40
ꢀ5
99
a Aldehyde (5 mmol), amine source (R0O2C;NdN;CO2R0)
48
84
99
(5 mmol), L-proline (10 mol %), dimethyloxosulfonium methylide
(7.5 mmol). b Isolated yield after column chromatographic purification.
c Determined from chiral HPLC analysis (Chiracel OD-H, Whelk-01
column; n-hexane/2-propanol).
2
3
Bn
71
90
100
100
tBu
ꢀ5
60
80
a Aldehyde (5 mmol), amine (R0O2C;NdN;CO2R0) (5 mmol),
L-proline (10 mol %), dimethyloxosulfonium methylide (7.5 mmol).
b Isolated yield after column chromatographic purification. c Deter-
mined from chiral HPLC analysis (Chiracel OD-H, Whelk-01 columns;
n-hexane/2-propanol). d Product is obtained as a single diastereomer as
determined from 1H, 13C NMR and HPLC analysis. e Refers to 2-[bis-
(3,5-bistrifluoromethylphenyl)trimethylsilanyloxymethyl]pyrrolidine is
used as catalyst.
The absolute configuration of the newly generated
amine center was assigned on the basis of the previously
established configuration of R-amino aldehydes.12a The
anti-stereochemistry in pyrazolidines 6aꢀk is proven un-
ambiguously from COSY and NOESY NMR studies as
well as 18 X-ray crystallographic analysis (Figure 2) and is
also in conformity with the FelkinꢀAhn model.19
Also (S)-R,R-diarylprolinol silyl ether as a modified
proline catalyst was found to be less effective for the
reaction (Table 1, footnote e). We then turned our atten-
tion to briefly investigate the scope of amine sources and
the results of which indicated that diisopropyl- and diben-
zylazadicarbxylates were found to be better candidates
(entries 1 and 2). Use of other solvents such as THF and
CH2Cl2 for the tandem protocol resulted in a sluggish
reaction with poor yields (∼30%).
With the optimized reaction conditions in hand,17b we
next examined the scope of the reaction. Aldehydes bear-
ing bromo, cyano, nitro, methoxy, and methylene-dioxy
groups on the aromatic nucleus and azide and benzyl ether
substitutions in aliphatic compounds were well-tolerated
under the reaction conditions. For all the cases studied,
the products 6aꢀk were indeed obtained in high yields
(65ꢀ80%) and excellent enantioselectivities (75ꢀ98% ee)
with dr >99% (Table 2).
Figure 2. ORTEP diagram of 6a (R0 = tBu).
A probable mechanistic pathway is shown in Scheme 2.
This pathway is supported by the following experimental
1
facts: (a) no aminoepoxide 5a was detected (GC and H
(18) The relative stereochemistry of 6a (R = But) was confirmed by
COSY and NOESY studies. A significant NOESY correlation was
observed between H5a and H4. There was no observed correlation
between H3ꢀH4 confirming the anti relationship between H3 and H4
(see below).
NMR) even at ꢀ40 °C when the reaction was monitored
every 10 min; (b) alternatively, 5a was prepared separately
in two steps from aldehyde A via a Wittig reaction
(Ph3PþMeIꢀ, KOBut, THF, 0ꢀ25 °C, 90%) followed by
epoxidation (MCPBA, CH2Cl2, 25 °C, 92%) and found to
be quite stable under the reaction conditions. This leads us
(19) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 18,
2199–2204.
2470
Org. Lett., Vol. 14, No. 10, 2012

Scheme 2. Probable Mechanistic Pathway
Scheme 3. Synthesis of anti-1,2-Aminoalcohol (6)
and HIV protease inhibitors,21c,d thus constituting an
important application of this methodology (Scheme 3).
Insummary, wehave described, for the first time, a novel
one-pot procedure for a sequential amination/Coreyꢀ
Chaykovsky reaction of aldehydes that leads to the synth-
esis of 4-hydroxypyrazolidine derivatives 6aꢀk with good
yields and excellent enantio- and diastereoselectivities. The
salient features of the methodology are as follows: (1)
metal-free synthesis, (2) milder reaction conditions, (3)
functional group tolerance, and (4) high yields with ex-
cellent enantio- and diastereoselectivity.
to believe that addition of sulfur ylide onto aldehyde A
generates the intermediate B. This in turn is followed by a
facile proton exchange20 from the carbamate nitrogen to
the basic oxide ion to give the stable species C, which then
subsequently undergoes intramolecular cyclization with
the removal of DMSO to afford the products 6aꢀk. A
single step transformation of 6a under catalytic hydroge-
nation conditions [Raney Ni, H2, (80 psig)] gave the
corresponding anti-1,2-aminoalcohol 7, which are com-
mon structural subunits present in phytospingosines21a,b
Acknowledgment. B.S.K. and V.V. thank CSIR, New
Delhi for a research fellowship. Authors also thank Dr. V. V.
Ranade, Chair and Head, Chemical Engineering and Pro-
cess Development Division for his constant encouragement.
(20) Attempts to deuterate the NH proton of carbamate A under
various reaction conditions to ascertain the proton exchange phenom-
ena were unsuccessful.
(21) (a) Karlsson, K.-A.; Martensson, E. Biochim. Biophys. Acta
1968, 152, 230–233. (b) Carter, H. E.; Hirschberg, C. B. Biochemistry
1968, 7, 2296–2300. (c) Erickson, J.; Neidhart, D. J.; VanDrie, J.;
Kempf, D. J.; Wang, X. C.; Norbeck, D. W.; Plattner, J. J.; Rittenhouse,
J. W.; Turon, M.; Wideburg, N.; Kohlbrenner, W. E.; Simmer, R.;
Helfrich, R.; Paul, D. A.; Knigge, M. Science 1990, 249, 527–533.
(d) Bursavich, M. G.; Rich, D. H. J. Med. Chem. 2002, 45, 541–558.
Supporting Information Available. Detailed experimen-
1
tal procedures, H and 13C NMR spectra for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 10, 2012
2471