Mono thiomalonates as thioester enolate equivalents - Enantioselective 1,4-addition reactions to nitroolefins under mild conditions

Article abstract of DOI:10.1039/c1ob06638b

Mono thiomalonates (MTMs) are introduced as thioester enolate equivalents. Asymmetric organocatalyzed conjugate addition reactions to nitroolefins proceed under mild conditions to afford synthetically useful γ-nitrothioesters with excellent yields and ena

Full text of DOI:10.1039/c1ob06638b

View Article Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
Dynamic Article Links
Cite this: Org. Biomol. Chem., 2012, 10, 110
www.rsc.org/obc
PAPER
Mono thiomalonates as thioester enolate equivalents—enantioselective
1,4-addition reactions to nitroolefins under mild conditions†‡
Paolo Clerici and Helma Wennemers*
Received 26th September 2011, Accepted 3rd October 2011
DOI: 10.1039/c1ob06638b
Mono thiomalonates (MTMs) are introduced as thioester enolate equivalents. Asymmetric
organocatalyzed conjugate addition reactions to nitroolefins proceed under mild conditions to afford
synthetically useful g-nitrothioesters with excellent yields and enantioselectivities.
Introduction
Catalytic asymmetric C–C bond formations between thioesters
and electrophiles remain an important challenge in organic
synthesis.1 The resulting chiral thioesters are versatile building
blocks since thioesters allow for further transformations into many
other functional groups such as ketones, aldehydes, or amides.2
The generation of thioester enolates under mild conditions is,
Scheme 1 Mono thiomalonates as thioester enolate equivalents.
however, challenging due to the comparatively low acidity of
the a-proton3 combined with the reactivity of thioesters towards
nucleophiles.4 In recent years mild organocatalytic approaches
utilizing either malonic acid half thioesters (MAHTs), dithioma-
lonates, or electron poor thioesters emerged.5–9 However, the
Results and discussion
tendency of MAHTs to decarboxylate without a concomitant C–
C bond formation and the comparatively low reactivity of the
thioester enolate precursors typically requires the use of large
Evaluation of MTMs and catalysts
We started our investigations by preparing and evaluating the
amounts of the catalyst (≥10 mol%), long reaction times and
carefully chosen reaction conditions.6–10 Thus, there is a need
for robust thioester enolate equivalents that react readily with
electrophiles in the presence of small amounts of an organocatalyst
to form the addition products in high yields and stereoselectivities.
Herein we describe mono thiomalonates (MTMs) bearing a
cleavable ester moiety as effective thioester enolate equivalents.
They were envisioned to provide the addition products of thioester
enolates with electrophiles after cleavage of the ester and decar-
boxylation (Scheme 1). We demonstrate the value of MTMs in
asymmetric organocatalytic reactions with nitroolefins providing
chiral g-nitrothioesters in excellent yields and enantioselectivities.
Furthermore, the synthetic versatility of the g-nitrothioesters for
subsequent transformations is highlighted.
reactivity of MTM 1 bearing an acid labile p-methoxybenzyl
(PMB) ester and an acid stable p-methoxyphenyl (PMP) thioester.
MTM 1 was easily obtained by reacting malonic acid first with
p-methoxybenzylalcohol and then p-methoxythiophenol using
DCC/DMAP as coupling reagent.11 The reactivity of MTM 1
was explored by allowing it to react with nitrostyrene in the
presence of 5 mol% of cinchona alkaloid urea derivatives 2–7
that had previously proven to be valuable for addition reactions
of malonates and MAHTs to nitroolefins.8,12 Satisfyingly, good
to excellent conversion to the conjugate addition product and
stereoselectivities were observed with all of the catalysts using
only a slight excess of 1.1 eq. of nitrostyrene with respect to the
MTM (Table 1, entries 1–6). Also the removal of the PMB group
by trifluoroacetic acid (TFA) and the subsequent base induced
decarboxylation proceeded cleanly.
The best results in terms of reactivity and enantioselectivity
were obtained with the epiquinidine thiourea derivative 6 using
toluene as solvent (Table 1, entry 5). The reactivity of 6 proved
to be sufficiently high to reduce the catalyst loading to as little as
1 mol% (Table 1, entry 11). Lowering the temperature significantly
improved the enantioselectivity. At -50 ◦C the g-nitrothioester was
obtained with an enantioselectivity of 98% ee and a yield of 95%
(Table 1, entry 13).13
Department of Chemistry, University of Basel, St. Johanns-Ring 19, CH-
4056 Basel, Switzerland. E-mail: Wennemers@unibas.ch; Fax: (+41) 61-
267-0976
† Dedicated to Prof. Alfredo Ricci.
‡ Electronic supplementary information (ESI) available: Experimental
details on the synthesis and analyses of the presented compounds. CCDC
reference number 820405. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c1ob06638b
110 | Org. Biomol. Chem., 2012, 10, 110–113
This journal is
The Royal Society of Chemistry 2012
©

View Article Online
Table 1 Conjugate addition reactions of MTM 1 to nitrostyrene cat-
alyzed by cinchona alkaloid derivatives 2–7
Table 2 Scope of conjugate addition reactions of MTM 1 to nitroolefins
entry
R1
mol (%)
yielda (%)
eeb (%)
1
2
3
4
5
Ph
1
1
1
1
1
1
5
1
5
3
1
3
5
20
20
95
96
92
> 98
> 98
> 98
82
> 98
> 98
96
98
85
98
> 98
91
98
99
98
99
98
94
97
99
> 99
97
98
98
91
91
C6H4-2-Cl
C6H4-4-Cl
C6H3-2,4-Cl2
C6H4-4-Br
C6H4-4-F
C6H4-4-NO2
C6H4-2-CF3
b-naphthyl
a-naphthyl
2-thiophene
C6H4-4-OCH3
C6H3-2,4-(OCH3)2
n-hexyl
6
entry cat.
mol (%) time (h) solvent T/◦C conv.a (%) eeb (%)
7c
8
1
2
3
4
5
6
7
8
9
10
11
12
13
2
3
4
5
6
7
6
6
6
6
6
6
6
5
5
5
5
5
5
5
5
5
3
1
1
1
24
6
6
24
6
6
24
24
24
12
24
24
24
toluene RT
toluene RT
toluene RT
toluene RT
toluene RT
toluene RT
CH2Cl2 RT
quant.
quant.
quant.
50
quant.
quant.
quant.
quant.
quant.
quant.
quant.
86 (S)
85 (S)
84 (S)
78 (S)
90 (R)
88 (R)
84 (R)
83 (R)
59 (R)
91 (R)
91 (R)
94 (R)
98 (R)
9d
10
11
12
13
14d,e
15d,e
c-hexyl
94
Et2O
EtOH
RT
RT
a Isolated yield. b Determined by chiral phase HPLC analysis. c Nitroolefin
was not fully soluble. d Reaction took 36 h for complete conversion. e 2 eq.
of nitroolefin with respect to 1 was used.
toluene RT
toluene RT
toluene -15 quant.
toluene -50 95c
stereochemistry at this stereogenic center is scrambled which has,
however, no consequence for the overall enantioselectivity of the
reaction since the stereogenic information at this center is lost
upon decarboxylation.
a Estimated by TLC analysis. b Determined by chiral phase HPLC analysis,
absolute configuration in brackets. c Isolated yield.
Reactions performed in the presence of only a urea derivative did
not provide product and in the presence of only a base (e.g. NEt3
or DABCO) or a base and a non-covalently linked urea derivative
product formation was significantly slower. Thus, the bifunctional
nature of the catalyst is crucial for the catalytic efficiency. Within
the catalyst structure the relative orientation of the base and the
thiourea moiety are important since other bifunctional molecules
bearing these functional groups (e.g. Takemoto catalyst14) exhibit
lower catalytic efficiency. More detailed studies on e.g. the strength
and geometry of intermolecular interactions between the MTM,
the nitroolefin and the catalyst are ongoing.
Substrate scope
With these reaction parameters defined, the scope of reactions
of MTM 1 with a variety of nitroolefins was explored. To our
delight, the conjugate addition reaction products were obtained
in high yields and excellent enantioselectivities for a range of
different b-substituted nitroolefins (Table 2). The best reactivities
were observed with electron poor aromatic nitroolefins (Table
2, entries 2–8), but also electron rich aromatic nitroolefins and
aliphatic nitroolefins reacted readily (Table 2, entries 9–15). The
latter typically required higher amounts of catalyst (3–20 mol%)
and in some cases longer reaction times, but provided the products
also in enantioselectivities of up to 99% ee.
Derivatisation of c-nitrothioesters
These results demonstrate that in comparison to MAHTs
that provide the same products when reacted with nitroolefins,8
the MTMs are significantly more reactive, and thereby allow
for the use of significantly lower amounts of the catalyst, near
equimolar amounts of the reactants and shorter reaction times.
Furthermore, the products were obtained in significantly higher
stereoselectivities and fewer side reactions occur. These features
outweigh the lower atom economy of the MTMs compared to
MAHTs and demonstrate their value as chemically robust yet
sufficiently reactive thioester enolate equivalents.
Initial studies were performed to evaluate the mechanism of
the reaction. The nucleophilic nature of the MTM stems from the
acidity of the a-proton that is higher compared to not only that of
the corresponding thioesters but also malonates.3 Consequently,
the a-proton is also easily abstracted within the initially formed
conjugate addition product of MTM 1 and the nitroolefins. This
is easily monitored by an exchange of the proton by deuterium
in the presence of e.g. deuterated methanol. As a result, the
Finally, we evaluated the versatility of the g-nitrothioesters for
transformations into other compounds and explored various
different functionalization strategies (Scheme 2).
For example, reduction of the nitro group of g-nitrothioester
8i led to the formation of g-butyrolactams, reduction of the
thioester allowed for access to g-nitroaldehydes or by a Fukuyama
coupling to g-nitroketones.2 In all of these transformations the
stereochemistry at the stereogenic center remained intact. These
examples demonstrate that a multitude of different building blocks
that can be further modified are easily accessible from the chiral
g-nitrothioesters.
Conclusions
In summary we have established mono thiomalonates as thioester
enolate equivalents and demonstrated their value in asymmet-
ric conjugate addition reactions with nitroolefins. Under mild
This journal is
The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 110–113 | 111
©

View Article Online
reextracted with CH2Cl2 (3 ¥ 80 ml each). The combined organic
phases were dried over MgSO4 and after a filtration, all volatiles
were removed at reduced pressure to yield a solid that was used
without further purification.
The solid was dissolved in anhydrous CH2Cl2 (75 mL) and 4-
methoxythiophenol (60.0 mmol, 8.4 g 1.2 eq) was added. The
solution was cooled to 0 ◦C and a solution of DCC (75.0 mmol,
15.5 g, 1.5 eq) in CH2Cl2 (25 mL) was added dropwise within
30 min. The reaction mixture was stirred for 30 min at 0 ◦C
and then at r.t. for two hours. The formed urea was removed by
filtration and all volatiles were removed at reduced pressure. The
crude compound was then purified by column chromatography
using a gradient of CH2Cl2/pentane from 7 : 3 to pure CH2Cl2 to
yield MTM 1 (13.8 g, 80%) as a white solid.
Scheme 2 Synthetic versatility of g-nitrothioesters.
1H NMR (400 MHz, CDCl3, 25 ◦C): d = 7.32–7.29 (m, 4H),
6.95 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H), 5.13 (s, 2H), 3.82
(s, 3H), 3.81 (s, 3H), 3.66 (s, 2H); 13C NMR (100 MHz, CDCl3):
d = 191.0, 166.2, 161.4, 160.2, 136.6, 130.7, 127.7, 117.9, 115.4,
114.4, 67.7, 55.8, 55.7, 49.3; IR (KBr) n 2937, 2840, 1733, 1695,
1250 cm-1; MS (ESI): 369 (M + Na); Elemental analysis calcd (%)
for C18H18O5S: C 62.41, H 5.24; found: C 62.56, H 5.20.
organocatalytic conditions synthetically versatile g-nitrothioesters
were obtained in excellent yields and stereoselectivities. Mono
thiomalonate derivatives bearing cleavable esters that are not
sensitive to acid but to e.g. light or hydrogenation are expected to
extend the usefulness of these thioester enolate equivalents further.
We are currently exploring the scope of the mono thiomalonates
in catalytic asymmetric addition reactions with other electrophiles
such as imines and aldehydes.
General procedure for the conjugate addition reactions
The nitroolefin (0.11 mmol, 1.1 equiv), MTM 1 (35.0 mg,
0.10 mmol), and the catalyst (0.001 mmol) were dissolved in
toluene (1 mL) in a capped vial at -50 ◦C. After stirring the
resulting solutions for 24 h, all volatiles were removed at reduced
pressure. The oily residue was then dissolved in a solution of
CH2Cl2 and TFA (2 : 1, 1 mL) and the mixture was stirred for
2 h. After removal of all the volatiles at reduced pressure, the
residue was dissolved in CH2Cl2 (0.5 mL) and DABCO (0.1 mol, 1
eq) was added. The mixture was stirred for 1 h and then purified by
column chromatography on silica gel (gradient of pentane/EtOAc
4 : 1 to 3 : 1; in the case of the aliphatic compounds a gradient of
pentane/EtOAc of 10 : 1 to 5 : 1 was used).
Experimental section
General aspects and materials
Materials and reagents were of the highest commercially available
grade and used without further purification. Reactions were
monitored by thin layer chromatography using Merck silica gel
60 F254 plates. Compounds were visualized by UV and KMnO4.
Flash chromatography was performed using Merck silica gel 60,
1
particle size 40–63 mm. H and 13C NMR spectra were recorded
on a Bruker DPX 400 spectrometer. Chemical shifts are reported
in ppm using TMS or the residual solvent peak as a reference.
HPLC analyses were performed on an analytical HPLC with a
diode array detector from Shimadzu. A Bruker Esquire 3000 Plus
was used for electrospray ionisation (ESI) mass spectrometry. The
1H and 13C NMR spectra as well as HPLC chromatograms for all
new compounds are provided in the supporting information‡.
Analytical data of conjugate addition product
(3R)-4-methoxyphenyl-4-nitro-3-phenylbutanethioate (8a)
◦
1H NMR (400 MHz, CDCl3, 25 C): d = 7.33 (m, 3H), 7.22 (m,
4H), 6.91 (d, J = 8.9 Hz, 2H), 4.75 (dd, J = 6.7 Hz, 12.7 Hz, 1H),
4.66 (dd, J = 8.2 Hz, 12.7 Hz, 1H), 4.05 (m, J = 7.5 Hz, 1H), 3.81 (s,
3H), 3.07 (d, J = 7.4 Hz, 2H); 13C NMR (100 MHz, CDCl3, 25 ◦C):
d = 195.9, 160.7, 137.7, 135.9, 129.2, 128.0, 127.4, 117.4, 114.8,
78.9, 55.3, 45.8, 40.2; MS (ESI): 332 (M + H); HPLC conditions:
Chiracel OD-H column with n-hexane/iPrOH (1 : 1, 40 ◦C) at
0.5 mL min-1, UV detection l = 254 nm: tR: (S) = 26.5 min, (R) =
31.1 min (98% ee). The data is in agreement with that reported
(ref. 8).13
Synthesis of monothiomalonate 1
Malonic acid (100.0 mmol, 10.4 g, 2.0 eq) was dissolved in
anhydrous acetonitrile (75 mL) in an argon atmosphere followed
by addition of 4-(dimethylamino)-pyridine (DMAP) (10 mmol,
1.2 g, 0.2 eq) and 4-methoxybenzyl alcohol (50 mmol, 6.9 g, 1.0
eq). The solution was cooled to 0 ◦C and a solution of N,N¢-
dicyclohexylcarbodiimide (DCC) (75 mmol, 15.5 g, 1.5 eq) in
anhydrous acetonitrile (25 ml) was added dropwise over 30 min.
The reaction mixture was stirred at 0 ◦C for 30 min and then for
additional 2 h at room temperature. The mixture was then filtered
to remove the dicyclohexylurea, and volatiles were removed at
reduced pressure. The crude mixture was re-dissolved in a mixture
of CH2Cl2 (100 mL) and saturated aqueous NaHCO3 (100 mL).
The two phases were separated and the aqueous phase was washed
twice with CH2Cl2. The pH of the aqueous phase was then adjusted
to pH 3 by addition of an aqueous solution of HCl (10%) and
Analytical data of conjugate addition product (3R)-4-
methoxyphenyl-3-(2-chlorophenyl)-4-nitrobutanethioate (8b)
1H NMR (400 MHz, CDCl3, 25 ◦C) d = 7.47–7.42 (m, 1H), 7.31–
7.21 (m, 5H), 6.98–6.91 (m, 2H), 4.86 (dd, J = 10.8, 5.1 Hz, 1H),
4.82 (dd, J = 10.8, 4.4 Hz, 1H), 4.55 (m, J = 7.0 Hz, 1H), 3.84
(s, 3H), 3.24–3.20 (m, 2H). 13C NMR (100 MHz, CDCl3) d =
196.4, 161.3, 136.4, 135.4, 134.2, 130.9, 129.7, 128.8, 127.8, 117.8,
115.4, 77.5, 55.8, 44.5, 37.6. MS (ESI) (%): 366 (M(35Cl) + H)
112 | Org. Biomol. Chem., 2012, 10, 110–113
This journal is
The Royal Society of Chemistry 2012
©

View Article Online
(100), 368 (M(37Cl) + H) (33). Elemental analysis calcd (%) for
C17H16ClNO4S: C 55.81, H 4.41, N 3.83; found: C 55.79, H 4.34,
N 3.83. HPLC: Chiracel OD-H column, n-hexane/i-PrOH (1 : 1,
40 ◦C) at 0.5 ml min-1, UV detection l = 254 nm: tR: (S) = 20.5 min,
(R) = 22.5 min (99% ee).
Utsumi, S. Kitagaki and C. F. Barbas III, Org. Lett., 2008, 10, 3405–
3408; (d) S. Rossi, M. Benaglia, F. Cozzi, A. Genoni and T. Benincori,
Adv. Synth. Catal., 2011, 353, 848–854.
7 (a) A. Ricci, D. Pettersen, L. Bernardi, F. Fini, M. Fochi, R. Perez
Herrera and V. Sgarzani, Adv. Synth. Catal., 2007, 349, 1037–1040;
(b) Y. Pan, C. W. Kee, Z. Jiang, T. Ma, Y. Zhao, Y. Yang, H. Xue and
C.-H. Tan, Chem.–Eur. J., 2011, 17, 8363–8370.
For the analytical data of the conjugate addition products 8c–8o
see the supporting information.
8 J. Lubkoll and H. Wennemers, Angew. Chem., Int. Ed., 2007, 46, 6841–
6844.
9 (a) M. Hatano, K. Moriyama, T. Maki and K. Ishihara, Angew. Chem.,
Int. Ed., 2010, 49, 3823–3826; (b) Z. Jiang, Y. Yang, Y. Pan, Y. Zhao, H.
Liu and C.-H. Tan, Chem.–Eur. J., 2009, 15, 4925–4930; (c) J. Xu, X.
Fu, R. Low, Y.-P. Goh, Z. Jiang and C.-H. Tan, Chem. Commun.,
2008, 5526–5528; (d) W. Ye, Z. Jiang, Y. Zhao, S. L. M. Goh, D.
Leow, Y.-T. Soh and C.-H. Tan, Adv. Synth. Catal., 2007, 349, 2454–
2458.
10 For studies on the reactivity of MAHTs see: (a) M. Furutachi, S. Mouri,
S. Matsunaga and M. Shibasaki, Chem.–Asian J., 2010, 5, 2351–2354;
(b) N. Blaquiere, D. G. Shore, S. Rousseaux and K. Fagnou, J. Org.
Chem., 2009, 74, 6190–6198; (c) K. C. Fortner and M. D. Shair, J.
Am. Chem. Soc., 2007, 129, 1032–1033; (d) N. Sorde´ and S. Matile,
Molecules, 2001, 6, 845–851; see also: (e) J. Blanchet, J. Baudoux, M.
Amere, M.-C. Lasne and J. Rouden, Eur. J. Org. Chem., 2008, 5493–
5506; (f) H. Brunner, J. Mu¨ller and J. Spitzer, Monatsh. Chem., 1996,
127, 845–858.
Acknowledgements
This work was supported by Bachem, the Swiss National Science
Foundation and the RTN REVCAT. H.W. is grateful to Bachem
for an endowed professorship
Notes and references
1 M. Benaglia, M. Cinquini and F. Cozzi, Eur. J. Org. Chem., 2000, 563–
572.
2 T. Miyazaki, X. Han-ja, H. Tokuyama and T. Fukuyama, Synlett, 2004,
477–480.
11 A MTM with a t-Bu instead of the PMB ester was also prepared and
proved to react readily with nitroolefins in the presence of the cinchona
alkaloids. However, generally the enantioselectivity was lower by ~10%
ee compared to that of the PMB protected MTM 1 that was therefore
used for all further studies. For details, see the supporting information‡.
12 (a) J. Ye, D. J. Dixon and P. S. Hynes, Chem. Commun., 2005, 4481–4483;
(b) B. Vakulya, S. Varga, A. Csa´mpai and T. Soo´s, Org. Lett., 2005, 7,
1967–1969; (c) S. H. McCooey and S. J. Connon, Angew. Chem., Int.
Ed., 2005, 44, 6367–6370.
13 The absolute configuration was determined as described in the
supporting information‡ by X-ray crystallography and polarimetric
measurements which are in agreement with an earlier report (R. E.
Zelle, Synthesis, 1991, 1023). Note that the absolute configuration
reported in ref. 8 was based on a comparison of our data with an
inaccurately reported absolute configuration.
3 F. G. Bordwell, Acc. Chem. Res., 1988, 21, 456–463.
4 For selected examples of metal-based approaches see: (a) M. Otsuka,
M. Yoshida, S. Kobayashi and M. Ohno, Tetrahedron Lett., 1981, 22,
2109–2112; (b) C. Gennari, M. G. Beretta, A. Bernardi, G. Moro, C.
Scolastico and R. Todeschini, Tetrahedron, 1986, 42, 893–909; (c) S.
Nagayama and S. Kobayashi, J. Org. Chem., 1997, 62, 232–233; (d) D.
A. Evans, C. S. Burgey, M. C. Kozlowski and S. W. Tregay, J. Am.
Chem. Soc., 1999, 121, 686–699; (e) G. P. Howell, S. P. Fletcher, K.
Geurts, B. ter Horst and B. L. Feringa, J. Am. Chem. Soc., 2006, 128,
14977–14985.
5 For examples of stoichiometric reactions, see: (a) S. J. Sauer, M. R.
Garnsey and D. M. Coltart, J. Am. Chem. Soc., 2010, 132, 13997–
13999; (b) G. Zhou, J. M. Yost, S. J. Sauer and D. M. Coltart, Org.
Lett., 2007, 9, 4663–4665.
6 (a) D. A. Alonso, S. Kitagaki, N. Utsumi and C. F. Barbas III, Angew.
Chem., Int. Ed., 2008, 47, 4588–4591; (b) M. C. Kohler, J. M. Yost, M.
R. Garnsey and D. M. Coltart, Org. Lett., 2010, 12, 3376–3379; (c) N.
14 T. Okino, Y. Hoashi and Y. Takemoto, J. Am. Chem. Soc., 2003, 125,
12672–12673.
This journal is
The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 110–113 | 113
©