“This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Catalysis, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see
https://pubs.acs.org/doi/abs/10.1021/acscatal.7b00360 ”.

Asymmetric [4+2] Annulation Reactions Catalyzed by a Robust,
Immobilized Isothiourea
Shoulei Wang,‡ Javier Izquierdo,‡ Carles Rodríguez-Escrich,‡ and Miquel A. Pericàs*‡§
‡

Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Av. Països Catalans 16, 43007 Tarragona, Spain.
§
Departament de Química Inorgànica i Orgànica, Universitat de Barcelona, 08080 Barcelona, Spain.
ABSTRACT: A polystyrene-supported isothiourea (1a) behaves as a highly efficient organocatalyst in a variety of formal [4+2]
cycloaddition reactions. The catalytic system has proven to be highly versatile, leading to six-membered heterocycles and spiroheterocycles bearing an oxindole moiety in high yields and excellent enantioselectivities (32 examples, including the novel oxindole spiropyranopyrazolones 8). The remarkable chemical stability of 1a under operation conditions results in high recyclability (11
cycles, accumulated TON of 76.8) and allows the implementation of an extended-operation continuous flow process (no decrease in
yield or ee after 18 h).

KEYWORDS. Isothioureas • Enantioselective Catalysis • Solid-Supported Catalysts • Spirocyclic Compounds • Oxindoles
Me

1. INTRODUCTION
Since their introduction by Birman and Okamoto in the last
decade,1 chiral isothioureas have become an important class of
enantioselective organocatalysts.2 As chiral Lewis base catalysts, isothioureas have been explored in a large variety of
asymmetric transformations, including acyl transfer,3 silyl
transfer,4 formal pericyclic5 and domino reactions.6 Considering the importance of this type of catalyst in organic synthesis
and our continuing interest toward the immobilization of homogeneous catalytic species,7 we recently synthesized a polystyrene-supported isothiourea organocatalyst that was successfully applied in the Michael addition/cyclization reaction with
tosylimine derivatives.8 However, applications of this new
immobilized isothiourea catalyst in new transformations have
not been investigated in depth. Herein, we report the first enantioselective formal [4+2] cycloaddition reactions between
several types of unsaturated heterocycles and in situ activated
arylacetic acids in a process catalyzed by an immobilized
isothiourea catalyst that can be operated in batch and flow.
Heterocyclic compounds containing nitrogen-nitrogen and
nitrogen-sulfur arrays are frequently encountered as privileged
structural frameworks in numerous bioactive natural products
and pharmaceuticals.9 Indeed, the pyrazolone, thiazolone or
spiro-oxindole pyrazolone scaffolds can be found in antiplatelet,10 anti-inflammatory,11 anticancer,12 kinase-inhibitor13 and
antibacterial14 compounds (Figure 1). In particular, chiral spirocyclic pyrazolones bearing a quaternary stereocenter (promising subsets of the spirocyclic family) are very interesting,
albeit hardly available from a synthetic perspective.15 Indeed,
despite some synthetic efforts devoted to the synthesis of functionalized pyranopyrazolone derivatives,16 the development of
an efficient methodology for the catalytic asymmetric construction of pyranothiazolones17 and spiro-pyranopyrazolones
bearing a quaternary stereocenter is still a challenging endeavor.

Me

Me

Me

Bn N
N

O
antiplatelet
H 2N

O
O
N
H
anti-inflammatory
H 2N
O
N
NC
NH
O
Me
N
R
antibacterial
N

O

O

N
R
S

NC
Ar

anticancer

Figure 1. Examples of Biologically Active Pyrazolone and Thiazolone Derivatives.

The exploitation of chiral isothioureas in asymmetric transformations via asymmetric ammonium enolate addition is a
well-developed and powerful synthetic strategy.18 Romo et al.
have pioneered the in situ generation of ammonium enolates
from carboxylic acids and their application to a range of aldollactonization reactions.19 Building upon this work, Smith et al.
have recently utilized chiral isothioureas to promote the intraand intermolecular asymmetric functionalization of carboxylic
acids through a Michael-lactonization cascade reaction,20
which has also been described with NHC catalysts.16d, 17, 21
However, the use of isothioureas to promote an asymmetric
Michael-lactonization sequence where a quaternary stereocenter is created remains underexplored due to the low reactivity
of most substrates. Given the manifold interest of heterocycles
of these classes, we wish to report a highly enantioselective
version of the ammonium enolate addition involving unsaturated heterocycles and thus leading to a variety of optically
pure, functionalized six-membered heterocycles bearing a
tertiary or quaternary stereocenter (Scheme 1).

Scheme 1. Formal [4+2] Cycloaddition with Unsaturated
Heterocycles.
Het

R1

O

O
+ R3

R2

nucleophilic
center

R3

R1 R2

O

electrophilic
center

O

BTM

Het

R3

Het

BTM

BTM O

R2

R1

quaternary
stereocenter

O

tertiary
stereocenter

2. RESULTS AND DISCUSSION
We initiated our study by investigating the reaction of alkylidene pyrazolone 2a with phenylacetic acid 3a, using
pivaloyl chloride as a reagent to activate in situ the carboxylic
acid (Table 1). Inspired by previous works, a protocol based
on immobilized isothiourea 1a, PivCl, and i-Pr2NEt in CH2Cl2
at room temperature led to full conversion and provided the
desired product in good diastereoselectivity and excellent enantioselectivity (entry 1). In contrast, when homogeneous benzotetramisole (BTM, 1b) was employed, only moderate diastereoselectivity was observed, albeit conversion and enantioselectivity remained the same (entry 2). This points out to an
intimate interplay of steric effects that takes place due to the
additional stereocenter present in 1a (the handle for immobilization).

Table 2. Scope of the [4+2] Cycloaddition: Alkylidene Pyrazolones.a

Table 1. Optimization of Reaction Conditions.a
Cat. 1a (10 mol%) Me
OH PivCl (2.0 equiv.)
i-Pr2NEt (2.5 equiv.) N

Me
N
N
O
Ph 2a

Ph Ph
+

O
3a
N
N N

O

Ph

N
S

N
Ph

CH2Cl2 (0.1 M)
2h

N

1a

showed negative impacts on either reactivity or selectivity
(entries 6 and 7). We next studied the effect of the relative
amounts of the different reactants (see the SI for details) and
found that reducing the amount of i-Pr2NEt to 2.0 equivalents
afforded the best result in terms of diastereo- and enantioselectivity (entry 8). On the other hand, decreasing the catalyst
loading to 5 mol% resulted in lower stereoselectivity (entry 9).
With the reaction conditions optimized for 2a, we investigated the substrate scope for this asymmetric cycloaddition
reaction. As shown in Table 2, the course of the reaction was
insensitive to electronic changes at the meta and para positions of the aromatic substituent R1 on alkylidenepyrazolones.
Specifically, substrates with these substitution patterns (2b-2g)
underwent reaction in good yields (71-84%), high diastereoselectivities (5:1 to 9:1 dr) and excellent enantioselectivities (9799% ee),	 both for electron-withdrawing or electron-donating
m- or p- substituents. The ortho-substituted derivative 2h required longer reaction times (6 h), but gave the desired product 4h in excellent diastereoselectivity (>20:1 dr), comparable
enantioselectivity (99% ee) and good yield (68%). Furthermore, 4i bearing a heteroaromatic 2-thienyl group was also
formed in good yield, excellent diastereoselectivity, and comparable ee (96%). On the other hand, the use of alkylsubstituted acetic acids failed to give good levels of conversion (see Supporting Information for unsuccessful substrates).

Ph
Ph

Me
+ Ph

N
O
4a

O

OH

R1

N
Ph

O

O
2

3a

Cat. 1a (10 mol%) Me
PivCl (2.0 equiv.)
i-Pr2NEt (2.0 equiv.)
N
CH2Cl2 (0.1 M)
N
2h
Ph

R1
Ph
O

O
4

Entry
N

Yield (%)
(4)b

drc

ee
(%)d

1

Ph (2a)

83 (4a)

9:1

99

2

4-Br-C6H4 (2b)

83 (4b)

9:1

99

Ph
N

S

R1 (2)

1b

Entry

Modification of std. conditions

Conv.
(%)b

drb

ee
(%)c

3

4-Cl-C6H4 (2c)

81 (4c)

7:1

98

4

82 (4d)

8:1

98

1

Standard conditions

> 95

8:1

98

4-F-C6H4 (2d)

5

5:1

99

Using 1b as the catalyst

> 95

3:1

98

4-Me-C6H4 (2e)

72 (4e)

2

6

84 (4f)

7:1

97

3

Using Et3N as the base

> 95

5:1

98

3-Cl-C6H4 (2f)

7

7:1

99

Using PhCOCl instead of PivCl

55

5:1

98

3-Me-C6H4 (2g)

71 (4g)

4

8

>20:1

99

With TsCl instead of PivCl

76

7:1

98

2-MeO-C6H4 (2h)

68 (4h)

5

9

2-thienyl (2i)

81 (4i)

6:1

96

6

With THF instead of CH2Cl2

90

3:1

98

7

With toluene instead of CH2Cl2

60

6:1

96

8

Using 2.0 equiv. i-Pr2NEt

> 95

9:1

99

9

Using 5 mol% catalyst

81

5:1

98

a
Reactions performed on a 0.1 mmol scale (see Supporting
Information). b Determined by 1H NMR spectroscopy. c Determined by chiral HPLC.

Evaluation of the effect of the base employed showed that
Et3N led to lower diastereoselectivity (entry 3). Changing the
activating reagent for PhCOCl and TsCl (entries 4 and 5) did
not improve the results. Subsequently, solvent screening

e

a

Reactions performed on a 0.1 mmol scale (see Supporting
Information). b Isolated yield. c Determined by 1H NMR spectroscopy. d Determined by chiral HPLC. e Reaction time: 6 h.

Next, the [4+2] cycloaddition with a variety of arylacetic acids was investigated under the optimized conditions (Scheme
2). A range of arylacetic acids with diverse electronic and
steric properties worked well, giving rise to cycloadducts 4j4n in good yields (73-86%), excellent ee’s (96-99%) and good
diastereoselectivities (5:1-13:1 dr). Acid 3o, bearing an Nmethylindole substituent, showed no decrease in yield or stereoselectivity.

Scheme 2. Scope of the [4+2] Cycloaddition: Arylacetic
Acids.
Cat. 1a (10 mol%)
Me
OH PivCl (2.0 equiv.)
i-Pr2NEt (2.0 equiv.)
N
O
CH2Cl2 (0.1 M)
N
2h
Ph
3

Me
Ph + R2

N
N
O
Ph 2a

Br

R2
O

O

4

Me

OMe

4j: 75%
7:1 dr
98% ee

Ph

4k: 82%
6:1 dr
98% ee

4l: 86%
6:1 dr
99% ee

OMe

NMe

OMe
4m: 73%
5:1 dr
98% ee

4n: 81%
13:1 dr
96% ee

4o: 85%
5:1 dr
97% ee

Dihydropyranothiazolones are another class of nitrogensulfur heterocycles present in several drug candidates. This
encouraged us to study their ability to be engaged as substrates
in an analogous transformation. Gratifyingly, cycloadducts 6
could be accessed under similar reaction conditions. Following
a brief screening of reaction conditions, the reaction of alkylidenethiazolone 5a with substituted arylacetic acids furnished
dihydropyranothiazolones (6a-6e, Scheme 3) in excellent enantio- (99%) and diastereoselectivities (>20:1 dr), with yields
ranging 68–77%.

ee). Based on this observation, we wondered whether an isatin
derivative of the pyrazolone, would undergo the annulation
reaction thanks to the less sterically demanding nature of the
substrate. This would give rise to functionalized dihydropyranopyrazolones bearing a spirocyclic quaternary stereocenter.
With this in mind, we first synthesized an N-methyl isatinderived pyrazolone and performed the cascade [4+2] reaction
at 0 ºC. To our delight, the corresponding spiropyranopyrazolone 8b was obtained in 88% yield with excellent enantioselectivity in a very short reaction time (30 min). The minor,
anti diastereoisomer was also isolated with high ee values. It is
worth mentioning that, to the best of our knowledge, this is the
first synthesis of optically pure spirocyclic oxindolepyranopyrazolone scaffolds.22 Biological studies to assess the
therapeutic potential of these unique structures are currently
underway.
Subsequent studies showed the generality of this approach
to assemble a range of optically active substituted spiropyranopyrazolones under the established optimal reaction conditions. As indicated in Scheme 4, variations in the electronic
properties of the substituents on the benzene ring of the arylacetic acid 3 were investigated and the corresponding spirocyclic adducts (8b-8g) were isolated in good yields (81-91%)
with high ee’s and moderate diastereoselectivities. To emphasize the generality of our approach, various N-substituted isatin-derived pyrazolones were also tested and participated
equally well in the reaction (8h-8j). Furthermore, the extension of the substrate range to electron-poor or electron-rich
substituted N-methyl isatin-derived pyrazolones was well tolerated, providing the [4+2] annulation products in good yields
and excellent ee’s (8k-8l).
The absolute configuration given for all of the dihydropyranopyrazolones 4, dihydropyranothiazolones 6 and spiropyranopyrazolones 8 is based on the X-ray analysis of the major
diastereoisomers 4b, 6a, 8c and minor diastereoisomer 8c´
(see Figure 2 and SI).

Scheme 3 Scope of Substituted Arylacetic Acids with a 5Alkylidene Thiazolone.
Ph
S
Ph
N
5a

OH

+ R2

O

O
3

Cat. 1a (10 mol%)
PivCl (2.0 equiv.)
i-Pr2NEt (2.0 equiv.)

Ph
Ph

CH2Cl2 (0.1 M)
6h

Ph

R2

S
N

O

6a

Me

6b: 70%
> 20:1 dr
99% ee

Me
6d: 71%
> 20:1 dr
99% ee

4b

6

F

6a: 77%
> 20:1 dr
99% ee

O

6c: 73%
> 20:1 dr
99% ee

Me
6e: 68%
> 20:1 dr
99% ee

With the aim of probing the versatility of this strategy, we
prepared different disubstituted alkylidenepyrazolones, which
would afford the corresponding cycloadducts bearing an allcarbon quaternary stereocenter (see Scheme 4 and SI). While
most disubstituted alkylidenepyrazolones did not engage in the
reaction, the isopropylidene derivative afforded the desired
product 8a in poor yield but excellent enantioselectivity (96%

8c

8c'

Figure 2. X-ray structures; 4b: CCDC 1519361; 6a: CCDC
1519360; 8c: CCDC 1519359; 8c’: CCDC 1519358.

From a practical perspective, the use of an immobilized
isothiourea catalyst offers the inherent advantages of easy
recovery and reuse. Under the standard conditions, we explored the recyclability of catalyst 1a in the reaction of alkylidene pyrazolone 2a with phenylacetic acid 3a as model substrates. After each run, the catalyst could be recovered by simple filtration and reused in the next cycle by adding fresh

Scheme 4. Scope of the Reaction Between Different Disubstituted Alkylidene Pyrazolones and Arylacetic Acids.
Ph
N N
Me

O

+

OH

R3

Cat. 1a (20 mol%)
PivCl (2.0 equiv.)
i-Pr2NEt (2.0 equiv.)

O
R1

Ph
N
N

O

O

R2

3

O

O

Ph
N
N

Ph

Ph

Me

8a: rt, 48 h
21% yield, 96% ee
O
Me
O
Ph
N
Me
N
O
Me
N
Me
8d: 91% yield,
3:1 dr, 98% ee

O
Ph

7

O

Ph
N
N
O Me

N
Boc
8h: 76% yield
3:1 dr, 97% ee

Me
CO2Me
48 h
< 5% yield
O
O
Ph
N
N
O
Me
N
Me
8e: 88% yield
3:1 dr, 97% ee
O
Ph
O
N
Ph
N
O Me
N
COtBu
8i: 75% yield
4:1 dr, 97% ee
Ph

reactants. Keeping the reaction time constant, nine consecutive
reaction cycles were performed with 10 mol% of resin 1a,
affording the cycloadducts with constant stereoselectivity and
only marginal erosion in the yield (Scheme 5). To gain insight
into the recyclability profile of 1a, the same catalyst was used
in two more cycles (reaching a total of 11) increasing the reaction time to 24 h. Under these conditions, product 4a was obtained in higher yields and slightly lower enantioselectivities.
The accumulated TON for the whole recycling experiment
was 76.8. Indeed, the robustness of this catalytic system was
further proven by implementing an 18-h continuous flow experiment that provided 2.74 g of 4a (67% yield and 99% ee) as
a single diastereomer (see section 7 of the SI for details).
The proposed catalytic cycle for these transformations
(Scheme 6) proceeds through initial in situ formation of the
mixed anhydride A from the arylacetic acid, followed by formation of the corresponding acyl ammonium species B. This
is deprotonated by pivalate (the amine is just a shuttle base)23
to generate an enolate (C) which undergoes stereoselective
conjugate addition (D), followed by lactonization, giving the
cycloadduct product E and regenerating the immobilized
isothiourea. The proposed approaches of dihydropyranopyrazolone 4 and dihydropyranothiazolone 6 are in accordance	
to previous reports and configurational analysis. Our current
working hypothesis involves an epimerization of the stereocenter a to the lactone C=O, a situation that has been observed
for related systems20e (see Section 9 in the SI for details).
Scheme 5. Recyclability Test.

R3

CH2Cl2 (0.1 M)
15-40 min, 0 ºC

O

Ph
N
N

O

O

R1

R2

O

Cl

Ph

O

Me
8

O

N
N

Ph

O
Me
N
Me
8b: 88% yield
2:1 dr, 96/83% ee
O
O

Ph
N
N

O
Me
N
Me
8f: 86% yield
3:1 dr, 87% ee
O
Ph

X

Me

Cat. 1a (10 mol%)
PivCl (2.0 equiv.)
OH i-Pr NEt (2.0 equiv.)
2

Ph
+ Ph
O
2a

Ph
N
N

O Me
N
Me
8k (X = Cl): 82%, 4:1 dr, 93% ee
8l (X = OMe): 92%, 3:1 dr, 96% ee

N
H
8j: 78% yield
2:1 dr, 98% ee

N
Ph

O

Ph

O Me

N

O
Me
N
Me
8c: 89% yield,
2.5:1 dr, 89/80% ee
O
O
S
Ph
N
N
O
Me
N
Me
8g: 81% yield
3:1 dr, 93% ee
O

Ph
N
N

O

Ph
N
N

O
3a

CH2Cl2 (0.1 M)
2h

Me

Ph
Ph

N
N
Ph

O

O

4a

100
80
60
40
20
0

Yield

ee

3. CONCLUSIONS
In summary, we have disclosed an asymmetric polystyrenesupported isothiourea catalyzed formal [4+2] cycloaddition of
unsaturated heterocycles with in situ activated arylacetic acids.
The annulation strategy described represents an efficient approach to access a series of dihydropyranopyrazolone and
dihydropyranothiazolone derivatives, as well as spiropyranopyrazolones bearing a quaternary stereocenter, in excellent yields and stereoselectivities. Compared to its homogeneous counterpart, 1a displays higher stereoselectivity and the
same reactivity. In addition, it can be recycled at least eleven
times by simple filtration of the reaction mixture. Finally, the
implementation of a continuous flow process with this catalytic resin illustrates the benefits of this approach. Further appli-

cation of the polystyrene-supported isothiourea catalyst and
biological evaluation of the heterocycles prepared is currently
underway.

Scheme 6. Proposed Catalytic Pathway.
O

R=
R1

R2

N
N N

R3
PivCl

RO

R3

O

Het

O
E

N

O

R3

Ph

S

O

S

O

R1

R3

R3

N

N
Het

O
OR

S
N

H

Ph

D

O

t-Bu
O
A
acylation

N

lactonization

R2

OH
i-Pr2NEt

N
OR
Ph

B
PivO

S

O

conjugate
addition

R3

Het

R1

O

N

R2

Ph

deprotonation

PivOH

N
OR
C

i-PrNEt2
i-PrNEt2·PivOH

ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Electronic Supplementary Information (ESI) available: synthetic
procedures, characterization data, copies of NMR spectra and
HPLC chromatograms (PDF)

AUTHOR INFORMATION
Corresponding Author
* E-mail: mapericas@iciq.es

ACKNOWLEDGMENT
Financial support from CERCA Programme / Generalitat de Catalunya, MINECO (grant CTQ2012-38594-C02-01 and Severo
Ochoa Excellence Accreditation 2014-2018: SEV-2013-0319) and
DEC Generalitat de Catalunya (Grant 2014SGR827) is acknowledged. The CELLEX Foundation is also gratefully acknowledged
for financing the High Throughput Experimentation (HTE) laboratory.

REFERENCES
1. (a) Birman, V. B.; Jiang, H.; Li, X.; Guo, L.; Uffman, E. W. J.
Am. Chem. Soc. 2006, 128, 6536-6537; (b) Birman, V. B.; Li, X. Org.
Lett. 2006, 8, 1351-1354; (c) Kobayashi, M.; Okamoto, S.
Tetrahedron Lett. 2006, 47, 4347-4350; (d) Birman, V. B.
Aldrichimica Acta 2016, 49, 23-33; (e) Merad, J.; Pons, J.-M.;
Chuzel, O.; Bressy, C. Eur. J. Org. Chem. 2016, 2016, 5589-5610.
2. (a) Díaz-de-Villegas, M. D.; Gálvez, J. A.; Badorrey, R.; LópezRam-de-Víu, M. P. Chem. Eur. J. 2012, 18, 13920-13935; (b)
Enriquez-Garcia, A.; Kundig, E. P. Chem. Soc. Rev. 2012, 41, 78037831; (c) Taylor, J. E.; Bull, S. D.; Williams, J. M. J. Chem. Soc. Rev.

2012, 41, 2109-2121; (d) Morrill, L. C.; Smith, A. D. Chem. Soc. Rev.
2014, 43, 6214-6226.
3. (a) Yang, X.; Birman, V. B. Adv. Synth. Catal. 2009, 351, 23012304; (b) Yang, X.; Birman, V. B. Angew. Chem. Int. Ed. 2011, 50,
5553-5555; (c) Yang, X.; Liu, P.; Houk, K. N.; Birman, V. B. Angew.
Chem. Int. Ed. 2012, 51, 9638-9642; (d) Yang, X.; Birman, V. B.
Chem. Eur. J. 2011, 17, 11296-11304; (e) Bumbu, V. D.; Birman, V.
B. J. Am. Chem. Soc. 2011, 133, 13902-13905; (f) Shiina, I.; Nakata,
K.; Ono, K.; Onda, Y.-s.; Itagaki, M. J. Am. Chem. Soc. 2010, 132,
11629-11641; (g) Liu, P.; Yang, X.; Birman, V. B.; Houk, K. N. Org.
Lett. 2012, 14, 3288-3291; (h) Li, X.; Jiang, H.; Uffman, E. W.; Guo,
L.; Zhang, Y.; Yang, X.; Birman, V. B. J. Org. Chem. 2012, 77,
1722-1737; (i) Bumbu, V. D.; Yang, X.; Birman, V. B. Org. Lett.
2013, 15, 2790-2793.
4. (a) Wang, L.; Akhani, R. K.; Wiskur, S. L. Org. Lett. 2015, 17,
2408-2411; (b) Clark, R. W.; Deaton, T. M.; Zhang, Y.; Moore, M. I.;
Wiskur, S. L. Org. Lett. 2013, 15, 6132-6135; (c) Akhani, R. K.;
Moore, M. I.; Pribyl, J. G.; Wiskur, S. L. J. Org. Chem. 2014, 79,
2384-2396; (d) Sheppard, C. I.; Taylor, J. L.; Wiskur, S. L. Org. Lett.
2011, 13, 3794-3797.
5. (a) Leverett, C. A.; Purohit, V. C.; Johnson, A. G.; Davis, R. L.;
Tantillo, D. J.; Romo, D. J. Am. Chem. Soc. 2012, 134, 13348-13356;
(b) Smith, S. R.; Douglas, J.; Prevet, H.; Shapland, P.; Slawin, A. M.
Z.; Smith, A. D. J. Org. Chem. 2014, 79, 1626-1639; (c) Morrill, L.
C.; Smith, S. M.; Slawin, A. M. Z.; Smith, A. D. J. Org. Chem. 2014,
79, 1640-1655.
6. (a) Liu, G.; Shirley, M. E.; Van, K. N.; McFarlin, R. L.; Romo,
D. Nature Chem. 2013, 5, 1049-1057; (b) Fukata, Y.; Asano, K.;
Matsubara, S. J. Am. Chem. Soc. 2015, 137, 5320-5323; (c) Robinson,
E. R. T.; Fallan, C.; Simal, C.; Slawin, A. M. Z.; Smith, A. D. Chem.
Sci. 2013, 4, 2193-2200; (d) Pandiancherri, S.; Ryan, S. J.; Lupton, D.
W. Org. Biomol. Chem. 2012, 10, 7903-7911; (e) Abbasov, M. E.;
Hudson, B. M.; Tantillo, D. J.; Romo, D. J. Am. Chem. Soc. 2014,
136, 4492-4495.
7. (a) Sagamanova, I.; Carles Rodríguez-Escrich, C.; Molnár, I. G.;
Sayalero, S.; Gilmour, R.; Pericàs, M. A. ACS Catal. 2015, 5, 62416248; (b) Pericàs, M. A.; Castellnou, D.; Rodríguez, I.; Riera, A.;
Solà, L. Adv. Synth. Catal. 2003, 345, 1305-1313; (c) Castellnou, D.;
Solà, L.; Jimeno, C.; Fraile, J. M.; Mayoral, J. A.; Riera, A.; Pericàs,
M. A. J. Org. Chem. 2005, 70, 433-438; (d) Martin-Rapun, R.;
Sayalero, S.; Pericàs, M. A. Green Chem. 2013, 15, 3295-3301; (e)
Popa, D.; Marcos, R.; Sayalero, S.; Vidal-Ferran, A.; Pericàs, M. A.
Adv. Synth. Catal. 2009, 351, 1539-1556; (f) Kasaplar, P.; Riente, P.;
Hartmann, C.; Pericàs, M. A. Adv. Synth. Catal. 2012, 354, 29052910; (g) Fan, X.; Rodríguez-Escrich, C.; Wang, S.; Sayalero, S.;
Pericàs, M. A. Chem. Eur. J. 2014, 20, 13089-13093.
8. Izquierdo, J.; Pericàs, M. A. ACS Catal. 2016, 6, 348-356.
9. (a) Elfahham, H. A.; Abdel-Galil, F. M.; Ibraheim, Y. R.;
Elnagdi, M. H. J. Heterocycl. Chem. 1983, 20, 667-670; (b) Khan, M.
A.; Cosenza, A. G.; Ellis, G. P. J. Heterocycl. Chem. 1982, 19, 10771085; (c) Hofmann, B.; Barzen, S.; Rödl, C. B.; Kiehl, A.; Borig, J.;
Živković, A.; Stark, H.; Schneider, G.; Steinhilber, D. J. Med. Chem.
2011, 54, 1943-1947; (d) Rudolph, J.; Chen, L.; Majumdar, D.;
Bullock, W. H.; Burns, M.; Claus, T.; Dela Cruz, F. E.; Daly, M.;
Ehrgott, F. J.; Johnson, J. S.; Livingston, J. N.; Schoenleber, R. W.;
Shapiro, J.; Yang, L.; Tsutsumi, M.; Ma, X. J. Med. Chem. 2007, 50,
984-1000.
10. Huang, L.-J.; Hour, M.-J.; Teng, C.-M.; Kuo, S.-C. Chem.
Pharm. Bull. 1992, 40, 2547-2551.
11. Kuo, S. C.; Huang, L. J.; Nakamura, H. J. Med. Chem. 1984,
27, 539-544.
12. Ghorab, M. M.; Ragab, F. A.; Heiba, H. I.; El-Hazek, R. M.
Eur. J. Med. Chem 2011, 46, 5120-5126.
13. Foloppe, N.; Fisher, L. M.; Howes, R.; Potter, A.; Robertson,
A. G. S.; Surgenor, A. E. Biorg. Med. Chem. 2006, 14, 4792-4802.
14. Mandha, S. R.; Siliveri, S.; Alla, M.; Bommena, V. R.;
Bommineni, M. R.; Balasubramanian, S. Bioorg. Med. Chem. Lett.
2012, 22, 5272-5278.
15. (a) Cassani, C.; Melchiorre, P. Org. Lett. 2012, 14, 5590-5593;
(b) Tan, B.; Candeias, N. R.; Barbas, C. F. Nature Chem. 2011, 3,
473-477; (c) Tan, B.; Candeias, N. R.; Barbas, C. F. J. Am. Chem.

Soc. 2011, 133, 4672-4675; (d) Jiang, X.; Shi, X.; Wang, S.; Sun, T.;
Cao, Y.; Wang, R. Angew. Chem. Int. Ed. 2012, 51, 2084-2087; (e)
Jiang, X.; Cao, Y.; Wang, Y.; Liu, L.; Shen, F.; Wang, R. J. Am.
Chem. Soc. 2010, 132, 15328-15333; (f) Chen, X.-H.; Wei, Q.; Luo,
S.-W.; Xiao, H.; Gong, L.-Z. J. Am. Chem. Soc. 2009, 131, 1381913825; (g) Bergonzini, G.; Melchiorre, P. Angew. Chem. Int. Ed.
2012, 51, 971-974; (h) Ma, M.; Zhu, Y.; Sun, Q.; Li, X.; Su, J.; Zhao,
L.; Zhao, Y.; Qiu, S.; Yan, W.; Wang, K.; Wang, R. Chem. Commun.
2015, 51, 8789-8792; (i) Wang, L.; Li, S.; Blümel, M.; Philipps, A.
R.; Wang, A.; Puttreddy, R.; Rissanen, K.; Enders, D. Angew. Chem.
Int. Ed. 2016, 55, 11110-11114; (j) Jiang, X.; Wang, R. Chem. Rev.
2013, 113, 5515-5546.
16. (a) Enders, D.; Grossmann, A.; Gieraths, B.; Düzdemir, M.;
Merkens, C. Org. Lett. 2012, 14, 4254-4257; (b) Jiang, X.; Liu, L.;
Zhang, P.; Zhong, Y.; Wang, R. Angew. Chem. Int. Ed. 2013, 52,
11329-11333; (c) Yetra, S. R.; Mondal, S.; Suresh, E.; Biju, A. T.
Org. Lett. 2015, 17, 1417-1420; (d) Zhang, H.-M.; Lv, H.; Ye, S. Org.
Biomol. Chem. 2013, 11, 6255-6257; (e) Wang, S.; RodriguezEscrich, C.; Pericàs, M. A. Org. Lett. 2016, 18, 556-559.
17. Lin, L.; Yang, Y.; Wang, M.; Lai, L.; Guo, Y.; Wang, R. Chem.
Commun. 2015, 51, 8134-8137.
18. (a) Gaunt, M. J.; Johansson, C. C. C. Chem. Rev. 2007, 107,
5596-5605; (b) Lee, A.; Younai, A.; Price, C. K.; Izquierdo, J.;
Mishra, R. K.; Scheidt, K. A. J. Am. Chem. Soc. 2014, 136, 1058910592; (c) Chen, X.-Y.; Gao, Z.-H.; Song, C.-Y.; Zhang, C.-L.;
Wang, Z.-X.; Ye, S. Angew. Chem. Int. Ed. 2014, 53, 11611-11615;
(d) Xie, Y.; Yu, C.; Li, T.; Tu, S.; Yao, C. Chem. Eur. J. 2015, 21,
5355-5359; (e) Jin, Z.; Jiang, K.; Fu, Z.; Torres, J.; Zheng, P.; Yang,
S.; Song, B.-A.; Chi, Y. R. Chem. Eur. J. 2015, 21, 9360-9363.
19. (a) Ma, G.; Nguyen, H.; Romo, D. Org. Lett. 2007, 9, 21432146; (b) Nguyen, H.; Ma, G.; Romo, D. Chem. Commun. 2010, 46,
4803-4805; (c) Liu, G.; Romo, D. Angew. Chem. Int. Ed. 2011, 50,
7537-7540; (d) Liu, G.; Shirley, M. E.; Romo, D. J. Org. Chem. 2012,
77, 2496-2500; (e) Purohit, V. C.; Matla, A. S.; Romo, D. J. Am.

Chem. Soc. 2008, 130, 10478-10479; (f) Leverett, C. A.; Purohit, V.
C.; Romo, D. Angew. Chem. Int. Ed. 2010, 49, 9479-9483.
20. (a) Belmessieri, D.; Morrill, L. C.; Simal, C.; Slawin, A. M. Z.;
Smith, A. D. J. Am. Chem. Soc. 2011, 133, 2714-2720; (b)
Belmessieri, D.; Cordes, D. B.; Slawin, A. M. Z.; Smith, A. D. Org.
Lett. 2013, 15, 3472-3475; (c) Joannesse, C.; Johnston, C. P.;
Concellón, C.; Simal, C.; Philp, D.; Smith, A. D. Angew. Chem. Int.
Ed. 2009, 48, 8914-8918; (d) Morrill, L. C.; Lebl, T.; Slawin, A. M.
Z.; Smith, A. D. Chem. Sci. 2012, 3, 2088-2093; (e) Morrill, L. C.;
Douglas, J.; Lebl, T.; Slawin, A. M. Z.; Fox, D. J.; Smith, A. D.
Chem. Sci. 2013, 4, 4146-4155; (f) Yeh, P.-P.; Daniels, D. S. B.;
Cordes, D. B.; Slawin, A. M. Z.; Smith, A. D. Org. Lett. 2014, 16,
964-967; (g) Stark, D. G.; Morrill, L. C.; Yeh, P.-P.; Slawin, A. M.
Z.; O'Riordan, T. J. C.; Smith, A. D. Angew. Chem. Int. Ed. 2013, 52,
11642-11646; (h) Simal, C.; Lebl, T.; Slawin, A. M. Z.; Smith, A. D.
Angew. Chem. Int. Ed. 2012, 51, 3653-3657; (i) Stark, D. G.; Young,
C. M.; O'Riordan, T. J. C.; Slawin, A. M. Z.; Smith, A. D. Org.
Biomol. Chem. 2016, 14, 8068-8073; (j) Robinson, E. R. T.; Walden,
D. M.; Fallan, C.; Greenhalgh, M. D.; Cheong, P. H.-Y.; Smith, A. D.
Chem. Sci. 2016, 7, 6919-6927.
21. (a) McCusker, E. O. B.; Scheidt, K. A. Angew. Chem. Int. Ed.
2013, 52, 13616-13620; (b) Yang, L.; Huang, W.; He, X.-H.; Yang,
M.-C.; Li, X.; He, G.; Peng, C.; Han, B. Adv. Synth. Catal. 2016, 358,
2970-2975; (c) Lv, H.; You, L.; Ye, S. Adv. Synth. Catal. 2009, 351,
2822-2826.
22. Kumarswamyreddy, N.; Kesavan, V. Org. Lett. 2016, 18, 13541357.
23. (a) Xu, S.; Held, I.; Kempf, B.; Mayr, H.; Steglich, W.; Zipse,
H. Chem. Eur. J. 2005, 11, 4751-4757; (b) Nakata, K.; Gotoh, K.;
Ono, K.; Futami, K.; Shiina, I. Org. Lett. 2013, 15, 1170-1173.

Table of Contents artwork
O
R3

PS-BTM
•Recyclable
•Flow Process

O

O
O +

t-Bu

O
Het

R3

Het

R2

O

N
N N

O
R1

Ph

N
S

N
PS-BTM

R1

R2

♦ 32 examples
♦ Up to 91% yield
♦ >20:1 dr, 99% ee
♦ TON 76.8

7