Ureas and Thioureas As Asymmetric Organocatalysts

Published on 16 November 2015 on https://pubs.rsc.org | doi:10.
1039/9781782626435-00196
CHAPTER 19
Ureas and Thioureas as

Asymmetric Organocatalysts
DIMITRIS LIMNIOS AND CHRISTOFOROS G. KOKOTOS*
Downloaded on 6/6/2021 4:37:55 PM.
Laboratory of Organic Chemistry, Department of Chemistry,

University of Athens, Panepistimiopolis 15771, Athens, Greece
*Email: ckokotos@chem.uoa.gr
19.1 Introduction
(Thio)urea organocatalysis refers to the use of orthologically designed urea
and thiourea molecules in order to catalytically accelerate various organic
transformations mainly through hydrogen-bonding interactions. The ability
of such molecules to mimic nature’s noncovalent interactions, acting like
weak Lewis acids, promotes the sustainability of this field compared to
traditional metal-based Brønsted acid catalysts. The key advantages of
(thio)urea organocatalysts are:1–7
water and air stable,

inexpensive and easy to prepare,
nontoxic,
immobilisation on a solid phase, catalyst recovery and reusability,
low catalyst-loadings (down to 0.001 mol%),
high TOF (turn-over-frequency) values (up to 5700 h1).
There are a number of elegant contributions in the field that have

already been reviewed in book chapters2–5 and reviews.6,7 Herein, our aim is
RSC Green Chemistry No. 41

Sustainable Catalysis: Without Metals or Other Endangered Elements, Part 2
Edited by Michael North
r The Royal Society of Chemistry 2016
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Ureas and Thioureas as Asymmetric Organocatalysts 197
to present some key examples of (thio)urea organocatalysts that provide

sustainability.
19.2 Early Attempts

Published on 16 November 2015 on https://pubs.rsc.org | doi:10.1039/9781782626435-00196
In 1994, Curran and Kuo reported N,N 0 -diphenylurea 1 as the first double
hydrogen-bonding organocatalyst for the allylation of a-sulfinyl radicals with
allyltributylstannane (Scheme 19.1).8 Utilising for the first time sub-
stoichiometric amounts of urea 1 (down to 20 mol%), minor acceleration of
the reaction rate was observed. One year later, they reported the use of the
same catalyst in a Claisen rearrangement, as well as for the first time, the use
of the thiourea analogue 2.9 Notably, neither a dimethylated analogue of the
urea catalyst, nor a corresponding benzanilide, which is able to form a single
hydrogen bond, was capable of promoting the reaction, thus indicating the
importance and necessity of having the double hydrogen-bond donation of
the thio(urea) group.

Later, the scientific community turned their attention mostly to the use of
a thiourea group, rather than a urea, mostly due to solubility and prepar-
ation issues. Also, thioureas show less self-association because the thio-
carbonyl group is a weaker hydrogen-bond acceptor and present lower pKa
values, thus leading to more stable catalyst–substrate transition states
(Scheme 19.2).10
CF3 CF3
CF3 1 CF3
X
O
O O
O O C8H17 N N C8H17
C8H17 N N C8H17
O H H O
O H H O
O
O
S 1: X = O
2: X = S
O
Me
Scheme 19.1 Curran and Kuo’s urea catalyst.
O
R R
N N X
H H
H2N NH2
O
pKa
R R
N N
X=O 29.6
H H X=S 21.1
Tendency to dimerize
Urea > Thiourea
Scheme 19.2 Carbonyl group shows greater dimerisation potency – urea/thiourea

acidity.
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198 Chapter 19
19.3 (Thio)ureas as Organocatalysts

19.3.1 Novel Induced Asymmetric Thio(urea) Hydrogen-bond
Catalysis
A pioneer in the field of the asymmetric (thio)urea organocatalysis was Eric

Jacobsen, who first reported a chiral (polymer-bound) Schiff base thiourea
derivative for asymmetric Strecker reactions optimised from parallel syn-
thetic libraries.11 These catalysts can be used either in solution or immo-
bilised to a polystyrene resin, with the latter retaining efficiency, after
repeated recycling.12 The key factors responsible for high enantioselectivities
were the presence of bulky substituents at both the amino acid position and
at the 3-position of the aromatic ring (Scheme 19.3).
In 2002, Jacobsen’s group reported an improved analogue for the
asymmetric Strecker reaction based on detailed mechanistic studies.13 Both
aldimines and ketimines underwent hydrocyanation with high enantio-

selectivities utilising thiourea 4 in just 1 mol% catalyst loading (Scheme 19.4).
O
1. 4 mol% catalyst
F3C N
N toluene, 15 h, 23 oC
HCN
2. TFAA R CN
R H
up to 99% yield
up to 95% ee
tBu X
H
R1 N
N N
H H 3a: R1 = Ph, X = S, R2 = OCH3
O N
3 3b: R1 = polystyrene, X = S, R2 = OCO(tBu)
HO 3c: R1 = Ph, X = O, R2 = OCO(tBu)
tBu R2
Scheme 19.3 First asymmetric thio(urea) catalyst. Enantioselective Strecker reaction.
Me tBu S
N
Me N N
H H
O N 4
HO
1 mol% O O
R2 R2
N But O tBu F3C N
R1 H HCN, toluene, -78 oC R1 H

86-99% ee
Scheme 19.4 Sustainable thiourea 4 for organocatalytic Strecker reaction.

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O O
Bn O
N P 4 (10 mol%) P R H2, Pd/C
Ar O H P R
O Ar O Ar O
Et2O O O
H R HN Ph NH2
Ar Ar 81–99% ee Ar
Boc OTBS Boc

N 1. 5 mol% 5, toluene NH O
H R OiPr 2. TFA R OiPr

86–98% ee
AcCl
2,6-lutidine
R 6 (5–10 mol%) R
N NAc
N Et2O, –78 oC N
H H
R' R'
85–95% ee
O NC OTMS
Br 7 (5 mol%), TMSCN Br
CF3CH2OH, CH2Cl2, –78 oC

86–98% ee
Me tBu S
tBu S
Ph N tBu S H
N N N
H H i-Bu2N Me N N
O N N N H H
H H O N
O N Ph 7
5 HO 6 Me
Me Me
tBu tBu
Scheme 19.5 Various transformations promoted by Jacobsen’s thiourea catalysts.
Since then, Jacobsen’s group have developed a variety of chiral thioureas

for a range of asymmetric transformations, involving mostly imine-type
nucleophilic addition (Scheme 19.5). Thiourea 4 was successfully utilised for
the asymmetric hydrophosphonylation of imines, which can give access to
enantiomerically enriched a-amino phosphonic acids.14 Moreover, analogue
5 was successfully utilised for asymmetric Mannich reactions of Boc-
protected imines,15 whereas analogue 6 showed great tolerance for the
acyl-Mannich reaction providing a route to enantioenriched heterocycles
from aromatic starting materials.16 In addition, analogue 6 was successfully
utilised for the first time for acyl-Pictet–Spengler-type reactions in the
enantioselective cyclisation of N-acyliminium ions generated in situ from
tryptamine.17 More recently, amino thiourea 7 was shown to promote the
highly enantioselective cyanosilylation of ketones.18 The sterically hindered
tertiary amine substituent plays a vital role with regard to both stereo-
induction and reactivity, thus a bifunctional mechanism is suggested
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200 Chapter 19
involving electrophile activation by the thiourea and nucleophilic activation

by the amine.
19.3.2 Monofunctional Thio(urea) Hydrogen-bond Catalysis

Schreiner and Wittkopp based on theoretical and experimental studies,
developed N,N 0 -bis[3,5-bis(trifluoromethyl)phenyl] thiourea 8, also known as
Schreiner’s thiourea.19 Initially, its catalytic activity was examined in a series
of Diels–Alder reactions and 1,3-dipolar cycloaddtions.20 Interestingly, the
effectiveness of the catalysts was substituent-dependent, rather than react-
ant or solvent dependent. In addition, a rigid thiourea is more effective than
one with flexible substituents (Scheme 19.6).
Since the introduction of the rigid and effective bis(trifluoromethyl)phenyl
motif, Schreiner’s catalyst has been successfully utilised in a variety of or-
ganic transformations. Initial reports concerning cyanation of nitrones with
trimethylsilyl cyanide or the addition of ketene silyl acetals to nitrones were

made by Takemoto, but required high catalyst loadings of 50 mol% and low
temperatures.21 Thiourea 8 was also utilised, in 10 mol% catalyst loading,
for the Mukaiyama-aldol reaction of benzaldehydes with a ketene silyl
acetal.21 Ortho-methoxy benzaldehyde showed the best results, presumably
due to a highly activated intermediate formed from both the oxygens of the
carbonyl and ether group with the thiourea catalyst (Scheme 19.7).
In 2004, Ricci and coworkers reported a sustainable Friedel–Crafts
alkylation of nitroalkenes with various aromatic and heteroaromatic
substrates utilising 10 mol% of thiourea 8 under solvent-free reaction
conditions.22 When applied to indoles, this method provides excellent
yields and high selectivities (Scheme 19.8). Additionally, alkylation at the
‘‘difficult’’ 2-position of the 3-methylindole was accomplished in a solvent-
free reaction with the assistance of microwave irradiation (MW).
In 2006, Kleiner and Schreiner reported an environmentally friendly
protocol for the synthesis of b-amino alcohols utilising thiourea 8 under
aqueous reaction conditions.23 Water acts synergistically, amplifying the
reaction yield through hydrogen-bond formation. Propene oxide and cyclo-
hexene oxide were used as substrates with a series of primary and secondary
O
8 (1 mol%)
solvent
O
CF3 8 CF3 CF3 CF3

S
S > S >
N N
F3C N N CF3 N N H H
H H H H
Scheme 19.6 Diels–Alder reaction promoted by Schreiner’s thiourea.

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amines as nucleophiles. Sterically hindered tert-butyl amine, as well as

dipropylamine gave the best yields (Scheme 19.9).
In the same year, Kotke and Schreiner reported the use of thiourea 8 as a
green and efficient organocatalyst for acid-free acetalisations.24 A great var-
iety of aldehydes and ketones were well tolerated utilising very low catalyst
loadings of 0.01–1 mol% at room temperature, furnishing the desired
acetals in 65–99% yield at turnover frequencies of around 600 h1. As
expected, aromatic and aliphatic aldehydes were well tolerated in short re-
action times, whereas less-reactive ketones required longer times affording
the desired products in moderate yields. The efficiency and practicality
of this protocol is highlighted by the clean conversion of acid-labile tert-
butyldimethylsilyl-protected aldehydes, as well as unsaturated aldehydes to
the corresponding acetals (Scheme 19.10).
List and coworkers reported in 2006 the use of Schreiner’s thiourea 8 in 2–5
mol% catalyst loading for the acylcyanation of imines with acetylcyanide.25
The corresponding N-acetylated amino nitriles, which are precursors of

a-aminoacids, were isolated in high yields, while the broad substrate scope of
the protocol involved both aromatic and aliphatic aldimines (Scheme 19.11).
R O OTMS R OH O
8 (10 mol%)
H H OEt
OEt
CH2Cl2, –40 oC
R H R
R = H , 36% yield
CF3 8 CF3 R = OMe, 65% yield
S
F3C N N CF3
H H
Me
O O
H
OMe
Scheme 19.7 Thiourea 8 catalyses the Mukaiyama aldol reaction.
R2 R2 E
N
8, 10 mol%, solvent free R3
Ar-H N E or or R
R1 N
NO2 R4 R5
R
E
up to 97% yield
E= NO2
R
R = Ph, C5H11
Scheme 19.8 Friedel–Crafts alkylation catalysed by thiourea 8.

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202 Chapter 19
R1 R2
N OH
O H OH R1 R2
O or
or N 2 N
8 (10 mol%) R R1
water, r.t. or 40 oC, 24 h
OH H
N OH OH O
OH
N N N
94 % yield 94 % yield 87 % yield 83 % yield
CF3 CF3
S
F3C N N CF3
H H
O
Nu
Scheme 19.9 Epoxide ring opening by amines catalysed by thiourea 8.
O 8 (0.01-1 mol%) OR3

3
R OH R1
R1 R2 r.t. , HC(OR3)3 R3O 2
R
OEt O
OEt
OEt O
OEt
94% yield (10 h) 92% yield (9 h) 91% yield (14 h)
O
EtO OEt OEt
O
OEt
OTBDMS
61% yield (98 h)
67% yield (93 h) 72% yield (98 h)
Scheme 19.10 Organocatalytic acid-free acetalisation utilising thiourea 8.
In 2007, Schreiner applied his thiourea 8 in developing a green

protocol for the protection of alcohols with tetrahydropyran (THP) under
neat reaction conditions.26 Utilising the privileged N,N 0 -bis[3,5-bis(tri-
fluoromethyl)phenyl]thiourea and a polystyrene-attached analogue, high
yields were observed even on a preparative scale. A remarkably broad sub-
strate scope was examined, while high turnover numbers (100 000) and
turnover frequencies (up to 5700 h1) were well established (Scheme 19.12).
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O
N Ph O
8 (2-5 mol%) Me N Ph
R H Me CN
CH2Cl 2, 0 oC
R CN
24-48 h
O
O O
Me N Ph
Me N Ph Me N Ph
CN
CN O CN
88% yield 64% yield 67% yield
Scheme 19.11 Catalytic acylcyanation of imines with acetylcyanide utilising

thiourea 8.
CF3 8 CF3
S
F3C N N CF3
H H
or
R-OH R
CF3 O O
O
S
1' - 3' alcohols 63-99% yield
cyanohydrins N N CF3 >50 examples
α-hydroxy carbonyls H H
aldols 0.001-1 mol%
oximes neat, r.t. or 50 °C
OTHP
OTHP S
OTHP OTHP
S
98% yield, 24 h 98% yield, 15 h 96% yield, 16 h 96% yield, 61 h
Ph OTHP
O OTHP
Ph OTHP OTHP
Ph O
polymer-bound catalyst polymer-bound catalyst polymer-bound catalyst
Scheme 19.12 Organocatalytic tetrahydropyranylation of hydroxy functionalities

utilising thiourea 8.
In 2008, Connon and coworkers reported a base-mediated protocol for

the synthesis of terminal epoxides from aldehydes and trimethylsulfonium
iodide utilising 5 mol% of urea analogue 9.27 Electron-rich and electron-
deficient aromatic aldehydes were well tolerated providing the corres-
ponding products in moderate to high yields. In the case of cyclohexyl
carboxaldehyde, an increase in the reaction time was required. It has to be
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204 Chapter 19
CF3 CF3
9
O
F3C N N CF3
H H
O O
5 mol%
R H R
S(CH3)3I (1.0 equiv.)
CH2Cl2 (0.34M)
50% NaOH (aq.), r.t.
O O OMe O
O
CF3 CF3
O
O F3C N N CF3
H H R
R H -S(CH3)2 O
NaOH O H
S S O R
I- S
R H
S
Scheme 19.13 Organocatalytic Corey–Chaykovsky epoxidation utilising urea 9.
highlighted that thiourea 8 was less effective than urea 9 probably because
of the higher acidity of the thiourea compared to the sulfonium methylide
(pKa in DMSO: 8 ¼ 13.4; 9 ¼ 19.6; S(CH3)3I ¼ 18.2). The proposed mechanism
involves initially the formation of the ylide in situ, which in turn attacks the
aldehyde. The nucleophilic attack of the ylide is believed to be accelerated
via a hydrogen bond-stabilised transition state. The resulting zwitterionic
intermediate is subjected to a ring closure leading to the epoxide
(Scheme 19.13).
Apart from the reports mentioned above, there are sustainable mono-
functional thioureas that successfully induce chirality. In 2007, Jacobsen
and coworkers reported the enantioselective Pictet–Spengler cyclisation of
hydroxylactams.28 Utilising as little as 0.1 mol% of thiourea 10, indolizinone
and quinolizinone products were afforded in high yields and high enan-
tioselectivities (Scheme 19.14) via a counterion transition state.28
In 2009, Smith and coworkers reported the enantioselective Mukaiyama–
Mannich reaction between imines and ketene acetals employing thiourea
11 as the organocatalyst.29 In an effort to mimic the positive cooperative
action of enzymes, ‘‘positive cooperativity’’ was introduced for the first time
in organocatalysis. Compared to simple analogue 12, hydrogen bond inter-
actions within rationally designed b-turn catalyst 11 enhanced efficiency and
turnover rates, while decreasing catalyst loading (Scheme 19.15).
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Me tBu S
N
O C5H11 N N
1-2
O H H N Ph
R2
N
10 Me
OH 5 mol%
R1 R1 O
N
o
N MTBE, TMSCl, –78 C to r.t. N R2
H 24-48 h H 1-2
O O O O
N N N N
F
N H N Ph N H NMe
H H H H
90% yield 68% yield 94% yield 63% yield
97% ee 85% ee 97% ee 92% ee
Me
C5H11 N tBu
S
O N
O H
H N
N Me
Cl N
Ph
N
H
Scheme 19.14 Enantioselective Pictet–Spengler cyclisation of hydroxylactams

employing thiourea 10.
Boc OTBS NHBoc

N catalyst 11 or 12 (5 mol%)
CO2iPr
Ph OiPr Ph
toluene, -40 °C, 48 h
CF3
CF3
O 11
12
N N
H H
O O
S S
N N N N
H H N H H N
Me Ph Me Ph
97% yield 72% yield

>99% ee 95% ee
Scheme 19.15 Asymmetric Mukaiyama–Mannich reaction catalysed by thiourea 11.

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206 Chapter 19
t-Bu S CF3
N
N N
O H H
CF3
13
O Me 15 mol% Me R
R
N 25 mol% HCl, 4Å MS, MTBE, –30 oC H
N
O
OH 72–120 h H
OMe Cl
Me Me Me
Me S
H H H
N H N N
O N O O
H O H H
H

89% ee 94% ee 92% ee 91% ee
Scheme 19.16 Enantioselective cationic polycyclisation promoted by thiourea 13.
In 2010, Jacobsen and coworkers reported a new thiourea catalyst for the
enantioselective cationic polycyclisation of hydroxylactams.30 The expansive
and polarisable moiety of 1,9-dihydropyrene in catalyst 13 proved optimal
for this transformation, evidently due to cation–p interactions stabilising
transition state. The tetracyclic adducts were afforded in moderate yields,
high enantioselectivities and as a single diastereomer (Scheme 19.16).
Two years later, Lin and Jacobsen reported a thiourea-catalysed ring
opening of episulfonium ions with indole derivatives.31 Employing thiourea
14, bearing a phenanthrene ring this time, high yields and enantioselec-
tivities were established (Scheme 19.17). The authors provided evidence of
a bifunctional activation through a synergic network of anion-binding,
cation–p and hydrogen-bond interactions.
19.4 Bifunctional Tertiary Amine Thio(ureas)

19.4.1 Takemoto’s Tertiary Amine Thiourea
In 2003, Takemoto and coworkers published the enantioselective Michael
addition of malonates to nitro-olefins catalysed by the first bifunctional
thiourea 15, providing the corresponding products in high yields and
enantioselectivities.32 The proposed mechanism involved a bifunctional
transition state, where activation of the nitro-olefin is promoted by the
thiourea group, while the activation of the malonate occurred by the tertiary
amine (Scheme 19.18).33
In an effort to expand the scope of the electrophiles, Takemoto
showed three years later that benzimides were able to perform a Michael
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t-Bu S CF3
N
N N
O H H
CF3 R1
14 R1
R1 SR2
10 mol% SR2
R3 R3
R1 O N
H 4-NBSA 7 mol%, 4Å MS, toluene, –30 oC N
HN CCl3 H
40–63 h
F
Ph Ph Ph
Ph Ph Ph
F F
SBn S SBn
SBn
Me
N N N
H N H H
H
93% ee 95% ee 81% ee 78% ee
t-Bu S CF3
N
N N
O H H
CF3
O O
attractive S
O R
non-covalent interactions
N
H
Scheme 19.17 Thiourea 14 catalyses ring opening of episulfonium ions with indole
derivatives.
reaction with malononitrile.34 Among the substrates, benzimides bearing a

methoxy group at the ortho-position showed the best results (Scheme 19.19).
1
H NMR and IR analysis revealed an intramolecular hydrogen-bonding
interaction between the NH of the imide and the methoxy group of the
aromatic ring. This interaction is believed to enhance the electrophilicity of
the N-alkenoyl moiety of the imide since the electron density of the nitrogen
atom is decreased. Furthermore, thiourea 15 was able to catalyse the
subsequent 1,2-addition of hard nucleophiles to the resulting dicyano
benzamides.
During the same year, Takemoto and coworkers reported the asymmetric
aza-Henry reaction of nitroalkanes with N-Boc imines utilising thiourea 15.35
Syn-b-Nitroamines were isolated in good diastereoselectivities and high
enantioselectivities, while the thiourea group was revealed to play a dual
role, both activating the substrates and inducing chirality. Various types
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208 Chapter 19
CF3
15
S
F3C N N
H H
R2O2C CO2R2
O O 10 mol% Me N Me
NO2
R1 R2 R2 NO2
O O toluene, r.t. R1
up to 95% yield
up to 93% ee
S chiral
scaffold
N N
H H N
R' R'
O O
N H
O O
R R
R
Scheme 19.18 Organocatalytic Michael addition of malonates to nitroalkenes and

benzimides utilising bifunctional thiourea 15.
O O NC CN
O O
R1 N 15 (10 mol%)
H NC CN R1 N
toluene H
MeO MeO
up to 93% ee
CF3
S
F3C N N
H H N
Me
Me
O O
R1 N
H
MeO
Scheme 19.19 Michael reaction of benzimides with malononitrile catalysed by

thiourea 15.
of nitroalkanes possessing aryl, ether, alcohol and ester functionalities

were well tolerated with high stereoselectivity. This method was successfully
applied in the synthesis of chiral vicinal diamines that are regularly
encountered in bioactive compounds (Scheme 19.20). Notably, again the
sustainability of Taketomoto’s protocols is supported by the fact that the
reaction required no additional reagents other than the catalyst.
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NHBoc
N
Boc 15 10 mol%
NO2
R2 NO2 R1
R1 toluene, r.t. R2
NHBoc
NHBoc NHBoc
NO2
O NO2 O NO2
F3C
OTf OH
94% yield 78% yield 74% yield
97:3 dr 93:7 dr 75:25 dr
95% ee 90% ee 90% ee
NO2
H
N
MsO HN Ph
Boc OMe
N Ph
H
80% yield
86:14 dr (-)CP-99,994
potent NK-1 antagonist
Scheme 19.20 Asymmetric aza-Henry reaction catalysed by thiourea 15.
19.4.2 Other Bifunctional Tertiary Amine Thio(ureas)

In 2005, Wang and coworkers reported a new bifunctional binaphthyl-
derived amine thiourea 16 as an efficient organocatalyst for the Morita–
Baylis–Hillman reaction of cyclohexenone with aliphatic, aromatic and
sterically hindered aldehydes.36 The design of the catalyst follows Takemoto’s
design of a bifunctional motif. This catalytic protocol provided access to
useful chiral allylic alcohol building blocks in high yields and high enan-
tioselectivities (Scheme 19.21).
The proposed reaction mechanism involves initially the activation of
cyclohexenone by the thiourea group and subsequently a Michael addition of
the tertiary amine at the b-position. The resulting enolate intermediate attacks
the aldehyde performing an aldol reaction. Finally, a retro-Michael addition
releases the catalyst to afford the product (Scheme 19.22). This mechanism
supports the experimental results of the authors; diethyl analogue 16b showed
similar enantioselectivities, but significant lower yield for the reaction
between 2-cyclohexen-1-one and 3-phenylpropionaldehyde, presumably
because of the difficulty of the amine to perform the Michael addition due to
‘‘confined space’’ in the presence of the more flexible ethyl substituents.
Wang’s group also published the use of thiourea 16 as an efficient orga-
nocatalyst for the asymmetric Michael addition of 2,4-pentadione to nitro-
olefins.37 Utilising just 1 mol% catalyst loading, high yields and remarkably
high enantioselectivities were observed. The proposed mechanism suggests
the simultaneous activation of the diketone and the nitro-olefin by the ter-
tiary amine and the thiourea group, respectively (Scheme 19.23).
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210 Chapter 19
16
S CF3
N N
H H
N CF3
O O OH
O 10 mol%
R
R H
MeCN, 0 oC
O OH O OH O OH O OH Cl

81% ee 80% ee 94% ee 60% ee
Scheme 19.21 Organocatalytic Morita–Baylis–Hillman reaction utilising thiourea 16.
chiral
S scaffold
N N O O OH
H H R H R
O
N
catalyst
release retro-Michael
Michael addition addition
chiral
S chiral
scaffold S scaffold
N N
N N
H H
O H H
O
R H O O
H
R
N
N
S CF3
S CF3
N N
N N H H
H H
N CF3
N CF3
16 16b
56% yield
83% yield
73% ee
71% ee
Scheme 19.22 Proposed mechanism for the asymmetric Morita–Baylis–Hillman

reaction.
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O O
O O
NO2 16 (1 mol%)
Ar
Et2O, r.t. NO2
Ar
O O O O O O
O O
NO2 NO2 NO2

NO2
Cl MeO F3C
95% ee 97% ee 97% ee 83% ee
chiral
S scaffold
N N
H H N
O O H
N O O
Scheme 19.23 Thiourea 16 as organocatalyst for the Michael addition of diketones

to nitro-olefins.
N
CF3
S OMe
H
F3C N N O2N
H H O
O N
17(10 mol%) R1
MeNO2
R1 R2
toluene, r.t., 122 h
R2
N
O2N CF3
O2N O
O
S OMe
H
F3C N N 18
Cl H H N
93% yield 94% yield catalytically inactive
96% ee 95% ee
Scheme 19.24 Asymmetric addition of nitromethane to trans-chalcones utilising

Cinchona-thiourea 17 as catalyst.
In 2005, Soós and coworkers introduced a novel bifunctional thiourea

organocatalyst based on a Cinchona alkaloid for the asymmetric conjugate
addition of nitromethane to trans-chalcones.38 Using 10 mol% of thiourea
17, various electron-rich and electron-poor chalcones were well tolerated
providing the desired adducts in high yields (80–94%) and very high enan-
tioselectivities (95–96%) (Scheme 19.24). It has to be highlighted that
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212 Chapter 19
O O
O O 17 (2-5 mol%)
R MeO OMe
MeO OMe NO2
toluene, -20 to 20 oC NO2
R
O O O O O O
O O
MeO OMe MeO OMe MeO OMe
NO2 NO2 NO2 MeO OMe
NO2
Me NO2
94% ee 90% ee 75% ee 86% ee
Scheme 19.25 Cinchona-thiourea 17 catalyses the Michael addition of malonates to

trans-b-nitroalkenes.
analogue 18, bearing the natural configuration of the alkaloid (8S,9R), was
completely inactive for this reaction. This indicates that the dual activators,
the thiourea and the amine group, need to a have a specific conformation for
optimum catalytic activity.
Shortly after Soós’ report, McCooey and Connon published the asym-
metric addition of dimethyl malonate to nitroalkenes utilising thiourea 17,
as well as urea analogues.39 A great variety of aromatic and aliphatic trans-
b-nitroalkenes provided the Michael adducts in good yields and with high
enantioselectivities in the presence of very low catalyst loading (2–5 mol%)
(Scheme 19.25). Again, the stereochemistry at the C8/C9 stereogonic cen-
tres was crucial in order for the bifunctional catalytic activity to occur. The
(8R,9R)-derivative 19 was also shown to catalyse an asymmetric Mannich-
type reaction between protected imines and malonates or b-ketoesters.40
Although high yields and enantioselectivities were accomplished utilising
10 mol% of the catalyst, the method lacked sustainability due to extended
cooling at 78 1C (3 days). A more sustainable protocol involving the
Michael addition of 5-aryl-1,3-dioxolan-4-ones to trans-b-nitro-olefins was
developed in the presence of Cinchona thiourea 19.41 Various easily ac-
cessible enolisable dioxolan-4-ones provided the Michael adducts in
moderate to high yields with moderate enantioselectivities and excellent
diasteroselectivities, just with the employment of 5 mol% of the catalyst
(Scheme 19.26). As far as the reaction mechanism is concerned, the authors
suggested deprotonation of the substrate at the acidic a-position by the
basic quinuclidine nitrogen, thus enabling nucleophilic addition to the
nitroalkene.
In 2007, Wang and coworkers reported the asymmetric tandem
thio-Michael-aldol reaction between a,b-unsaturated oxazolidinones and
2-mercaptobenzahydes using the (8S,9S)-Cinchona derivative 20 as the
organocatalyst.42 This method gave access to versatile chiral thiochromanes
in a one pot-synthesis, forming three stereogenic centres from achiral
starting materials. High yields and high enantioselectivities were obtained,
while very low catalyst loading (1 mol%) and room temperature enhanced
the protocol’s sustainability (Scheme 19.27). Again, a bifunctional mech-
anism is proposed, where the oxazolidinone is activated by the thiourea
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N
CF3
S
H
F3C N N
O H H N O O CF3
O CF3
R 19 (5 mol%)
NO2
O CF3 O CF3
Ar toluene or CH2Cl2, 0 °C O2N Ar
R
2-72 h
O O CF3 O O
O O CF3 O CF3
O CF3
O CF3 O CF3 O CF3
O2N Ph O2N O2N
O2N O CF3
Ph Ph Ph
S
CF3 Br
Br
73% ee 66% ee 60% ee 60% ee

>98% de >98% de >98% de >98% de
Scheme 19.26 Asymmetric Michael reaction between 5-aryl-1,3-dioxolan-4-ones and

trans-b-nitro-olefins utilising thiourea 19.
N
CF3
S OMe
H
O O O F3C N N
H H N OH O O
R1 H N O 20 (1 mol%)
N O
R1
SH R2 1,2-dichloroethane, r.t. 2
S R
1-10 h
Me OH O O OH O O OH O O
OH O O
N O N O N O
N O
Me S Ph S S
S Ph
S
99% ee 99% ee 93% ee 91% ee
N
CF3
S OMe
H
F3C N N
H H N
dual activation H
mode O O
S
O N R1
H
2
R
O
Scheme 19.27 Asymmetric Michael-aldol reaction promoted by the bifunctional

thiourea 20.
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214 Chapter 19
group and the tertiary amine deprotonates the thiol, initiating a thio-
Michael addition and the tandem pathway.
In the same year, Ricci and coworkers reported the use of a Cinchona-
derived thiourea for the asymmetric aza-Michael addition of O-benzyl-
hydroxylamine to trans-chalcones.43 Although 20 mol% catalyst loading,

temperatures of 4–20 1C and 1.2 equiv. of O-benzylhydroxylamine were em-
ployed, the observed enantioselectivities were relatively low (30–60%).
Based on his first designed catalyst,32 Takemoto and coworkers reported
in that year the use of a newly developed bifunctional thiourea 21 for the
enantioselective Petasis-type reaction of quinolones with organoboric
acids.44 Moderate yields but very high enantioselectivities were estab-
lished. The introduction of a hydroxy group on the catalyst enabled che-
lation with the vinylboronic acid inducing nucleophilic attack of the latter
to the thiourea-activated electrophile (Scheme 19.28). Phenyl chloro-
formate was used as acylating reagent for the activation of quinolone,
whereas the use of water, as proton source, and NaHCO3, as base for the
removal of boron-containing acidic byproducts, enhanced yield and
enantioselectivity.
In 2009, Takemoto and coworkers reported a more sustainable protocol
for the enantioselective Michael addition of organoboric acids to g-hydroxyl
enones in the presence of the novel iminophenol-type thiourea organoca-
talyst 22.45 Utilising 10 mol% catalyst loading in toluene at room tempera-
ture reaction, high yields and high enantioselectivies were afforded
(Scheme 19.29). Experimental data showed that the hydroxy groups in both
the catalyst and the substrate were essential for the progress of the reaction,
therefore the authors suggested that mixed boronates were formed from
both the catalyst and the substrates.
In 2011, Wang and coworkers reported a highly efficient protocol for
the asymmetric aza-Henry reaction of cyclic trifluoromethyl ketimines.46
Utilising just 1 mol% of O-benzyl Cinchona-derived thiourea 23 biologically
interesting chiral trifluoromethyl dihydroquinazolinone adducts were
afforded in high yields (up to 97%) and high enantioselectivities (up to 98%
enantiomeric excess) at room temperature (Scheme 19.30). In addition, this
methodology was successfully applied in the synthesis of anti-HIV drug
candidate DPC 083.
In the same year, Cinchona alkaloid derivative 24 was shown to catalyse a
Mannich-type reaction of imines bearing a benzothiazole group with diethyl
malonate.47 A 10 mol% catalyst loading and imine:malonate ratio of 1 : 1.2,
at room temperature provided for the first time b-amino esters in good yields
and high enantioselectivities (Scheme 19.31).
Meanwhile, Rueping and coworkers reported a sustainable protocol for
the enantioselective domino reaction of cyclohexa-1,2-dione with a variety of
substituted b-nitrostyrenes giving access for the first time to complex,
polyfunctionalised bicyclo[3.2.1]octan-8-ones.48 Utilising Cinchona derivative
25 in just 1–2 mol% loading, while maintaining a diketone-nitro-olefin ratio
CF3
S
F3C N N
H H N
21 (10 mol%) Me
R1 R2 R3 B(OH)2 R1 R2
HO
R4
N R4
CH2Cl2, PhOCOCl, NaHCO3, H2O N
-78 oC to -40 oC CO2Ph
R3
24 h
Br Me
N N N N
CO2Ph CO2Ph CO2Ph CO2Ph
OMe CF3 CF3
97% ee 95% ee 95% ee 96% ee
Ureas and Thioureas as Asymmetric Organocatalysts
CF3
S
F3C N N Me
H H N
B
HO O
O Cl O
Ph
Ph
O N OPh
N
Scheme 19.28 Asymmetric Petasis-type reaction catalysed by chelating thiourea 21.

215
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216 Chapter 19
F3C S
NH N
NH
HO OMe R2
O F3C
B(OH)2 22 (10 mol%) O
HO R2
R1 HO
toluene, r. t. R1
OMe OMe OMe

OMe OMe OMe S
O
O O O HO
HO HO HO
F

98% ee 97% ee 92% ee 91% ee
Scheme 19.29 Enantioselective Michael addition of a,b-unsaturated ketones with

alkenylboronic acids catalysed by thiourea 22.
CF3
S
HN N CF3
H
OBn
R
CF3 N 23 (1 mol%) F3C NO2
H N
N RCH2NO2
N O toluene, r.t. X N O
X PMB PMB
F3C F3C MeOF3C

NO2 NO2 NO2 F3C
Cl PMB NO2
NH NH NH Cl
NH
N O N O N O
PMB PMB PMB N O
PMB
97% yield 91% yield 89% yield Diastereomer I :49% yield, 88% ee
95% ee 95% ee 98% ee Diastereomer II :23% yield, 82% ee
O2N
F3C F3C
Cl Cl
NH NH
N O N O
PMB H
DPC 083
Scheme 19.30 Enantioselective aza-Henry reaction of cyclic trifluoromethyl

ketimines catalysed by thiourea 23.
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N H H Cl
N N
MeO S
Cl CF3
N O O 24 (10 mol%) N
R1 N R1 NH
S R2 EtO OEt xylene, r.t., 72-96 h S R2
EtO2C
CO2Et
Me Me Me Me
N N F N N
NH NH NH S NH
S S S S
EtO2C EtO2C EtO2C EtO2C
CO2Et CO2Et CO2Et CO2Et
89% ee 91% ee 80% ee 88% ee
Scheme 19.31 Asymmetric Mannich-type reaction catalysed by Cinchona thiourea 24.

N
CF3
S
H
F3C N N O
O H H N
NO2 HO
O 25 (1-2 mol%)
R2 R2
R1 toluene, r.t., 24–48 h O2N R1
O
O
O O HO
HO
HO HO F
Me O2N
O2N
O2N Ph O2N Ph
OMe
1:3.3 dr 1:33 dr 1:1.7 dr 1:2 dr
92, 94% ee 92% ee 94, 97% ee 93, 95% ee
Scheme 19.32 Enantioselective domino reaction of cyclohexa-1,2-dione with a var-

iety of substituted b-nitrostyrenes using thiourea 25.
of 1.2 : 1 at room temperature, the adducts were afforded in good yields and
with high enantioselectivities (Scheme 19.32)
In 2012, Casiraghi and coworkers reported the first and sole example of
the organocatalytic asymmetric vinylogous Michael (AVM) reaction of
3-alkylidene oxindoles with nitro-olefins.49 High yields and exceptional
levels of regio-, diastereo-, and enantioselectivity were obtained employing
Cinchona derivative 17 at 5 mol% loading (Scheme 19.33). Remarkably,
a reactants’ ratio of even 1 : 1 could be employed, thus enhancing
sustainability.
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218 Chapter 19
R3
2 2
R R NO2
Me
3 17 (5 mol%)
R
O NO2 O
1 N toluene 0.1M, -15 °C to r.t. N

R R1
PG PG
Br
O
Me NO2
Me NO2 Me NO2
Me NO2
O
O O
O N
N N
Cl N Moc
Boc Moc
Moc
>20:1 dr 16:1 dr >20:1 dr 10:1 dr
>99% ee >99% ee >99% ee >99% ee
E
R2 R2
thiourea H N
O O S
N R1 N H N
R1
PG PG
Scheme 19.33 Organocatalytic asymmetric vinylogous Michael (AVM) reaction

of 3-alkylidene oxindoles with nitro-olefins promoted by
thiourea 17.
More recently, Pihko introduced bifunctional tertiary amine-thioureas

26 and 27 for the Mannich reaction of Boc-imines with malonates.50
Dimethylamino-tertiary amine thiourea 26 proved ideal for aliphatic
imines, while the Cinchona derivative 27 provided the best results
for aromatic substrates. Catalyst loadings as low as 1 mol% could be em-
ployed providing the products in high yields and excellent enantioselec-
tivities (Scheme 19.34). Notably, both catalysts presented ‘‘cooperative
assistance’’ via intermolecular hydrogen bonding, as first shown by Smith
in 2009.29
In the same year, Ellman and coworkers reported the asymmetric addition
of cyclohexyl Meldrum’s acid to b- and a,b-disubstituted nitroalkenes
employing N-sulfinyl urea 28.51 The corresponding adducts were obtained in
high yields, and high diastereo- and enantioselectivities, under very mild
reaction conditions (Scheme 19.35). The sustainability of this new method is
enhanced by the mole scale preparation of a key precursor to the commercial
drug Lyrica, using catalyst 28 at only 0.2 mol% loading. In addition,
a,b-disubstituted products were efficiently converted to g-amino acid de-
rivatives without epimerisation at either stereocentre.
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O O Boc 26 or 27 (1-10 mol%) NHBoc

N
RO1
OR 1 2 CO2R1
R2 H toluene, 0 °C or -40 °C, 14-48 h R
CO2R1
NHBoc NHBoc NHBoc NHBoc

CO2Me CO2Me O CO2Bn CO2Me
CO2Me CO2Me CO2Bn CO2Me

99.2% ee 93.4% ee 99% ee 96.8% ee
CF3
CF3 O
O N N CF3
N N CF3 H H
H H O
S
O
S N NH
H
N N N
H H N N H
Me Me
26 OMe
27
Scheme 19.34 Enantioselective Mannich reaction employing thioureas 26 and 27.
19.5 Primary Amine-(Thio)urea-mediated

Reactions
19.5.1 Asymmetric 1,4-Conjugate Addition Reactions
Among the organic transformations for the construction of new carbon–
carbon and C–X bonds, the Michael reaction is considered one of the most
powerful methodologies. Most primary amine-(thio)ureas catalyse the
asymmetric Michael addition.52 Herein, we will categorise the reactions ac-
cording to the Michael acceptor, with nitro compounds being the most
popular, as the nitro group is well recognised by the thiourea moiety,
forming strong hydrogen bonds.
The first primary amine-thioureas as effective bifunctional organocatalysts
were reported in 2006. Tsogoeva and Wei synthesised a thiourea based on
(1S,2S)-diphenylethylene-1,2-diamine and a chiral arylethyl moiety, for the
Michael reaction between aliphatic ketones and aromatic nitro-olefins
(Scheme 19.36).53 Utilising catalyst 29 (15 mol%) and acetone as the Michael
donor, the Michael products were obtained in high yields (84–99%) and
enantioselectivities (90–91% enantiomeric excess). When cyclohexanone 31
was employed, product 33 was obtained in high yields (82 and 89%, re-
spectively), good diastereoselectivity (up to 83 : 17 syn:anti) and excellent
enantioselectivity (96 and 98% enantiomeric excess, respectively).
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220 Chapter 19
O O
S
N N
H H N
O O
O O NO2 28 (0.2-3 mol%)
R1 O O
O R2 toluene, 0 oC or –40 oC, 14–48 h NO2
R1
O
R2
O O O O O O
O O O O
O O O O O O
O O O O
NO2 NO2 NO2
NO2 NO2 Ph Ph Ph
Ph n-Pr
Me Bn n-Bu
95% yield 94% yield 90% yield 74% yield 70% yield
98% ee 94% ee 97:3 dr 98:2 dr 99:1 dr
93% ee 90% ee 83% ee
OH OH
O O TsOH*H2O O [H] O
toluene, 90 oC NO2 NH2
O O
NO2 24 h
90% yield Lyrica
over 2 steps
full conversion
92% ee
Scheme 19.35 Asymmetric addition of cyclohexyl Meldrum’s acid to nitroalkenes

employing chiral sulfinyl urea 28.
Around the same time, Huang and Jacobsen reported a highly sustainable
process utilising the amino acid-derived primary amine-thiourea 34 as the
catalyst for the asymmetric Michael addition of ketones to aromatic and
aliphatic nitroalkenes (Scheme 19.37).54 The catalyst loading could be re-
duced to 10 mol% and the reagent ratio was decreased to 5 : 1, when acetone
or ethyl ketones were employed. In the latter case, branched products
bearing contiguous tertiary stereocentres were obtained in good regio- and
diastereoselectivity (6 : 1 to 20 : 1 dr), favouring the anti-isomers, and excel-
lent enantioselectivity in almost all cases (86–99% enantiomeric excess). The
acid counterpart was necessary, in order to suppress the double Michael
addition. When acetophenone was employed, the reagent ratio could be
reduced to almost stoichiometric (1.1 : 1 ketone:nitroalkene) and high yields
and enantioselectivities were obtained.
Jacobsen and coworkers also realised the first enantioselective Michael
addition of a,a-disubstituted aldehydes to aliphatic and aromatic nitro-
alkenes (Scheme 19.38).55 The difficulty in the employment of disubstituted
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Ph S
Ph
N N
H H
NH2
29
29 O Ar
O 15 mol%
NO2 NO2
+ Ar
H2O (2 equiv.)
AcOH (15 mol%)
toluene, r.t. 30
84–99% yield, 90–91% ee
O 29 O Ph
15 mol% NO2
NO2
+ Ph
H2O (2 equiv.)
AcOH (15 mol%)
31 32 toluene, r.t. 33
82% yield, 80:20 syn:anti, 96% ee
Scheme 19.36 Enantioselective Michael addition of ketones to nitroalkenes

promoted by Tsogoeva’s catalyst.
Me tBu S
N
Bn N N
H H
O NH2
34
34 O R3
O 10–20 mol%
NO2 NO2
+ R3 R2
R2 PhCO2H (0–2 mol%) 1
R
R1 toluene, r.t.
50-94% yield, 6–20:1 dr, 86–99% ee
34 O Ph
O 10 mol%
+ Ph NO2 NO2
Ph Ph
toluene, r.t., 48 h
83% yield, 99% ee
Scheme 19.37 Enantioselective Michael addition of ketones to nitroalkenes

promoted by Jacobsen’s chiral primary amine-thiourea.
aldehydes lies in the fact that usually secondary amine catalysts fail to
promote enamine formation. Among a variety of catalysts, thiourea 35
bearing a secondary amide moiety afforded the best catalytic results. It has
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222 Chapter 19
H tBu S
N
Bn N N
H H
O 35 NH2
O O R2
R 1 NO2 35 20 mol% NO2
H + R2 H
H2O (5 equiv.) 1
R Me
Me CH2Cl2, 24 h, r.t.
R1, R2 = aromatic, aliphatic 34-98% yield, 2.1-50:1 dr, 92-99% ee
Scheme 19.38 Michael addition of disubstituted aldehydes to nitroalkenes pro-

moted by a chiral primary amine-thiourea.
to be highlighted that catalyst 34, which was the catalyst of choice for
the corresponding reaction with ketones, afforded the product in lower

yields and selectivities, while catalysts lacking the amide functionality
proved to be inactive. A broad substrate scope was reported affording the
products in good to high yields (up to 98%), together with excellent enan-
tioselectivities (92–99% enantiomeric excess) and good diastereoselectivities
(up to 410 : 1 dr).
A novel primary amine-thiourea consisting of a bulky saccharide moiety
was developed by Ma and coworkers for the addition of aromatic methyl
ketones to nitroalkenes.56 However, the methodology suffered from a pro-
longed reaction time, albeit delivering the products in moderate to excellent
yields (46–99%) and in high enantioselectivity (94–98% enantiomeric ex-
cess). A further drawback was the lack of tolerance for aliphatic nitroalkenes.
The synthesis of novel chiral primary amine-thioureas based on tert-butyl
esters of natural (S)-a-amino acids was later reported by Kokotos and
Kokotos for the Michael addition of acetone and acetophenone to aromatic
nitroalkenes.57 Although the reaction with acetophenone produced the
products with high enantioselectivity (92–96% enantiomeric excess), albeit
in low to moderate yields (27–68%), while the reactions with acetone pro-
ceeded with good to quantitative yields (42–100%) and good to high enan-
tiomeric excesses (73–91% enantiomeric excess). In an effort to provide a
more sustainable protocol, Kokotos and coworkers provided an improved
catalyst by replacing the (1S, 2S)-diamine moiety with its (1R, 2R)-
counterpart.58 The improved catalyst 36 could be employed in a lower
catalyst loading of 5–10 mol% and a reagent ratio (ketone:nitroalkene 5 : 1)
(Scheme 19.39). The scope and limitations of this protocol were explored
using a variety of aromatic methyl ketones and acetone along with a series of
aromatic nitroalkenes. The Michael adducts were delivered in high to
quantitative yields (73–99%) and with excellent enantioselectivity (94–99%
enantiomeric excess). The importance of this methodology was highlighted
in the efficient syntheses of the biologically active GABA analogues (S)- and
(R)-Baclofen and (S)-Phenibut.
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36 O Ar
O
+ NO2 NO2
R Ar R
CHCl3, r.t.
O
R = aromatic, Me
Ph 73–99% yield
O S
94->99% ee
O Ph
N N
H H
O NH2
36
Cl Cl
O
36
Ph
5 mol%
+ O O
NO2 NO2 NH2.HCl
Ph HO
99%, >99% ee (S)-Baclofen

Cl
Scheme 19.39 Catalyst 36-promoted Michael reaction between methyl ketones and
nitroalkenes. Efficient synthesis of (S)-Baclofen.
5 mol% 37 / AcOH
or
O 15 mol% 38 O R2
+ 2 NO2 NO2
R1 R R1
CH2Cl2, r.t.
OAc
AcO S Me Me
AcO O
N N
OAc H H NH2 S S
37 H H
N N N N
H H (1S,2S)-38 H H (1R,2R)-38
R1 = Me NH2 NH2
R2 = aromatic
R1 = R2 = aromatic R1 = R2 = aromatic
76–94% yield
54–90% yield 56–92% yield
88–96% ee
98–>99 ee 98–>99 ee
Scheme 19.40 Enantioselective Michael addition of methyl ketones to aromatic

nitroalkenes utilising catalysts 37 and 38.
Gu and coworkers reported an improved protocol for the Michael reaction

between acetone and aromatic nitroalkenes by employing Ma’s saccharide-
derived catalyst 37 combined with acetic acid as cocatalyst (Scheme 19.40,
left).59 The acidic counterpart enhanced the performance of the catalytic
system delivering the products in high yields (76–94%) and with high to
excellent enantioselectivity (88–96% enantiomeric excess), whilst the catalyst
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224 Chapter 19
loading could be reduced to 5 mol%. Furthermore, Wang and coworkers

designed a new class of bifunctional primary amine-thioureas based on
dehydroabietic amine for the asymmetric addition of aromatic methyl ke-
tones to nitrostyrenes.60 Both enantiomers of the products could be ob-
tained simply by switching the configuration of the 1,2-diaminocyclohexane

moiety of the catalyst (Scheme 19.40). In addition, the reaction was per-
formed on a multigram scale without loss in stereoselectivity and the
products were readily transformed into synthetically useful chiral pyrroli-
dine carboxylic acids.
The first highly anti-selective conjugate addition of aldehydes to nitro-
olefins was demonstrated by Barbas and Uehara.61 The reversal of the
selectivity was the outcome of a designed strategy to control the E/Z
configuration of the reactive enamine. The authors showed that the use of
(tert-butyldimethylsilyl-oxy)acetaldehyde as the nucleophile could stabilise
the intermediate enamine via hydrogen-bonding interactions to the
Z-configuration, resulting in a predominant anti-selective addition

(Scheme 19.41). The best catalyst proved to be catalyst 39, which resembles
Takemoto’s thiourea but has a primary amino group in lieu of a tertiary one.
This elegant protocol gave rise to functionalised anti-Michael products in
good to high yields (57–83%) and excellent diastereo- (up to 98 : 2 dr) and
enantioselectivities (97–99% enantiomeric excess).
In the next few years, the use of isobutyraldehyde as the nucleophile in
conjugate additions to aromatic nitroalkenes received a lot of attention. He
and coworkers reported a chiral thiourea that could efficiently catalyse this
transformation,62 while Chen and coworkers employed a catalyst combining
the 1,2-diaminocyclohexane moiety with the privileged Cinchona alkaloid
scaffold.63 A more sustainable protocol was provided by Ma and coworkers,
where catalyst 40, based on a beyerane skeleton, was found to promote the
same transformation both in organic solvents (up to 92% yield and 98%
39 R
OHC 20 mol%
+ NO2 OHC NO2
R CH2Cl2, r.t.
OTBS
OTBS
57–83% yield, 12:1–49:1 dr, 97–99% ee
S H CF3
N O TBS
Ar N N S
H
H F3 C N N
O H H
NH2
N R 39
O
TS
Scheme 19.41 Highly anti-selective Michael addition of aldehydes to aromatic

nitroalkenes.
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O 40 O Ar
(10 mol%)
NO2 NO2
H + Ar H
H2O, r.t.
62–89% yield, 90–93% ee
S
N
H HN
COOEt H2N
40
Scheme 19.42 Organocatalysed addition of isobutyraldehyde to aromatic nitroalk-

enes in water.
enantiomeric excess in chloroform) and in water (up to 89% yield and 93%
enantiomeric excess) (Scheme 19.42).64 Again, both enantiomers of the
product could be obtained by altering the 1,2-diaminocyclohexane moiety
stereochemistry from (1R,2R) to (1S,2S) without loss of activity or selectivity.
In 2012, the first polymer supported bifunctional primary amine-ureas
were developed by Portnoy and coworkers.65 This heterogeneous catalytic
system was tested in the Michael addition of acetone, cyclic ketones and
aldehydes to aromatic nitro-olefins leading to activities and selectivities
unprecedented for immobilised catalysts. Catalyst 41 based on (1R,2R)-
diphenylethylene-1,2-diamine and a L-valine spacer provided the Michael
products in yields ranging from 23 to 99% and in high enantioselectivity
(up to 99% enantiomeric excess) (Scheme 19.43). Unfortunately, recovery of
the polymer-catalyst and reuse was only tested for 3 cycles, maintaining the
high levels of enantioselectivity, but with a significant loss in the yield.
Melchiorre and coworkers employed Jacobsen’s thiourea 34 in order to
promote the reaction between hydroxy-substituted indoles and aryl
nitroalkenes (Scheme 19.44).66 The authors also demonstrated the necessity
for both the primary amine group and the thiourea functionality. Altering
the configuration of the stereogenic centres of the catalyst led to a significant
drop of the enantioselectivity highlighting the importance of matching the
configuration of the chiral moieties in the catalyst’s structure in order to
have optimum catalytic activity.
The first intramolecular Michael reaction catalysed by a primary amine-
thiourea was reported by Lu and coworkers.67 The synthesis of trans-
dihydrobenzofurans proceeded in high yields and enantioselectivities, albeit
in unsatisfactory diastereoselectivity (trans/cis: 88/12) utilising catalyst 42
(Scheme 19.45). To address the poor selectivity, after the end of the reaction
the mixture was heated under reflux, which resulted in the transformation of
the cis-isomer to the thermodynamically favourable trans-isomer, via an
enamine-mediated enolisation.
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226 Chapter 19
O Ph
O Ph
N N
H H
O NH2
41
O 41 O Ar
30 mol% NO2
R1 + NO2 R1
Ar
R2 PhCO2H (20 mol%) R2
solvent
82–99% yield, up to 4:1 dr, 86-96% ee
O 41 O Ar
R2 30 mol% NO2
H + NO2 H
Ar
R 1 PhCO2H (20 mol%) R1 R2
solvent
23–93% yield, up to 99:1 dr, 38–99% ee
Scheme 19.43 Polymer-supported chiral primary amine-urea catalysed conjugate

addition of ketones and aldehydes to nitroalkenes.
NO2 Ar
Ar
HO NO2
+
34 (20 mol%)
OH R2 O
CH2Cl2, r.t., 16 h N
R1
R2 O
N 50-98% yield
R1 2:1 to 4:1 dr
66–95% ee
R1: H, Me, Bn
Scheme 19.44 Primary amine-thiourea catalysed the reaction between nitroalkenes

and 3-hydroxy-substituted oxindoles.
NO2
42 (20 mol%)
NO2 O
4-NBA (10 mol%)
R R
O CH2Cl2, 20 oC, then reflux 8 h O
O 91–>99% yield, up to 98:2 dr, 94–>99% ee
OAc
NH2
O H H
AcO N N
AcO Ph
OAc
S Ph
42
Scheme 19.45 Asymmetric intramolecular Michael reaction promoted by a chiral

primary amine-thiourea catalyst.
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R2
36
O O
NO2 15 mol%
1 + R2 NO2
R CHCl3, 80 oC R1
71–100% yield, 82–99% ee
Scheme 19.46 Michael addition reaction between methyl ketones and nitrodienes.
Nitroalkenes have the lion’s share of applications as Michael acceptors

in organocatalysed processes. In contrast, nitrodienes are far less utilised,
although the additional double bond offers endless possibilities for further
functionalisation. Wu and coworkers were the first to apply a bifunctional
primary amine-thiourea for the asymmetric Michael addition of aryl methyl
ketones to aromatic nitrodienes.68 The adducts were obtained in moderate
to high yields (55–83%) and in excellent enantioselectivity (94–98% enan-
tiomeric excess), albeit a high catalyst loading of 30 mol% and prolonged

reaction times (4 days) were employed. Later, Ma and coworkers utilised
their saccharide-derived primary amine-thioureas to promote the asym-
metric Michael addition of aromatic and aliphatic ketones to aromatic
nitrodienes.69 Tsakos and Kokotos developed a more sustainable conjugate
addition of methyl ketones to aromatic nitrodienes utilising the bifunctional
primary amine-thiourea catalyst 36.70 Both acetone and substituted
acetophenones were applied, providing the products in high to excellent
yields and enantioselectivities (Scheme 19.46). It should be noted that
the reaction took place at elevated temperatures without any loss of
enantioselectivity.
Primary and secondary aminocatalysts can activate a,b-unsaturated ke-
tones and aldehydes by the reversible formation of an iminium ion. On the
contrary, only primary amine–thiourea catalysts exist in the literature in-
volving iminium activation of enones and enals. A multifunctional primary
amine-thiourea derived from the Cinchona alkaloid scaffold and the 1,2-
diaminocyclohexane moiety was reported by Liang, Ye and coworkers as
catalysing the asymmetric Michael reaction between nitroalkanes and
enones via iminium activation (Scheme 19.47).71 The authors invoked a
multifunctional catalytic pathway, wherein the tertiary amine deprotonates
the pronucleophile, the thiourea functionality arranges the nucleophile via
hydrogen-bonding interactions and the primary amine activates the enone
via iminium ion formation. When cyclic enones were employed, the reaction
proceeded in high yields and enantioselectivities (up to 98% enantiomeric
excess), albeit in poor diastereoselectivity (up to 2.5 : 1 dr), while the use of
acyclic enones provided high yields but lower enantioselectivities (up to 86%
enantiomeric excess).
Subsequently, the highly enantioselective Michael addition of malonates
and 1,2,4-triazole to cyclic and acyclic enones, as well as the first phospha-
Michael reaction of cyclic enones and diaryl phosphine oxides was
reported using a similar catalyst.72–74 In 2012, Huang, Wang and coworkers
demonstrated that primary amine-thiourea 39 can efficiently catalyse the
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228 Chapter 19
H N
43
NH
N
S NH
NH2
O O
43 R4
NO2 R5
10 mol%
+ NO2
n R1 R4 R5 EtOAc n R1
R3 R2 R3 R2
25–92% yield, up to 2.5:1 dr, 80–98% ee
n = 0, 1, 2
R3
43 O2N R2
O NO2 O
10 mol%
+ 1
R1 R2 R3 EtOAc R
60–98% yield, 73–86% ee
Scheme 19.47 Asymmetric Michael addition of nitroalkanes to enones utilising

catalyst 43.
Cl
Cl
O 39 10 mol% N
N N
N PhCOOH
R Me + N
N toluene, r.t. N O
N
H
R Me
88% yield, 93% ee
Scheme 19.48 Asymmetric Michael addition of purines to enones.
aza-Michael addition of purine bases to a,b-unsaturated ketones that could

lead to the synthesis of enantioenriched non-natural nucleoside analogues
(Scheme 19.48).75
Mei and coworkers utilised primary amine thiourea 44 based on the
(1S,2S)-diphenylethylene-1,2-diamine backbone for the enantioselective
Michael reaction between 4-hydroxycoumarin and a,b-unsaturated ketones
(Scheme 19.49).76 The products were isolated in high to excellent yields
(up to 97%) and in good to high enantiomeric excesses (up to 95% enan-
tiomeric excess). This method gives access to enantiopure (S)-warfarin,
which is an anticoagulant agent.
View Online
Ph S
Ph
N N Ph
H H
OH NH2 OH R2 O
O 44
20 mol% R1
+ R2 R1
O O 1,4–dioxane, r.t.
O O
80–97% yield, 86–95% ee

OH Ph O
O O
(S)-Warfarin
97% yield
95% ee (>99% after recrystallization)
Scheme 19.49 Asymmetric Michael reaction between 4-hydroxycoumarin and enones.
O O
39 (2-5 mol%)
COOR5 Benzoic acid (4-10 mol%)
R1 + R1
2 R6 toluene COOR5
R R3 4
R R R32
R4 R6
53-96% yield, 1:1 dr, 81–98% ee
39 (5 mol%)
O R1 O
CO2Me Benzoic acid (2.5 mol%)
MeO2C
R1 R2 + R2
CO2Me toluene, 50 oC, 20 h
CO2Me
62-96% yield, 91–97% ee
Scheme 19.50 Asymmetric conjugate addition of malonates to cyclic and acyclic

enones.
Kwiatkowski and coworkers utilised thiourea 39 in order to provide a

practical and straightforward Michael addition of malonates and other
nucleophiles to cyclic and acyclic enones, catalysed by primary amine
thiourea 39 in the presence of benzoic acid as cocatalyst.77 The advantages of
this highly sustainable protocol were the low catalyst loading (0.5–5 mol%)
and the ability to increase the temperature without any loss of enantios-
electivity. The products were obtained in good yields and in high enantios-
electivity (up to 98% enantiomeric excess) (Scheme 19.50).
Melchiorre and coworkers disclosed a primary amine-thiourea-mediated
iminium ion activation of a,b-unsaturated aldehydes. Catalyst 45 was
applied successfully leading to high efficiency and stereocontrol in the
challenging synthesis of compounds containing contiguous quaternary and
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230 Chapter 19
R3
R1 45 (10 mol%) R1 CHO
R2 O
PhCO2H (50 mol%) R2
O + R3 H
N toluene, r.t. 5 d N
H H
47–85% yield, up to >19:1 dr, 73–93% ee
CF3
N N CF3
H H
NH2
45
Scheme 19.51 Asymmetric Michael addition of oxindoles to enals.

O
O
O 46 (1 mol%)
H2O (15 mol%) O N R3
R1 + N R3
H
CHCl3, r.t. H
R2 R1 R2 O
O
68–93% yield, up to 5.5:1 dr, 91–99% ee
N N
H H
NH2
46
Scheme 19.52 Chiral primary amine-thiourea catalysed conjugate addition of

aldehydes to maleimides.
tertiary chiral centres (Scheme 19.51).78 The authors suggested a plausible

bifunctional activation mode, in which the thiourea functionality activated
the oxindole by stabilising its enol form and the primary amine activated
the unsaturated aldehyde via iminium ion formation. The products were
obtained in good yields (47–85%) and in high stereoselectivity (up to419 : 1
diastereomeric ratio and 93% enantiomeric excess), unfortunately the
reaction time was quite long.
From the various conjugate addition reactions of nucleophiles to a,b-
unsaturated carbonyl compounds, the use of maleimides as the Michael
acceptor deserves special mention. Xue and coworkers developed a highly
sustainable protocol for the Michael addition of a,a-disubstituted aldehydes
to maleimides (Scheme 19.52).79 Remarkably, using 1 mol% of the simple
bifunctional thiourea catalyst 46 and water as additive, the reaction pro-
ceeded smoothly to afford a-branched succinimides in high yields and with
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O O
47 R1
R1 EWG
20 mol%
+ EWG
X n toluene, 90 oC X n
R2 R2
n = 0, 1
31–96% yield, >95:5 dr, 72–99% ee
Ph S
Ph
N N Ph
H H
NH2
47
Scheme 19.53 Organocatalysed Michael addition of 2-alkylcycloalkanones to a,b-

unsaturated electrophiles.
excellent enantioselectivity. Further applications of thiourea catalysts have

also been reported for the same transformation, but higher catalyst loadings
were required.80–83
In 2012, Kang and Carter reported the organocatalysed conjugate addition
of racemic 2-alkylcycloalkanones to electron-deficient alkenes leading to a,a-
disubstituted cycloalkanones containing an all carbon quaternary chiral
centre.84 In the presence of 20 mol% of bifunctional primary amine-thiourea
47 at 90 1C, five- and six-membered cyclic ketones underwent clean reaction
with a series of a,b-unsaturated electrophiles to provide the Michael prod-
ucts in satisfactory yields (31–96%) and in high enantioselectivity (up to 99%
enantiomeric excess) (Scheme 19.53). Interestingly, only the imine derived
from a primary aminocatalyst can tautomerise to the more substituted
enamine, while, a secondary amine preferentially generates the less-
hindered undesired enamine.
19.5.2 Asymmetric Aldol Reactions

The asymmetric aldol reaction is one of the most studied transformations in
the field of organocatalysis. After the early 1970s discoveries on the Hajos–
Wiechert reaction and the landmark contribution on the intermolecular
aldol reaction catalysed by proline in 2000 by List, Lerner and Barbas III, a
rapid growth in the number of organocatalytic studies involving the enan-
tioselective aldol reaction has been witnessed. Herein, we will concentrate
on the asymmetric direct aldol reaction that proceeds through enamine
catalytic pathways. Paradoxically, in spite of the spectacular advances that
have been made in the area of aminocatalysis, little progress has been made
in the development of (thio)urea-based aminocatalysts for the enantiose-
lective aldol reaction and only a handful of primary amine-(thio)urea cata-
lysts have been reported to date. Ma and coworkers utilised their thiourea
catalyst 37 in the asymmetric aldol reaction of trifluoroacetaldehyde hemi-
acetal with aromatic ketones (Scheme 19.54).85 This protocol gave access to
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232 Chapter 19
37 (15 mol%)
OH O OH O
H2O (5 mol%)
+
F3C O R1 CH2Cl2, r.t. F3C R1
13–54% yield, 50–68% ee
Scheme 19.54 Enantioselective aldol reaction of trifluoroacetaldehyde methyl

hemiacetal with aromatic ketones.
CF3
Ph S
Ph
N N CF3
H H
O NH2 O
O 48
OR2 20 mol%
+ R1 R1 OH
PhCO2H (50 mol%) O

Me O
toluene, 4 oC, 48 h
OR2
F3C 32–91% yield, 46–94% ee
S CF3
Ph
N
Ph N H
H
H
HN O
O OR2
TS
Scheme 19.55 Direct vinylogous aldol reaction promoted by a chiral bifunctional

primary amine-thiourea.
potentially biologically interesting b-hydroxy b-trifluoromethyl compounds,

albeit in low to moderate yields (up to 54%) and in mediocre enantioselec-
tivity (up to 68%).
Later, Melchiorre and coworkers accomplished a challenging direct viny-
logous aldol reaction of 3-methyl-2-cyclohexen-1-one with a-keto esters
utilising a bifunctional primary amine-thiourea.86 Catalyst 48 based on the
(1R,2R)-diphenylethylene-1,2-diamine backbone combined with benzoic acid
as cocatalyst promoted the reaction by means of a concomitant activation of
both reacting partners (see TS in Scheme 19.55), the ketone via dienamine
catalysis and the ester via hydrogen-bonding interactions (Scheme 19.55).
19.5.3 Asymmetric Mannich Reactions

The asymmetric Mannich reaction represents one of the most useful
transformations for the synthesis of b-amino carbonyl compounds and their
View Online
R1 H
O O 49 N
NH O
15 mol% O
N CO2Et +
R1 N EtO2C *
H R2 R3 toluene, r.t., 6–60 h
R2 R3
45–89% yield,up to 13:1 regioselectivity

up to 2.5:1 dr anti:syn, 82–>99% ee
S
N
N H
H
H2N
49
Scheme 19.56 The sole example of primary amine-thiourea catalysed Mannich

reaction.
derivatives, containing two adjacent stereogenic centres. The utility of this

reaction stems from the abundance of the amino group in natural products
and biologically active molecules. Surprisingly enough, there is only one
report documented for the primary amine-thiourea-promoted Mannich
reaction. The reaction between unmodified ketones and a-hydrazonoesters
was reported by Tsogoeva and coworkers utilising thiourea 49
(Scheme 19.56)87 The b-amino carbonyl products were obtained in moderate
to high yields (45–89%) and excellent enantioselectivities (up to499% en-
antiomeric excess). A possible limitation to the method was the use of
nonsymmetrical ketones where the products were obtained in mediocre
regioselectivity, albeit in excellent enantioselectivity.
19.5.4 Asymmetric Cycloaddition Reactions

In 2011, Jacobsen and coworkers developed a dual catalyst system consisting
of a chiral primary amine-thiourea and an achiral thiourea for the intra-
molecular [5 þ 2] cycloaddition based on oxidopyrylium intermediates
(Scheme 19.57).88 This cooperative catalytic system provided easy access
to tricyclic structures in moderate yields (37–77%) and good to high
enantioselectivities (80–95% enantiomeric excess). Schreiner’s thiourea 8
is proposed to be a carboxylate-binding agent, acting in cooperation with
primary amine-thiourea 50.
One year later, Vicario and coworkers developed an unprecedented
[2 þ 2] cycloaddition reaction of a,b-unsaturated aldehydes with a-hydroxy-
methylnitroalkenes (Scheme 19.58).89 The addition of the achiral thiourea 8
proved to be essential for achieving high levels of efficiency and enantio-
control, since it served to activate the electrophile through hydrogen-
bonding interactions, while prolinol ether 51 served to activate the
nucleophile by means of dienamine catalysis. The [2 þ 2] cycloaddition
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234 Chapter 19
Ph CF3 CF3
S
S
N N
H H F3C N N CF3
Ph NH2
H H
50 8
O O
50 (15 mol%)
8 (15 mol%)
p-MeSBzO O
AcOH (15 mol%) O
toluene, 40 oC
72% yield, 91% ee
CF3 CF3
Ph
S
S
N CF3 N N
F3C N H H
Ph NH
H H
O O
TS O
Ac
Scheme 19.57 Enantioselective organocatalytic [5 þ 2] cycloaddition reaction.
NO2 8 (20 mol%) O2N

O
R2 51 (20 mol%) R2
1 O
R +
H toluene, –20 oC, 72 h
OH R1 OH
H
38–91% yield, 85–95% ee
CF3 CF3
Ph
Ph
S
OTMS
N F3C N N CF3
H H H
51
8
Scheme 19.58 Enantioselective organocatalytic [2 þ 2] cycloaddition reaction.
followed by a sequential hemiacetalisation annulation gave rise to functio-

nalised cyclobutanes in moderate to high yields (38–91%) and in high
enantioselectivity of up to 95% enantiomeric excess.
Finally, Jacobsen and coworkers developed a highly enantioselective
synthesis of indolo- and benzoquinolizidine derivatives via a formal aza-
Diels–Alder reaction of enones with cyclic imines utilising catalyst
52 (Scheme 19.59).90 The products were obtained in high to excellent yields
(50–99%) and high enantioselectivities (92–99% enantiomeric excess).
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Me t-Bu S
Ph N
N N
H H
Ph O NH2
52
O
N R1 52 (5 mol%) R2 3
Me N R
+
N AcOH (5 mol%)
Ts R2 R3 N R1
toluene, 4 oC
Ts
O
50–>99% yield, 92–99% ee
Scheme 19.59 Highly enantioselective aza-Diels–Alder reaction promoted by a pri-

mary amine-thiourea.
R1
39 (20 mol%)
Br AcOH (10 mol%)
O O
Et3N (100 mol%)
R
H + R1
H2O (100 mol%)
Me R1 R1 Me R
toluene, r.t. R1
R1 : H, F, Cl, Br 52–70% yield, 85–94% ee

R :aryl
F3C
F3C N N
H H HN
Br
TS Me R
Ar Ar
Scheme 19.60 Asymmetric a-alkylation of arylpropionaldehydes promoted by a

primary amine-thiourea.
19.5.5 Asymmetric a-Alkylation Reactions

The asymmetric a-alkylation of carbonyl compounds constitutes one of the
fundamental organic transformations for the construction of carbon–carbon
bonds, and has long been the ‘‘Achilles heel’’ for asymmetric aminocatalysis.
Towards a solution to this long-standing problem, Jacobsen and coworkers
have shown that the enantioselective a-alkylation of a-arylpropionaldehydes
with diarylbromonethane can be carried out under the catalysis of primary-
amine thiourea 39 (Scheme 19.60).91 Catalyst 39 reacted with the aldehyde to
form an enamine, followed by a SN-1-type substitution induced by the
bromide anion.
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236 Chapter 19
19.5.6 Asymmetric Domino Reactions

In recent years, organocatalytic domino and cascade reactions have attracted the
interest of researchers, because they can lead to the formation of complex
structures in high stereoselectivities in an operationally straightforward manner.

In 2009, Xu and coworkers reported the first primary amine-thiourea 53 cata-
lysed domino Michael–Henry reaction of 2-aminobenzaldehydes with nitroalk-
enes to generate functionalised 3-nitro-1,2-dihydroquinolines (Scheme 19.61).92
Ye and coworkers reported the use of a multifunctional primary amine-
thiourea catalyst for the stereoselective synthesis of oxazine and oxazolidine
derivatives through a cascade two-step process.93 Unfortunately, the reaction
time was quite long (3–9 days). Recently, Barbas and coworkers utilised
primary amine-thiourea 54 for a domino Michael-aldol reaction that led
to the construction of bispirooxindoles that contained three quaternary
centres in high yields and excellent selectivities (Scheme 19.62).94
O
53 (20 mol%)
NO2
H NO2 PhCO2H (20 mol%)
R1 + R 2 R1
NH2 4Å MS, i-PrOH, r.t. N R2
H
37–70% yield, 52–90% ee
S
N N
H H
NH2
53
Scheme 19.61 Primary amine-thiourea catalysed domino Michael–Henry reaction

of 2-aminobenzaldehydes and nitroalkenes.
Ac
R4
R1 N
O R3 O
3 54 OH
R O +
R4 R1
N 15–20 mol%
Ac R2 O
N R2 O
N
Bn
Bn
up to 94% yield, >99:1 dr, 96% ee
NH2
N
H H
N N
S OMe
54
N
Scheme 19.62 Organocatalysed domino Michael-aldol reaction for the construction

of bispiro-oxindoles.
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19.6 Secondary Amine-(Thio)urea-Mediated

Reactions
19.6.1 Asymmetric 1,4-Conjugate Addition Reactions
Proline derivatives possess a prominent position among the aminocatalysts

utilised for carbonyl activation. In combination with the readily tunable
properties of the (thio)urea functionality for electrophile activation, the de-
velopment of bifunctional chiral pyrrolidine-based (thio)ureas was a rational
extension. In 2006, Tang and coworkers reported thiourea 55 that can
catalyse the conjugate addition reaction between cyclohexanone and
nitroalkenes (Scheme 19.63).95 In the presence of 20 mol% of chiral thiourea
55 and butyric acid as the cocatalyst, the syn-products were delivered in high
yields (up to 98%) and in excellent diastereo- (up to499 : 1 dr) and enan-
tioselectivities (up to 98% enantiomeric excess). In addition to aromatic
nitroalkenes, aliphatic nitroalkenes were also tolerated, but required a long

reaction time (6 days).
Utilising a similar catalyst, Xiao and coworkers were able to lower the
catalyst loading to 10 mol% and were able to perform the reaction in
water.96,97 Additionally, secondary amine-thioureas based on a saccharide
scaffold have been shown to catalyse the same transformation.98 For the
same reaction, Chen, Xiao and coworkers designed novel multifunctional
organocatalysts that combine the privileged structures of pyrrolidine and
Cinchona alkaloids, connected by a thiourea motif (Scheme 19.64).99
Thiourea 56 derived from L-proline and cinchonidine, together with ben-
zoic acid as cocatalyst, were identified as the optimum catalytic system for
this transformation, delivering the products in high yields (75–98%) and in
high to excellent diastereo- and enantioselectivity (up to 98 : 2 diastereomeric
ratio and 96% enantiomeric excess).
In the same vein, Wang and coworkers developed a prolinamide-based
chiral thiourea containing multiple sites for hydrogen binding, for the
O R1
55 (20 mol%)
NO2
n-Butyric acid (10 mol%)
+
neat, 0 oC
NO2
R1
63–99% yield, up to >99:1 dr, 88–98% ee
CF3
N N CF3
N H H
H
55
Scheme 19.63 Secondary amine-thiourea for the asymmetric Michael reaction

between cyclohexanone and nitroalkenes.
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238 Chapter 19
O
56 (10 mol%) O R1
PhCO2H (10 mol%) NO2
NO2
+ R1
n-hexane, r.t.
75–98% yield, up to 98:2 dr, 82–96% ee
S
N
NH H N
H
56 N
Scheme 19.64 Multifunctional secondary amine-thiourea designed for the asym-

metric addition of cyclic ketones to nitroalkenes.
O O R2
57
NO2
NO2 2.5 mol%
+ R2
X 4-NBA, H2O
X
THF, r.t.
R1 R1
85–100% yield, up to 99:1 dr, 95–98% ee
N
N
H S N Ph
H
57
Scheme 19.65 Application of catalyst 57 to the asymmetric Michael addition of

cyclic ketones to aromatic nitroalkenes.
asymmetric addition of aldehydes and acetone to substituted nitrostyr-

enes.100,101 In 2011, Kokotos and coworkers designed a novel class of pyr-
rolidine-based bifunctional organocatalysts bearing a five- or six-membered
cyclised thiourea moiety (thiohydantoin or thioxotetrahydropyrimidin-4-one
ring respectively).102 These catalysts provided a highly sustainable process,
since the catalyst loading required was only 2.5 mol%. The optimum catalyst
of this series (57) was examined in the asymmetric Michael addition of cyclic
ketones to aromatic nitroalkenes, producing the products in high yields (up
to 100%) and with excellent stereoselectivities (up to 99 : 1 diastereomeric
ratio and 98% enantiomeric excess) (Scheme 19.65).
Recently, Kokotos and coworkers presented the asymmetric
Michael addition of cyclic ketones to aryl nitrodienes, by employing the
pyrrolidine/thioxotetrahydropyrimidinone catalyst 57 in the presence of
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R2
1
R
O O
57 (10 mol%)
NO2
NO2 4-NBA, H2O
R2
+
R1 toluene, r.t.
n n
n = 0, 1, 2
57–93% yield, up to 98:2 dr, 73–98% ee
Scheme 19.66 Pyrrolidine/thioxotetrahydropyridiminone 57 used in the Michael

reaction between cyclic ketones and aromatic nitrodienes.
4-nitrobenzoic acid and water as additives (Scheme 19.66).103 This

methodology provided a broad substrate scope with respect to the elec-
trophile, providing the products in good to high yields (57–93%) and with
high selectivities (up to 98 : 2 diastereomeric ratio and 98% enantiomeric

excess).
19.6.2 Asymmetric Aldol Reactions

The first examples of bifunctional thiourea-mediated direct aldol reactions
was described by Tzeng and coworkers.104 They employed proline-derived
thiourea 58 bearing a bulky camphor moiety in the aldol reaction between
cyclohexanone and aromatic aldehydes using water as the reaction
medium. This environmentally benign methodology afforded the anti-
products in yields ranging from 26 to 95% and in high stereoselectivity
(up to410 : 1 diastereomeric ratio and499% enantiomeric excess)
(Scheme 19.67). To account for the high efficiency and selectivity of the
catalyst in water, the authors suggested that the catalyst and the substrates
are held in close proximity by the surrounding water molecules forcing the
reaction to take place in a hydrophobic microenvironment, while the
dodecylbenzylsulfonic acid (DBSA) additive plays a crucial role acting as a
surfactant.
Cui and coworkers designed novel polymer supported pyrrolidine-
thioureas applied in aqueous medium.105,106 The immobilised organocata-
lysts 59 and 60 were found to be efficient in low catalyst loading
(2–2.5 mol%) and could be recovered and reused for at least three cycles
without any loss of their activity or selectivity (Scheme 19.68).
Kokotos and coworkers investigated the use of prolinamide-based
thioureas as bifunctional organocatalysts for the direct aldol reaction.107,108
The amide and the thiourea functionalities, tethered by a chiral diamine
motif, offered multiple hydrogen bonding sites for electrophile activation,
while the pyrrolidine skeleton served to activate the nucleophile via enamine
catalysis. Thiourea 61 proved to provide the best catalyst in the presence
of 4-nitrobenzoic acid as cocatalyst at low temperature and delivered the
anti-aldol products in moderate to high yields and in high to excellent
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240 Chapter 19
O OH O
O 58 (20 mol%)
DBSA (20 mol%)
R1
+ R1 H
H2O, 2–7 d
DBSA = dodecylbenzylsulfonic acid
26–95% yield, up to >10:1 dr, 73–>99% ee
O
N S
H HN
O
TBDPSO NH HN
O Me
58 Me
Scheme 19.67 Enantioselective organocatalytic direct aldol reaction in water.
O 59 (8 mol%) OH O
O or
60 (2 mol%) R1
+ R1 H
H2O, 6–15 d
14–87% yield, up to 3:1 dr, 15–97% ee

O S H H
59: R = N N
R N
N N N H
N H H H
H 60: R = (CH2)12
Scheme 19.68 Polymer-supported pyrrolidine-thiourea catalysed direct aldol reac-

tion in aqueous medium.
diastereo- and enantioselectivity (up to 99 : 1 diastereomeric ratio and 99%

enantiomeric excess). (Scheme 19.69). In addition, Moutevelis-Minakakis
and Kokotos and coworkers developed prolinamide-ureas for the same
reaction.109
The direct aldol reaction, in which a ketone is used as the electrophilic
partner, is considered a challenging task, giving access to synthetically
useful chiral tertiary alcohols. To this end, Kokotos reported that prolina-
mide-thiourea 61 consisting of di-tert-butyl aspartate and (1S,2S)-dipheny-
lethylene-1,2-diamine can be successfully employed in the aldol reaction
between ketones and perfluoroalkyl ketones, providing tertiary alcohols
bearing a perfluoroalkyl moiety in good to high yields (45–99%) and with
good enantiomeric excess (up to 81%) (Scheme 19.70).110 It has to be high-
lighted that only 2 mol% of the catalyst was required.
View Online
O O OH
O 61 (10 mol%)
4-NBA (10 mol%) R3
+ H R3
R1
R2 toluene, –20 oC, 24 h R1 R2
40–100% yield, up to 99:1 dr, 92–99% ee
O Ph
Ph
N
H HN S
N
H
HN CO2tBu
61
CO2tBu
Scheme 19.69 Prolinamide-based thiourea catalyst developed for the direct aldol
reaction.
O
O O
61 (2 mol%) HO
+ R2
R1 Rf R2 o
toluene, 0 C, 44 h R1 Rf
45–99% yield, 53:46 dr, 48–81% ee
Scheme 19.70 Direct aldol reaction of ketones with perfluoroalkyl ketones catalysed
by a prolinamide-thiourea.
19.6.3 Asymmetric Mannich Reactions

In 2009, Peng and coworkers developed the first highly enantioselective anti-
Mannich addition of aldehydes and ketones to p-methoxyphenyl-(PMP)-pro-
tected a-iminoglyoxylate utilising pyrrolidine-based bifunctional thiourea 62
(Scheme 19.71).111 The reaction proceeded smoothly with a broad range of
aliphatic aldehydes and ketones, delivering products containing adjacent
stereocentres in high yields (up to 94%) and stereoselectivities (up to499 : 1
diastereomeric ratio and499% enantiomeric excess). Later, the same group
successfully applied the same catalyst in the anti-Mannich reaction of alde-
hydes with Boc- or Cbz-protected aldimines, either preformed112 or generated
in situ.113 To account for the excellent stereochemical outcome, the authors
have proposed a transition-state model, where the nucleophile is activated
through enamine formation, the bulky silylether protecting group of the
catalyst shields effectively the re-face of the enamine double bond allowing
attack only from the si-face, and the thiourea moiety activates the Mannich
acceptor through hydrogen-bonding interactions with the imine’s nitrogen.
19.6.4 Asymmetric a-Alkylation Reactions

Trifonidou and Kokotos utilised catalyst 57 in order to catalyse the a-
alkylation of ketones by means of SN-1 type reactions of alcohols.114
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242 Chapter 19
F3C H H
N N OTBDPS
S
N
F3C H
62
PMP PMP
N O O HN
62 (5–10 mol%)
+ R1
H CO2Et R1 CO2Et
ClCH2CH2Cl
R2 R2
63–94% yield, up to 9:1 regioselectivity, up to >99:1 dr, 82– >99% ee
R3
O R3 O HN
N 62 (5 mol%)
R2
H + H R4
R4 CHCl3, 0 oC 2
R1 R1 R
70–95% yield, up to 96:4 dr anti:syn, 92– >99% ee
R3 R3
O O HN
HN 62 (5 mol%)
+ H R2
H
R2 SO2Ar KF, CHCl3,
R1 R1
–20 or 0 oC
70–98% yield, up to >99:1 dr, 92– >99% ee
Scheme 19.71 Secondary amine-thiourea mediated Mannich addition reactions

of ketones and aldehydes to preformed or in situ generated
imines.
Pyrrolidine-thioxotetrahydropyrimidinone catalyst 57 in the presence of

4-nitrobenzoic acid cocatalyst effectively catalysed the asymmetric re-
action of cyclic ketones with substituted benzhydrol to afford the a-
alkylated products in moderate to quantitative yields and in low to high
enantiomeric excesses (up to 80%) (Scheme 19.72). According to the
authors, the stereochemical outcome of the reaction indicates some type
of interactions between the generated carbocation and the thioxotetrahy-
dropyrimidinone ring of the catalyst, in lieu of steric shielding, hence
leading to a front-face attack from the nucleophilic enamine (see TS in
Scheme 19.72).
19.6.5 Asymmetric Nitro-Mannich Reaction

Li, Chen and coworkers synthesised a new secondary amine-thiourea,
thiourea 63, for the enantioselective nitro-Mannich reaction of nitroacetates
to Boc-imines (Scheme 19.73).115
View Online
NMe2
OH
O 57 (10 mol%) O
4-NBA (10 mol%)
R1 + R1
CH2Cl2, r.t., 44 h
R2 Me2N NMe2 R2
NMe2
21–98% yield, 16–80% ee

O
N
N
S N Ph
H
Ar
Me2N TS
Scheme 19.72 Asymmetric a-alkylation of ketones promoted by a pyrrolidine-based

chiral thiourea.
NO2 Boc O2N

N 63 (10 mol%) NHBoc
+ R H
R CO2Me
R1 xylene, 4A MS MeO2C R1
–20 oC, 72 h
38–86% yield, 3.8:1 to 17.2:1 dr, 91–96% ee
CF3
Ph S
Ph
N N CF3
H H
NH
63
Scheme 19.73 Asymmetric nitro-Mannich reaction promoted by a secondary amine-

thiourea 63.
19.6.6 Asymmetric Reduction of Ketones

Falck and coworkers introduced secondary amine-thiourea 64 as a highly
enantioselective catalyst for the reduction of ketones (Scheme 19.74).116
Among a number of reducing agents, catecholborane afforded the best re-
sults leading to enantioenriched alcohols in good to high yields and from
moderate to excellent enantioselectivities.
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244 Chapter 19
O HO H
64 (10 mol%)
Ar R Ar R
catecholborane
toluene, 4A MS
–46 oC, 24 h
60–95% yield, 47–97% ee
H H
N N CF3
S
NH
64 CF3
Ph
Scheme 19.74 Asymmetric reduction of ketones promoted by a secondary amine-

thiourea 64.
NO2
O R
55 (20 mol%)
NO2 O
4-MBA (20 mol%)
+
n R OAc neat, r.t. H H
X
X
n = 0, 1 27–94% yield, 77–98% ee
CF3
N N CF3 N
N H Ph
H H
NO2
O
N O
OAc TS2
Michael addition
TS1
Michael/elimination step
Scheme 19.75 Michael-elimination–Michael reaction catalysed by a pyrrolidine-

based thiourea catalyst.
19.6.7 Asymmetric Domino Reactions

Tang, Li and coworkers employed thiourea 55 in an asymmetric domino
Michael–elimination–Michael reaction to afford a bicyclo[3.3.1] skeleton
with four stereogenic centres (Scheme 19.75).117 Upon catalysis, in the
View Online
O
O
57 (20 mol%) H
4-NBA (20 mol%), H2O
+ NO2
R1 R1
THF, r.t., 24 h
HO
O NO2
70–86% yield, 90–96% ee

O
O
57 (10 mol%) H
4-NBA (10 mol%), H2O R3
NO2
+ R2
R2
R3 THF, r.t., 24 h
HO
O NO2
56–91% yield, 86–97% ee

N
N
S N Ph
H
O O
N
O
Ar TS
Scheme 19.76 Highly enantioselective synthesis of bicyclo[3.2.1]octan-2-ones

through a domino Michael–Henry process.
presence of 4-methoxybenzoic acid cocatalyst, five- and six-membered cyclic

ketones reacted with nitroallylic acetates, delivering the bicyclic products
as a single diastereomer and in high to excellent enantioselectivity (up to
98% enantiomeric excess). The authors suggested synergistic activation
of both substrates through covalent and hydrogen bonding interactions
(TS1 in Scheme 19.75) and a sequential conjugate addition annulation step
(TS2 in Scheme 19.75).
Very recently, Kokotos and coworkers developed a highly enantioselective
domino Michael–Henry reaction between 1,4-cyclohexanedione and
aromatic nitroalkenes or nitrodienes, which led to a range of unique
bicyclo[3.2.1]octan-2-ones bearing four continuous stereogenic centres
(Scheme 19.76).118 Utilising catalyst 57 together with 4-nitrobenzoic acid
and water as additives, the products were obtained in high yields and ex-
cellent enantioselectivities (up to 97% enantiomeric excess) as a single
diastereoisomer. The authors suggested a concomitant activation of both
substrates, the 1,4-dione via enamine formation and the electrophile via
hydrogen-bonding interaction with the catalyst’s acidic proton (see TS in
Scheme 19.76).
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246 Chapter 19
19.7 Miscellaneous Sustainable Bifunctional

Thio(ureas)
In 2004, Nagasawa and coworkers reported a novel bis-thiourea organoca-
talyst for the Baylis–Hillman reaction.119 The bifunctional activation of both

the nucleophile and the electrophile proceeds through hydrogen-bond for-
mation each with one thiourea group of the catalyst. Although the protocol
involved neat reaction conditions, a catalyst loading of 40 mol% was re-
quired to provide the products in moderate enantioselectivities (33–90%
enantiomeric excess), thus decreasing sustainability. One year later, Naga-
sawa’s group reported a more sustainable protocol for the asymmetric Henry
reaction utilising bifunctional guanidine-thiourea 65.120 Various cyclic ali-
phatic and branched aliphatic aldehydes were well tolerated, providing the
nitroaldol adducts in satisfactory yields and enantioselectivities
(Scheme 19.77). The authors suggested a dual activation transition state as
depicted in scheme 19.77, where nitromethane is activated by the guanidine

group and the aldehyde by the thiourea group.
In 2005, Ricci and coworkers published the first organocatalytic enantio-
selective Friedel–Crafts alkylation of indoles with nitroalkenes utilising
simple thiourea 66.121 In general, moderate yields and enantioselectivities
were observed for this difficult transformation, utilising 20 mol% catalyst
C18H37
H H N X H H
F3C N N N N CF3
N N
S H H S
Ph Ph
O CF3 65 (10 mol%) CF3
OH
CH3NO2 NO2
R H toluene:H2O 1:1, KI (50 mol%) R
0 oC, 5-45 h
OH OH OH OH
NO2 OH NO2
NO2 NO2 NO2
Ph
91% yield 76% yield 85% yield 79% yield 70% yield
92% ee 82% ee 88% ee 55% ee 88% ee
C18H37
N
H
N N Ph
H H N S
H
O O N Ar
N H
dual activation O
H anti-conformation
R of the aldehyde
Scheme 19.77 Asymmetric nitroaldol reaction catalysed by bifunctional thiourea 65.

View Online
loading at 24 1C for 72 h. The simple operational procedure and synthetic

versatility of the adducts rendered this protocol efficient for the synthesis
of chiral target compounds such as tryptamines and 1,2,3,4-tetrahydro-b-
carbolines (Scheme 19.78). The authors proposed a bifunctional mechanism
involving the simultaneous activation of indole by the hydroxy group and

nitro-olefin by the thiourea group.
In 2006, Berkessel and coworkers reported a new and improved iso-
phoronediamine-derived bisthiourea organocatalyst for the asymmetric
Morita–Baylis–Hillman reaction.122 Employing 20 mol% of catalyst 67
and N,N,N 0 ,N 0 -tetramethylisophoronediamine (TMIPDA) as base under
neat reaction conditions, the adduct of 2-cyclohexen-1-one with cyclohex-
anecarbaldehyde was obtained in 75% yield and 96% enantiomeric excess
CF3
S
F3C N N R3
2 H H OH
R R2 NO2
R1 66 (20 mol%)
R3
NO2 R1
N CH2Cl2, -24 oC, 72 h N
H H
Ph Ph
O
NO2 MeO NO2 NO2
MeO NO2
N N N
H H N H
H
85% ee 89% ee 73% ee 81% ee
Ph Ph
Ph
NO2 Pd/C 10%
HCOONH4 NH2 PhCHO NH
N MeOH Pictet-Spengler N Ph
H N
H cyclization H
tryptamine 1,2,3,4-tetrahydro-β-carboline
CF3
S
F3C N N
H H O H
O O H
bifunctional N
mode N
Ph
Scheme 19.78 Asymmetric Friedel–Crafts alkylation of nitroalkenes.

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248 Chapter 19
Me
Me
NH
NH
HN Me S
S CF3
NH
F3C
F3C OH O
O O 67 (20 mol%)
CF3
H
neat, TMIPDA, 10 oC
75% yield
96% ee
Me
Me
N S
H N CF3
N Me
H H
S
N O
TMIPDA = N H O CF3
N
F3C H
R
CF3 R3N
Scheme 19.79 Enantioselective Morita–Baylis–Hillman reaction of 2-cyclohexen-1-

one with cyclohexanecarbaldehyde utilising bisthiourea 67.
(Scheme 19.79). The reaction mechanism again involves a bifunctional

transition state: one thiourea group activates the nucleophile and the other
activates the electrophile.
Lassaletta and coworkers reported in 2007 the asymmetric conjugate
addition of formaldehyde N,N-dialkylhydrazones to b,g-unsaturated a-keto
esters.123 Utilising 10 mol% of 68 [(1S,2R)-enantiomer of Ricci’s catalyst], the
corresponding products were afforded in high yields and good enantio-
selectivities (Scheme 19.80).
In 2008, Rabalakos and Wulff reported unique bifunctional DMAP-
thiourea 69 for the enantioselective Michael addition of nitralkanes
to nitro-olefins.124 High asymmetric inductions were afforded (91–95%
enantiomeric excess) at only 2 mol% catalyst loading. The authors
suggested that the thiourea moiety activates the nitro-olefin, while the
4-dimethylaminopyridine unit serves a dual role deprotonating the
nitroalkane and stabilising the resulting nitronate anion via hydrogen
bonding (Scheme 19.81). Notably, enantioselectivities increased with de-
creasing catalyst loading.
More recently, Barbas and coworkers published the enantioselective
synthesis of carbazolespirooxindole derivatives via a Diels–Alder cyclisa-
tion catalysed by C2-symmetric bisthiourea 70.125 Mild conditions
were utilised, providing the pentacyclic adducts in high yields and high
enantiopurity, in an incredibly fast reaction time (o10 min) (Scheme 19.82).
Mechanistic studies indicated activation of methyleneindoline via hydro-
gen-bond interactions, where the a-NH group at the vinylindole is essential
View Online
CF3
S
F3C N N N
H H OH N
O O
N 68 (10 mol%)
N OEt EtO
R R
CH2Cl2, –45 or –60 oC , 72 h
H H O O
N N N
N
N N N
N O O
O O
EtO Me EtO EtO
EtO
Me
O Me O O
O
80% ee 78% ee 72% ee 78% ee
Scheme 19.80 Enantioselective addition of formaldehyde N,N-dialkylhydrazones to

b,g-unsaturated a-keto esters promoted by thiourea 68.
CF3
S
N N CF3
H H
H N
N
N
Me Me
69 (2 mol%) NO2
R NO2 NO2
Ar benzene, 25 C o R NO2
Ar
NO2
NO2 NO2 NO2
NO2
NO2 NO2 NO2
MeO
Br
Me Me CF3
N
chiral S
scaffold N N CF3
N N
H H H H
O O O O
N N
R
Ar
Scheme 19.81 Enantioselective nitro-Michael reaction employing thiourea 69.

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250 Chapter 19
F3C S S CF3
NH HN
R1 NH HN
70 (15 mol%) R1
F3C CF3
2 2 N
R O R H
N N hexane, r.t. N O
H Boc <10 min Boc
MeO2C MeO2C BnO2C NC

N N N N
H H H H
N O Cl N O N O N O
Boc Boc Boc Boc

>99:1 dr >99:1 dr >99:1 dr >99:1 dr
96% ee 94% ee 95% ee 92% ee
MeO2C
70 (15 mol%) 50% conversion
1.5:1 dr
N O 0% ee
N
Me
Boc
Scheme 19.82 Enantioselective Diels–Alder reaction employing thiourea 70.
for obtaining high stereocontrol. In addition, this practical protocol

recycles the organocatalyst and the solvent, thus enhancing the sustain-
ability of this method.
19.8 Conclusions
In conclusion, there are a number of ureas and thioureas that have been
successfully employed as organocatalysts in numerous organic transforma-
tions taking advantage of their ability to interact through hydrogen bonding.
The (thio)urea functionality has been combined with tertiary, primary and
secondary amines to provide efficient bifunctional organocatalysts. The key-
advantages that (thio)urea organocatalysts have, is the low catalyst loading
that can be employed and the simple reaction conditions, allowing orga-
nocatalysed transformations to be utilised for applications in chemical and
pharmaceutical industries.
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Ureas and Thioureas As Asymmetric Organocatalysts

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Published on 16 November 2015 on https://pubs.rsc.org | doi:10.

Ureas and Thioureas as

Laboratory of Organic Chemistry, Department of Chemistry,

water and air stable,

There are a number of elegant contributions in the field that have

RSC Green Chemistry No. 41

Ureas and Thioureas as Asymmetric Organocatalysts 197

to present some key examples of (thio)urea organocatalysts that provide

19.2 Early Attempts

the thio(urea) group.

Scheme 19.1 Curran and Kuo’s urea catalyst.

Scheme 19.2 Carbonyl group shows greater dimerisation potency – urea/thiourea

19.3 (Thio)ureas as Organocatalysts

A pioneer in the field of the asymmetric (thio)urea organocatalysis was Eric

aldimines and ketimines underwent hydrocyanation with high enantio-

Scheme 19.3 First asymmetric thio(urea) catalyst. Enantioselective Strecker reaction.

R1 H HCN, toluene, -78 oC R1 H

Scheme 19.4 Sustainable thiourea 4 for organocatalytic Strecker reaction.

Ureas and Thioureas as Asymmetric Organocatalysts 199

Boc OTBS Boc

H R OiPr 2. TFA R OiPr

CF3CH2OH, CH2Cl2, –78 oC

Scheme 19.5 Various transformations promoted by Jacobsen’s thiourea catalysts.

Since then, Jacobsen’s group have developed a variety of chiral thioureas

involving electrophile activation by the thiourea and nucleophilic activation

19.3.2 Monofunctional Thio(urea) Hydrogen-bond Catalysis

trimethylsilyl cyanide or the addition of ketene silyl acetals to nitrones were

CF3 8 CF3 CF3 CF3

Scheme 19.6 Diels–Alder reaction promoted by Schreiner’s thiourea.

Ureas and Thioureas as Asymmetric Organocatalysts 201

amines as nucleophiles. Sterically hindered tert-butyl amine, as well as

The corresponding N-acetylated amino nitriles, which are precursors of

Scheme 19.7 Thiourea 8 catalyses the Mukaiyama aldol reaction.

Scheme 19.8 Friedel–Crafts alkylation catalysed by thiourea 8.

water, r.t. or 40 oC, 24 h

94 % yield 94 % yield 87 % yield 83 % yield

Scheme 19.9 Epoxide ring opening by amines catalysed by thiourea 8.

O 8 (0.01-1 mol%) OR3

94% yield (10 h) 92% yield (9 h) 91% yield (14 h)

Scheme 19.10 Organocatalytic acid-free acetalisation utilising thiourea 8.

In 2007, Schreiner applied his thiourea 8 in developing a green

Ureas and Thioureas as Asymmetric Organocatalysts 203

88% yield 64% yield 67% yield

Scheme 19.11 Catalytic acylcyanation of imines with acetylcyanide utilising

Scheme 19.12 Organocatalytic tetrahydropyranylation of hydroxy functionalities

In 2008, Connon and coworkers reported a base-mediated protocol for

93% yield, 20 h 91% yield, 38 h 57% yield, 40 h 90% yield, 133 h

Scheme 19.13 Organocatalytic Corey–Chaykovsky epoxidation utilising urea 9.

Ureas and Thioureas as Asymmetric Organocatalysts 205

Scheme 19.14 Enantioselective Pictet–Spengler cyclisation of hydroxylactams

Boc OTBS NHBoc

97% yield 72% yield

Scheme 19.15 Asymmetric Mukaiyama–Mannich reaction catalysed by thiourea 11.

51% yield 72% yield 75% yield 77% yield

Scheme 19.16 Enantioselective cationic polycyclisation promoted by thiourea 13.

19.4 Bifunctional Tertiary Amine Thio(ureas)

Ureas and Thioureas as Asymmetric Organocatalysts 207

reaction with malononitrile.34 Among the substrates, benzimides bearing a

Scheme 19.18 Organocatalytic Michael addition of malonates to nitroalkenes and

Scheme 19.19 Michael reaction of benzimides with malononitrile catalysed by

of nitroalkanes possessing aryl, ether, alcohol and ester functionalities

Ureas and Thioureas as Asymmetric Organocatalysts 209

Scheme 19.20 Asymmetric aza-Henry reaction catalysed by thiourea 15.