Organocatalytic SOMO reactions of copper(I)-acetylide and alkylindium compounds with aldehydes

Article abstract of DOI:10.2478/s11696-014-0564-4

The derivatisation of aldehydes in their α-position is an important facet of organic synthesis. Organocatalytic radical reactions afford α-functionalised aldehydes via a SOMO activation pathway. New organo-SOMO reactions of aldehydes with copper(I)-acetylide and alkylindium reagents are detailed. These reactions proceed well under the catalysis of chiral imidazolidinones. The corresponding functionalised aldehydes were obtained with acceptable yields, but with only low enantiomeric ratios.

Full text of DOI:10.2478/s11696-014-0564-4

Chemical Papers 68 (8) 1113–1120 (2014)
DOI: 10.2478/s11696-014-0564-4
ORIGINAL PAPER
Organocatalytic SOMO reactions of copper(I)-acetylide
and alkylindium compounds with aldehydes
Pavol Tisovský, Mária Mečiarová, Radovan Šebesta*
Department of Organic Chemistry, Faculty of Natural Sciences, Comenius University,
Mlynská dolina CH-2, 842 15 Bratislava, Slovakia
Received 3 December 2013; Revised 30 January 2014; Accepted 30 January 2014
The derivatisation of aldehydes in their α-position is an important facet of organic synthesis.
Organocatalytic radical reactions afford α-functionalised aldehydes via a SOMO activation path-
way. New organo-SOMO reactions of aldehydes with copper(I)-acetylide and alkylindium reagents
are detailed. These reactions proceed well under the catalysis of chiral imidazolidinones. The cor-
responding functionalised aldehydes were obtained with acceptable yields, but with only low enan-
tiomeric ratios.
c
ꢀ 2014 Institute of Chemistry, Slovak Academy of Sciences
Keywords: organocatalysis, SOMO activation, acetylide, alkylindium
Introduction
cerium(IV) nitrate, CAN), Cu(OSO2CF3)2 (copper(II)
trifluoromethanesulphonate, Cu(OTf)2), copper(II)
trifluoroacetate (Cu(TFA)2), CuCl2, [Fe(phen)3]
(PF6)3 and FeCl3.
Asymmetric organocatalysis relies on two ma-
jor activation modes. The activation of electrophiles
can be performed via the LUMO-lowering strategy,
such as iminium salt-formation or hydrogen-bonding.
On the other hand, nucleophiles can be activated
through HOMO-rising, typically achieved by enamine-
formation (Dalko, 2007). There is, however, a third
concept, the so-called SOMO (singly-occupied molec-
ular orbital) activation. These organo-SOMO reac-
tions constitute a novel concept for enantioselective
α-substitution of carbonyl compounds, especially alde-
hydes, which proceed through a radical mechanism.
Aldehydes react with chiral secondary amines to give
enamines, which can be readily oxidised to cation rad-
icals. These cation radicals undergo coupling reactions
with a variety of compounds, so-called somophiles, to
give enantio-enriched α-substituted aldehydes (Fig. 1)
(Beeson et al., 2007).
SOMO catalysis has been applied successfully
in a variety of reactions. The allylation of vari-
ous aldehydes (Beeson et al., 2007) and cyclic ke-
tones (Mastracchio et al., 2010) with π-rich olefinic
silanes resulted in important chiral intermediates, in-
cluding five-, six- and seven-membered carbocycles
and heterocycles (Pham et al., 2011a). The reac-
tions of SOMO-activated aldehydes with enolsilanes
gave enantio-enriched γ-ketoaldehydes (Jang et al.,
2007). Organocatalytic SOMO-vinylation of aldehydes
yielded products with formyl- and vinyl-moieties on
the stereogenic centre (Kim & McMillan, 2008). The
α-arylation of aldehydes via organo-SOMO catalysis
is a promising method for the synthesis of pharma-
cologically active molecules, e.g. (–)-tashiromin (Ban-
well et al., 2004), (S)-ketoprofen (Allen & McMillan,
2011) and other medicinal agents (Harvey et al., 2011).
Chiral tetrahydronaphthalene derivatives were pre-
pared by intramolecular SOMO α-arylation of alde-
hydes (Nicolaou et al., 2009; Conrad et al., 2009; Um
Chiral imidazolidinones were deemed the best cata-
lysts for these transformations (MacMillan & Rendler,
2012). The oxidising agents most commonly used in
SOMO reactions are (NH4)2Ce(NO3)6 (diammonium
*Corresponding author, e-mail: radovan.sebesta@fns.uniba.sk

1114
P. Tisovský et al./Chemical Papers 68 (8) 1113–1120 (2014)
Fig. 1. SOMO-catalysed α-derivatisation of aldehydes.
2-Benzyl-2,4-diphenylbut-3-ynal was formed as a by-
product in the synthesis of polysubstituted pyrroles
from substituted alkynoles with a 10–37 % yield (Teo
et al., 2013). Aldehydes with a double or triple bond
were prepared by a two-step process. The first step
was the reaction of epoxysilanes with organometallic
reagents. The accrued diols were then oxidised with
et al., 2010). SOMO-catalysed [4+2] cyclo-additions
of aromatic aldehydes with styrenes and dienes pro-
vided cyclic products with high regioselectivity and
stereoselectivity (Jui et al., 2010). Similarly, the [3+2]
cyclo-addition of aldehydes and conjugated olefins af-
forded pyrrolidine derivatives under SOMO-catalysis
(Jui et al., 2012). SOMO-catalysed carbo-oxidation
of styrenes in the presence of cerium ammonium ni-
trate gave γ-nitrate-α-alkyl aldehydes, valuable build-
ing blocks of enantio-enriched butyrolactones, pyrro-
lidines and α-formyl homobenzylation adducts (Gra-
ham et al., 2008). Oxidative enantioselective alde-
hyde nitroalkylation with silyl nitronates is an efficient
method for the synthesis of β-nitroaldehydes, which
are versatile synthons in the synthesis of β-amino
acids and 1,3-aminoalcohols (Wilson et al., 2009).
The enantioselective α-benzylation of aldehydes with
electron-deficient aryl and heteroaryl bromides using
photoredox-organocatalysis afforded enantio-enriched
α-benzyl aldehydes, which are important synthons in
the synthesis of angiogenesis inhibitors (Shih et al.,
2010). Enantio-enriched α-chloroaldehydes, prepared
using LiCl as a chlorine source under organo-SOMO
catalysis, are reactive intermediates in the synthesis
of terminal aziridines, α-chloro alcohols, α-cyano al-
cohols, terminal epoxides, α-hydroxy acids, α-amino
acids, etc. (Amatore et al., 2009). Carbonyl and car-
boxyl compounds with a trifluoromethyl group on the
stereogenic centre at an α-position were prepared by
SOMO-catalysed asymmetric α-trifluoromethylation.
These compounds are versatile synthons for medic-
inal agents and agrochemicals synthesis (Nagib et
al., 2009; Allen & McMillan, 2010; Pham et al.,
2011a, 2011b). Enantioselective α-oxidation of alde-
hydes with TEMPO using a synergistic combination
of copper and organocatalysis afforded versatile syn-
thons for natural products and medicinal agents (Si-
monovich et al., 2012). Zhu et al. (2012) described the
direct oxidation of 3-arylpropanals to 3-arylacroleins
promoted by SOMO catalysis.
Pb(OAc)4
to give the target aldehydes with an over-
all yield of 31–77 % (Chauret et al., 1999).
In addition, some of the resulting products could
be useful for their biological properties. For instance,
alkynales were used in the synthesis of fused tetrahy-
dropyranones, which are common building blocks in
biologically active molecules (Ciesielski et al., 2013).
As noted above, a variety of different somophiles
have been described to date. However, very little at-
tention has been devoted to organometallic reagents
as somophiles. Accordingly, it was decided to expand
the methodology of SOMO organocatalysis by ap-
plying organometallic compounds as somophiles. Us-
ing copper(I)-acetylides, a triple bond was introduced
into a molecule of aldehdyde. Various organoindium
compounds were used for introduction of the alkyl or
alkenyl side-chain.
Experimental
All reactions were carried out in an argon inert
atmosphere. Solvents were dried and purified by stan-
dard methods prior to use. FTIR spectra were ob-
tained with Thermo Scientific Nicolet iS10 spectrom-
eter. NMR spectra (300 MHz for 1H; 75 MHz for 13C)
were recorded on a Varian Mercury plus instrument.
Chemical shifts are referenced to the tetramethylsi-
lane (TMS) as internal standard. Flash chromatog-
raphy was performed on Merck silica gel 60. Thin-
layer chromatography (TLC) was performed on Merck
TLC-plates silica gel 60 F
254. Enantiomeric excesses
were determined using HPLC on a Chiralcel OD-H,
Chiralpak AD-H or Chiralpak AS-H (Daicel Chemi-
cal Industries) column using a mixture of isopropyl
alcohol (IPA) and hexane as a mobile phase and de-
tection with UV-detector at 254 nm. Copper(I) pheny-
lacetylide (II) (not commercially available) was syn-
thesised following the previously described procedure
(Shi et al., 2008). Catalyst C-V was prepared using
the recognised method (Samulis & Tomkinson, 2011).
Aldehydes with alkyl, alkenyl or alkynyl chains
were often prepared by multi-step synthesis with low
yields. One of the intermediates in the total synthe-
sis of (+)-frondosin A, 4-(dimethyl(phenyl)silyl)-2,2-
dimethylbut-3-ynal, was prepared in a four-step pro-
cess from commercially available 2-methylbut-3-yn-2-
ol with an overall yield of 15 % (Barry et al., 2007).

P. Tisovský et al./Chemical Papers 68 (8) 1113–1120 (2014)
Table 1. Physical and spectral data of prepared compounds
1115
Compound
Physical and spectral data
Reference
FTIR (neat), ν˜/cm−1: 3435, 2960, 2933, 2860, 2112, 1728, 1490, 1416, 1380, 1071, This article
961, 890, 802, 757, 728, 690, 651
1
—
H NMR (300 MHz, CDCl3), δ: 9.72 (d, J = 6.4 Hz, 1H, CH O), 7.55–7.51 (m, 2H,
—
HC in Ph), 7.38–7.31 (m, 3H, HC in Ph), 3.61 (td, J = 7.4 Hz, J = 6.4 Hz, 1H, CH),
1.79 (dt, J = 7.4 Hz, J = 7.0 Hz, 2H, CH2), 1.33–1.24 (m, 8H, 4 × CH2), 0.87 (t, J
= 6.9 Hz, 3H, CH3)
13
—
C NMR (75 MHz, CDCl3), δ: 200.7 (C O), 128.5 (CH), 128.3 (CH), 122.7 (CHq
—
IIIa
—
—
in Ph), 89.4 (C—C), 78.6 (C—C), 43.6 (CH), 32.3 (CH2), 31.8 (CH2), 28.4 (CH2),
—
—
25.7 (CH2), 22.7 CH2), 14.1 (CH3)
HRMS, m/z (found/calc.): 229.1590/229.1592 ([M + H]+ , C16H21O)
HPLC (Chiralpak OD-H; IPA/hexane (ϕr = 3 : 97); 1 mL min−1; λ = 254 nm): tR
(major) = 29.13 min, tR (minor) = 35.46 min
FTIR (neat), ν˜/cm−1: 2985, 2143, 1560, 923, 756
Herrmann et al.
1H NMR (300 MHz, CDCl3), δ: 7.56–7.50 (m, 4H, HC in Ph), 7.39–7.29 (m, 6H, HC (2001)
IV
in Ph)
FTIR (neat), ν˜/cm−1: 3318, 3023, 2920, 2855, 2362, 2340, 1596, 1495, 1465, 1379, Joosten et al.
1262, 1029, 964, 801, 738, 691, 669, 617, 492, 419 (2010)
1
—
H NMR (300 MHz, CDCl3), δ: 9.71 (d, J = 7.7 Hz, 1H, (CH O), 7.41–7.20 (m, 5H,
—
—
HC in Ph), 6.61 (d, J = 15.9 Hz, 1H, CH CH), 6.31 (ddd, J = 4.3 Hz, J = 9.0 Hz,
J = 15.9 Hz, 1H, CH CH), 2.73 (m, 1H, CH), 2.39 (dd, J = 7.0 Hz, J = 7.0 Hz, 2H,
—
—
—
CH2), 1.52 (dt, J = 7.3 Hz, J = 6.6 Hz, 2H, CH2), 1.33–1.24 (m, 8H, 4 × CH2), 0.87
(t, J = 6.9 Hz, 3H, CH3)
C NMR (75 MHz, CDCl3), δ: 204.1 (C O), 136.4 (CHq in Ph), 128.5 (C C),
128.6 (CH), 127.9 (CH), 127.8 (CH), 117.4 (C C), 52.8 (CH), 31.8 (CH2), 31.1
VIIa
13
—
—
—
—
—
—
(CH2), 29.3 (CH2), 22.7 (CH2), 14.1 (CH3)
HPLC (Chiralpak AD-H; IPA/hexane (ϕr = 5 : 95); 1 mL min−1; λ = 254 nm): tR
(major) = 17.34 min, tR (minor) = 20.18 min
FTIR (neat), ν˜/cm−1: 3442, 2932, 2870, 1732, 1456, 1442, 1410, 1250, 1061, 930, 720, Joosten et al.
692, 537 (2010)
1
—
H NMR (300 MHz, CDCl3), δ: 9.70 (d, J = 7.3 Hz Hz, 1H, CH O), 5.63 (ddt, J
—
—
—
—
= 17.1 Hz, J = 10.5 Hz, J = 7.4 Hz, 1H, CH CH2), 4.85–4.75 (m, 2H, CH CH2),
—
2.69 (tdt, J = 7.3 Hz, J = 7.3 Hz, J = 7.0 Hz, 1H, CH), 2.41 (dd, J = 7.4 Hz, J =
7.0 Hz, 2H, CH2), 1.51 (dt, J = 7.3 Hz, J = 6.6 Hz, 2H, CH2), 1.41–1.28 (m, 8H,
4 × CH2),0.86 (t, J = 7.0 Hz, 3H, CH3)
VIIb
13
—
—
—
—
C NMR (75 MHz, CDCl3), δ: 204.5 (C O), 135.7 (C C), 115.7 (C C), 52.5
—
—
(CH), 31.8 (CH2), 31.7 (CH2), 29.3 (CH2), 27.8 (CH2), 22.7 (CH2), 14.3 (CH3)
HPLC (Chiralpak OD-H; IPA/hexane (ϕr = 5 : 95); 1 mL min−1; λ = 216 nm): tR
(major) = 26.54 min, tR (minor) = 31.27 min
FTIR (neat), ν˜/cm−1: 3442, 2965, 2932, 2870, 1732, 1456, 1220, 1170, 1061, 720, 503 Kato et al. (1997)
1
—
H NMR (300 MHz, CDCl3), δ: 9.71 (d, J = 7.2 Hz, 1H, CH O), 2.57 (dqd, J =
—
7.8 Hz, J = 6.2 Hz, J = 4.8 Hz, 1H, CH), 1.68–1.54 (m, 4H, 2 × CH2), 1.33–1.27 (m,
16H, 8 × CH2), 0.88 (t, J = 5.8 Hz, 6H, 2 × CH3)
13
—
C NMR (75 MHz, CDCl3), δ: 204.3 (C O), 50.9 (CH), 31.8 (CH2), 28.8 (CH2),
—
26.9 (CH2), 22.7 (CH2), 14.2 (CH3)
GC (Lipodex E, γ-cyclodextrin, 100◦C, 122 kPa): tR (major) = 12.5 min, tR (minor)
= 13.7 min
VIIc
VIId
FTIR (neat), ν˜/cm−1: 3027, 2960, 2922, 2854, 2360, 2342, 1723, 1685, 1600, 1496, Afewerki et al.
1452, 1260, 1074, 1014, 963, 794, 737, 693, 670, 493
(2012)
1
—
H NMR (300 MHz, CDCl3), δ: 9.76 (d, J = 1.8, 1H, CH O), 7.46–7.21 (m, 10H,
—
—
HC in Ph), 6.61 (d, J = 15.9 Hz, 1H, CH CHPh), 6.31 (ddd, J = 4.3 Hz, J = 9.0 Hz,
J = 15.9 Hz, 1H, CH CHPh), 2.87 (d, J = 7.4 Hz, 2H, CH2), 2.84 (tdt, J = 7.4 Hz,
—
—
—
J = 7.4 Hz, J = 7.1 Hz, 1H, CH), 2.43 (dd, J =7.1 Hz, J = 7.0 Hz, 2H, CH2)
13
—
C NMR (75 MHz, CDCl3), δ: 202.3 (C O), 138.0 (CHq in Ph), 136.4 (CHq in Ph),
—
—
128.8 (C C), 128.6 (CH), 128.5 (CH), 128.1 (CH), 127.9 (CH), 126.1 (CH), 114.8
—
—
(C C), 54.9 (CH), 34.7 (CH2), 30.7 (CH2)
—
HPLC (Chiralpak AS-H; IPA/hexane (ϕr = 3 : 97); 0.5 mL min−1; λ = 254 nm): tR
(major) = 32.19 min, tR (minor) = 43.74 min

1116
P. Tisovský et al./Chemical Papers 68 (8) 1113–1120 (2014)
Table 1. (continued)
Compound
Physical and spectral data
Reference
FTIR (neat), ν˜/cm−1: 3032, 2983, 1724, 1602, 1498, 1454, 1442, 1409, 1211, 1081, Zhao et al. (2011)
1031, 929, 751, 700, 691, 537, 506
1
—
—
—
H NMR (300 MHz, CDCl3), δ: 9.72 (d, J = 7.5 Hz, 1H, CH O), 7.31–7.24 (m,
—
2H, HC in Ph), 7.24–7.12 (m, 3H, HC in Ph), 5.69 (m, 1H, CH CH2), 4.93 (m, 1H,
CH CH2), 3.08 (m, 1H, CH), 2.75 (m, 2H, CH2), 2.29 (m, 1H, CH2), 2.10 (m, 1H,
—
—
CH2)
VIIe
13C NMR (75 MHz, CDCl3), δ: 204.2 (C=O), 139.9 (CHq in Ph), 135.4 (C C), 128.9
—
—
—
(CH), 128.8 (CH), 126.8 (CH), 117.2 (C C), 51.5 (CH), 37.1 (CH2), 36.2 (CH2)
—
HPLC (Chiralpak AD-H; IPA/hexane (ϕr = 5 : 95); 0.75 mL min−1; λ = 254 nm):
tR (major) = 23.41 min, tR (minor) = 26.67
FTIR (neat), ν˜/cm−1: 3032, 2965, 2928, 1724, 1602, 1498, 1454, 1172, 1081, 1031, Li et al. (2012)
751, 700, 506
1
—
H NMR (300 MHz, CDCl3), δ: 9.74 (d, J = 7.5 Hz, 1H, CH O), 7.30–7.24 (m,
—
2H, HC in Ph), 7.24–7.12 (m, 3H, HC in Ph), 3.07 (m, 1H, CH2), 2.71 (m, 1H, CH),
2.64 (m, 1H, CH2), 1.56 (d, J = 15.5 Hz, 2H, CH2), 1.33–1.27 (m, 8H, 4 × CH2),
1.00–0.96 (t, J = 7.0 Hz, 3H, CH3)
VIIf
13
—
C NMR (75 MHz, CDCl3), δ: 205.1 (C O), 139.9 (CHq in Ph), 128.9 (CH), 128.8
—
(CH), 126.7 (CH), 51.4 (CH), 38.1 (CH2), 31.9 (CH2), 31.6 (CH2), 29.3 (CH2), 27.6
(CH2), 22.9 (CH2), 14.0 (CH3)
HPLC (Chiralpak AD-H; IPA/hexane (ϕr = 5 : 95); 1 mL min−1; λ = 254 nm): tR
(major) = 22.11 min, tR (minor) = 26.63
General procedure for SOMO reactions with
copper(I) phenylacetylide (II)
stirred at ambient temperature for 24 h. The reac-
tion mixture was poured into Et2O (20 mL), filtered
through a pad of SiO2, washed with Et2O (20 mL)
and concentrated under diminished pressure. The re-
sulting residue was purified by column chromatogra-
phy (SiO2, hexane/EtOAc (ϕr = 7 : 1)) to provide the
title compound.
Method B. A mixture of alkyl bromide (0.5 mmol),
indium (1 mmol, 115 mg), CuCl (1 mmol, 99 mg),
DMA (3 mL), catalyst (20 mole %), aldehyde
(0.25 mmol), NaHCO3 (0.5 mmol, 42 mg), water
(0.5 mmol, 8 L) and CAN (0.625 mmol, 342.6 mg)
in a 25 mL vial was purged with argon for 1 min
and placed in an ultrasound cleaning bath for 24 h.
The reaction mixture was then poured into Et2O
(20 mL), filtered through SiO2, washed with diethyl
ether (20 mL), concentrated under reduced pressure
and the residue was purified by column chromatogra-
phy as in method A.
A solution of catalyst (20 mole %) in acetone
(1 mL) was prepared in a flame-dried flask at
–78◦C under argon atmosphere. In the following or-
der, aldehyde (0.25 mmol), copper(I) phenylacetylide
(0.5 mmol, 82 mg), NaHCO3 (0.5 mmol, 42 mg), wa-
ter (0.5 mmol, 8 L), CAN (0.5 mmol, 274 mg) were
added to the mixture. After purging the solution with
argon for 1 min, the mixture was heated to –40◦C and
stirred at this temperature for 24 h. The cold reac-
tion mixture was poured into diethyl ether (20 mL)
and filtered through a pad of SiO2, washed with Et2O
(20 mL) and concentrated under reduced pressure.
The resulting residue was purified by column chro-
matography (SiO2, hexane/EtOAc (ϕr = 7 : 1)) to
provide the title compound.
General procedures for synthesis
of alkylindium reagent from alkyl bromide
Method C. A mixture of alkyl bromide (0.5 mmol),
indium (1 mmol, 115 mg), CuCl (1 mmol, 99 mg) and
THF (3 mL) in a 25 mL vial was heated in a microwave
reactor at 70◦C for 2 h followed by the addition of cat-
alyst (20 mole %), aldehyde (0.25 mmol), NaHCO3
(0.5 mmol, 42 mg), water (0.5 mmol, 8 L) and CAN
(0.625 mmol, 342.6 mg). The resulting mixture was
purged with argon for 1 min and stirred vigorously
at ambient temperature for 24 h. The reaction mix-
ture was poured into Et2O (20 mL), filtered through
SiO2, washed with Et2O (20 mL), concentrated under
diminished pressure and the residue was purified by
column chromatography as in method A.
Method A. A mixture of alkyl bromide (0.5 mmol),
indium (1 mmol, 115 mg), CuCl (1 mmol, 99 mg) and
dimethyl acetamide (DMA) (3 mL, analytical grade)
in a 25 mL vial was stirred vigorously at 100◦C for
24 h. Next, the clear upper solution was carefully
separated from the black bottom precipitate using
a syringe and added to another vial charged with
the catalyst (20 mole %), aldehyde (0.25 mmol) and
NaHCO3 (0.5 mmol, 42 mg). Water (0.5 mmol, 8 L)
and CAN (0.625 mmol, 343 mg) were added, the re-
sulting mixture was purged with argon for 1 min and
Method D. A mixture of catalyst (20 mole %), alde-

P. Tisovský et al./Chemical Papers 68 (8) 1113–1120 (2014)
1117
Fig. 2. Organocatalysts used in this study (tBu denotes tert-butyl; Bn is benzyl).
Table 2. SOMO reactions of aldehyde Ia with copper(I) phenylacetylide (II)
Entry
Catalyst
Temperature/◦C
Yield of III/%
Yield of IV/%
e.r. of III
1
2
3
4
5
6
7
8
9
Cat-I · HCl
Cat-I · HCl
Cat-I · HCl
Cat-I · HCl
Cat-I · HCl
Cat-V
Cat-I · DCA
Cat-III · TFA
Cat-IV · HCl
Pyrrolidine
Cat-I · HCl
–50◦C
–40◦C
–30◦C
–20◦C
+5◦C
–40◦C
–40◦C
–40◦C
–40◦C
–40◦C
+10◦C
17
61
0
0
0
10
0
0
0
0
0
0
40 : 60
58 : 42
47
54
60
63
43
56
52
61
70
–
–
–
50 : 50
–
–
–
–
–
10
11
0
hyde (0.25 mmol), NaHCO3 (0.5 mmol, 42 mg), water
(0.5 mmol, 8 L) and CAN (0.625 mmol, 342.6 mg)
was added to a stirred mixture of alkyl bromide
(0.5 mmol), indium (1 mmol, 115 mg), CuCl (1 mmol,
99 mg) and dimethyl acetamide (DMA) (3 mL) in a
25 mL vial. The resulting mixture was then purged
with argon for 1 min, stirred vigorously at ambient
temperature for 24 h and processed as in method C.
was isolated with a 47–60 % yield (Table 2, entries 3–
5). The reaction at ambient temperature resulted in a
complex mixture of products. The reaction of aldehyde
Ib with copper(I) phenylacetylide (II ) at –40◦C again
afforded only the homo-coupling product IV with a
62 % yield. Using catalyst Cat-V at –40◦C, product
IIIa was isolated with a 10 % yield as a racemic mix-
ture and product IV was isolated with a 63 % yield
(Table 2, entry 6). The reaction with aldehyde Ib un-
der the same reaction conditions did not proceed. Both
product IIIa as well as product IV were absent in the
reaction mixture. When catalysts Cat-I· DCA (DCA
= dichloroacetic acid), Cat-III· TFA (TFA = trifluo-
roacetic acid), Cat-IV· HCl, as well as pyrrolidine were
used at –40◦C in the reactions of Ia with II, product
IIIa was again absent in the reaction mixture and only
the product of homo-coupling IV was isolated with a
43–61 % yield (Table 2, entries 7–10). In respect of the
radical mechanism of these reactions, an attempt was
made to improve their course using ultrasonic irradi-
ation. However, sonication of the reaction mixture of
Ia with II using Cat-I·HCl as a catalyst at 10◦C for
8 h in an ultrasonic cleaning bath (20 kHz) resulted in
the formation of only the homo-coupling product IV
with a 70 % yield (Table 2, entry 11).
Results and discussion
Typically, asymmetric organocatalytic SOMO re-
actions are performed with various chiral imidazolidi-
nones. The organocatalysts used in this study are de-
picted in Fig. 2.
The investigation commenced with a reaction of
octanal (Ia) with copper(I) phenylacetylide (II ) un-
der various conditions. Copper(I) phenylacetylide (II )
is insoluble in dimethoxyethane (DME), THF and
MeCN, hence the reaction did not proceed in these
solvents. The only suitable solvent for the reaction
was acetone with CAN as an oxidant and NaHCO3
as a base. The stability of compound II under the
reaction conditions was also evaluated and no decom-
position of this compound was observed after 24 h.
The reaction of Ia with II using catalyst Cat-I· HCl at
–50◦C afforded product IIIa with only a 17 % yield.
Increasing the reaction temperature to –40◦C resulted
in enhancing the yield of product IIIa to 61 %. Un-
fortunately, these reactions proceeded with practically
no enantioselectivity (Table 2, entries 1 and 2). Fur-
ther increases in the reaction temperature to –30◦C,
–20◦C and 5◦C incurred a change of reaction mech-
anism and only the product of homo-coupling (IV )
In addition, organo-SOMO reactions of aldehydes
with organoindium compounds were studied. These
somophiles were prepared from the corresponding
halides, indium powder and CuCl (methods A and C)
then used in reactions with aldehydes. Alternatively,
these reactions were performed as a one-pot process
(methods B and D) (Fig. 4).
A reaction of octanal (Ia) with separately prepared
alkylindium VIa in DMA using catalyst Cat-I·HCl af-

1118
P. Tisovský et al./Chemical Papers 68 (8) 1113–1120 (2014)
Fig. 3. SOMO reactions of aldehydes Ia, Ib with copper(I) phenylacetylide (II). Reaction conditions: i) organocatalyst (20 mole %),
CAN, NaHCO3, H2O, acetone, 24 h.
Fig. 4. SOMO reactions of aldehydes Ia, Ib with organoindium compounds VIa–VIc. Reactions conditions: i) In, CuCl;
ii) organocatalyst (20 mole %), CAN, NaHCO3, H2O, solvent.
Table 3. SOMO reactions of aldehydes with organoindium compounds
Entry
Aldehyde
RInX2
Catalyst
Methoda
Product
Yield/%
e.r.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Ia
Ia
Ia
Ia
Ia
Ia
Ia
Ia
Ia
Ib
Ib
Ib
Ib
Ib
Ib
VIa
VIa
VIa
VIb
VIb
VIc
VIc
VIc
VIc
VIa
VIa
VIb
VIb
VIc
VIc
Cat-I · HCl
Cat-I · HCl
Cat-I · HCl
Cat-IV · HCl
Cat-I · HCl
Cat-I · HCl
Cat-I · HCl
Cat-II
A
B (12 h)
B (12 h)
B (24 h)
C
VIIa
VIIa
VIIa
VIIb
VIIb
VIIc
VIIc
VIIc
VIIc
VIId
VIId
VIIe
VIIe
VIIf
VIIf
60
40
32
12
34
0
32
40
28
41
52
34
17
30
–
57 : 43
47 : 53
50 : 50
50 : 50
–
D
–
B (24 h)
D
B (24 h)
A
B (24 h)
A
B (24 h)
A
50 : 50
50 : 50
48 : 52
42 : 58
50 : 50
50 : 50
53 : 47
56 : 44
–
Cat-II
Cat-II
Cat-II
Cat-II
Cat-II
Cat-II
Cat-II
B (24 h)
a) Method A: preparation of RCH2InX2 at 100◦C for 24 h; reaction of RCH2InX2 with aldehyde at ambient temperature for 48 h;
method B: one-pot reaction for 12 h or 24 h under ultrasonic irradiation; method C: preparation of RCH2InX2 at 70◦C under
microwave irradiation for 2 h; reaction of RCH2InX2 with aldehyde at ambient temperature for 24 h; method D: one-pot reaction
at ambient temperature for 24 h.
forded product VIIa with a 60 % yield (Table 3, en-
try 1). When this reaction was performed as a one-pot
process under ultrasonic irradiation, the yield of prod-
uct VIIa declined to 40 % with catalyst Cat-I·HCl
and to 32 % with catalyst Cat-IV· HCl (Table 3,
entries 1–3). The products were obtained as virtu-
ally racemic mixtures. Product VIIb was obtained
with a 12 % yield as a racemic mixture using cat-
alyst Cat-I· HCl when the reaction mixture was ir-
radiated in an ultrasonic cleaning bath for 24 h. A
somewhat better yield (34 %) of compound VIIb was
obtained when the reaction of Ia with somophile VIb
(prepared under microwave irradiation at 70◦C for
2 h) proceeded in THF with Cat-I· HCl (Table 3,
entries 4 and 5). The one-pot reaction of hexyl io-
dide, metallic indium, CuCl and Ia using Cat-I· HCl
as the catalyst did not proceed at ambient temper-
ature for 24 h (method D). Only the starting ma-
terial was detected in the reaction mixture. When
this reaction proceeded under ultrasonic irradiation
(method B) for 24 h, the product was isolated with
a 32 % yield as a racemate. The reaction of hexyl
iodide, indium, CuCl and Ia with catalyst Cat-II un-
der standard conditions afforded product VIIc with
a 40 % yield. In contrast with the reaction with
Cat-I· HCl, sonication of the reaction mixture for 24 h

P. Tisovský et al./Chemical Papers 68 (8) 1113–1120 (2014)
1119
decreased the yield slightly to 28 % (Table 3, entries
6–9).
Angewandte Chemie International Edition, 48, 5121–5124.
DOI: 10.1002/anie.200901855.
Banwell, M. G., Beck, D. A. S., & Smith, J. A. (2004). The in-
fluence of chiral auxiliaries and catalysts on the selectivity of
intramolecular conjugate additions of pyrrole to N-tethered
Michael acceptors. Organic & Biomolecular Chemistry, 2,
157–159. DOI: 10.1039/b312552a.
Beeson, T. D., Mastracchio, A., Hong, J. B., Ashton, K., &
MacMillan, D. W. C. (2007). Enantioselective organocatal-
ysis using SOMO activation. Science, 316, 582–585. DOI:
10.1126/science. 1142696.
Ciesielski, J., Leboeuf, D., Stern, H. A., & Frontier, A. J.
(2013). Gold(III) chloride-catalyzed 6-endo-trig oxa-Michael
addition reactions for diastereoselective synthesis of fused
tetrahydropyranones. Advanced Synthesis & Catalysis, 355,
2077–2082. DOI: 10.1002/adsc.201300265.
Chauret, D. C., Chong, J. M., & Ye, Q. (1999). A route to
enantiomerically-enriched α-silyl aldehydes from 2,3-epoxy
alcohols. Tetrahedron: Asymmetry, 10, 3601–3614. DOI:
10.1016/s0957-4166(99)00383-3.
Conrad, J. C., Kong, J., Laforteza, B. N., & MacMillan,
D. W. C. (2009). Enantioselective α-arylation of aldehy-
des via organo-SOMO catalysis. An ortho-selective aryla-
tion reaction based on an open-shell pathway. Journal of
the American Chemical Society, 131, 11640–11641. DOI:
10.1021/ja9026902.
Dalko, P. I. (Ed.) (2007). Enatioselective organocatalysis: Re-
actions and experimental procedures. Weinheim, Germany:
Wiley-VCH.
Graham, T, H., Jones, C. M., Jui, N, T., & MacMillan, D. W.
C. (2008). Enantioselective organo-singly occupied molecular
orbital catalysis: The carbo-oxidation of styrenes. Journal
of the American Chemical Society, 130, 16494–16495. DOI:
10.1021/ja8075633.
Harvey, J. S., Simonovich, S. P., Jamison, C. R., & MacMillan,
D. W. C. (2011). Enantioselective α-arylation of carbonyls
via Cu(I)-bisoxazoline catalysis. Journal of the American
Chemical Society, 133, 13782–13785. DOI: 10.1021/ja2060
50b.
The reaction of Ib with VIa using catalyst Cat-II
(method A) afforded compound VIId with a 41 %
yield. A better yield (52 %) of the aldehyde VIId was
achieved by a one-pot reaction under ultrasonic irra-
diation for 24 h (method B) (Table 3, entries 10 and
11). Unlike with VIa, the reaction of Ib with VIb af-
forded 34 % of the product VIIe using method A and
only 17 % of the product VIIe was achieved after the
one-pot reaction (method B) (Table 3, entries 12 and
13). Compound VIIf was obtained after the reaction of
aldehyde Ib and organoindium VIc with a 30 % yield
(method A), but the reaction did not proceed under
ultrasonic irradiation as a one-pot process (Table 3,
entries 14 and 15).
Conclusions
Copper(I) phenylacetylide was demonstrated to
be a rather poor SOMO-phile, because it has a
distinct propensity for homo-coupling under SOMO
reaction conditions. However, under proper condi-
tions, the product of its SOMO reaction, 2-(2-
phenylethynyl)octanal (IIIa) can be isolated with a
61 % yield using imidazolidinone catalyst, Cat-I ·HCl.
The reactions of various aldehydes with organoindium
compounds gave α-alkylated aldehydes with fair yields
(up to 60 %) but with only low enantiomeric purities.
The application of ultrasonic irradiation improved the
reaction course in some cases.
Acknowledgements. The authors are grateful for the finan-
cial support received from the Slovak Grant Agency VEGA,
grant no. 1/0543/11, and the Slovak Research and Develop-
ment Agency, grant no. APVV-0067-11. This publication is the
result of the project implementation: 26240120025 supported by
the Research & Development Operational Programme funded
by the European Regional Development Fund. We also wish to
thank Prof. Štefan Toma for his fruitful discussions.
Herrmann, W. A., B¨ohm, V. P. W., Gst¨ottmayr, C. W. K.,
Grosche, M., Reisinger, C. P., & Weskamp, T. (2001). Syn-
thesis, structure and catalytic application of palladium(II)
complexes bearing N-heterocyclic carbenes and phosphines.
Journal of Organometallic Chemistry, 617–618, 616–628.
DOI: 10.1016/s0022-328x(00)00722-1.
Jang, H. Y., Hong, J. B., & MacMillan, D. W. C. (2007). Enan-
tioselective organocatalytic singly occupied molecular orbital
activation: The enantioselective α-enolation of aldehydes.
Journal of the American Chemical Society, 129, 7004–7005.
DOI: 10.1021/ja0719428.
Joosten, A., Lambert, E., Vasse, J. L., & Szymoniak, J. (2010).
Diastereoselective access to trans-2-substituted cyclopenty-
lamines. Organic Letters, 12, 5128–5131. DOI: 10.1021/ol102
038x.
References
Afewerki, S., Ibrahem, I., Rydfjord, J., Breistein, P., & Cór-
dova, A. (2012). Direct regiospecific and highly enantios-
elective intermolecular α-allylic alkylation of aldehydes by
a combination of transition-metal and chiral amine cata-
lysts. Chemistry - A European Journal, 18, 2972–2977. DOI:
10.1002/chem.201103366.
Allen, A. E.,
& MacMillan, D. W. C. (2010). The pro-
Jui, N. T., Lee, E. C. Y., & MacMillan, D. W. C. (2010). Enan-
tioselective organo-SOMO cascade cycloadditions: A rapid
approach to molecular complexity from simple aldehydes
and olefins. Journal of the American Chemical Society, 132,
10015–10017. DOI: 10.1021/ja104313x.
ductive merger of iodonium salts and organocatalysis: A
non-photolytic approach to the enantioselective α-trifluoro-
methylation of aldehydes. Journal of the American Chemical
Society, 132, 4986–4987. DOI: 10.1021/ja100748y.
Allen, A. E, & MacMillan, D. W. C. (2011). Enantioselective α-
arylation of aldehydes via the productive merger of iodonium
salts and organocatalysis. Journal of the American Chemical
Society, 133, 4260–4263. DOI: 10.1021/ja2008906.
Jui, N. T., Garber, J. A. O., Gadini Finelli, F., & MacMillan, D.
W. C. (2012). Enantioselective organo-SOMO cycloadditions:
A catalytic approach to complex pyrrolidines from olefins and
aldehydes. Journal of the American Chemical Society, 134,
11400–11403. DOI: 10.1021/ja305076b.
Amatore, M., Beeson, T. D., Brown, S. P.,
& MacMil-
lan, D. W. C. (2009). Enantioselective linchpin cataly-
sis by SOMO catalysis: An approach to the asymmetric
α-chlorination of aldehydes and terminal epoxide formation.
Kato, M., Komoda, K., Namera, A., Sakai, Y., Okada, S., Ya-
mada, A., Yokoyama, K., Migita, E., Minobe, Y., & Tani,
T. (1997). Pyrrole butyric acid derivatives as inhibitors of

1120
P. Tisovský et al./Chemical Papers 68 (8) 1113–1120 (2014)
steroid 5α-reductase. Chemical & Pharmaceutical Bulletin,
45, 1767–1776. DOI: 10.1248/cpb.45.1767.
Kim, H., & MacMillan, D. W. C. (2008). Enantioselective
organo-SOMO catalysis: The α-vinylation of aldehydes.
Journal of the American Chemical Society, 130, 398–399.
DOI: 10.1021/ja077212h.
Shi, W., Luo, Y., Luo, X., Chao, L., Zhang, H., Wang, J., & Lei,
A. (2008). Investigation of an efficient palladium-catalyzed
C(sp)–C(sp) cross-coupling reaction using phosphine–olefin
ligand: Application and mechanistic aspects. Journal of
the American Chemical Society, 130, 14713–14720. DOI:
10.1021/ja8049436.
Li, Y., Hu, H. B., Zheng, X. D., Zhu, J. H., & Liu, L. P. (2012).
Composition and antimicrobial activity of essential oil from
the aerial part of Artemisia annua. Asian Journal of Chem-
istry, 24, 1091–1093.
Shih, H. W., Vander Wal, M. N., Grange, R. L., & MacMillan,
D. W. C. (2010). Enantioselective α-benzylation of aldehy-
des via photoredox organocatalysis. Journal of the American
Chemical Society, 132, 13600–13603. DOI: 10.1021/ja106
593m.
Simonovich, S. P., Van Humbeck, J. F., & MacMillan, D. W.
C. (2012). A general approach to the enantioselective α-
oxidation of aldehydes via synergistic catalysis. Chemical
Science, 3, 58–61. DOI: 10.1039/c1sc00556a.
Teo, W. T., Rao, W., Koh, M. J., & Chan, P. W. H. (2013).
Gold-catalyzed domino aminocyclization/1,3-sulfonyl migra-
tion of N-substituted N-sulfonyl-aminobut-3-yn-2-ols to 1-
substituted 3-sulfonyl-1H-pyrroles. The Journal of Organic
Chemistry, 78, 7508–7517. DOI: 10.1021/jo401083m.
Um, J. M., Gutierrez, O., Schoenebeck, F., Houk, K. N., &
MacMillan, D. W. C. (2010). Nature of intermediates in
organo-SOMO catalysis of α-arylation of aldehydes. Jour-
nal of the American Chemical Society, 132, 6001–6005. DOI.
10.1021/ja9063074.
Wilson, J. E., Casarez, A. D., & MacMillan, D. W. C. (2009).
Enantioselective aldehyde α-nitroalkylation via oxidative
organocatalysis. Journal of the American Chemical Society,
131, 11332–11334. DOI: 10.1021/ja904504j.
Zhao, X., Liu, D., Guo, H., Liu, Y., & Zhang, W. (2011). C–N
bond cleavage of allylic amines via hydrogen bond activa-
tion with alcohol solvents in Pd-catalyzed allylic alkylation
of carbonyl compounds. Journal of the American Chemical
Society, 133, 19354–19357. DOI: 10.1021/ja209373k.
Zhu, J., Yu, S., Lu, W., Deng, J., Li, J., & Wang, W. (2012). Di-
rect oxidative conversion of 3-aryl propionaldehydes to 3-aryl
acroleins promoted by SOMO catalysis. Tetrahedron Letters,
53, 1207–1209. DOI: 10.1016/j.tetlet.2011.12.131.
MacMillan, D. W. C., & Rendler, S. (2012). Enantioselective
organo-SOMO catalysis: a novel activation mode for asym-
metric synthesis. In M. Christmann, & S. Bräse (Eds.),
Asymmetric synthesis II: More methods and applications
(Chapter 12, pp. 87–94). Weinheim, Germany: Wiley-VCH.
Mastracchio, A., Warkentin, A. A., Walji, A. M., & MacMil-
lan, D. W. C. (2010). Direct and enantioselective α-allylation
of ketones via singly occupied molecular orbital (SOMO)
catalysis. Proceedings of the National Academy of Sciences
of the United States of America, 107, 20648–20651. DOI:
10.1073/pnas.1002845107.
Nagib, D. A., Scott, M. E., & MacMillan, D. W. C. (2009).
Enantioselective α-trifluoromethylation of aldehydes via pho-
toredox organocatalysis. Journal of the American Chemical
Society, 131, 10875–10877. DOI: 10.1021/ja9053338.
Pham, P. V., Ashton, K., & MacMillan, D. W. C. (2011a).
The intramolecular asymmetric allylation of aldehydes via
organo-SOMO catalysis: A novel approach to ring construc-
tion. Chemical Science, 2, 1470–1473. DOI: 10.1039/c1sc00
176k.
Pham, P. V., Nagib, D. A., & MacMillan, D. W. C (2011b). Pho-
toredox catalysis: A mild, operationally simple approach to
the synthesis of α-trifluoromethyl carbonyl compounds Ange-
wandte Chemie International Edition, 50, 6119–6122. DOI:
10.1002/anie.201101861.
Nicolaou, K. C., Reingruber, R., Sarlah, D., & Bräse, S.
(2009). Enantioselective intramolecular Friedel–Crafts-type
α-arylation of aldehydes. Journal of the American Chemical
Society, 131, 2086–2087. DOI: 10.1021/ja809405c.
Samulis, L., & Tomkinson, N. C. O. (2011). Preparation of
the MacMillan imidazolidinones. Tetrahedron, 67, 4263–4267.
DOI: 10.1016/j.tet.2011.04.009.