Rhodium-catalyzed conjugate addition of arylindium reagents to α,β-unsaturated carbonyl compounds

Article abstract of DOI:10.1016/j.tet.2011.11.075

A novel rhodium-catalyzed conjugate addition of indium reagents to electron deficient olefins is reported. The reaction takes place in THF/MeOH at 110 °C using arylindium dichlorides, a rhodium(I)-binap complex as catalyst, and α,β-unsaturated ketones and

Full text of DOI:10.1016/j.tet.2011.11.075

Tetrahedron 68 (2012) 1606e1611
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Rhodium-catalyzed conjugate addition of arylindium reagents to
carbonyl compounds
a,b-unsaturated
*
*
ꢀ
ꢀ ꢀ
Ruben Tato, Ricardo Riveiros, Jose Perez Sestelo , Luis A. Sarandeses
~
~
Departamento de Química Fundamental, Universidade da Coruna, Campus da Zapateira, s/n, E-15071 A Coruna, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel rhodium-catalyzed conjugate addition of indium reagents to electron deficient olefins is re-
ported. The reaction takes place in THF/MeOH at 110 ꢀC using arylindium dichlorides, a rhodium(I)-binap
Received 2 September 2011
Received in revised form 8 November 2011
Accepted 24 November 2011
Available online 8 December 2011
complex as catalyst, and a,b-unsaturated ketones and lactones in good yields (45e94%). The addition of
MeOH is crucial for an efficient transformation and NMR studies seem to indicate that promotes the
catalytic cycle leaving the indium organometallic unaltered. The use of chiral non-racemic ligands allows
performing the reaction with moderate enantioselectivities.
Dedicated to the memory of Professor Rafael
Suau
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Conjugate addition
Organoindium compounds
Rhodium
1. Introduction
conjugate addition of triorganoindium compounds to a,b-un-
saturated ketones, esters, and nitriles.2 This reaction takes place
with aryl and alkylindium reagents but only one of the three groups
attached to indium is transferred.
In recent years, indium(III) organometallics have been shown as
useful reagents in fundamental organic transformations and pro-
vide an alternative to other well-established organometallic re-
agents.1 Typically, the use of organoindium compounds is
associated with a transition metal complex as catalyst and trans-
metallation is a key step of the process. Accordingly, in a program
devoted to the development of new synthetic applications of in-
dium compounds, we have discovered that triorganoindium re-
agents (R3In) participate efficiently in metal-catalyzed reactions,
such as conjugate addition (Ni catalyzed),2 cross-coupling reactions
(Pd and Ni catalyzed),3 and allylic and propargylic substitution
reactions (Cu and Pd catalyzed).4,5 It is remarkable the ability of
R3In to transfer the three organic groups in the palladium-catalyzed
cross-coupling reaction.6
Since then, the rhodium-catalyzed conjugate addition reaction
of organoboron species to activated olefins has been developed as
a modern method for the formation of carbonecarbon bonds under
mild conditions in good yields.8 More recently, other organome-
tallic species have also been applied,9 including a report showing
the utility of diphenylindium hydroxide.10 In an effort to enlarge the
scope of indium reagents in conjugate addition reactions, we de-
cided to study further the rhodium-catalyzed conjugate addition of
indium organometallics to a,b-unsaturated carbonyl compounds.
2. Results and discussion
The 1,4-conjugate addition of organometallic reagents to elec-
tron deficient olefins is a fundamental process for carbonecarbon
bond formation in organic synthesis.7 This reaction has been clas-
sically associated with organocopper chemistry but nowadays
other organometallic species can be used by means of transition
metal catalysis. In our group we discovered the nickel-catalyzed
As starting point, we tried to apply the methodology developed
for the rhodium-catalyzed conjugate addition of organoboron
compounds to electron deficient olefins.8a In our first attempt, we
found that the reaction of triphenylindium (1.0 equiv) with 2-
cyclohexen-1-one (1) in THF at 80 ꢀC, using [Rh(cod)Cl]2 (4%) and
(ꢁ)-binap (8%) as catalytic system, afforded the conjugate addition
product 2a in 41% yield after 6 h (Table 1, entry 1). Alternatively,
other rhodium complexes, such as Rh(acac)(cod), or different
bidentate phosphine ligands (davephos, dppf) gave similar results
(entries 2e4), and the use of substoichiometric quantities of Ph3In
returned lower yields. Although these results probe the utility of
* Corresponding authors. Tel.: þ34 981 167 000; fax: þ34 981 167 065; e-mail
ꢀ
addresses: sestelo@udc.es (J. Perez Sestelo), qfsarand@udc.es, luis.sarandeses@udc.es
(L.A. Sarandeses).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.11.075

R. Tato et al. / Tetrahedron 68 (2012) 1606e1611
1607
Table 1
(1.2 equiv) reacted with 1 under the optimized conditions to afford
2a in a good 93% yield (entry 14), although it should be noted that
the atom efficiency of this reaction is lower than using PhInCl2.
Unfortunately, using 0.6 equiv of Ph2InCl the yield decreased to 58%
(entry 15), a result that can be explained by to the lower reactivity
of the Ph2InCl reagent.
Reactions of indium reagents with 2-cyclohexen-1-one (1) under rhodium catalysis
Once the experimental conditions for the rhodium-catalyzed
conjugate addition of dichlorophenylindium to 2-cyclohexen-1-
one were optimized (2.4 equiv of MeOH, 110 ꢀC, Table 2, entry 1),
we explored the versatility of the methodology by using
other unsaturated carbonyl compounds and different mono-
arylindium reagents. Following this approach, we found that
dichlorophenylindium reacted efficiently with enones, such as
2-cyclopenten-1-one (3), 2-cyclohepten-1-one (4), and the acyclic
enone 5, to afford the corresponding conjugate addition products
(7a, 8a, and 9a, respectively) in good yields (63e80%, entries 5, 8,
and 10). Additionally, the rhodium-catalyzed reaction of PhInCl2
Entry In reagenta Rh catalyst
Ligand
(ꢁ)-binap 80 ꢀ
Conditionsa
Yieldc (%)
1
2
3
4
Ph3In (1.0)
Ph3In (1.0)
Ph3In (1.0)
Ph3In (1.0)
[Rh(cod)Cl]2
C
C
C
C
C
41
35
40
39
45
54
30
48
57
94
83
75
34
93
58
Rh(acac)(cod)b (ꢁ)-binap 80 ꢀ
[Rh(cod)Cl]2
[Rh(cod)Cl]2
davephos 80 ꢀ
dppf
80 ꢀ
5
6
7
8
PhInCl2 (1.2) [Rh(cod)Cl]2
PhInCl2 (1.2) [Rh(cod)Cl]2
PhInCl2 (1.2) [Rh(cod)Cl]2
PhInCl2 (1.2) [Rh(cod)Cl]2
PhInCl2 (1.2) [Rh(cod)Cl]2
PhInCl2 (1.2) [Rh(cod)Cl]2
PhInCl2 (1.2) [Rh(cod)Cl]2
PhInCl2 (1.2) [Rh(cod)Cl]2
PhInCl2 (1.2) [Rh(cod)Cl]2
Ph2InCl (1.2) [Rh(cod)Cl]2
Ph2InCl (0.6) [Rh(cod)Cl]2
(ꢁ)-binap 80 ꢀ
(ꢁ)-binap 110 ꢀC
(ꢁ)-binap H2O (1.2), 80 ꢀ
C
(ꢁ)-binap MeOH (1.2), 80 ꢀ
(ꢁ)-binap MeOH (2.4), 80 ꢀ
C
C
C
C
9
with the a,b-unsaturated lactone 6 also occurs in a good 76% yield,
giving the lactone 10a.
10
11
12
13
14
15
(ꢁ)-binap MeOH (2.4), 110 ꢀ
(ꢁ)-binap MeOH (3.6), 110 ꢀ
(ꢁ)-binap H2O (2.4), 110 ꢀ
C
(ꢁ)-binap KOH (2.4), 110 ꢀ
C
Table 2
(ꢁ)-binap MeOH (2.4), 110 ꢀ
C
C
Reaction of arylindium dichlorides with a,b-unsaturated carbonyl compounds
(ꢁ)-binap MeOH (2.4), 110 ꢀ
a
In parentheses, number of equivalents with respect to 1.
Catalyst (8%) was used.
Isolated yield.
b
c
organoindium reagents in rhodium-catalyzed conjugation addition
reactions, the low yield led us to look for a more efficient procedure.
In an effort to improve the efficiency of the reaction, we studied
the reactivity of monoorganoindium dihalides (RInX2). Although
indium organometallic chemistry is generally associated with tri-
organoindium compounds, RInCl2 can be prepared from equi-
Entry
a
,
b
-Unsaturated
R
Product
Yielda (%)
compounds
1
2
3
4
Ph
2a
2b
2c
2d
94
69
46
66
4-CF3eC6H4
4-FeC6H4
3-FeC6H4
11
molecular amounts of organometallic reagent and InCl3 or from
aryl iodides using In(0).12 Under the previous conditions, we found
that the reaction of PhInCl2 (1.2 equiv) with 1 gave the conjugate
addition product in 45% yield as a single reaction product, after 6 h
at 80 ꢀC (entry 5) and 54% yield when the reaction is carried out at
110 ꢀC (entry 6). It is worth noting that although the same chemical
yield when using Ph3In was obtained, the atom economy is
higher.13
5
6
7
Ph
7a
7b
7c
80
57
56
4-CF3eC6H4
4-FeC6H4
In the rhodium-catalyzed reaction of arylboronic acids to
unsaturated ketones the addition of water increases the efficiency
of the process, presumably because the hydrolysis of an (oxa-
a,b-
8
9
Ph
8a
8b
70
62
4-CF3eC6H4
p-
allyl)rhodium intermediate favors the regeneration of the rhodium
active catalyst.14 Taking into account that the hydrolysis of alkyl and
arylindium reagents is relatively slow,6a,11b and the presence of
stoichiometric amounts of water are tolerated,6a,10,15 we studied the
effect of a protic cosolvent in the conjugate addition reactions using
monoorganoindium dihalides.
10
11
Ph
9a
9b
63
45
4-CF3eC6H4
Under the previous conditions (1.2 equiv of PhInCl2, 80 ꢀC), we
observed that the addition of 1.2 equiv of H2O to the reaction
mixture led to a lower yield (30%, entry 7). However, the addition
of 1.2 equiv of methanol retained the yield (48%, entry 8) and
2.4 equiv slightly increased the yield up to 57% (entry 9).16,17
Additionally, when the reaction temperature was increased to
110 ꢀC, the conjugate addition product was obtained in a high 94%
yield (entry 10). On the other hand, the use of larger amounts of
MeOH or water as proton source gave lower yields (entries 11
and 12).18
As in the rhodium-catalyzed conjugate addition of boronic acids
we also explored the reaction under basic conditions.9 In this case
we found that the use of KOH (2.4 equiv) as additive gave the
conjugate addition product in lower yields (34%, entry 13). Finally,
we also found that other organoindium species, such as Ph2InCl
12
Ph
10a
76
13
14
15
4-CF3eC6H4
4-FeC6H4
3-FeC6H4
10b
10c
10d
58
47
56
a
Isolated yield.
The scope of the conjugate addition reaction was extended
to functionalized arylindium dichlorides, such as 4-trifluoro-
methylphenylindium dichloride, 4-fluorophenylindium dichloride,
and 3-fluorophenylindium dichloride. The reaction of 4-
trifluoromethylphenylindium dichloride with the enones 1, 3, 4,
and 5 and with the lactone 6, provided the conjugate addition
products 2b, 7b, 8b, 9b, and 10b, in good yields (45e69%, entries 2,

1608
R. Tato et al. / Tetrahedron 68 (2012) 1606e1611
6, 9, 11, and 13). Analogously, the reaction of 4- and 3-
fluorophenylindium dichloride with the previous enones and lac-
tone also afforded the addition products in moderate to good yields
(46e66%, entries 3, 4, 7, 14, and 15).
After studying the rhodium-catalyzed conjugate addition of
monoarylindium reagents with various
a,b-unsaturated carbonyl
compounds, we turned our interest into the development of
enantioselective reactions by using chiral non-racemic catalyst.
Under the optimized reaction conditions, the reaction of PhInCl2
with 1 using (S)-binap (8%) as catalyst afforded, after 6 h at 110 ꢀC,
the conjugate addition product 2a in 96% yield and 40% ee (Table 3,
entry 1). Other chiral ligands afforded moderate enantioselectiv-
ities, with the best results obtained using (S)-segphos (85% yield,
52% ee, entry 2). Non-biaryl ligands, such as (R)-MeO-biphep,
(R,R)-dipamp, (R)-(S)-josiphos, (S,S)-diop, and (1R,4R)-2,5-
diphenylbicyclo[2.2.2]octa-2,5-diene gave lower enantioselectiv-
ities (33e94% yield, 8e18% ee).
Table 3
Reaction of PhInCl2 with 2-cyclohexen-1-one under asymmetric catalysis
Scheme 1. Proposed catalytic cycle for the rhodium-catalyzed conjugate addition of
arylindium dichlorides to enones. Key: (a) Transmetallation. (b) Coordination to the
electron-deficient olefin. (c) Alkene insertion into the RheAr bond. (d) Methanolysis of
the (oxa-p-allyl)rhodium intermediate.
3. Conclusions
Entry
Ligand
Yielda (%)
eeb (%)
In summary, arylindium dihalides react with
a,b-unsaturated
1
2
3
(S)-binap
(S)-segphos
(R,R)-quinoxP*
96
85
65
40 (S)
52 (S)
35 (R)
carbonyl ketones and lactones under rhodium(I) catalysis in THF at
110 ꢀC. The reaction proceeds efficiently when methanol (2.4 equiv)
is added to the reaction mixture. NMR studies seem to indicate that
the organoindium reagents remain unaltered and MeOH promotes
the catalytic cycle. Additionally, when chiral ligands are used the
conjugate addition reaction proceeds with moderate enantiose-
lectivity. Further studies about the reactivity of organoindium re-
agents with other unsaturated carbonyl systems, as well as the
development of a highly enantioselective version are under in-
vestigation and will be reported in due course.
a
Isolated yield.
Determined by HPLC using a Chiralcel OD-H column.
b
In order to gain insight about the reaction mechanism, the
structure of the organoindium reagents prepared was studied by
13C NMR.19 Initially, we found that the mixture of equimolar
amounts of PhLi and InCl3 in THF provides, after stirring at room
temperature overnight, a 21:79 ratio of Ph2InCl and PhInCl2.20 This
Schlenk-type equilibrium show correspondence with the observa-
tion by Clark in methylindium halides,11a and more recently by
Baba in allyl,21 homoallyl,22 and alkenylindium species.23 When the
reaction mixture is heated 1 h at 80 ꢀC, the equilibrium is displaced
to the 3:97 ratio, and to 0:100 after 1 h at 110 ꢀC, a result repro-
duced during the preparation of dimethylindium chloride.11a Al-
though the presence of Ph3In could be envisaged as kinetic initial
product,11a this compound is not detected, probably due to an
equilibration process during the preparation and acquisition of
NMR data.
The influence of the methanol in the reaction mixture was
also studied by NMR. When MeOH (2 equiv) was added to the
PhInCl2 reagent prepared as before, the 13C NMR spectra showed
the reagents Ph2InCl/PhInCl2 in the same 7:93 ratio, and when
the reaction mixture was heated at 110 ꢀC for 1 h, PhInCl2 was
the only product detected. These results seem to indicate that
the nucleophilic displacement of the chlorine atoms in PhInCl2
is not produced.20 This behavior is coincident with pre-
viously results about the stability of organoindium halides
in aqueous media.21c,24 Therefore it seems that the role of MeOH
in the rhodium-catalyzed conjugate addition reactions is asso-
ciated with the generation of the catalytic specie and/or the
methanolysis of the oxoallyl rhodium enolate intermediate
(Scheme 1).
4. Experimental section
4.1. General methods
All reactions were carried out in flame dried glassware, under
argon atmosphere, using standard gastight syringes, cannulae, and
septa. Reaction temperatures refer to external bath temperatures.
Anhydrous THF was obtained by distillation from the sodium ketyl of
benzophenone. a,b-Unsaturated carbonyl compounds were purified,
immediately before use, by distillation in a high-vacuum line and
were trapped at ꢂ78 ꢀC in a dry ice-acetone bath. Dry MeOH and all
other commercially available reagents were used as received. Orga-
nolithium reagents were titrated prior to use. Organic extracts were
dried over anhydrous MgSO4, filtered, and concentrated by using
a rotary evaporator at aspirator pressure. TLC was carried out on
precoated silica gel 60 F254 plates (layer thickness 0.2 mm) and
components were located by observation under UV light and by
treating the plates with a phosphomolybdic acid or p-anisaldehyde
solutions. Flash column chromatography was performed on silica gel
(230e400 mesh). 1H and 13C NMR spectra were recorded in CDCl3 at
300 MHz and 75 MHz, respectively, at ambient temperature, and
calibrated to the solvent peak. 13C NMR spectra of organoindium
species were recorded inTHF-d8 at 125 MHz, at room temperature, in
an NMR spectrometer equipped with a cryoprobe, and calibrated to
the solvent peak.20 DEPT spectroscopy was used to assign carbon

R. Tato et al. / Tetrahedron 68 (2012) 1606e1611
1609
types. Mass spectra were obtained with EI ionization at 70 eV. IR
spectra were recorded on an FT-IR spectrometer with an ATR (At-
tenuatedTotalReflectance) accessory. The enantioselectivityof chiral
products was determined by comparison of the chiral stationary
phase HPLC traces with those of the corresponding racemic products.
The absolute configurations of the products were assigned by com-
parison with published data.
192 (84, Mþ), 135 (100); HRMS (EI): Mþ, found 192.0943. C12H13OF
requires 192.0945.
4.3.4. 3-(3-Fluorophenyl)cyclohexanone (2d)27. Yellow oil (89 mg,
66%); nmax 1709, 2866, 2935 cmꢂ1
; dH (300 MHz, CDCl3) 1.74e1.90
(m, 2H), 2.06e2.20 (m, 2H), 2.32e2.63 (m, 4H), 2.96e3.07 (m, 1H),
6.89e7.01 (m, 3H), 7.25e7.32 (m, 1H); dC (75 MHz, CDCl3) 25.3
4
(CH2), 32.5 (CH2), 41.0 (CH2), 44.3 (d, JCF 1.7 Hz, CH), 48.6 (CH2),
2
2
4
113.4 (d, JCF 21.4 Hz, CH), 113.5 (d, JCF 21.0 Hz, CH), 122.2 (d, JCF
4.2. Dichloroorganoindium reagents
2.8 Hz, CH), 130.1 (d, 3JCF 8.3 Hz, CH), 146.9 (d, 3JCF 6.8 Hz, C), 163.0
(d, JCF 245.9 Hz, CF), 210.3 (C); m/z (EI) 192 (93, Mþ), 149 (100);
1
Dichloroarylindium reagents were prepared by the dropwise
addition of the corresponding aryllithium reagent (1 equiv, w1.5 M
in dry THF) to a solution of InCl3 (1.1 equiv, w0.5 M in dry THF) at
ꢂ78 ꢀC and warming to room temperature during 4 h. Phenyl-
lithium was commercially available and was used as received. Other
aryllithium reagents were prepared by the dropwise addition of n-
BuLi (1.0 equiv, 2.0 M in hexanes) to a solution of the corresponding
bromoaryl compound (1.0 equiv, w0.5 M in dry THF) at ꢂ78 ꢀC and
stirring for 30 min.
HRMS (EI): Mþ, found 192.0941. C12H13OF requires 192.0945.
4.3.5. 3-Phenylcyclopentanone (7a)28. Yellow oil (115 mg, 80%);
nmax 3028, 2961, 1737 cmꢂ1
; dH (300 MHz, CDCl3) 1.93e2.08 (m,
1H), 2.25e2.53 (m, 4H), 2.64e2.73 (m, 1H), 3.38e3.50 (m, 1H),
7.24e7.29 (m, 3H), 7.34e7.39 (m, 2H); dC (75 MHz, CDCl3) 31.1 (CH2),
38.8 (CH2), 42.2 (CH), 45.7 (CH2), 126.7 (3ꢃ CH), 128.6 (2ꢃ CH),
143.0 (C), 218.3 (C); m/z (EI) 160 (100, Mþ); HRMS (EI): Mþ, found
160.0881. C11H12O requires 160.0883.
4.3.6. 3-[4-(Trifluoromethyl)phenyl]cyclopentanone
yellow oil (85 mg, 57%); nmax 2916, 2848, 1741 cmꢂ1
(7b)29. Pale
dH (300 MHz,
4.3. General procedure for the rhodium-catalyzed 1,4-
addition
;
CDCl3) 1.94e2.09 (m, 1H), 2.27e2.55 (m, 4H), 2.66e2.75 (m, 1H),
3.43e3.55 (m, 1H), 7.38 (d, J 8.1 Hz, 2H), 7.61 (d, J 8.1 Hz, 2H); dC
(75 MHz, CDCl3) 30.9 (CH2), 38.6 (CH2), 42.0 (CH), 45.4 (CH2), 124.1
To
(0.08 mmol) in dry THF (2 mL) placed in an argon filled Schlenk
tube, a solution of ArInCl2 (1.2 mmol, w0.3 M in dry THF), the
a
solution of [Rh(cod)Cl]2 (0.04 mmol) and (ꢁ)-binap
3
(q, 1JCF 271.9 Hz, CF3), 125.6 (q, JCF 3.8 Hz, 2ꢃ CH), 127.1 (2ꢃ CH),
2
a
,
b-
129.0 (q, JCF 32.5 Hz, C), 147.1 (C), 217.3 (C); m/z (EI) 228 (87, Mþ),
unsaturated carbonyl compound (1 mmol) and dry MeOH
(2.4 mmol) were successively added. The resulting mixture was
heated at 110 ꢀC for 4e6 h and then the reaction was quenched by
the addition of a few drops of MeOH. The mixture was concentrated
and EtOAc (25 mL) was added. The organic phase was successively
washed with aqueous HCl (5%, 15 mL), saturated aqueous NaHCO3
(15 mL) and brine (15 mL), then dried, filtered, and concentrated.
The residue was purified by flash chromatography (EtOAc/hexanes)
to afford the 1,4-addition products.
172 (100); HRMS (EI): Mþ, found 228.0752. C12H11OF3 requires
228.0757.
4.3.7. 3-(4-Fluorophenyl)cyclopentanone (7c)30. Yellow oil (64 mg,
56%); nmax 2960, 1739 cmꢂ1
; dH (300 MHz, CDCl3) 1.89e2.03 (m,
1H), 2.24e2.52 (m, 4H), 2.63e2.71 (m, 1H), 3.35e3.47 (m, 1H),
6.99e7.07 (m, 2H), 7.19e7.25 (m, 2H); dC (75 MHz, CDCl3) 31.3
2
(CH2), 38.8 (CH2), 41.5 (CH), 45.8 (CH2), 115.4 (d, JCF 21.2 Hz, 2ꢃ
3
4
CH), 128.1 (d, JCF 7.8 Hz, 2ꢃ CH), 138.7 (d, JCF 3.2 Hz, C), 161.6 (d,
1JCF 244.9 Hz, CF), 217.9 (C); m/z (EI) 178 (100, Mþ); HRMS (EI): Mþ,
found 178.0782. C11H11OF requires 178.0788.
4.3.1. 3-Phenylcyclohexanone (2a)25. Pale yellow oil (168 mg, 94%);
nmax 3027, 2934, 2865, 1707 cmꢂ1
; dH (300 MHz, CDCl3) 1.75e1.95
(m, 2H), 2.07e2.20 (m, 2H), 2.35e2.65 (m, 4H), 2.97e3.08 (m, 1H),
7.22e7.27 (m, 3H), 7.32e7.38 (m, 2H); dC (75 MHz, CDCl3) 25.5
(CH2), 32.7 (CH2), 41.1 (CH2), 44.7 (CH), 48.9 (CH2), 126.5 (2ꢃ CH),
126.7 (CH), 128.7 (2ꢃ CH), 144.3 (C), 210.9 (C); m/z (EI) 174 (100,
Mþ); HRMS (EI): Mþ, found 174.1037. C12H14O requires 174.1039. In
the reactions using chiral ligands, the enantiomeric excess was
determined by HPLC (Chiralcel OD-H, hexane/i-PrOH¼98:2, 1.0 mL/
min, 254 nm) tR (S)¼12.5 min, tR (R)¼13.8 min.
4.3.8. 3-Phenylcycloheptanone (8a)28. Yellow oil (92 mg, 70%); nmax
3027, 2925, 2854, 1696 cmꢂ1
; dH (300 MHz, CDCl3) 1.45e1.58 (m,
1H), 1.66e1.82 (m, 2H), 1.95e2.13 (m, 3H), 2.58e2.73 (m, 3H),
2.87e3.00 (m, 2H), 7.17e7.24 (m, 3H), 7.27e7.34 (m, 2H); dC
(75 MHz, CDCl3) 24.1 (CH2), 29.2 (CH2), 39.2 (CH2), 42.7 (CH), 43.9
(CH2), 51.2 (CH2), 126.3 (CH), 126.4 (2ꢃ CH), 128.6 (2ꢃ CH), 146.9
(C), 213.4 (C); m/z (EI) 188 (97, Mþ), 104 (100); HRMS (EI): Mþ,
found 188.1190. C13H16O requires 188.1196.
4.3.2. 3-[4-(Trifluoromethyl)phenyl]cyclohexanone
brown oil (118 mg, 69%); nmax 2938, 1708 cmꢂ1
(2b)26. Light
dH (300 MHz,
4.3.9. 3-[4-(Trifluoromethyl)phenyl]cycloheptanone (8b)31. Colorless
;
oil (107 mg, 62%); nmax 2929, 1698 cmꢂ1
; dH (300 MHz, CDCl3)
CDCl3) 1.69e1.94 (m, 2H), 2.08e2.22 (m, 2H), 2.35e2.65 (m, 4H),
3.04e3.14 (m, 1H), 7.34 (d, J 8.1 Hz, 2H), 7.59 (d, J 8.1 Hz, 2H); dC
(75 MHz, CDCl3) 25.3 (CH2), 32.4 (CH2), 41.0 (CH2), 44.4 (CH), 48.4
(CH2), 124.1 (q, 1JCF 271.9 Hz, CF3), 125.6 (q, 3JCF 3.8 Hz, 2ꢃ CH),126.9
(2ꢃ CH), 129.0 (q, 2JCF 32.4 Hz, C), 148.1 (C), 210.2 (C); m/z (EI) 242
(81, Mþ), 199 (100); HRMS (EI): Mþ, found 242.0907. C13H13OF3
requires 242.0913.
1.44e1.58 (m, 1H), 1.66e1.80 (m, 2H), 1.98e2.11 (m, 3H), 2.52e2.68
(m, 3H), 2.89e3.01 (m, 2H), 7.30 (d, J 8.1 Hz, 2H), 7.56 (d, J 8.1 Hz,
2H); dC (75 MHz, CDCl3) 24.0 (CH2), 29.1 (CH2), 38.9 (CH2), 42.5
1
(CH), 43.8 (CH2), 50.7 (CH2), 124.1 (q, JCF 271.9 Hz, CF3), 125.6 (q,
2
3JCF 3.8 Hz, 2ꢃ CH), 126.8 (2ꢃ CH), 128.7 (q, JCF 32.5 Hz, C), 150.7
(C), 212.6 (C); m/z (EI) 256 (71, Mþ), 199 (100); HRMS (EI): Mþ,
found 256.1068. C14H15OF3 requires 256.1070.
4.3.3. 3-(4-Fluorophenyl)cyclohexanone (2c)27. Light brown oil
4.3.10. 5-Methyl-4-phenyl-2-hexanone (9a)28. Pale yellow oil
(50 mg, 46%); nmax 3344, 2916, 2848, 1707 cmꢂ1
;
dH (300 MHz,
(82 mg, 63%); nmax 3028, 2958, 2928, 2872, 1711 cmꢂ1
; dH
CDCl3) 1.74e1.90 (m, 2H), 2.01e2.20 (m, 2H), 2.32e2.63 (m, 4H),
2.96e3.06 (m, 1H), 6.98e7.06 (m, 2H), 7.15e7.22 (m, 2H); dC
(75 MHz, CDCl3) 25.3 (CH2), 32.8 (CH2), 41.1 (CH2), 43.9 (CH), 49.0
(300 MHz, CDCl3) 0.75 (d, J 6.7 Hz, 3H), 0.94 (d, J 6.7 Hz, 3H),
1.78e1.90 (m, 1H), 1.99 (s, 3H), 2.79e2.82 (m, 2H), 2.89e2.96 (m,
1H), 7.14e7.22 (m, 3H), 7.25e7.31 (m, 2H); dC (75 MHz, CDCl3) 20.3
(CH3), 20.7 (CH3), 30.5 (CH3), 33.3 (CH), 47.6 (CH2), 48.0 (CH), 126.2
(CH), 128.1 (2ꢃ CH), 128.2 (2ꢃ CH), 143.2 (C), 208.3 (C); m/z (EI) 190
2
3
(CH2), 115.4 (d, JCF 21.2 Hz, 2ꢃ CH), 127.9 (d, JCF 7.9 Hz, 2ꢃ CH),
140.0 (d, 4JCF 3.2 Hz, C),161.5 (d, 1JCF 244.7 Hz, CF), 210.7 (C); m/z (EI)

1610
R. Tato et al. / Tetrahedron 68 (2012) 1606e1611
(12, Mþ), 132 (100); HRMS (EI): Mþ, found 190.1349. C13H18O re-
quires 190.1352.
spectra for compounds prepared. Supplementary data related to
this article can be found online at doi:10.1016/j.tet.2011.11.075.
4.3.11. 5-Methyl-4-[4-(trifluoromethyl)phenyl]-2-hexanone (9b)32
Colorless oil (61 mg, 45%); nmax 2962, 1716 cmꢂ1
dH (300 MHz,
.
References and notes
;
1. For reviews on synthetic applications of indium, see: (a) Cintas, P. Synlett 1995,
1087e1096; (b) Li, C.-J.; Chan, T.-H. Tetrahedron 1999, 55, 11149e11176; (c)
Ranu, B. C. Eur. J. Org. Chem. 2000, 2347e2356; (d) Podlech, J.; Maier, T. C.
Synthesis 2003, 633e655; (e) Nair, V.; Ros, S.; Jayan, C. N.; Pillai, B. S. Tetrahedron
CDCl3) 0.74 (d, J 6.7 Hz, 3H), 0.94 (d, J 6.7 Hz, 3H), 1.79e1.91 (m, 1H),
2.02 (s, 3H), 2.75e2.91 (m, 2H), 2.98e3.06 (m, 1H), 7.27 (d, J 8.1 Hz,
2H), 7.53 (d, J 8.1 Hz, 2H); dC (75 MHz, CDCl3) 20.2 (CH3), 20.5 (CH3),
30.5 (CH3), 33.0 (CH), 47.2 (CH2), 47.5 (CH), 124.2 (q, 1JCF 271.8 Hz,
CF3), 125.0 (q, 3JCF 3.8 Hz, 2ꢃ CH), 128.5 (q, 2JCF 32.3 Hz, C) 128.5 (2ꢃ
CH), 147.7 (C), 207.3 (C); m/z (EI) 258 (2, Mþ), 200 (100); HRMS (EI):
Mþ, found 258.1219. C14H17OF3 requires 258.1226.
ꢀ
2004, 60, 1959e1982; (f) Auge, J.; Lubin-Germain, N.; Uziel, J. Synthesis 2007,
1739e1764; (g) Yadav, J. S.; Antony, A.; George, J.; Reddy, B. V. S. Eur. J. Org.
Chem. 2010, 591e605.
ꢀ
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~
2. Perez, I.; Perez Sestelo, J.; Maestro, M. A.; Mourino, A.; Sarandeses, L. A. J. Org.
Chem. 1998, 63, 10074e10076.
ꢀ
ꢀ
3. (a) Perez, I.; Perez Sestelo, J.; Sarandeses, L. A. Org. Lett. 1999, 1, 1267e1269; (b)
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ꢀ
Perez, I.; Perez Sestelo, J.; Sarandeses, L. A. J. Am. Chem. Soc. 2001, 123,
4.3.12. Tetrahydro-4-phenyl-2H-pyran-2-one (10a)33. Colorless oil
ꢀ
ꢀ
4155e4160; (c) Pena, M. A.; Perez, I.; Perez Sestelo, J.; Sarandeses, L. A. Chem.
Commun. 2002, 2246e2247; (d) Pena, M. A.; Perez Sestelo, J.; Sarandeses, L. A.
Synthesis 2003, 780e784; (e) Pena, M. A.; Perez Sestelo, J.; Sarandeses, L. A.
Synthesis 2005, 485e492; (f) Pena, M. A.; Perez Sestelo, J.; Sarandeses, L. A. J.
Org. Chem. 2007, 72, 1271e1275; (g) Caeiro, J.; Perez Sestelo, J.; Sarandeses, L. A.
Chem.dEur. J. 2008, 14, 741e746; (h) Riveiros, R.; Saya, L.; Perez Sestelo, J.;
(116 mg, 76%); nmax 3028, 2956, 1727 cmꢂ1
; dH (300 MHz, CDCl3)
ꢀ
ꢀ
1.97e2.10 (m, 1H), 2.14e2.23 (m, 1H), 2.64 (dd, J 17.6, 10.6 Hz, 1H),
2.92 (ddd, J 17.6, 6.0, 1.6 Hz, 1H), 3.19e3.30 (m, 1H), 4.39 (ddd, J 11.4,
10.3, 3.9 Hz,1H), 4.51 (ddd, J 11.4, 4.9, 3.9 Hz,1H), 7.21e7.31 (m, 3H),
7.34e7.40 (m, 2H); dC (75 MHz, CDCl3) 30.2 (CH2), 37.4 (CH), 37.4
(CH2), 68.6 (CH2), 126.4 (2ꢃ CH), 127.2 (CH), 128.9 (2ꢃ CH), 142.8
(C), 170.6 (C); m/z (EI) 176 (100, Mþ); HRMS (EI): Mþ, found
176.0829. C11H12O2 requires 176.0832.
ꢀ
ꢀ
ꢀ
Sarandeses, L. A. Eur. J. Org. Chem. 2008, 1959e1966; (i) Mosquera, A.; Riveiros,
ꢀ
R.; Perez Sestelo, J.; Sarandeses, L. A. Org. Lett. 2008, 10, 3745e3748; (j)
ꢀ
Bouissane, L.; Perez Sestelo, J.; Sarandeses, L. A. Org. Lett. 2009, 11, 1285e1288.
ꢀ
4. (a) Rodríguez, D.; Perez Sestelo, J.; Sarandeses, L. A. J. Org. Chem. 2003, 68,
ꢀ
2518e2520; (b) Rodríguez, D.; Perez Sestelo, J.; Sarandeses, L. A. J. Org. Chem.
2004, 69, 8136e8139.
5. (a) Riveiros, R.; Rodríguez, D.; Perez Sestelo, J.; Sarandeses, L. A. Org. Lett. 2006,
8, 1403e1406; (b) Riveiros, R.; Perez Sestelo, J.; Sarandeses, L. A. Synthesis 2007,
ꢀ
4.3.13. Tetrahydro-4-[4-(trifluoromethyl)phenyl]-2H-pyran-2-one
ꢀ
(10b)33. Yellow oil (92 mg, 58%); nmax 2925, 1730 cmꢂ1
; dH
3595e3598.
6. (a) Takami, K.; Yorimitsu, H.; Shinokubo, H.; Matsubara, S.; Oshima, K. Org. Lett.
2001, 3,1997e1999;(b)Lee, P. H.; Lee, S. W.;Lee, K. Org. Lett. 2003, 5,1103e1106;(c)
Lehmann, U.; Awasthi, S.; Minehan, T. Org. Lett. 2003, 5, 2405e2408; (d) Barbero,
M.; Cadamuro, S.; Dughera, S.; Giaveno, C. Eur. J. Org. Chem. 2006, 4884e4890; (e)
(300 MHz, CDCl3) 2.00e2.13 (m, 1H), 2.17e2.27 (m, 1H), 2.64 (dd, J
17.6, 10.6 Hz, 1H), 2.95 (ddd, J 17.6, 6.0, 1.6 Hz, 1H), 3.28e3.39 (m,
1H), 4.42 (ddd, J 11.5, 10.4, 3.8 Hz, 1H), 4.54 (ddd, J 11.5, 5.0, 3.8 Hz,
1H), 7.35 (d, J 8.1 Hz, 2H), 7.64 (d, J 8.1 Hz, 2H); dC (75 MHz, CDCl3)
30.0 (CH2), 37.1 (CH2), 37.3 (CH), 68.3 (CH2), 126.0 (q, 3JCF 3.8 Hz, 2ꢃ
CH),126.9 (2ꢃ CH),127.5 (q, 1JCF 271.6 Hz, CF3),129.6 (q, 2JCF 32.6 Hz,
C), 146.6 (C), 169.9 (C); m/z (EI) 244 (90, Mþ), 172 (100); HRMS (EI):
Mþ, found 244.0703. C12H11O2F3 requires 244.0706.
ꢀ
ꢀ
ꢀ
Font-Sanchis, E.; Cespedes-Guirao, F. J.; Sastre-Santos, A.; Fernandez-Lazaro, F. J.
Org. Chem. 2007, 72, 3589e3591; (f) Lee, W.; Kang, Y.; Lee, P. H. J. Org. Chem. 2008,
73, 4326e4329; (g) Zhang, L.; Luo, Y.; Wu, J. Synlett 2010, 1845e1848.
7. (a) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis; Pergamon:
Oxford, UK, 1992; (b) Kozlowski, J. A. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, UK, 1991; Vol. 4, Chapter 1.4, pp
169e198; (c) Alexakis, A. In Transition Metals for Organic Synthesis; Beller, M.,
Bolm, C., Eds.; Wiley-VCH: Weinheim, 1998; Vol. 1, Chapter 3.10, pp 504e513.
8. (a) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829e2844; (b) Fagnou, K.;
Lautens, M. Chem. Rev. 2003, 103, 169e196; (c) Chan, A. S. C.; Kwong, F. Y.; Lu, G. In
Comprehensive Organometallic Chemistry III; Mingos, D. M. P., Crabtree, R. H., Eds.;
4.3.14. 4-(4-Fluorophenyl)tetrahydro-2H-pyran-2-one (10c)34. Pale
yellow oil (48 mg, 47%); nmax 2955, 2919, 1727 cmꢂ1
; dH (300 MHz,
CDCl3) 1.95e2.08 (m, 1H), 2.13e2.22 (m, 1H), 2.60 (dd, J 17.6,
10.6 Hz, 1H), 2.92 (ddd, J 17.6, 5.9, 1.7 Hz, 1H), 3.19e3.29 (m, 1H),
4.39 (ddd, J 11.5, 10.4, 3.8 Hz, 1H), 4.51 (ddd, J 11.5, 5.0, 3.8 Hz, 1H),
7.01e7.09 (m, 2H), 7.15e7.22 (m, 2H); dC (75 MHz, CDCl3) 30.4 (CH2),
36.8 (CH), 37.6 (CH2), 68.5 (CH2), 115.8 (d, 2JCF 21.4 Hz, 2ꢃ CH), 127.9
(d, 3JCF 8.0 Hz, 2ꢃ CH),138.5 (d, 4JCF 3.3 Hz, C),161.8 (d, 1JCF 245.8 Hz,
CF), 170.3 (C); m/z (EI) 194 (53, Mþ), 135 (100); HRMS (EI): Mþ,
found 194.0735. C11H11O2F requires 194.0738.
Elsevier: Oxford,ˇ UK, 2007; Vol.10, Chapter 10.08, pp 369e401; (d) Pucheault, M.;
Darses, S.; Genet, J.-P. Eur. J. Org. Chem. 2002, 3552e3557; (e) Edwards, H. J.;
Hargrave, J. D.; Penrose, S. D.; Frost, C. G. Chem. Soc. Rev. 2010, 39, 2093e2105.
9. For a review, see: Hargrave, J. D.; Allen, J. C.; Frost, C. G. Chem.dAsian J. 2010, 5,
386e396.
10. Miura, T.; Murakami, M. Chem. Commun. 2005, 5676e5677.
11. (a) Clark, H. C.; Pickard, A. L. J. Organomet. Chem. 1967, 8, 427e434;
(b) Beachley, O. T., Jr.; Rusinko, R. N. Inorg. Chem. 1979, 18, 1966e1968;
(c) Schumann, H.; Hartmann, U.; Wassermann, W. Polyhedron 1990, 9,
353e360; (d) Crittendon, R. C.; Beck, B. C.; Su, J.; Li, X.-W.; Robinson, G. H.
Organometallics 1999, 18, 156e160.
12. (a) Chen, Y.-H.; Knochel, P. Angew. Chem., Int. Ed. 2008, 47, 7648e7651; (b)
Papoian, V.; Minehan, T. J. Org. Chem. 2008, 73, 7376e7379.
13. The indium present in the reaction media could be recovered by electro-
chemical deposition, see: Prenner, R. H.; Binder, W. H.; Schmid, W. Liebigs Ann.
Chem. 1994, 73e78.
4.3.15. 4-(3-Fluorophenyl)tetrahydro-2H-pyran-2-one (10d). Light
brown oil (71 mg, 56%); nmax 2923, 2853, 1727 cmꢂ1
; dH (300 MHz,
CDCl3) 1.97e2.10 (m, 1H), 2.16e2.25 (m, 1H), 2.62 (dd, J 17.6, 10.7 Hz,
1H), 2.94 (ddd, J17.6, 5.9,1.6 Hz,1H), 3.21e3.31 (m,1H), 4.40 (ddd, J11.5,
10.4, 3.8 Hz, 1H), 4.52 (ddd, J 11.5, 4.9, 3.8 Hz, 1H), 6.90e7.02 (m, 3H),
7.30e7.38 (m, 1H); dC (75 MHz, CDCl3) 30.1 (CH2), 37.2 (d, 4JCF 1.8 Hz,
14. Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc. 2002, 124,
5052e5058.
15. Chen, Y.-H.; Sun, M.; Knochel, P. Angew. Chem., Int. Ed. 2009, 48, 2236e2239.
16. For the use of MeOH in conjugate addition reactions of boron reagents to
a,b-
2
2
CH), 37.3 (CH2), 68.4 (CH2), 113.5 (d, JCF 21.7 Hz, CH), 114.2 (d, JCF
21.0 Hz, CH),122.0 (d, 4JCF 2.9 Hz, CH),130.5 (d, 3JCF 8.4 Hz, CH),145.2 (d,
3JCF 6.8 Hz, C), 163.1 (d, 1JCF 246.9 Hz, CF), 170.1 (C); m/z (EI) 194 (100,
Mþ); HRMS (EI): Mþ, found 194.0734. C11H11O2F requires 194.0738.
unsaturated compounds, see: (a) Hirano, K.; Yorimitsu, H.; Oshima, K. Org. Lett.
2007, 9, 1541e1544; (b) Shintani, R.; Tsutsumi, Y.; Nagaosa, M.; Nishimura, T.;
Hayashi, T. J. Am. Chem. Soc. 2009, 131, 13588e13589.
17. Initially, we consider the possibility that the addition of a protic cosolvent could
replace the chlorine atoms in the indium species (see Ref. 6a). For this reason,
the amount of H2O or MeOH added is stoichiometrically related with the
amount of PhInCl2.
Acknowledgements
18. Reactions in the absence of the phosphine ligand afforded low yields of the
conjugate addition product (<25%).
19. The structure of the organoindium species was determined by 13C NMR ac-
cordingly to the literature, see Ref. 6a and: Adak, L.; Yoshikai, N. J. Org. Chem.
2011, 76, 7563e7568 For further experimental details see Supplementary data.
20. For further details, see the Supplementary data.
ꢀ
We are grateful to the Ministerio de Ciencia e Innovacion (Spain,
~
CTQ2006-06166 and CTQ2009-07180), Universidade da Coruna,
and FEDER for financial support.
21. (a) Yasuda, M.; Haga, M.; Baba, A. Organometallics 2009, 28, 1998e2000; (b)
Yasuda, M.; Haga, M.; Baba, A. Eur. J. Org. Chem. 2009, 5513e5517; (c) Yasuda,
M.; Haga, M.; Nagaoka, Y.; Baba, A. Eur. J. Org. Chem. 2010, 5359e5363.
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132e139; (b) Kiyokawa, K.; Yasuda, M.; Baba, A. Organometallics 2011, 30,
2039e2043.
Supplementary data
Experimental procedures for the characterization of organo-
indium compounds by 13C NMR experiments and copies of NMR

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