Enantioselective nickel-catalyzed cross-coupling reactions of trialkynylindium reagents with racemic secondary benzyl bromides

Article abstract of DOI:10.1002/chem.200701035

The first enantioselective sp-sp³ cross-coupling reaction between alkynyl organometals and racemic benzyl bromides is reported. The coupling is performed at room temperature by using NiBr₂.diglyme and (S)-(/Pr)-Pybox as the catalytic

Full text of DOI:10.1002/chem.200701035

FULL PAPER
DOI: 10.1002/chem.200701035
Enantioselective Nickel-CatalyzedCross-Coupling Reactions of
Trialkynylindium Reagents with Racemic Secondary Benzyl Bromides
[a]
Jorge Caeiro, JosØ PØrez Sestelo,* andLuis A. Sarandeses*
Abstract: The first enantioselective sp–sp3 cross-coupling reaction between alkynyl
organometals and racemic benzyl bromides is reported. The coupling is performed
at room temperature by using NiBr2·diglyme and (S)-(iPr)-Pybox as the catalytic
system and trialkynylindium reagents as nucleophiles. The reaction is stereocon-
vergent, both enantiomers of the racemic benzyl bromide are converted into one
enantiomer of the product, and stereospecific. The reaction takes place efficiently
in good yields and with high atom economy, as the triorganoindium reagents trans-
fer the three organic groups attached to indium (only 40 mol% of R3In is used).
Keywords: asymmetric catalysis
·
benzyl bromides cross-coupling
·
reactions · indium organometallics ·
nickel catalysis
Introduction
desired b-hydride elimination.[3] Benzyl halides are particu-
larly interesting alkyl electrophiles, as they readily undergo
oxidative addition, and do not suffer b-hydride elimination.
Their utility in cross-coupling reactions has been proven
with aryl and alkenyl metals,[4] but the alkynylation of
benzyl halides is still a difficult task.[5] In 2001, our group re-
ported the first efficient coupling reaction between primary
benzyl halides and alkynyl organometallics by using organo-
indium reagents.[1b] Recently, Negishi has extended this reac-
tivity to organozinc reagents.[5b] Nevertheless, the palladium-
catalyzed cross-coupling of alkynylindium compounds with
primary benzyl halides constitutes the method of choice to
perform the sp-benzyl coupling in organic synthesis.[6]
Despite of the interest, the reactivity with secondary benzyl
halides still remains undeveloped. In this paper, we describe
the first catalytic enantioselective sp–sp3 cross-coupling reac-
tion between alkynylindium reagents and racemic secondary
benzyl electrophiles.
Indium organometallics are useful reagents in metal-cata-
lyzed cross-coupling reactions.[1,2] The main features of
indium reagents are their high versatility, their non-toxicity,
and their ability to transfer all three metal-attached groups
to the electrophile. Arepresentative example of this useful-
ness is the particularly effective sp–sp3 palladium-catalyzed
cross-coupling reaction between alkynylindium reagents and
benzyl halides (Scheme 1).[1b]
Scheme 1. Palladium-catalyzed cross-coupling reactions of trialkynylin-
dium reagents with benzyl bromide.
Metal-catalyzed cross-coupling reactions using alkyl hal-
ides have traditionally faced significant limitations, associat-
ed with low reactivity in the oxidative addition step and un-
Results andDiscussion
According to our previous experience, we explored the reac-
tion of a secondary benzyl halide, such as a-methylbenzyl-
bromide (1) with tri(phenylethynyl)indium (40 mol%) in re-
[a] Dr. J. Caeiro, Prof. Dr. J. PØrez Sestelo, Prof. Dr. L. A. Sarandeses
Departamento de Química Fundamental
Universidade da CoruÇa, 15071 ACoruÇa (Spain)
Fax : (+34)981-167-065
fluxing THF by using [PdACHTRE(UNG dppf)2] (dppf=1,1’-bis(diphenyl-
phosphino)ferrocene; 2 mol%) as the catalyst. Under these
reaction conditions, the cross-coupling product 2 was ob-
tained in 65% yield (Table 1, entry 1), a slightly lower yield
than that obtained by using the primary benzyl bromide.
This result can be reasonably attributed to the lower reactiv-
E-mail: sestelo@udc.es
qfsarand@udc.es
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2008, 14, 741 – 746
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
741

Table 1. Reaction of 1 with tri(phenylethynyl)indium under various catalytic systems.
Entry
Catalyst
[Pd(dppf)Cl2] (2%)
[Pd2A(dba)3] (2%), (Rp,R)-Josiphos I (4%)
[Pd2A(dba)3] (2%), (Rp,R,R,Rp)-Mandyphos III (4%)
[Pd2A(dba)3] (2%), (R)-BINAP (4%)
Solvent
T [8C]
t [h]
Yield [%]
ee [%][a]
1
2
3
4
5
6
7
8
G
THF
THF
THF
THF
reflux
reflux
reflux
reflux
reflux
RT
RT
RT
RT
40
21
24
24
24
24
20
20
140
72
120
65
<5
<5
22
11
42
30
70
12
45
–
–
–
10
–
87
82
84
–
E
N
G
C
NiBr2·diglyme (4%), (S)-(iPr)-Pybox (8%)
NiBr2·diglyme (4%), (S)-(iPr)-Pybox (8%)
THF
DMA/THF 1:1
DMA/THF 1:1
DMA/THF 1:1
DMA/THF 1:1
DMA/THF 1:1
[Ni
A
NiBr2·diglyme (10%), (S)-(iPr)-Pybox (13%)
NiBr2·diglyme (4%), (S)-(Ph)-Pybox (8%)
NiBr2·diglyme (10%), (S)-(iPr)-Pybox (13%)
9
10
87
[a] The enantiomeric excess was determined by HPLC analysis.
ity of the secondary center toward oxidative addition and
the competitive b-hydride elimination process. Based on
these results, we looked for a ferrocenyl-based chiral cata-
lyst that could allow the reaction enantioselectively. To this
end, we tried the reaction by using the commercially avail-
able chiral ligands (Rp,R)-Josiphos I and (Rp,R,R,Rp)-Man-
yield, but using NiBr2·diglyme at room temperature for
140 h, the reaction was complete and the coupling product 2
was obtained in 70% yield with high enantioselectivity
(84% ee, Table 1, entry 8).[10] Other chiral ligands, such as
(S)-(Ph)-Pybox, or different reaction conditions, led to
lower yields, although maintaining the same level of enan-
tioselectivity (ꢀ85% ee; Table 1, entries 9 and 10).
dyphos III (2–4 mol%) combined with [Pd2ACHTR(EUNG dba)3] (dba=
(E,E)-dibenzylideneacetone; 2 mol%) as
a
palladium
This novel reaction constitutes, to the best of our knowl-
edge, the first enantioselective alkynyl–alkyl (sp–sp3) cross-
coupling. Other noteworthy features of this approach are:
1) that the reaction is stereoconvergent, that is, both enan-
tiomers of the racemic starting material are preferentially
transformed into one enantiomer of the product, 2) that the
reaction shows high atom economy, that is, the organoindi-
um reagent transfers more than one of its organic groups to
the electrophile, 3) that all the catalyst components are com-
mercially available and air-stable, and 4) that the reaction
proceeds at room temperature without any special require-
ments. Additionally, we also found that the reaction is ste-
reospecific; the reaction with the R enantiomer of (iPr)-
Pybox afforded 3 (enantiomer of 2) in a similar yield and
enantioselectivity (67% yield, 82% ee; Table 2, entry 2).
After having established optimal reaction conditions, we
proceeded to extend the reaction to other alkynylindium re-
agents and various benzyl bromides. In this study, we found
that reaction of a-methylbenzylbromide (1) with tri[(6-me-
thoxy-2-naphthalenyl)ethynyl]indium or tri[(3-thienyl)ethy-
nyl]indium gives the corresponding coupling products (4 and
5, respectively) in satisfactory yields and with high enantio-
selectivities (60–65% yield, 85–87% ee; Table 2, entries 3
and 4). The reaction of reagents that transfer a conjugate
enyne moiety afforded the coupling product in lower yield,
although maintaining a similar level of enantioselectivity
(35% yield, 84% ee; Table 2, entry 5). Interestingly, the re-
source. Unfortunately, we observed lower reactivity and the
coupling product 2 was only obtained in very low yields
(Table 1, entries 2 and 3). The reaction with other chiral bi-
dentate phosphine ligands, such as (R)-BINAP (BINAP=
2R,3S,2,2’-bis(diphenylphosphino)-1,1’-binaphthyl; 4 mol%),
afforded the reaction product in low yield and enantioselec-
tivity (22%, 10% ee; Table 1, entry 4).[7]
These results led us to assay the reaction under nickel cat-
alysis. In this field, interesting sp3–sp3 cross-coupling reac-
tions have been described by using nickel catalysts and
Pybox-type ligands.[8] In our first attempt, the reaction of
racemic a-methylbenzylbromide (1) with tri(phenylethynyl)-
indium (40 mol%) by using NiBr2·diglyme (4 mol%) and
(S)-(iPr)-Pybox (8 mol%), in THF at reflux, afforded the
cross-coupling product 2 in 11% yield after a 20 h reaction,
with low conversion of the starting benzyl bromide and with
considerable amounts of the diyne resulting from reductive
dimerization of the alkynylindium reagent (Table 1, entry 5).
When the same reaction was performed at room tempera-
ture by using a 1:1 mixture of DMA/THF (DMA=dimethyl-
acetamide) as the solvent, we reduced the amount of diyne
and the yield of the coupling product 2 rose up to 42%,
with high enantioselectivity (87% ee; Table 1, entry 6).[9] En-
couraged by these results, we set out to optimize the reac-
tion conditions. The use of other nickel catalysts, such as
[NiACHTREUNG(cod)2] (cod=1,5-cyclooctadienyl) did not improve the
742
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 741 – 746

Cross-Coupling Reactions
FULL PAPER
Table 2. Results of the nickel-catalyzed cross-coupling reaction of trialkynylin-
dium reagents with 1.
lower stability of the reaction products. The reactivity of the
benzyl bromide 1-bromobenzocyclobutene (10) was also
studied. In these cases, the reactions with the various trial-
kynylindium reagents afforded stable coupling products, al-
though with low enantioselectivity (57–82% yield, 6–7% ee;
Table 3, entries 5–8).
Although the mechanism for this enantioselective cross-
coupling reaction has not been established, according to
previous mechanistic studies about the oxidative addition of
Pd0 to benzyl halides,[11] the stereoconvergence of the reac-
tion could be explained by two possible pathways after the
Entry Alkyne
Product
Yield ee
[%]
[%]
1
70
84
82
À
formation of the Ni Ca bond: 1) a nucleophilic exchange
process with Ni0 to afford the most stable or reactive of the
two diastereomeric intermediates of the nickel complex
with the chiral ligand or 2) a rearrangement through a
planar sp2-benzyl species. In this last situation, the genera-
tion of a benzyl radical associated with a nickel(I) complex
could be proposed, in a similar scenario to that proposed by
Stille[12] and Vivic[13] for nickel-catalyzed cross-coupling re-
actions. This proposal could also explain the lack of enantio-
selectivity when 1-bromobenzocyclobutene (10) is used as
the electrophile, because of the difficulty of isomerization
through a planar sp2-benzocyclobutene intermediate.
2[a]
67
60
3
85[b]
4
5
6
7
65
35
30
57
87[b]
84[b]
77[b]
Conclusion
We have described the first enantioselective cross-coupling
reaction between racemic secondary benzyl bromides and
trialkynylindium reagents by using a commercially available
catalytic system. The reaction occurs efficiently, as indium
organometallics can transfer more than one organic group
to the electrophile, and with high enantioselectivity. Current
efforts are focused towards the application of this methodol-
ogy to other organoindium reagents and different secondary
electrophiles.
[c]
–
[a] Reaction performed with (R)-(iPr)-Pybox (13 mol%) as the ligand. [b] The
absolute configuration of the reaction product was not determined. [c] The per-
centage ee could not be determined by HPLC analysis.
Experimental Section
action of 1 with the trialkynylindium derivative of ethyl pro-
piolate afforded the allene 7 as the only product in 30%
yield with good enantioselectivity (77% ee). The formation
of related allenes was also observed by Buchwald in the
Heck alkynylation of benzyl chlorides at high temperatures
by using an excess of base.[5d] On the other hand, the reac-
tion of the benzyl bromide 1 with alkynylsilanes, such as
tris(trimethylsilylethynyl)indium, gave the corresponding
cross-coupling product 8 in 57% yield (Table 2, entry 7).
During our work, we also explored the reaction of trialky-
nylindium reagents with other benzylic substrates (Table 3).
The reaction of the previously prepared trialkynylindium re-
agents with 1-bromoindane (9), under the conditions de-
scribed above, also afforded the corresponding cross-cou-
pling products in satisfactory yields and with high enantiose-
lectivities (40–65% yield, 80–84% ee; Table 3, entries 1–4).
In these cases, the lower yields can be attributed to the
General methods: All reactions were conducted in flame-dried glassware
under a positive pressure of argon. Reaction temperatures refer to exter-
nal bath temperatures. THF was dried by distillation from the sodium
ketyl of benzophenone. All other commercially available reagents were
used as received. Racemic 1-bromoindane (9) was prepared by following
a previously published procedure.[8b] Liquid reagents or reagent solutions
were added by syringe or cannula. Organic extracts were dried over an-
hydrous Na2SO4, filtered, and concentrated by using a rotary evaporator
at aspirator pressure (20–30 mmHg). TLC was effected on silica gel 60
F254 (layer thickness 0.2 mm) and components were located by observa-
tion under UV light and/or by treating the plates with a phosphomolyb-
dic acid or p-anisaldehyde reagent followed by heating. Flash chromatog-
raphy was performed on silica gel 60 (230–400 mesh) by Stillꢁs method.[14]
NMR spectra were performed in Bruker Avance 300 or Bruker Avance
500 spectrometers in CDCl3 by using the residual solvent signal at d=
7.26 (1H) or 77.0 ppm (13C) as internal standard. DEPT was used to
assign carbon types. LR-EIMS were measured on a Thermo Finnigan
Trace MS spectrometer at 70 eV. The HRMS were measured on a
Thermo Finnigan MAT 95XP spectrometer. IR spectra were taken with a
Bruker Vector 22. Optical rotation values were determined at room tem-
Chem. Eur. J. 2008, 14, 741 – 746
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
743

L. A. Sarandeses, J. PØrez Sestelo, J. Caeiro
Table 3. Results of the nickel-catalyzed cross-coupling reaction of trial-
kynylindium reagents with benzyl bromides 9 and 10.
Pybox as the catalyst, 97 mg of 2 (70%, 84% ee) was formed; however,
with (R)-(iPr)-Pybox as the catalyst, 93 mg of 3 (67%, 82% ee) was
formed. 1H NMR (300 MHz, CDCl3, 258C): d=7.53–7.30 (m, 10H), 4.04
(q, 3J(H,H)=7.1 Hz, 1H), 1.64 ppm (d, 3J(H,H)=7.1 Hz, 3H); 13C NMR
ACHTERNGU ACHTREUGN
(75 MHz, CDCl3, 258C): d=143.3 (C), 131.6 (2”CH), 128.5 (2”CH),
128.2 (2”CH), 127.7 (CH), 126.9 (2”CH), 126.6 (CH), 123.7 (C), 92.6
(C), 82.4 (C), 32.4 (CH), 24.5 ppm (CH3); MS (70 eV, EI): m/z (%): 206
(53) [M+], 191 [M+ÀCH3] (100), 189 (25), 165 (14), 128 (17); HRMS
(EI): m/z: calcd for C16H14: 206.1090 [M+]; found: 206.1090; HPLC:
(Chiralcel OD-H): eluent: hexane, flow: 0.5 mLminÀ1
.
(S)-1,3-Diphenylbutane:[16] Amixture of (1-methyl-3-phenyl-2-propynyl)-
benzene 2 (prepared from reaction of 1 with tri(phenylethynyl)indium
and (S)-(iPr)-Pybox as the catalyst, 39 mg, 0.368 mmol, 84% ee) and Pd/
C (4 mg, 10% Pd) in hexane (2 mL) was hydrogenated for 5 h (balloon
pressure). After this time, the mixture was filtered through a short pad of
Celite. Concentration under reduced pressure afforded (S)-1,3-diphenyl-
butane (37 mg, 95%) as a colorless oil. [a]2D0 = +12.1 cm3 gÀ1 dmÀ1 (c=
1.85 gcmÀ3 in CHCl3) (lit.[16] [a]D20 = À11.6 cm3 gÀ1 dmÀ1 (c=1.57 gcmÀ3 in
CHCl3)); data for the R enantiomer: 1H NMR (300 MHz, CDCl3, 258C):
Entry Benzyl
bromide
Alkyne
Product[a] Yield [%] ee [%]
1
2
9
11
12
65
60
82
81
d=7.37–7.15 (m, 10H), 2.76 (m, 1H), 2.55 (m, 2H), 1.95 (m, 2H),
3
1.13 ppm (d, J
A
3
13
56
84
2-Methoxy-6-(3-phenyl-1-butynyl)naphthalene (4): According to the gen-
eral procedure, the reaction of (Æ)-a-methylbenzylbromide (1, 128 mg,
4
5
14
15
40
81
80
6
0.692 mmol)
with
tri[(6-methoxy-2-naphthalenyl)ethynyl]indium
(0.28 mmol) afforded, after purification by column chromatography (1%
Et2O/hexanes), compound 4 as a white solid (119 mg, 60%, 85% ee).
M.p. 71–728C; 1H NMR (300 MHz, CDCl3, 258C): d=7.93–7.12 (m,
10
11H), 4.07 (q, 3J(H,H)=7.1 Hz, 1H), 3.94 (s, 3H), 1.66 ppm (d, 3J-
ACHTREUNG
6
16
57
6
AHCTREUNG
(H,H)=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3, 258C): d=158.1 (C),
143.4 (C), 133.8 (C), 131.0 (CH), 129.3 (CH), 129.1 (CH), 128.6 (2”CH),
128.5 (C), 126.9 (2”CH), 126.6 (2”CH), 119.2 (CH), 118.6 (C), 105.7
(CH), 92.2 (C), 82.8 (C), 55.3 (CH3), 32.5 (CH), 24.5 ppm (CH3); MS
(70 eV, EI): m/z (%): 286 [M+] (75), 271 [M+ÀCH3] (100), 228 (40), 226
(22); HRMS (EI): m/z: calcd for C21H18O: 286.1352 [M+]; found:
286.1365; HPLC (Chiralcel OJ): eluent: iPrOH/hexane (10:90), flow:
7
8
17
18
65
82
7
7
1.0 mLminÀ1
.
[a] The absolute configuration of the reaction products was not deter-
mined.
3-(3-Phenyl-1-butynyl)thiophene (5): According to the general proce-
dure, the reaction of (Æ)-a-methylbenzylbromide (1, 130 mg,
0.700 mmol) with tri[(3-thienyl)ethynyl]indium (0.28 mmol) afforded,
after purification by column chromatography (hexanes), compound 5 as a
colorless oil (97 mg, 65%, 87% ee). 1H NMR (300 MHz, CDCl3, 258C):
perature in a JASCO DIP-1000 Digital polarimeter. HPLC analyses were
performed on a Hewlett Packard HP1100 Series system by using Daicel
Chiralcel columns.
d=7.49–7.13 (m, 7H), 4.00 (q, 3J
AHCTREUNG
(H,H)=7.1 Hz, 1H), 1.61 ppm (d, 3J-
ACHTREUNG
(H,H)=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3, 258C): d=143.2 (C),
Trialkynylindium reagents: According to previously reported methods,[1b]
trialkynylindium compounds were prepared by treatment of the corre-
sponding alkynyllithium reagents (3 equiv) with InCl3 (1.1 equiv) in dry
THF at À788C and warming to room temperature. Alkynyllithium re-
agents were prepared from the corresponding alkynes (1.0 equiv) by
treatment with nBuLi (1.0 equiv) in dry THF at À788C and warming to
room temperature, except in the case of ethyl propiolate and 2-ethynyl-6-
methoxynaphthalene which were metallated and used at À788C.
General procedure for the nickel-catalyzed enantioselective cross-cou-
pling reaction: Asolution of NiBr 2·diglyme (25 mg, 0.07 mmol) and (S)-
(iPr)-Pybox (25 mg, 0.09 mmol) in dry DMA(4 mL) was placed in an
argon-filled Schlenk tube. After stirring for 15 min at room temperature,
the benzyl bromide (0.7 mmol) and a solution of R3In in dry THF
(0.07m, 0.28 mmol, 4 mL) were successively added, and the resulting mix-
ture was stirred at room temperature for 140 h. The reaction was
quenched by addition of a few drops of MeOH and diluted with Et2O
(25 mL). The organic phase was washed successively with aqueous HCl
(5%, 30 mL), saturated aqueous NaHCO3 (30 mL) and brine (30 mL),
then dried and concentrated. The residue was purified by flash chroma-
tography and enantiomer excess was determined by HPLC on Daicel
130.0 (CH), 128.5 (2”CH), 127.9 (CH), 126.9 (2”CH), 126.7 (CH), 125.0
(CH), 122.7 (C), 92.1 (C), 77.4 (C), 32.4 (CH), 24.4 ppm (CH3); MS
(70 eV, EI): m/z (%): 212 [M+] (41), 197 [M+ÀCH3] (100), 178 (13);
HRMS (EI): m/z: calcd for C14H12S: 212.0654 [M+]; found: 212.066;
HPLC (Chiralcel OD-H), eluent: hexane, flow: 0.5 mLminÀ1
.
(4-Cyclohexenyl-3-butyn-2-yl)benzene (6): According to the general pro-
cedure, the reaction of (Æ)-a-methylbenzylbromide (1, 130 mg,
0.700 mmol) with tri(1-cyclohexenylethynyl)indium (0.28 mmol) afforded,
after purification by column chromatography (hexanes), compound 6 as a
colorless oil (52 mg, 35%, 84% ee). 1H NMR (300 MHz, CDCl3, 258C):
d=7.42–7.23 (m, 5H), 6.09 (m, 1H), 3.88 (q, 3J
2.18–2.07 (m, 4H), 1.69–1.57 (m, 4H), 1.51 ppm (d, 3J
AHCTREUNG
ACHTREUNG
3H); 13C NMR (75 MHz, CDCl3, 258C): d=143.7 (C), 133.7 (CH), 128.4
(2”CH), 126.9 (2”CH), 126.5 (CH), 120.9 (C), 89.7 (C), 84.2 (C), 32.3
(CH), 29.5 (CH2), 25.6 (CH2), 24.7 (CH3), 22.4 (CH2), 21.6 ppm (CH2);
MS (70 eV, EI): m/z (%): 210 [M+] (56), 195 [M+ÀCH3] (72), 167 (100),
129 (62), 105 (76); HRMS (EI): m/z: calcd for C16H18: 210.1403 [M+];
found: 210.1401; HPLC (Chiralcel OD-H): eluent: hexane, flow:
0.5 mLminÀ1
.
Ethyl 4-phenyl-2,3-pentadienoate (7):[17] According to the general proce-
dure, the reaction of (Æ)-a-methylbenzylbromide (1, 130 mg,
0.700 mmol) with tri(3-methoxy-3-oxo-1-propynyl)indium (0.28 mmol) af-
forded, after purification by column chromatography (hexanes), com-
pound 7 as a yellow oil (43 mg, 30%, 77% ee). 1H NMR (300 MHz,
Chiralpak columns.
[15]
(1-Methyl-3-phenyl-2-propynyl)benzenes 2 and3
:
According to the
general procedure, the reaction of (Æ)-a-methylbenzylbromide (1,
125 mg, 0.678 mmol) with tri(phenylethynyl)indium (0.27 mmol) afford-
ed, after purification by column chromatography (hexanes), (1-methyl-3-
phenyl-2-propynyl)benzenes 2 and 3 as a colorless oil. With (S)-(iPr)-
CDCl3, 258C): d=7.42–7.25 (m, 5H), 5.90 (q, JACHTRE(UNG H,H)=2.9 Hz, 1H), 4.26
744
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 741 – 746

Cross-Coupling Reactions
FULL PAPER
(q, 3J
ACHTREUNG
G
G
(C), 127.3 (CH), 126.9 (CH), 124.8 (CH), 124.4 (CH), 108.8 (C), 85.5 (C),
37.5 (CH), 34.8 (CH2), 31.7 (CH2), 0.16 ppm (3”CH3); MS (70 eV, EI):
m/z (%): 214 [M+] (32), 199 [M+ÀCH3] (34), 117 (69), 84 (92), 73 (100);
HRMS (EI): m/z: calcd for C14H18Si: 214.1172 [M+]; found: 214.1168;
165.7 (C), 134.4 (C), 128.6 (2”CH), 127.8 (CH), 126.2 (2”CH), 105.4
(C), 89.8 (CH), 60.9 (CH2), 16.2 (CH3), 14.3 ppm (CH3); IR (CHCl3): n˜ =
1948 (C=C=C), 1718 cmÀ1 (C=O); MS (70 eV, EI): m/z (%): 202 [M+]
(20), 174 (38), 158 (25), 129 (100); HRMS (EI): m/z: calcd for C13H14O2:
202.0988 [M+]; found: 202.0987; HPLC (Chiralcel OD-H): eluent:
iPrOH/hexane 0.5:99.5, flow: 0.5 mLminÀ1
HPLC (Chiralcel OD-H): eluent: hexane, flow: 0.5 mLminÀ1
.
1-(Phenylethynyl)-1,2-dihydrocyclobutabenzene (15): According to the
general procedure, the reaction of (Æ)-1-bromobenzocyclobutane (10,
126 mg, 0.690 mmol) with tri(phenylethynyl)indium (0.28 mmol) afford-
ed, after purification by column chromatography (hexanes), compound
15 as a colorless oil (113 mg, 81%, 6% ee). 1H NMR (300 MHz, CDCl3,
(3-Phenyl-1-butynyl)trimethylsilane (8):[18] According to the general pro-
cedure, the reaction of (Æ)-a-methylbenzylbromide (1, 132 mg,
0.722 mmol) with tris(trimethylsilylethynyl)indium (0.29 mmol) afforded,
after purification by column chromatography (hexanes), compound 8 as a
colorless oil (82 mg, 57%). 1H NMR (300 MHz, CD2Cl2, 258C): d=7.42–
258C): d=7.50–7.15 (m, 9H), 4.49 (dd, J
ACHTREUNG
(dd, J(H,H)=13.7, 5.5 Hz, 1H), 3.42 ppm (dd, JACHTREUNG
G
1H); 13C NMR (75 MHz, CDCl3, 258C): d=145.2 (C), 143.6 (C), 131.6
(2”CH), 128.2 (2”CH), 128.0 (CH), 127.7 (CH), 127.4 (CH), 123.6 (C),
123.2 (CH), 122.1 (CH), 89.7 (C), 82.3 (C), 38.9 (CH2), 32.6 ppm (CH);
MS (70 eV, EI): m/z (%): 204 [M+] (88), 202 (100), 101 (20); HRMS
(EI): m/z: calcd for C16H12: 204.0934 [M+]; found: 204.0934; HPLC
7.25 (m, 5H), 3.80 (q, 3J(H,H)=7.1 Hz, 1H), 1.49 (d, 3J
ACTHERNGU ACHTRE(UGN H,H)=7.1 Hz,
3H), 0.20 ppm (s, 9H); 13C NMR (75 MHz, CD2Cl2, 258C): d=143.6 (C),
128.9 (2”CH), 127.3 (2”CH), 127.0 (CH), 109.9 (C), 86.4 (C), 32.2
(CH), 24.8 (CH3), 0.2 ppm (3”CH3); MS (70 eV, EI): m/z (%): 202 [M+]
(11), 187 [M+ÀCH3] (43), 159 (18), 105 (100); HRMS (EI): m/z: calcd
for C13H18Si: 202.1172 [M+]; found: 202.1168.
(Chiralcel OD-H): eluent: iPrOH/hexane 0.5:99.5, flow: 0.5 mLminÀ1
.
2-[(1,2-Dihydrocyclobutabenzen-1-yl)ethynyl]-6-methoxynaphthalene
(16): According to the general procedure, the reaction of (Æ)-1-bromo-
benzocyclobutane (10, 128 mg, 0.700 mmol) with tri[(6-methoxy-2-naph-
thalenyl)ethynyl]indium (0.28 mmol) afforded, after purification by
1-(Phenylethynyl)-2,3-dihydro-1H-indene (11):[19] According to the gener-
al procedure, the reaction of (Æ)-1-bromoindane (9, 140 mg, 95%,
0.675 mmol) with tri(phenylethynyl)indium (0.27 mmol) afforded, after
purification by column chromatography (hexanes), compound 11 as a
white solid (96 mg, 65%, 82% ee). M.p. 79–818C; 1H NMR (300 MHz,
column chromatography (hexanes), compound 16 as
(113 mg, 55%, 6% ee). M.p. 83–848C; 1H NMR (300 MHz, CDCl3,
258C): d=7.90–7.11 (m, 10H), 4.52 (dd, J(H,H)=5.5, 2.8 Hz, 1H), 3.93
(s, 3H), 3.74 (dd, J(H,H)=13.9, 5.6 Hz, 1H), 3.44 ppm (dd, J(H,H)=
a white solid
CDCl3, 258C): d=7.54–7.25 (m, 9H), 4.25 (t, 3J
ACHTRE(UNG H,H)=8.5 Hz, 1H),
AHCTREUNG
3.12–2.90 (m, 2H), 2.63 (m, 1H), 2.25 ppm (m, 1H); 13C NMR (75 MHz,
CDCl3, 258C): d=143.6 (C), 142.9 (C), 131.7 (CH), 128.2 (CH), 127.7
(CH), 127.0 (CH), 126.6 (CH), 124.5 (CH), 124.3 (CH), 123.7 (C), 91.5
(C), 81.6 (C), 36.8 (CH), 34.4 (CH2), 31.5 ppm (CH2); MS (70 eV, EI):
m/z (%): 218 [M+] (100), 203 [M+ÀCH3] (51), 189 (14), 115 (34); HRMS
(EI): m/z: calcd for C17H14: 218.1090 [M+]; found: 218.1086; HPLC
A
ACHTREUNG
13.9, 2.9 Hz, 1H); 13C NMR (75 MHz, CDCl3, 258C): d=158.1 (C), 145.3
(C), 143.6 (C), 133.8 (C), 131.1 (CH), 129.2 (CH), 129.1 (CH), 128.4 (C),
128.0 (CH), 127.4 (CH), 126.6 (CH), 123.2 (CH), 122.1 (CH), 119.2
(CH), 118.4 (C), 105.7 (CH), 89.3 (C), 82.7 (C), 55.2 (CH3), 39.0 (CH2),
32.8 ppm (CH); MS (70 eV, EI): m/z (%): 284 [M+] (72), 269 [M+ÀCH3]
(22), 241 (100); HRMS (EI): m/z: calcd for C21H16O: 284.1196 [M+];
found: 284.1200; HPLC (Chiralcel OD-H): eluent: iPrOH/hexane
(Chiralcel OD-H): eluent: hexane, flow: 0.5 mLminÀ1
2-[(2,3-Dihydro-1H-inden-1-yl)ethynyl]-6-methoxynaphthalene (12): A c-
cording to the general procedure, the reaction of (Æ)-1-bromoindane (9,
138 mg, 97%, 0.678 mmol) with tri[(6-methoxy-2-naphthalenyl)ethynyl]-
indium (0.27 mmol) afforded, after purification by column chromatogra-
phy (1% Et2O/hexanes), compound 12 as a white solid (121 mg, 60%,
81% ee). M.p. 100–1018C; 1H NMR (300 MHz, CDCl3, 258C): d=7.90–
0.5:99.5; flow: 0.5 mLminÀ1
.
3-[(1,2-Dihydrocyclobutabenzen-1-yl)ethynyl]thiophene (17): According
to the general procedure, the reaction of (Æ)-1-bromobenzocyclobutane
(10, 128 mg, 0.700 mmol) with tri[(3-thienyl)ethynyl]indium (0.28 mmol)
afforded, after purification by column chromatography (hexanes), com-
pound 17 as a colorless oil (96 mg, 65%, 7% ee). 1H NMR (300 MHz,
7.11 (m, 10H), 4.27 (t, 3J
ACHTRE(UNG H,H)=8.5 Hz, 1H), 3.93 (s, 3H), 3.12–2.90 (m,
2H), 2.64 (m, 1H), 2.26 ppm (m, 1H); 13C NMR (75 MHz, CDCl3, 258C):
d=158.1 (C), 143.7 (C), 143.0 (C), 133.8 (C), 131.0 (CH), 129.3 (CH),
129.2 (CH), 128.5 (C), 127.1 (CH), 126.6 (2”CH), 124.5 (CH), 124.3
(CH), 119.2 (CH), 118.7 (C), 105.8 (CH), 91.1 (C), 82.0 (C), 55.3 (CH3),
36.9 (CH), 34.5 (CH2), 31.5 ppm (CH2); MS (70 eV, EI): m/z (%): 298
[M+] (100), 283 [M+ÀCH3] (30), 252 (33), 239 (23); HRMS (EI): m/z:
calcd for C22H18O: 298.1352 [M+]; found: 298.1350; HPLC (Chiralcel
CDCl3, 258C): d=7.42–7.11 (m, 7H), 4.45 (dd, J
ACHTREUNG
3.70 (dd, J(H,H)=14.0, 5.5 Hz, 1H), 3.36 ppm (dd, JACHTREUNG
A
1H); 13C NMR (75 MHz, CDCl3, 258C): d=145.1 (C), 143.5 (C), 129.9
(CH), 128.0 (2”CH), 127.4 (CH), 125.0 (CH), 123.2 (CH), 122.5 (C),
122.1 (CH), 89.2 (C), 77.4 (C), 38.2 (CH2), 32.6 ppm (CH); MS (70 eV,
EI): m/z (%): 210 [M+] (100), 165 (73); HRMS (EI): m/z: calcd for
C14H10S: 210.0498 [M+]; found: 210.0493; HPLC (Chiralcel OD-H):
eluent: hexane, flow: 0.5 mLminÀ1
.
OJ): eluent: iPrOH/hexane 30:70, flow: 1.0 mLminÀ1
[(1,2-Dihydrocyclobutabenzen-1-yl)ethynyl]trimethylsilane (18): Accord-
ing to the general procedure, the reaction of (Æ)-1-bromobenzocyclobu-
tane (10, 126 mg, 0.690 mmol) with tris(trimethylsilylethynyl)indium
(0.28 mmol) afforded, after purification by column chromatography (hex-
anes), compound 18 as a colorless oil (113 mg, 82%, 7% ee). 1H NMR
3-[(2,3-Dihydro-1H-inden-1-yl)ethynyl]thiophene (13): According to the
general procedure, the reaction of (Æ)-1-bromoindane (9, 140 mg, 97%,
0.689 mmol) with tri[(3-thienyl)ethynyl]indium (0.28 mmol) afforded,
after purification by column chromatography (hexanes), compound 13 as
a white solid (87 mg, 56%, 84% ee). M.p. 64–658C; 1H NMR (300 MHz,
(300 MHz, CDCl3, 258C): d=7.29–7.03 (m, 4H), 4.28 (dd, J
ACHTREUNG
CDCl3, 258C): d=7.52–7.13 (m, 7H), 4.22 (t, 3J
ACHTRE(UNG H,H)=8.5 Hz, 1H),
3.0 Hz, 1H), 3.62 (dd, J(H,H)=13.9, 5.6 Hz, 1H), 3.30 (dd, JACHTREUNG
G
3.10–2.89 (m, 2H), 2.61 (m, 1H), 2.24 ppm (m, 1H); 13C NMR (75 MHz,
CDCl3, 258C): d=143.5 (C), 142.9 (C), 130.0 (CH), 127.9 (CH), 127.1
(CH), 126.6 (CH), 125.0 (CH), 124.5 (CH), 124.3 (CH), 122.7 (C), 91.0
(C), 76.6 (C), 36.8 (CH), 34.3 (CH2), 31.5 ppm (CH2); MS (70 eV, EI):
m/z (%): 224 [M+] (100), 208 (21), 191 (29), 178 (21); HRMS (EI): m/z:
calcd for C15H12S: 224.0654 [M+]; found: 224.0654; HPLC (Chiralcel
14.1, 2.9 Hz, 1H), 0.20 ppm (s, 9H); 13C NMR (75 MHz, CDCl3, 258C):
d=145.0 (C), 143.6 (C), 127.9 (CH), 127.4 (CH), 123.1 (CH), 122.0 (CH),
106.4 (CH), 86.3 (C), 38.8 (CH2), 32.9 (CH), 0.1 ppm (3”CH3); MS
(70 eV, EI): m/z (%): 200 [M+] (4), 185 [M+ÀCH3] (100), 172 (17), 141
(23); HRMS (EI): m/z: calcd for C13H16Si: 200.1016 [M+]; found:
200.1011; HPLC (Chiralcel OD-H): eluent: hexane, flow: 0.4 mLminÀ1
.
OD-H): eluent: hexane, flow: 0.5 mLminÀ1
.
[(2,3-Dihydro-1H-inden-1-yl)ethynyl]trimethylsilane (14): According to
the general procedure, the reaction of (Æ)-1-bromoindane (9, 142 mg,
97%, 0.700 mmol) with tris(trimethylsilylethynyl)indium (0.28 mmol) af-
forded, after purification by column chromatography (hexanes), com-
pound 14 as a colorless oil (60 mg, 40%, 80% ee). 1H NMR (300 MHz,
Acknowledgements
CDCl3, 258C): d=7.36 (m, 1H), 7.24–7.15 (m, 3H), 4.00 (dd, J
A
This research was supported by the Spanish Ministerio de Educación y
Ciencia (CTQ2006–06166), the Xunta de Galicia (PGIDIT04P-
XIC10308PN), and the FEDER.
9.0, 8.5 Hz, 1H), 2.95–2.85 (m, 2H), 2.49 (m, 1H), 2.05 (m, 1H),
0.17 ppm (s, 9H); 13C NMR (75 MHz, CDCl3, 258C): d=143.8 (C), 143.5
Chem. Eur. J. 2008, 14, 741 – 746
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
745

L. A. Sarandeses, J. PØrez Sestelo, J. Caeiro
schalle, A. Kirschning, Org. Lett. 2006, 8, 135–138; d) M. Rega, P.
Candal, C. JimØnez, J. Rodríguez, Eur. J. Org. Chem. 2007, 934–
942; e) A. Meyer, M. Brꢃnjes, F. Taft, T. Frenzel, F. Sasse, A.
Kirschning, Org. Lett. 2007, 9, 1489–1492.
[1] For contributions from this group see: a) I. PØrez, J. PØrez Sestelo,
L. A. Sarandeses, Org. Lett. 1999, 1, 1267–1269; b) I. PØrez, J. PØrez
Sestelo, L. A. Sarandeses, J. Am. Chem. Soc. 2001, 123, 4155–4160;
c) M. A. Pena, I. PØrez, J. PØrez Sestelo, L. A. Sarandeses, Chem.
Commun. 2002, 2246–2247; d) M. A. Pena, J. PØrez Sestelo, L. A.
Sarandeses, Synthesis 2003, 780–784; e) M. A. Pena, J. PØrez Seste-
lo, L. A. Sarandeses, Synthesis 2005, 485–492; f) M. A. Pena, J.
PØrez Sestelo, L. A. Sarandeses, J. Org. Chem. 2007, 72, 1271–1275.
[2] For references from other groups see: a) J. Y. Legros, G. Primault,
J. C. Fiaud, Tetrahedron 2001, 57, 2507–2514; b) K. Takami, H. Yori-
mitsu, K. Oshima, Org. Lett. 2002, 4, 2993–2995; c) M. X. Qian,
Z. H. Huang, E. Negishi, Org. Lett. 2004, 6, 1531–1534; d) V. Gopal-
samuthiram, W. D. Wulff, J. Am. Chem. Soc. 2004, 126, 13936–
13937; e) B. W. Fausett, L. S. Liebeskind, J. Org. Chem. 2005, 70,
4851–4853; f) M. Barbero, S. Cadamuro, S. Dughera, C. Giaveno,
Eur. J. Org. Chem. 2006, 4884–4890.
[3] a) D. J. Cꢂrdenas, Angew. Chem. 2003, 115, 398–401; Angew. Chem.
Int. Ed. 2003, 42, 384–387; ; b) M. R. Netherton, G. C. Fu, Adv.
Synth. Catal. 2004, 346, 1525–1532; c) M. R. Netherton, G. C. Fu in
Palladium in Organic Synthesis (Ed.: J. Tsuji), Springer-Verlag,
Berlin, 2005, pp. 85–108; d) D. A. Powell, T. Maki, G. C. Fu, J. Am.
Chem. Soc. 2005, 127, 510–511; e) F. Gonzꢂlez-Bobes, G. C. Fu, J.
Am. Chem. Soc. 2006, 128, 5360–5361.
[7] In all three cases, the conversion was less than 30%, and the starting
compound a-methylbenzylbromide was the main compound recov-
ered after reaction.
[8] a) C. Fischer, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 4594–4595;
b) F. O. Arp, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 10482–10483.
[9] The enantiomeric excess was determined by HPLC; for further de-
tails, see the Supporting Information.
[10] The configuration of the reaction product was determined by com-
plete hydrogenation of the alkyne and comparison of optical rota-
tion with the saturated product see: a) C. Fouquey, J. Jacques, Bull.
Soc. Chim. Fr. 1973, 618–621; b) N. Galdi, C. Della Monica, A.
Spinella, L. Oliva, J. Mol. Catal. A 2006, 243, 106–110.
[11] a) K. S. Y. Lau, P. K. Wong, J. K. Stille, J. Am. Chem. Soc. 1976, 98,
5832–5840; b) J. K. Stille, K. S. Y. Lau, Acc. Chem. Res. 1977, 10,
434–442; c) Y. Becker, J. K. Stille, J. Am. Chem. Soc. 1978, 100,
838–844; d) D. Milstein, J. K. Stille, J. Am. Chem. Soc. 1979, 101,
4992–4998.
[12] J. K. Stille, A. B. Cowell, J. Organomet. Chem. 1977, 124, 253–261.
[13] a) T. J. Anderson, G. D. Jones, D. A. Vicic, J. Am. Chem. Soc. 2004,
126, 8100–8101; b) G. D. Jones, C. McFarland, T. J. Anderson, D. A.
Vicic, Chem. Commun. 2005, 4211–4213.
[14] W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43, 2923–2925.
[15] S. K. De, R. A. Gibbs, Tetrahedron Lett. 2005, 46, 8345–8350.
[16] N. Galdi, C. Della Monica, A. Spinella, L. Oliva, J. Mol. Catal. A
2006, 243, 106–110.
[17] W. Runge, Z. Naturforsch. B 1977, 32B, 1296–1303.
[18] G. A. Ville, K. P. C. Vollhardt, M. J. Winter, Organometallics 1984, 3,
1177–1187.
[19] U. Azzena, S. Cossu, O. De Lucchi, G. Licini, L. Pasquato, G. Valle,
Gazz. Chim. Ital. 1990, 120, 557–568.
[4] For a review on Pd-catalyzed benzylation see: E. Negishi, F. Liu, in
Handbook of Organopalladium Chemistry for Organic Synthesis
(Ed.: E. Negishi), Wiley, New York, 2002, pp. 551–589, Chapter
III.2.9.
[5] a) L. R. Pottier, J.-F. Peyrat, M. Alami, J.-D. Brion, Tetrahedron
Lett. 2004, 45, 4035–4038; b) M. Qian, E. Negishi, Tetrahedron Lett.
2005, 46, 2927–2930; c) G. W. Kabalka, M.-L. Yao, S. Borella, Org.
Lett. 2006, 8, 879–881; d) C. H. Larsen, K. W. Anderson, R. E.
Tundel, S. L. Buchwald, Synlett 2006, 2941–2946.
[6] a) V. Gopalsamuthiram, W. D. Wulff, J. Am. Chem. Soc. 2004, 126,
13936–13937; b) C. Mukai, T. Hirose, S. Teramoto, S. Kitagaki, Tet-
rahedron 2005, 61, 10983–10994; c) T. Frenzel, M. Brꢃnjes, M. Quit-
Received: July 5, 2007
Published online: October 11, 2007
746
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 741 – 746