Cross-coupling of nonactivated primary and secondary alkyl halides with aryl Grignard reagents catalyzed by chiral iron pincer complexes

Article abstract of DOI:10.1055/s-0034-1380136

Iron(III) bisoxazolinylphenylamido (bopa) pincer complexes are efficient precatalysts for the cross-coupling of nonactivated primary and secondary alkyl halides with phenyl Grignard reagents. The reactions proceed at room temperature in moderate to excellent yields. A variety of functional groups can be tolerated. The enantioselectivity of the coupling of secondary alkyl halides is low.

Full text of DOI:10.1055/s-0034-1380136

SYNTHESIS
0
0
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8
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1
1
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3
7
-
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1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 1726–1732
paper
1726
G. Bauer et al.
Paper
Synthesis
Cross-Coupling of Nonactivated Primary and Secondary Alkyl
Halides with Aryl Grignard Reagents Catalyzed by Chiral Iron
Pincer Complexes
Gerald Bauer
Chi Wai Cheung
catalyst (5 mol%)
N
Xile Hu*
+
PhMgCl
R
X
R
Ph
THF
conditions
O
N
Fe
N
O
Laboratory of Inorganic Synthesis and Catalysis, Institute
of Chemical Sciences and Engineering, Ecole Polytech-
nique Fédérale de Lausanne (EPFL), ISIC-LSCI, BCH 3305,
Lausanne 1015, Switzerland
R = alkyl
X = Br, I
Cl Cl
R
R
catalyst
R = i-Pr (S), Ph (R), Bn (S), t-Bu (S)
xile.hu@epfl.ch
Received: 14.11.2014
Accepted: 07.01.2015
Published online: 11.02.2015
DOI: 10.1055/s-0034-1380136; Art ID: ss-2014-c0696-st
refluxing diethyl ether. The yields were slightly lower than
in Nakamura’s case, yet a slow addition of Grignard re-
agents was not necessary.6 By slightly modifying the reac-
tion conditions of Nakamura’s system, Bedford et al. was
able to expand the iron catalysis. By precoordiantion of
iron(III) chloride with various amine, phosphine, phosphite,
arsine, and carbene ligands, they were able to reduce the
amount of ligands used from excess to stoichiometric
amount (with respect to the catalyst).8 Bedford et al. also
showed that well-defined iron(III) salen complex are active
towards the Kumada coupling of alkyl halides with aryl
Grignard reagents without additives.9 In these salen sys-
tems, the color turns black upon addition of Grignard re-
agents, suggesting the formation of iron nanoparticles. In a
further study, preformed and in situ generated nanoparti-
cles proved to be equally active.10 Fürstner et al. applied an
[Fe(C2H4)4][Li(tmeda)]2 in the cross coupling of various pri-
mary and secondary alkyl halides.7 The reaction was car-
ried out at –20 °C in a tetrahydrofuran solution. This reac-
tion shows a remarkable chemoselectivity in the presence
of various functional groups. Following these pioneering
studies, many reports of iron-catalyzed alkyl–aryl Kumada
coupling appeared. However, to the best of our knowledge,
there was no precedent for iron-catalyzed enantioselective
alkyl–aryl coupling.
To achieve enantioselective cross coupling, a strong and
modular chiral ligand framework is required. This is chal-
lenging for iron as previous studies suggested that some
iron complexes decomposed during cross coupling to give
iron nanoparticles, which were the catalytically active spe-
cies.9,10 We chose the tridentate bisoxazolinylphenylamido
(bopa) pincer ligand for iron. We thought that the chelating
pincer ligand should stabilize iron ion in different oxidation
states and prevent the formation of iron nanoparticles. Fur-
thermore, the ligand system is module and modification of
the chiral oxazoline units can be easily done. Herein, we re-
Abstract Iron(III) bisoxazolinylphenylamido (bopa) pincer complexes
are efficient precatalysts for the cross-coupling of nonactivated primary
and secondary alkyl halides with phenyl Grignard reagents. The reac-
tions proceed at room temperature in moderate to excellent yields. A
variety of functional groups can be tolerated. The enantioselectivity of
the coupling of secondary alkyl halides is low.
Key words Kumada coupling, iron pincer complex, alkyl halide, aryl
Grignard reagent, enantioselectivity
Carbon–carbon cross-coupling reactions are amongst
the most ubiquitous synthetic methods in organic chemis-
try. Although many advances in C–C coupling have been
made, the use of alkyl electrophiles as the coupling part-
ners is still challenging, due to the comparatively high bar-
rier for the oxidative addition of alkyl electrophile to the
metal center, and the competing β-hydrogen elimination of
the metal–alkyl intermediate.1 Reaction protocols involving
Pd and Ni catalysts have been well established and broadly
used.2 In recent years, iron catalysts have been increasingly
applied in the field of C–C coupling reactions3 thanks to its
low cost, low toxicity, and high abundance, as well as the
high functional group tolerance and high reactivity of iron-
catalyzed reactions.4–7
In 2004, Nakamura et al. reported the iron-catalyzed
Kumada cross-coupling of secondary alkyl halides with aryl
Grignard reagents.5 Simple iron(III) chloride salts in the
presence of tetramethylethylenediamine (TMEDA) in tetra-
hydrofuran at –78 to 0 °C were utilized to generate alkylar-
ene products in 45–99% yields; the reactions required a
slow addition of Grignard reagents and TMEDA. Hayashi et
al. were able to couple primary and secondary alkyl halides
with aryl Grignard reagents in the presence of Fe(acac)3 in
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1726–1732

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G. Bauer et al.
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Synthesis
Table 1 Optimization of Reaction Conditionsa
1 (5 mol%)
port that these iron–bopa complexes are indeed very active
catalyst for the coupling of both secondary and primary al-
kyl halides with phenyl Grignard reagents at ambient tem-
perature (Scheme 1). In contrast to most previous reports,
the coupling proceeds smoothly without any additives. Fur-
thermore, the chelating bopa ligand remains on the iron
center during catalysis. The synthetic utility of this catalyst
system is demonstrated by the coupling of a large number
of functionalized substrates. We also describe preliminary
attempts towards enantioselective alkyl–aryl coupling us-
ing these chiral complexes.
additive
Ph
Ph
PhMgCl
+
I
Ph
THF
temp, 15 min
Entry
Cat., additive (mol%)
Temp ( °C)
Yield (%)b
1
2
1a, DMA (16)
1b, DMA (16)
1c, DMA (16)
1c, DMA (5)
1c, TMEDA (5)
1c, O-TMEDA (5)c
1c, NMP (5)
1c, –
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
47
53
56
57
60
50
47
69
78
89
95
28
3
4
1 (5 mol%)
PhMgCl
+
5
R
X
R
Ph
THF
6
conditions
R = alkyl
X = Br, I
7
8
N
9
1c, –
0
10
11
12
1c, –
–20
–40
r.t.
O
N
Fe
N
O
1a R = i-Pr (S)
1b R = Ph (R)
1c R = Bn (S)
1d R = t-Bu (S)
1c, –
Cl Cl
1c, –d
R
R
a Conditions: 2-iodo-1-phenylbutane (0.5 mmol), PhMgCl (0.55 mmol),
catalyst (5 mol%), dodecane (as internal standard) in THF (4.0 mL).
b Yields were determined by GC (dodecane as internal standard; 100% con-
version).
Scheme 1
c Bis[2-(N,N-dimethylamino)ethyl] ether.
We commenced our investigations on the cross-cou-
pling of 2-iodo-1-phenylbutane with phenylmagnesium
chloride (1.1 equiv) in tetrahydrofuran using DMA (dimeth-
ylacetamide) as additive at room temperature in the pres-
ence of 5 mol% iron catalyst (Table 1). All complexes 1a–c
showed similar activity, giving yields of about 50%. Complex
1c was taken for further screening because it was the best
catalyst among the three. Complex 1d was not included in
the screening as it was introduced only in a later stage of
this work.
The effect of additive was investigated next. The amount
of DMA was lowered from 16 mol% (Table 1, entries 1–3) to
5 mol% (1 equiv to catalyst, entry 4), and the yield remained
the same. Changing to different additives such as TMEDA,
O-TMEDA, and NMP (entries 5–7) did not significantly
change the yields. To our surprise, a higher yield (69%) was
obtained without any additive (entry 8). Lowering the tem-
perature (entries 9–11) further increased the yield; at
–40 °C, the yield was 95%. Changing the solvent from tetra-
hydrofuran to diethyl ether (entry 12) lowered the yield to
28% at room temperature. Although the highest yield was
d Et2O was used as a solvent.
obtained at –40 °C, it was decided to investigate the scope
of the coupling at room temperature for the convenience of
experiments.
The optimized coupling conditions at room temperature
were applied for the coupling of various primary alkyl ha-
lides (Table 2, entries 1–7) as well as cyclic and acyclic sec-
ondary alkyl halides (entries 8–14). Both alkyl iodides and
bromides reacted smoothly to give the corresponding prod-
ucts in generally high to excellent yields. The protocol toler-
ates a range of functional groups, including ethers (entries
3, 5, and 9), carbamates (entry 14), N-heterocycles (entries
2 and 7), Boc-protected piperidine (entry 13), and tetrahy-
dropyran (entries 10, 11). Base-sensitive ester- (entries 4
and 12) and ketone- (entry 7) containing compounds were
coupled with a high chemoselectivity despite the use of
Grignard reagent. Natural-product-derived compounds, in-
cluding 3-iodocholestene, cholestenyl-6-iodohexanoate,
and menthyl-6-iodohexanoate (Table 3, entries 1–3), were
also coupled in moderate to good yields.
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Table 2 Cross-Coupling Reaction of Alkyl Halides with Phenyl Grignard
1d (5 mol%)
Entry Halide
Product
Yield (%)a
I
Ph
O
+
PhMgCl
R
Ph
R
X
THF
R = alkyl
X = Br, I
(1.0 equiv)
r.t., 1 h
11
92e
O
Entry Halide
Product
Yield (%)a
F
F
92b,c
82c
I
Ph
1
I
Ph
6
6
12
71f
COOEt
COOEt
I
Ph
2
83
N
N
I
Ph
3
3
13
88
N
N
O
Br
O
Ph
Boc
Boc
3
4
68
83
3
3
O
O
Bn
Bn
O
O
O
O
14
65
N
N
O
Ph
O
5 I
5
I
Ph
a Isolated yields at 100% conversion.
b Reaction at –40 °C.
MeO
MeO
c Catalyst 1b was used.
5
6
98
57
d Starting material recovered: 25%.
Br
Ph
e Mixture of diastereoisomers: 66:34 (dr for RX = 91:9).
f Mixture of diastereoisomers: 52:48 (dr for RX = 81:19).
Br
Ph
Having demonstrated the catalytic efficiency of this
iron-pincer system, the enantioselective C–C coupling reac-
tions were studied. Three different substrates were chosen
(Table 4) and the reaction was performed at the previously
optimized conditions using the chiral iron precatalysts.
These substrates were chosen because the two enantiomers
of the products could be readily separated by chiral HPLC,
and because previous report showed that the phenyl group
could be an effective directing group in nickel-catalyzed en-
antioselective alkyl–alkyl coupling.11 When the phenyl
group is at the β-position of the alkyl iodide, nearly no en-
antioselectivity was obtained for all four iron catalysts (Ta-
ble 4, entries 1–4). More encouraging results were obtained
for substrates with a phenyl group at the α-position of the
alkyl halide. The tert-butyl-substituted bopa ligand gave
the highest enantiomeric excess (ee), in the range of 15–
20%. Although only low enantiomeric excesses were ob-
tained in these experiments, the results demonstrate that a
bopa-based ligand system is capable of inducing enantiose-
lectivity. They also confirm the homogenous nature of the
iron catalysis.
O
O
57
I
Ph
7
(25)d
N
N
3
3
X
Ph
95b,c (X = I)
88c (X = I)
93c (X = Br)
8
9
90
75
I
Ph
MeO
I
MeO
Ph
10
O
O
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Synthesis
Table 3 Cross-Coupling of Natural-Product-Derived Compounds with Phenyl Grignard
1d (5 mol%)
+
R
Ph
PhMgCl
R
X
THF
r.t., 1 h
R = alkyl
X = Br, I
(1.0 equiv)
Entry
Halide
Product
Yield (%)a
O
O
1
83
O
O
4
4
I
Ph
3
3
2
53
H
H
I
Ph
3
3
3
85
H
H
O
O
O
O
4
4
I
Ph
a Isolated yields at 100% conversion.
b Mixture of stereoisomers: 81:19 (dr for RX = 100:0).
To conclude, we have found an iron-complex system
that allows the coupling of nonactivated and functionalized
alkyl halides with phenyl Grignard reagents. The coupling is
rapid and tolerates a wide range of different functional
groups. Naturally derived compounds could be coupled in
high chemoselectivity. Enantioselectivity, albeit low, is
demonstrated.
sieves (3 Å). (S)-2-Amino-3,3-dimethylbutan-1-ol (L-tert-leucinol)
was purchased from TCI. The following chemicals were synthesized:
2,2′-iminodibenzoic acid,12 (S)-(+)-2-amino-3-methylbutan-1-ol (L-
valinol),13 (R)-(–)-phenylglycinol,13 L-(–)-2-amino-3-phenylpropan-
1-ol (L-phenylalaninol),13 2,2′-iminodibenzoyl chloride,14 Bopa-R
(R = i-Pr, Ph, Bn, t-Bu),14 and [Fe(Bopa-R)Cl2] (R = i-Pr, Ph, Bn, t-
Bu),14,15 All known primary and secondary halides were either com-
mercially available or prepared according to the literature proce-
dures.4,16
NMR spectra were recorded on a Bruker Avance 400 spectrometer. 1H
NMR chemical shifts were referenced to TMS (δ = 0) or the residual
solvent peak (abbreviation ovrlp: overlapping signals). GC measure-
ments were conducted on a PerkinElmer Clarus 400 GC equipped
with an FI-detector. GC-MS measurements were conducted on an
Agilent 7980A GC equipped with Agilent 5975C MS and an FI-detec-
tor.
All manipulations were carried out under an inert N2 atmosphere us-
ing standard Schlenk or glove box techniques. The solvents were puri-
fied and dried using a two column solid-state purification system (In-
novative Technology, NJ, USA). They were transferred to the glove box
in a Strauss-flask without exposure to air. The solvents were stored
over molecular sieves (3 Å). CDCl3 was purchased from Armar Chemi-
cals, and was degassed and stored over dried and activated molecular
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G. Bauer et al.
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Synthesis
Table 4 Enantiomeric Excess in the Cross-Coupling of Alkyl Iodides
with Phenyl Grignard in the Presence of 5 mol% 1
(3S,8S,9S,10R,13R,14S,17R)-10,13-Dimethyl-17-[(R)-6-methylhep-
tan-2-yl]-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-
cyclopenta[a]phenanthren-3-yl 6-Iodohexanoate (Table 3, Entry
3)
1 (5 mol%)
+ 4-MeOC6H4MgCl
R
X
4-MeOC6H4
R
Following the general procedure, 6-bromohexanoic acid (1.95 g, 10
mmol), cholesterol (4.25 g, 11 mmol), DCC (2.06 g, 10 mmol), DMAP
(24 mg, 0.20 mmol), and NaI (7.50 g, 50 mmol) were used to prepare
the title product; yield: 4.28 g (7.01 mmol, 70%); white powder.
1H NMR (400 MHz, CDCl3): δ = 5.37 (d, J = 4.7 Hz, 1 H), 4.66–4.57 (m, 1
H), 3.19 (t, J = 7.0 Hz, 2 H), 2.32–2.27 (ovrlp, 4 H), 2.04–1.93 (ovrlp, 2
H), 1.90–1.81 (ovrlp, 5 H), 1.68–1.24 (m, 16 H), 1.19–0.94 (ovrlp, 12
H), 0.91 (d, J = 6.5 Hz, 3 H), 0.87–0.85 (ovrlp, 6 H), 0.68 (s, 3 H).
THF
–40 °C, 15 min
Entry Substrate
Product
4-MeOC6H4
Ph
Catalyst Yield (%)a ee (%)
1
2
3
1a
1b
1c
1d
83
>95
73
0
1
1
3
I
Ph
4
77
13C NMR (100 MHz, CDCl3): δ = 172.9, 139.7, 122.7, 74.0, 56.8, 56.2,
50.1, 42.4, 39.8, 39.6, 38.3, 37.1, 36.7, 36.3, 35.9, 34.5, 33.2, 32.01,
31.95, 30.0, 28.3, 28.1, 27.9, 24.4, 24.1, 23.9, 23.0, 22.7, 21.1, 19.4,
18.8, 12.0, 6.7.
5
1a
1b
1c
1d
84
92
94
7
3
5
6
7
8
Ph
Ph
Ph
4-MeOC6H4
I
I
>95
19
9
10
11
12
1a
1b
1c
1d
88
86
86
71
8
13
8
Ph
Screening of Coupling Reactions (Tables 1 and 4); General Proce-
dure
4-MeOC6H4
16
a Yields were determined by GC (dodecane as internal standard; conversion
100%).
Alkyl halide (0.5 mmol) and dodecane (60 μL) were dissolved in THF
(3.0 mL) and a stock solution of [Fe(Bopa-R)Cl2] 1 (25 mM, 1.0 mL)
was added. The solution was brought to the corresponding tempera-
ture and PhMgCl (1.85 M in THF, 0.3 mL) was added over a time peri-
od of 5 min. The reaction mixture stirred for another 10 min and was
quenched with H2O (20 mL). The solution was acidified with aq 1 M
HCl and extracted with CH2Cl2 (3 × 20 mL). The crude extract was
dried (Na2SO4) and analyzed by GC. The solvent was then further
evaporated and the product was purified for HPLC measurement by
chromatography on silica gel (0 to 1% EtOAc in hexanes).
The Grignard reagents were titrated prior to every use following the
literature procedure.17
Primary Alkyl Iodides (Table 3, Entries 1 and 2); General Proce-
dure
A 250 mL conical flask equipped with a Teflon-coated magnetic stir-
rer was charged with 6-bromohexanoic acid (1.0 equiv), natural prod-
uct alcohol (1.1 equiv), N,N′-dicyclohexylcarbodiimide (DCC, 1.0
equiv), 4-dimethylaminopyridine (DMAP, 2 mol%), and CH2Cl2 (100
mL). The reaction mixture was stirred at r.t. overnight. The mixture
was then filtered, and the filtrate was washed with aq ~1 M HCl (~100
mL). The organic fraction was dried in vacuo to give a crude alkyl bro-
mide, which was introduced into a 250 mL round-bottomed flask
equipped with a Teflon-coated magnetic stirrer, followed by the addi-
tion of NaI (5 equiv), acetone (50 mL), and H2O (5 mL). The reaction
mixture was then heated at 60 °C until all alkyl bromide was con-
sumed as determined by GC analysis. After cooling to r.t., the mixture
was concentrated in vacuo, and the residue was partitioned between
CH2Cl2 (50 mL) and H2O (100 mL). The aqueous solution was extracted
with CH2Cl2 (2 × 50 mL). The combined organic fractions were con-
centrated in vacuo, and the residue was purified by flash chromatog-
raphy on silica gel using a mixture of hexanes and EtOAc as an eluent
to afford the respective alkyl iodide.
Substrate Scope of Coupling Reactions (Tables 2 and 3); General
Procedure
Alkyl halide (Method A: 0.5 mmol, Method B: 0.25 mmol) was dis-
solved in THF [3.0 mL (A)/1.5 mL (B)] and a stock solution (25 mM) of
[Fe(Bopa-tBu)Cl2] (1d) [1.0 mL (A)/0.5 mL (B)] was added. Afterwards
PhMgCl (1.00 M) [0.5 mL (A)/0.25 mL (B)] was added over a time peri-
od of 15 min. The solution was stirred for another 45 min. Method A:
The reaction was then quenched with H2O (20 mL), acidified with aq
1 M HCl, and extracted with CH2Cl2 (3 × 20 mL). The crude extract was
dried (Na2SO4) and further purified by chromatography on silica gel
(eluent: 1% to 45% EtOAc in hexanes). Method B: The reaction was
quenched by adding EtOH (0.5 mL). The reaction mixture was trans-
ferred on a preparative TLC plate and then further separated (eluent:
EtOAc–hexanes).
1-Phenyloctane (Table 2, Entry 1)18
Method A: yield at r.t.: 78 mg (82%), at –40 °C: 87 mg (92%); colorless
liquid.
1H NMR (400 MHz, CDCl3): δ = 7.32–7.28 (m, 2 H), 7.23–7.17 (m, 3 H),
2.63 (t, J = 7.8 Hz, 2 H), 1.64 (quint, J = 6.0 Hz, 2 H), 1.39–1.29 (m, 10
H), 0.91 (t, J = 6.9 Hz, 3 H).
2-Isopropyl-4-methylcyclohexyl 6-Iodohexanoate (Table 3, Entry
1)
Following the general procedure, 6-bromohexanoic acid (2.54 g, 13
mmol), (±)-menthol (2.24 g, 14.3 mmol), DCC (2.68 g, 13 mmol),
DMAP (32 mg, 0.20 mmol), and NaI (9.74 g, 65 mmol) were used to
prepare the title product; yield: 2.43 g 6.39 mmol, 49%); yellow liquid.
9-(3-Phenylpropyl)-9H-carbazole (Table 2, Entry 2)16
Method A: yield: 118 mg (83%); white solid; mp 110–112 °C.
1H NMR (400 MHz, CDCl3): δ = 4.64–4.58 (m, 1 H), 3.11 (t, J = 7.0 Hz, 2
H), 2.23 (t, J = 7.5 Hz, 2 H), 1.94–1.88 (m, 1 H), 1.84–1.74 (ovrlp, 3 H),
1.63–1.54 (ovrlp, 4 H), 1.47–1.33 (ovrlp, 4 H), 1.04–0.78 (ovrlp, 9 H),
0.69 (d, J = 6.8 Hz, 3 H).
1H NMR (400 MHz, CDCl3): δ = 8.10 (d, J = 7.7 Hz, 2 H), 7.63–7.38 (m, 3
H), 7.38–7.11 (m, 10 H), 4.33 (t, J = 7.3 Hz, 2 H), 2.72 (t, J = 7.7 Hz, 2 H),
2.23 (quint, J = 7.5 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 172.7, 73.8, 46.9, 40.9, 34.3, 34.2, 33.1,
31.3, 29.9, 26.2, 23.9, 23.3, 22.0, 20.7, 16.3, 6.4.
(3-Phenoxypropyl)benzene (Table 2, Entry 3)16
Method B: yield: 36 mg (68%); yellow oil.
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Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.37–7.12 (m, 7 H), 6.95–6.85 (m, 3 H),
3.97 (t, J = 6.1 Hz, 2 H), 2.82 (t, J = 7.5 Hz, 2 H), 2.13 (quint, J = 6.9 Hz, 2
H).
13C NMR (101 MHz, CDCl3): δ (mixture of stereoisomers) =128.59,
128.57, 128.09 (d, J = 8.0 Hz), 127.48 (d, J = 8.0 Hz), 127.15, 126.73,
126.45, 126.23, 115.30 (d, J = 21.2 Hz), 115.13 (d, J = 21.3 Hz), 79.29,
73.45, 68.71, 62.81, 42.07, 41.52, 35.93, 35.46, 33.26, 32.12.
5-Phenylpentyl Acetate (Table 2, Entry 4)19
Ethyl 3-Phenylcyclohexanecarboxylate (Table 2, Entry 12)
Method A: yield: 86 mg (83%); yellow oil.
Method A: yield: 82 mg (71%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.35–7.24 (m, 2 H), 7.15–7.21 (m, 3 H),
4.05 (t, J = 6.7 Hz, 2 H), 2.62 (t, J = 7.7 Hz, 2 H), 2.03 (s, 3 H), 1.45
(quint, J = 7.5 Hz, 4 H), 1.40 (quint, J = 7.6 Hz, 2 H).
1H NMR (400 MHz, CDCl3): δ (mixture of cis- and trans-isomers) =
7.43–7.12 (m, 5 H), 4.34–4.03 (m, 2 H), 2.85–1.40 (m, 10 H), 1.38–1.23
(m, 3 H).
1-Methoxy-4-(2-phenethyl)benzene (Table 2, Entry 5)20
13C NMR (101 MHz, CDCl3): δ (mixture of cis- and trans-isomers) =
175.72, 175.12, 146.90, 146.65, 128.40, 128.33, 126.86, 126.80,
126.15, 125.94, 60.21, 60.19, 43.86, 43.67, 39.90, 39.75, 36.45, 34.86,
33.49, 33.26, 28.57, 27.20, 25.87, 23.02, 14.34, 14.24.
Method A: yield: 104 mg (98%); white solid; mp 58–60 °C.
1H NMR (400 MHz, CDCl3): δ = 7.30–7.26 (m, 2 H), 7.22–7.15 (m, 3 H),
7.11–7.06 (m, 2 H), 6.85–6.78 (m, 2 H), 3.79 (s, 3 H), 2.92–2.82 (m, 4
H).
HRMS (APCI): m/z [M + H]+ calcd for [C15H21O2]+: 233.1542; found:
233.1544.
1,2-Diphenylethane (Table 2, Entry 6)21
tert-Butyl 4-Phenylpiperidine-1-carboxylate (Table 2, Entry 13)21
Method A: yield: 52 mg (57%); colorless oil.
Method A: yield: 115 mg (88%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.35–7.29 (m, 4 H), 7.27–7.19 (m, 6 H),
2.95 (s, 4 H).
1H NMR (400 MHz, CDCl3): δ = 7.30 (m, 2 H), 7.25–7.16 (m, 3 H), 4.24
(dd, J = 9.6, 8.0 Hz, 2 H), 2.80 (t, J = 12.1 Hz, 2 H), 2.64 (tt, J = 12.1, 3.5
Hz, 1 H), 1.82 (m, 2 H), 1.64 (m, 2 H), 1.48 (s, 9 H).
1-[1-(3-Phenylpropyl)-1H-pyrrol-2-yl]ethanone (Table 2, Entry 7)21
Method B: yield: 32 mg (57%); yellow oil.
Benzyl 3-Phenylazetidine-1-carboxylate (Table 2, Entry 14)
1H NMR (400 MHz, CDCl3): δ = 7.33–7.28 (m, 2 H), 7.24–7.16 (m, 3 H),
6.99 (dd, J = 4.1, 1.7 Hz, 1 H), 6.85 (dd, J = 2.4, 1.8 Hz, 1 H), 6.15 (dd, J =
4.1, 2.5 Hz, 1 H), 4.36 (t, J = 7.2 Hz, 2 H), 2.69–2.61 (t, J = 7.8 Hz, 2 H),
2.46 (s, 3 H), 2.10 (quint, J = 7.5 Hz, 2 H).
Method A: yield: 87 mg (65%); light yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.45–7.26 (m, 10 H), 5.15 (d, J = 13.9
Hz, 2 H), 4.44 (t, J = 8.8 Hz, 2 H), 4.10 (dd, J = 8.8, 6.1 Hz, 2 H), 3.82
(ddt, J = 12.3, 8.8, 6.1 Hz, 1 H).
1,3-Diphenylbutane (Table 2, Entry 8)22
13C NMR (101 MHz, CDCl3): δ = 142.17, 137.01, 129.09, 128.79,
128.35, 128.30, 127.41, 127.03, 66.99, 34.24, 0.31.
HRMS (ESI): m/z [M + Na]+ calcd for [C17H17NO2 + Na]+: 290.1157;
Method A: for X = Br, yield at r.t.: 98 mg (93%); for X = I, yield at r.t.: 86
mg (88%), at –40 °C: 100 mg (95%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.42–7.13 (m, 10 H), 2.75 (hext, J = 7.1
found: 290.1170.
Hz, 1 H), 2.61–2.47 (m, 2 H), 2.02–1.86 (m, 2 H), 1.31 (d, J = 7.0 Hz, 3
H).
Menthyl 6-Phenylhexanoate (Table 3, Entry 1)
Method B: yield: 66 mg (83%); colorless oil.
1-Methoxy-4-(2-phenylpropyl)benzene (Table 2, Entry 9)22
1H NMR (400 MHz, CDCl3): δ = 7.43–7.05 (m, 5 H), 4.67 (td, J = 10.9,
4.3 Hz, 1 H), 2.72–2.50 (m, 2 H), 2.28 (t, J = 7.5 Hz, 2 H), 2.03–1.81 (m,
2 H), 1.67–1.24 (m, 10 H), 0.86 (ddd, J = 56.1, 27.3, 7.2 Hz, 12 H).
13C NMR (101 MHz, CDCl3): δ = 173.37, 142.55, 128.39, 128.28,
125.68, 73.93, 47.03, 40.96, 35.80, 34.67, 34.29, 31.39, 31.14, 28.79,
26.27, 25.01, 23.42, 22.06, 20.79, 16.31.
Method A: yield: 102 mg (90%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.34–7.23 (m, 2 H), 7.23–7.11 (m, 3 H),
6.98 (d, J = 8.7 Hz, 2 H), 6.77 (d, J = 8.7 Hz, 2 H), 3.77 (s, 3 H), 3.01–2.83
(m, 2 H), 2.71 (dd, J = 13.3, 8.1 Hz, 1 H), 1.23 (d, J = 6.8 Hz, 3 H).
4-Phenyltetrahydro-2H-pyran (Table 2, Entry 10)23
HRMS (APCI): m/z [M + Na]+ calcd for [C22H34O2 + Na]+: 353.2457;
Method A: yield: 61 mg (75%); white solid; mp 42–44 °C.
found: 353.2447.
1H NMR (400 MHz, CDCl3): δ = 7.40–7.20 (m, 5 H), 4.15–4.07 (m, 2 H),
3.56 (td, J = 11.5, 2.7 Hz, 2 H), 2.78 (tt, J = 11.5, 4.4 Hz, 1 H), 1.94–1.75
(m, 4 H).
3-Phenylcholest-5-ene (Table 3, Entry 2)25
Method B: yield: 59 mg (53%); white solid; mp 126–129 °C.
1H NMR (400 MHz, CDCl3): δ = 7.40–7.12 (m, 5 H), 5.45 (s, 0.2 H), 5.35
(d, J = 4.7 Hz, 0.8 H), 2.52–2.52 (m, 2 H), 2.06–1.94 (m, 3 H), 1.87–1.70
(m, 4 H), 1.61–1.34 (m, 12 H), 1.17–1.00 (m, 14 H), 0.94–0.90 (m, 3 H),
0.87 (dd, J = 6.5, 1.7 Hz, 6 H), 0.69 (d, J = 8.6 Hz, 3 H).
2-(4-Fluorophenyl)-4-phenyltetrahydro-2H-pyran (Table 2, Entry
11)24
Method A: yield: 118 mg (92%); yellow oil.
1H NMR (400 MHz, CDCl3): δ (mixture of stereoisomers) = 7.4 –7.31
(m, 14 H), 7.27–7.14 (m, 11 H), 7.11–6.95 (m, 7 H), 4.91 (t, J = 5.0 Hz, 1
H), 4.47 (dd, J = 11.2, 2.0 Hz, 2 H), 4.34–4.25 (m, 2 H), 3.89–3.71 (m, 5
H), 3.11–3.02 (m, 1 H), 2.96 (ddd, J = 16.0, 10.2, 3.9 Hz, 2 H), 2.39–2.23
(m, 3 H), 2.06–2.02 (m, 2 H), 1.97–1.81 (m, 5 H), 1.80–1.67 (m, 2 H),
1.28–1.20 (m, 2 H).
HRMS (APCI): m/z [M + H]+ calcd for [C33H51]+: 447.3985; found:
447.3988.
3-Cholest-5-enyl 6-Phenylhexanoate (Table 3, Entry 3)
Method B: yield: 119 mg (85%); yellowish oil.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1726–1732

1732
G. Bauer et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.32–7.20 (m, 2 H), 7.11–7.18 (m, 3 H),
5.30 (m, 1 H), 4.64–4.57 (dt, J = 15.5, 7.5 Hz, 1 H), 2.60 (t, J = 7.6 Hz, 2
H), 2.27 (dd, J = 15.1, 7.7 Hz, 4 H), 2.02–1.95 (t, J = 15.7 Hz, 2 H), 1.89–
1.78 (m, 3 H), 1.69–1.43 (m, 12 H), 1.39–1.25 (m, 8 H), 1.17–1.06 (m, 6
H), 1.01 (s, 3 H), 0.92 (d, J = 6.1 Hz, 3 H), 0.89–0.82 (m, 6 H), 0.66 (s, 4
H).
Weinheim, 2008, 147–176. (d) Fürstner, A.; Martin, R. Chem.
Lett. 2005, 34, 624. (e) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L.
Chem. Rev. 2004, 104, 6217.
(4) Cheung, C. W.; Ren, P.; Hu, X. Org. Lett. 2014, 16, 2566.
(5) Nakamura, M.; Matsuo, K.; Ito, S.; Nakamura, E. J. Am. Chem. Soc.
2004, 126, 3686.
(6) Nagano, T.; Hayashi, T. Org. Lett. 2004, 6, 1297.
(7) Martin, R.; Fürstner, A. Angew. Chem. Int. Ed. 2004, 43, 3955.
(8) (a) Bedford, R. B.; Bruce, D. W.; Frost, R. M.; Hird, M. Chem.
Commun. 2005, 4161. (b) Bedford, R. B.; Betham, M.; Bruce, D.
W.; Danopoulos, A. A.; Frost, R. M.; Hird, M. J. Org. Chem. 2005,
71, 1104.
13C NMR (101 MHz, CDCl3): δ = 173.25, 142.60, 139.77, 128.48,
128.36, 125.75, 122.70, 73.81, 56.79, 56.24, 50.12, 42.42, 39.84, 39.64,
38.26, 37.11, 36.70, 36.30, 35.92, 35.85, 34.71, 32.02, 31.97, 31.22,
28.82, 28.36, 28.14, 27.91, 25.03, 24.41, 23.96, 22.96, 22.70, 21.15,
19.45, 18.84, 11.98.
HRMS (ESI): m/z [M + K]+ calcd for [C39H60O2 + K]+: 599.4230; found:
599.4226
(9) Bedford, R. B.; Bruce, D. W.; Frost, R. M.; Goodby, J. W.; Hird, M.
Chem. Commun. 2004, 2822.
(10) Bedford, R. B.; Betham, M.; Bruce, D. W.; Davis, S. A.; Frost, R. M.;
Hird, M. Chem. Commun. 2006, 1398.
(11) Saito, B.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 6694.
(12) Paul, A.; Ladame, S. Org. Lett. 2009, 11, 4894.
(13) McKennon, M. J.; Meyers, A. I.; Drauz, K.; Schwarm, M. J. Org.
Chem. 1993, 58, 3568.
Acknowledgment
This work is supported by a European Research Council starting grant
(No. 257096).
(14) See the experimental section.
(15) Inagaki, T.; Phong, L. T.; Furuta, A.; Ito, J.-i.; Nishiyama, H. Chem.
Eur. J. 2010, 16, 3090.
Supporting Information
(16) Di Franco, T.; Boutin, N.; Hu, X. Synthesis 2013, 45, 2949.
(17) Love, B. E.; Jones, E. G. J. Org. Chem. 1999, 64, 3755.
(18) Matsubara, K.; Ishibashi, T.; Koga, Y. Org. Lett. 2009, 11, 1765.
(19) Lee, J.-Y.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 5616.
(20) Dreher, S. D.; Lim, S.-E.; Sandrock, D. L.; Molander, G. A. J. Org.
Chem. 2009, 74, 3626.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380136.
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References
(21) Vechorkin, O.; Proust, V.; Hu, X. J. Am. Chem. Soc. 2009, 131,
9756.
(22) Denmark, S. E.; Cresswell, A. J. J. Org. Chem. 2013, 78, 12593.
(23) Aikawa, H.; Tago, S.; Umetsu, K.; Haginiwa, N.; Asao, N. Tetrahe-
dron 2009, 65, 1774.
(1) Frisch, A. C.; Beller, M. Angew. Chem. Int. Ed. 2005, 44, 674.
(2) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111, 1417.
(3) (a) Sherry, B. D.; Fürstner, A. Acc. Chem. Res. 2008, 41, 1500.
(b) Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48,
2656. (c) Leitner, A. Iron-Catalyzed Cross-Coupling Reactions, In
Iron Catalysis in Organic Chemistry; Plietker, B., Ed.; Wiley-VCH:
(24) Reddy, U. C.; Bondalapati, S.; Saikia, A. K. J. Org. Chem. 2009, 74,
2605.
(25) Li, L.-J.; Lu, B.; Li, T.-S.; Li, J.-T. Synth. Commun. 1998, 28, 1439.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1726–1732