Atroposelective radical aryl migration reactions from sulfur to carbon

Article abstract of DOI:10.1016/j.tet.2008.08.111

The paper describes stereoselective radical aryl migration reactions from sulfur in sulfonates to aryl radicals for the synthesis of axially chiral biaryls. A chirality center in secondary benzylic sulfonates is used to diastereoselectively (atroposelectively) install a stereogenic axis via a 1,5 aryl migration reaction. Atroposelectivity has not been investigated in stereoselective radical chemistry before. Good yields (53-82%) but low selectivities (up to 2 to 1) were obtained.

Full text of DOI:10.1016/j.tet.2008.08.111

Tetrahedron 64 (2008) 11852–11859
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Atroposelective radical aryl migration reactions from sulfur to carbon
y
*
Birte Schulte, Roland Fro¨hlich , Armido Studer
Organisch-Chemisches Institut, Westfa¨lische Wilhelms-Universita¨t, Corrensstraße 40, 48149 Mu¨nster, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The paper describes stereoselective radical aryl migration reactions from sulfur in sulfonates to aryl
radicals for the synthesis of axially chiral biaryls. A chirality center in secondary benzylic sulfonates is
used to diastereoselectively (atroposelectively) install a stereogenic axis via a 1,5 aryl migration reaction.
Atroposelectivity has not been investigated in stereoselective radical chemistry before. Good yields (53–
82%) but low selectivities (up to 2 to 1) were obtained.
Received 30 May 2008
Accepted 12 August 2008
Available online 20 September 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
NMe3$HCl as bases.14,15 The syntheses of 1–6 are described in
(Scheme 2) Section 3.
Functionalized biaryls are often used as ligands in catalytic
asymmetric synthesis.1 Moreover, biaryls occur in many natural
products2 and they are also found as components in new organic
materials.3,4 Biaryls are most often prepared by using transition
metals to couple the two arene subunits.1,5 In addition, radical
chemistry has been successfully used for biaryl synthesis. In pio-
neering studies Motherwell showed that biaryls can be prepared
via 1,4 as well as 1,5 aryl migration reactions from sulfur to aryl
radicals (Scheme 1).6–8 Readily available arenesulfonates as well as
arenesulfonamides were used as starting materials in these re-
actions. Radical biaryl synthesis was also achieved via aryl migra-
tion from phosphorous to aryl radicals in phosphonates9 and from
silicon to aryl radicals in phenylsilylethers.10 Importantly, radical
aryl migration from sulfur11 or silicon12 to secondary alkyl radicals
was used for stereoselective C(sp2)–C(sp3)-bond formation. To the
best of our knowledge radical aryl migration has not been applied
to stereoselectively synthesize axially chiral biaryls.1b,13 We as-
sumed that the chirality center in secondary benzylic sulfonates
might be used to diastereoselectively (atroposelectively) install
a stereogenic axis via a 1,5 aryl migration reaction (see Scheme 1).
Herein we present first results on atroposelective radical aryl mi-
gration reactions from sulfur to aryl radicals.
Radical aryl migrations were best conducted by slow addition
(syringe pump, 7 h) of a benzene solution of Bu3SnH (1.5 equiv) and
V-40 (1,10-azobis(cyclohexane-1-carbonitrile), 1.0 equiv) to a solu-
tion of the arenesulfonate (8–13) in refluxing benzene (0.03 M) to
afford the corresponding aryl transfer products 14–18 in 53–84%
yield (Scheme 3, Table 1). Aryl transfer reaction with 8 under these
conditions gave the desired biaryls 14a and 14b in good yields with
moderate selectivity (14a: 30%, 14b: 54%). By using AIBN (a, -
a0
azobisisobutyrodinitrile) as an initiator the aryl transfer products
were isolated in a slightly lower combined yield with the same
selectivity (14a: 24%, 14b: 43%). We also ran the reaction at rt by
using Et3B/O2 as an initiator under otherwise identical conditions.
However, selectivity was not improved (14a/14b¼1:1.8) and
a slightly lower combined yield was obtained (50%). Importantly,
the two diastereoisomers were readily separated by flash chro-
matography (SiO2). The relative configuration of 14a and 14b was
O
S
R
O
X
R
XH
Bu3SnH, AIBN
I
benzene, reflux
[6]
X = O, NR'
2. Results and discussion
R1
R1
O
S
O O
Radical precursors 8–13 were readily prepared in good yields
(60–82%) from the corresponding secondary benzylic alcohols 1–6
and sulfonyl chloride 7 in CH2Cl2 by using NEt3 in combination with
HO
R2
this work
X
OMe
OMe
R2
X = I, Br
Scheme 1. Radical aryl migration for the preparation of biaryls.
* Corresponding author. Tel.: þ49 (0)251 8333291; fax: þ49 (0)251 8336523.
E-mail address: studer@uni-muenster.de (A. Studer).
y
X-ray structure analysis.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.08.111

B. Schulte et al. / Tetrahedron 64 (2008) 11852–11859
11853
C15
C14
R1
OH
R1
O
S
.
C16
NMe3 HCl
X
O O
C13
C18
NEt3, rt
CH2Cl2
X
OMe
Cl
+
S
C6
C7
R2
O O
C17
R2
R3
1-6
OMe
C5
R3
7
8-13
C12
C9
C10
C8
C4
1, 8 (R1 = Me, R2 = R3 = H, X = Br)
2, 9 (R1 = Me, R2 = R3 = H, X = I)
3, 10 (R1 = R2 = Me, R3 = H, X = Br)
4, 11 (R1 = Me, R2 = H, R3 = F, X = Br)
5, 12 (R1 = Me, R2 = H, R3 = CO2Me, X = Br)
6, 13 (R1 = i-Pr, R2 = R3 = H, X = Br)
8
(82%)
(66%)
C3
9
C11
10 (70%)
11 (65%)
12 (70%)
13 (60%)
O2
C2
O1
C19
C1
Scheme 2. Preparation of radical precursors 8–13.
14a
unambiguously assigned by X-ray analysis (Fig. 1).16 As expected,
reaction with iodide 9 under optimized conditions (Bu3SnH,
1.5 equiv; V-40, 1.0 equiv; benzene reflux) gave the same selectiv-
ity. The two diastereoisomers 14a and 14b were isolated in 20% and
36% yield, respectively. Reaction of 9 with (Me3Si)3SiH in benzene
in the presence of pyridine and catalytic amounts of I2 with
dioxygen as an initiator at rt did not result in product formation.17
C1
C15
O1
C14
C16
C13
C2
C8
C4
C6
C17
C3
C7
C18
C5
C9
C12
R1
O
S
O O
R1
C10
R1
HO
HO
C11
X
O2
OMe
+
OMe
OMe
R2
C19
R2
R2
R3
8-13
R3
14b-18b
R3
14a-18a
14b
Figure 1. Molecular structure of biaryls 14a and 14b.
Scheme 3. Atroposelective radical aryl migration. Conditions: Bu3SnH (1.5 equiv),
V-40 (1.0 equiv), syringe pump, 7 h, refluxing benzene. Only one enantiomer drawn.
For specification of R1, R2, and R3 see Scheme 2 and Table 1.
radical aryl migration reaction with sulfonate 10. Biaryls 15a and
15b were isolated in 21% and 32% yield, respectively. It is obvious
that a substituent in meta-position to the attacking radical should
not alter the selectivity to a large extent. In fact, the fluorinated
sulfonate 11 delivered the diastereoisomers 16a and 16b in a 1:2
atroposelectivity in 60% combined yield. A similar result was ach-
ieved with ester 12 (17a: 23%, 17b: 43%).
To improve atroposelectivity, we replaced the methyl group at
the benzylic position by a sterically more demanding isopropyl
group (/13). However, selectivity could not be improved. The two
isomers 18a and 18b were formed as a 1:1.8 mixture of di-
astereoisomers in 60% combined yield. The relative configuration of
18b was assigned by X-ray analysis (Fig. 2). Since the two isomers
a and b of 14 and 18 showed characteristic behavior during SiO2-
chromatography (isomer a eluted far faster than b), the relative
configuration of the isomers of all other products (15–17) was
assigned in analogy. The assignment of the relative configuration
was further supported by the characteristic chemical shifts of the
benzylic OH proton of the isomeric biaryls in the 1H NMR spectra.
To influence atroposelectivity, we also tested a system bearing
a methyl substituent at the ortho-position of the attacking aryl
radical. Disappointingly, an even lower selectivity was obtained for
C20
C13
C19
C12
C14
C18
C17
C15
C11
O1
C16
C10
C2
Table 1
C3
Diastereoselective radical aryl migration with sulfonates 8–13 (S.M.¼starting
C7
C9
C1
material)
C8
S.M.
R1
R2
R3
a (yield)
b (yield)
8
9
10
11
12
13
Me
Me
Me
Me
Me
i-Pr
H
H
Me
H
H
H
H
H
F
14a (30%)
14a (20%)
15a (21%)
16a (19%)
17a (23%)
18a (21%)
14b (54%)
14b (36%)
15b (32%)
16b (40%)
17b (43%)
18b (39%)
O2
C6
C4
C5
C21
18b
Figure 2. Molecular structure of biaryl 18b.
CO2Me
H
H

11854
B. Schulte et al. / Tetrahedron 64 (2008) 11852–11859
We suggest the following mechanism for the radical aryl mi-
a MKII Golden Gate Single Reflection ATR System. ESI-MS and HRMS
were performed using a Bruker MicroTof. We were not able to get
mass spectra of compounds 7–13. TLC was carried out on Merck
silica gel 60 F254 plates; detection by UV or dipping into a solution of
Ce(SO4)2$H2O (10 g), phosphormolybdic acid hydrate (25 g), concd
H2SO4 (60 mL) and H2O (0.94 L) or NaHCO3 (5.0 g), KMnO4 (1.5 g)
and H2O (0.20 L) followed by heating. Flash chromatography (FC)
gration reaction (Scheme 4). Aryl radical 19 undergoes intra-
molecular ipso attack at the naphthyl group of the sulfonate to form
a stabilized radical of type 20 (only one resonance structure
drawn). Since only moderate selectivities were obtained we do not
want to speculate about the low energy transition state for the
formation of the major isomer b. Rearomatization then affords the
alkoxysulfonyl radical 21, which is probably slowly reduced with tin
hydride to give 22.11b SO2 extrusion eventually leads to 23. Large
amounts of tin hydride (1.5 equiv) and V-40 (1.0 equiv) were nec-
essary in order to get quantitative conversion in these aryl migra-
tion reactions. We believe that the reduction of the alkoxysulfonyl
radical 21 with tin hydride is a very inefficient reaction that prob-
ably leads to chain termination. Moreover, compounds of type 22
can presumably also react with tin hydride in an ionic reaction
consuming additional tin hydride. As already observed for aryl
migration reactions to alkyl radicals, aryl transfers were not suc-
cessful with (Me3Si)3SiH as also observed in the present study for
aryl migrations to aryl radicals (see above). We believe that the
alkoxysulfonyl radical 21 is not reduced with (Me3Si)3SiH.
was carried out on Merck or Fluka silica gel 60 (40–63
argon pressure of about 0.1–0.5 bar.
mm) with an
3.2. General procedure (GP1) for the NaBH4 reduction
The acetophenone derivative was dissolved in ethanol and
cooled to 0 ꢀC. NaBH4 was added in one portion. The suspension
was stirred for 10 min at 0 ꢀC, then allowed to warm to rt and
stirred at that temperature for 12 h. After addition of satd aq NH4Cl
most of the ethanol was evaporated in vacuo. Diethylether was
added to the remaining solution, which was subsequently washed
with satd aq NH4Cl and brine. The organic phase was dried
(MgSO4), evaporated, and FC finally yielded the desired alcohol.
3.3. 1-(2-Bromophenyl)ethanol (1)
O
O
Prepared according to GP1 using 20-bromoacetophenone
(5.00 mL, 37.1 mmol), NaBH4 (5.60 g, 148 mmol, 4 equiv) in ethanol
(150 mL). Purification by FC (pentane/diethylether 8:1) afforded
1-(2-bromophenyl)ethanol (1, 7.32 g, 36.4 mmol, 98%) as a colorless
O
S
S
R1
R2
O
O
R1
R1
O
S
O
O O
MeO
OMe
O
oil. 1H NMR (300 MHz, CDCl3)
d
7.56 (dd, J¼7.7, 1.7 Hz, 1H, CHCBr),
R2
R2
7.49 (dd, J¼7.7, 1.2 Hz, 1H, CHCCBr), 7.32 (m, 1H, CHaryl), 7.11 (ddd,
20
21
19
J¼7.8, 7.5, 1.8 Hz, 1H, CHaryl), 5.20 (q, J¼6.3 Hz, 1H, CHOH), 2.66 (br s,
1H, OH),1.44 (d, J¼6.3 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3)
d
144.6
Bu3SnH
(C),132.4 (CH),128.5 (CH),127.7 (CH),126.6 (CH),121.5 (C), 68.9 (CH),
23.5 (CH3); IR (neat, cmꢁ1) 3323 br m, 2976 m,1568 m,1469 m,1429
m,1369 m,1199 m,1128 m,1091 s,1024 s,1005 s, 899 m, 752 s; HRMS
(ESI) calcd for [MþNa]þ: 222.9729; found: 222.9755; Anal. calcd for
C8H9BrO: C 47.79, H 4.51; found: C 47.76, H 4.53.
O
OH
R1
S
HO
R1
O
SO2
+
OMe
OMe
R2
R2
3.4. 1-(2-Iodophenyl)ethanol (2)
23
22
Scheme 4. Proposed mechanism of biaryl formation.
Prepared according to GP1 using 20-iodoacetophenone (0.30 mL,
2.1 mmol), NaBH4 (0.32 g, 8.5 mmol, 4 equiv) in ethanol (21 mL).
Purification by FC (pentane/diethylether 5:1) afforded 1-(2-iodo-
phenyl)ethanol (2, 0.52 g, 2.1 mmol, 99%) as a colorless oil. 1H NMR
In summary, we presented first examples on atroposelective
radical aryl migration reactions from sulfur in sulfonates to aryl rad-
icals. The starting sulfonates were readily prepared. Although the
present study was conducted with racemic sulfonates, enantiomeri-
cally pure radical precursor can be prepared from the corresponding
alcohols that are accessible via various methods. The aryl migration
reaction delivered the axially chiral biaryls in good yields. However,
only moderate atroposelectivity was achieved. It is important to note
that the two diastereoisomers formed were readily separated.
(300 MHz, CDCl3)
d
7.76 (d, J¼7.9 Hz, 1H, CHCI), 7.50 (dd, J¼7.8,
1.3 Hz, 1H, CHCCI), 7.34 (dd, J¼7.6, 7.5 Hz, 1H, CHaryl), 6.93 (ddd,
J¼7.7, 7.5, 1.3 Hz, 1H, CHaryl), 5.00 (q, J¼6.3 Hz, 1H, CHOH), 2.66 (m,
1H, OH), 1.39 (d, J¼6.3 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3)
d
147.4 (C), 139.0 (CH), 128.9 (CH), 128.5 (CH), 126.2 (CH), 97.0 (C),
73.4 (CH), 23.7 (CH3); IR (neat, cmꢁ1) 3320 br m, 2973 m, 1566 m,
1464 m, 1430 m, 1198 m, 1125 m, 1088 m, 1066 m, 1003 s, 898 m,
752 s; HRMS (ESI) calcd for [MþNa]þ: 270.9590; found: 270.9596;
Anal. calcd for C8H9IO: C 38.73, H 3.66; found: C 38.64, H 3.72.
3. Experimental section
3.1. General
3.5. 1-(2-Bromo-3-methylphenyl)ethanol (3)
All reactions involving air or moisture sensitive reagents or in-
termediates were carried out in heat gun dried glassware under an
argon atmosphere and were performed using standard Schlenk
techniques. All solvents for extraction and flash chromatography
were distilled before use. Acetic acid was purchased from Merck
and used as received.
To a solution of 2-bromo-3-methylbenzoic acid (0.50 g,
2.3 mmol) in methanol (6 mL) 2,2-dimethoxypropane (1.4 mL,
11 mmol, 5 equiv) and hydrochloric acid (12 M, 0.39 mL, 4.7 mmol,
2 equiv) were added. The reaction mixture was heated at reflux
over night, cooled and most of the solvent was removed in vacuo.
The residue was taken up in diethylether and washed with water.
The organic extract was dried over MgSO4 and evaporated to dry-
ness to give methyl 2-bromo-3-methylbenzoate (0.50 g, 2.2 mmol,
1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were recor-
ded on a Bruker DPX 300 (at 300 K) or a Varian Inova 500 (at 298 K)
spectrometer. Chemical shifts
the solvent residual peak or SiMe4
dard. IR spectra were recorded on a Digilab FTS 4000 equipped with
d
in parts per million are referenced to
94%). 1H NMR (300 MHz, CDCl3)
7.33 (d, J¼7.5 Hz, 1H, CHCCH3), 7.22 (dd, J¼7.5, 7.5 Hz, 1H, CHCHCH),
3.92 (s, 3H, OCH3), 2.44 (s, 3H, CH3).
d
7.45 (d, J¼7.5 Hz, 1H, CHCCO),
(d¼0 ppm) as an internal stan-

B. Schulte et al. / Tetrahedron 64 (2008) 11852–11859
11855
The methylester derivative (1.1 g, 4.8 mmol) was dissolved in
toluene (25 mL), cooled toꢁ78 ꢀC and diisobutylalumium hydride
(DIBAL, 1 M in heptane; 5.6 mL, 5.6 mmol, 1.2 equiv) was added via
syringe pump over 1 h. After additional stirring for 1 h atꢁ78 ꢀC the
reaction mixture was poured into a suspension of ice water and
dichloromethane and stirred for 30 min. The mixture was extracted
with diethylether (3ꢂ50 mL) and the combined organic layers were
washed with brine and dried (Na2SO4). The residue was purified by
FC (pentane/diethylether 20:1/6:1) to yield 2-bromo-3-methyl-
benzaldehyde (0.63 g, 3.2 mmol, 69%). 1H NMR (300 MHz, CDCl3)
To
a
solution of 3-bromo-4-ethylbenzoic acid (2.16 g,
9.48 mmol) in methanol (25 mL) 2,2-dimethoxypropane (5.8 mL,
47 mmol, 5 equiv) and hydrochloric acid (12 M, 1.6 mL, 19 mmol,
2 equiv) were added. The reaction mixture was heated at reflux
over night, cooled and most of the solvent was removed in vacuo.
The residue was taken up in diethylether and washed with water.
The organic extract was dried over MgSO4 and evaporated to dry-
ness to give methyl 3-bromo-4-ethylbenzoate (1.71 g, 7.07 mmol,
75%). 1H NMR (300 MHz, CDCl3)
d 8.18 (s, 1H, CHCCBr), 7.88 (dd,
J¼7.9, 1.2 Hz, 1H, CHaryl), 7.27 (d, J¼7.9 Hz, 1H, CHaryl), 3.90 (s, 3H,
OCH3), 2.78 (q, J¼7.5 Hz, 1H, CH2), 1.23 (t, J¼7.5 Hz, 1H, CH3).
According to a procedure reported by Wakselman19 the meth-
ylester derivative (1.71 mg, 7.07 mmol) was dissolved in acetic acid
(175 mL) and a solution of CrO3 (1 M; 1.77 g, 17.7 mmol, 2.5 equiv)
in acetic acid and water (95:5) was added dropwise via syringe
pump over 1 h. After being stirred at rt over night, the reaction
mixture was diluted with water (800 mL) and extracted with
diethylether (3ꢂ100 mL). The combined organic layers were
washed with satd aq NaOH, dried over MgSO4 and the solvent was
evaporated.
d
10.3 (s, 1H, CHO), 7.65 (ddd, J¼7.7, 1.9, 0.52 Hz, 1H, CHCCO), 7.40
(ddd, J¼7.5, 1.8, 0.60 Hz, 1H, CHCCH3), 7.25 (dd, J¼7.6, 7.6 Hz, 1H,
CHCHCH), 2.40 (s, 3H, CH3).
The aldehyde derivative (0.53 g, 2.7 mmol) was dissolved in
tetrahydrofuran (15 mL) and the solution was heated to 80 ꢀC.
MeMgCl (3.0 M in tetrahydrofuran; 1.4 mL, 4.1 mmol,1.5 equiv) was
added dropwise and the suspension was heated to reflux for an-
other 3 h. After cooling to rt, the reaction mixture was hydrolyzed
with satd aq NH4Cl and extracted with dichloromethane
(3ꢂ30 mL). The combined organic layers were dried over MgSO4
and the solvents were removed in vacuo. FC (pentane/diethylether
3:1) finally yielded 1-(2-bromo-3-methylphenyl)ethanol (3) as
a colorless oil (0.55 g, 2.6 mmol, 95%). 1H NMR (300 MHz, CDCl3)
Crude methyl 4-acetyl-3-bromobenzoate (1.61 g, 6.27 mmol)
was reduced according to GP1 using NaBH4 (308 mg, 8.15 mmol,
1.3 equiv) in methanol (56 mL). Purification by FC (pentane/diethyl-
ether 20:1/3:1) afforded methyl 3-bromo-4-(1-hydroxy-ethyl)-
benzoate (5) as a colorless oil (679 mg, 2.63 mmol, 37% over two
d
7.39 (br d, J¼7.7 Hz, 1H, CHaryl), 7.21 (dd, J¼7.6, 7.5 Hz, 1H, CHaryl),
7.13 (dd, J¼7.4, 1.2 Hz, 1H, CHaryl), 5.27 (q, J¼6.4 Hz, 1H, CHOH), 2.41
(s, 3H, CH3), 2.28 (br s, 1H, OH), 1.45 (d, J¼6.4 Hz, 3H, OCHCH3); 13
C
steps). 1H NMR (300 MHz, CDCl3)
d
8.14 (d, J¼1.6 Hz, 1H, CHCBr),
NMR (75 MHz, CDCl3)
d
145.1 (C), 138.3 (C), 129.6 (CH), 127.3 (CH),
7.96 (dd, J¼8.1, 1.6 Hz, 1H, CHCO2CH3), 7.66 (d, J¼7.81 Hz, 1H,
CHCCOH), 5.24 (q, J¼6.4 Hz, 1H, CHOH), 3.90 (s, 3H, OCH3), 2.33 (br
s, 1H, OH), 1.46 (d, J¼6.4 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3)
124.3 (C), 123.9 (CH), 69.5 (CH), 23.7 (CH3), 23.5 (CH3); IR (neat,
cmꢁ1) 3285 br m, 2971 m, 1445 m, 1410 m, 1367 m, 1331 m, 1267 m,
1107 s, 1061 s, 1009 s, 856 m, 775 s, 709 s; HRMS (ESI) calcd for
[MþNa]þ: 236.9885; found: 236.9888; Anal. calcd for C9H11BrO: C
50.26, H 5.22; found: C 50.33, H 5.22.
d
165.7 (C), 149.7 (C), 133.8 (CH), 130.5 (C), 128.9 (CH), 126.6 (CH),
121.3 (C), 69.1 (CH), 52.3 (CH3), 23.5 (CH3); IR (neat, cmꢁ1) 3395 br
m, 2976 m, 1724 s, 1707 s, 1560 m, 1435 m, 1390 m, 1285 s, 1254 s,
1198 m, 1099 m, 1038 m, 765 m; HRMS (ESI) calcd for [MþNa]þ:
280.9784; found: 280.9782; Anal. calcd for C10H11BrO3: C 46.36, H
4.28; found: C 46.59, H 4.48.
3.6. 1-(2-Bromo-4-fluorophenyl)ethanol (4)
Prepared according to GP1 using 20-bromo-40-fluoro-
acetophenone (0.50 g, 2.3 mmol), NaBH4 (0.35 g, 9.2 mmol,
4 equiv) in ethanol (20 mL). Purification by FC (pentane/diethyl-
ether 5:1) afforded 20-bromo-40-fluoroacetophenone (4) as a col-
3.8. 1-(2-Bromophenyl)-2-methylpropan-1-ol (6)
Isopropyl chloride (0.98 mL, 11 mmol, 1.3 equiv) was added
dropwise to a well-stirred suspension of magnesium turnings
(0.26 g, 11 mmol, 1.3 equiv) in anhydrous diethylether (20 mL). The
reaction mixture was stirred for 1 h and kept at reflux for 90 min.
2-Bromobenzaldehyde (1.0 mL, 8.5 mmol) was added dropwise and
the mixture was heated to reflux for another 3 h. After cooling to rt,
the reaction mixture was hydrolyzed with hydrochloric acid (6 M).
The organic layer was washed with satd aq NaHSO3, satd aq
NaHCO3 and water, dried over MgSO4 and the solvent was evapo-
rated in vacuo. The crude alcohol was purified by FC (pentane/
diethylether 8:1) to yield 1-(2-bromophenyl)-2-methylpropan-1-ol
(6) as a colorless oil (0.74 g, 3.3 mmol, 38%). 1H NMR (300 MHz,
orless oil (0.50 g, 2.3 mmol, 99%). 1H NMR (300 MHz, CDCl3)
d 7.50
(dd, J¼8.3, 6.4 Hz,1H, CHaryl), 7.22 (dd, J¼8.2, 2.4 Hz,1H, CHaryl), 7.02
(ddd, J¼8.2, 8.1, 2.4 Hz,1H, CHaryl), 5.14 (q, J¼6.3 Hz,1H, CHOH), 2.85
(br s, 1H, OH), 1.40 (d, J¼6.3 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3)
d
161.3 (d, 1J(C,F)¼250 Hz, C), 140.5 (d, 4J(C,F)¼3.4 Hz, C), 127.6 (d,
3J(C,F)¼8.4 Hz, CH), 121.3 (d, 3J(C,F)¼9.5 Hz, C), 119.61 (d,
2J(C,F)¼24.4 Hz, CH), 114.8 (d, 2J(C,F)¼20.8 Hz, CH), 68.5 (CH), 23.7
(CH3); IR (neat, cmꢁ1) 3348 br m, 2976 m, 1597 m, 1484 s, 1369 m,
1225 m, 1095 m, 1011 m, 869 m, 632 s; HRMS (ESI) calcd for
[MþNa]þ: 240.9635; found: 240.9624; Anal. calcd for C8H8BrFO: C
43.86, H 3.68; found: C 43.93, H 3.59.
CDCl3)
d
7.50 (d, J¼8.0 Hz, 1H, CHaryl), 7.46 (d, J¼7.8 Hz, 1H, CHaryl),
3.7. Methyl 3-bromo-4-(1-hydroxyethyl)benzoate (5)
7.30 (dd, J¼7.6, 7.5 Hz, 1H, CHaryl), 7.10 (m, 1H, CHaryl), 4.84 (q,
J¼5.9 Hz, 1H, CHOH), 2.39 (br s, 1H, OH), 2.03 (m, 1H, CH(CH3)2),
0.95 (d, J¼7.2 Hz, 3H, C(CH3)CH3), 0.93 (d, J¼7.0 Hz, 3H, C(CH3)CH3);
4-Ethylbenzoic acid (1.76 g, 11.7 mmol) was treated according to
a procedure reported by Fleifel18 with nitric acid (65%, 7.8 mL),
distilled water (5.9 mL), acetic acid (100%, 35 mL) and bromine
13C NMR (75 MHz, CDCl3)
d 142.9 (C), 132.5 (CH), 128.5 (CH), 128.2
(CH), 127.3 (CH), 122.6 (C), 77.4 (CH), 33.9 (CH), 19.4 (CH3), 16.8
(CH3); IR (neat, cmꢁ1) 3389 br m, 2966 m, 1467 m, 1436 m, 1099 m,
1003 s, 751 s; HRMS (ESI) calcd for [MþNa]þ: 251.0042; found:
251.022; Anal. calcd for C10H13BrO: C 52.42, H 5.72; found: C 52.56,
H 5.68.
(663 mL, 12.9 mmol, 1.1 equiv). A solution of AgNO3 (1.98 g,
11.7 mmol) in water (5.9 mL) was added via syringe pump over 1 h
and the reaction mixture was stirred for 3 h at rt. The suspension
was then poured into ice cold water and the precipitate was col-
lected. The solid residue, which consisted of the organic acid and
silver bromide, was treated with Na2CO3 and the silver bromide
was filtered off. The aqueous phase was acidified with hydrochloric
acid (12 M) and the precipitate formed was filtered off. The color-
less solid product 3-bromo-4-ethylbenzoic acid (2.56 g, 11.2 mmol,
96%) was dried and recrystallized from ethanol.
3.9. 2-Methoxynaphthalene-1-sulfonyl chloride (7)
A solution of chlorosulfonic acid (10.6 mL, 158 mmol, 2.5 equiv)
in dichloromethane (30 mL) was added to a solution of 2-
methoxynaphthalene (10.0 g, 63.2 mmol) in dichloromethane

11856
B. Schulte et al. / Tetrahedron 64 (2008) 11852–11859
(70 mL) atꢁ12 ꢀC over 1 h. The reaction was allowed to warm to
0 ꢀC and stirred at that temperature for 10 min. After warming to rt,
the reaction was stopped upon addition of ice cold water and the
aqueous layer was extracted with dichloromethane (3ꢂ100 mL).
The combined organic layers were dried over MgSO4 and evapo-
rated to dryness to afford the sulfonyl chloride 7 as a pale yellow
(2ꢂCH), 117.1 (C), 112.8 (CH), 95.8 (C), 83.7 (CH), 56.9 (CH3), 23.2
(CH3).
3.13. 1-(2-Bromo-3-methylphenyl)ethyl 2-methoxynaphthal-
ene-1-sulfonate (10)
solid (4.36 g, 17.0 mmol, 27%). 1H NMR (300 MHz, CDCl3)
d 8.94 (d,
According to GP2 1-(2-bromo-3-methylphenyl)ethanol (3,
150 mg, 0.701 mmol) was treated with NEt3 (146 mL, 1.05 mmol,
J¼8.8 Hz, 1H, CHaryl), 8.11 (d, J¼9.2 Hz, 1H, CHaryl), 7.81 (d, J¼8.1 Hz,
1H, CHaryl), 7.67 (ddd, J¼8.8, 7.0, 1.3 Hz, 1H, CHaryl), 7.47 (ddd, J¼8.1,
7.0, 1.0 Hz,1H, CHaryl), 7.32 (d, J¼9.2 Hz,1H, CHaryl), 4.14 (s, 3H, CH3);
1.5 equiv), NMe3$HCl (67 mg, 0.70 mmol), and 2-methoxynaph-
thalene-1-sulfonyl chloride (7, 269 mg, 1.05 mmol, 1.5 equiv) in
dichloromethane (7 mL). FC (pentane/diethylether 3:1/1:1; 1 vol
% NEt3) gave the sulfonate 10 as a colorless oil (213 mg, 0.492 mmol,
70%).
13C NMR (75 MHz, CDCl3)
d 159.0 (C), 139.0 (CH), 130.0 (CH), 129.4
(C), 129.0 (CH), 128.6 (C), 125.1 (CH), 123.2 (CH), 113.2 (CH), 57.5
(CH3). One quaternary carbon was not detected. IR (neat, cmꢁ1
)
1H NMR (300 MHz, CDCl3)
d
8.98 (d, J¼9.0 Hz,1H, CHaryl), 7.91 (d,
1509 m, 1468 m,1365 s, 1283 m, 1248 m, 1171 s,1153 s,1061 m, 1027
m, 811 s, 761 m, 748 m, 658 m; Anal. calcd for C11H9ClO3S: C 51.47, H
3.53; found: C 51.62, H 3.64.
J¼9.1 Hz, 1H, CHaryl), 7.71 (d, J¼8.1 Hz, 1H, CHaryl), 7.56 (ddd, J¼8.8,
6.9, 1.4 Hz, 1H, CHaryl), 7.38 (ddd, J¼7.8, 6.9, 0.9 Hz, 1H, CHaryl), 7.23
(m, 1H, CHaryl), 7.10 (d, J¼9.1 Hz, 1H, CHaryl), 7.00–6.93 (m, 2H,
CHaryl), 6.11 (q, J¼6.5 Hz, 1H, CHOSO2R), 3.88 (s, 3H, OCH3), 2.22 (s,
3H, CCH3), 1.56 (d, J¼6.5 Hz, 3H, CHCH3); 13C NMR (75 MHz, CDCl3)
3.10. General procedure (GP2) for the sulfonylation
According to a procedure reported by Tanabe14 the alcohol was
dissolved in dichloromethane and treated with NEt3 and
NMe3$HCl. The reaction mixture was cooled to 0 ꢀC and the sulfonyl
chloride was added slowly as a dichloromethane solution (0.5 mL
CH2Cl2). The reaction was stirred for 1 h at that temperature, was
then allowed to warm up to rt and stirred for additional 3 h at rt.
The reaction was stopped upon addition of water and the aqueous
layer was extracted with dichloromethane (three times). The
combined organic layers were washed with brine and dried over
MgSO4. The solvents were removed in vacuo and FC finally yielded
the desired sulfonate.
d
158.4 (C), 139.9 (C), 136.9 (C), 136.6 (CH), 131.1 (C), 130.0 (CH),
128.8 (CH), 128.7 (C), 128.4 (CH), 126.8 (CH), 125.0 (CH), 124.4 (CH),
124.3 (CH),123.4 (C),117.4 (C),112.9 (CH), 79.8 (CH), 56.9 (CH3), 23.5
(CH3), 23.0 (CH3).
3.14. 1-(2-Bromo-4-fluorophenyl)ethyl 2-methoxynaphthal-
ene-1-sulfonate (11)
According to GP2 1-(2-bromo-4-fluorophenyl)ethanol (4,
200 mg, 0.913 mmol) was treated with NEt3 (190 mL, 1.37 mmol,
1.5 equiv), NMe3$HCl (87 mg, 0.91 mmol), and 2-methoxynaph-
thalene-1-sulfonyl chloride (7, 351 mg, 1.37 mmol, 1.5 equiv) in
dichloromethane (10 mL). FC (pentane/diethylether 5:1/1:1; 1 vol
3.11. 1-(2-Bromophenyl)ethyl 2-methoxynaphthalene-1-
sulfonate (8)
%
NEt3) gave the sulfonate 11 as
a
colorless oil (260 mg,
0.594 mmol, 65%).
According to GP2 1-(2-bromophenyl)ethanol (1, 200 mg,
1.00 mmol) was treated with NEt3 (207 mL, 1.49 mmol, 1.5 equiv),
1H NMR (300 MHz, CDCl3)
d
8.83 (d, J¼8.6 Hz,1H, CHaryl), 7.81 (d,
J¼9.2 Hz, 1H, CHaryl), 7.60 (d, J¼8.1 Hz, 1H, CHaryl), 7.46 (m, 1H,
CHaryl), 7.33–7.16 (m, 2H, CHaryl), 7.02 (d, J¼9.2 Hz, 1H, CHaryl), 6.88
(dd, J¼8.2, 2.6 Hz, 1H, CHaryl), 6.67 (ddd, J¼8.5, 8.4, 2.6 Hz, 1H,
CHaryl), 5.87 (q, J¼6.5 Hz, 1H, CHOSO2R), 3.80 (s, 3H, OCH3), 1.44 (d,
NMe3$HCl (95 mg, 1.0 mmol), and 2-methoxynaphthalene-1-sul-
fonyl chloride (7, 382 mg, 1.49 mmol, 1.5 equiv) in dichloromethane
(9 mL). FC (pentane/diethylether 3:1; 1 vol % NEt3) gave the sulfo-
nate 8 as a colorless oil (345 mg, 0.821 mmol, 82%). 1H NMR
J¼6.5 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3)
d 161.4 (d,
(300 MHz, CDCl3)
d
8.98 (dd, J¼9.0, 0.7 Hz, 1H, CHaryl), 7.92 (d,
1J(C,F)¼251.6 Hz, C), 158.5 (C), 136.8 (CH), 135.5 (d, 4J(C,F)¼3.6 Hz,
C), 131.0 (CH), 130.1 (C), 129.0 (C), 128.9 (CH), 128.8 (CH), 128.6 (d,
3J(C,F)¼12.4 Hz, CH), 124.4 (d, 3J(C,F)¼11.7 Hz, C), 120.7 (C), 119.1 (d,
2J(C,F)¼24.5 Hz, CH), 117.2 (CH), 114.6 (d, 2J(C,F)¼21.3 Hz, CH), 112.8
(CH), 78.5 (CH), 57.0 (CH3), 23.1 (CH3).
J¼9.1 Hz, 1H, CHaryl), 7.71 (dd, J¼8.1, 1.3 Hz, 1H, CHaryl), 7.58 (m, 1H,
CHaryl), 7.42–7.35 (m, 2H, CHaryl), 7.26 (dd, J¼8.0, 1.2 Hz, 1H, CHaryl),
7.14–7.04 (m, 2H, CHaryl), 7.00 (ddd, J¼8.0, 7.4, 1.7 Hz, 1H, CHaryl),
6.01 (q, J¼6.5 Hz, 1H, CHOSO2R), 3.88 (s, 3H, OCH3), 1.57 (d,
J¼6.5 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3)
d 158.5 (C), 139.5 (C),
136.7 (CH), 132.1 (CH), 131.1 (C), 129.2 (CH), 128.9 (CH), 128.7
(C), 128.5 (CH), 127.6 (CH), 127.3 (CH), 124.4 (CH), 124.3 (CH), 120.7
(C), 117.2 (C), 112.8 (CH), 79.1 (CH), 56.9 (CH3), 23.1 (CH3).
3.15. Methyl 3-bromo-4-(1-{[2-methoxy-1-naphthylsulfonyl]-
oxy}ethyl)benzoate (12)
3.12. 1-(2-Iodophenyl)ethyl 2-methoxynaphthalene-1-
sulfonate (9)
According to GP2 methyl 3-bromo-4-(1-hydroxyethyl)benzoate
(5, 122 mg, 0.473 mmol) was treated with NEt3 (99 mL, 0.71 mmol,
1.5 equiv), NMe3$HCl (45 mg, 0.47 mmol), and 2-methoxynaph-
thalene-1-sulfonyl chloride (7, 181 mg, 0.709 mmol, 1.5 equiv) in
dichloromethane (5 mL). FC (pentane/diethylether 8:1/1:1; 1 vol
% NEt3) gave the sulfonate 12 as a colorless oil (158 mg, 0.331 mmol,
70%).
According to GP2 1-(2-iodophenyl)ethanol (2, 200 mg,
0.806 mmol) was treated with NEt3 (168 mL, 1.21 mmol, 1.5 equiv),
NMe3$HCl (77 mg, 0.81 mmol), and 2-methoxynaphthalene-
1-sulfonyl chloride (7, 309 mg, 1.21 mmol, 1.5 equiv) in dichloro-
methane (8 mL). FC (pentane/diethylether 3:1; 1 vol % NEt3) gave
the sulfonate 9 as a colorless oil (249 mg, 0.532 mmol, 66%). 1H
1H NMR (300 MHz, CDCl3)
d
8.96 (d, J¼8.9 Hz, 1H, CHaryl), 7.95
(m, 2H, CHaryl), 7.72 (m, 2H, CHaryl), 7.59 (m, 1H, CHaryl), 7.47 (d,
J¼8.2 Hz, 1H, CHaryl), 7.39 (dd, J¼7.6, 7.4 Hz, 1H, CHaryl), 7.13 (dd,
J¼9.2, 1.8 Hz, 1H, CHaryl), 6.02 (q, J¼6.5 Hz, 1H, CHOSO2R), 3.91 (s,
3H, OCH3), 3.88 (s, 3H, COOCH3), 1.58 (d, J¼6.5 Hz, 3H, CH3); 13C
NMR (300 MHz, CDCl3)
d
8.87 (d, J¼9.1 Hz, 1H, CHaryl), 7.78 (d,
J¼9.2 Hz, 1H, CHaryl), 7.58 (d, J¼8.0 Hz, 1H, CHaryl), 7.47–7.36 (m, 2H,
CHaryl), 7.28–7.20 (m, 2H, CHaryl), 7.02–6.93 (m, 2H, CHaryl), 6.66
(ddd, J¼7.7, 7.4, 1.6 Hz, 1H, CHaryl), 5.71 (q, J¼6.4 Hz, 1H, CHOSO2R),
3.73 (s, 3H, OCH3), 1.42 (d, J¼6.4 Hz, 3H, CH3); 13C NMR (75 MHz,
NMR (75 MHz, CDCl3)
d 165.2 (C), 158.5 (C), 144.3 (C), 136.9 (CH),
133.3 (CH), 131.0 (2ꢂC), 129.6 (CH), 128.7 (C), 128.6 (CH), 128.3 (CH),
127.5 (CH), 124.6 (CH), 124.3 (CH), 120.5 (C), 117.1 (C), 112.9
(CH), 78.5 (CH), 57.0 (CH3), 52.4 (CH3), 22.7 (CH3).
CDCl3)
d 158.5 (C), 142.5 (C), 138.7 (CH), 136.8 (CH), 131.0 (C), 129.4
(CH), 128.9 (CH), 128.7 (C), 128.5 (CH), 128.1 (CH), 127.2 (CH), 124.4

B. Schulte et al. / Tetrahedron 64 (2008) 11852–11859
11857
3.16. 1-(2-Bromophenyl)-2-methylpropyl 2-methoxynaphtha-
lene-1-sulfonate (13)
905 m, 811 m, 758 m, 730 m; HRMS (ESI) calcd for
[MþNa]þ: 301.1199; found: 301.1209; X-ray crystal structure
analysis of 14a: formula C19H18O2, M¼278.33, colorless
crystal 0.20ꢂ0.10ꢂ0.07 mm, a¼19.7811(11), c¼7.7299(4) Å,
According to GP1 2-(2-bromophenyl)-2-methylpropan-1-ol (6,
250 mg, 1.10 mmol) was treated with NEt3 (229
mL, 1.65 mmol,
V¼3024.6(3) Å3, rcalcd¼1.222 g cmꢁ3
,
m
¼0.616 mmꢁ1
, empirical
1.5 equiv), NMe3$HCl (105 mg, 1.10 mmol), and 2-methoxynaph-
thalene-1-sulfonyl chloride (7, 421 mg, 1.65 mmol, 1.5 equiv) in
dichloromethane(10 mL). FC(pentane/diethylether5:1/2:1;1 vol%
NEt3) gave the sulfonate 13 as a colorless oil (295 mg, 0.658 mmol,
60%).
absorption correction (0.887ꢃTꢃ0.958), Z¼8, tetragonal, space
group I4 (No. 79),
l
¼1.54178 Å, T¼223(2) K,
u and 4 scans, 6777
reflections collected (ꢄh, ꢄk, ꢄl), [(sin
q)/l
]¼0.60 Åꢁ1, 1983 in-
dependent (Rint¼0.038) and 1924 observed reflections [Iꢅ2
s(I)],
194 refined parameters, R¼0.034, wR2¼0.089, Flack parameter
1H NMR (300 MHz, CDCl3)
d
8.91 (d, J¼9.0 Hz,1H, CHaryl), 7.76 (d,
0.2(3), max. (min.) residual electron density 0.11 (ꢁ0.12) e Åꢁ3
,
J¼9.1 Hz, 1H, CHaryl), 7.59 (d, J¼8.1 Hz, 1H, CHaryl), 7.50 (m, 1H,
CHaryl), 7.30 (m,1H, CHaryl), 7.10 (m, 2H, CHaryl), 6.93 (d, J¼9.1 Hz,1H,
CHaryl), 6.88–6.73 (m, 2H, CHaryl), 5.62 (q, J¼6.9 Hz, 1H, CHOSO2R),
3.83 (s, 3H, OCH3), 2.05 (m, 1H, CH(CH3)2), 1.00 (d, J¼6.7 Hz, 3H,
CH(CH3)CH3), 0.75 (d, J¼6.9 Hz, 3H, CH(CH3)CH3); 13C NMR
hydrogen atoms calculated and refined as riding atoms.
3.19.2. Diastereoisomer 14b
1H NMR (300 MHz, CDCl3)
d
7.91 (d, J¼9.1 Hz,1H, CHaryl), 7.84 (dd,
J¼7.7, 1.5 Hz, 1H, CHaryl), 7.75 (d, J¼7.8 Hz, 1H, CHaryl), 7.50 (ddd,
J¼7.8, 7.7, 1.3 Hz, 1H, CHaryl), 7.43–7.29 (m, 4H, CHaryl), 7.26–7.22 (m,
1H, CHaryl), 7.15 (br d, J¼7.7 Hz, 1H, CHaryl), 4.55 (q, J¼6.4 Hz, 1H,
CHOH), 3.82 (s, 3H, OCH3), 2.57 (br s, 1H, OH), 1.26 (d, J¼6.4 Hz, 3H,
(75 MHz, CDCl3)
d 159.0 (C), 142.9 (C), 138.9 (CH), 132.4 (CH), 130.0
(CH), 129.4 (C), 129.0 (CH), 128.5 (C), 128.4 (CH), 128.3 (C), 128.2
(CH), 127.2 (CH), 125.0 (CH), 123.1 (CH), 122.5 (C), 113.3 (CH),
77.3 (CH), 57.4 (CH3), 33.9 (CH), 19.3 (CH3), 16.6 (CH3).
CH3); 13C NMR (75 MHz, CDCl3)
d 153.2 (C),144.6 (C),134.5 (C),134.0
(C), 131.0 (CH), 129.4 (CH), 129.2 (C), 128.3 (CH), 127.9 (CH), 127.5
(CH), 126.5 (CH), 125.3 (CH), 125.2 (CH), 123.8 (CH), 123.7 (C), 113.5
(CH), 67.0 (CH), 56.8 (CH3), 22.5 (CH3); IR (neat, cmꢁ1) 3415 br m,
2972 m, 2924 m, 1622 m, 1592 m, 1509 m, 1465 m, 1331 m, 1259 s,
1075 s, 906 m, 812 m, 758 m, 731 m; HRMS (ESI) calcd for [MþNa]þ:
301.1199; found: 301.1220; X-ray crystal structure analysis of 14b:
formula C19H18O2, M¼278.33, colorless crystal 0.30ꢂ0.15ꢂ0.10 mm,
3.17. General procedure (GP3) for the aryl migration reaction
The sulfonate was dissolved in benzene (0.03 M) and heated to
80 ꢀC. A solution of Bu3SnH and V-40 in benzene (1 mL) was added
by syringe pump over 7 h. After complete addition stirring was
continued at that temperature for 30 min. The solution was then
allowed to cool to rt and water and diethylether were added. The
organic phase was washed with satd aq NH4Cl and brine and was
dried over MgSO4. The solvents were evaporated and the crude
residue was filtered over a KF–SiO2 column20 (10:90). FC (SiO2) fi-
nally yielded the desired biaryl.
a¼25.3009(7), b¼7.9281(2), c¼30.0895(9) Å,
b
¼96.208(1)ꢀ,
V¼6000.2(3) Å3, rcalcd¼1.232 g cmꢁ3
,
m
¼0.621 mmꢁ1, empirical ab-
sorption correction (0.836ꢃTꢃ0.941), Z¼16, monoclinic, space
group C2/c (No. 15),
reflections collected (ꢄh, ꢄk, ꢄl), [(sin
l
¼1.54178 Å, T¼223(2) K,
u and 4 scans, 21,629
q)/l
]¼0.60 Åꢁ1, 5284 in-
dependent (Rint¼0.058) and 4150 observed reflections [Iꢅ2
s(I)], 386
3.18. 1-[2-(2-Methoxy-1-naphthyl)phenyl]ethanol (14a
and 14b)
refined parameters, R¼0.046, wR2¼0.112, max. (min.) residual
electron density 0.17 (ꢁ0.15) e Åꢁ3, two almost identical molecules
in the asymmetric unit, hydrogen atoms calculated and refined as
riding atoms.
According to GP3 with 1-(2-bromophenyl)ethyl 2-methoxy-
naphthalene-1-sulfonate (8, 150 mg, 0.356 mmol), Bu3SnH (144 mL,
0.534 mmol, 1.5 equiv), and V-40 (87 mg, 0.36 mmol, 1.0 equiv)
in benzene (12 mL). Purification by FC (pentane/diethylether
20:1/3:1) afforded the separated diastereoisomers 14a (29.7 mg,
0.107 mmol, 30%) and 14b (53.5 mg, 0.192 mmol, 54%) as colorless
oils.
3.20. 1-[2-(2-Methoxy-1-naphthyl)-3-methylphenyl]ethanol
(15a and 15b)
According to GP3 with 1-(2-bromo-3-methylphenyl)ethyl 2-
methoxynaphthalene-1-sulfonate (10, 100 mg, 0.230 mmol),
Bu3SnH (93 mL, 0.35 mmol, 1.5 equiv), and V-40 (56 mg, 0.23 mmol,
3.19. 1-[2-(2-Methoxy-1-naphthyl)phenyl]ethanol (14a
and 14b)
1.0 equiv) in benzene (8 mL). Purification by FC (pentane/dieth-
ylether 10:1/3:1) afforded the separated diastereoisomers 15a
(14.0 mg, 0.0479 mmol, 21%) and 15b (21.3 mg, 0.073 mmol, 32%) as
colorless oils.
According to GP3 with 1-(2-iodophenyl)ethyl 2-methoxynaph-
thalene-1-sulfonate (9, 286 mg, 0.612 mmol), Bu3SnH (247 mL,
0.917 mmol, 1.5 equiv), and V-40 (149 mg, 0.612 mmol, 1.0 equiv)
in benzene (20 mL). Purification by FC (pentane/diethylether
20:1/3:1) afforded the separated diastereoisomers 14a (34 mg,
0.122 mmol, 20%) and 14b (61 mg, 0.219 mmol, 36%) as colorless
oils.
3.20.1. Diastereoisomer 15a
1H NMR (300 MHz, CDCl3)
d
7.93 (d, J¼9.1 Hz, 1H, CHaryl), 7.85
(dd, J¼7.3, 1.7 Hz, 1H, CHaryl), 7.57 (d, J¼7.8 Hz, 1H, CHaryl), 7.49–7.28
(m, 5H, CHaryl), 7.08 (d, J¼7.7 Hz, 1H, CHaryl), 4.41 (d, J¼6.4 Hz, 1H,
CHOH), 3.85 (s, 3H, OCH3), 1.83 (s, 3H, CH3), 1.56 (br s, 1H, OH), 1.22
(d, J¼6.4 Hz, 3H, OCHCH3); 13C NMR (75 MHz, CDCl3)
d 153.2 (C),
3.19.1. Diastereoisomer 14a
144.4 (C), 137.5 (C), 134.2 (C), 133.4 (C), 129.5 (CH), 129.3 (C), 129.2
(CH),128.2 (CH),128.1 (CH),126.8 (CH),124.6 (CH),123.9 (CH),122.7
(CH), 122.4 (C), 113.5 (CH), 67.3 (CH), 56.6 (CH3), 22.4 (CH3), 20.2
(CH3); IR (neat, cmꢁ1) 3415 br m, 2969 m, 2927 m, 2857 m, 1622 m,
1593 m, 1508 m, 1461 m, 1378 m, 1331 m, 1253 s, 1092 m, 1063 s,
1020 m, 907 s, 809 m, 732 s; HRMS (ESI) calcd for [MþNa]þ:
315.1356; found: 315.1357.
1H NMR (300 MHz, CDCl3)
d
7.83 (d, J¼9.1 Hz, 1H, CHaryl), 7.78–
7.73 (m, 1H, CHaryl), 7.67 (dd, J¼7.7, 0.9 Hz, 1H, CHaryl), 7.42 (ddd,
J¼7.7, 7.6, 1.4 Hz, 1H, CHaryl), 7.36–7.14 (m, 5H, CHaryl), 7.07 (br d,
J¼7.6 Hz, 1H, CHaryl), 4.42 (q, J¼6.4 Hz, 1H, CHOH), 3.78 (s, 3H,
OCH3), 1.62 (br s, 1H, OH), 1.23 (d, J¼6.4 Hz, 3H, CH3); 13C NMR
(75 MHz, CDCl3)
d 154.0 (C), 144.99 (C), 134.1 (C), 133.7 (C), 131.0
(CH), 129.4 (CH), 128.9 (C), 128.2 (CH), 127.9 (CH), 127.3 (CH),
126.7 (CH), 125.4 (CH), 124.7 (CH), 123.6 (CH), 123.2 (C), 113.2 (CH),
67.5 (CH), 56.2 (CH3), 24.1 (CH3); IR (neat, cmꢁ1) 3399 br m, 2968 m,
2923 m, 1621 m, 1592 m, 1508 m, 1464 m, 1331 m, 1259 s, 1063 s,
3.20.2. Diastereoisomer 15b
1H NMR (300 MHz, CDCl3)
d
7.93 (d, J¼9.0 Hz, 1H, CHaryl), 7.85
(dd, J¼7.4, 1.4 Hz, 1H, CHaryl), 7.57 (d, J¼7.8 Hz, 1H, CHaryl), 7.49–7.28

11858
B. Schulte et al. / Tetrahedron 64 (2008) 11852–11859
(m, 5H, CHaryl), 7.08 (d, J¼7.8 Hz, 1H, CHaryl), 3.93 (d, J¼6.4 Hz, 1H,
CHOH), 3.85 (s, 3H, OCH3), 2.26 (br s, 1H, OH), 1.83 (s, 3H, CH3), 1.23
3H, CHaryl), 7.17 (m, 1H, CHaryl), 4.53 (q, J¼6.4 Hz, 1H, CHOH), 3.88
(s, 3H, OCH3), 3.83 (s, 3H, OCH3), 1.67 (br s, 1H, OH), 1.30 (d,
(d, J¼6.4 Hz, 3H, OCHCH3); 13C NMR (75 MHz, CDCl3)
d
153.2 (C),
J¼6.4 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3)
d 167.0 (C), 154.2 (C),
144.4 (C), 137.5 (C), 134.2 (C), 133.4 (C), 133.4 (C), 129.4 (CH), 129.3
(C), 129.2 (CH), 128.2 (CH), 128.1 (CH), 126.8 (CH), 124.6 (CH), 123.9
(CH), 122.6 (CH), 113.5 (CH), 67.2 (CH), 56.5 (CH3), 22.4 (CH3), 20.2
(CH3); IR (neat, cmꢁ1) 3425 br m, 2965 m, 2928 m, 1622 m, 1593 m,
1508 m, 1461 m, 1377 m, 1331 s,1254 m, 1147 m, 1063 s, 1019 m, 809
m; HRMS (ESI) calcd for [MþNa]þ: 315.1356; found: 315.1343.
150.3 (C), 134.3 (C), 133.4 (CH), 132.5 (CH), 129.8 (CH), 129.4 (CH),
129.3 (C), 128.9 (C), 127.0 (CH), 125.6 (CH), 125.3 (C), 124.4 (CH),
123.8 (CH), 122.1 (C), 113.1 (CH), 67.3 (CH), 56.2 (CH3), 52.0 (CH3),
24.2 (CH3); IR (neat, cmꢁ1) 3420 br m, 2950 m, 2930 m, 1712 s, 1623
m, 1595 m, 1510 m, 1438 m, 1289 m, 1251 s, 1222 m, 1123 m, 1060 m,
1005 m, 905 m, 821 m, 732 s; HRMS (ESI) calcd for [MþNa]þ:
359.1254; found: 359.1253.
3.21. 1-[4-Fluoro-2-(2-methoxynaphthyl)phenyl]ethanol (16a
and 16b)
3.22.2. Diastereoisomer 17b
1H NMR (300 MHz, CDCl3)
d
8.17 (dd, J¼8.2, 1.8 Hz, 1H, CHaryl),
According to GP3 with 1-(2-bromo-4-fluorophenyl)ethyl 2-
methoxynaphthalene-1-sulfonate (11,151 mg, 0.344 mmol), Bu3SnH
(139 mL, 0.516 mmol, 1.5 equiv), and V-40 (84 mg, 0.34 mmol,
7.95 (d, J¼9.0 Hz, 1H, CHaryl), 7.90–7.82 (m, 3H, CHaryl), 7.44–7.31 (m,
3H, CHaryl), 7.19 (m, 1H, CHaryl), 4.62 (q, J¼6.3 Hz, 1H, CHOH), 3.89 (s,
3H, OCH3), 3.83 (s, 3H, OCH3), 2.44 (br s, 1H, OH), 1.24 (s, 3H, CH3);
1.0 equiv) in benzene (12 mL). Purification by FC (pentane/dieth-
ylether 20:1/2:1) afforded the separated diastereoisomers 16a
(20.0 mg, 0.068 mmol, 19%) and 16b (41.1 mg, 0.139 mmol, 40%) as
colorless oils.
13C NMR (75 MHz, CDCl3)
d 166.9 (C), 153.3 (C), 149.9 (C), 134.7 (C),
133.8 (C),132.4 (CH),129.9 (CH),129.5 (CH),129.3 (2ꢂC),128.0 (CH),
126.8 (CH), 125.6 (CH), 124.9 (CH), 124.0 (CH), 122.6 (C), 113.4 (CH),
66.9 (CH), 56.8 (CH3), 52.0 (CH3), 22.7 (CH3); IR (neat, cmꢁ1) 3425 br
m, 2972 m, 2936 m, 1717 s, 1593 m, 1509 m, 1436 m, 1293 m, 1265 s,
1215 m, 1079 m, 1065 m, 1004 m, 906 m, 809 m, 729 s; HRMS (ESI)
calcd for [MþNa]þ: 359.1254; found: 359.1259.
3.21.1. Diastereoisomer 16a
1H NMR (300 MHz, CDCl3)
d
7.93 (d, J¼9.1 Hz, 1H, CHaryl), 7.84
(dd, J¼6.2, 3.3 Hz, 1H, CHaryl), 7.72 (dd, J¼8.7, 5.9 Hz, 1H, CHaryl),
7.41–7.32 (m, 3H, CHaryl), 7.26–7.15 (m, 2H, CHaryl), 6.87 (dd, J¼9.1,
2.7 Hz, 1H, CHaryl), 4.45 (q, J¼6.3 Hz, 1H, CHOH), 3.83 (s, 3H, OCH3),
1.56 (br s, 1H, OH), 1.26 (d, J¼6.4 Hz, 3H, CH3); 13C NMR (75 MHz,
3.23. 1-[2-(2-Methoxy-1-naphthyl)phenyl]-2-methyl propan-
1-ol (18a and 18b)
CDCl3)
d
161.9 (d, 1J(C,F)¼246 Hz, C), 154.0 (C), 141.0 (d,
According to GP3 with 1-(2-bromophenyl)-2-methylpropyl 2-
methoxynaphthalene-1-sulfonate(13,156 mg, 0.348 mmol), Bu3SnH
(141 mL, 0.522 mmol, 1.5 equiv), and V-40 (85 mg, 0.35 mmol,
1.0 equiv) in benzene (12 mL). Purification by FC (pentane/dieth-
ylether 20:1/2:1) afforded the separated diastereoisomers 18a
(13.4 mg, 0.044 mmol, 21%) and 18b (25.0 mg, 0.818 mmol, 39%) as
colorless oils.
4J(C,F)¼3.1 Hz, C), 136.1 (C), 133.3 (C), 129.8 (CH), 128.9 (C), 128.1
(CH),127.2 (d, 3J(C,F)¼8.6 Hz, CH),127.1 (CH),124.4 (CH),123.8 (CH),
121.1 (C), 117.5 (d, 2J(C,F)¼20.8 Hz, CH), 115.1 (d, 2J(C,F)¼21.0 Hz,
CH), 113.1 (CH), 66.9 (CH), 56.2 (CH3), 24.3 (CH3); IR (neat, cmꢁ1
)
3410 br m, 2934 m, 2841 m, 1611 m, 1593 m, 1510 m, 1333 m, 1259 s,
1176 m, 1062 s, 907 m, 809 m, 731 m, 632 s; HRMS (ESI) calcd for
[MþNa]þ: 319.1105; found: 319.1103.
3.23.1. Diastereoisomer 18a
3.21.2. Diastereoisomer 16b
1H NMR (300 MHz, CDCl3)
d
7.91 (d, J¼9.0 Hz, 1H, CHaryl), 7.84
1H NMR (300 MHz, CDCl3)
d
7.93 (d, J¼9.1 Hz, 1H, CHaryl), 7.84
(m, 1H, CHaryl), 7.68 (dd, J¼7.7, 1.0 Hz, 1H, CHaryl), 7.50 (ddd, J¼7.8,
7.6, 1.2 Hz, 1H, CHaryl), 7.43–7.21 (m, 5H, CHaryl), 7.16 (dd, J¼7.6,
1.1 Hz, 1H, CHaryl), 3.92 (d, J¼7.7 Hz, 1H, CHOH), 3.81 (s, 3H, OCH3),
2.03 (m, 1H, CH(CH3)2), 1.66 (br s, 1H, OH), 0.84 (d, J¼6.6 Hz, 3H,
CH(CH3)CH3), 0.63 (d, J¼6.8 Hz, 3H, CH(CH3)CH3); 13C NMR
(m, 1H, CHaryl), 7.70 (dd, J¼8.7, 5.9 Hz, 1H, CHaryl), 7.42–7.32 (m,
3H, CHaryl), 7.25–7.14 (m, 2H, CHaryl), 6.87 (dd, J¼9.2, 2.8 Hz, 1H,
CHaryl), 4.51 (q, J¼6.5 Hz, 1H, CHOH), 3.85 (s, 3H, OCH3), 2.40 (br s,
1H, OH), 1.26 (d, J¼6.5 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3)
d
161.9 (d, 1J(C,F)¼247 Hz, C), 153.2 (C), 140.7 (d, 4J(C,F)¼3.1 Hz, C),
(75 MHz, CDCl3) d 153.3 (C),143.5 (C),135.5 (C),133.9 (C),131.1 (CH),
136.6 (d, 3J(C,F)¼8.0 Hz, C), 133.3 (C), 129.9 (CH), 129.3 (C), 128.0
(CH), 127.2 (d, 3J(C,F)¼8.5 Hz, CH), 126.8 (CH), 124.9 (CH), 124.0
(CH), 122.5 (d, 4J(C,F)¼1.5 Hz, C), 117.5 (d, 2J(C,F)¼20.8 Hz, CH),
115.1 (d, 2J(C,F)¼20.9 Hz, CH), 113.4 (CH), 66.5 (CH), 56.8 (CH3),
22.7 (CH3); IR (neat, cmꢁ1) 3415 br m, 2970 m, 2935 m, 2842 m,
1621 m, 1593 m, 1510 m, 1470 m, 1333 m, 1265 s, 1176 m, 1063 m,
1020 m, 886 m, 809 m; HRMS (ESI) calcd for [MþNa]þ: 319.1105;
found: 319.1106.
129.4 (C), 129.3 (CH), 128.3 (CH), 127.8 (CH), 127.2 (CH), 126.3 (CH),
126.3 (CH), 125.6 (CH), 124.0 (C), 123.8 (CH), 113.5 (CH), 77.3 (CH),
56.9 (CH3), 32.7 (CH), 19.3 (CH3), 19.2 (CH3); IR (neat, cmꢁ1) 3435 br
m, 2968 m, 1623 m, 1593 m, 1509 m, 1464 m, 1382 m, 1333 m, 1247
s, 1064 s, 1004 s, 905 m, 802 s; HRMS (ESI) calcd for [MþNa]þ:
329.1523; found: 329.1518.
3.23.2. Diastereoisomer 18b
1H NMR (300 MHz, CDCl3)
d
7.92 (d, J¼9.0 Hz, 1H, CHaryl), 7.87–
3.22. Methyl 4-(1-hydroxyethyl)-3-(2-methoxy-1-
naphthyl)benzoate (17a and 17b)
7.81 (m, 1H, CHaryl), 7.68 (dd, J¼7.8 Hz, 1H, CHaryl), 7.51 (ddd, J¼7.8,
7.6, 1.1 Hz, 1H, CHaryl), 7.43–7.29 (m, 5H, CHaryl), 7.17 (dd, J¼7.6,
1.1 Hz, 1H, CHaryl), 3.93 (d, J¼6.6 Hz, 1H, CHOH), 3.84 (s, 3H, OCH3),
2.48 (br s, 1H, OH), 2.05 (m, 1H, CH(CH3)2), 0.91 (d, J¼6.6 Hz, 3H,
CH(CH3)CH3), 0.44 (d, J¼6.6 Hz, 3H, CH(CH3)CH3); 13C NMR
According to GP3 with methyl 3-bromo-4-(1-{[2-methoxy-1-
naphthylsulfonyl]oxy}ethyl) benzoate (12, 261 mg, 0.546 mmol),
Bu3SnH (221
mL, 0.819 mmol, 1.5 equiv), and V-40 (133 mg,
(75 MHz, CDCl3) d 153.3 (C),143.5 (C),135.5 (C),133.9 (C),131.1 (CH),
0.546 mmol, 1.0 equiv) in benzene (18 mL). Purification by FC
(pentane/diethylether 10:1/1:1) afforded the separated di-
astereoisomers 17a (43 mg, 0.128 mmol, 23%) and 17b (79 mg,
0.235 mmol, 43%) as colorless oils.
129.4 (CH), 129.3 (C), 128.3 (CH), 127.8 (CH), 127.3 (CH), 126.4 (CH),
126.3 (CH), 125.6 (CH), 124.0 (C), 123.8 (CH), 113.5 (CH), 77.3 (CH),
56.9 (CH3), 32.7 (CH), 19.3 (CH3), 19.2 (CH3); IR (neat, cmꢁ1) 3345 br
m, 2961 m, 2922 m, 2870 m, 2839 m, 1621 m, 1593 m, 1509 m, 1465
m, 1384 m, 1329 m, 1257 s, 1066 m, 1012 m, 908 s, 809 s, 729 s;
HRMS (ESI) calcd for [MþNa]þ: 329.1512; found: 329.1512;
X-ray crystal structure analysis of 18b: formula C21H22O2,
M¼306.39, colorless crystal 0.50ꢂ0.20ꢂ0.20 mm, a¼11.1518(2),
3.22.1. Diastereoisomer 17a
1H NMR (300 MHz, CDCl3)
7.94 (d, J¼9.1 Hz, 1H, CHaryl), 7.89–7.80 (m, 3H, CHaryl), 7.41–7.30 (m,
d
8.17 (dd, J¼8.2, 1.8 Hz, 1H, CHaryl),

B. Schulte et al. / Tetrahedron 64 (2008) 11852–11859
11859
4. Roncali, J. Chem. Rev. 1992, 92, 711–738.
b¼26.1286(6), c¼12.2533(3) Å,
b
¼104.684(1)ꢀ, V¼3453.76(13) Å3,
5. (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174–238; (b)
Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200–205; (c) Seregin, I. V.; Gevorgyan,
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6. (a) Motherwell, W. B.; Pennell, A. M. K. J. Chem. Soc., Chem. Commun. 1991, 877–
879; (b) da Mata, M. L. E. N.; Motherwell, W. B.; Ujjainwalla, F. Tetrahedron Lett.
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Tetrahedron Lett. 1997, 38, 141–144; (d) Bonfand, E.; Forslund, L.; Motherwell,
rcalcd¼1.178 g cmꢁ3
,
m
¼0.581 mmꢁ1, empirical absorption correc-
tion (0.760ꢃTꢃ0.893), Z¼8, monoclinic, space group P21/c (No. 14),
l
¼1.54178 Å, T¼223(2) K,
u
and
)/
4 scans, 33,708 reflections col-
lected (ꢄh, ꢄk, ꢄl), [(sin
q
l
]¼0.59 Åꢁ1
,
6046 independent
(I)], 423 refined
(Rint¼0.043) and 5574 observed reflections [Iꢅ2
s
parameters, R¼0.043, wR2¼0.122, max. (min.) residual electron
density 0.15 (ꢁ0.22) e Åꢁ3, two almost identical molecules in the
asymmetric unit, hydrogen atoms calculated and refined as riding
atoms.
´
W. B.; Vazquez, S. Synlett 2000, 475–478.
7. Review on radical arly migration reactions, see: Studer, A.; Bossart, M. Tetra-
hedron 2001, 57, 9649–9667.
8. Homolytic aromatic substitutions: (a) Studer, A.; Bossart, M. In Radicals in
Organic Synthesis; Renaud, P., Sibi, M., Eds.; Wiley-VCH: Weinheim, 2001; Vol.
2, pp 62–80; (b) Bowmann, W. R.; Storey, J. M. D. Chem. Soc. Rev. 2007, 36,
1803–1822.
9. Clive, D. L. J.; Kang, S. Tetrahedron Lett. 2000, 41, 1315–1319.
10. Studer, A.; Bossart, M.; Vasella, T. Org. Lett. 2000, 2, 985–988.
11. (a) Studer, A.; Bossart, M. Chem. Commun. 1998, 2127–2128; (b) Bossart, M.;
Fa¨ssler, R.; Schoenberger, J.; Studer, A. Eur. J. Org. Chem. 2002, 2742–2757.
12. (a) Studer, A.; Bossart, M.; Steen, H. Tetrahedron Lett. 1998, 39, 8829–8832; (b)
Amrein, S.; Bossart, M.; Vasella, T.; Studer, A. J. Org. Chem. 2000, 65, 4281–4288.
13. Review: Wallace, T. W. Org. Biomol. Chem. 2006, 4, 3197–3210.
14. Yoshida, Y.; Sakakura, Y.; Aso, N.; Okada, S.; Tanabe, Y. Tetrahedron 1999, 55,
2183–2192.
CCDC 689499 (14b), 689500 (18b), and 689501 (14a) contain the
supplementary crystallographic data for this paper. These data can
be obtained free of charge at www.ccdc.cam.ac.uk/conts/retrie-
ving.html [or from the Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: þ44(1223)336 033, E-
mail: deposit@ccdc.cam.ac.uk].
Acknowledgements
15. The studies were conducted on racemic alcohols.
We thank the Fonds der Chemischen Industrie and Novartis
Pharma AG (Young Investigator Award to A.S.) for financial support.
16. Data sets were collected with a Nonius KappaCCD diffractometer. Programs
used: data collection COLLECT (Nonius, B. V., 1998), data reduction Denzo-SMN
(Otwinowski, Z.; Minor W. Methods Enzymol. 1997, 276, 307–326), absorption
correction Denzo (Otwinowski, Z.; Borek, D.; Majewski, W.; Minor, W. Acta
Crystallogr. 2003, A59, 228–234), structure solution SHELXS-97 (Sheldrick, G. M.
Acta Crystallogr. 1990, A46, 467–473), structure refinement SHELXL-97 (Shel-
drick, G. M. Acta Crystallogr. 2008, A64, 112–122), graphics SCHAKAL (Keller, E.,
1997).
17. Curran, D. P.; Keller, A. I. J. Am. Chem. Soc. 2006, 128, 13706–13707.
18. Fleifel, A. M. J. Org. Chem. 1960, 25, 1024–1025.
19. Joyeau, R.; Yadav, L. D. S.; Wakselman, M. J. Chem. Soc., Perkin Trans. 1 1987,
1899–1907.
References and notes
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