Atropo-diastereoselective coupling of aryllithiums and arynes — variations around the chiral auxiliary

Article abstract of DOI:10.1016/j.tet.2016.01.047

The atropo-selective coupling of in situ generated arynes and aryllithiums bearing various chiral auxiliaries ortho to lithium (tert-butylsulfoxide, para-tolylsulfoxide, tartrate-derived chiral diethers and oxazolines) is described. Chiral oxazolines showed the best results in terms of yields of coupling products. Different reaction parameters like the nature of the aryne precursor, the oxazoline, the alkyllithium base or the solvent revealed to be crucial for obtaining good yields and for diastereoselection.

Full text of DOI:10.1016/j.tet.2016.01.047

Tetrahedron xxx (2016) 1e13
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journal homepage: www.elsevier.com/locate/tet
Atropo-diastereoselective coupling of aryllithiums and arynes d
variations around the chiral auxiliary
a
,
a
,
b
,
a,b,
David Augros y, Boubacar Yalcouye y, Anaïs Berthelot-Br eꢀ hier y,
a,
b,
b
a
, ,
a
, ,
y
Matthieu Chess eꢀ y, Sabine Choppin , Armen Panossian y, Frederic R. Leroux
*
ꢀ ꢀ
*
a
CNRS e Universit ꢀe de Strasbourg (ECPM), UMR 7509, COHA, 25 Rue Becquerel, 67087 Strasbourg, France
b
CNRS e Universit ꢀe de Strasbourg (ECPM), UMR 7509, SynCat, 25 Rue Becquerel, 67087 Strasbourg, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The atropo-selective coupling of in situ generated arynes and aryllithiums bearing various chiral
auxiliaries ortho to lithium (tert-butylsulfoxide, para-tolylsulfoxide, tartrate-derived chiral diethers and
oxazolines) is described. Chiral oxazolines showed the best results in terms of yields of coupling prod-
ucts. Different reaction parameters like the nature of the aryne precursor, the oxazoline, the alkyllithium
base or the solvent revealed to be crucial for obtaining good yields and for diastereoselection.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 21 November 2015
Received in revised form 21 January 2016
Accepted 26 January 2016
Available online xxx
Keywords:
Biaryl
Aryne
CeC coupling
Atropo-diastereoselective
Organolithium
Sulfoxide
Oxazoline
Diether
1. Introduction
natural products or their use as biologically active compounds,
chiral ligands for catalysis, chiral auxiliaries for asymmetric syn-
Among the methods allowing access to the biphenyl backbone,
the addition of an aromatic carbanion onto a 1,2-didehydroarene,
i.e., an ortho-aryne, was postulated by Gilman in the late 1950s in
thesis or optically active organic materials. The most widespread
strategies are the resolution of pre-constructed biaryls and the
atropo-selective coupling of two aromatic partners. We first
4
1
the reaction of ortho-dihalobenzenes with butyllithium. However,
tackled the resolution strategy by taking advantage of a specificity
of the ARYNE coupling, namely the regeneration of a carbon-
exchangeable halogen bond in position 2 of the biaryl product, to
introduce a chiral sulfinyl auxiliary enabling desymmetrization or
deracemization of the biaryl, separation of atropo-diastereomers,
this halogen/lithium interconversion-based method remained
rather dormant for several decades while the magnesium-based
2
counterpart was intensively studied by Hart. We started reinves-
tigating the former in 2001 and then extended its scope to access
various biaryls, which could be derivatized to prepare phosphorous
3
g
and lastly functionalization by sulfoxide/lithium exchange. We
then investigated the atropo-diastereoselective ARYNE coupling,
where a coupling partner bears a chiral auxiliary prior to the cou-
ligands, and we clarified the mechanism of the reaction (Scheme
3
1
). This ‘ARYNE coupling’ is actually a chain reaction, proceeding
5
,3i
via sequential halogen/lithium exchanges, and finally yields 2-
halobiphenyls that can be functionalized further. Once having de-
veloped efficient conditions for the ARYNE coupling, we became
interested in its application to the preparation of axially chiral
biaryls. Indeed, the synthesis of axially stereoenriched biaryls re-
mains an active research field motivated by their presence in
pling, so as to yield atropo-diastereomers of the desired biaryl.
We wish, in the present paper, to describe our efforts towards
this aim.
2. Results and discussion
In the development of the atropo-diastereoselective version of
the ARYNE coupling, the choice of the chiral auxiliary and its lo-
cation onto the coupling partners were critical. First, the auxiliary
should be able to bind to lithium, in order to produce more rigid
*
Corresponding authors. E-mail addresses: armen.panossian@unistra.fr (A.
Panossian), frederic.leroux@unistra.fr (F.R. Leroux).
y
www.coha-lab.org.
http://dx.doi.org/10.1016/j.tet.2016.01.047
0
040-4020/Ó 2016 Elsevier Ltd. All rights reserved.
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2
D. Augros et al. / Tetrahedron xxx (2016) 1e13
2.1. Aryl tert-butyl sulfoxides
In our first attempt towards the atropo-diastereoselective
ARYNE coupling, we chose aryl tert-butyl sulfoxides as pronu-
3
i
cleophiles. The known chemical stability of the tert-butyl sulfinyl
group towards lithium or magnesium bases, as well as its efficient
stereoinductive power in directed lithiatione diastereoselective
7
trapping sequences on aromatic compounds, were solid advan-
tages for the potential success of the ARYNE coupling. After
a preliminary study with aryl tert-butyl sulfoxides 1aed, prepared
by trapping of the corresponding aryllithiums with (S)-di-tert-
butyl thiosulfinate, we soon realized that the usual ARYNE cou-
pling conditions (1 equiv of BuLi to generate the aryllithium nu-
cleophile, followed by addition of 1 equiv of a 1,2-dibromobenzene
as aryne precursor) were ineffective to produce the expected
3
i
biaryls (Table 1). We assumed a low reactivity of the 2-lithioaryl
0
0
sulfoxide and/or of the 2-lithio-2 -(tert-butyl sulfinyl)-1,1 -bi-
phenyl in the halogen/lithium exchange reaction with the bromi-
nated aryne precursor, thus blocking respectively the initiation
and/or the propagation of the chain reaction (Scheme 1). We
solved this problem by concomitantly replacing the dibrominated
aryne precursors by the corresponding 1-bromo-2-iodobenzenes
and adding a small amount of additional BuLi after introduction
of the aryne precursor so as to trigger the generation of the aryne
3
i
(
Table 1). Interestingly, in the case of tert-butyl 2-lithiophenyl
sulfoxide, lacking a substituent in position 3 of the aromatic ring,
the coupling could take place even with a less-reactive ortho-
dibromobenzene aryne precursor, although with complete ab-
sence of atropo-stereoselectivity (Table 1, entry 9). The 3-
substituent is therefore a critical parameter in the chain reaction.
2.2. Aryl para-tolyl sulfoxides
Aryl para-tolyl sulfoxides were then considered as appealing
alternative substrates in the atropo-diastereoselective ARYNE
coupling. Indeed, unlike the corresponding tert-butyl sulfoxides,
aryl p-tolyl sulfoxides can be easily converted into diversely func-
tionalized arenes by sulfoxide/metal exchange using lithium or
Scheme 1. Mechanism of the ARYNE coupling.
8
magnesium bases da valuable asset for the derivatization of
biaryls, as others and ourselves already demonstrated.9 Yet, for
this very same reason, an iodine substituent had to be introduced in
position 2 of aryl para-tolyl sulfoxides to allow their use as sub-
strates in the ARYNE coupling. Indeed, one could generate the
aryllithium nucleophile in situ by direct lithiation either with
a lithium amide (lithium di-iso-propylamide or lithium 2,2,6,6-
tetramethylpiperidide) or an alkyllithium. But the first strategy
produces 1 equiv of secondary amine, which can then add onto the
,3g
transition states and, consequently, lead to higher stereoselectivity.
Therefore, an oxygen- and/or nitrogen-bearing auxiliary was
needed. Second, to avoid regioselectivity issues during the addition
of the aryllithium nucleophile onto the aryne, the auxiliary should
be located on the former, not on the latter. Indeed, as shown by
Meyers, a competition between kinetic and thermodynamic addi-
tions onto the aryne can take place when an oxazoline is placed
6
ortho to the triple bond. Last, we chose to investigate several chiral
10
aryne, and the second strategy leads to competitive desulfinyla-
auxiliaries, bound to the arene ring through sulfur, oxygen and
carbon, so as to access a variety of 2-substituted biphenyls after
transformation of the auxiliary (Scheme 2). The results obtained
with the different kinds of auxiliaries are summarized hereafter.
tion by BuLi. Therefore, the best way to generate the desired 2-
lithioaryl p-tolyl sulfoxide was via iodine/lithium exchange on
substrates 6aeb, as the exchange was reported to be selective for
11
iodine on 2-iodophenyl p-tolyl sulfoxide. Thus, substrates 6aeb
Scheme 2. Chiral auxiliaries for the atropo-diastereoselective ARYNE coupling.
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D. Augros et al. / Tetrahedron xxx (2016) 1e13
3
Table 1
Atropo-diastereoselective ARYNE coupling of aryl tert-butyl sulfoxides
R1
R2
T ( C)
ꢂ
Aryne precursor
X
Product
n
Yielda (%)
d.r.b
Entry
S.M.
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1b
1b
1c
1d
OMe
OMe
OMe
OMe
OMe
Cl
H
H
H
H
H
H
H
ꢁ78
ꢁ78
ꢁ35
ꢁ78
ꢁ78
ꢁ78
ꢁ78
ꢁ78
ꢁ78
2a
2a
2a
2b
2c
2b
2d
2b
2c
Br
Br
Br
I
Br
I
I
I
Br
3a
3a
3a
3b
4a
3c
4b
3d
4c
0
0
0
0
d
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
d
d
100:0c
d
79:21d
100:0c
54:46
51:49
c
20
0
51
13
82
51
Cl
OCH
H
2
O
H
a
Combined yield of both atropo-diastereomers.
Diastereomeric ratio measured by 1H NMR of the crude mixture.
Only one atropo-diastereomer could be isolated, whose configuration could not be ascertained; formation of the other atropo-isomer could not be ruled out.
b
c
d
3i
S
The absolute configuration of the major atropo-diastereomer was shown to be (S ,aS).
were prepared from the corresponding bromoarenes by bromine/
lithium exchange and trapping with Andersen’s reagent or
explanation for the formation of 8 is depicted in Scheme 6. Internal
attack of the biaryllithium onto the sulfinyl group would lead, via
an oxysulfurane intermediate, to a ligand-coupling reaction, pos-
8
(
ꢀ)-methyl p-tolyl sulfinate, followed by lithiation with LDA and
trapping with molecular iodine (Scheme 3).
sibly by 1,2-migration of the tolyl group from sulfur to the arylic
Scheme 3. Synthesis of the starting aryl para-tolyl sulfoxides.
The use of sulfoxides 6aeb in the ARYNE coupling with 1-
bromo-2-iodobenzene under the best conditions developed for
tert-butyl sulfoxides3 proved unsuccessful. The hydrolyzed arenes
N
carbon in an S Ar fashion, providing a sulfenate anion, which
would finally be trapped by iodomethane.
i
5
aeb were recovered after work-up, along with some unreacted
iodoarenes 6aeb, the aryne precursor, and compounds derived
2.3. Aryl diethers
from its homocoupling (Scheme 4). An increase of the temperature
ꢂ
ꢂ
to ꢁ50 C or even 0 C prior to addition of the benzyne precursor
did not allow for formation of the desired biarylic coupling product.
Interestingly, on the other hand, when a second equivalent of
BuLi was added to the mixture after introduction of 1-bromo-2-
iodobenzene onto the solution of aryllithium derived from
In parallel to our study on sulfur-based chiral directing groups,
we investigated oxygen-based auxiliaries. We started by preparing
substrates 16a,b, bearing a diether as chiral auxiliary derived from
hydrobenzoin or tartaric acid (Scheme 7). This strategy was in-
spired by the work of Lipshutz on atroposelective intramolecular
oxidative arylearyl couplings, which we wished to transpose to
our intermolecular arylearyne coupling. 16a,b were synthesized
from 3-chlorophenol, which was O-alkylated with MOMCl, then
ortho-lithiated with sec-BuLi before being trapped with iodine. The
oxygen atom was then unprotected under acidic conditions to af-
ford the key 3-chloro-2-iodophenol 12, which underwent a Mitsu-
nobu reaction with the appropriate mono-silylated chiral diol 13 or
17. After removal of the silyl group, methylation of the free alcohol
yielded the desired substrates 16a,b.
12
(
ꢀ)-6b, and the reaction mixture was allowed to stir for 12 h before
addition of iodomethane in order to trap the expected biaryllithium
intermediate, no desired biaryl 7b was observed but instead an
unexpected ortho-terphenyl 8, apart from the methylated aryl-
sulfoxide 9 (Scheme 5). Noteworthily, compound 8 was obtained as
a mixture of diastereomers in a ratio of 7:1, and the major one was
z
recrystallized, thus confirming the structure of 8 and the relative
configuration of the major atropo-isomer (Fig. 1). A possible
Before engaging into the ARYNE coupling of these substrates
with ortho-dihalobenzenes, we first assessed them in an iodine/
lithium exchange-methylation sequence as model reaction. It
appeared that in all conditions tested, the hydrobenzoin derivative
z
CCDC 1445035 contains the supplementary crystallographic data for this
compound. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre.
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4
D. Augros et al. / Tetrahedron xxx (2016) 1e13
Scheme 4. Attempted ARYNE coupling starting from aryl para-tolyl sulfoxides.
Scheme 5. Formation of the unexpected ortho-terphenyl compounds 8.
the deiodinated phenol ether, produced by protonation of the
corresponding aryllithium. Compounds 21a,b were obtained with
modest diastereomeric ratios of 60:40 for 21a and 62:38 for 21b. As
expected, 2d gave no improvement of diastereoselectivity, since
attack of the aryllithium nucleophile takes place regioselectively on
the position which is meta to both the TMS and methyl groups, i.e.,
3
e,13
away from steric bulk.
The moderate diastereomeric ratios in
comparison with tert-butylsulfoxide 3c could be caused by the
dynamic structure of the aryllithium and biaryllithium in-
termediates, which could exist as different species in equilibrium,
where the tartrate-derived polyether auxiliary could coordinate
lithium through different oxygen atoms (Scheme 9).
Fig. 1. ORTEP drawing of the major atropo-diastereomer of 8 obtained by X-ray dif-
fraction crystallography.
z
16a afforded, at best, 50% yield of the expected compound, which
was obtained along with numerous unidentified side-products. On
the other hand, the tartrate derivative 16b underwent clean iodine/
2
.4. Aryloxazolines
ꢂ
lithium exchange with BuLi at ꢁ78 C in THF and quantitative
After these studies on sulfur- and oxygen-based chiral auxilia-
methylation after 1 h of reaction time. Encouraged by this model
ries for the atropo-diastereoselective ARYNE coupling, we turned
towards chiral oxazolines, so as to access biphenyls substituted by
a carbon group in position 2. The oxazoline group is a well-known
chiral inductor, and a well-known directing group in polar organ-
ometallic chemistry. Moreover, it was used successfully as chiral
N
auxiliary in arylearyl couplings via an S Ar process involving 2-(2-
reaction, we then opposed 16b to a few ortho-bromoiodobenzenes
5
2
b,d and 20b (Scheme 8), in the coupling conditions that we had
optimized in the case of aryllithium nucleophiles bearing a co-
ordinating group ortho to lithiumdnamely tert-butyl sulfinyl and
oxazolin-2-yl groups.5 We were pleased to obtain coupling
products 21a and 21b, in 59 and 53% yields, respectively (Scheme
14
,3i
14bed,15
magnesioaryl)oxazolines, the Meyers reaction.
We were
8
). Aryne precursor 20b, on the other hand, gave no biaryl prod-
eager to evaluate the parent 2-(2-lithioaryl)oxazolines in the
atropo-diastereoselective ARYNE coupling. Actually, in an attempt
to functionalize achiral 2-(3-chlorophenyl)oxazolines through
lithiation, Meyers already observed an undesired benzyne
uct, which seems surprising since it served as efficient coupling
partner in the reactions with 2-lithioaryloxazolines. In all cases, the
only side-product observed in the reactions of 16b with 2b,d was
Scheme 6. Tentative explanation for the formation of 8.
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D. Augros et al. / Tetrahedron xxx (2016) 1e13
5
Scheme 7. Synthesis of the key phenol 12 and of the chiral diether-bearing substrates 16a,b.
Scheme 8. Atropo-diastereoselective coupling of chiral diether-bearing substrate 16b.
We therefore assessed aryloxazolines 22aed in the ARYNE
5
coupling with 2b or 2d (Table 2). The aryllithium nucleophile was
generated by direct lithiation or by halogen/lithium exchange. The
expected biaryls 23aee were formed along with a side-product, the
corresponding fluorenones 24aed resulting from the cyclization of
the biaryllithium intermediate followed by hydrolysis during work-
upda side-reaction related to that of Scheme 6 in the case of p-tolyl
sulfoxides. This indicates that the rate of intramolecular attack of
the carbanion onto the oxazoline is almost comparable to the rate
of intermolecular trapping with iodine via iodine/lithium exchange
(see Scheme 1). Considering that the fluorenone byproduct and the
desired biaryl are both formed from the same biaryllithium, the
total coupling yield has to be taken into account, which ranges from
48 to 79%. Unfortunately, axial chirality is lost in the planar fluo-
renone, which thus constitutes an issue. Nevertheless, biaryls
23aee showed axial stereoenrichment, with a narrow 66:34e71:29
range of d.r. The diastereoselectivity seems to be slightly influenced
Scheme 9. Dynamic structure of the aryllithium intermediate derived from tartrate.
formation and subsequent attack of aryllithium species onto the 3-
(
oxazolin-2-yl)benzyne (Scheme 10); the attack was not regiose-
lective due to competitive kinetic and thermodynamic controls
6
promoted by the oxazoline directing group. In our case, we plan-
ned to locate the oxazoline group onto the nucleophile, not the
benzyne, so as to overcome such regioselectivity issues and to
better induce atropo-selectivity, by formation of a stereoisomeri-
cally well-defined metallacycle by coordination of the oxazoline to
lithium (Scheme 10); this coordination was expected to take place
via the nitrogen atom of the oxazoline in ethereal solvents, as
shown by Reich.16 For this same reason, we first targeted oxazolines
2
2
by the size of the R group, with a 66:34 d.r. for R ¼iPr and a 69:31
2
1
d.r. for R ¼tBu (Table 2, entries 2e3). The impact of the R group is
less easily rationalized. When comparing entries 1, 2 and 4, where
the same 2-(2-lithioaryl)oxazoline is formed except for the R
1
bearing a stereocenter
a
to nitrogen, so as to bring chirality closest
to the arylearyl bond to be created.
substituent, the d.r. decreases from 71:29 for Me to 66:34 for both
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6
D. Augros et al. / Tetrahedron xxx (2016) 1e13
Scheme 10. Meyers’ oxazolinylbenzyne reaction with alkyl- and aryllithiums and our ARYNE coupling strategy with the oxazoline on the nucleophile.
Table 2
Atropo-diastereoselective ARYNE coupling of chiral aryloxazolines with aryne precursors 2b,d
Entry
S.M.
R1
R2
X
Aryne precursor
Biaryl
Yielda (%)
d.r.b
Fluorenone
Yielda (%)
Total coupling yield (%)
1
2
3
4
5
22a
22b
22c
22d
22b
Me
Cl
Cl
Br
Cl
iPr
iPr
tBu
iPr
iPr
Br
H
H
I
2b
2b
2b
2b
2d
23a
23b
23c
23d
23e
31
53
56
46
41
71:29
66:34
69:31
66:34
66:34
24a
24b
24b
24c
24d
26
23
23
20
7
57
76
79
66
48
H
a
Combined yield of both atropo-diastereomers.
b
Diastereomeric ratio measured by 1H NMR of the crude mixture.
Cl and Br. This trend might seem odd, considering that the relative
size of these groups as 2-substituents of biphenyls has been eval-
uated through the determination of specific thermodynamic in-
crements, which attribute a comparable size for Me and Cl, but
a larger one for Br.17 Finally, and unsurprisingly, the diaster-
eoselectivity remained unchanged when using aryne precursor 2d
instead of 2b (entries 2 and 5), since nucleophilic addition takes
place away from both the methyl and TMS groups.
However, the comparison of entries 2 and 5 of Table 2 delivered
useful additional information; indeed, while the uncongested
aryne precursor 2b led to a 2.3:1 ratio of biaryl with regard to
fluorenone, analogue 2d afforded a much better 5.9:1 ratio in favor
of the desired biaryl. This difference might indicate that cyclization
is disturbed by the proximity of the TMS group and the resulting
oxazolidine (Scheme 11-a).
fluorenone, we imagined introducing two trimethylsilyl groups on
each side of the triple bond of the aryne. The second TMS group
would avoid competitive regioselectivity of the nucleophilic ad-
dition onto the aryne, and ensure the presence of a bulky group
ortho to the newly formed arylearyl bond (Scheme 11-b and -c).
The coplanarization of the two aromatic rings and, hence, the
formation of the fluorenone would then be more difficult. To im-
plement this approach, we chose aryne precursors 20a,b (Scheme
5
8), as we were interested in using the atropodiastereoselective
18
ARYNE coupling in the formal synthesis of (ꢁ)-steganacin, which
bears a benzodioxole moiety (Table 3). 20a,b were initially ob-
tained from 5-bromobenzodioxole by regioselective bromination
or iodination, followed by double trimethylsilylation in in situ
trapping conditions. The iodination step towards 20b was initially
carried out using molecular iodine and silver(I) trifluoroacetate in
5
Consequently, inspired by the result obtained in the case of
stoichiometric amount. We later improved this synthesis using
2
3e/24d, and in order to avoid formation of the undesired
the less expensive combination of N-iodosuccinimide and
Scheme 11. The cyclization issue and the role of bulky substituents in the vicinity of the aryne triple bond.
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D. Augros et al. / Tetrahedron xxx (2016) 1e13
7
Table 3
Atropo-diastereoselective ARYNE coupling of chiral aryloxazolines with bis-silylated aryne precursor 20b
Entry
S.M.
Biaryl
Yielda (%)
d.r.b
1
2
3
4
5
6
7
25a
25b
25c
25d
25e
25f
25g
25g
25h
26a
26b
26c
26d
26e
26f
26g
26g
26h
51
67
52
65
45
0
52:48
56:44
61:39
65:35
52:48
d
c
0
d
d
c,d
8
9
40
56:44
d
0
a
Combined yield of both atropo-diastereomers.
b
c
Diastereomeric ratio measured by 1H NMR of the crude mixture.
Approximate yield, as the biaryl could not be thoroughly isolated from inseparable impurities.
The initial bromine/lithium exchange was performed at ꢁ100 ꢂC instead of ꢁ78 ꢂC.
d
trifluoroacetic acid (see the experimental part). With 20a,b in
hand, we evaluated them in the coupling with aryloxazolines. The
dibrominated precursor 20a soon proved inefficient in the cou-
pling and unable to avoid the formation of the fluorenone. Indeed,
bromine/lithium exchange is slower than iodine/lithium ex-
change, whose rate is comparable with that of the undesired cy-
clization (vide supra). On the other hand 20b led to the expected
biaryls without any cyclized product. Aryloxazolines 25aec,e,
prepared by condensation of various amino-alcohols onto 2-
bromo-3,4,5-trimethoxybenzoic acid, were thus converted to the
For a better understanding of the reaction, we carried out
a variation of different parameters (Table 4). Aryloxazoline 25b was
chosen as test substrate, as it led to a reasonable yield and an im-
provable diastereoselectivity (Table 3, entry 2). First, in THF with
tert-butyllithium as the base, we examined the influence of the rate
of addition of the solution of aryne precursor 20b. Whether added
dropwise quickly or very slowly, no sensible change in yield nor d.r.
was noted (Table 4, entries 1e2). The temperature of that solution
2
of 20b (T ) before cannulation onto the solution of aryllithium
seemed to not have any influence on diastereoselectivity as well,
although a small decrease in yield was observed (entries 1 and 3).
Lowering the temperature of the reaction mixture prior to addition
desired biphenyls 26aec,e under conditions developed for bulky
aryne precursors,3
e,13
with 45e67% yields, which is acceptable for
such congested biphenyls (Table 3, entries 1e3,5). Phenyl-
substituted compounds 25d,g gave unclean reactions and 26d,g
were always formed together with unidentified inseparable
byproducts (entries 4 and 8). Unexpectedly, 25f,h completely
failed to react under the same conditions (entries 6 and 9). This
disparity in reactivity is assumed to arise from side-reactions due
1
of the aryne precursor (T ) caused a drop in yield but again, no
change in d.r. (entries 1 and 4). Having both temperatures T
1
and T
2
ꢂ
equal to ꢁ78 C did not give any visible improvement. We then
evaluated butyllithium instead of tert-butyllithium as the base to
perform the initial lithium/bromine exchange; despite a similar d.r.,
an increased yield was obtained (entries 3 and 6), which might
seem surprising since halogen/lithium exchanges with tBuLi are
usually cleaner than with BuLi, the latter sometimes leading to al-
kylation or protonation products by reaction with butyl halide.
Interestingly, by moving back to tert-butyllithium, but changing the
solvent to toluene, we observed a reversal and improvement of
diastereoselectivity (38:62 in toluene vs 54:46 in THF; entries 5 and
10), while the yield decreased from 61 to 42%. The nature of the
aggregates of aryllithium species, generated during the ARYNE
coupling process, appears therefore to be critical, but remains dif-
ficult to rationalize with the available information. This di-
astereomeric ratio could be improved further by using BuLi (25:75,
to the acidity of the benzylic proton
a to a heteroatom in 25d,g,h
with regard to aryllithium intermediates, and from different, un-
productive aggregation states in the case of 25f,h. Concerning the
modest diastereomeric ratios in 26aed, we proposed a competi-
tion between different steric bulks in the approach of the aryne to
the aryllithium nucleophile and in the transition state, caused by
the TMS groups of the aryne derived from 20b. On the other hand,
the poor diastereoselectivity in the reactions of 25e,g might simply
be due to the remoteness of the stereogenic element with regard
to the site of nucleophilic attack, as lithium is assumed to be co-
5
ordinated to nitrogen (vide supra).
Please cite this article in press as: Augros, D.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.01.047

8
D. Augros et al. / Tetrahedron xxx (2016) 1e13
Table 4
unexpected terphenyl product, arising from ligand coupling at
sulfur. Tartrate-derived chiral diethers yielded the coupling prod-
ucts with moderate diastereoselectivity, ascribed to a dynamic
equilibrium between differently coordinated aryllithium in-
termediates, leading to competing transition states. Oxazolines
gave the most abundant results in terms of coupling, after an
evaluation of different reaction parameters. In particular, the nature
of the aryne precursor, the oxazoline, the alkyllithium base or the
solvent was decisive for obtaining good yields and for diaster-
eoselection. Based on these results, it appears critical to use a chiral
auxiliary, which is not prone to a cyclizing attack by the biar-
yllithium intermediate, leading to loss of axial chirality and side-
reactions. Alternately, the formation of the undesired cyclized
product can be avoided by first, using an iodinated aryne precursor,
since intermolecular in situ iodine/lithium exchange becomes
faster than intramolecular attack on the auxiliary, and second, by
introducing bulky trimethylsilyl groups on both sides of the aryne
triple bond, so as to hinder the rotation around the arylearyl bond
and thus the undesired cyclization. With the collected results in
hand, it will now become possible to avoid pitfalls and to design
Variation of reaction parameters in the atropo-diastereoselective ARYNE coupling of
2
5b with 20ba
ꢂ
( C) n Yieldb (%) d.r. ((S,aR)/(S,aS))c
ꢂ
Entry RLi
Solvent
T
1
( C) T
2
1
2
3
4
5
6
7
8
9
1
1
1
tert-BuLi
THF
THF
THF
THF
THF
THF
THF
ꢁ35
ꢁ35
ꢁ35
ꢁ78
ꢁ78
ꢁ35
ꢁ78
rt.
rt.
1.2
1.2
1.2
1.2
1.2
1.2
1
67
68
57
49
61
75
63
32
34
42
56:44
54:46
54:46
54:46
54:46
52:48
54:46
(35:65) 31:69
(27:73) 25:75
38:62
38:62
56:44
d
tert-BuLi
tert-BuLi
tert-BuLi
tert-BuLi
BuLi
BuLi
BuLi
BuLi
tert-BuLi
ꢁ35
rt.
ꢁ78
ꢁ35
ꢁ78
ꢁ78
ꢁ78
ꢁ78
ꢁ78
ꢁ78
e
Toluene ꢁ78
Toluene ꢁ78
Toluene ꢁ78
1
e
1,2
1,2
1,2
0
1
2
f
suitable chiral auxiliaries towards a truly efficient atropo-
diastereoselective ARYNE coupling, both in terms of yield and
diastereoselectivity.
tert-BuLi rev. Toluene ꢁ78
41
f
g
tert-BuLi rev. THF
ꢁ78
1,2 <25
a
ꢂ
General procedure: to a solution of substrate 26 b at ꢁ78 C was added a solu-
tion of butyllithium (1 equiv) or tert-butyllithium (2 equiv). After stirring for 15 min,
the reaction vessel was transferred to a bath at temperature T . A solution of the
aryne precursor 20 b at temperature T in the same solvent was cannulated onto the
4. Experimental section
1
2
reaction mixture, which was then allowed to stir from T
1
to rt over 15 h.
4.1. General methods
b
Combined yield of both atropo-diastereomers.
c
S,aR)-26b/(S,aS)-26b diastereomeric ratio measured by 1H NMR of the crude
(
Starting materials, if commercially available, were purchased
mixture; absolute configuration of each diastereomer had been performed via X-ray
diffraction crystallography.
5
and used as received after checking their purity. When known
compounds had to be prepared according to literature procedures,
pertinent references are given. Air and moisture-sensitive materials
were stored in Schlenk tubes under argon. Et O and THF were dried
2
by distillation over sodium/benzophenone after the characteristic
dark blue or purple color of mono- or disodium diphenyl ketyl had
d
The solution of 20b was added at a very slow rate.
e
1
In the H NMR spectrum of the crude, the signal of an impurity was overlapping
with the signal of the minor atropomer of 26b, giving an underestimated d.r. value
in brackets); the d.r. of the mixture of atropomers after purification is given without
brackets.
(
f
ꢂ
C
The order of addition was reversed: a solution of the substrate (25b) at ꢁ78
ꢂ
was added onto a ꢁ78 C solution of tert-BuLi in the solvent.
2 2 2
been found to persist. CH Cl was dried over CaH under argon.
g
The yield was estimated to be inferior to 25% by 1H NMR analysis of the crude
Diisopropylamine and triethylamine were dried over KOH under
argon. Anhydrous toluene was bought from SigmaeAldrich and
used as received. Melting ranges (mp) given were found to be re-
producible after recrystallization, unless stated otherwise
(‘decomp.’), and are uncorrected. Thin-Layer chromatography (TLC)
was carried out on 0.25 mm Merck silica-gel (60-F254). Column
chromatography was carried out on silica gel by using MERCK silica
reaction mixture.
entry 9) instead of tBuLi (38:62, entry 10) in toluene, but at the
expense of yield, which decreased to 34%. We also observed a slight
decrease of diastereoselectivity when using only 1 equiv of 20b
instead of 1.2 (entries 8e9), presumably due to a reduced rate of the
attack of the aryllithium onto the aryne when the latter is present
in lower amounts. Last but not least, the order of addition in the
generation of the aryllithium derived from 26b appeared irrelevant
in toluene (entries 10e11), but not in THF, where the reverse ad-
dition gave a dramatic drop of yield (entry 12) in comparison with
the normal addition (entry 5). It is noteworthy that for all reactions
in toluene, the main side-product was the protodebrominated
substrate, indicating a diminished reactivity of the aryllithium in
the halogen/lithium exchange with 20b and in the attack onto the
aryne, which is assumed to be caused by the higher aggregation
state of that intermediate in the apolar non-coordinating solvent.
(40e63 mm). Butyllithium (1.6 M in hexanes, SigmaeAldrich) and
tert-butyllithium (1.7 M in pentanes, SigmaeAldrich) were used as
solutions and their concentrations were determined following the
Wittig-Harborth Double Titration method ((total base)ꢁ(residual
19
base after reaction with 1,2-dibromoethane)). NMR spectra were
1
13
13
recorded on Bruker Avance300 ( H NMR¼300 MHz,
C
C
1
NMR¼75.5 MHz) and Bruker Avance400 ( H NMR¼400 MHz,
NMR¼100.6 MHz). Chemical shifts were referred on partial deu-
1
13
terated chloroform (
d
[ H]¼7.26 and accordingly
d
[
C]¼77.16 ppm)
and given in ppm on the d-scale. Multiplicities were abbreviated as
s (singlet), bs (broad singlet) d (doublet), t (triplet), q (quartet) and
m (multiplet). Coupling constants were given in Hz. The spectra
were processed with programs Bruker TOPSPIN 2.1, Mestrelab
MestReNova lite 5.2.5 or NMRTEC NMRnotebook. IR-spectra of neat
3
. Conclusion
Ô
products were recorded on Perkin Elmer’s Spectrum One . Mass
The atropo-selective coupling of in situ generated arynes and
spectra and elementary analysis were carried out by the Analytical
Service of the University of Strasbourg. The angles of rotation were
measured on a Perkin Elmer Polarimeter 341 and denoted as spe-
aryllithiums bearing various chiral auxiliaries ortho to lithium was
performed. tert-Butyl sulfoxides gave low to high yields of the
coupling product with variable diastereoselectivity. para-Tolyl
sulfoxides, on the other hand, were unable to produce the desired
biaryls, mainly because of a lack of reactivity of the 2-lithiophenyl
p-tolyl sulfoxide intermediates towards halogen/lithium exchange
and/or trapping by the aryne; yet they afforded in one case an
2
0
D
cific rotations: [a] . The Radiocrystallography Service of the Uni-
versity of Strasbourg carried out Crystal X-ray diffraction analyses.
When two diastereomers of unknown absolute configuration were
obtained, they were referred to as ‘atropo-diastereomer 1’ and
‘atropo-diastereomer 2’.
Please cite this article in press as: Augros, D.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.01.047

D. Augros et al. / Tetrahedron xxx (2016) 1e13
9
Compounds 1aec, 2c,13 3bed,3i (S)-5a, (S)- and (ꢀ)-5b, (S)-
3
i
20
21
chlorophenol (5.00 g, 38.9 mmol) in acetone (97 mL, C¼0.4 mol/
2
23
5
5
5
5
5
6
(
a,2 17, 20a,b,5 22aed, 23aed, 24aec, 25aeh, 26aee,g,
S,aR)- and (S,aS)-26b, and 27 were synthesized in our previous
L). The suspension was stirred vigorously and the temperature of
5
5
ꢂ
the reaction mixture was decreased to 0 C. Methoxymethyl chlo-
reports or according to literature.
ride (MOMCl) (4.44 mL, 58.4 mmol, 1.5 equiv) was added to the
reaction mixture. Then, the reaction mixture was allowed to gently
reach 25 C. Water was added (90 mL) and the reaction mixture was
ꢂ
4
.2. Synthesis of coupling partners
diluted with ethyl acetate (90 mL). The layers were separated and
the aqueous layer was extracted with diethyl ether (3ꢃ90 mL). The
combined organic layers were washed with brine (90 mL), dried
4
.2.1. (S)-(tert-Butyl sulfinyl)benzene (1d).7b A pre-cooled solution
of (S)-tert-butyl tert-butanethiosulfinate (1 equiv, 745 mg,
3
.83 mmol) in THF (18.6 mL, C¼0.2 mol/L) was added to a solution
2 4
over Na SO , filtered and evaporated to dryness. The crude residue
was purified by column chromatography on silica gel (eluent:
ꢂ
of phenyllithium* in diethyl ether (2 equiv, 7.66 mmol) at ꢁ78 C.
ꢂ
After 2 h at ꢁ78 C, water was added (10 mL). The layers were
pentane) to afford 10 as a colorless liquid (6.04 g, 35.0 mmol, 90%).
1
separated and the aqueous layer was extracted with dichloro-
H NMR (CDCl
3
, 300 MHz):
d
¼7.22 (t, J¼8.1 Hz, 1H), 7.08 (t,
methane (2ꢃ10 mL). The combined organic layers were dried over
J¼2.1 Hz, 1H), 7.01 (dt, J¼8.1, 0.6 Hz,1H), 6.95 (ddd, J¼8.1, 2.1, 0.6 Hz,
13
Na
2
SO
4
, filtered and evaporated to dryness. The crude product was
1H), 5.18 (s, 2H, CH2), 3.50 (s, 3H, Me) ppm. C NMR (CDCl
75 MHz): OMe), 134.8 (CIV, CCl), 130.2, 122.0,
¼158.0 (CIV, COCH
116.8, 114.6, 94.5 (CH ), 56.1 (CH ) ppm.
3
,
purified by column chromatography on silica gel (eluent: cyclo-
hexane/AcOEt 7/3) to afford (S)-(tert-butyl sulfinyl)benzene 1d as
d
2
2
3
a colorless solid (587 mg, 3.22 mmol, 84%).
1
H NMR (CDCl
3
, 300 MHz):
d
¼7.54e7.51 (m, 2H), 7.43e7.41 (m,
4.2.5. 1-Chloro-2-iodo-3-(methoxymethoxy)benzene
(11). sec-
13
3
H), 1.10 (s, 9H, CMe
3
) ppm. C NMR (CDCl , 75 MHz):
3
d
¼140.1 (CIV
,
Butyllithium (1.4 M in cyclohexane, 29.0 mL, 40.6 mmol, 2 equiv)
was added dropwise to a solution of 1-chloro-3-(methoxymethoxy)
benzene 10 (3.50 g, 20.3 mmol) in THF (203 mL, C¼0.1 mol/L)
CS(O)CMe
CMe
found 205.0655.
3
), 131.1, 128.3 (2C), 126.3 (2C), 55.8 (C
4
, CMe ), 22.9
H14OSNa calcd 205.0658,
3
þ
(
3
) ppm. HRMS (ESI) [MþNa] for C10
ꢂ
cooled to ꢁ78 C. The reaction mixture was stirred during 2.5 h at
2
0
ꢂ
[
a
]
D
¼ꢁ171.5 (c 1, CHCl
3
).
ꢁ78 C. A solution of iodine (7.72 g, 30.4 mmol, 1.5 equiv) in tet-
ꢂ
Mp¼87e89 C.
rahydrofuran (30 mL, C¼1 mol/L) was added to the reaction mix-
ture in one portion and the cooling bath was removed immediately.
Once the mixture had warmed up to rt, it was quenched by addition
[*Phenyllithium was prepared by adding tert-butyllithium
(
1.7 M in pentane, 2.0 equiv) to iodobenzene (1 equiv) in diethyl
ꢂ
ether (4 mL/mmol iodobenzene) and stirring for 30 min at ꢁ78 C.
The absence of tert-butyllithium was verified by means of a Gilman
test II reaction.]24
2 2 3
of a saturated aqueous solution of Na S O (200 mL). The layers
were separated and the aqueous layer was extracted with diethyl
ether (3ꢃ200 mL). The combined organic layers were dried over
2 4
Na SO , filtered and evaporated to dryness. The crude compound 11
ꢂ
4
.2.2. (2-Bromo-3-iodo-5-tolyl)trimethylsilane (2d). At 0 C and
(5.70 g, 19.1 mmol, 94%) was used directly in the next step without
under argon, butyllithium (1.6 M in hexanes, 2 equiv, 50.0 mL,
0.0 mmol) was added to solution of 2,2,6,6-
tetramethylpiperidine (2 equiv, 13.5 mL, 80.0 mmol) in THF
40 mL, C¼2.0 mol/L). This solution of LTMP was then added
dropwise by cannula to a solution of 3-iodo-4-bromotoluene
purification.
1
8
a
H NMR (CDCl
3
, 300 MHz):
d
¼7.23 (t, J¼8.1 Hz, 1H), 7.16 (dd,
J¼8.1, 1.2 Hz, 1H), 6.97 (dd, J¼8.1, 1.2 Hz, 1H), 5.27 (s, 2H, CH2), 3.53
13
(
(s, 3H, Me) ppm. C NMR (CDCl
COCH OMe), 139.8 (CIV, CCl), 129.7, 122.9, 112.3, 95.2 (CH
CI), 56.5 (Me) ppm.
3
, 75 MHz):
d
¼157.9 (CIV
,
,
2
2
), 92.5 (C
4
(
(
1
equiv, 5.70 mL, 40.0 mmol) and trimethylsilyl chloride
ꢂ
2 equiv,10.2 mL, 80.0 mmol) in THF (40 mL, C¼1.0 mol/L) at ꢁ78 C.
ꢂ
4.2.6. 3-Chloro-2-iodophenol (12).26 Concentrated HCl (20 mL) was
added dropwise to a solution of 1-chloro-2-iodo-3- (methox-
ymethoxy)benzene 11 (5.64 g,18.9 mmol) in methanol (33 mL). The
reaction mixture turned into a white emulsion. MeOH (20 mL) was
added and the reaction mixture became homogeneous. After stir-
The reaction mixture was stirred for 45 min at ꢁ78 C, then
ꢂ
quenched with MeOH (80 mL) at ꢁ78 C followed by water (80 mL)
ꢂ
at 25 C. The layers were separated and the aqueous layer was
extracted with diethyl ether (3ꢃ160 mL). The combined organic
2 4
layers were dried over Na SO , filtered and evaporated to dryness
ꢂ
to afford a yellow oil. The crude mixture was crystallized from
ring for 12 h at 25 C, water was added (50 mL) followed by diethyl
ether (50 mL). The layers were separated and the aqueous layer was
ꢂ
methanol at ꢁ20 C to afford a colorless solid (11.7 g, 31.7 mmol,
7
9%).
extracted with diethyl ether (3ꢃ50 mL). The combined organic
1H NMR (CDCl
J¼1.8 Hz, 1H), 2.24 (s, 3H, Me), 0.37 (s, 9H, SiMe
CDCl , 75 MHz):
04.1 (CIV), 20.5 (Me), ꢁ0.27 (SiMe
, 300 MHz):
d
¼7.72 (d, J¼1.5 Hz, 1H), 7.17 (d,
3
2 4
layers were dried over Na SO , filtered and evaporated to dryness.
13
3
) ppm. C NMR
The crude residue was purified by column chromatography on silica
gel (eluent: pentane/AcOEt 8/2) to afford 3-chloro-2-iodophenol 12
(
1
3
d
¼143.6 (CIV), 142.0, 137.9 (CIV), 136.7, 133.0 (CIV),
3
) ppm. Elemental analysis calcd
as a colorless solid (4.43 g, 17.4 mmol, 92%).
ꢂ
1
(
%) C 32.54, H 3.82; found C 32.39, H 3.93. Mp¼76e78 C.
H NMR (CDCl
3
, 300 MHz):
d
¼7.19 (t, J¼6.0 Hz, 1H), 7.05 (dd,
J¼6.0, 1.2 Hz, 1H), 6.89 (dd, J¼6.0, 1.2 Hz, 1H), 5.51 (s, 1H, OH) ppm.
13
4
.2.3. (S)- and (ꢀ)-1-Chloro-2-iodo-3-(p-tolylsulfinyl)benzene ((S)-
and (ꢀ)-6b). Compounds (S)-6b (3.50 g, 9.29 mmol, 93%) and
ꢀ)-6b (3.58 g, 9.50 mmol, 95%) were prepared analogously to 6a,
starting from (S)- and (ꢀ)-5b (2.51 g, 10 mmol).
C NMR (CDCl
3
, 75 MHz):
d¼156.6 (CIV, COH),138.5 (CIV, CCl),130.2,
121.6, 112.8, 91.1 (CIV, CI) ppm. Elemental analysis calcd (%) C 28.32,
H 1.58; found C 28.65, H 1.96. Mp¼54e56 C.
ꢂ
(
1
H NMR (CDCl
J¼8.1 Hz, 2H), 7.59e7.54 (m, 2H), 7.24 (d, J¼7.8 Hz, 2H), 2.36 (s, 3H,
Me) ppm. 13C NMR (CDCl
, 75 MHz):
¼151.4 (CIV), 142.6 (CIV), 141.2
IV), 140.0 (CIV), 131.5, 130.4, 130.2 (2C), 127.3 (2C), 124.8, 97.9 (CIV),
1.6 (Me) ppm. Elemental analysis calcd (%) C 41.46, H 2.68; found
3
, 300 MHz):
d
¼7.96e7.88 (m, 1H), 7.66 (d,
4.2.7. (1R,2R)-2-((tert-Butyldimethylsilyl)oxy)-1,2-diphenylethanol
(13). (R,R)-(þ)-Hydrobenzoin (107 mg, 0.5 mmol) and imidazole
(85 mg, 1.25 mmol, 2.5 equiv) were charged in a dry Schlenk tube
equipped with a stirring bar. Dry dichloromethane (2.5 mL,
C¼0.2 mol/L) was added. The reaction mixture was stirred until
3
d
(
C
2
ꢂ
ꢂ
C 41.38, H 2.86. Mp¼137e139 C.
complete dissolution of solids, and then cooled to 0 C. tert-Butyl-
dimethylsilyl chloride (TBDMSCl) (90 g, 0.6 mmol, 1.2 equiv) was
4
.2.4. 1-Chloro-3-(methoxymethoxy)benzene (10).25 Potassium car-
added in one portion to the reaction mixture, which was allowed to
ꢂ
bonate (27.0 g, 195 mmol, 5 equiv) was added to a solution of 3-
reach 25 C over 12 h. A saturated aqueous solution of NH
4
Cl
Please cite this article in press as: Augros, D.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.01.047

10
D. Augros et al. / Tetrahedron xxx (2016) 1e13
(
10 mL) was added and the reaction mixture was diluted with
and iodomethane (239
m
L, 3.84 mmol, 3.2 equiv) was added rapidly.
ꢂ
dichloromethane (10 mL). The layers were separated and the
The mixture was then stirred at 25 C during 12 h. Water was added
(0.5 mL). The layers were separated and the aqueous layer was
extracted with hexane (3ꢃ1 mL). The combined organic layers were
aqueous layer was extracted with dichloromethane (3ꢃ10 mL). The
2 4
combined organic layers were dried over Na SO , filtered and
evaporated to dryness. The crude residue was purified by column
2 4
dried over Na SO , filtered and evaporated to dryness. The crude
chromatography on silica gel (eluent: pentane/AcOEt 8/2) to afford
residue was purified by column chromatography on silica gel (el-
uent: pentane/AcOEt 8/2) to afford 16a as a colorless solid (562 mg,
13 as a colorless oil (155 mg, 0.47 mmol, 94%). [Note: when per-
formed on a larger scale starting from 1.97 g of the diol, the reaction
gave an unoptimized yield of 65%]
1.21 mmol, >99%).
1
H NMR (CDCl
3
, 300 MHz):
d
¼7.33e7.30 (m, 2H), 7.23e7.16 (m,
1
H NMR (CDCl
3
, 300 MHz):
d
¼7.23e7.20 (m, 6H), 7.11e7.06 (m,
8H), 6.86e6.84 (m, 2H), 6.30 (t, J¼4.5 Hz, 1H), 5.24 (d, J¼5 0.7 Hz,
13
4
H), 4.64e4.57 (m, 2H), 3.31 (d, J¼2.1 Hz,1H, OH), 0.91 (s, 9H, CMe
3
),
1H, CHOAr), 4.46 (d, J¼6.0 Hz,1H, CHOMe), 3.15 (s, 3H, Me) ppm.
C
13
Ar
ꢁ
0.04 (s, 3H, SiMe), ꢁ0.22 (s, 3H, SiMe) ppm. C NMR (CDCl
3
,
NMR (CDCl
3
, 75 MHz):
d¼157.8 (CIV, C O), 139.7 (CIV), 137.7 (CIV),
7
5 MHz):
d¼140.8 (CIV, CCHOSi), 139.9 (CIV, CCHOH),127.9 (2C), 127.8
137.2 (CIV), 129.3, 128.5 (2C), 128.2 (2C), 128.1, 128.0, 127.9 (2C),
127.5 (2C), 121.7 (C HCCl), 111.2 (C HCO), 92.0 (CIV, CI), 86.7
Ar
Ar
(
2
2C), 127.6, 127.5, 127.1 (2C), 127.1 (2C), 80.8 (CHOSi), 79.4 (CHOH),
5.8 (SiCMe ), 18.2 (CIV, SiCMe
mental analysis calcd (%) C 73.12, H 8.59; found C 73.01, H 8.63.
HRMS (ESI) [MþNa] for C20
þ
3
3
), ꢁ4.61 (Me), ꢁ5.26 (Me) ppm. Ele-
(CHOMe), 84.3 (CHOAr), 57.6 (Me) ppm. HRMS (ESI) [MþNa] for
C
21
H
18ClIO
2
Na calcd 486.993; found 486.992.
þ
ꢂ
H
28
O
2
SiNa calcd 351.176; found 351.175.
Mp¼115e117 C.
4
.2.8. tert-Butyl((1R,2S)-2-(3-chloro-2-iodophenoxy)-1,2-
4.2.11. (((2S,3R)-1,4-Bis(benzyloxy)-3-(3-chloro-2-iodophenoxy)bu-
tan-2-yl)oxy) (tert-butyl)dimethylsilane (18). Compound 18 was
synthesized analogously to 14 starting from 17 (918 mg, 2.20 mmol)
and 12 (617 mg, 2.42 mmol, 1.1 equiv). The crude material was
purified by column chromatography on silica gel (eluent: pentane/
diphenylethoxy)dimethylsilane (14). In a dry Schlenk flask equipped
with a stirring bar were introduced 13 (1.97 g, 6.00 mmol), 12
(
6
1.68 g, 6.60 mmol, 1.1 equiv) and triphenylphosphine (1.73 g,
.60 mmol, 1.1 equiv). The flask was purged with a weak stream of
argon. THF was added (60 mL, C¼0.1 mol/L). The mixture was
AcOEt 8/2) to afford 18 as a pale yellow oil (1.16 g, 1.78 mmol, 81%).
ꢂ
1
stirred until complete dissolution of the solids, and cooled to 0 C.
H NMR (CDCl
3
, 400 MHz):
d
¼7.28e7.18 (m, 10H), 7.06 (t,
Diisopropyl azodicarboxylate (1.30 mL, 6.60 mmol, 1.1 equiv) was
J¼8.0 Hz,1H), 7.00 (d, J¼8.0 Hz,1H), 6.82 (d, J¼8.0 Hz,1H), 4.65e4.62
(m, 1H), 4.45 (d, J¼9.2 Hz, 2H), 4.43 (d, J¼8.0 Hz, 2H), 4.14e4.10 (m,
1H), 3.83 (dd, J¼10.8, 2.8 Hz, 1H), 3.72 (dd, J¼17.2, 10.8 Hz, 1H),
ꢂ
added dropwise and the reaction mixture was stirred from 0 C to
ꢂ
2
5 C during 12 h. The crude reaction mixture was concentrated to
dryness, taken up in dichloromethane and concentrated again. The
crude residue was purified by column chromatography on silica gel
3.57e3.56 (m, 2H), 0.80 (s, 9H, SiCMe
3
), 0.00 (s, 3H, SiMe), ꢁ0.03 (s,
13
Ar
3H, SiMe) ppm. C NMR (CDCl
3
,101 MHz):
d
¼159.3 (CIV, C O), 139.6
(
eluent: pentane/AcOEt 8/2) to afford 14 as a colorless solid (1.69 g,
(CIV), 138.2 (CIV), 138.1 (CIV), 129.6, 128.4 (2C), 128.3 (2C), 127.7 (2C),
127.6, 127.6 (2C), 127.5, 121.8 (C HCCl), 111.6 (C HCO), 92.7 (CIV, CI),
Ar
Ar
3
.00 mmol, 50%).
1
H NMR (CDCl
3
, 300 MHz):
d
¼7.71 (dd, J¼7.5, 1.2 Hz, 2H),
80.8, 73.5 (CII), 73.4 (CII), 71.5 (CII), 71.3, 69.5 (CII), 25.9 (SiCMe
(CIV, SiCMe
for C30 38ClIO
3
), 18.1
þ
7
.59e7.41 (m, 8H), 7.10e7.08 (m, 2H), 6.55e6.51 (m, 1H), 5.27 (d,
J¼7.2 Hz, 1H), 5.10 (d, J¼7.2 Hz, 1H), 0.91 (s, 9H, CMe ), ꢁ0.16 (s, 6H,
SiMe , 75 MHz):
) ppm. 13C NMR (CDCl
¼157.7 (CIV, C O), 141.9
IV), 139.6 (CIV), 137.8 (CIV), 129.2, 128.1 (3C), 128.0 (2C), 127.8 (2C),
3
), ꢁ4.51 (SiMe), ꢁ4.73 (SiMe) ppm. HRMS (ESI) [MþNa]
3
H
4
SiNa calcd 675.116; found 675.107.
Ar
2
3
d
(
C
4.2.12. (2S,3R)-1,4-Bis(benzyloxy)-3-(3-chloro-2-iodophenoxy)bu-
Ar
Ar
ꢂ
1
27.7 (2C), 127.7, 121.5 (C HCCl), 111.1 (C HCO), 91.9 (CIV, CI), 85.8,
tan-2-ol (19). To a 0 C solution of 18 (999 mg, 1.53 mmol) in THF
7
8.1, 25.7 (SiCMe
3
), 18.0 (CIV, SiCMe
3
), ꢁ5.04 (SiMe), ꢁ5.65 (SiMe)
(7.7 mL, C¼0.2 mol/L) was added a solution of tetra-n-buty-
þ
ppm. HRMS (ESI) [MþNa] for C26
H
30ClIO SiNa calcd 587.065;
2
lammonium fluoride (1 M in THF, 3.06 mL, 3.06 mmol, 2 equiv).
ꢂ
ꢂ
found 587.064. Mp¼99e101 C.
The reaction mixture was allowed to warm to 25 C while stirring
over 12 h, then neutralized with a saturated aqueous solution of
4
.2.9. (1R,2S)-2-(3-Chloro-2-iodophenoxy)-1,2-diphenylethan-1-ol
4
NH Cl. The organic and aqueous layers were separated and the
ꢂ
(15). To a 0 C solution of 14 (740 mg, 1.31 mmol) in THF (6.5 mL,
aqueous layer was extracted with diethyl ether (3ꢃ7 mL). The
C¼0.2 mol/L) was added a solution of tetra-n-butylammonium
combined organic layers were washed with brine (7 mL), dried
fluoride (1 M in THF, 2.62 mL, 2.62 mmol, 2 equiv). The reaction
2 4
over Na SO , filtered and evaporated to dryness. The crude resi-
due was purified by column chromatography on silica gel (eluent:
pentane/AcOEt 8/2) to afford 19 as a pale yellow oil (776 mg,
ꢂ
mixture was allowed to warm to 25 C while stirring over 12 h, then
was neutralized with a saturated aqueous solution of NH Cl. The
4
layers were separated and the aqueous layer was extracted with
1.44 mmol, 94%).
1
diethyl ether (3ꢃ6 mL). The combined organic layers were washed
H NMR (CDCl
3
, 400 MHz):
d
¼7.28e7.11 (m, 10H), 7.06 (t,
with brine (6 mL), dried over Na
2
SO
4
, filtered and evaporated to
J¼8.0 Hz, 1H), 6.99 (dd, J¼8.0, 1.2 Hz, 1H), 6.77 (dd, J¼8.4, 1.2 Hz,
1H), 4.50e4.35 (m, 5H), 4.07e4.00 (m, 1H), 3.80 (dd, J¼10.8, 3.6 Hz,
1H), 3.71 (dd, J¼10.8, 5.6 Hz, 1H), 3.65e3.59 (m, 2H), 2.56 (d,
dryness. The crude residue was purified by column chromatogra-
phy on silica gel (eluent: pentane/AcOEt 8/2) to afford 15 as a col-
orless oil (580 mg, 1.29 mmol, 98%).
13
Ar
J¼6.0 Hz, 1H) ppm. C NMR (CDCl
3
, 101 MHz):
d
¼158.8 (CIV, C O),
1
H NMR (CDCl
3
, 300 MHz):
d
¼7.24e7.15 (m, 8H), 7.06e7.03 (m,
139.7 (CIV), 137.8 (CIV), 137.7 (CIV), 129.7, 128.4 (2C), 128.4 (2C), 127.9
Ar
Ar
2
5
H), 6.89e6.87 (m, 2H), 6.32e6.29 (m, 1H), 5.24 (d, J¼5.1 Hz, 1H),
(3C), 127.7, 127.6 (2C), 122.4 (C HCCl), 112.1 (C HCO), 93.0 (CIV, CI),
79.8, 73.6 (CII), 73.5 (CII), 70.5, 70.2 (CII), 69.6 (CII) ppm.
13
.09 (t, J¼4.5 Hz, 1H), 2.58 (d, J¼4.2 Hz, 1H, OH) ppm. C NMR
Ar
(
(
(
CDCl
3
, 75 MHz):
d¼157.5 (CIV, C O), 139.7 (CIV), 138.9 (CIV), 135.5
C
C
IV), 129.5, 128.4, 128.3 (2C), 128.0 (3C), 127.5 (2C), 127.3 (2C), 122.1
4.2.13. (2R,3S)-1,4-Bis(benzyloxy)-2-(3-chloro-2-iodophenoxy)-3-
methoxybutane (16b). Compound 16b was synthesized analogously
to 16a starting from 19 (700 mg, 1.30 mmol). The crude residue was
purified by column chromatography on silica gel (eluent: pentane/
AcOEt 8/2) to afford 16b as a pale yellow oil (603 mg, 1.09 mmol,
84%).
Ar
Ar
HCCl), 111.5 (C HCO), 92.3 (CIV, CI), 85.4, 76.9 ppm.
4
.2.10. (1S,2R)-1-(3-Chloro-2-iodophenoxy)-2-methoxy-1,2-
diphenylethane (16a). A solution of 15 (540 mg, 1.20 mmol) in THF
(
(
0.48 mL, C¼2.5 mol/L) was added dropwise to a cooled suspension
ꢂ
1H NMR (CDCl
J¼8.4 Hz, 1H), 7.10 (d, J¼7.6 Hz, 1H), 6.87 (d, J¼8.4 Hz, 1H),
0
C) of NaH (40.3 mg, 1.68 mmol, 1.4 equiv) in THF (0.37 mL,
3
, 400 MHz):
d
¼7.37e7.23 (m, 10H), 7.18 (t,
ꢂ
C¼4.6 mol/L). The mixture was stirred at 0 C for additional 10 min
Please cite this article in press as: Augros, D.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.01.047

D. Augros et al. / Tetrahedron xxx (2016) 1e13
11
ꢂ
ꢂ
4
3
.75e4.71 (m, 1H), 4.62e4.47 (m, 4H), 3.91e3.70 (m, 5H), 3.52 (s,
a ꢁ78 C solution of 2c in THF onto the reaction medium at ꢁ78 C,
followed by 0.2 equiv of BuLi. The product was purified by column
chromatography on silica gel (eluent: cyclohexane/AcOEt 7/3). (S)-
H, OMe) ppm. 13C NMR (CDCl
, 101 MHz):
d
¼158.9 (CIV, C O),
Ar
3
139.7 (CIV), 138.1 (CIV), 137.9 (CIV), 129.6, 128.3 (4C),127.7 (2C), 127.6,
Ar
Ar
0
127.5, 127.5 (2C), 122.0 (C HCCl), 111.5 (C HCO), 92.7 (CIV, CI), 79.4,
(2-Bromo-2 -(tert-butylsulfinyl)-5-methylbiphenyl-3-yl)trime-
7
8.9, 73.5 (CII), 73.5 (CII), 69.1 (CII), 68.2 (CII), 58.7 (OMe) ppm. HRMS
thylsilane 4c was obtained as a 1:1 mixture of two atropo-
diastereomers as a pale yellow oil (237 mg, 0.560 mmol, 51%). At-
tempts to obtain correct elemental analysis failed probably due to
þ
(
ESI) [MþNa] for C25
4
H26ClIO Na calcd 575.0457; found 575.0504.
4
.2.14. 5-Bromo-6-iodo-4,7-bis(trimethylsilyl)benzo[d][1,3]dioxole
the enclosure of solvent in the oil.
5
1
(20b) dalternative procedure. Under an argon atmosphere, N-
H NMR (CDCl
diastereoisomers): d
7.32e7.22 (m, 3H), 7.19e7.14 (m, 1H), 7.01 (d, J¼1.8 Hz, 1H), 2.33 (s,
3H, Me), 2.31 (s, 3H, Me), 1.05 (s, 9H, S(O)CMe ), 1.02 (s, 9H, S(O)
CMe ), 0.41 (s, 9H, SiMe ), 0.40 (s, 9H, SiMe ) ppm. C NMR (CDCl
75 MHz) (mixture of the two atropo-diastereoisomers):
¼142.8
3
, 300 MHz) (mixture of the two atropo-
¼8.05e7.97 (m, 2H), 7.62e7.41 (m, 5H),
iodosuccinimide (14.4 g, 64.2 mmol, 1.2 equiv) was dissolved in dry
acetonitrile (180 mL) at room temperature, then 5-Bromo-1,3-
benzodioxole (6.44 mL, 53.5 mmol) and trifluoroacetic acid
3
13
(
3.97 mL, 53.5 mol, 1 equiv) were added. The reaction mixture was
3
3
3
3
,
stirred at room temperature for 4 days, sheltered from light, con-
centrated, redissolved in ethyl acetate and quenched with satd.
NaHSO
d
(CIV), 142.2 (CIV), 141.9 (CIV), 141.6 (CIV), 140.1 (CIV), 139.8 (CIV), 139.0
(CIV), 138.3 (CIV), 136.8 (CIV), 136.5 (CIV), 135.9, 135.7, 134.8, 134.1,
132.4, 131.3, 130.1, 130.0, 128.4 (CIV), 128.3 (CIV), 128.1, 128.0, 127.0,
3
. The aqueous layer was extracted with AcOEt, and the
SO , then concen-
combined organic layers were dried over Na
2
4
trated. The residue was crystallized from ethanol to afford 5-
bromo-6-iodo-1,3-benzodioxole as pale brown needles (14.0 g,
126.6, 57.3 (CIV, S(O)CMe
3
), 57.2 (CIV, S(O)CMe
3
), 23.4 (S(O)CMe
3
),
22.9 (S(O)CMe
ppm.
3
), 20.9 (Me, dia1þdia2), ꢁ0.1 (SiMe
3
, dia1þdia2)
4
3.0 mmol, 80%). The product was subsequently bis-
5
trimethylsilylated following our previous procedure, and crude
0b was directly crystallized from ethanol without column chro-
2
4.3.3. 2-(((2R,3S)-1,4-Bis(benzyloxy)-3-methoxybutan-2-yl)oxy)-6-
0
0
matography to afford 20b as white crystals (18.9 g, 40.0 mmol, 93%).
Analytical data of 5-bromo-6-iodo-1,3-benzodioxole and 20b were
identical to those of our previous report.
chloro-2 -iodo-1,1 -biphenyl (21a). Compound 21a was prepared
following the general procedure from 16b (276 mg, 0.5 mmol) and
2b (64
m
L, 0.5 mmol, 1 equiv) using BuLi as the base and adding
ꢂ
ꢂ
a ꢁ78 C solution of 2b in THF onto the reaction medium at ꢁ78 C,
followed by 0.2 equiv of BuLi. 21a was obtained as a mixture of two
atropo-diastereoisomers with a diastereoisomeric ratio of 60:40.
The crude residue was purified by column chromatography on silica
gel (eluent: pentane/AcOEt 8/2) to afford 21a as a pale yellow oil
(186 mg, 0.296 mmol, 59%).
4
.3. Representative general procedure for the atropo-
diastereoselective ARYNE coupling
A solution of butyllithium (1 equiv, 1.6 M in hexanes) or tert-
butyllithium (2 equiv, 1.7 M in pentanes) was added dropwise to
a solution of aryllithium precursor (1 equiv) in dry THF (2.5 mL/
Atropo-diastereoisomer 1 (74 mg, 0.12 mmol, 24%): 1H NMR
ꢂ
ꢂ
mmol) under argon at ꢁ78 C. The mixture was stirred at ꢁ78 C for
(CDCl
3
, 400 MHz):
d
¼7.81 (dd, J¼8.0, 0.8 Hz, 1H), 7.28e7.15 (m,
1
5 min and was then warmed up to the desired temperature. Either
10H), 7.12e7.10 (m, 2H), 7.06 (dd, J¼7.2, 1.2 Hz, 1H), 7.01 (td, J¼8.8,
0.8 Hz, 2H), 6.94 (td, J¼7.6, 1.6 Hz, 1H), 4.55e4.52 (m, 1H), 4.42e30
(m, 4H), 3.66e3.61 (m, 1H), 3.50e3.41 (m, 4H), 3.13 (s, 3H, OMe)
a rt solution of aryne precursor (1 or 1.2 equiv) in dry THF (2.5 mL/
mmol) or the neat aryne precursor was added dropwise. If required,
butyllithium (0.2 equiv) was added dropwise to the reaction me-
13
Ar
ppm. C NMR (CDCl
3
, 101 MHz):
d
¼156.4 (CIV, C O), 141.8 (CIV),
dium. The mixture was stirred for 15 h from the desired tempera-
138.6, 138.2 (CIV), 138.2 (CIV), 134.4 (CIV), 133.2 (CIV), 130.7, 129.5,
129.0, 128.4 (2C), 128.3 (2C), 127.9, 127.7 (2C), 127.6, 127.5, 127.4
(2C), 121.7, 112.2, 100.7 (CIV, CI), 79.8, 78.1, 73.4 (CII), 73.3 (CII), 69.1
(CII), 68.9 (CII), 58.8 (OMe) ppm.
ꢂ
ture to 25 C, quenched with water and extracted with Et
2
O. The
combined organic layers were dried with Na
2
SO
4
and concentrated
under reduced pressure. The crude product was purified by column
chromatography on silica gel, eluting with hexane/EtOAc or pen-
tane/EtOAc mixtures.
Atropo-diastereoisomer 2 (111 mg, 0.18 mmol, 35%): 1H NMR
(CDCl
3
, 400 MHz):
d
¼7.79 (dd, J¼8.0, 0.8 Hz, 1H), 7.29e7.12 (m,
1
2H), 7.02 (d, J¼8.0 Hz, 1H),6.98 (d, J¼8.4 Hz, 1H), 6.917 (td, J¼8.0,
0
0
4
.3.1. (S
S
)-2 -tert-Butyl sulfinyl-6 -chloro-2-iodo-5-methyl-3-
1.6 Hz, 1H), 6.88 (dd, J¼7.6, 1.6 Hz, 1H), 4.55e4.52 (m, 1H),
0
trimethylsilyl-1,1 -biphenyl (4b). Compound 4b was prepared fol-
lowing the general procedure from 1b (238 mg, 1.1 mmol) and 2d
4.42e4.27 (m, 4H), 3.68e3.59 (m, 2H), 3.40e3.31 (m, 2H),
13
3
3.20e3.16 (m, 1H), 3.15 (s, 3H, OMe) ppm. C NMR (CDCl ,
Ar
(
406 mg, 1.1 mmol, 1 equiv) using BuLi as the base and adding
101 MHz):
(CIV), 134.3 (CIV), 133.0 (CIV), 130.6, 129.5, 128.9, 128.3 (2C), 128.3
(2C), 127.8, 127.7 (2C), 127.6, 127.6 (2C), 127.5, 121.6, 111.7, 100.7 (CIV
d¼156.2 (CIV, C O), 141.7 (CIV), 138.7, 138.3 (CIV), 138.1
ꢂ
ꢂ
a ꢁ78 C solution of 2d in THF onto the reaction medium at ꢁ78 C,
followed by 0.2 equiv of BuLi. The product was purified by column
chromatography on silica gel (eluent: pentane/AcOEt 7/3). Only one
atropo-diastereoisomer was isolated as a pale yellow oil (72.2 mg,
,
CI), 79.8, 77.4, 73.6 (CII), 73.6 (CII), 69.1 (CII), 68.5 (CII), 58.5 (OMe)
ppm.
0
.143 mmol, 13%). Attempt to obtain correct elemental analysis
HRMS (ESI) [MþNa]þ for C31
4
H30ClIO Na calcd 651.077; found
failed probably due to the enclosure of solvent in the oil.
651.072.
1
H NMR (CDCl
dd, J¼8.1, 1.2 Hz, 1H), 7.54 (t, J¼7.8 Hz, 1H), 7.22 (d, J¼2.1 Hz, 1H),
.93 (d, J¼1.8 Hz, 1H), 2.31 (s, 3H, Me), 1.09 (s, 9H, S(O)CMe ), 0.45
s, 9H, SiMe , 75 MHz):
) ppm. 13C NMR (CDCl
¼147.6 (CIV), 143.7
IV), 143.4(CIV), 140.7 (CIV), 137.3, 136.0 (CIV), 134.3, 134.3 (CIV),
32.5, 129.4, 126.0, 105.9 (CIV, CI), 57.9 (CIV, S(O)CMe ), 23.7 (3C,
3
, 300 MHz):
d
¼7.92 (dd, J¼7.8, 1.2 Hz, 1H), 7.64
(
6
4.3.4. 2-(((2R,3S)-1,4-Bis(benzyloxy)-3-methoxybutan-2-yl)oxy)-6-
0
0
3
chloro-2 -iodo-5-methyl-3-trimethylsilyl-1,1 -biphenyl
(21b). Compound 21b was prepared following the general pro-
cedure from 16b (200 mg, 0.36 mmol) and 2d (134 mg, 0.36 mmol,
(
(
3
3
d
C
ꢂ
1
3
1 equiv) using BuLi as the base and adding a ꢁ78 C solution of 2d
ꢂ
S(O)CMe
3
), 21.0 (Me), 0.2 (3C, SiMe
3
) ppm.
in THF onto the reaction medium at ꢁ78 C, followed by 0.2 equiv of
BuLi. 21b was obtained as
a
mixture of two atropo-
0
4
.3.2. (S
S
)-2-Bromo-2 -(tert-butylsulfinyl)-5-methyl-3-
diastereoisomers with a diastereoisomeric ratio of 62:38. The
crude residue was purified by column chromatography on silica gel
(eluent: pentane/AcOEt 8/2) to give 21b as a pale yellow oil
(137 mg, 0.19 mmol, 53%). Only one atropo-diastereoisomer could
0
trimethylsilyl-1,1 -biphenyl (4c). Compound 4c was prepared fol-
lowing the general procedure from 1d (201 mg, 1.1 mmol) and 2c
(
354 mg, 1.1 mmol, 1 equiv) using BuLi as the base and adding
Please cite this article in press as: Augros, D.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.01.047

12
D. Augros et al. / Tetrahedron xxx (2016) 1e13
ꢂ
be isolated in atropo-diastereoisomerically pure form (85 mg,
0.53 mmol, 1 equiv) was added at ꢁ78 C. Butyllithium (1.6 M in
0
.12 mmol, 33%).
hexanes, 331
m
L, 0.53 mmol, 1 equiv) was added very slowly to the
1
ꢂ
H NMR (CDCl
3
, 400 MHz):
d
¼7.26e7.15 (m, 9H), 7.12e7.10 (m,
reaction medium at ꢁ78 C. The mixture was stirred for 12 h at
ꢂ
ꢂ
2
1
3
3
H), 7.05 (d, J¼2.4 Hz, 1H), 7.02 (d, J¼8.4 Hz, 1H), 6.99 (d, J¼8.0 Hz,
H), 6.86 (d, J¼1.6 Hz, 1H), 4.55e4.52 (m, 1H), 4.45e4.29 (m, 4H),
.66e3.62 (m, 1H), 3.52e3.48 (m, 2H), 3.44e3.41 (m, 2H), 3.10 (s,
ꢁ78 C. Iodomethane (99
m
L, 1.59 mmol, 3 equiv) was added at
ꢂ
ꢁ78 C and the reaction mixture was allowed to reach 25 C. Water
was added (2 mL). The layers were separated and the aqueous layer
was extracted with ethyl acetate (3ꢃ2 mL). The combined organic
1
3
H, OMe), 2.15 (s, 3H, Me), 0.36 (s, 9H, SiMe
3
) ppm. C NMR (CDCl
¼156.5 (CIV, C O), 146.1 (CIV), 142.3 (CIV), 138.3 (CIV),
38.2 (CIV), 136.7 (CIV), 136.3, 134.6 (CIV), 134.5 (CIV), 131.8, 129.3,
28.3 (2C),128.3 (2C),127.7 (2C),127.6,127.5,127.3 (2C),121.6,112.0,
3
,
Ar
101 MHz):
d
2 4
layers were dried over Na SO , filtered and evaporated to dryness.
1
1
A mixture of two racemic atropo-diastereomers (aR*,R
(aS*,R *)-8 was obtained with a diastereoisomeric ratio of 86:14.
S
*)-8 and
S
1
5
06.3 (CIV, CI), 79.9, 78.2, 73.4 (CII), 73.3 (CII), 69.1 (CII), 68.8 (CII),
The crude mixture was purified by column chromatography on
silica gel (eluent: pentane/AcOEt 7/3) (58 mg, 0.17 mmol, 32%).
8.9 (OMe), 20.9 (Me), 0.06 (3C, SiMe
3
) ppm. HRMS (ESI) [MþNa]þ
1
for C35 40ClIO
H
4
SiNa calcd 737.132; found 737.134.
(ꢀ)-(aR*,R
S
*)-8 (50 mg, 0.15 mmol, 28%): H NMR (CDCl
3
,
4
00 MHz):
d
¼7.86e7.84 (m, 1H), 7.56e7.54 (m, 2H), 7.51 (dd, J¼8.0,
0
0
0
0
4.3.5. (4S)-2-(6-Chloro-2 -iodo-5 -methyl-3 -(trimethylsilyl)-(1,1 -bi-
1.2 Hz, 1H), 7.45 (t, J¼7.6 Hz, 1H), 7.41e7.39 (m, 1H), 7.35 (dd, J¼7.6,
phenyl)-2-yl)-4-isopropyl-4,5- dihydrooxazole (23e) and 5-chloro-3-
methyl-1-(trimethylsilyl)-9H-fluoren-9-one (24d). Compound 23e
was prepared following the general procedure from 22b (246 mg,
1.2 Hz, 1H), 6.99 (s, 4H), 2.44 (s, 3H, S(O)Me), 2.25 (s, 3H, Me) ppm.
13
C NMR (CDCl
3
, 101 MHz):
d
¼144.0 (CIV), 143.9 (CIV), 137.1 (CIV),
136.5 (CIV), 135.1 (CIV), 134.4 (CIV), 134.0 (CIV), 132.0, 130.1, 129.9,
129.3 (3C), 129.1, 128.6 (2C), 128.4, 123.1, 42.3 (S(O)Me), 21.1 (Me)
ppm.
1.1 mmol) and 2d (406 mg, 1.1 mmol, 1 equiv) using BuLi as the base
ꢂ
and adding a ꢁ78 C solution of 2d in THF onto the reaction me-
ꢂ
*)-8 (7 mg, 0.02 mmol, 4%): 1H NMR (CDCl
dium at ꢁ78 C, followed by 0.2 equiv of BuLi. 23e was obtained as
(ꢀ)-(aS*,R
S
3
,
a mixture of two atropo-diastereoisomers with a diastereoisomeric
ratio of 66:34. The crude residue was purified by column chroma-
tography (eluent: hexane/AcOEt 8/2) to give 23e as a pale yellow oil
400 MHz):
d
¼7.89 (dd, J¼8.0, 1.2 Hz, 1H), 7.51 (td, J¼7.6, 1.2 Hz, 1H),
7.44 (td, J¼7.6, 1.2 Hz, 2H), 7.35 (t, J¼7.6 Hz, 1H), 7.28 (dd, J¼8.0,
1.6 Hz, 1H), 7.25 (dd, J¼7.6, 1.2 Hz, 1H), 6.91 (d, J¼2.8 Hz, 4H), 2.19 (s,
13
(
(
84.5 mg, 0.165 mmol, 15%) and 24d as a yellow solid byproduct
23.2 mg, 0.0770 mmol, 7%). Further purification by column chro-
3
3H, S(O)Me), 1.96 (s, 3H, Me) ppm. C NMR (CDCl , 101 MHz):
d
¼144.3 (CIV), 143 0.1 (CIV), 137.3 (CIV), 136.9 (CIV), 136.5 (CIV), 134.9
matography gave both atropo-diastereomers of 23e separately.
(CIV), 134.6 (CIV), 132.2, 130.6, 129.7 (2C), 129.7, 129.7, 128.8 (2C),
128.7, 128.6, 124.1, 41.9 (S(O)Me), 21.0 (Me) ppm.
Compound 23e, atropo-diastereoisomer 1 (pale yellow oil)
1
HRMS (ESI) [MþNa]þ for C20
(
56 mg, 0.11 mmol, 10%): H NMR (CDCl
3
, 300 MHz):
d¼7.68 (dd,
H17ClOSNa calcd 363.058; found
J¼7.8, 0 0.9 Hz,1H), 7.49 (dd, J¼8.1, 0.9 Hz,1H), 7.29 (t, J¼7.8 Hz,1H),
.07 (d, J¼2.1 Hz, 1H), 6.85 (d, J¼1.8 Hz, 1H), 4.95 (dd, J¼9.3, 7.8 Hz,
H), 3.82e3.74 (m, 1H), 3.65 (t, J¼7.8 Hz, 1H), 2.22 (s, 3H, Me),
), 0.67 (s, 3H, CHMe ), 0.37 (s,
, 75 MHz):
¼162.4 (CIV, CNO),
363.057.
7
1
Acknowledgements
1.50e1.41 (m, 1H), 0.69 (s, 3H, CHMe
2
2
9
H, SiMe
3
) ppm. 13C NMR (CDCl
3
d
This work was supported by the CNRS (Centre National de la
Recherche Scientifique, France). B. Y. is very grateful to the Malian
government for a doctoral grant. A.B.B. thanks the ‘Minist eꢁ re de
l’Education Nationale et de la Recherche’ (France) for an MENRT
Ph.D. grant. D. A., A. P. and F. L. thank the French ‘Agence Nationale
pour la Recherche’ (ANR-14-CE06-0003-01, ChirNoCat) for financial
support.
145.7 (CIV), 143.9 (CIV), 143.5 (CIV), 136.1 (2C, one CIV), 134.6 (CIV),
131.3,130.9,130.2 (CIV),128.6,128.0,105.6 (CIV, CI), 72.7 (CHCHMe
2
),
),
7
0
0.2 (CII, CH
.0 (3C, SiMe
Compound 23e, atropo-diastereoisomer 2 (pale yellow oil)
2
), 32.5 (CHMe
2
), 20.8 (Me), 18.4 (CHMe
2
), 18.3 (CHMe
2
3
) ppm.
1
(
28 mg, 0.055 mmol, 5%): H NMR (CDCl
3
, 300 MHz):
d
¼8.17 (s, 1H),
7
4
.89 (d, J¼7.5 Hz, 1H), 7.31e7.28 (m, 2H), 7.10 (t, J¼7.8 Hz, 1H),
.49e4.43 (m, 1H), 3.99e3.86 (m, 2H), 2.39 (s, 3H, Me), 2.13e1.98
References and notes
(
m, 1H), 1.03 (d, J¼6.6 Hz, 3H, CHMe ), 0.84 (d, J¼6.9 Hz, 3H,
2
13
CHMe
2
), 0.30 (s, 9H, SiMe
3
) ppm. C NMR (CDCl
3
, 75 MHz):
1. (a) Gilman, H.; Gorsich, R. D. J. Am. Chem. Soc. 1956, 78, 2217e2222; (b) Gilman,
H.; Gaj, B. J. J. Org. Chem. 1957, 22, 447e449.
d
¼164.3 (CIV, CNO), 140.1 (CIV), 139.7 (CIV), 136.5 (CIV), 136.4, 135.8
IV), 134.5 (CIV), 132.9, 129.4 (CIV), 128.1, 125.8, 125.1, 102.7 (CIV, CI),
9.2 (CHCHMe ), 65.0 (CII, CH ), 31.0 (CHMe ), 22.1 (Me), 20.5
), 19.2 (CHMe
2
. (a) Harada, K.; Hart, H.; Frank Du, C. J. J. Org. Chem. 1985, 50, 5524e5528; (b)
Hart, H.; Harada, K.; Du, C. J. F. J. Org. Chem. 1985, 50, 3104e3110; (c) Du, C. J. F.;
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(
C
6
2
2
2
(
CHMe
2
2
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3
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881e890.
þ
HRMS (ESI) [MþH] for C22
H28ClINOSi calcd 512.067; found
3
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512.070.
1
Compound 24d: H NMR (CDCl
3
, 300 MHz):
d¼7.95 (s, 1H), 7.45
2010, 2953e2955; (d) Bonnafoux, L.; Gramage-Doria, R.; Colobert, F.; Leroux, F.
(
1
d, J¼7.2 Hz, 1H), 7.32 (d, J¼8.1 Hz, 1H), 7.22 (s, 1H), 7.13 (t, J¼7.8 Hz,
R. Chem. Eur. J. 2011, 17, 11008e11016; (e) Diemer, V.; Begaud, M.; Leroux, F. R.;
Colobert, F. Eur. J. Org. Chem. 2011, 341e354; (f) Diemer, V.; Berthelot, A.;
Bayardon, J.; Jug eꢀ , S.; Leroux, F. R.; Colobert, F. J. Org. Chem. 2012, 77, 6117e6127;
13
3 3
H), 2.38 (s, 3H), 0.29 (s, 9H, SiMe ) ppm. C NMR (CDCl , 75 MHz):
d
¼194.9 (CIV, C]O), 145.5 (CIV), 145.5 (CIV), 142.5 (CIV), 141.7 (CIV),
(g) Leroux, F. R.; Berthelot, A.; Bonnafoux, L.; Panossian, A.; Colobert, F. Chem.
1
38.0 (CIV), 137.6 (CIV), 137.3, 137.1, 130.9, 130.4 (CIV), 126.8, 123.4,
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R. Tetrahedron 2014, 70, 1431e1436; (i) Berthelot-Br eꢀ hier, A.; Panossian, A.;
2
3
3.7 (Me), 0.0 (3C, SiMe ) ppm.
0
Colobert, F.; Leroux, F. R. Org. Chem. Front. 2015, 2, 634e644.
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Gresser, M. J.; Garner, J.; Breuning, M. Angew. Chem., Int. Ed. 2005, 44,
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.4. Rearrangement of 2-chloro-2 -lithio-6-(p-toluene-
4
0
sulfinyl)-1,1 -biphenyl
5
384e5427; (b) Wallace, T. W. Org. Biomol. Chem. 2006, 4, 3197e3210; (c)
Kozlowski, M. C.; Morgan, B. J.; Linton, E. C. Chem. Soc. Rev. 2009, 38,
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0
00
4
.4.1. (ꢀ)-(aR*)-6 -Chloro-4 -methyl-2-((R*)-methylsulfinyl)-
3
2
0
0
00
0
00
1,1 :2 ,1 -terphenyl ((aR*,R
S
0
*)-8) & (ꢀ)-(aS*)-6 -chloro-4 -methyl-2-
00
(
(
(R*)-methylsulfinyl)-1,1’:2 ,1 -terphenyl ((aS*,R
S
*)-8). Butyllithium
4
1.6 M in hexanes, 331 mL, 0.53 mmol, 1 equiv) was added to a so-
5
. Yalcouye, B.; Berthelot-Br eꢀ hier, A.; Augros, D.; Choppin, S.; Chess eꢀ , M.; Colobert,
F.; Panossian, A.; Leroux, F. R. Eur. J. Org. Chem. 2015, http://dx.doi.org/10.1002/
ejoc.201501503
lution of (ꢀ)-6b (200 mg, 0.53 mmol, 1 equiv) in THF (2.7 mL,
ꢂ
C¼0.2 mol/L) at ꢁ78 C. 1-Bromo-2-iodobenzene 2b (68
mL,
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