Cine Substitution with Arylzinc Reagents: Scope and Mechanistic Studies

Article abstract of DOI:10.1021/acs.joc.6b00074

The unexpected ability of arylzinc reagents bearing electron-donating substituents to react in a Friedel-Crafts fashion (cine) with electrophiles like perpivaloylated glucoside bromide and benzhydryl bromides in competition with organometallic coupling (ipso) is shown. The stereoelectronic factors required to promote the cine reactivity versus the classical ipso, and the mechanism of this alternative pathway, have been investigated. The Wheland intermediate is deprotonated intramolecularly in a 1,2-shift but also in a longer-range shift, leaving in this case the C-Zn untouched. In the latter case, it is possible to take advantage of this result for further functionalization.

Full text of DOI:10.1021/acs.joc.6b00074

Article
pubs.acs.org/joc
Cine Substitution with Arylzinc Reagents: Scope and Mechanistic
Studies
Santiago Barroso,*,† Sebastien Lemaire,† Vittorio Farina,† Andreas K. Steib,‡ Romain Blanc,‡
́
and Paul Knochel‡
†Pharmaceutical Development and Manufacturing Sciences, Janssen Pharmaceutica, Turnhoutseweg 30, 2340 Beerse, Belgium
‡Department of Chemistry and Biochemistry, Ludwig-Maximilians University of Munchen, Butenandtstrasse 5-12, Haus F, 81377
̈
Munchen, Germany
̈
S
* Supporting Information
ABSTRACT: The unexpected ability of arylzinc reagents bearing electron-donating substituents to react in a Friedel−Crafts
fashion (cine) with electrophiles like perpivaloylated glucoside bromide and benzhydryl bromides in competition with
organometallic coupling (ipso) is shown. The stereoelectronic factors required to promote the cine reactivity versus the classical
ipso, and the mechanism of this alternative pathway, have been investigated. The Wheland intermediate is deprotonated
intramolecularly in a 1,2-shift but also in a longer-range shift, leaving in this case the C−Zn untouched. In the latter case, it is
possible to take advantage of this result for further functionalization.
examples are those involving a benzyne intermediate5 and
INTRODUCTION
■
the von Richter reaction.6 Rare examples are found for
Because of their importance as bioactive compounds, C‑glyco-
reactions where the unsaturated derivative acts as a
sides are a popular area of research for organic and medicinal
nucleophile. One of the best documented ones is the reaction
chemists.1 The recent market introduction of new antidiabetic
of vinyl stannanes in Stille coupling, where the substitution can
SGLT-2 inhibitors like Canagliflozin (1) and Dapagliflozin (2)
occur not only at the carbon bearing the trialkyltin group but
dramatically strengthened the role of C‑glycosides as synthetic
also on the adjacent one.7 It has also been shown that
targets (Figure 1).2
tributylstannyl-substituted furans and thiophenes react with the
benzhydryl cation at a remote position with respect to the one
occupied by the tin atom.8 Another example of cine reactivity is
found in the reaction of electron-rich arylsilanes with
electrophiles, which can lead to ipso or cine products
depending on the conditions employed.9
Related to our discovery is the report that bis(meta-
anisyl)cadmium can undergo acylation either at the meta (ipso
substitution) or at the para (cine substitution) position.10
Figure 1. New SGLT-2 inhibitors as breakthrough antidiabetic
therapy.
However, to the best of our knowledge, no cine reactivity has
been described for arylzinc reagents. Our initial results led us
to a comprehensive mechanistic study, which led to the first
synthetic applications of this unusual reaction mode.
Following up on our recent communication on the direct,
noncatalyzed coupling of aryl- and heteroarylzinc compounds
with bromosugars in toluene/di-n-butyl ether (DBE), we
RESULTS
■
attempted the coupling of meta-substituted arylzinc reagents in
order to broaden the scope of our new reaction.3 We were
Given the unusual observations described in Scheme 1, we
decided to carry out a comprehensive analysis of product
very surprised to observe that coupling reactions of meta-
anisylzinc species (meta-4) with bromosugar 5, in addition to
the expected product meta-6, led to a large amount of cine-
distribution and extend the reaction to related ortho- and para-
substituted anisylzinc derivatives.11 For completeness, we
substitution product para-6 (Scheme 1).
Some examples of cine substitution reactions of arylmetallic
Received: January 12, 2016
compounds are reported in the literature.4 Well-known
© XXXX American Chemical Society
A
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Scheme 1. Cine Substitution with meta-Anisylzinc Reagents
a b
,
Table 1. Yield and Product Distribution of ipso, cine, and tele Products
a
Reaction conditions: dianisylzinc 4a (3.5 mmol) or anisylzinc bromide 4b (6.7 mmol), di-n-butyl ether (2.6 or 5.2 mL respectively), toluene (25
b
c
mL), bromosugar 5 (6.4 mmol), 85 °C. i = ipso (in bold), c = cine, t = tele. Total yields were determined by GC using tetradecane as an internal
standard.
decided to compare also the reactivity of diarylzinc species 4a
with their arylzinc bromide counterparts 4b (Table 1).
As shown in Table 1, we detected in each case a certain
amount of cine products (new substituent ortho to the original
C−Zn bond) and even tele-products (new substituent meta to
the original C−Zn bond). We observed very small amounts of
these unexpected compounds with the organozinc reagents
ortho-4a/b and para-4a/b. Diarylzinc and arylzinc bromide
species gave very similar results for these isomers. However, as
noted before, large amounts of cine products were obtained
with the meta-organozinc reagent meta-4a (entry 3) and,
especially, with arylzinc bromide reagent meta-4b (entry 4). In
B
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Table 2. Effect of organolithium−zinc ratio
a
b
entry equiv of ZnBr2
formal species cine % α-ortho cine % β-ortho ipso % α-meta ipso % β-meta cine % α-para cine % β-para % yield (overall)
1
2
3
4
5
6
7
8
9
0.25
0.33
0.55
1.05
1.05
2.00
2.00
1.05
1.05
R4ZnLi2
R3ZnLi
R2Zn
0.9
1.4
2.1
5.4
6.4
8.0
12.5
6.5
6.5
2.7
3.9
5.1
7.4
7.9
9.4
10.8
7.4
9.9
1.4
1.3
1.5
2.2
2.4
3.4
5.4
2.4
2.7
83.7
67.9
59.2
39.7
42.5
36.2
25.8
38.3
39.1
0.8
2.9
10.5
22.6
26.9
34.4
29.7
29.0
25.8
32.3
30.4
16
40
58
50
nd
nd
nd
60
61
5.2
RZnBr
RZnBr
RZn2Br3
RZn2Br3
RZnBr
RZnBr
10.9
11.1
14.0
19.7
13.1
11.4
c
d
e
f
a
b
c
Added from a 25% solution of ZnBr2·LiBr in nBu2O. Yields were measured by GC using tetradecane as an internal standard. The amount of DBE
d
was doubled after the transmetalation. In this case, 1.0 equiv of solid ZnBr2 and solid LiBr were added after the transmetalation with 1.0 equiv of
25% ZnBr2·LiBr solution in DBE. Reaction ran at 55 °C for 18 h. Reaction ran at 114 °C for 35 min.
e
f
addition, α/β ratios were markedly different for the three
isomeric products: whereas the ipso substitution product was
formed with an α/β ratio as high as 1:39 with the meta-4a
reagent, for the cine product, the α/β ratios ranged from 1:5
(entry 3, para-6) to a very low 1:1.4 (entry 4, ortho-6). In this
regard, arylzinc bromide species proved to be less selective
than the corresponding diarylzinc species.
equimolar amounts of bromosugar 5 and diarylzinc meta-4a
are used, as shown in Table 3.
Table 3. Evolution of the Isomer Distribution in the
Reaction of 5 Using One Equivalent of meta-4a
time (min)
β-meta-6 (ipso)
% β-para-6 (cine)
% others isomers
1
89%
79%
73%
66%
59%
7%
16%
20%
26%
31%
4%
5%
The study on the meta-anisyl system was extended to
organozinc reagents obtained by using various ratios of ZnBr2
and meta-anisyllithium in the transmetalation step, changing
the Zn/Ar ratio from 1:4 to 2:1, i.e., ranging from formal
tetraarylzincates to arylzinc halides containing extra zinc halide
(Table 2).3a The formal tetraarylzincate (entry 1) gave the
highest selectivity toward the ipso-β product, although in very
low yield. The use of two equivalents of ZnBr2 led to the
lowest selectivity (entry 7). Excess of DBE slightly favored the
ipso product (entry 5). The temperature did not have a
significant effect on the product distribution (entries 8 and 9).
After studying the product distribution, we decided to
monitor product formation over time. Because the reaction
mixtures were heterogeneous,12 we could not obtain reliable
kinetic data. We did notice, however, that arylzinc bromide
meta-4b reacts more readily than diarylzinc meta-4a. Using a
large excess of diarylzinc reagent meta-4a, we observed a lag
phase, resulting in a sigmoidal curve. However, the reaction
with an excess of arylzinc bromide meta-4b did not show a lag
phase, evolving similarly to a first order reaction.
The sigmoidal evolution observed with excess meta-4a may
be the consequence of small amounts of the more reactive
meta-4b being formed with the progress of the reaction, i.e., an
autocatalytic behavior.13 Because arylzinc bromide species react
at a faster rate than diarylzinc species, the reaction is
accelerated up to a steady state phase. In the final stage,
when the concentration of bromosugar becomes very low, the
reaction rate decreases. This may result in the sigmoidal
behavior observed.
10
30
60
120
7%
8%
10%
We then extended the reaction scope of this organometallic
coupling to other organozinc reagents (Table 4). First, we
tested highly electron-rich dimethoxyphenylzinc derivatives
prepared by standard methods. When the C−Zn bond is
located at a position activated by the two methoxy groups (7
and 8), only the expected ipso products were obtained. In
strong contrast, di(3,5-dimethoxyphenyl)zinc (9) did not lead
to any significant amount of ipso product 20. In this case, the
combined electron-releasing properties of the two methoxy
substituents overcame the nucleophilicity of the C−Zn bond,
and cine product 19 was preferentially obtained with a
selectivity of 88%.
We also examined the influence of a phenyl group as a
substituent in the meta- and para- positions. Consistent with
the limited electron-releasing ability of this substituent, less
than 1% of cine product was obtained with organozinc
bromides 10 and 11. Interestingly, whether the phenyl group
was meta or para was irrelevant regarding the amounts of cine
product (entries 4 and 5). In the presence of other weakly
electron-donating groups, namely methyl, cine products were
detected, although in a low proportion, amounting up to 2.5%
(para-22 α+β, entries 6 and 7).
Dimethylphenylzinc derivatives (entry 8 and 9) also gave
predominant ipso substitution. Interestingly, organozinc
reagents derived from an electron-rich heterocycle like
thiophene (entries 10−12) were also able to deliver cine
products in significant proportions, although rigorously
speaking, it is impossible to distinguish between cine and tele
substitution. In the case of compounds 17a and 17b, where the
When diarylzinc species meta-4a is used for the coupling, the
isomer distribution of the product changes over time. This is a
consequence of the formation of monoarylzinc bromide meta-
4a, which has a faster reaction rate although with a lower ipso/
cine selectivity. This change is especially evident when
C
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Table 4. Scope of the Reaction with the Bromosugar 5 as the Electrophile
a
b
Using 1.5 equiv of the organozinc reagent. Yields were measured by GC using tetradecane as an internal standard. Selectivity was determined by
c
d
GC A%. The compound could not be identified, but we observed other small isomers appearing in GCMS. Other isomers were present in small
amounts, but they could not be identified.
D
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most activated C-2 position is free, the cine products amounted
to up to 22% of the product mixture.
However, a similar reaction using anisole and bromosugar 5
as electrophile gave only traces of product 6 after prolonged
heating (Scheme 2, reaction 2). The use of the more
nucleophilic 1,3-dimethoxybenzene (30) only led to a
combined yield of 2.4% for products 18 and 19 (Scheme 2,
reaction 3).
To understand whether the cine mode of reactivity was
unique to bromosugars, we also investigated benzhydryl
bromide (27) as the electrophile and examined its reaction
with ortho-, meta-, and para-dianysilzinc. Substrate 27 proved
to be a very reactive electrophile and coupling occurred
smoothly at room temperature. As shown in Table 5, in all
We hoped to shed some light on the mechanism of this
unusual reaction by preparing deuterium-labeled diarylzinc 31a
and treating it with bromosugar 5 under standard conditions.
We obtained the expected mixture of ipso- and cine-
Table 5. Product Distribution of the Reaction between
a
1
Diarylzincs 4a and Benzhydryl Bromide 28
substitution products. GC-MS and H NMR analysis of the
products after quenching with NH4Cl (Scheme 3, reaction 1)
showed that (cine) ortho-32 and (ipso) meta-32 retained 100%
of their deuterium label. However, the (cine) para product was
a mixture of nondeuterated para-6 and deuterated para-32, the
latter being a result of an apparent 1,2-deuterium shift. As
shown in Table 6, we observed larger amounts of 1,2-
deuterium shift (ortho-32 and para-6) with arylzinc bromide
species relative to those of the corresponding diarylzinc
reagents. Another noteworthy finding was that α anomers have
a higher proportion of 1,2-D shift products than those of β
anomers.
distribution of products
diarylzinc reagent
% ortho
% meta
% para
ortho-4a
meta-4a
para-4a
(ipso) 38%
(cine) 9%
(tele) 8%
(cine) 0%
(ipso) 6%
(cine) 0%
(tele) 62%
(cine) 85%
(ipso) 92%
a
Reaction conditions: iodoanisole (3.0 g, 12.8 mmol), toluene (39
We repeated the experiments, quenching this time with
iodine, to determine any arylzinc species present in the
reaction product. GC/MS analysis of samples quenched with
iodine (Scheme 3, reaction 2) showed that the cine-para
product was composed solely of deuterated para-32. Although
the nondeuterated para-6 was missing, we found that this
compound was quantitatively replaced by the same proportion
of a new peak corresponding to iodinated compound para-33,
whose structure was confirmed by NMR. This confirms that, at
the end of the reaction, before the quench, there is a
substantial presence of cine product still containing the original
C−Zn bond.
To investigate the nature (intra- vs intermolecular) of the
1,2-hydrogen(deuterium) shift, we carried out a crossover
study (Scheme 4). First, a slight excess of bromosugar 5 was
added to a 1:1 solution of labeled compounds 31b and 34.
Analysis of the products showed no crossover. From a parallel
experiment using a limiting amount of bromosugar 5, we
mL), nBuLi (14.7 mmol), ZnBr2·LiBr in DBE (7.05 mmol, 0.55
equiv), benzhydryl bromide 27 (2.7 g, 10.9 mmol), 0 °C.
cases, para-28 was the major product. For the zinc reagents
ortho-4a and para-4a, both ipso and tele products were
obtained, whereas no cine reaction took place. With
dianysilzinc meta-4a, cine substitution predominated, and
only 6% of ipso product was obtained.
We also ran a series of control experiments using anisole
(29) or 1,3-dimethoxybenzene (30) to evaluate the intrinsic
nucleophilicity of the aromatic ring in the absence of the C−
Zn bond and rule out direct Friedel−Crafts reactions of
“quenched” organozinc species.14 Thus, we stirred a solution
of the highly reactive benzhydryl bromide 27 and anisole (29)
in the presence of ZnBr2·LiBr (Scheme 2, reaction 1). Within
2 h at room temperature, more than 70% of conversion was
achieved, obtaining 28 mainly as the para isomer.
Scheme 2. Control Experiments with Aromatic Reagents Lacking a C−Zn Bond
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a
Scheme 3. Deuterium-Labeling Experiment
a
For clarity, the α anomers are not depicted. For indicative ratios of all products (with nondeuterated reagents), see Table 1.
with iodine, it afforded aryl iodide 43 in 49% yield. The latter
underwent a Negishi coupling in 81% yield (Scheme 5b)15 as
well as a sequence of lithiation and addition to benzaldehyde
(Scheme 5c).
Table 6. Proportion of Apparent 1,2-Deuterium Shift in the
Reaction between 5 and Deuterated meta-Anysilzinc Species
a
31a As Determined by D Retention
reagent
β-ortho
α-ortho
β-para
α-para
Furthermore, intermediate 41 could also be transmetalated
to the corresponding organocopper reagent to furnish a direct,
one-pot acylation (Scheme 5d), albeit in low yield. Particularly
remarkable was the Friedel−Crafts/allylation sequence that
yielded 48 from 41 in 58% yield (Scheme 5e). Although the
yields of these transformations are still modest in terms of
synthetic value, further optimization may be possible, and we
are now focusing on better defining these tandem function-
alization processes. Results will be communicated in due
course.
R2Zn 31a
nd
nd
35%
47%
60%
63%
RZnBr 31b
61%
79%
a
Analyzed using GCMS.
calculated a small D kinetic isotope effect of around 1.07 for
the cine substitution pathway.
We also analyzed the anisole formed in these reactions and
found anisole-d2 (29-d2) in equal amounts to product para-6.
To establish whether the D retention pathway and the reaction
leading to D loss had the same or different molecularity, we
carried out a series of dilution experiments. To perform such
experiments, we prepared soluble organozinc reagent 37. We
carried out two series of experiments, one with a constant
DBE/substrate ratio, and a second with a constant DBE/
toluene ratio, thus accounting for any cosolvent effect. As
shown in Table 7, the influence of dilution on the proportion
of 1,2-deuterium shift is essentially nil, showing that the
processes studied have the same molecularity.
We considered the possibility that the unusual reactivity
displayed by these arylzinc species could be of synthetic utility.
We postulated that, if the 1,2-proton shift could be avoided,
perhaps using a strong base to scavenge the resulting proton,
two different electrophiles could be introduced in a sequential,
one-pot procedure via organozinc intermediate 41, which
normally would lead to product 42 after acidic quenching
(Scheme 5a).
DISCUSSION
■
As a result of our findings, we propose the mechanism
depicted in Scheme 6. The nucleophilic addition of the
arylzinc reagent to the oxocarbenium intermediate generated
from the glycosyl halide leads either to the expected ipso
coupling or to the competing cine substitution, which can be
considered a Friedel−Crafts reaction, generating Wheland
intermediate 49. Then, this highly reactive intermediate faces
two competing pathways: the first one (A) is a proton quench
by the vicinal C−Zn bond (i.e., 1,2-D(H) shift), giving product
para-32. In the alternative pathway B, the proton (deuteron) is
quenched by another species containing a C−Zn bond, leading
to intermediate para-50 and labeled anisole 29-d2, both of
which are duly detected in a 1:1 ratio
The control experiments show that these products are not
due to quenched anisole reacting in a Friedel−Crafts mode but
derive directly from the anisylzinc reagent. The small
secondary KIE in the cine-substitution process suggests that
Indeed, intermediate 41 could be generated in the presence
of TMPZnCl·LiCl (Scheme 5a), which presumably forms
heteroleptic organozinc species with meta-4a; upon quenching
a
Scheme 4. Crossover Experiment
a
For clarity, only para (cine) products are depicted.
F
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Table 7. Dilution Experiments
constant equiv of DBE
constant concentration of DBE
a
dilution
1
3
9
1
3
9
38/39 ratio
54:46
54:46
49:51
49:51
51:49
43:57
a
Dilution measured as the total volume divided by the volume of stock solution of 37 added to the reaction. Ratios determined by GCMS.
Scheme 5. Synthetic Applications of cine Substitution
the formation of the Wheland intermediate is rate determining,
i.e., in the key step, the C−H bond is not yet cleaved, only
rehybridized. The crossover study and the dilution experiments
clearly prove that both path A and B in Scheme 5 are
intramolecular. This is a very surprising result: it is not difficult
to believe that the 1,2-proton shift that leads to D retention
(path A) occurs intramolecularly, but we are forced to
acknowledge that transfer of a proton to another molecule
or arylzinc reagent is also intramolecular. Because the
diarylzinc reagent leads mostly to the ipso product, and we
have shown that the cine substitution originates mostly after
the induction period forming arylzinc halides (Table 3), it
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Scheme 6. Proposed Mechanism of the Anomalous Coupling with meta-Anisylzinc Reagents
follows that the cine-substitution process takes place from
dimeric or oligomeric arylzinc halide species and that proton
transfer within these aggregates is kinetically competitive with
the 1,2-H shift.16
More difficult to interpret are the observations that the cine
process is less β-selective than the ipso substitution process, as
it is not clear how the α-glycosides form. We have provided
evidence that β-selectivity originates, in the desired ipso mode,
from anchimeric participation of the pivaloyl group at C-2.3a
Conversely, α-selectivity could originate from an unlikely
participation of the C-6 pivaloyl group, from the reaction of a
simple oxocarbenium intermediate or through SN2 of an
intermediate β-bromosugar anomer.
Any one of these pathways may be responsible for the
production of the α-anomer, and somehow the cine-
substitution transition state may be better disposed energeti-
cally to accommodate these pathways. Likewise, the specific
geometry of this novel transition state is more compatible with
substantial 1,2-H migration than longer-range shifts within
arylzinc aggregates. More specific explanations at this point
would be sheer conjecture.
currently dominated by their Ni- and Pd-catalyzed reactions.
We have also shed preliminary light onto the mechanistic
details of this novel process but much is left to be done in
terms of understanding the structure and reactivity of these
complex organozinc reagents in toluene/DBE solution, both
with α-bromosugars but especially with other activated
electrophiles. In this area, ab initio calculations may be very
useful, especially if solution structures of these organozinc
reagents in our reaction media can be pinpointed. We believe
that our newly reported solvent system offers a great advantage
over traditional THF in which the organozinc reagents may be
too unstable to undergo many useful synthetic transformations
that are now, for the first time, possible in a toluene-rich
medium at high temperatures.20 Further work in this area will
be reported soon.
EXPERIMENTAL SECTION
■
General Methods. Unless otherwise indicated, all reactions were
carried out with magnetic stirring and in flame-dried glassware under
an inert atmosphere. Syringes used to transfer reagents and solvents
were dried and purged with argon or nitrogen prior to use.
Solvents used for the reactions were purchased anhydrous in sealed
bottles containing molecular sieves and used as received under an
inert atmosphere. nBuLi was used as a 25% solution in heptane. All
other reagents were used as received. Zinc bromide was used as a
solution of ZnBr2·LiBr in nBu2O with a ZnBr2 content of 25% w/w.
Reactions were monitored by gas chromatography (GC and GC-
MS) or thin layer chromatography (TLC). TLC was performed on
silica gel (Merck 60, F-254) and visualized by UV detection.
Purification via column chromatography was performed using silica
gel 60 (40−63 mm 230−400 mesh ASTM from Merck) or using
preparative high-performance liquid chromatography (Kromasil C18)
in 0.25% ammonium carbonate in water and acetonitrile (20:80 to
0:100).
CONCLUSIONS
■
In conclusion, we have demonstrated that arylzinc reagents
bearing electron-donating substituents may react with activated
electrophiles, such α-bromosugars or benzhydryl bromides, via
a Friedel−Crafts mechanism in close competition with direct
organometallic coupling. The Friedel−Crafts mechanism
consists of two competing intramolecular pathways, one of
which leaves the C−Zn bond untouched. The selectivity
between the different pathways is determined by the nature of
the organozinc reagent but is insensitive to concentration. In
comparison with diarylzinc species, arylzinc bromides are
poorly selective toward the ipso coupling but more selective
toward 1,2-H shift in the case of cine products. We have shown
that this unexpected reactivity could be synthetically useful and
allows us to add two electrophiles in a 1,2-fashion onto an
electron-rich arylzinc reagent. This may open up new avenues
in the chemistry of C−Zn bond-containing species, which is
NMR spectra were recorded in CDCl3, and chemical shifts (δ) are
reported in parts per million (ppm). Mass spectra and high resolution
mass spectra (HRMS) were recorded using electrospray ionization
(ESI) and a TOF analyzer. GCs analysis was performed using a
Hewlett-Packard column with 5% phenylmethylpolysiloxane (length =
15 m, diameter = 0.25 mm, film thickness = 0.25 mm) or an Rxi-1HT
(df = 0.1 μm, diameter = 0.32 mm, length = 30 m).
H
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General Procedure for the Coupling of Organozinc Reagents
with Bromosugar 5 (Procedure A). A dry, argon-flushed 50 mL flask
was charged with the corresponding iodoarene (6.4 mmol),
tetradecane (2.5 mmol) as internal standard, and anhydrous toluene
(25 mL). n-BuLi (6.7 mmol, 1.05 equiv) was slowly added dropwise
at −10 °C, and then the reaction was allowed to warm to 0 °C.17 The
reaction was monitored at this temperature until samples quenched
with MeOH showed full iodine−lithium exchange by HPLC analysis.
Subsequently, a solution of ZnBr2·LiBr in (nBu)2O (0.55 or 1.05
equiv) was added dropwise, and the reaction mixture was heated
slowly to 60 °C.18 Bromosugar 5 (1.0 equiv)19 was added in one
portion, and the reaction mixture was heated to 85 °C and stirred
until full conversion was achieved. Reactions were monitored by GC
(quantitative) and HPLC (qualitative) analysis. Two solutions were
prepared each time: the first one by quenching a sample of the
reaction with an aqueous solution of NH4Cl solution. A second
sample was quenched with a solution of I2 in MTBE followed by aq
sodium sulfite treatment. In both cases, only the organic layer was
analyzed. Upon full conversion of one of the reactants, the reaction
was quenched with a sat. aqueous NH4Cl, and the organic layer was
quantitatively analyzed by GC.
126.7, 126.5, 80.8, 76.4, 73.5, 71.8, 67.7, 61.6, 38.6, 38.52, 38.5, 38.3,
27.0, 26.91, 26.88, 26.7. HRMS (EI) calcd for [C38H52O9 + H]
653.3684, found 653.3679.
2,3,4,6-Tetra-O-pivaloyl 1-(Biphenyl-4-yl)-1-deoxy-β-D-glucopyr-
1
anose (α-para-21). H NMR (300 MHz, CDCl3): δ 7.59 (d, J =
8.3 Hz, 2H), 7.51 (d, J = 5.8 Hz, 2H), 7.48 (d, J = 5.1 Hz, 2H), 7.34
(t, J = 7.4 Hz, 2H), 7.24 (t, J = 7.2 Hz, 1H), 5.77−5.59 (m, 1H),
5.34−5.31 (m, 2H), 5.08 (t, J = 9.3 Hz, 1H), 4.02−3.89 (m, 2H),
3.55 (ddd, J = 9.6, 5.2, 2.4 Hz, 1H), 1.09 (s, 9H), 1.07 (s, 9H), 1.02
(s, 9H), 0.95 (s, 9H). 13C{1H} NMR (75 MHz, CDCl3): δ 178.0,
177.3, 177.0, 176.6, 141.0, 140.2, 134.3, 129.1, 128.8, 127.6, 127.1,
127.0, 73.5, 71.1, 70.4, 70.1, 68.6, 62.3, 38.8, 38.74, 38.68, 27.2, 27.1,
27.0. HRMS (EI) calcd for [C38H52O9 + H] 653.3684, found
653.3683.
2,3,4,6-Tetra-O-pivaloyl 1-(Biphenyl-4-yl)-1-deoxy-β-D-glucopyr-
1
anose (β-para-21). H NMR (300 MHz, CDCl3): δ 7.52−7.44 (m,
4H), 7.39−7.31 (m, 4H), 7.26 (t, J = 7.2 Hz, 1H), 5.39 (t, J = 9.3 Hz,
1H), 5.29 (t, J = 9.5 Hz, 1H), 5.24 (t, J = 9.5 Hz, 1H), 4.39 (d, J =
9.7 Hz, 1H), 4.16 (dd, J = 12.4, 1.6 Hz, 1H), 4.07 (dd, J = 12.5, 3.9
Hz, 1H), 3.81 (ddd, J = 9.7, 3.5, 1.6 Hz, 1H), 1.16 (s, 9H), 1.10 (s,
9H), 1.05 (s, 10H), 0.82 (s, 9H). 13C{1H} NMR (75 MHz, CDCl3):
δ 178.0, 177.3, 176.3, 176.0, 141.8, 140.5, 135.1, 128.7, 128.2, 127.4,
127.0, 80.7, 76.6, 73.7, 72.0, 67.9, 61.8, 38.8, 38.71, 38.67, 38.5, 27.14,
27.07, 27.0, 26.9. HRMS (EI) calcd for [C38H52O9 + H] 653.3684,
found 653.3681.
Yields and ratios obtained with the different substrates are reported
in Tables 1−3.
2,3,4,6-Tetra-O-pivaloyl 1-(2-Anisyl)-1-deoxy-β-D-glucopyranose
(β-ortho-6). The NMR spectral data match published data.3a
2,3,4,6-Tetra-O-pivaloyl 1-(4-Anisyl)-1-deoxy-β-D-glucopyranose
(β-meta-6). 1H NMR (300 MHz, CDCl3): δ 7.22 (t, J = 7.9 Hz, 1H),
6.91 (d, J = 7.8 Hz, 1H), 6.88 (d, J = 2.2 Hz, 1H), 6.83 (dd, J = 8.2,
2.6 Hz, 1H), 5.42 (t, J = 9.3 Hz, 1H), 5.32 (t, J = 9.6 Hz, 1H), 5.25
(t, J = 9.5 Hz, 1H), 4.39 (d, J = 9.8 Hz, 1H), 4.21 (dd, J = 12.4, 1.9
Hz, 1H), 4.11 (dd, J = 12.5, 4.0 Hz, 1H), 3.85 (ddd, J = 9.7, 3.9, 1.9
Hz, 1H), 3.78 (s, 3H), 1.22 (s, 9H), 1.16 (s, 9H), 1.10 (s, 9H), 0.89
(s, 9H). 13C{1H} NMR (75 MHz, CDCl3): δ 178.0, 177.3, 176.4,
176.0, 159.5, 137.6, 129.3, 120.2, 114.8, 112.9, 80.8, 76.5, 73.7, 72.1,
67.9, 61.8, 55.2, 38.9, 38.8, 38.7, 38.5, 27.2, 27.09, 27.07, 27.0. IR
ATR ν (cm−1): 2975, 2873, 1734, 1615, 1588, 1482, 1461, 1398,
1367, 1269, 1174, 1154, 1134, 1095, 1077, 1040, 983, 939, 916, 890,
876, 786, 772, 761, 702. HRMS (EI) calcd for [C33H50O10 + H]
607.3477, found 607.3473.
2,3,4,6-Tetra-O-pivaloyl 1-(3-Toluyl)-1-deoxy-β-D-glucopyranose
1
(β-meta-22). H NMR (300 MHz, CDCl3): δ 7.24−7.15 (m, 1H),
7.12 (d, J = 6.5 Hz, 3H), 5.41 (t, J = 9.3 Hz, 1H), 5.32 (t, J = 9.5 Hz,
1H), 5.23 (t, J = 9.5 Hz, 1H), 4.37 (d, J = 9.8 Hz, 1H), 4.21 (dd, J =
12.4, 1.7 Hz, 1H), 4.11 (dd, J = 12.4, 3.9 Hz, 1H), 3.84 (ddd, J = 9.7,
3.8, 1.8 Hz, 1H), 2.30 (s, 3H), 1.22 (s, 9H), 1.16 (s, 9H), 1.10 (s,
9H), 0.88 (s, 9H). 13C{1H} NMR (75 MHz, CDCl3): δ 178.1, 177.3,
176.3, 176.0, 137.8, 136.0, 129.7, 128.3, 128.2, 124.9, 80.9, 76.5, 73.7,
72.2, 67.9, 61.8, 38.9, 38.72, 38.68, 38.5, 27.2, 27.08, 27.05, 26.9, 21.3.
HRMS (EI) calcd for [C33H50O9 + H] 591.3528, found 591.3524.
2,3,4,6-Tetra-O-pivaloyl 1-(4-Tolyl)-1-deoxy-β-D-glucopyranose
(β-para-22). The NMR spectral data match published data.3a
2,3,4,6-Tetra-O-pivaloyl 1-(2,4-Dimethylphenyl)-1-deoxy-β-D-glu-
1
copyranose (β-23). H NMR (300 MHz, CDCl3): δ 7.17 (d, J = 7.8
2,3,4,6-Tetra-O-pivaloyl 1-(2-Anisyl)-1-deoxy-β-D-glucopyranose
(β-para-6). The NMR spectral data match published data.3a
2,3,4,6-Tetra-O-pivaloyl 1-(2,6-Dimethoxyphenyl)-1-deoxy-β-D-
glucopyranose (β-18). The NMR spectral data match published
data.3a
Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.93 (s, 1H), 5.52−5.37 (m, 2H),
5.31 (t, J = 9.5 Hz, 1H), 4.64 (d, J = 9.3 Hz, 1H), 4.19 (d, J = 12.3
Hz, 1H), 4.07 (dd, J = 12.4, 4.1 Hz, 1H), 3.85 (ddd, J = 10.0, 3.9, 1.5
Hz, 2H), 2.40 (s, 3H), 2.25 (s, 3H), 1.20 (s, 9H), 1.16 (s, 9H), 1.11
(s, 9H), 0.85 (s, 9H). 13C{1H} NMR (75 MHz, CDCl3): δ 178.0,
177.4, 176.4, 176.2, 138.4, 136.6, 131.4, 130.8, 127.7, 126.8, 77.7,
76.7, 74.0, 71.1, 67.9, 61.9, 38.8, 38.7, 38.4, 27.2, 27.07, 27.06, 26.8,
21.0, 19.4. HRMS (EI) calcd for [C34H52O9 + H] 605.3684, found
605.3682
2,3,4,6-Tetra-O-pivaloyl 1-(2,4-Dimethoxyphenyl)-1-deoxy-β-D-
1
glucopyranose (β-19). H NMR (300 MHz, CDCl3): δ 7.20 (d, J
= 8.5 Hz, 1H), 6.41 (dd, J = 8.5, 2.3 Hz, 1H), 6.30 (d, J = 2.3 Hz,
1H), 5.43−5.27 (m, 2H), 5.24 (t, J = 9.6 Hz, 1H), 4.85 (d, J = 9.0
Hz, 1H), 4.12 (dd, J = 12.4, 1.6 Hz, 1H), 4.02 (dd, J = 12.4, 3.8 Hz,
1H), 3.79 (ddd, J = 10.3, 3.7, 1.8 Hz, 1H), 3.71 (6H), 1.15 (s, 9H),
1.09 (s, 9H), 1.05 (s, 9H), 0.79 (s, 9H). 13C{1H} NMR (75 MHz,
CDCl3): δ 178.1, 177.3, 176.4, 176.3, 161.1, 158.5, 129.4, 116.8,
104.4, 98.2, 76.5, 74.0, 71.4, 68.0, 61.9, 55.3, 38.83, 38.71, 38.69, 38.5,
27.2, 27.1, 26.7. HRMS (EI) calcd for [C34H52O11 + H] 637.3582,
found 637.3576.
2,3,4,6-Tetra-O-pivaloyl 1-(Biphenyl-3-yl)-1-deoxy-β-D-glucopyr-
anose (α-meta-21). 1H NMR (300 MHz, CDCl3): δ 7.78−7.45
(m, 5H), 7.45−7.24 (m, 34), 5.70 (t, J = 8.7 Hz, 1H), 5.44−5.27 (m,
2H), 5.13 (t, J = 9.1 Hz, 1H), 4.09−3.92 (m, 2H), 3.71−3.59 (m,
1H), 1.11 (s, 9H), 1.06 (s, 9H), 1.04 (s, 9H), 0.97 (s, 9H). 13C{1H}
NMR (75 MHz, CDCl3): δ 178.0, 177.2, 177.0, 176.6, 141.6, 140.5,
136.0, 128.8, 127.5, 127.3, 127.02, 126.96, 73.6, 71.1, 70.4, 68.4, 62.3,
38.73, 38.67, 27.2, 27.1, 27.0, 26.9. HRMS (EI) calcd for [C38H52O9 +
H] 653.3684, found 653.3681.
2,3,4,6-Tetra-O-pivaloyl 1-(3,5-Dimethylphenyl)-1-deoxy-β-D-glu-
1
copyranose (β-24). H NMR (300 MHz, CDCl3): δ 7.02−6.71 (m,
3H), 5.40 (t, J = 9.2 Hz, 1H), 5.32 (t, J = 9.5 Hz, 1H), 5.21 (t, J = 9.5
Hz, 1H), 4.34 (d, J = 9.8 Hz, 1H), 4.22 (dd, J = 12.4, 1.7 Hz, 1H),
4.10 (dd, J = 12.4, 3.9 Hz, 1H), 3.83 (ddd, J = 9.6, 3.6, 1.7 Hz, 1H),
2.26 (s, 6H), 1.23 (s, 9H), 1.16 (s, 9H), 1.10 (s, 9H), 0.89 (s, 9H).
13C{1H} NMR (75 MHz, CDCl3): δ 178.1, 177.3, 176.3, 176.0, 137.7,
136.0, 130.5, 125.4, 80.9, 76.4, 73.8, 72.3, 67.9, 61.8, 38.9, 38.73,
38.69, 38.5, 27.2, 27.09, 27.06, 26.9, 21.2. HRMS (EI) calcd for
[C34H52O9 + H] 605.3684, found 605.3680.
2,3,4,6-Tetra-O-pivaloyl 1-(2-Thienyl)-1-deoxy-β-D-glucopyra-
nose (β-25). The NMR spectral data match published data.3a
2,3,4,6-Tetra-O-pivaloyl 1-(2-Thienyl)-1-deoxy-β-D-glucopyra-
nose (β-26). The compound could only be purified as a mixture
with its isomer β-25. Selected peaks for the product are described. 1H
NMR (300 MHz, CDCl3): δ 7.19−7.13 (m, 2H), 6.98 (dd, J = 4.4,
1.9 Hz, 1H), 5.27 (d, J = 9.2 Hz, 1H), 5.19 (t, J = 9.5 Hz, 1H), 5.17
(t, J = 9.5 Hz, 1H), 4.44 (d, J = 9.8 Hz, 1H), 4.09 (dd, J = 12.4, 1.8
Hz, 1H), 3.99 (dd, J = 12.4, 4.2 Hz, 1H), 3.73 (ddd, J = 10.0, 4.1, 1.9
Hz, 1H), 1.10 (s, 9H), 1.05 (s, 9H), 1.00 (s, 9H), 0.80 (s, 9H).
13C{1H} NMR (75 MHz, CDCl3): δ 178.1, 177.3, 176.3, 176.2, 137.2,
2,3,4,6-Tetra-O-pivaloyl 1-(Biphenyl-3-yl)-1-deoxy-β-D-glucopyr-
anose (β-meta-21). 1H NMR (300 MHz, CDCl3): δ 7.67−7.47
(m, 4H), 7.38 (dt, J = 19.6, 6.1 Hz, 5H), 5.55−5.29 (m, 3H), 4.50 (d,
J = 9.5 Hz, 1H), 4.25 (d, J = 11.8 Hz, 1H), 4.15 (dd, J = 12.4, 3.7 Hz,
1H), 3.89 (d, J = 8.4 Hz, 1H), 1.23 (s, 9H), 1.18 (s, 9H), 1.13 (s,
9H), 0.86 (s, 9H). 13C{1H} NMR (75 MHz, CDCl3): δ 177.7, 177.0,
176.0, 175.8, 141.1, 140.5, 136.4, 128.61, 128.58, 127.6, 127.2, 126.9,
126.4, 126.3, 124.6, 76.5, 76.4, 73.6, 71.7, 67.9, 61.8, 38.9, 38.8, 38.7,
I
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The Journal of Organic Chemistry
Article
38.6, 27.2, 27.10, 27.07, 26.9. HRMS (EI) calcd for [C30H46O9S + H]
583.2935, found 583.2934.
Synthesis of 2-Deutero-1-iodo-3-(3-phenylpropoxy)benzene
(52). In a flask, 3-bromopropylbenzene (23.0 g, 116 mmol), 3-
bromophenol (21.0 g, 1.05 equiv), potassium carbonate (20.8 g, 1.3
equiv), and DMF (70 mL) were mixed and stirred at 80 °C until full
conversion. Then, the reaction was diluted with water and extracted
thrice with heptane. The combined organics were washed twice with
NaOH (2 M) and brine, dried over Na2SO4, and filtered, and finally,
the volatiles were removed under reduced pressure. The crude
showed a high purity and was brought directly into the next step. At
this point, procedure C described above was followed to yield the
Coupling of Bromobenzhydryl Bromide (30) with Dianisylzinc
Reagents (Procedure B). A dry and argon-flushed 50 mL flask was
charged with the corresponding iodoanisole (3.00 g, 12.8 mmol),
tetradecane (0.5 g, 2.5 mmol) as internal standard, and anhydrous
toluene (39 mL). nBuLi (13.4 mmol, 1.05 equiv) was slowly added
dropwise at −10 °C, and then the reaction was allowed to warm to 0
°C. The reaction was monitored at that temperature until samples
quenched with MeOH showed full iodine−lithium exchange by
HPLC analysis. Subsequently, a solution of ZnBr2·LiBr in nBu2O
(7.05 mmol, 0.55 equiv) was added dropwise. Benzhydryl bromide 27
(2.68 g, 10.9 mmol, 0.85 equiv) was added in one portion, and the
reaction mixture was stirred at 0 °C until full conversion. Upon full
conversion of one of the reactants, the reaction was quenched with
sat. aqueous NH4Cl, and the organic layer was analyzed by GC.
1-Benzhydryl-2-methoxybenzene (ortho-28). The NMR spectral
data match published data.21
1
final product as a colorless oil in 50% overall yield. H NMR (300
MHz, CDCl3): δ 7.26−7.00 (m, 6H), 6.84 (d, J = 8.3 Hz, 1H), 6.72
(dd, J = 8.3, 2.2 Hz, 1H), 3.77 (t, J = 6.2 Hz, 2H), 2.66 (t, J = 7.6 Hz,
2H), 1.95 (p, J = 6.5 Hz, 2H). 13C{1H} NMR (75 MHz, CDCl3): δ
159.6, 141.4, 130.7, 129.5 (C−D), 128.6, 128.5, 126.1, 123. 7, 114.3,
94.4, 67.1, 32.1, 30.8. HRMS (EI) calcd for [C15H14DIO] 339.0230,
found 339.0191.
Synthesis of 1-(Trideuteromethoxy)-3-iodoanisole (53). Iodo-
methane-d3 (5.0 g, 34.5 mmol) was added to a mixture of 3-
iodophenol (8.35 g, 1.1 equiv) and potassium carbonate (5.24 g, 1.1
equiv) in DMF (35 mL). The mixture was stirred at room
temperature until full conversion. Then, the reaction was diluted
with water and extracted thrice with heptane. The organic layer was
washed twice with NaOH (2 M) and brine and dried over Na2SO4,
and finally, the volatiles were removed under reduced pressure. The
resulting oil (8.0 g, 98% yield) showed sufficient purity and was used
1-Benzhydryl-3-methoxybenzene (meta-28). The NMR spectral
data match published data.22
1-Benzhydryl-4-methoxybenzene (para-28). The NMR spectral
data match published data.21
Synthesis of 4-Deutero-3-iodoanisole (51) (Procedure C). A dry
and nitrogen-flushed 250 mL Schlenk-tube was charged with 3-
bromoanisole (30.0 g, 160 mmol), and anhydrous THF (110 mL)
was added. nBuLi (168 mmol, 1.05 equiv; 2.5 M solution in heptane)
was added dropwise at −78 °C, and the reaction mixture was stirred
at −78 °C for 30 min (HPLC analysis showed full conversion). Then,
chlorotrimethylsilane (19.2 g, 1.10 equiv) was slowly added, and the
mixture was allowed to slowly reach room temperature. Upon full
conversion (∼15 min), water was added, and the volatiles were
partially removed under reduced pressure. The mixture was diluted
with MTBE and washed with water. The organic layer was treated
with activated charcoal, filtered, and concentrated.
Without further purification, the crude product was diluted with
AcOH (480 mL), and water (7 mL) was added. The mixture was
cooled to 10 °C, and bromine (1.0 equiv) was added dropwise
(reaction is almost immediate) until full conversion. An aqueous
solution of NaHSO3 was added to quench residual bromine, and then
the volatiles were removed under reduced pressure. The crude
product was diluted in MTBE and washed twice with NaOH (2 M)
and brine. The organic layer was treated with Na2SO4 and activated
charcoal and then filtered. The solvent was removed under reduced
pressure, and the crude product was dried twice by azeotropic
distillation of toluene, also under reduced pressure.
Without further purification, the crude product was dissolved in
anhydrous THF (110 mL). nBuLi (168 mmol, 1.05 equiv; 2.5 M
solution in heptane) was added dropwise at −78 °C, and the reaction
mixture was stirred at −78 °C for 30 min (HPLC analysis showed full
conversion). The aryllithium intermediate was then quenched by
addition of CH3OD (3.0 equiv). Volatiles were partially removed
under reduced pressure, and the mixture was diluted with MTBE and
washed with water and brine. The organic layer was treated with
activated charcoal, filtered, and concentrated. The crude product was
dissolved in anhydrous CH2Cl2 (400 mL), and a solution of ICl (1.0
equiv) in CH2Cl2 (30 mL) was slowly added over 5 h at −40 °C.
After warming to room temperature, the reaction was quenched with
aqueous NaHSO3, and CH2Cl2 was partially removed under reduced
pressure. The crude was diluted with MTBE and washed with water
and brine. The organic layer was dried with Na2SO4, treated with
activated charcoal, and concentrated. Column chromatography (SiO2;
hexane) furnished 27.0 g of product 51 (72% yield) as a colorless oil.
1H NMR (300 MHz, CDCl3): δ 7.16 (d, J = 2.5 Hz, 1H), 6.91 (d, J =
1
without further purification. H NMR (300 MHz, CDCl3): δ 7.29 (d,
J = 7.7 Hz, 1H), 7.26 (t, J = 2.2 Hz, 1H), 7.00 (t, J = 8.0 Hz, 1H),
6.87 (dd, J = 9.5, 2.5 Hz, 1H). 13C{1H} NMR (75 MHz, CDCl3): δ
160.1, 130.7, 129.7, 122.9, 113.7, 94.3. HRMS (EI) calcd for
[C7H4D3IO] 236.9730, found [M]+ 236.9658.
Experiments with Labeled Materials (Scheme 3). 4-Deutero-3-
iodoanisole was employed as a starting material using procedure A.
Quantitative results are shown in Table 6. Analyses were performed
by GCMS. The mass spectra of each chromatographic peak
corresponding to the products were analyzed. The ratios of 1,2-
deuteron or 1,2-proton shifts were calculated from the relative
isotopic abundance of selected fragmentations in the mass spectra.
The peaks at m/z = 203, 287, and 300 (M, not deuterated) are
representative of a molecular fragment containing the aryl moiety and
can be used for that purpose. The abundance of molecules with M +
1 mass due to natural 13C content was taken into account, and the
pertinent subtraction was performed in our calculations.
For the para isomer, the proportion of 1,2-shift was calculated from
samples quenched with NH4Cl. In that case, the M +1 peaks
represent the abundance of product with the 1,2-deuterium shift.
For the ortho isomer, the 1,2-shift was calculated from samples
quenched with MeOD. In that case, the M + 1 peak represents the
abundance of product with the 1,2-proton shift. The M + 2 peak
represents the uptake of a second deuterium from MeOD, which
corresponds to the pathway with C−Zn bond conservation.
Illustrative MS spectra from GCMS separation for both types of
quenching, in addition to those with I2 quenching, are shown in the
Supporting Information.
2,3,4,6-Tetra-O-pivaloyl 1-(2-Deutero-5-methoxyphenyl)-1-
deoxy-β-D-glucopyranose (β-meta-32). Although NH4Cl quenching
was used for the mechanistic investigations, for product character-
ization purposes, the reaction was quenched with MeOD to
exclusively afford β-meta-32 (vs β-meta-6). 1H NMR (300 MHz,
CDCl3): δ 7.15 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 2.4 Hz, 1H), 6.77
(dd, J = 8.2, 2.5 Hz, 1H), 5.36 (t, J = 9.3 Hz, 1H), 5.26 (t, J = 9.6 Hz,
1H), 5.18 (t, J = 9.5 Hz, 1H), 4.33 (d, J = 9.8 Hz, 1H), 4.15 (dd, J =
12.4, 1.7 Hz, 1H), 4.05 (dd, J = 12.4, 4.0 Hz, 1H), 3.79 (ddd, J = 9.7,
3.8, 1.7 Hz, 1H), 3.72 (s, 3H), 1.15 (s, 9H), 1.10 (s, 9H), 1.04 (s,
9H), 0.83 (s, 9H). 13C{1H} NMR (75 MHz, CDCl3): δ 178.0, 177.3,
176.3, 176.0, 159.4, 137.4, 129.2, 119.9, 114.7, 112.8, 80.7, 76.5, 73.7,
72.0, 67.9, 61.8, 55.1, 38.8, 38.7, 38.67, 38.5, 27.14, 27.06, 27.0, 26.9.
IR ATR ν (cm−1): 2976, 2874, 1734, 1610, 1582, 1480, 1462, 1438,
1397, 1367, 1275, 1259, 1174, 1153, 1134, 1094, 1077, 1050, 1038,
8.4 Hz, 1H), 6.77 (dd, J = 8.4, 2.5 Hz, 1H), 3.68 (s, 3H). 13C{1H}
NMR (75 MHz, CDCl3): δ 160.0, 130.6, 129.7 (C−D), 129.41,
129.07, 122.88, 113.68, 94.20, 55.31. IR ATR ν (cm−1): 3002, 2935,
2834, 1580, 1560, 1460, 1434, 1403, 1336, 1293, 1271, 1230, 1222,
1181, 1150, 1126, 1054, 1030, 979, 873, 861, 842, 817, 714, 682, 667.
HRMS (EI) calcd for [C7H6DIO] 234.9604, found 234.9599.
J
DOI: 10.1021/acs.joc.6b00074
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The Journal of Organic Chemistry
Article
998, 983, 939, 918, 906, 890, 876, 837, 774, 761. HRMS (EI) calcd
for [C33H50DO10] 608.3540, found 608.3536.
2,3,4,6-Tetra-O-pivaloyl 1-(2-Deutero-4-(3-phenylpropoxy)-
phenyl)-1-deoxy-β-D-glucopyranose (β-para-39). HRMS (EI) calcd
for [C41H57DO10 + NH4] 729.4436, found 729.4639.
2,3,4,6-Tetra-O-pivaloyl 1-(2-Deutero-4-methoxyphenyl)-1-
deoxy-β-D-glucopyranose (β-para-32). 1H NMR (300 MHz,
CDCl3): δ 7.19 (d, J = 9.2 Hz, 1H), 6.78 (dt, J = 4.1, 2.1 Hz,
3H), 5.35 (t, J = 9.3 Hz, 1H), 5.25 (t, J = 9.3 Hz, 1H), 5.19 (t, J = 9.3
Hz, 1H), 4.30 (d, J = 9.8 Hz, 1H), 4.13 (dd, J = 12.4, 1.7 Hz, 1H),
4.04 (dd, J = 12.4, 4.0 Hz, 1H), 3.78 (ddd, J = 9.7, 3.7, 1.8 Hz, 1H),
3.71 (s, 3H), 1.15 (s, 10H), 1.10 (s, 9H), 1.04 (s, 9H), 0.82 (s, 9H).
13C{1H} NMR (75 MHz, CDCl3): δ 178.1, 177.3, 176.3, 176.1, 160.0,
129.1, 128.2, 113.7, 113.6, 80.5, 76.4, 73.7, 72.0, 67.9, 61.9, 55.2, 38.8,
38.73, 38.69, 38.5, 27.2, 27.08, 27.05, 26.9. IR ATR ν (cm−1): 2973,
2873, 1735, 1610, 1582, 1480, 1462, 1439, 1398, 1367, 1318, 1275,
1259, 1250, 1172, 1155, 1133, 1095, 1078, 1066, 1038, 999, 983, 939,
918, 892, 876, 836, 830, 823, 804, 773, 761, 656. HRMS (EI) calcd
for [C33H50DO10] 608.3540, found 608.3539.
4,4′-((4-Methoxyphenyl)methylene)bis(methylbenzene) (42). A
dry and argon-flushed 10 mL Schlenk tube was charged with 3-
iodoanisole (1 mmol) and anhydrous toluene (3.5 mL). nBuLi (1.05
mmol; 2.4 M solution in heptane) was added dropwise at 0 °C, and
the reaction mixture was stirred at 0 °C for 1 h. Subsequently, ZnBr2·
LiBr (0.55 mmol, 25% weight in nBu2O) was added dropwise, and
the reaction mixture was allowed to warm to room temperature.
Bis(p-tolyl)bromomethane (40) (1 mmol, 1 M in toluene) was
added, and the reaction mixture was stirred at room temperature for
15 min. The mixture was quenched with brine and extracted with
EtOAc. Removal of the solvent and purification via flash
chromatography (SiO2; hexane/EtOAc 10:1) furnished 244 mg of
1
product 42 (0.81 mmol, 81% yield). H NMR (300 MHz, CDCl3): δ
6.96−7.15 (m, 10 H), 6.79−6.87 (m, 2 H), 5.44 (s, 1 H), 3.79 (s, 3
H), 2.33 (s, 6 H). 13C{1H} NMR (75 MHz, CDCl3): δ 157.9, 141.5,
136.5, 135.6, 130.3, 129.2, 128.9, 113.3, 55.3, 55.2, 21.0. IR ATR ν
(cm−1): 3019, 3000, 2921, 2861, 2834, 1607, 1578, 1510, 1496, 1463,
1454, 1442, 1413, 1327, 1309, 1284, 1247, 1214, 1179, 1160, 1110,
1089, 1039, 1021, 995, 953, 944, 911, 869, 848, 807, 792, 767, 716,
701, 660. HRMS (EI) calcd for [C22H22O] 302.1671, found 302.1659.
Ethyl 2′-(Di-p-tolylmethyl)-5′-methoxy-[1,1′-biphenyl]-4-carbox-
ylate (45). A dry and argon-flushed 10 mL Schlenk tube was charged
with 3-iodoanisole (1 mmol) and anhydrous toluene (3.5 mL). nBuLi
(1.05 mmol; 2.4 M solution in heptane) was added dropwise at 0 °C,
and the reaction mixture was stirred at 0 °C for 1 h. Subsequently,
ZnBr2·LiBr (0.55 mmol, 25% weight in nBu2O) was added dropwise,
and the reaction mixture was allowed to warm to room temperature.
At −20 °C, TMPZnCl·LiCl (1.4 equiv; 1.2 M in THF) was added,
and then bis(p-tolyl)bromomethane (40) (1 mmol, 1 M in toluene)
was added. The reaction mixture was allowed to warm to room
temperature and then stirred for 2 h. The mixture was cooled to 0 °C,
and I2 (2 mmol; 2 M in THF) was added dropwise. The mixture was
quenched with a sat. aqueous Na2S2O3 solution and extracted with
EtOAc. Removal of the solvent and purification via flash
chromatography (SiO2; hexane/Et2O 30:1) furnished 209.9 mg of
intermediate 43 (0.49 mmol, 49% yield), which was dissolved in THF
(0.2 mL). Pd(OAc)2 (2 mol %) and SPhos (4 mol %) were added to
the mixture, and 4-(ethoxycarbonyl)phenylzinc chloride (44, 0.75
mmol, 0.48 M in THF) was added dropwise.23 The reaction mixture
was stirred at 50 °C for 1 h. The reaction mixture was quenched with
a sat. aqueous NH4Cl solution and extracted with EtOAc. Removal of
the solvent and purification via flash chromatography (SiO2; hexane/
2,3,4,6-Tetra-O-pivaloyl 1-(2-Iodo-4-methoxyphenyl)-1-deoxy-β-
1
D-glucopyranose (β-para-33). H NMR (300 MHz, CDCl3): δ 7.33
(d, J = 2.6 Hz, 1H), 7.28 (d, J = 8.7 Hz, 1H), 6.90 (dd, J = 8.8, 2.6
Hz, 1H), 5.47 (t, J = 9.2 Hz, 1H), 5.39 (t, J = 9.4 Hz, 1H), 5.28 (t, J
= 9.6 Hz, 1H), 4.81 (d, J = 9.6 Hz, 1H), 4.20 (dd, J = 12.4, 1.8 Hz,
1H), 4.08 (dd, J = 12.4, 4.6 Hz, 1H), 3.92 (ddd, J = 9.3, 4.1, 1.3 Hz,
1H), 3.76 (s, 3H), 1.21 (s, 9H), 1.17 (s, 9H), 1.12 (s, 9H), 0.90 (s,
9H). 13C{1H} NMR (75 MHz, CDCl3): δ 178.1, 177.3, 176.5, 176.4,
160.1, 130.3, 128.9, 124.6, 114.5, 83.2, 76.8, 73.8, 71.6, 68.1, 62.0,
55.5, 38.9, 38.78, 38.75, 38.6, 27.21, 27.15, 27.1, 26.9. HRMS (EI)
calcd for [C33H50IO10] 733.2443, found 733.2438.
Crossover Experiments (Scheme 4). A 1:1 mixture of 1-
(trideuteromethoxy)-3-iodoanisole and 4-deutero-3-iodoanisole was
employed as starting material. Procedure A was used with the
following modifications: (a) First, only 0.07 equiv of bromosugar 5
was added. After a while, a sample was taken and quenched with I2,
and the ratio of para-32 to para-35 was measured. This ratio
corresponds, approximately, to the deuterium kinetic isotope effect in
the 1,2-shift mechanism. (b) Then, an additional 0.93 equiv of
bromosugar 5 was added, and the reaction was quenched upon full
conversion.
Mass spectra (GCMS) corresponding to the mixture of the
different meta (ipso) and para (cine) products are shown in the
Supporting Information. Upon quenching with I2, no crossover
products were found.
Dilution Experiments (Table 6). 2-Deutero-1-iodo-3-(3-
phenylpropoxy)benzene (52) was employed as a starting material
using Procedure A just for the preparation of the organozinc reagent.
Then, three different vials were charged, each with approximately 6
mL of the organozinc solution, 1 equiv of bromosugar 5, and a certain
amount of toluene (a = 0 mL, b = 12 mL, c = 48 mL). The reactions
were then stirred at 80 °C until completion and quenched with
NH4Cl, and the isotopic abundance of the meta-products was
analyzed by GCMS.
1
Et2O 10:1) furnished 180 mg of product 45 (40% overall yield). H
NMR (300 MHz, CDCl3): δ 1.41 (t, J = 7.05 Hz, 3 H), 2.31 (s, 6 H),
3.80 (s, 3 H), 4.40 (q, J = 7.00 Hz, 2 H), 5.35 (s, 1 H), 6.77 (d, J =
2.76 Hz, 1 H), 6.80−6.91 (m, 5 H), 6.98−7.09 (m, 5 H), 7.21 (m, J =
8.02 Hz, 2 H), 8.00 (m, J = 8.29 Hz, 2 H). 13C{1H} NMR (75 MHz,
CDCl3): δ 14.4, 21.0, 51.6, 55.3, 61.0, 113.5, 114.9, 128.9, 129.15,
129.23, 131.4, 133.9, 135.5, 141.6, 142.3, 146.3, 157.5, 166.5. IR ATR
ν (cm−1): 2979, 2922, 1714, 1604, 1574, 1566, 1510, 1487, 1464,
1444, 1399, 1367, 1308, 1270, 1220, 1210, 1176, 1108, 1098, 1039,
1016, 909, 889, 873, 853, 838, 808, 790, 772, 767, 732, 716, 707, 668,
656. HRMS (EI) calcd for [C31H30O3] 450.2195, found 450.2161.
(2-(Di-p-tolylmethyl)-5-methoxyphenyl) (Phenyl)methanol (46).
A dry and argon-flushed 10 mL Schlenk tube was charged with 3-
iodoanisole (1 mmol) and anhydrous toluene (3.5 mL). nBuLi (1.05
mmol; 2.4 M solution in heptane) was added dropwise at 0 °C, and
the reaction mixture was stirred at 0 °C for 1 h. Subsequently, ZnBr2·
LiBr (0.55 mmol, 25% weight in nBu2O) was added dropwise, and
the reaction mixture was allowed to warm to room temperature. At
−20 °C, TMPZnCl·LiCl (1.4 equiv; 1.2 M in THF) was added, and
then bis(p-tolyl)bromomethane (40) (1 mmol, 1 M in toluene) was
added. The reaction mixture was allowed to warm to room
temperature and was then stirred for 2 h. The mixture was cooled
to 0 °C, and I2 (2 mmol; 2 M in THF) was added dropwise. The
mixture was quenched with a sat. aqueous Na2S2O3 solution and
extracted with EtOAc. Removal of the solvent and purification via
A second round of reactions was set in the same way but adding
nBu2O to the vials in such a way that the concentration would be the
same in the three vials. An MS spectrum showing a mixture of 38 and
39 is included in the Supporting Information.
2,3,4,6-Tetra-O-pivaloyl 1-(4-(3-Phenylpropoxy)phenyl)-1-deoxy-
β-D-glucopyranose (β-para-38). The NMR corresponds to a sample
1
synthesized from nondeuterated organozinc reagent. H NMR (300
MHz, CDCl3): δ 7.27−7.07 (m, 7H), 6.76 (d, J = 8.7 Hz, 2H), 5.35
(t, J = 9.3 Hz, 1H), 5.25 (t, J = 9.4 Hz, 1H), 5.17 (t, J = 9.4 Hz, 1H),
4.29 (d, J = 9.8 Hz, 1H), 4.13 (dd, J = 12.4, 1.8 Hz, 1H), 4.04 (dd, J
= 12.4, 3.9 Hz, 1H), 3.87 (dd, J = 6.1, 3.2 Hz, 1H), 3.83 (dd, J = 6.0,
3.3 Hz, 1H), 3.78 (ddd, J = 9.7, 3.8, 1.9 Hz, 1H), 2.72 (t, J = 7.5 Hz,
2H), 2.07−1.94 (m, 2H), 1.15 (s, 9H), 1.10 (s, 9H), 1.04 (s, 9H),
0.82 (s, 9H). 13C{1H} NMR (75 MHz, CDCl3): δ 178.1, 177.3,
176.4, 176.1, 159.5, 141.4, 129.1, 128.5, 128.4, 128.2, 125.9, 114.3,
80.6, 76.4, 73.7, 72.0, 67.9, 66.8, 61.9, 38.9, 38.74, 38.7, 38.5, 32.0,
30.7, 27.2, 27.1, 27.06, 26.9. HRMS (EI) calcd for [C41H59O10]
711.4103, found 711.4097.
K
DOI: 10.1021/acs.joc.6b00074
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
flash chromatography (SiO2; i-hexane/Et2O 30:1) furnished 209.9 mg
of intermediate 43 (0.49 mmol, 49% yield), which was dissolved in
THF (1 mL). nBuLi (1 mmol, 2.4 M solution in heptane) was added
dropwise at −78 °C, and the reaction mixture was stirred at −78 °C
for 1 h. Subsequently, benzaldehyde (1 mmol) was added dropwise,
and the reaction mixture was allowed to warm to room temperature.
The reaction mixture was quenched with a sat. aqueous NH4Cl
solution and extracted with EtOAc. Removal of the solvent and
purification via flash chromatography (SiO2; hexane/EtOAc 4:1)
1.11 Hz, 1 H), 5.51 (s, 1 H), 5.21−5.36 (m, 1 H), 4.21 (q, J = 7.10
Hz, 2 H), 3.76 (s, 3 H), 3.51 (s, 2 H), 2.31 (s, 6 H), 1.22−1.35 (m, 3
H). 13C{1H} NMR (75 MHz, CDCl3): δ 167.0, 158.0, 141.0, 140.1,
138.1, 135.6, 135.2, 131.0, 129.2, 128.9, 125.8, 116.1, 111.4, 60.8,
55.1, 51.3, 35.0, 21.0, 14.2. IR ATR ν (cm−1): 3018, 2981, 2922,
2835, 1714, 1630, 1607, 1578, 1511, 1498, 1464, 1454, 1444, 1428,
1408, 1390, 1368, 1324, 1310, 1285, 1250, 1184, 1159, 1131, 1112,
1093, 1041, 1022, 949, 926, 860, 848, 808, 794, 768, 727, 716, 701,
684. HRMS (EI) calcd for [C28H30O3] 414.2195, found 414.2171.
1
furnished 122.6 mg of product 46 (0.3 mmol, 30% overall yield). H
NMR (300 MHz, CDCl3): δ 7.30−7.33 (m, 2 H), 7.25−7.29 (m, 3
H), 7.12 (d, J = 2.74 Hz, 1 H), 7.08 (d, J = 7.80 Hz, 2 H), 6.98 (m, J
= 8.01 Hz, 2 H), 6.91 (m, J = 8.01 Hz, 2 H), 6.78 (d, J = 8.64 Hz, 1
H), 6.72 (dd, J = 8.64, 2.74 Hz, 1 H), 6.68 (d, J = 8.01 Hz, 2 H), 5.92
(s, 1 H), 5.55 (s, 1 H), 3.77 (s, 3 H), 2.32 (s, 3 H), 2.27 (s, 3 H).
13C{1H} NMR (75 MHz, CDCl3): δ 158.2, 143.0, 142.7, 141.1, 140.5,
135.9, 135.6, 133.7, 131.3, 129.22, 129.18, 129.1, 128.9, 128.5, 127.7,
127.1, 112.8, 112.5, 72.6, 55.2, 50.7, 21.0, 20.9. IR ATR ν (cm−1):
3436, 3021, 2922, 2857, 2835, 1736, 1606, 1577, 1510, 1491, 1463,
1453, 1425, 1377, 1308, 1285, 1236, 1185, 1156, 1110, 1088, 1077,
1040, 1032, 1020, 936, 911, 878, 867, 847, 809, 799, 764, 726, 716,
699, 665. HRMS (EI) calcd for [C29H28O2] 408.2089, found
408.2066.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b00074.
■
S
Mass spectra from the labeling studies and NMR spectra
for all new compounds and intermediates (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: sbarroso@its.jnj.com.
Notes
■
(2-(Di-p-tolylmethyl)-5-methoxyphenyl) (Thiophen-2-yl)-
methanone (47). A dry and argon-flushed 10 mL Schlenk tube
was charged with 3-iodoanisole (1 mmol) and anhydrous toluene (3.5
mL). nBuLi (1.05 mmol; 2.4 M solution in heptane) was added
dropwise at 0 °C, and the reaction mixture was stirred at 0 °C for 1 h.
Subsequently, ZnBr2·LiBr (0.55 mmol, 25% weight in nBu2O) was
added dropwise, and the reaction mixture was allowed to warm to
room temperature. At −20 °C, TMPZnCl·LiCl (1.4 equiv; 1.2 M in
THF) was added, and then bis(p-tolyl)bromomethane (40) (1 mmol,
1 M in toluene) was added. The reaction mixture was allowed to
warm to room temperature and was then stirred for 2 h. The mixture
was cooled to −20 °C, and CuCN·2LiCl (1 mmol; 1 M in THF) was
added dropwise. Thiophene-2-carbonyl chloride (2 mmol) was added,
and the reaction mixture was stirred for 1 h at room temperature. The
mixture was quenched with brine and extracted with EtOAc. Removal
of the solvent and purification via flash chromatography (SiO2;
hexane/Et2O 10:1) furnished 90.7 mg of product 47 (0.22 mmol,
The authors declare no competing financial interest.
REFERENCES
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1
22% yield). H NMR (300 MHz, CDCl3): δ 7.64−7.74 (m, 1 H),
7.60 (dd, J = 4.98, 1.11 Hz, 1 H), 7.36−7.47 (m, 1 H), 7.09−7.21 (m,
2 H), 6.88−7.02 (m, 9 H), 5.74 (s, 1 H), 3.78 (s, 3 H), 2.25 (s, 6 H).
13C{1H} NMR (75 MHz, CDCl3): δ 190.1, 159.6, 157.1, 144.4, 140.5,
140.1, 139.4, 135.7, 135.5, 134.9, 134.8, 134.6, 134.2, 131.4, 129.4,
128.8, 127.9, 127.7, 121.7, 118.6, 115.3, 113.8, 113.2, 55.5, 55.4, 51.0,
20.9. IR ATR ν (cm−1): 3090, 3001, 2920, 2835, 1728, 1638, 1604,
1573, 1511, 1493, 1462, 1451, 1426, 1410, 1354, 1288, 1227, 1183,
1147, 1111, 1086, 1077, 1036, 1022, 994, 949, 928, 914, 860, 805,
790, 777, 740, 723, 684, 656. HRMS (EI) calcd for [C27H24O2S]
412.1497, found 412.1472.
(3) (a) Lemaire, S.; Houpis, I. N.; Xiao, T.; Li, J.; Digard, E.;
Gozlan, C.; Liu, R.; Gavryushin, A.; Diene, C.; Wang, Y.; Farina, V.;
̀
Knochel, P. Org. Lett. 2012, 14, 1480−1483. (b) The Ingleson group
has independently reported on the scope of direct C(sp2)-C(sp3)
coupling of diarylzinc reagents under conditions that are very similar
to ours. See: Dunsford, J. J.; Clark, E. R.; Ingleson, M. J. Angew.
Chem., Int. Ed. 2015, 54, 5688−5692.
Ethyl 2-(2-(Di-p-tolylmethyl)-5-methoxybenzyl)acrylate (48). A
dry and argon-flushed 10 mL Schlenk tube was charged with 3-
iodoanisole (1 mmol) and anhydrous toluene (3.5 mL). nBuLi (1.05
mmol; 2.4 M solution in heptane) was added dropwise at 0 °C, and
the reaction mixture was stirred at 0 °C for 1 h. Subsequently, ZnBr2·
LiBr (0.55 mmol, 25% weight in nBu2O) was added dropwise, and
the reaction mixture was allowed to warm to room temperature. At
−20 °C, TMPZnCl·LiCl (1.4 equiv; 1.2 M in THF) was added, and
then bis(p-tolyl)bromomethane (40) (1 mmol, 1 M in toluene) was
added. The reaction mixture was allowed to warm to room
temperature and was then stirred for 2 h. The mixture was cooled
to −20 °C, and CuCN·2LiCl (0.1 mmol; 1 M in THF) was added
dropwise. Allyl bromide (2 mmol) was added, and the reaction
mixture was stirred for 15 min at room temperature. The mixture was
quenched with brine and extracted with EtOAc. Removal of the
solvent and purification via flash chromatography (SiO2; hexane/Et2O
́
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1
20:1) furnished 240.4 mg of product 48 (0.58 mmol, 58% yield). H
Chem. 1987, 334, 263−267. (c) Ishibashi, H.; Sakashita, H.; Ikeda, M.
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NMR (300 MHz, CDCl3): δ 7.06 (d, J = 8.02 Hz, 4 H), 6.91 (d, J =
8.02 Hz, 4 H), 6.78−6.84 (m, 1 H), 6.60−6.74 (m, 2 H), 6.24 (d, J =
L
DOI: 10.1021/acs.joc.6b00074
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The Journal of Organic Chemistry
Article
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(11) In all cases, the quenching of the organometallic species with
iodine exclusively gave the starting aryl iodide; we never observed any
isomerization of the organometallic compounds.
(12) Diarylzinc meta-4 gives a colloidal solution, whereas meta-4b
gives a very fine precipitate. On the other hand, bromosugar 5 is
freely soluble in pure toluene, but its complexation to zinc species
causes precipitation. Analysis of the supernatant of the resulting
mixtures indeed showed a much lower concentration of organozinc
species 4a/b, bromosugar 5, and products 6 in comparison to the
solid phase.
(13) Reaction of 4a with 1 equiv of 5 generates 1 equiv of 4b as a
byproduct. Furthermore, the reaction of 4b generates ZnBr2, which
together with one equiv of 4a forms two equiv of 4b via Schlenk-like
equilibrium.
(14) A hypothetical Friedel−Crafts reaction of anisole coming from
the quenching of organozinc 4 would generate HBr, which would
quench more 4, generating anisole again.
(15) (a) Mosrin, M.; Knochel, P. Org. Lett. 2008, 10, 2497−2500.
(b) Haag, B.; Mosrin, M.; Ila, H.; Malakhov, V.; Knochel, P. Angew.
Chem., Int. Ed. 2011, 50, 9794−9824.
(16) We are currently studying the structure of these species in
solution by DOSY NMR spectroscopy. Results will be reported
separately.
(17) In all cases, we made the organozinc reagents starting with
iodoarenes except for the following cases: 1,3-dimethoxybenzene was
directly deprotonated with nBuLi (Table 3, entry 1); 1-bromo-3,5-
dimethoxybenzene was converted overnight with Mg and Et2O to its
Grignard reagent, titrated, and then transmetallated to the organozinc
(entry 4); and 3-bromobiphenyl was used for the transmetalation,
which was carried out at 60 °C (entry 4).
(18) See scheme above, e.g, for diarylzinc species, n = 0.55 equiv was
used, whereas for arylzinc bromides, n = 1.05 equiv was used. More
information regarding the different organozinc species generated is
found in Table 2.
(19) In the reactions starting with (meta-, ortho-, or para)-
iodoanisole, 1.0 equiv of bromosugar 5 was added, whereas for
reactions with other substrates, 0.67 equiv of 5 was added (limiting
reagent for yield calculations).
(20) Ref 3a discloses the opening of the THF ring to form 4-
chlorobutanol by arylzinc chloride upon warming along with
decomposition of bromosugar 5. In addition, ref 3b points to THF
as a strong ligand for diarylzinc species, which prevents the formation
of Ar2Zn(X-alkyl)n species, a presumably key step in the coupling.
(21) Aoyama, T.; Hayakawa, M.; Ogawa, S.; Nakajima, E.;
Mitsuyama, E.; Iwabuchi, T.; Takido, T.; Kodomari, M. Synlett
2014, 25, 2493−2497.
(22) Sun, Y.-Y.; Yi, J.; Lu, X.; Zhang, Z.-Q.; Xiao, B.; Fu, Y. Chem.
Commun. 2014, 50, 11060−11062.
(23) (a) Negishi, E. Acc. Chem. Res. 1982, 15, 340−348. (b) Piller, F.
M.; Appukkuttan, P.; Gavryushin, A.; Helm, M.; Knochel, P. Angew.
Chem., Int. Ed. 2008, 47, 6802−6806. (c) Johansson Seechurn, C. C.
C.; Kitching, M. O.; Colacot, T. J.; Snieckus, V. Angew. Chem., Int. Ed.
2012, 51, 5062−5085.
M
DOI: 10.1021/acs.joc.6b00074
J. Org. Chem. XXXX, XXX, XXX−XXX