Nickel-mediated inter- and intramolecular reductive cross-coupling of unactivated alkyl bromides and aryl iodides at room temperature

Article abstract of DOI:10.1002/chem.201200190

A nickel-mediated intermolecular reductive cross-coupling reaction of unactivated alkyl bromides and aryl iodides at room temperature has been developed and successfully extended to less explored intramolecular versions and tandem cyclization-intermolecular cross-coupling. Highly stereoselective (or stereospecific) synthesis of linear-fused perhydrofuro[2,3-b]furan (pyran) and spiroketal skeletons allows rapid access to these useful building blocks, which would be potentially valuable in the synthesis of relevant natural products. A rational explanation for the formation of contiguous stereogenic centers is given. Copyright

Full text of DOI:10.1002/chem.201200190

FULL PAPER
DOI: 10.1002/chem.201200190
Nickel-Mediated Inter- and Intramolecular Reductive Cross-Coupling of
Unactivated Alkyl Bromides and Aryl Iodides at Room Temperature
Chang-Song Yan,[a] Yu Peng,*[a] Xiao-Bo Xu,[a] and Ya-Wen Wang[b]
Abstract: A nickel-mediated intermo-
lecular reductive cross-coupling re-
stereoselective (or stereospecific) syn-
thesis of linear-fused perhydrofuro[2,3-
b]furan (pyran) and spiroketal skele-
tons allows rapid access to these useful
building blocks, which would be poten-
tially valuable in the synthesis of rele-
vant natural products. A rational ex-
planation for the formation of contigu-
ous stereogenic centers is given.
ACHTUNGTRENNUNG
A
and aryl iodides at room temperature
has been developed and successfully
extended to less explored intramolecu-
lar versions and tandem cyclization-in-
termolecular cross-coupling. Highly
Keywords: alkyl halides · domino
reaction
· cyclization · nickel ·
reduction · cross-coupling
Introduction
Transition-metal-catalyzed C C coupling reactions[1] are
among the most valuable transformations in organic synthe-
sis, and their importance was recognized by the scientific
community with a 2010 Nobel Prize in chemistry.[2] Whereas
aryl and alkenyl halides are suitable substrates for the cou-
pling, alkyl halides are challenging because the intermedi-
ates generated from oxidative addition with transition
metals have the tendency to participate in competitive side
reactions (reductions and/or b-hydride elimination re-
ꢀ
Scheme 1. Synthetic tactics for functionalized arene derivatives.
ACHTUNGTRENNUNG
actions).[3] On the other hand, the need for organometallic
reagents as the coupling partner put constrains on cost, sus-
tainability, availability, tolerance of functional groups, and/
or the need for protecting groups, which might be especially
true during the synthesis of complex molecules. Thus, ap-
proaches featuring in situ generation of Grignard[4a] or orga-
nozinc[4b,c] reagents have already emerged and alternative
approaches are still in high demand. Recently, Weix[5a,b] and
Gosmini[5c] independently disclosed promising catalytic re-
ductive cross-coupling (CRCC) reactions between alkyl
halides and aryl halides; however, intramolecular CRCC
and tandem reductive cross-coupling reactions remain large-
ly unexplored (Scheme 1). Herein, we report our results that
we have obtained by using a readily accessible and extreme-
ly cheap Ni0 complex.
Results and Discussion
We began by examining intermolecular reductive coupling
between 4-fluoroiodobenzene and 2-phenylethyl bromide
(1.2 equiv) by using [Ni0·2EC·Py] as the catalyst. This nickel
catalyst can be readily prepared in situ from a mixture of
Zn/NiCl2/pyridine/ethyl crotonate (EC) (see the Experimen-
tal Section and the Supporting Information) according to
a similar procedure for the generation of [Ni0·2MA·Py]
(MA= methyl acrylate).[6a] Notably, ethyl crotonate as the p
ligand[7] to Ni0 is preferred over methyl acrylate because the
latter may interfere with the desired cross-coupling reaction
as a reactive Michael acceptor.[6b] As shown in Table 1, with
a stoichiometric amount of [Ni0·2EC·Py] generated in situ,
the intended cross-coupling indeed occurred in N,N-di-
[a] C.-S. Yan, Prof. Dr. Y. Peng, X.-B. Xu
State Key Laboratory of Applied Organic Chemistry and
College of Chemistry and Chemical Engineering
Lanzhou University
Lanzhou 730000 (P.R. of China)
Fax : (+ 86)931-8912582
E-mail: pengyu@lzu.edu.cn
[b] Prof. Dr. Y.-W. Wang
Key Laboratory of Nonferrous Metal Chemistry and
Resources Utilization of Gansu Province and
College of Chemistry and Chemical Engineering
Lanzhou University
AHCTUNGTREGmNNUN ethylformamide (DMF) at room temperature, and the de-
sired product 1a was formed in 24% yield (Table 1,
entry 1); the major side reaction was homo-coupling of 2-
phenylethyl bromide, and homo-dimer[8] 1a’ was formed in
Lanzhou 730000 (P.R. of China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200190.
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Table 1. Optimization of conditions for reductive cross-coupling.[a]
Entry
NiCl2
Solvent
t [h]
Yield [%] (1a/1a’)
1
2
3
4
5
6
7
8
9
1
DMF
DMF
DMF
DMF
dioxane
MeOH
CH3CN
CH3CN[e]
CH3CN
1
4
8
15
24
8
8
8
10
24:71
49:36
38:60
39:56
8:30[d]
34:60
47:58
63[f]:37
54:44
0.5
0.3
0.3[c]
0.3
0.3
0.3
0.3
0.15
[a] Reaction conducted on 1 mmol scale. A mixture of Zn (3 equiv to
ArI), NiCl2 (indicated by table), EC (3 equiv to Ni), and Py (0.5 mL) was
employed to generate [Ni0·2EC·Py] at 558C; a solution of two halides in
solvent (4 mL) was added to the Ni0 complex dropwise over a 10 min
Scheme 2. Intermolecular cross-coupling with aryl iodides (1 mmol
scale); the isolated product yield is shown. [a] Employing NiCl2
(0.5 equiv) and EC (1.5 equiv).
1
period at RT. [b] The yield was estimated by H NMR spectroscopic anal-
ysis with diethyl phthalate as internal standard. [c] NiCl2·6H2O was
added. [d] Most of two halides remained. [e] 8 mL. [f] The isolated prod-
uct yield was 60%.
reaction. With a phenyliodide bearing a methylenedioxy
group as the substrate, the desired coupling product 1j was
also obtained in moderate yield. In addition, other aromatic
iodides including 2-iodo-6-methoxy naphthalene, N-methyl-
5-iodoindole, and N-methyl-4-iodoindole worked equally
well, leading to cross-coupling products in acceptable yields
(1k–m). Positional tolerance on the benzene ring was then
investigated, and both ortho- and meta-iodoanisole were
found to provide the desired products (1o and 1n).
We then examined the scope of the reaction with alkyl
bromides using 4-iodoanisole as the coupling partner, and
found that a wide range of functional groups on the bromide
were suitable (Scheme 3). The functional groups assessed in-
71% yield. Most of the 4-fluoroiodobenzene could be recov-
ered during the short reaction time as demonstrated in
Table 1 (entry 1), but reduction and homo-coupling of this
aryl iodide also took place when the reaction was prolonged.
Notably, without using ethyl crotonate, no reaction was ob-
served.[9] Similar results were obtained with catalytic
amounts of this Ni0 complex, although the reactions were
slower (Table 1, entries 2 and 3). The use of hydrated NiCl2
(Table 1, entry 4) did not improve the reaction. Screening al-
ternative solvents (Table 1, entries 5–8) eventually identified
acetonitrile as optimal; under these conditions, 1a was iso-
lated in 60% yield by employing 30 mol% catalyst, and the
formation of undesired 1a’ was somewhat suppressed. Nota-
bly, competitive reduction except the respective homo-cou-
pling of two halides also takes place without slow addition
of the substrates (see footnote [a] in Table 1 and the Sup-
porting Information). In the presence of 15 mol% Ni0,
a slightly decreased yield of 1a was also obtained (Table 1,
entry 9). The present catalytic system has a few salient fea-
tures: the reactions proceed at room temperature, no glove
box operation is necessary, broad functional group tolerance
can be achieved, and the Ni0 complex can be generated
from air-stable and inexpensive materials.[10]
With the above optimized conditions in hand, reductive
cross-couplings of various functionalized aryl iodides with
2-phenylethyl bromide were then investigated (Scheme 2).
To our delight, phenyl iodides with either electron-donating
groups (OMe, NMe2, or SMe) or electron-withdrawing
groups (CO2Et, COMe, or CF3) reacted smoothly, affording
the corresponding cross-coupled products (1b–g) in accepta-
ble yields. Moreover, 4-iodophenol (1h) was also suitable,
which demonstrates the mild nature of this reaction because
its relatively acidic proton did not interfere in the reaction.
A pinacol boronate moiety was also tolerated, again reflect-
ing the mild nature of this chemistry, and the product (1i)
could be further elaborated by subsequent Suzuki coupling
Scheme 3. Intermolecular cross-coupling with alkyl bromides (1 mmol
scale); the isolated product yield is shown. [a] Employing alkyl bromide
(2 equiv), NiCl2 (0.5 equiv), and EC (1.5 equiv). [b] Employing 4-iodoani-
sole (2 equiv), NiCl2 (0.5 equivꢁ2), and EC (1.5 equivꢁ2).
cluded electrophilic groups, such as ester (2a) and nitrile
(2b) and a range of protected nucleophilic moieties, such as
OTBS (2c), OTHP (2d), NPhth (2 f), and acetal (2g). In
particular, compound 2e (with a free hydroxyl group) was
also formed without incident in this cross-coupling reaction.
With the goal of achieving potential application in the total
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Nickel-Mediated Reductive Cross-Coupling
FULL PAPER
synthesis of complex natural products, the chiral alkyl bro-
mide degraded from andrographolide (see the Supporting
Information) was subjected to this cross-coupling reaction,
and 2h was isolated in 47% yield, which is acceptable con-
sidering the presence of the acid-labile acetonide and a po-
tentially labile terminal alkene. Interestingly, double aryla-
tions of 1,4-dibromobutane proceeded smoothly, and sym-
metrical 2i was obtained in 55% yield. Activated alkyl
halides,[11] such as a-bromo ester and benzyl bromide were
also tried, and the corresponding products 2j and 2k were
isolated in serviceable yields.
establish optimized conditions for the realization of this in-
teresting idea. Initial reactions indicated that the conversion
rate of 5a is much faster than that of 4-iodoanisole under
identical Ni0 catalysis conditions. Thus, 5a should not be
added until 4-iodoanisole was introduced into the reaction
system (see footnote [a] in Table 2 and the Experimental
Section). As shown in Table 2, only a 20% yield of 6a was
Table 2. Optimization of conditions for tandem cyclization/intermolecu-
lar cross-coupling.[a]
Extension of this intermolecular Ni0-catalyzed reductive
cross-coupling to the intramolecular counterpart was then
explored. As shown in Scheme 4, a range of indoline and
Entry
T1 [8C]
T2 [8C]
t2 [h]
Yield of 6a [%][b]
1
2
3
4
5
6
7
8
0
RT
RT
RT
RT
RT
50
0
RT
50
50
50
1
1
0.5
1
1.5
1
20
32
46
50
59 (58)[c]
80
45
51
50
50
1
1
50
50[d]
[a] Reaction conducted on 1.0 mmol scale. A mixture of Zn (3.0 mmol,
195 mg), NiCl2 (0.3 mmol, 39 mg), EC (0.9 mmol, 0.12 mL), and Py
(0.5 mL) were employed to generate [Ni0·2EC·Py] at 558C. Then a solu-
tion of 4-iodoanisole (1.6 mmol, 375 mg) in CH3CN (1.0 mL) was added
to the Ni(0) complex dropwise within t1 (2 min) at a temperature of T1.
A solution of b-bromo acetal 5a in CH3CN (3 mL) was added to the
above mixture dropwise over a t2 period at a temperature of T2. The
progress of reaction was monitored by TLC. [b] The yield was estimated
1
Scheme 4. Intramolecular cross-coupling for benzo-heterocycles. [a] The
side products resulting from reduction (27%) and homo-coupling (20%)
were also isolated.
by H NMR spectroscopic analysis with diethyl phthalate as internal stan-
dard. [c] Isolated product yield. [d] Compound 5a was dissolved in
CH3CN (6 mL).
tetrahydroquinoline products (4a–h) with various functional
groups can be easily prepared in gram scale through intra-
molecular reductive coupling in the presence of one equiva-
lent of Ni0.[12] Slightly better yields could be obtained by
conducting the reactions in DMF as solvent, instead of ace-
tonitrile. The present method is reminiscent of the seminal
obtained when both starting materials were added at 08C
(Table 2, entry 1). A slightly increased yield could be ob-
tained when the reaction was conducted at room tempera-
ture (Table 2, entry 2). Employing higher temperature (up
to 508C) and prolonging the addition time of 5a led to a fur-
ther increase in the yield of the expected product 6a
(Table 2, entries 3 and 4). Eventually, the best conditions
were found for this essential two-step transformation and
59% yield (77% per step) of 6a was achieved (Table 2,
entry 5). Still higher temperatures (808C) gave inferior re-
sults (Table 2, entry 6) due to instability of the Ni0 complex.
A slight decrease in the yield was observed when the whole
reaction event was run at 508C either in optimized or more
dilute concentration (Table 2, entries 7 and 8). Scheme 5a
shows more cases based on this cascade, in which formal
5-exo-trig cyclizations of alkyl bromides 5 precede intermo-
lecular reductive cross-couplings, with various aromatic io-
dides having electron-donating groups (OMe or SMe) or
electron-withdrawing groups (CO2Et or F). Other aromatic
iodides including 2-iodo-6-methoxy naphthalene, N-methyl-
ꢀ
work on C C bond formation undertaken by Corey and
Semmelhack by using stoichiometric p-allylnickel halides,[13]
which are generated from volatile, flammable, and highly
toxic [Ni(CO)4]. Similarly, dihydrobenzofuran 4j and chro-
mans 4i and 4k were prepared in useful yields. Attempts to
construct challenging medium-ring compounds such as
2,3,4,5-tetrahydro-1-benzoxepine (4l) led to low yields due
to competitive reduction and intermolecular homo-coupling
ꢀ
reactions. This intramolecular C C cross-coupling strategy
provides an approach to these useful structural motifs that
ꢀ
ꢀ
complements those based on C N and C O coupling re-
actions, which often require rather harsh conditions.[14]
These reductive cross-coupling reactions, either intermo-
lecular or intramolecular, can be interlaced by reactions
ACHTUNGTRENNUNG
ꢀ
ꢀ
with tethered C C double bonds, leading to double C C
bond formations in a tandem fashion. First, we chose
4-iodoanisole and b-bromo acetal 5a as a model partner to
ACHTUNGTRENNUNG
6
N
ACHTUNGTRENNUNG
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6041

Y. Peng et al.
Scheme 6. Bidirectional elaboration of 4-IpBPE by sequential cross-cou-
pling catalyzed by Ni and Pd, respectively.
direct utilization of a bifunctional (electrophilic and nucleo-
philic) building block and provides an alternative approach
to the standard masking/unmasking strategy with this kind
of haloboronic acids in the field of cross-coupling re-
AHCTUNGTRENNUNG
actions.[22]
The above cascade reaction could also be readily extend-
ed to an unprecedented tandem cyclization/intramolecular
reductive coupling. As shown in Scheme 7a, substrate
Scheme 5. Stereoselective cyclization/intermolecular cross-coupling (con-
ditions given in Table 2).
found in some natural products and pharmaceuticals,[15] and
were formed with excellent endo-diastereoselectivity and in
fairly good yields. The cis/syn stereochemistries were as-
1
signed through extensive analysis of their respective H–1H
COSY and NOE spectra (exemplified in the cases of 6a and
6j),[16] and were consistent with the results of previous stud-
ies in which arylboronic acids or monoaryltin reagents were
employed.[17] In addition, this cascade reaction[18] readily
converted b-bromo ketals 7 into [5,5]- and [5,6]-spiroketal
skeletons 8 as the sole diastereomers with one anomeric
effect[19] (Scheme 5b). The structural assignment was con-
firmed from the X-ray crystal structure of 8b’,[20] which was
prepared from 8b under standard conditions. More impor-
tantly, the spiroketal structure in 8 can be also found in nu-
merous biologically active natural products such as insect
pheromones, polyether antibiotics, and spongistatins/altohyr-
tins.[21]
This cascade reaction could also be suitable for gram-
scale synthesis, as exemplified in the case of b-bromo acetal
5b and 4-iodophenyl boronate pinacol ester (4-IpBPE;
Scheme 6). After site-selective, tandem coupling of this am-
phiphilic synthon (4-IpBPE) catalyzed by Ni0, the untouched
BACHTUNGTRENNUNG
CTHUNGTRENNUNG
[dppf=1,1’-bis(diphenylphosphino)ferrocene], and eventual-
ly biphenyl derivative 6l’ was isolated in 91% yield. The
whole transformation shown in Scheme 6 represents the
Scheme 7. Stereospecific cyclization/intramolecular cross-coupling.
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Chem. Eur. J. 2012, 18, 6039 – 6048

Nickel-Mediated Reductive Cross-Coupling
FULL PAPER
b-bromo acetal 10a, was prepared by electrophilic alkoxy-
bromination of 2,3-dihydrofuran in the presence of allyl al-
cohol 9, which, in turn, was synthesized from o-iodo benzoic
acid through a five-step sequence (see the Supporting Infor-
mation). When 10a was subjected to a stoichiometric
amount of the Zn/[Ni0·2EC·Py] system,[12] the linear fused
tetracycle product 11a was isolated in 60% yield as the only
diastereomeric isomer (Scheme 7b, top). The relative config-
uration of 11a (cis-anti-trans) was unambiguously estab-
lished by a single-crystal analysis (Figure 1a).[20] Notably,
Scheme 8. Proposed mechanism.
an RNiIIIR’X species,[24,25] which could undergo subsequent
reductive elimination to furnish the desired cross-coupling
0
ꢀ
product R R’ while regenerating Ni catalyst upon Zn re-
duction. However, the involvement of radical species gener-
ated from halides by a single-electron transfer (SET) pro-
cess[26] from the [Ni0·2EC·Py] complex cannot be ruled out
because it could readily rationalize the tandem reactions
demonstrated in Scheme 5, Scheme 6, and Scheme 7. A ra-
tional analysis (illustration with 5a as an example) of these
intriguing cascades, which provide contiguous stereocenters
in excellent diastereoselectivity, is given in Scheme 8b. Ho-
Figure 1. a) X-ray crystal structure of 11a. b) X-ray crystal structure of
11b.
0
ꢀ
molysis of C Br through a SET process with Ni affords sec-
ondary radical species I, which adopts a pseudochair confor-
mation in which the alkyl substituents prefer to occupy
equatorial positions whereas the alkoxy substituent occupies
the axial position.[27] This stereochemical arrangement could
be further favored by an anomeric effect.[19] Next, a stereose-
lective radical cyclization reaction would take place in a
5-exo-trig fashion, affording intermediate II with three ster-
eodefined contiguous stereocenters. The above primary radi-
cal II would then coordinate with previously generated
[LnNiIBr]. The resulting NiII species III could follow similar
steps to those mentioned in the intermolecular reductive
cross-coupling (Scheme 8a), and eventually convert into
ꢀ
two C C bonds and four contiguous stereogenic centers
were simultaneously formed in this single-step reaction. A
similar stereospecific cascade also occurred with the diaste-
reomeric and more polar acetal bromide 10b, affording the
diastereomeric tetracycle 11b in a slightly higher yield
under the same conditions (Scheme 7b, bottom). Its cis-syn-
trans ring fusion was again established from its X-ray crystal
structure (Figure 1b).[20] It is noteworthy that an analogous
tricycle moiety with this particular fused relationship has
been previously reported by Hoffman and co-workers, who
employed an atom-transfer radical reaction.[23] Moreover,
this methodology can be successfully extended to the stereo-
specific synthesis of spiroketals 13 with a [5,5,6,6]-tetracyclic
skeleton[16] starting from analogous di-iodide 12
(Scheme 7c).
perhydrofuroACTHNUGTRENNUG[2,3-b]furanACHTUGNTREN(NNGU pyran) products 6.
Conclusion
3
2
[28]
ꢀ
Based on previous mechanistic hypotheses on the reduc-
tive coupling of alkyl halides,[5a,8b] a similar mechanism for
our reactions is proposed in Scheme 8a. Firstly, oxidative ad-
dition of alkyl bromide (or aryl iodide) to Ni0 (generated in
situ) gives an RNiIIX species that is subjected to reduction
by stoichiometric Zn. A second oxidative addition of the re-
sulting RNiI intermediate with a second halide would form
We have developed a direct method for Csp Csp bond
construction based on a reductive cross-coupling reaction
catalyzed by an [Ni0·2EC·Py] complex generated in situ
under exceptionally mild conditions. The first reductive cy-
ACHUTNGRENcNUG lization/interACHUTNGTREN(NNGU intra)molecular cross-coupling cascades were
also achieved, affording versatile structural motifs with ex-
cellent stereoselectivities.
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6043

Y. Peng et al.
HRMS (ESI): m/z calcd for C12H15NO2Na+: 228.0995 [M+Na]+; found:
228.0998.
Experimental Section
Compound 4d:[32] Prepared as a yellow solid (42% yield) according to
General Procedure D. Rf =0.47 (PE/EtOAc=4:1); m.p. 77–798C
(EtOAc); 1H NMR (400 MHz, CDCl3): d=7.79 (d, J=8.4 Hz, 1H), 7.47
(d, J=8.0 Hz, 2H), 7.26–7.16 (m, 3H), 7.06 (dt, J=7.6, 0.8 Hz, 1H), 7.00
(d, J=7.6 Hz, 1H), 3.80 (t, J=1.6 Hz, 2H), 2.44 (t, J=6.8 Hz, 2H), 2.37
(s, 3H), 1.67–1.59 ppm (m, 2H); 13C NMR (100 MHz, CDCl3): d=143.4,
136.9, 136.8, 130.6, 129.5 (2C), 129.0, 127.1 (2C), 126.4, 124.9, 124.9, 46.5,
26.6, 21.6, 21.5 ppm; IR (film): n˜ =2947, 1599, 1489, 1453, 1345, 1163,
1089, 847, 760, 689, 578 cmꢀ1; HRMS (APCI): m/z calcd for C16H18NO2S+
: 288.1053 [M+H]+; found: 288.1057.
Compound 4e:[32] Prepared as a colorless oil (52% yield) according to
General Procedure D. Rf =0.34 (PE/EtOAc=4:1); 1H NMR (400 MHz,
CDCl3): d=7.69 (d, J=8.4 Hz, 1H), 7.17 (t, J=6.8 Hz, 1H), 7.13 (d, J=
6.4 Hz, 1H), 7.07 (t, J=7.6 Hz, 1H), 3.81 (t, J=7.5 Hz, 2H), 2.89 (s, 3H),
2.85 (t, J=6.8 Hz, 2H), 2.03–1.97 ppm (m, 2H); 13C NMR (100 MHz,
CDCl3): d=136.9, 129.7, 129.1, 126.8, 124.5, 122.6, 46.5, 38.6, 27.0,
22.2 ppm; IR (film): n˜ =3010, 2935, 2878, 1601, 1576, 1486, 1449, 1336,
1317, 1280, 1230, 1152, 1083, 974, 844, 758 cmꢀ1;HRMS (ESI): m/z calcd
for C10H13NO2SNa+: 234.0565 [M+Na]+; found: 234.0565.
General: For product purification by flash column chromatography, silica
gel (200–300 mesh) and petroleum ether (PE; b.p. 60–908C) were used.
All solvents were purified and dried by standard techniques and distilled
prior to use. All organic extracts were dried over Na2SO4 or MgSO4,
unless otherwise noted. All experiments were conducted under an argon
or nitrogen atmosphere in oven-dried or flame-dried glassware with mag-
netic stirring, unless otherwise specified. NMR spectra were measured
with a Bruker AM-400 MHz spectrometer. All 1H NMR chemical shifts
(d) are reported relative to residual protic solvent (CHCl3: d=7.26 ppm),
and all 13C NMR chemical shifts (d) are reported relative to the solvent
(CHCl3: d=77.00 ppm). Mass spectra were measured with a Bruker Dal-
tonics APEX II 47e FT-ICR spectrometer with ESI and APCI (positive
or negative ion mode). Infrared spectra were recorded with a Nicolet FT-
170SX FTIR spectrophotometer. The following chemicals were pur-
chased and used as received: Zn (99.9%, powder), NiCl2 (99.9%), pyri-
dine (99.5%, SuperDry, with molecular sieves), DMF (99.8%, SuperDry,
with molecular sieves), CH3CN (99.9%, SuperDry, with molecular
sieves), 4-iodoanisole (98%), 2-phenylethyl bromide (98%). Ethyl croto-
nate was prepared by etherification of crotonic acid. Most of the aryl io-
dides can be synthesized from commercially available aryl bromides
through Br–Li exchange followed by I2 quench.[29] Following a literature
procedure,[30] 4-iodophenylboronic acid pinacol ester was prepared from
4-iodophenyl boronic acid with pinacol. General Procedure A for
Scheme 2 and Scheme 3, and General Procedures B and C were used for
the preparation of dihalides 3; further details can be found in the Sup-
porting Information.
Compound 4 f: Prepared as a colorless crystal (53% yield) according to
General Procedure D. Rf =0.58 (PE/EtOAc=4:1); m.p. 55–578C
(EtOAc); 1H NMR (400 MHz, CDCl3): d=7.85 (d, J=8.8 Hz, 1H), 7.81
(d, J=8.8 Hz, 1H), 7.77 (s, 1H), 4.26 (q, J=7.2 Hz, 2H), 3.88 (s, 3H),
3.78 (t, J=6.0 Hz, 2H), 2.80 (t, J=6.4 Hz, 2H), 1.95 (t, J=6.4 Hz, 2H),
1.33 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=166.8,
154.6, 142.5, 130.1, 129.3, 127.4, 124.6, 123.1, 62.1, 51.8, 45.1, 27.5, 23.0,
14.4 ppm; IR (film): n˜ =2981, 2951, 1715, 1611, 1577, 1500, 1440, 1375,
1318, 1283, 1235, 1196, 1107, 1049, 769 cmꢀ1; HRMS (ESI): m/z calcd for
C14H17NO4Na+: 286.1055 [M+Na]+; found: 286.1055.
Intramolecular reductive cross-coupling for benzo-heterocycles 4 (Gener-
al Procedure D): Ethyl crotonate (1.9 mL, 15 mmol) was added at RT to
a stirred slurry of Zn (975 mg, 15 mmol) in pyridine (5 mL). Under vigo-
rous stirring, NiCl2 (640 mg, 5 mmol) was added to the above mixture.
The temperature rose to 558C, then the mixture was heated, and stirring
was continued for 15 min. The resulting red brown [Ni0·2EC·Py] complex
was cooled to RT, and a solution of dihalide (5 mmol) in DMF (50 mL)
was added dropwise over a 30 min period. After 2 h, the mixture was fil-
tered through a short plug of silica (elution with 80 mL Et2O) and
washed with HCl (1 n), water, and brine, dried over MgSO4, filtered, and
concentrated. The crude product was purified by flash chromatography
on silica gel to afford the desired products.
Compound 4g: Prepared as a colorless oil (57% yield) according to Gen-
eral Procedure D. Rf =0.58 (PE/EtOAc=4:1); 1H NMR (400 MHz,
CDCl3): d=8.39 (s, 1H), 7.65 (dd, J=8.0, 1.6 Hz, 1H), 7.12 (d, J=8.0 Hz,
1H), 4.26 (q, J=7.2 Hz, 2H), 3.88 (s, 3H), 3.76 (t, J=6.0 Hz, 2H), 2.80
(t, J=6.4 Hz, 2H), 1.94 (t, J=6.4 Hz, 2H), 1.32 ppm (t, J=7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=166.9, 154.6, 138.2, 134.9, 128.5, 128.0,
125.1, 124.3, 61.9, 51.9, 44.5, 27.6, 23.0, 14.4 ppm; IR (film): n˜ =2950,
1718, 1611, 1503, 1437, 1378, 1304, 1261, 1203, 1138, 1105, 1052, 763 cmꢀ1
;
HRMS (APCI): m/z calcd for C14H18NO4+: 264.1230 [M+H]+; found:
264.1231.
Compound 4a: Prepared as a colorless solid (41% yield) according to
General Procedure D. Rf =0.62 (PE/EtOAc=4:1); m.p. 58–598C
(EtOAc); 1H NMR (400 MHz, CDCl3): d (rotamers)[31] =7.71 (brs, 1H),
7.41–7.29 (m, 5H), 7.15 (d, J=7.2 Hz, 2H), 6.95 (t, J=7.2 Hz, 1H), 5.26
(brs, 2H), 4.05 (t, J=7.2 Hz, 2H), 3.12 ppm (t, J=8.4 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d=152.8, 142.5, 136.4, 130.9, 128.6, 128.2, 128.0,
127.5, 124.7, 122.6, 114.8, 66.9, 47.4, 27.5 ppm; IR (film): n˜ =3113, 3065,
Compound 4h: Prepared as a colorless oil (52% yield) according to Gen-
eral Procedure D. Rf =0.58 (PE/EtOAc=4:1); 1H NMR (400 MHz,
CDCl3): d=8.08 (s, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.18 (d, J=8.0 Hz,
1H), 4.24 (q, J=7.2 Hz, 2H), 3.80 (t, J=6.0 Hz, 2H), 2.82 (t, J=6.4 Hz,
2H), 1.97 (t, J=6.4 Hz, 2H), 1.34 ppm (t, J=7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=154.6, 138.5, 133.4, 129.0, 128.4 (q,
32.0 Hz), 124.1 (q, J(C,F)=271.0 Hz), 120.8 (q, J(C,F)=3.0 Hz), 119.7 (q,
(C,F)=4.0 Hz), 62.2, 44.7, 27.5, 22.9, 14.4 ppm; 19F NMR (376 MHz,
JACHTUNGTRENNUNG(C,F)=
2959, 2923, 1700, 1600, 1492, 1446, 1420, 1369, 1322, 1211, 1140, 1036,
G
ACHTUNGTRENNUNG
+
750, 695 cmꢀ1;HRMS (APCI): m/z calcd for C16H16NO2
[M+H]+; found: 254.1172.
: 254.1176
JACHTUNGTRENNUNG
CDCl3): d=ꢀ62.50 ppm; IR (film): n˜max =2941, 1709, 1619, 1585, 1510,
1432, 1379, 1329, 1262, 1207, 1168, 1123, 1078, 890, 818, 768 cmꢀ1; HRMS
(ESI): m/z calcd for C13H14F3NO2Na+: 296.0874 [M+Na]+; found:
296.0877.
Compound 4i:[32] Prepared as a colorless oil (54% yield) according to
General Procedure D. Rf =0.73 (PE/EtOAc=4:1); 1H NMR (400 MHz,
CDCl3): d=6.92 (d, J=8.4 Hz, 1H), 6.43 (dd, J=8.4, 2.8 Hz, 1H), 6.36
(d, J=2.8 Hz, 1H), 4.16 (t, J=5.2 Hz, 2H), 3.75 (s, 3H), 2.72 (t, J=
6.4 Hz, 2H), 2.01–1.95 ppm (m, 2H); 13C/DEPT NMR (100 MHz,
CDCl3): d=159.0 (s), 155.5 (s), 130.2 (s), 114.3 (d), 107.0 (d), 101.5 (d),
66.5 (t), 55.3 (q), 24.2 (t), 22.5 (t) ppm; IR (film): n˜max =2934, 2865, 1619,
1583, 1505, 1443, 1306, 1275, 1203, 1155, 1115, 1061, 837 cmꢀ1; HRMS
(ESI): m/z calcd for C10H13O2+: 165.0910 [M+H]+; found: 165.0912.
Compound 4b: Prepared as a colorless oil (62% yield) according to Gen-
eral Procedure D. Rf =0.32 (PE/EtOAc=10:1); 1H NMR (400 MHz,
CDCl3): d=7.71 (d, J=8.0 Hz, 1H), 7.41–7.29 (m, 5H), 7.16–7.12 (m,
1H), 7.08 (d, J=7.2 Hz, 1H), 7.02–6.98 (m, 1H), 5.24 (s, 2H), 3.79 (t, J=
6.2 Hz, 2H), 2.76 (t, J=6.4 Hz, 2H), 1.97–1.90 ppm (m, 2H); 13C NMR
(100 MHz, CDCl3): d=154.7, 138.1, 136.5, 130.0, 128.6, 128.5, 128.03,
127.95, 126.0, 123.9, 123.7, 67.4, 44.9, 27.3, 23.4 ppm; IR (film): n˜ =2947,
1705, 1493, 1455, 1392, 1322, 1259, 1205, 1135, 1021, 759, 698 cmꢀ1
;
HRMS (APCI): m/z calcd for C17H18NO2+: 268.1332 [M+H]+; found:
268.1335.
Compound 4c:[32] Prepared as a colorless oil (53% yield) according to
General Procedure D. Rf =0.55 (PE/EtOAc=4:1); 1H NMR (400 MHz,
CDCl3): d=7.68 (d, J=8.0 Hz, 1H), 7.17–7.13 (m, 1H), 7.08 (d, J=
6.8 Hz, 1H), 7.00 (td, J=7.2, 0.8 Hz, 1H), 4.24 (q, J=7.2 Hz, 2H), 3.76
(t, J=6.0 Hz, 2H), 2.77 (t, J=6.6 Hz, 2H), 1.97–1.91 (m, 2H), 1.32 ppm
(t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=154.9, 138.3, 129.9,
128.5, 125.9, 123.9, 123.5, 61.7, 44.7, 27.4, 23.4, 14.5 ppm; IR (film): n˜ =
Compound 4j: Prepared as a colorless oil (49% yield) according to Gen-
eral Procedure D. Rf =0.38 (PE/EtOAc=10:1); 1H NMR (400 MHz,
CDCl3): d=7.57 (dd, J=7.6, 1.2 Hz, 1H), 7.42 (d, J=1.2 Hz, 1H), 7.30
(d, J=7.6 Hz, 1H), 4.61 (t, J=8.8 Hz, 2H), 4.30 (t, J=6.6 Hz, 2H), 3.25
(t, J=8.6 Hz, 2H), 1.77–1.70 (m, 2H), 1.47 (dt, J=15.2, 7.6 Hz, 2H),
0.97 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=166.5,
2979, 2940, 1705, 1492, 1377, 1321, 1259, 1204, 1174, 1136, 1056, 761 cmꢀ1
;
6044
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 6039 – 6048

Nickel-Mediated Reductive Cross-Coupling
FULL PAPER
160.0, 132.5, 130.7, 124.5, 122.3, 110.0, 71.4, 64.8, 30.7, 29.7, 19.2,
13.7 ppm; IR (film): n˜ =2960, 2933, 1715, 1590, 1493, 1430, 1285, 1266,
1213, 1107, 1080, 990, 954, 760 cmꢀ1; HRMS (APCI): m/z calcd for
C13H17O3+: 221.1172 [M+H]+; found: 221.1169.
16.0 ppm; IR (film): n˜ =2947, 2864, 1600, 1493, 1439, 1371, 1204, 1106,
1009, 957, 831, 723 cmꢀ1; HRMS (ESI): m/z calcd for C14H18O2SNa+:
273.0925 [M+Na]+; found: 273.0921.
Compound 6d: Prepared as a colorless oil (51% yield) according to Gen-
eral Procedure E. Rf =0.21 (PE/EtOAc=4:1); 1H NMR (400 MHz,
CDCl3): d=7.98 (d, J=8.4 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H), 5.72 (d, J=
4.8 Hz, 1H), 4.37 (q, J=7.2 Hz, 2H), 3.97 (dd, J=15.6, 7.6 Hz, 1H), 3.87
(q, J=7.6 Hz, 2H), 3.55 (dd, J=11.2, 8.8 Hz, 1H), 2.84–2.72 (m, 3H),
2.70–2.64 (m, 1H), 2.03–1.96 (m, 1H), 1.91–1.82 (m, 1H), 1.39 ppm (t,
J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=166.4, 145.2, 129.9
(2C), 128.7, 128.3 (2C), 109.7, 71.9, 69.0, 60.9, 45.4, 43.5, 33.8, 25.1,
14.3 ppm; IR (film): n˜max =2951, 2870, 1715, 1611, 1575, 1451, 1368, 1278,
1179, 1108, 1019, 927, 866, 763, 708 cmꢀ1; HRMS (ESI): m/z calcd for
C16H20O4Na+: 299.1259 [M+Na]+; found: 299.1262.
Compound 4k: Prepared as a colorless oil (63% yield) according to Gen-
eral Procedure D. Rf =0.39 (PE/EtOAc=10:1); 1H NMR (400 MHz,
CDCl3): d=7.50 (dd, J=7.8, 1.2 Hz, 1H), 7.46 (s, 1H), 7.08 (d, J=7.8 Hz,
1H), 4.29 (t, J=6.4 Hz, 2H), 4.20 (t, J=5.2 Hz,2H), 2.82 (t, J=6.4 Hz,
2H), 2.05–1.99 (m, 2H), 1.76–1.69 (m, 2H), 1.47 (dt, J=15.2, 7.6 Hz,
2H), 0.97 ppm (t, J=7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
166.5, 154.7, 129.7, 129.7, 127.5, 121.1, 117.9, 66.5, 64.7, 30.7, 25.1, 22.0,
19.2, 13.7 ppm; IR (film): n˜ =2959, 2936, 2871, 1716, 1575, 1422, 1285,
1249, 1214, 1094, 1013, 761 cmꢀ1
; HRMS (APCI): m/z calcd for
C14H19O3+: 235.1329 [M+H]+; found: 235.1326.
Compound 4l: Prepared as a colorless oil (25% yield) according to Gen-
eral Procedure D. Rf =0.48 (PE/EtOAc=10:1); 1H NMR (400 MHz,
CDCl3): d=7.67 (d, J=1.2 Hz, 1H), 7.65 (s, 1H), 7.18 (d, J=7.6 Hz,
1H), 4.30 (t, J=6.6 Hz, 2H), 4.01 (t, J=5.2 Hz, 2H), 2.86 (t, J=5.6 Hz,
2H), 2.00–1.97 (m, 2H), 1.76–1.70 (m, 4H), 1.50–1.44 (m, 2H), 0.97 ppm
(t, J=7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=166.3, 160.2, 141.1,
130.4, 129.8, 124.7, 122.4, 73.7, 64.7, 34.5, 32.3, 30.7, 25.9, 19.3, 13.8 ppm;
IR (film): n˜max =2957, 2933, 2870, 1718, 1610, 1573, 1496, 1419, 1381,
1286, 1215, 1179, 1121, 1097, 1036, 981, 765 cmꢀ1; HRMS (APCI): m/z
calcd for C15H21O3+: 249.1485 [M+H]+; found: 249.1481.
Compound 6e: Prepared as a colorless oil (54% yield) according to Gen-
eral Procedure E. Rf =0.26 (PE/EtOAc=4:1); 1H NMR (400 MHz,
CDCl3): d=7.75 (d, J=8.0 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 5.71 (d, J=
4.8 Hz, 1H), 3.96 (dd, J=16.0, 7.6 Hz, 1H), 3.89–3.83 (m, 2H), 3.56 (dd,
J=10.0, 8.4 Hz, 1H), 2.79–2.73 (m, 2H), 2.74 (t, J=7.2 Hz, 1H), 2.70–
2.61 (m, 1H), 2.04–1.96 (m, 1H), 1.90–1.82 (m, 1H), 1.34 ppm (s, 12H);
13C NMR (100 MHz, CDCl3): d=143.2, 135.1 (2C), 127.8 (2C), 109.8, 83.7
(2C), 72.1, 69.1, 45.4, 43.6, 34.0, 25.1, 24.8 (4C) ppm (the boron-bound
carbon was not detected due to quadrupolar relaxation of boron); IR
(film): n˜ =2977, 2866, 1611, 1518, 1451, 1399, 1362, 1272, 1145, 1089,
1018, 961, 859, 661 cmꢀ1; HRMS (ESI): m/z calcd for C19H27NaO4B+:
353.1903 [M+Na]+; found: 353.1903.
Highly stereoselective cyclization/intermolecular cross-coupling reactions
catalyzed by [Ni0·2EC·Py] complex (General Procedure E): Ethyl croto-
nate (0.12 mL, 0.9 mmol) was added to a stirred slurry of Zn (195 mg,
3 mmol) in pyridine (0.5 mL) at RT. Under vigorous stirring, NiCl2
(38 mg, 0.3 mmol) was added to the above mixture. Then the tempera-
ture rose to 558C, then the mixture was heated, and stirring was contin-
ued for 15 min. The resulting red brown [Ni0·2EC·Py] complex was
cooled to RT, to which the solution of 4-iodoanisole (1.6 mmol, 375 mg)
in CH3CN (1.0 mL) was added dropwise over 2 min. Then, the tempera-
ture rose and the mixture was heated to 508C again, and the solution of
b-bromo acetal 5 or ketal 7 (1 mmol) in CH3CN (3 mL) was added
slowly to the above mixture over a 1.5 h period at this temperature.
After 1.5 h, the mixture was filtered with a short plug of silica (elution
with 30 mL Et2O), washed with water and brine, dried over MgSO4, fil-
tered, and concentrated. The crude product was purified by flash chroma-
tography on silica gel to afford the desired products 6 or 8.
Compound 6 f: Prepared as a colorless oil (54% yield) according to Gen-
eral Procedure E. Rf =0.26 (PE/EtOAc=4:1); 1H NMR (400 MHz,
CDCl3): d=7.40 (s, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.03 (d, J=8.4 Hz,
1H), 7.02 (d, J=3.2 Hz, 1H), 6.41 (d, J=3.2 Hz, 1H), 5.70 (d, J=4.8 Hz,
1H), 3.96 (q, J=8.0 Hz, 1H), 3.90–3.83 (m, 2H), 3.76 (s, 3H), 3.59 (dd,
J=10.4, 8.4 Hz, 1H), 2.86–2.66 (m, 4H), 2.10–2.02 (m, 1H), 1.91–
1.82 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=135.4, 130.6, 129.1,
128.6, 122.1, 119.9, 109.8, 109.2, 100.4, 72.3, 69.1, 45.5, 44.4, 33.7, 32.8,
25.1 ppm; IR (film): n˜max =3100, 2946, 2873, 1719, 1619, 1572, 1513, 1492,
1448, 1337, 1302, 1245, 1156, 1078, 1005, 951, 884, 799, 724 cmꢀ1; HRMS
(APCI): m/z calcd for C16H20NO2+: 258.1489 [M+H]+; found: 258.1495.
Compound 6g; Prepared as a colorless oil (49% yield) according to Gen-
eral Procedure E. Rf =0.26 (PE/EtOAc=4:1); 1H NMR (400 MHz,
CDCl3): d=7.11 (d, J=8.0 Hz, 1H), 7.67 (t, J=7.6 Hz, 1H), 7.06 (d, J=
3.2 Hz, 1H), 6.91 (d, J=7.2 Hz, 1H), 6.48 (d, J=3.2 Hz, 1H), 5.72 (d, J=
4.4 Hz, 1H), 3.98 (q, J=8.0 Hz, 1H), 3.87 (dd, J=14.0, 7.2 Hz, 2H), 3.79
(s, 3H), 3.63 (dd, J=14.0, 8.4 Hz, 1H), 3.06–2.92 (m, 2H), 2.91–2.86 (m,
1H), 2.85–2.76 (m, 1H), 2.13–2.04 (m, 1H), 1.94–1.84 ppm (m, 1H);
13C NMR (100 MHz, CDCl3): d=136.7, 132.2, 128.5, 127.6, 121.7, 118.6,
109.8, 107.5, 98.9, 72.5, 69.2, 45.7, 42.7, 32.9, 31.1, 25.2 ppm; IR (film):
Compound 6a was prepared as a colorless oil (58% yield) according to
General Procedure E. Rf =0.31 (PE/EtOAc=2:1); 1H NMR (400 MHz,
CDCl3): d=7.09 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.4 Hz, 2H), 5.71 (d, J=
4.8 Hz, 1H), 3.95 (dd, J=12.0, 7.2 Hz, 1H), 3.90–3.84 (m, 2H), 3.79 (s,
3H), 3.55 (t, J=8.8 Hz, 1H), 2.79–2.71 (m, 1H), 2.69–2.60 (m, 3H), 2.03–
1.98 (m, 1H), 1.89–1.83 ppm (m, 1H); 13C/DEPT NMR (100 MHz,
CDCl3): d=158.1 (s), 132.0 (s), 129.2 (d, 2C), 114.0 (d, 2C), 109.8 (d),
72.2 (t), 69.1 (t), 55.2 (q), 45.4 (d), 44.0 (d), 32.9 (t), 25.1 (t) ppm; IR
(film): n˜ =2950, 2864, 1612, 1583, 1513, 1461, 1371, 1300, 1247, 1180,
1111, 1032, 923, 832, 750 cmꢀ1; HRMS (ESI): m/z calcd for C14H18O3Na+:
257.1154 [M+Na]+; found: 252.1156.
n˜max =3047, 2940, 2858, 1653, 1610, 1582, 1496, 1446, 1339, 1298, 1242,
+
1083, 1004, 958, 750 cmꢀ1; HRMS (ESI): m/z calcd for C16H20NO2
258.1489 [M+H]+; found: 258.1484.
:
Compound 6h; Prepared as colorless crystals (56% yield) according to
General Procedure E. Rf =0.16 (PE/EtOAc=4:1); m.p. 131–1338C
(EtOAc); 1H NMR (400 MHz, CDCl3): d=7.68 (d, J=8.0 Hz, 1H), 7.67
(d, J=8.4 Hz, 1H), 7.54 (s, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.14 (dd, J=8.8,
2.4 Hz, 1H), 7.12 (s, 1H), 5.72 (d, J=4.4 Hz, 1H), 3.98 (dd, J=15.6,
7.2 Hz, 1H), 3.91 (s, 3H), 3.90–3.85 (m, 2H), 3.61 (t, J=8.4 Hz, 1H),
2.91–2.82 (m, 2H), 2.81–2.72 (m, 2H), 2.10–2.02 (m, 1H), 1.93–1.84 ppm
(m, 1H); 13C NMR (100 MHz, CDCl3): d=157.4, 135.1, 133.2, 129.1,
128.9, 127.4, 127.1, 126.4, 119.0, 109.9, 105.7, 72.2, 69.1, 55.3, 45.5, 43.7,
33.8, 25.2 ppm; IR (film): n˜max =2948, 2860, 1633, 1606, 1484, 1457, 1390,
1266, 1230, 1113, 1077, 1029, 1004, 941, 858 cmꢀ1; HRMS (ESI): m/z
calcd for C18H20O3Na+: 307.1310 [M+Na]+; found: 307.1315.
Compound 6b: Prepared as a colorless oil (60% yield) according to Gen-
eral Procedure E. Rf =0.31 (PE/EtOAc=4:1); 1H NMR (400 MHz,
C6D6): d=7.13 (d, J=7.6 Hz, 2H), 7.10–7.05 (m, 1H), 6.89 (d, J=8.4 Hz,
2H), 5.73 (d, J=4.8 Hz, 1H), 3.72–3.69 (m, 1H), 3.69 (t, J=7.6 Hz, 1H),
3.58 (dd, J=8.0, 5.2 Hz, 1H), 3.33 (td, J=8.0, 3.2 Hz, 1H), 2.26–2.15 (m,
4H), 1.49–1.42 (m, 1H), 1.33–1.26 ppm (m, 1H); 13C NMR (100 MHz,
C6D6): d=140.9, 129.1 (d, 2C), 129.0 (d, 2C), 126.8, 110.5, 72.5, 69.1, 45.9,
44.4, 34.2, 25.6 ppm; IR (film): n˜ =3026, 2947, 2864, 1602, 1493, 1452,
1370, 1203, 1109, 1076, 1009, 954, 748, 701 cmꢀ1; HRMS (ESI): m/z calcd
for C13H16O2Na+: 227.1048 [M+Na]+; found: 227.1049.
Compound 6c: Prepared as a colorless oil (63% yield) according to Gen-
eral Procedure E. Rf =0.28 (PE/EtOAc=2:1); 1H NMR (400 MHz,
CDCl3): d=7.20 (d, J=8.4 Hz, 2H), 7.10 (d, J=8.4 Hz, 2H), 5.71 (d, J=
4.8 Hz, 1H), 3.95 (dd, J=15.6, 7.2 Hz, 1H), 3.89–3.84 (m, 2H), 3.55 (t,
J=8.4 Hz, 1H), 2.80–2.73 (m, 1H), 2.72–2.60 (m, 3H), 2.47 (s, 3H), 2.04–
1.95 (m, 1H), 1.90–1.82 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=
136.9, 136.0, 128.8 (2C), 127.1 (2C), 109.7, 72.0, 69.0, 45.4, 43.7, 33.2, 25.1,
Compound 6i; Prepared as a colorless oil (58% yield) according to Gen-
eral Procedure E. Rf =0.39 (PE/EtOAc=4:1); 1H NMR (400 MHz,
CDCl3): d=7.12 (dd, J=8.4, 5.6 Hz, 2H), 6.97 (t, J=8.4 Hz, 2H), 5.28 (d,
J=3.6 Hz, 1H), 3.87 (t, J=8.0 Hz, 1H), 3.81–3.73 (m, 2H), 3.65 (d, J=
8.0 Hz, 1H), 2.72 (dd, J=12.4, 6.4 Hz, 1H), 2.69–2.56 (m, 2H), 1.98–1.91
(m, 1H), 1.78–1.71 (m, 1H), 1.64–1.51 ppm (m, 3H); 13C NMR
(100 MHz, CDCl3): d=161.4 (d, JACTHNUGRTENNUG(C,F)=243.0 Hz), 135.7 (d, JACHTUNGTRENNUNG(C,F)=
Chem. Eur. J. 2012, 18, 6039 – 6048
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6045

Y. Peng et al.
3.0 Hz), 129.7 (d, J
(C,F)=8.0 Hz, 2C), 115.3 (d, J
E
(PE/EtOAc=4:1); m.p. 128–1308C (EtOAc/Hexane); 1H NMR
(400 MHz, CDCl3): d=7.74 (d, J=8.0 Hz, 2H), 7.18 (d, J=8.0 Hz, 2H),
5.27 (d, J=3.6 Hz, 1H), 3.87 (t, J=8.0 Hz, 1H), 3.78 (t, J=7.6 Hz, 2H),
3.64 (dd, J=8.4, 2.4 Hz, 1H), 2.76 (t, J=6.8 Hz, 1H), 2.75–2.61 (m, 2H),
1.97–1.90 (m, 1H), 1.77–1.73 (m, 1H), 1.62–1.52 (m, 3H), 1.34 ppm (s,
12H); 13C NMR (100 MHz, CDCl3): d=143.4, 135.0 (2C), 127.8 (2C),
101.9, 83.7 (2C), 69.8, 61.0, 42.3, 36.5, 33.6, 24.8 (4C), 23.1, 19.5 ppm (the
boron-bound carbon was not detected due to quadrupolar relaxation of
boron); IR (film): n˜max =2976, 2936, 2870, 1611, 1518, 1444, 1400, 1361,
1322, 1274, 1144, 1089, 1021, 950, 861, 662 cmꢀ1; HRMS (ESI): m/z calcd
for C20H29O4BNa+: 367.2051 [M+Na]+; found: 367.2046.
Compound 6j; Prepared as a colorless crystal (60% yield) according to
General Procedure E. Rf =0.40 (PE/EtOAc=2:1); m.p. 42–448C
(EtOAc); 1H NMR (400 MHz, CDCl3): d=7.07 (d, J=8.4 Hz, 2H), 6.82
(d, J=8.4 Hz, 2H), 5.27 (d, J=3.6 Hz, 1H), 3.87 (t, J=8.0 Hz, 1H), 3.81
(s, 3H), 3.80–3.73 (m, 2H), 3.66–3.63 (m, 1H), 2.71–2.61 (m, 2H), 2.60–
2.53 (m, 1H), 1.98–1.91 (m, 1H), 1.77–1.73 (m, 1H), 1.63–1.47 ppm (m,
3H); 13C NMR (100 MHz, CDCl3): d=158.0, 132.1, 129.2 (2C), 113.9
(2C), 102.0, 69.9, 61.0, 55.2, 42.7, 36.6, 32.4, 23.2, 19.5 ppm; IR (film): n˜ =
2937, 2870, 1612, 1583, 1513, 1462, 1403, 1301, 1248, 1179, 1144, 1111,
1022, 948, 901, 869, 816 cmꢀ1; HRMS (ESI): m/z calcd for C15H20O3Na+:
271.1310 [M+Na]+; found: 271.1312.
Complex [PdCl2dppf·CH2Cl2] (74 mg, 0.087 mmol, 10 mol%) and finely
ground anhydrous K3PO4 (1.48 g, 7 mmol, 8.0 equiv) were added to a so-
lution of 6l (300 mg, 0.87 mmol) and 4-iodoanisole (285 mg, 1.22 mmol,
1.4 equiv) in DMSO (10 mL) at RT under argon. The reaction mixture
was maintained at 408C with stirring for 4 h, then the reaction was
cooled to RT and transferred to a separating funnel, diluting with EtOAc
(60 mL). The organic layers were washed with water (10 mL) and brine
(10 mL), dried over MgSO4, filtered, and concentrated under reduced
pressure. The resulting crude residue was purified by flash column chro-
matography (PE/EtOAc=5:1) on silica gel to furnish the desired product
6l’ as colorless crystals (257 mg, 91%). Rf =0.45 (PE/EtOAc=4:1); m.p.
Compound 6k: Prepared as a colorless oil (53% yield) according to Gen-
eral Procedure E. Rf =0.31 (PE/EtOAc=4:1); 1H NMR (400 MHz,
CDCl3): d=7.97 (d, J=8.0 Hz, 2H), 7.24 (d, J=8.0 Hz, 2H), 5.28 (d, J=
4.0 Hz, 1H), 4.37 (q, J=7.2 Hz, 2H), 3.87 (t, J=8.0 Hz, 1H), 3.81–3.73
(m, 2H), 3.64 (d, J=11.2 Hz, 1H), 2.84–2.73 (m, 1H), 2.71–2.65 (m, 2H),
1.98–1.92 (m, 1H), 1.78–1.71 (m, 1H), 1.67–1.51 (m, 3H), 1.39 ppm (t,
J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=166.3, 145.4, 129.7
(2C), 128.5, 128.3 (2C), 101.8, 69.6, 60.9, 60.7, 42.1, 36.5, 33.4, 23.0, 19.5,
14.2 ppm; IR (film): n˜max =2939, 2871, 1715, 1610, 1575, 1446, 1413, 1368,
1278, 1178, 1144, 1108, 1021, 948, 903, 871, 764, 711 cmꢀ1; HRMS (ESI):
m/z calcd for C17H22O4Na+: 313.1416 [M+Na]+; found: 313.1420.
1
125–1278C (EtOAc); H NMR (400 MHz, CDCl3): d=7.52 (d, J=8.4 Hz,
2H), 7.48 (d, J=8.0 Hz, 2H), 7.21 (d, J=8.0 Hz, 2H), 6.98 (d, J=8.8 Hz,
2H), 5.30 (d, J=3.6 Hz, 1H), 3.93 (t, J=8.0 Hz, 1H), 3.85 (s, 3H), 3.83–
3.77 (m, 2H), 3.66 (d, J=8.8 Hz, 1H), 2.80–2.69 (m, 2H), 2.65 (dd, J=
12.0, 7.2 Hz, 1H), 2.02–1.96 (m, 1H), 1.83–1.75 (m, 1H), 1.65–1.54 ppm
(m, 3H); 13C NMR (100 MHz, CDCl3): d=159.1, 138.8, 138.5, 133.4,
128.7 (2C), 127.9 (2C), 126.8 (2C), 114.2 (2C), 102.0, 69.9, 61.0, 55.3, 42.5,
36.6, 33.0, 23.2, 19.6 ppm; IR (film): n˜ =3029, 2937, 2868, 1608, 1582,
1526, 1499, 1458, 1403, 1249, 1179, 1143, 1111, 1019, 946, 904, 815,
737 cmꢀ1; HRMS (ESI): m/z calcd for C21H24O3Na+: 347.1623 [M+Na]+;
found: 347.1628.
Compound 8a: Prepared as a colorless oil (54% yield) according to Gen-
eral Procedure E. Rf =0.43 (PE/EtOAc=4:1); 1H NMR (400 MHz,
CDCl3): d=7.09 (d, J=8.4 Hz, 2H), 6.82 (d, J=8.4 Hz, 2H), 3.97–3.93
(m, 1H), 3.90 (t, J=8.4 Hz, 2H), 3.78 (s, 3H), 3.62 (t, J=8.4 Hz, 1H),
2.72 (d, J=8.0 Hz, 2H), 2.51 (h, J=8.0 Hz, 1H), 2.14 (dd, J=13.2,
9.2 Hz, 1H), 2.07–2.00 (m, 2H), 2.07–2.00 ppm (m, 3H); 13C/DEPT NMR
(100 MHz, CDCl3): d=157.9 (s), 132.9 (s), 129.5 (d, 2C), 115.1 (s), 113.8
(d, 2C), 72.1 (t), 67.2 (t), 55.2 (q), 40.9 (t), 40.7 (d), 38.4 (t), 35.8 (t), 24.4
(t) ppm; IR (film): n˜max =2941, 2880, 1612, 1583, 1513, 1461, 1341, 1300,
1246, 1178, 1113, 1022, 953, 920, 826 cmꢀ1; HRMS (ESI): m/z calcd for
C15H20O3Na+: 271.1310 [M+Na]+; found: 271.1312.
Stereospecific cyclization/intramolecular cross-coupling mediated by
[Ni0·2EC·Py] complex; preparation of b-bromo acetals 10a and 10b: To
an oven-dried round bottom flask was added N-bromosuccinimide
(534 mg, 3.0 mmol) and anhydrous CH2Cl2 (4 mL). The resulting suspen-
sion was cooled to ꢀ408C and 2,3-dihydrofuran (0.17 mL, 2.2 mmol) was
added dropwise over a 5 min period followed by addition of allyl alcohol
9 (548 mg, 2.0 mmol) in CH2Cl2 (4 mL) dropwise over a 10 min period.
The reaction mixture was slowly warmed to RT over a 2 h period and
then diluted with Et2O (30 mL) and poured into a separating funnel con-
taining H2O (10 mL). The aqueous layer was extracted with Et2O (2ꢁ
30 mL), and the combined organic layers were washed with brine
(10 mL), dried over MgSO4, filtered, and concentrated under reduced
pressure. The resulting crude residue was carefully purified by flash
column chromatography (hexane as eluent) on silica gel (300–400 mesh)
to furnish the desired (less polar) 10a and (more polar) 10b (1:1, 305 mg,
36%).
Compound 10a: Colorless oil; Rf =0.54 (PE/EtOAc=10:1); 1H NMR
(400 MHz, CDCl3): d=7.82 (d, J=7.6 Hz, 1H), 7.26–7.23 (m, 2H), 7.21–
7.19 (m, 1H), 6.89 (t, J=7.4 Hz, 1H), 5.82–5.73 (m, 1H), 5.30–5.23 (m,
2H), 5.17 (s, 1H), 4.37 (q, J=7.2 Hz, 1H), 4.17 (d, J=6.0 Hz, 1H), 3.90
(q, J=8.0 Hz, 1H), 3.21 (t, J=7.6 Hz, 1H), 2.91 (d, J=6.8 Hz, 2H), 2.38
(td, J=14.4, 8.4 Hz, 1H), 2.09–2.04 ppm (m, 1H); 13C/DEPT NMR
(100 MHz, CDCl3): d=141.2 (s), 139.3 (d), 136.8 (d), 131.1 (d), 128.0 (d),
127.7 (d), 118.1 (t), 104.7 (d), 101.1 (s), 75.6 (d), 66.1 (t), 50.2 (d), 46.2
(t), 33.8 (t) ppm; IR (film): n˜max =3057, 2949, 2897, 1643, 1586, 1562,
1466, 1435, 1316, 1201, 1066, 1014, 926, 751 cmꢀ1; HRMS (ESI): m/z
calcd for C14H16O2BrINa+: 444.9271 [M+Na]+; found: 444.9290.
Compound 8b; Prepared as a colorless oil (52% yield) according to Gen-
eral Procedure E. Rf =0.42 (PE/EtOAc=10:1); 1H NMR (400 MHz,
CDCl3): d=7.08 (d, J=8.4 Hz, 2H), 6.81 (d, J=8.4 Hz, 2H), 3.94 (t, J=
8.0 Hz, 1H), 3.87 (td, J=11.6, 3.2 Hz, 1H), 3.78 (s, 3H), 3.64–3.62 (m,
1H), 3.61 (t, J=8.4 Hz, 1H), 2.70 (d, J=8.0 Hz, 2H), 2.51 (q, J=8.0 Hz,
1H), 1.89 (dd, J=13.2, 9.6 Hz, 1H), 1.84–1.75 (m, 1H), 1.72 (d, J=
6.0 Hz, 1H), 1.69–1.26 ppm (m, 5H); 13C/DEPT NMR (100 MHz,
CDCl3): d=157.9 (s), 133.1 (s), 129.5 (d, 2C), 113.8 (d, 2C), 106.3 (s),
72.1 (t), 61.7 (t), 55.2 (q), 44.2 (t), 40.2 (d), 38.8 (t), 34.2 (t), 25.1 (t), 20.0
(t) ppm; IR (film): n˜max =2940, 2868, 1612, 1512, 1246, 1178, 1077, 1037,
1013, 979, 808 cmꢀ1; HRMS (APCI): m/z calcd for C16H23O3+: 263.1642
[M+H]+; found: 263.1635.
Bidirectional elaboration of 4-IpBPE by sequential cross-coupling cata-
lyzed by Ni and Pd: Ethyl crotonate (0.40 mL, 3.0 mmol) was added to
a stirred slurry of Zn (644 mg, 9.9 mmol) in pyridine (2.0 mL) at RT.
Under vigorous stirring, NiCl2 (127 mg, 1.0 mmol) was added to the
above mixture. Then the temperature rose, and the mixture was heated
to 558C, and stirring was continued for 40 min. The resulting red brown
[Ni0·2EC·Py] complex was cooled to RT, and a solution of 4-iodophenyl
boronate pinacol ester (3.3 mmol, 1.09 g) in CH3CN (4.0 mL) was added
dropwise over 5 min. Then, the temperature rose, and the mixture was
heated to 508C again, and the solution of b-bromo acetal 5b (1.1 g,
5 mmol) in CH3CN (12 mL) was added slowly to the above mixture over
a 1.5 h period at this temperature. After 2 h, the mixture was filtered
through a short plug of silica (elution with 100 mL Et2O) and washed
with water and brine, dried over MgSO4, filtered, and concentrated. The
crude product was purified by flash chromatography on silica gel to
afford the desired products 6l as colorless crystals (588 mg, 57% yield),
which were dissolved in EtOAc and hexane. After a few days, colorless
crystals were obtained by slow evaporation of solvent at RT. Rf =0.37
Compound 10b: Colorless oil; Rf =0.49 (PE/EtOAc=10:1); 1H NMR
(400 MHz, CDCl3): d=7.84 (d, J=8.0 Hz, 1H), 7.29–7.25 (m. 1H), 7.20
(dd, J=7.6, 1.6 Hz, 1H), 6.93 (td, J=7.6, 1.6 Hz, 1H), 5.92–5.84 (m, 1H),
5.22 (d, J=17.2 Hz, 1H), 5.15 (d, J=10.4 Hz, 1H), 5.02 (s, 1H), 4.25 (dd,
J=13.6, 6.4 Hz, 1H), 4.12–4.03 (m, 2H), 3.97 (d, J=4.8 Hz, 1H), 2.99–
2.91 (m, 2H), 2.54–2.45 (m, 1H), 2.14–2.08 ppm (m, 1H); 13C NMR
(100 MHz, CDCl3): d=140.5, 139.5, 137.9, 131.4, 128.4, 128.0, 116.0,
107.9, 100.8, 77.8, 66.8, 50.0, 46.3, 33.5 ppm; IR (film): n˜ =3057, 2924,
6046
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 6039 – 6048

Nickel-Mediated Reductive Cross-Coupling
FULL PAPER
2898, 1643, 1585, 1562, 1465, 1435, 1317, 1255, 1199, 1089, 1020, 923,
1054, 1016, 925, 964, 751 cmꢀ1
;
HRMS (ESI): m/z calcd for
C15H18O2I2Na+: 506.9288 [M+Na]+; found: 506.9289.
750 cmꢀ1
;
HRMS (ESI): m/z calcd for C14H16O2BrINa+: 444.9271
[M+Na]+; found: 444.9270.
Compounds 13a and 13b: Prepared according to the above procedure
for 11a. The compounds could be carefully separated by flash column
chromatography (PE/EtOAc=15:1!PE/EtOAc=8:1) on silica gel.
Ethyl crotonate (0.37 mL, 3 mmol) was added to a stirred slurry of Zn
(195 mg, 3 mmol) in pyridine (0.5 mL) at RT. Under vigorous stirring,
NiCl2 (128 mg, 1 mmol) was added to the above mixture. Then the tem-
perature rose, and the mixture was heated to 558C, and stirring was con-
tinued for 15 min. The resulting red brown [Ni0·2EC·Py] complex was
cooled to RT, and a solution of b-bromo acetal 10a (423 mg, 1 mmol) in
CH3CN (10 mL) was added dropwise over a 30 min period. After 1.5 h,
the mixture was filtered through a short plug of silica (elution with
30 mL Et2O) and washed with water and brine, dried over MgSO4, fil-
tered, and concentrated. The crude product was purified by flash chroma-
tography on silica gel to afford the desired product 11a (130 mg, 60%),
which was dissolved in EtOAc and hexane. After a few days, colorless
crystals were obtained by slow evaporation of solvent at RT. Rf =0.28
(PE/EtOAc=10:1); m.p. 66–698C (Hexane); 1H NMR (400 MHz,
CDCl3): d=7.16–7.13 (m, 4H), 5.80 (d, J=5.2 Hz, 1H), 4.04 (t, J=
8.2 Hz, 1H), 3.93–3.87 (m, 1H), 3.62 (td, J=10.8, 5.6 Hz, 1H), 3.17 (ddd,
J=34.4, 15.2, 5.0 Hz, 2H), 2.95 (t, J=13.2 Hz, 1H), 2.72 (t, J=14.4 Hz,
1H), 2.63–2.57 (m, 1H), 2.03–1.93 (m, 1H), 1.80 (dd, J=12.0, 3.6 Hz,
1H), 1.70–1.60 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=135.5,
134.6, 130.3, 129.3, 126.2, 109.2, 79.0, 67.0, 48.4, 45.8, 35.6, 33.8, 30.8 ppm;
IR (film): n˜ =3061, 3015, 2927, 2877, 1603, 1487, 1451, 1354, 1257, 1110,
Compound 13a: Yield: 35%; colorless crystal; Rf =0.46 (PE/EtOAc=
4:1); m.p. 44–468C (Hexane); 1H NMR (400 MHz, CDCl3): d=7.16–7.10
(m, 4H), 4.01–3.91 (m, 2H), 3.85 (td, J=10.4, 6.4 Hz, 1H), 3.21 (dd, J=
15.2, 5.2 Hz, 1H), 3.04 (dd, J=16.0, 4.8 Hz, 1H), 2.82 (t, J=14.0 Hz,
1H), 2.71 (t, J=14.0 Hz, 1H), 2.38 (dd, J=12.6, 7.4 Hz, 1H), 2.19–2.08
(m, 2H), 2.04 (t, J=12.0 Hz, 1H), 1.99–1.96 ppm (m, 3H); 13C NMR
(100 MHz, CDCl3): d=136.0, 134.7, 130.3, 129.3, 126.1, 126.0, 115.4, 79.0,
67.4, 42.5, 41.8, 37.5, 35.7, 34.0, 24.8 ppm; IR (film): n˜ =3062, 2930, 2886,
1603, 1582, 1489, 1448, 1327, 1264, 1150, 1107, 1068, 1018, 942, 891,
748 cmꢀ1; HRMS (APCI): m/z calcd for C15H19O2+: 231.1380 [M+H]+;
found: 231.1373.
Compound 13b: Yield: 27%; colorless crystal; Rf =0.42 (PE/EtOAc=
4:1); m.p. 38–408C (Hexane); 1H NMR (400 MHz, CDCl3): d=7.16–7.10
(m, 4H), 4.10 (td, J=8.0, 3.6 Hz, 1H), 3.83 (q, J=8.0 Hz, 1H), 3.63 (td,
J=10.8, 5.6 Hz, 1H), 3.20 (dd, J=15.2, 5.2 Hz, 1H), 3.10 (dd, J=16.0,
4.8 Hz, 1H), 2.94 (t, J=14.0 Hz, 1H), 2.63 (t, J=14.0 Hz, 1H), 2.32 (dd,
J=12.2, 6.2 Hz, 1H), 2.28–2.19 (m, 1H), 2.18–2.07 (m, 2H), 1.99–1.91 (m,
2H), 1.84 ppm (t, J=12.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=
135.9, 134.9, 130.3, 129.3, 126.1, 126.0, 115.0, 80.6, 67.9, 41.8, 41.2, 36.9,
36.5, 34.0, 24.4 ppm; IR (film): n˜max =3063, 2924, 2852, 1604, 1576, 1489,
1446, 1331, 1263, 1142, 1114, 1074, 1026, 973, 864, 834, 747 cmꢀ1; HRMS
(ESI): m/z calcd for C15H19O2+: 231.1380 [M+H]+; found: 231.1387.
1074, 1033, 978, 941, 858, 741 cmꢀ1
; HRMS (APCI): m/z calcd for
C14H17O2+: 217.1223 [M+H]+; found: 217.1218.
Compound 11b: Prepared according to the above procedure for 11a.
Pure 11b was dissolved in EtOAc and hexane and colorless crystals were
obtained by slow evaporation of solvent at RT after a few days. Rf =0.28
(PE/EtOAc=10:1); m.p. 65–688C (hexane); 1H NMR (400 MHz,
CDCl3): d=7.15 (s, 4H), 5.88 (d, J=4.8 Hz, 1H), 4.00–3.90 (m, 2H),
3.88–3.84 (m, 1H), 3.26 (dd, J=15.2, 5.2 Hz, 2H), 3.03–2.96 (m, 2H),
2.84–2.76 (m, 2H), 2.12 ꢀ2.04 (m, 1H), 1.96–1.91 ppm (m, 2H); 13C/
DEPT NMR (100 MHz, CDCl3): d=135.5 (s), 134.2 (s), 130.2 (d), 129.3
(d), 126.18 (d), 126.16 (d), 109.7 (d), 78.0 (d), 69.4 (t), 45.1 (d), 44.5 (d),
36.2 (t), 30.6 (t), 24.9 (t) ppm; IR (film): n˜ =3060, 3020, 2965, 2932, 2889,
Acknowledgements
This work was supported by NSFC (Nos. 20802029 and 21172096), and
the “111” Project, the Scientific Research Foundation for the Returned
Overseas Chinese Scholars, the Fundamental Research Funds for the
Central Universities (lzujbky-2012-57), and Program for Changjiang
Scholars and Innovative Research Team in University (IRT1138) of
MoE. We appreciate the invaluable help and insightful suggestions of
Professor Wei-Dong Li (Nankai University) and Professor Liming Zhang
(UCSB).
2858, 1604, 1488, 1454, 1349, 1313, 1248, 1158, 1109, 1081, 1016, 970, 928,
+
865, 836, 742, 695 cmꢀ1
;
HRMS (APCI): m/z calcd for C14H17O2
:
217.1223 [M+H]+; found: 217.1217.
Preparation of b-bromo acetals 12a and 12b: To an oven-dried round-
bottom flask was added N-iodosuccinimide (540 mg, 2.4 mmol) and anhy-
drous CH2Cl2 (2 mL). The resulting suspension was cooled to ꢀ408C and
a solution of allyl alcohol 9 (548 mg, 2.0 mmol) in CH2Cl2 (4 mL) was
added dropwise over a 5 min period. After 2 min, a solution of 2-methyl-
enetetrahydrofuran[33] (2.2 mmol) in CH2Cl2 (4 mL) was added dropwise
over a 10 min period. The reaction mixture was stirred for 30 min then
diluted with Et2O (30 mL) and poured into a separating funnel contain-
ing water (10 mL). The aqueous layer was extracted with Et2O (2ꢁ
30 mL), and the combined organic layers were washed with brine
(10 mL), dried over MgSO4, filtered, and concentrated under reduced
pressure. The resulting crude residue was carefully purified by flash
column chromatography (hexane as eluent) on silica gel to furnish the
desired b-iodo acetal 12a and 12b (869 mg, 90%). Colorless oil; Rf =0.47
[1] a) A. de Meijere, P. J. Stang, in Metal-Catalyzed Cross-Coupling Re-
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Angew. Chem. Int. Ed. 2003, 42, 384–387; c) M. R. Netherton, G. C.
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Beller, Angew. Chem. 2005, 117, 680–695; Angew. Chem. Int. Ed.
2005, 44, 674–688; e) X. Hu, Chem. Sci. 2011, 2, 1867–1886.
(PE/EtOAc=10:1); 1H NMR (400 MHz, CDCl3):
d (inseparable iso-
mers)=7.82 (d, J=7.2 Hz, 2H), 7.23 (d, J=7.6 Hz, 3H), 7.18 (dd, J=7.6,
1.6 Hz, 1H), 6.89 (td, J=7.6, 2.0 Hz, 2H), 6.00 (ddd, J=17.3, 10.2,
7.2 Hz, 1H), 5.76 (ddd, J=17.3, 10.4, 6.8 Hz, 1H), 5.24 (d, J=17.2 Hz,
1H), 5.13 (d, J=18.4 Hz, 1H), 5.09 (d, J=11.2 Hz, 1H), 5.04 (d, J=
10.4 Hz, 1H), 4.60–4.55 (m, 1H), 4.42 (q, J=7.2 Hz, 1H), 3.94 (td, J=
8.0, 4.8 Hz, 1H), 3.87 (q, J=7.6 Hz, 1H), 3.66 (q, J=8.0 Hz, 1H), 3.37 (q,
J=10.8 Hz, 2H), 3.13 (d, J=10.8 Hz, 1H), 3.06 (td, J=8.0, 4.8 Hz, 1H),
3.01–2.90 (m, 3H), 2.85 (td, J=13.6, 4.8 Hz, 1H), 2.12–2.06 (m, 2H),
2.04–1.94 (m, 3H), 1.92–1.82 (m, 1H), 1.72–1.57 ppm (m, 2H); 13C NMR
(100 MHz, CDCl3): d=141.3, 140.9, 139.6, 139.3, 139.2, 132.0, 131.9,
128.2, 128.0, 127.8, 127.7, 115.3, 114.7, 107.7, 107.5, 101.1, 101.0, 72.33,
72.28, 70.1, 69.7, 47.6, 47.3, 37.9, 36.8, 24.7, 24.5, 10.9, 9.4 ppm; IR (film):
n˜max =3057, 2976, 2953, 2886, 1642, 1562, 1464, 1434, 1321, 1248, 1141,
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3
3
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[32] This compound has been previously described; the corresponding
reference can be found in the Supporting Information.
[33] For the preparation, see the Supporting Information.
Received: January 18, 2012
Published online: March 30, 2012
6048
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Chem. Eur. J. 2012, 18, 6039 – 6048