Diastereoselective Pd-Catalyzed Domino Heck/Arylborylation Sequence Forming Borylated Chromans

Article abstract of DOI:10.1055/s-0035-1561567

A diastereoselective palladium-catalyzed domino Heck/arylborylation of aryl iodides yielding an alkylboronate containing a chroman is reported. The generated alkylpalladium(II) intermediate is intercepted with bis(pinacolato)diboron (B₂pin₂) in good yield as a single diastereomer.

Full text of DOI:10.1055/s-0035-1561567

SYNTHESIS
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©
Georg Thieme Verlag Stuttgart · New York
2016, 48, 1483–1490
1483
paper
Synthesis
H. Yoon et al.
Paper
Diastereoselective Pd-Catalyzed Domino Heck/Arylborylation
Sequence Forming Borylated Chromans
Hyung Yoon
2 3
Pd (dba) (2 mol%)
B2pin2 (1.5 equiv)
KOAc (1.5 equiv)
Me
Bpin
Young Jin Jang
Mark Lautens*
I
R2
R1
R1
DMF, 80 °C, 4 h
O
Me
O
R2
Davenport Research Laboratories, Department of Chemistry,
University of Toronto, 80 St. George Street, Toronto, Ontario,
M5S 3H6, Canada
1
4
3 examples
4–88% yield
20:1 dr
>
mlautens@chem.utoronto.ca
Received: 08.01.2016
Accepted: 14.01.2016
Published online: 07.03.2016
DOI: 10.1055/s-0035-1561567; Art ID: ss-2016-z0013-op
nucleophiles and stereoselective methods were investigat-
ed by various groups. Additionally, this class of reaction was
applied towards the synthesis of natural products.8 How-
ever, the application of this type of reaction toward the syn-
thesis of stereoselective and heterocyclic alkylboronates
still remains scarce.
,9
Abstract A diastereoselective palladium-catalyzed domino Heck/aryl-
borylation of aryl iodides yielding an alkylboronate containing a chro-
man is reported. The generated alkylpalladium(II) intermediate is inter-
cepted with bis(pinacolato)diboron (B pin ) in good yield as a single
2
2
diastereomer.
A
Key words palladium, Heck reaction, alkylboronate, diastereoselec-
tive, chroman, benzopyran
=
R
H
PdII
R
X
Pd0
β-Hydride elimination
R
R
Nuc
Organoboronates are valuable reagents due to their ease
of preparation and high susceptibility toward functional-
ization. The increased use and demand of highly function-
alized and/or stereochemically defined organoboronates
prompts the development of novel and stereoselective
X = Cl, Br, I, or OTf
B
Alkylpalladium(II)
Intermediate
Nuc
R ≠ H
Nuc = CN, NR1R2, [M]R
1
Scheme 1 General Pd-catalyzed intramolecular Heck reaction (A) and
domino Heck/anion capture reaction (B)
methods to introduce carbon–boron bonds. General meth-
ods to install organoboronates include Pd-catalyzed Miyaura
2
borylation, quenching trialkyl borates with organometallic
3
4
reagents, and C–H borylation reactions. Despite numerous
reports, methods to construct structurally complex and ste-
reodefined alkylboronates still remain scarce. In this regard,
we envisioned an intramolecular Pd-catalyzed domino
Heck/arylborylation sequence to access a new class of steri-
cally encumbered alkylboronates in a catalytic manner.
The Pd-catalyzed intramolecular Heck reaction has
been intensely investigated and applied towards the syn-
thesis of various natural products [Scheme 1,(A)].5 Con-
trary to the Heck reaction, the resulting alkylpalladium(II)
intermediate can be intercepted by various nucleophiles in
the absence of β-hydrogens [Scheme 1 (B)]. Pioneered by
the group of Grigg, nucleophiles including cyanides,
amines, and organozinc and organotin reagents are applica-
In recent years, groups such as Cárdenas and Bäckvall
have developed the Pd-catalyzed borylative cyclization se-
quences involving polyunsaturated substrates to produce
various alkylboronates (Scheme 2).10 Encouraged by these
findings, we sought to develop a Pd-catalyzed domino
Heck/arylborylation sequence.
During the preparation of this manuscript, Van der Eycken
reported a useful microwave-assisted Pd-catalyzed domino
Heck/arylborylation sequence of o-iodoanilides to form [(2-
oxoindolin-3-yl)methyl]boronates (Scheme 2).11 Compli-
mentary to their recent findings, we report the first highly
diastereoselective Pd-catalyzed domino Heck/arylboryla-
tion sequence of tethered aryl iodides to furnish borylated
chromans (Scheme 2).
,6
7
ble to this class of reactions. Since the initial reports, novel
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484
Synthesis
H. Yoon et al.
Paper
Cárdenas (2007): Pd-catalyzed borylative cyclization of 1,6-enynes10
tuted aryl groups were tolerated in good to excellent yields
2f–h, 74–88% yield). A thienyl group was also tolerated and
(
R1
R1
Pd(OAc)2 (5 mol%)
B2pin2 (1.1 equiv)
MeOH (1 equiv)
afforded the final product 2i in 73% yield. Aryl iodides bear-
ing aliphatic groups, 1j and 1k, cyclized in moderate to
good yield to produce the respective alkylboronates 2j and
2k (56% and 70% yield, respectively). Iodopyridyl group was
tolerated in modest yields with prolonged reaction times
while, iodoquinolinols were tolerated under the standard
reaction conditions in good yield (2l and 2m, 44% and 78%
yield, respectively). Unfortunately, when ortho-substituted
aryl iodide 1n was used, no reactivity was observed even
with higher catalyst loading or longer reaction times. Nota-
bly, under the optimal conditions, aryl iodides bearing an
amine linker did not react to form the respective borylated
isoquinolines.
Z
R2
Z
Toluene, 50 °C
Bpin
R2
R3
R3
Van der Eycken (2015): Pd-catalyzed domino Heck/Arylborylation11
Pd(PPh3)4 (2 mol%)
B2pin2 (2 equiv)
R3
Bpin
O
I
O
R1
Na2CO3 (2 equiv)
R3
R1
N
R2
MeCN/H2O (9:1)
MW, 120 °C
N
R2
This work
Pd source
B2pin2
Me
Bpin
R2
I
R2
R1
We propose a plausible mechanism in line with those
previously postulated for both the Pd-catalyzed domino
Heck cascade reactions and Miyaura borylation (Scheme
R1
O
Me
O
Scheme 2 Recent advances in Pd-catalyzed domino borylation reac-
tions
2,7
4
). The aryl iodide 1a undergoes oxidative addition and
carbopalladation forming the alkylpalladium(II) intermedi-
ate B. The high diastereoselectivity of the carbopalladation
13,14
Subjecting the aryl iodide 1a to Pd (dba) (2 mol%),
forming B is consistent with previous literature.
The
2
3
KOAc (1.5 equiv), and bis(pinacolato)diboron (B pin ) (1.5
trans-adduct is thought to form exclusively from the mini-
mized axial–axial interactions. Intermediate B then trans-
metalates with KOAc to form the acetoxypalladium(II) in-
2
2
equiv) in DMF at 80 °C for 4 hours was found to be the opti-
mal conditions. The tethered aryl iodide 1a furnished the
desired alkylboronate 2a in 82% yield and >20:1 dr, and the
relative stereochemistry was unambiguously confirmed by
X-ray crystallography (see Supporting Information). A se-
ries of variation experiments were performed to examine
the effects of changes to the optimal conditions (Table 1). It
should be noted that in all cases, no direct borylation oc-
curred forming the respective arylboronate.
Table 1 Diastereoselective Pd-Catalyzed Domino Heck/Arylborylation:
Effect on Reaction Parameters
Pd2(dba)3 (2 mol%)
B2pin2 (1.5 equiv)
KOAc (1.5 equiv)
Me
Bpin
Ph
I
Ph
O
Me
DMF, 80 °C, 4 h
O
Solvents less polar than DMF, like toluene and 1,4-diox-
ane, led to none of the desired product (entries 2 and 3).
1a
optimal conditions
2a
1
0
Other Pd sources including those reported by Cárdenas
Entry
Variation from ‘optimal’ conditions
Yield (%)a,b
12
and Buchwald, produced the desired product with consis-
tent dr but in lower yields (entries 4 and 5, respectively).
The incorporation of bidentate ligands such as DPPF led to
no reactivity (entry 6). Acetate bases were found to be the
optimal bases as opposed to carbonates and alkylamines
1
2
3
4
5
6c
7
8
9
none
80 (82)
0
toluene instead of DMF
1,4-dioxane instead of DMF
0
Pd(OAc)
2
instead of Pd
2
dba
3
73
74
0
(entries 7–9). Attempts to lower the equivalents of KOAc
Pd XPhos G1 instead of Pd
2
dba
3
and B pin led to full conversion but a lower yield of the de-
2
2
sired product (entries 10 and 11). Lastly, aryl bromides and
aryl chlorides led to incomplete conversion into 2a (entries
DPPF added
NaOAc instead of KOAc
52
45
9
12 and 13).
K
2
CO
N instead of KOAc
1.1 equiv instead of 1.5 equiv of KOAc
3
instead of KOAc
With the optimized conditions in hand, we evaluated
Et
3
the scope of the reaction (Scheme 3). It should be noted
that each of the examples listed 2a–m produced exclusively
the trans-diastereomer (>20:1 dr). Electron-rich aryl iodide
1
0
1
62
47
43
16
1
1.1 equiv instead of 1.5 equiv of B
ArBr instead of ArI
2 2
pin
1c cyclized in good yield with prolonged reaction time (2c,
12
13
62% yield, 12 h). Trifluoromethyl-bearing aryl iodide 1b af-
ArCl instead of ArI
forded 2b in excellent yield (88% yield). Multisubstituted
aryl iodides 1d and 1e produced the desired products 2d
and 2e in 75% and 72% yield, respectively, with higher cata-
lyst loading. Electron-rich, electron-poor, and ortho-substi-
a
Determined by 1H NMR analysis of the crude reaction mixtures using
1,3,5-trimethoxybenzene as internal standard.
b
Yield in parentheses are isolated yields.
Reaction was run with 4 mol% DPPF.
c
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Synthesis
H. Yoon et al.
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Pd2(dba)3 (2 mol%)
B2pin2 (1.5 equiv)
KOAc (1.5 equiv)
Me
Bpin
R2
I
R2
R1
R1
DMF, 80 °C, 4 h
O
a-1n
Me
O
1
2a-2m
20:1 dr
>
Me
Bpin
Me
Bpin
Me
Me
Bpin
Ph
Me
Bpin
Ph
Me
Bpin
Ph
O
Me
Bpin
F
F
O
O
O
R
O
O
O
Ph
OMe
72% yield (2e)
R
75% yieldc (2d)
c
0.2 mmol
2% yield (2a)
R = CF3, 88% yield (2b)
R = OMe, 62% yieldb (2c)
R = CF , 88% yield (2f)
75% yield (2h)
3
8
R = OMe, 74% yield (2g)
Me
Bpin
Ph
Me
Bpin
Ph
Me
Bpin
N
Cl
I
Ph
I
Ph
O
O
N
R
Me
O
R
O
Me
N
78% yield (2m)
44% yieldb (2l)
R = 3-thienyl, 73% yield (2i)
R = cyclohexyl, 56% yield (2j)
R = n-pentyl, 70% yield (2k)
no product observed (1n)
R = H, Me, Bn, Ts
no product observed
Scheme 3 Diastereoselective Pd-catalyzed domino Heck/arylborylation: reaction scope. Reactions performed on a 0.2-mmol scale unless otherwise
a
b
c
stated; yields shown are isolated yields. 2.75-mmol scale, 1 mol% catalyst loading, 0.2 M. 12 h. 4 mol% catalyst.
termediate C. The bound acetoxy group assists in the trans-
erate yield (45% yield). The oxidation of the alkylboronate to
15
metalation with B pin to generate intermediate D.
the alcohol 3b proceeded in near quantitative yield (99%
2
2
Finally, C–B reductive elimination regenerates Pd(0) and the
desired alkylboronate 2a.
yield).17 A Pd-catalyzed Suzuki reaction of 2a was accom-
1
8
plished using a variation of a method outlined by Molander
and Capretta19 producing the desired product 3c in moder-
ate yield (44% yield).
Me
Bpin
Ph
I
2a
In conclusion, we have developed a highly diastereose-
lective Pd-catalyzed domino Heck/arylborylation of aryl io-
dides yielding alkylboronate-containing chromans in yields
up to 88% as a single diastereomer. In addition, we were
able to demonstrate the functional group convertibility of
the alkylboronate to other synthetically useful moieties.
Ph
1a
O
O
Me
Pd0
Bpin
I
Me
PdII
PdII
Ph
A
L
L
D
O
Me
O
Ph
All non-aqueous reactions were performed in flame-dried round-bot-
tom flasks sealed with a fitted rubber septum under an inert atmo-
sphere of argon unless otherwise stated. All reactions were magneti-
cally stirred and elevated temperatures were reported as the tem-
perature of the surrounding oil bath. Reactions were monitored by
pinBOAc
I
OAc
PdII
Bpin Bpin
PdII
Me
Me
L
L
C
B
1
TLC or by crude H NMR analysis of a worked up aliquot. TLC visual-
O
Ph
O
Ph
ization was performed under a UV lamp or KMnO /CAM stain devel-
4
oped with heat. Solvent evaporation was conducted by rotary evapo-
ration at the appropriate temperature and pressure. Unless stated
otherwise, all reagents were used as received and the following reac-
tion solvents were distilled under anhydrous conditions over the ap-
propriate drying agent and transferred under argon via a syringe.
CH Cl was distilled over CaH , THF was distilled over Na (1%) and
KI
KOAc
Scheme 4 Postulated mechanism of diastereoselective Pd-catalyzed
domino Heck/arylborylation
2
2
2
The gram-scale reaction occurred smoothly with con-
sistent yield and selectivity to give the model substrate 2a
with 1 mol% catalyst at 0.2 M (80% yield). Derivatization of
the alkylboronate to various functional groups was per-
formed (Scheme 5). A Cu(I)-catalyzed Chan–Lam coupling
benzophenone (1%), 1,4-dioxane was distilled over Na (1%), and ben-
zophenone (1%), and Et N was distilled over KOH. DMF was distilled
3
over 5-Å molecular sieves and stored over 5-Å molecular sieves (water
content was kept lower than 50 ppm). 1,3,5-Trimethoxybenzene was
crushed into a fine powder by a mortar and pestle, dried overnight in
vacuo and stored in a desiccator. All reported yields reflect spectro-
16
outlined by Watson yielded the desired amide 3a in mod-
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Synthesis
H. Yoon et al.
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Me
NHBz
Ph
A
O
45% yield, 3a
Me
Bpin
Ph
Pd2(dba)3 (1 mol%)
B2pin2 (1.5 equiv)
KOAc (1.5 equiv)
Me
OH
I
Ph
B
O
DMF (0.2 M)
O
Me
O
Ph
80 °C, 4 h
2.75 mmol scale
2a
99% yield, 3b
80% yield
Me Ph
C
O
Ph
44% yield, 3c
Scheme 5 Gram-scale diastereoselective Pd-catalyzed domino Heck/arylborylation and derivatization. Reaction conditions: (A) benzamide, CuBr, di-
tert-butyl peroxide, NaOTMS, t-BuOH, 75 °C. (B) 30% H O , 3 M NaOH, THF, 0 °C. (C) PhI, Pd(OAc) , 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phos-
2
2
2
phadamantane, t-BuOK, toluene, 100 °C.
scopically ( H NMR) pure material unless otherwise stated. H and 13C
NMR spectra of catalytic starting material and products were ob-
tained on the Agilent DD2 500 equipped with a 5-mm Xsens Cold
1
1
1
H NMR (500 MHz, CDCl ): δ = 7.51–7.47 (m, 2 H), 7.43–7.39 (m, 2 H),
3
7.39–7.35 (m, 1 H), 7.35–7.31 (m, 1 H), 7.11 (ddd, J = 8.0, 7.0, 1.5 Hz, 1
H), 6.93–6.89 (m, 2 H), 5.28 (dd, J = 12.0, 2.0 Hz, 1 H), 2.27 (dd, J =
14.0, 2.0 Hz, 1 H), 1.93 (ddd, J = 14.0, 12.0, 1.5 Hz, 1 H), 1.47 (s, 3 H),
1.44–1.40 (m, 2 H), 1.27 (d, J = 1.5 Hz, 12 H).
1
13
Probe. The starting material precursor H and C NMR spectra were
obtained from one of the following spectrometers: Varian NMR sys-
tem 400, Bruker Avance III 400, Varian Mercury 400, or Varian Mercu-
13
C NMR (126 MHz, CDCl ): δ = 153.43, 142.35, 132.74, 128.40,
3
19
ry 300. All F NMR spectra were obtained on the Varian Mercury 300
and Varian Mercury 400. Measurements were carried out at 23 °C.
1
3
27.56, 127.06, 126.59, 125.88, 120.37, 117.05, 83.13, 74.42, 45.60,
3.43, 29.25, 24.96, 24.89.
1
The solvent resonance was used as the internal standard for H NMR
11B NMR (128 MHz, CDCl
): δ = 33.00.
13
3
(
CDCl δ = 7.26) and C NMR (CDCl δ = 77.0); J values are rounded off
3
3
to the nearest 0.5 Hz. All accurate mass values were obtained from the
following spectrometers: Agilent 6538 Q-TOF (ESI) and JEOL Accu-
TOF-DART. Melting points were obtained on a Fisher-Johns Melting
Point Apparatus and uncorrected. IR spectra were obtained as a neat
film or dissolved in CHCl3 on a NaCl disk using a Shimadzu FTIR-
HRMS (DART): m/z [M + NH ] calcd for C23H29BO + NH : 382.25535;
4 3 4
found: 382.25588.
4,4,5,5-Tetramethyl-2-{[(2R,4S)-4-methyl-2-phenyl-7-(trifluoro-
methyl)chroman-4-yl]methyl}-1,3,2-dioxaborolane (2b)
8400S FT-IR spectrophotometer.
Column chromatography (hexanes/EtOAc 5:1) gave 2b (76 mg, 0.176
mmol, 88%) as a clear, colorless oil.
Pd-Catalyzed Domino Heck/Arylborylation: General Procedure
IR (neat): 3032, 2978, 2932, 1578, 1506, 1456, 1427, 1325, 1275,
To a flame-dried or oven-dried 2-dram vial cooled under argon, the
aryl iodide (1 equiv), Pd (dba) (4 mol% Pd), B pin (1.5 equiv), and
–1
1215, 1124, 1089, 1067, 1017, 970 cm
.
2
3
2
2
1
H NMR (500 MHz, CDCl ): δ = 7.52–7.47 (m, 3 H), 7.46–7.41 (m, 2 H),
3
KOAc (1.5 equiv) were added and allowed to purge for 10 min. DMF
0.1 M) was added. A Teflon-lined screw cap was fitted on the 2-dram
7.38–7.33 (m, 1 H), 7.22–7.19 (m, 1 H), 7.19–7.15 (m, 1 H), 5.34 (dd,
(
J = 12.0, 2.0 Hz, 1 H), 2.33 (dd, J = 14.0, 2.0 Hz, 1 H), 1.95 (ddd, J = 14.0,
vial, which was sealed with Teflon tape and place in a preheated oil
1
2.0, 1.0 Hz, 1 H), 1.50 (s, 3 H), 1.47–1.38 (m, 2 H), 1.29 (s, 12 H).
1
bath at 80 °C for 4 h. Once TLC or H NMR analysis confirmed full con-
13
C NMR (126 MHz, CDCl ): δ = 153.60, 141.60, 136.47 (q, J = 1.0 Hz),
version of the starting material, the mixture was cooled to r.t. Once
3
1
2
4
29.40 (q, J = 32.5 Hz), 128.47, 127.78, 127.24, 125.77, 124.01 (q, J =
72.0 Hz), 116.77 (q, J = 4.0 Hz), 114.31 (q, J = 4.0 Hz), 83.29, 74.79,
5.08, 33.56, 28.95, 24.90, 24.83.
cooled, the reaction was extracted with EtOAc/H O (3 ×) and the com-
2
bined extracts were dried (Na SO ) and passed through a 2-cm plug
2
4
of silica gel in a pipette using EtOAc. The pure chroman was obtained
via flash column chromatography (silica gel) using the indicated mo-
bile phase.
11
B NMR (128 MHz, CDCl ): δ = 32.79.
3
19
F NMR (377 MHz, CDCl ): δ = –62.56.
3
HRMS (DART): m/z [M + NH ] calcd for C24H28BF O + NH : 450.24273;
found: 450.24332.
4
3
3
4
4
,4,5,5-Tetramethyl-2-{[(2R,4S)-4-methyl-2-phenylchroman-4-
yl]methyl}-1,3,2-dioxaborolane (2a)
Column chromatography (hexanes/EtOAc 10:1) gave 2a (60 mg, 0.164
mmol, 82%) as a white solid; mp 74–75 °C.
2
-{[(2R,4S)-7-Methoxy-4-methyl-2-phenylchroman-4-yl]methyl}-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2c)
IR (neat): 3065, 3032, 2976, 2930, 1607, 1578, 1485, 1447, 1356,
Column chromatography (hexanes/EtOAc 10:1) gave 2c (49 mg, 0.124
mmol, 62%) as a clear, colorless oil.
–1
1
327, 1220, 1145, 1066, 1011, 970 cm .
IR (neat): 3030, 2976, 2932, 1620, 1504, 1418, 1354, 1321, 1248,
–1
1
198, 1161, 1144, 1119, 1082, 1041 cm .
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Synthesis
H. Yoon et al.
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1
H NMR (500 MHz, CDCl ): δ = 7.54–7.50 (m, 2 H), 7.46–7.41 (m, 2 H),
.38–7.32 (m, 1 H), 7.30 (d, J = 8.5 Hz, 1 H), 6.55 (dd, J = 8.5, 2.5 Hz, 1
IR (neat): 3030, 2978, 2930, 2911, 1622, 1578, 1485, 1449, 1356,
1325, 1221, 1165, 1125, 1066, 1017 cm .
3
–1
7
H), 6.50 (d, J = 2.5 Hz, 1 H), 5.30 (dd, J = 12.0, 2.0 Hz, 1 H), 3.79 (s, 3 H),
1
H NMR (500 MHz, CDCl ): δ = 7.75–7.61 (m, 4 H), 7.44–7.38 (m, 1 H),
.18–7.12 (m, 1 H), 7.00–6.93 (m, 2 H), 5.39 (dd, J = 12.0, 1.0 Hz, 1 H),
.35 (dd, J = 14.0, 2.0 Hz, 1 H), 1.92 (ddd, J = 14.0, 12.0, 1.0 Hz, 1 H),
3
2.26 (dd, J = 14.0, 2.0 Hz, 1 H), 1.94 (dd, J = 12.0, 1.5 Hz, 1 H), 1.47 (s, 3
7
2
H), 1.41 (s, 2 H), 1.29 (s, 12 H).
13
C NMR (126 MHz, CDCl ): δ = 158.67, 154.24, 142.18, 128.37,
1.51 (s, 3 H), 1.49–1.44 (m, 2 H), 1.32 (s, 12 H).
3
1
4
27.56, 127.26, 125.86, 124.98, 107.52, 101.31, 83.05, 74.71, 55.13,
5.79, 32.96, 29.38, 24.92, 24.84.
13
C NMR (126 MHz, CDCl ): δ = 152.97, 146.48 (q, J = 1.0 Hz), 132.67,
3
129.63 (q, J = 32.5 Hz), 127.16, 126.53, 126.04, 125.30 (q, J = 3.5 Hz),
11
B NMR (128 MHz, CDCl ): δ = 33.11.
123.83 (q, J = 272.0 Hz), 120.71, 117.01, 83.19, 73.76, 45.49, 33.42,
3
2
9.16, 24.90, 24.86.
HRMS (DART): m/z [M + H] calcd for C24H32BO : 395.23936; found:
4
11
395.23874.
B NMR (128 MHz, CDCl ): δ = 32.78.
3
19
F NMR (377 MHz, CDCl ): δ = –62.39.
3
2
-{[(2R,4S)-6,7-Difluoro-4-methyl-2-phenylchroman-4-yl]meth-
HRMS (DART): m/z [M + NH ] calcd for C24H28BF O + NH : 450.24273;
found: 450.24317.
4
3
3
4
yl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2d)
Column chromatography (hexanes/EtOAc 10:1) gave 2d (60 mg, 0.15
mmol, 75%) as a clear, colorless oil.
2-{[(2R,4S)-2-(4-Methoxyphenyl)-4-methylchroman-4-yl]meth-
IR (neat): 3066, 2978, 2940, 1506, 1456, 1423, 1354, 1329, 1281,
yl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2g)
–1
1194, 1142, 1030, 970 cm .
Column chromatography (hexanes/EtOAc 6:1) gave 2g (58 mg, 0.148
mmol, 74%) as a white solid; mp 82–84 °C.
1
H NMR (500 MHz, CDCl ): δ = 7.50–7.40 (m, 4 H), 7.37–7.33 (m, 1 H),
3
7
.20 (dd, J = 12.0, 9.0 Hz, 1 H), 6.71 (dd, J = 11.5, 7.0 Hz, 1 H), 5.26 (dd,
IR (neat): 2976, 2930, 1578, 1516, 1485, 1447, 1327, 1302, 1248,
J = 12.0, 2.0 Hz, 1 H), 2.23 (dd, J = 14.0, 2.0 Hz, 1 H), 1.91 (ddd, J = 14.0,
1
Hz, 12 H).
–1
1221, 1175, 1144, 1119, 1076, 1037 cm
.
2.0, 1.0 Hz, 1 H), 1.45 (s, 3 H), 1.38 (d, J = 4.0 Hz, 2 H), 1.29 (d, J = 2.5
1
H NMR (500 MHz, CDCl ): δ = 7.43–7.39 (m, 2 H), 7.36 (dd, J = 8.0, 1.5
3
Hz, 1 H), 7.10 (ddd, J = 8.0, 7.0, 1.5 Hz, 1 H), 6.98–6.92 (m, 2 H), 6.93–
6.86 (m, 2 H), 5.22 (dd, J = 12.0, 2.0 Hz, 1 H), 3.84 (s, 3 H), 2.22 (dd, J =
13
C NMR (126 MHz, CDCl ): δ = 149.59 (dd, J = 9.5, 2.0 Hz) overlapping
3
1
1
48.39 (dd, J = 247.0, 13.0 Hz), 144.71 (dd, J = 239.0, 13.0 Hz), 141.60,
28.52, 128.42 (t, J = 4.0 Hz), 127.86, 125.86, 114.54 (dd, J = 18.5, 1.0
1
1
4.0, 2.0 Hz, 1 H), 1.93 (ddd, J = 14.0, 12.0, 1.0 Hz, 1 H), 1.47 (s, 3 H),
.40 (d, J = 5.5 Hz, 2 H), 1.26 (s, 12 H).
Hz), 105.63 (d, J = 19.5 Hz), 83.34, 74.89, 45.46, 33.45, 29.27, 24.96,
2
13
C NMR (126 MHz, CDCl ): δ = 159.13, 153.54, 134.43, 132.70,
3
4.89.
127.25, 127.01, 126.61, 120.29, 117.03, 113.83, 83.10, 74.09, 55.29,
11
B NMR (128 MHz, CDCl ): δ = 32.86.
3
45.42, 33.45, 29.30, 24.96, 24.87.
1
9
F NMR (377 MHz, CDCl ): δ = –139.57 to –139.78 (m), –148.28 to
11
3
B NMR (128 MHz, CDCl ): δ = 33.16.
3
–148.48 (m).
HRMS (DART): m/z [M + NH ] calcd for C24H31BNO + NH : 412.26591;
4
4
4
HRMS (DART): m/z [M + NH ] calcd for C23H27BF O + NH : 418.23650;
found: 418.23632.
4
2
3
4
found: 412.26627.
4
,4,5,5-Tetramethyl-2-{[(2R,4S)-4-methyl-2-(o-tolyl)chroman-4-
(
1
2R,4S)-8-Methoxy-4-methyl-2-phenyl-4-[(4,4,5,5-tetramethyl-
,3,2-dioxaborolan-2-yl)methyl]chroman-6-carbaldehyde (2e)
yl]methyl}-1,3,2-dioxaborolane (2h)
Column chromatography (hexanes/EtOAc 6:1) gave 2h (57 mg, 0.15
mmol, 75%) as a white solid; mp 75–77 °C.
Column chromatography (hexanes/EtOAc 5:1) gave 2e (61 mg, 0.144
mmol, 72%) as a white solid; mp 103–104 °C.
IR (neat): 2976, 29, 2928, 1598, 1485, 1449, 1356, 1325, 1227, 1165,
IR (neat): 2976, 2933, 2837, 1684, 1582, 1480, 1452, 1391, 1354,
1
–1
1144, 1119, 1011, 970 cm
.
–1
278, 1261, 1236, 1215, 1144, 1078, 1009 cm .
1
H NMR (500 MHz, CDCl ): δ = 7.61 (dd, J = 7.5, 1.0 Hz, 1 H), 7.40 (dd,
3
1
H NMR (500 MHz, CDCl ): δ = 9.83 (s, 1 H), 7.55 (d, J = 2.0 Hz, 1 H),
3
J = 7.5, 1.5 Hz, 1 H), 7.33–7.27 (m, 1 H), 7.27–7.22 (m, 1 H), 7.22–7.18
7
.48–7.44 (m, 2 H), 7.42–7.36 (m, 2 H), 7.34–7.29 (m, 1 H), 7.27–7.25
(
(
m, 1 H), 7.13 (ddd, J = 8.0, 7.5, 1.5 Hz, 1 H), 6.97–6.89 (m, 2 H), 5.48
dd, J = 12.0, 2.0 Hz, 1 H), 2.45 (s, 3 H), 2.33 (dd, J = 14.0, 2.0 Hz, 1 H),
(m, 1 H), 5.36 (dd, J = 12.0, 2.0 Hz, 1 H), 3.90 (s, 3 H), 2.30 (dd, J = 14.0,
2
1
.0 Hz, 1 H), 1.96–1.87 (m, 1 H), 1.49 (s, 3 H), 1.40 (q, J = 15.0 Hz, 2 H),
.25 (d, J = 5.5 Hz, 12 H).
1.86 (ddd, J = 14.0, 12.0, 1.0 Hz, 1 H), 1.49–1.43 (m, 5 H), 1.26 (s, 12 H).
13
C NMR (126 MHz, CDCl ): δ = 153.70, 140.32, 134.42, 132.81,
3
1
3
C NMR (126 MHz, CDCl ): δ = 191.14, 149.42, 149.11, 141.22,
3
130.22, 127.29, 127.03, 126.77, 126.27, 125.57, 120.38, 117.07, 83.12,
1
5
33.09, 128.93, 128.50, 127.83, 125.86, 124.47, 107.15, 83.30, 75.47,
6.08, 45.21, 33.50, 28.97, 24.94, 24.89.
71.34, 44.11, 33.61, 29.32, 24.93, 24.82, 18.86.
11
B NMR (128 MHz, CDCl ): δ = 33.16.
3
1
1
B NMR (128 MHz, CDCl ): δ = 33.51.
3
HRMS (DART): m/z [M + NH ] calcd for C24H31BNO + NH : 396.27100;
found: 396.27101.
4
3
4
HRMS (DART): m/z [M + H] calcd for C25H32BO : 423.23428; found:
4
5
23.23405.
4
,4,5,5-Tetramethyl-2-{[(2R,4S)-4-methyl-2-(thiophen-3-yl)chro-
4
,4,5,5-Tetramethyl-2-({(2R,4S)-4-methyl-2-[4-(trifluorometh-
man-4-yl]methyl}-1,3,2-dioxaborolane (2i)
yl)phenyl]chroman-4-yl}methyl)-1,3,2-dioxaborolane (2f)
Column chromatography (hexanes/EtOAc 10:1) gave 2i (54 mg, 0.146
mmol, 73%) as a white solid; mp 68–70 °C.
Column chromatography (hexanes/EtOAc 10:1) gave 2f (76 mg, 0.176
mmol, 88%) as a clear, colorless oil.
IR (neat): 2976, 2930, 1578, 1485, 1449, 1356, 1327, 1219, 1144,
–1
1115, 1005, 847, 700 cm .
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 1483–1490

1
488
Synthesis
H. Yoon et al.
Paper
1
1
H NMR (500 MHz, CDCl ): δ = 7.36 (dd, J = 8.0, 1.5 Hz, 1 H), 7.31 (dd,
H NMR (500 MHz, CDCl ): δ = 8.17 (dd, J = 4.5, 1.5 Hz, 1 H), 7.48–7.44
3
3
J = 5.0, 1.0 Hz, 1 H), 7.13 (ddd, J = 3.5, 1.0, 1.0 Hz, 1 H), 7.09 (ddd, J =
(m, 2 H), 7.43–7.38 (m, 2 H), 7.36–7.31 (m, 1 H), 7.15 (dd, J = 8.0, 1.5
Hz, 1 H), 7.03 (dd, J = 8.0, 4.5 Hz, 1 H), 5.25 (dd, J = 12.0, 2.0 Hz, 1 H),
2.34 (dd, J = 14.0, 2.0 Hz, 1 H), 2.06 (ddd, J = 14.0, 12.0, 1.0 Hz, 1 H),
1.54–1.49 (m, 4 H), 1.26 (m, 13 H).
8
7
.0, 7.0, 1.5 Hz, 1 H), 7.03 (dd, J = 5.0, 3.5 Hz, 1 H), 6.91 (ddd, J = 8.0,
.0, 1.5 Hz, 1 H), 6.88 (dd, J = 8.0, 1.5 Hz, 1 H), 5.54–5.50 (m, 1 H), 2.39
(dd, J = 14.0, 2.0 Hz, 1 H), 2.08 (dd, J = 14.0, 12.0 Hz, 1 H), 1.48 (s, 3 H),
1
.38 (s, 2 H), 1.25 (d, J = 1.5 Hz, 12 H).
13
C NMR (126 MHz, CDCl ): δ = 151.77, 149.73, 141.44, 141.31,
3
13
C NMR (126 MHz, CDCl ): δ = 153.02, 145.38, 132.48, 127.07,
128.49, 127.84, 125.92, 124.04, 122.19, 83.07, 74.93, 45.83, 36.27,
3
1
3
26.61, 126.54, 124.81, 124.15, 120.61, 117.07, 83.15, 70.58, 45.30,
3.41, 29.38, 24.96, 24.83.
27.87, 24.95, 24.88.
11
B NMR (128 MHz, CDCl ): δ = 33.07.
3
11
B NMR (128 MHz, CDCl ): δ = 32.96.
3
HRMS (DART): m/z [M + NH ] calcd for C22H28BO + NH : 366.22405;
4
3
4
HRMS (DART): m/z [M + NH ] calcd for C21H27BO S + NH : 388.21177;
found: 366.22475.
4
3
4
found: 388.21152.
(2R,4S)-6-Chloro-4-methyl-2-phenyl-4-[(4,4,5,5-tetramethyl-
2
-{[(2R,4S)-2-Cyclohexyl-4-methylchroman-4-yl]methyl}-4,4,5,5-
1,3,2-dioxaborolan-2-yl)methyl]-3,4-dihydro-2H-pyrano[3,2-
h]quinoline (2m)
tetramethyl-1,3,2-dioxaborolane (2j)
Column chromatography (hexanes/EtOAc 10:1) gave 2j (41 mg, 0.112
Column chromatography (hexanes/EtOAc 6:1) gave 2m (70 mg, 0.156
mmol, 56%) as a clear, colorless oil.
mmol, 78%) as a yellow solid; mp 96–98 °C.
IR (neat): 2976, 2926, 2853, 1578, 1485, 1449, 1356, 1325, 1269,
IR (neat): 2976, 2930, 1578, 1516, 1485, 1447, 1327, 1302, 1248,
–1
–1
1233, 1163, 1144, 1111, 1069, 1045 cm
.
1221, 1175, 1144, 1119, 1076, 1037 cm
.
1
1
H NMR (500 MHz, CDCl ): δ = 7.31 (dd, J = 8.0, 1.5 Hz, 1 H), 7.05 (ddd,
H NMR (500 MHz, CDCl ): δ = 8.95 (dd, J = 4.0, 1.5 Hz, 1 H), 8.46 (dd,
3
3
J = 8.0, 7.0, 1.5 Hz, 1 H), 6.88–6.81 (m, 1 H), 6.79 (dd, J = 8.0, 1.0 Hz, 1
H), 3.96 (ddd, J = 12.0, 6.0, 1.5 Hz, 1 H), 2.11–2.00 (m, 2 H), 1.88–1.77
J = 8.5, 1.5 Hz, 1 H), 7.69 (s, 1 H), 7.60–7.53 (m, 2 H), 7.47 (dd, J = 8.5,
4.0 Hz, 1 H), 7.44–7.36 (m, 2 H), 7.34–7.28 (m, 1 H), 5.44 (dd, J = 12.0,
2.0 Hz, 1 H), 2.34 (dd, J = 14.0, 2.0 Hz, 1 H), 2.06 (ddd, J = 14.0, 12.0, 1.0
Hz, 1 H), 1.55–1.37 (m, 5 H), 1.26 (d, J = 7.1 Hz, 12 H).
13
(m, 3 H), 1.78–1.70 (m, 1 H), 1.68–1.56 (m, 2 H), 1.45 (s, 3 H), 1.41–
1.12 (m, 19 H).
13
C NMR (126 MHz, CDCl ): δ = 153.87, 133.21, 126.81, 126.58,
C NMR (126 MHz, CDCl ): δ = 149.81, 147.93, 141.56, 140.79,
3
3
1
2
19.78, 116.78, 82.99, 76.29, 42.58, 39.27, 32.90, 29.54, 28.61, 28.36,
6.69, 26.28, 26.21, 24.96, 24.95.
132.57, 130.36, 128.50, 127.74, 126.22, 125.47, 125.44, 121.56,
121.37, 83.34, 75.49, 45.84, 33.97, 28.94, 24.98, 24.88.
11
11
B NMR (128 MHz, CDCl ): δ = 33.10.
B NMR (128 MHz, CDCl ): δ = 33.50.
3
3
HRMS (DART): m/z [M + H] calcd for C23H36BO : 371.27525; found:
HRMS (DART): m/z [M + NH ] calcd for C26H29BClO + NH : 450.20073;
3
4
3
4
371.27648.
found: 450.20092.
4,4,5,5-Tetramethyl-2-{[(2S,4S)-4-methyl-2-pentylchroman-4-
Chan–Lam Coupling: N-{[(2R,4S)-4-Methyl-2-phenylchroman-4-
yl]methyl}-1,3,2-dioxaborolane (2k)
yl]methyl}benzamide (3a)
Column chromatography (hexanes/EtOAc 9:1) gave 2k (50 mg, 0.14
mmol, 70%) as a clear, colorless oil.
To a flame-dried or oven-dried 1-dram vial cooled under argon, ben-
zamide (24.2 mg, 0.2 mmol, 1 equiv), 2a (109.2 mg, 0.3 mmol, 1.5
equiv), CuBr (5.7 mg, 0.04 mmol, 20 mol%), NaOTMS (45 mg, 0.4
mmol, 2 equiv), and di-tert-butyl peroxide (110 μL, 0.6 mmol, 3
equiv) were added and allowed to purge for 10 min. t-BuOH (0.4 M)
was added. A Teflon-lined screw cap was fitted on the 1-dram vial,
which was sealed with Teflon tape and place in a preheated oil bath at
IR (neat): 2976, 2457, 2932, 2861, 1578, 1485, 1447, 1387, 1356.
–1
1
327, 1231, 1165, 1144, 1121 cm .
1
H NMR (500 MHz, CDCl ): δ = 7.32 (dd, J = 8.0, 1.5 Hz, 1 H), 7.05 (ddd,
3
J = 8.0, 7.0, 1.5 Hz, 1 H), 6.89–6.81 (m, 1 H), 6.79 (dd, J = 8.0, 1.5 Hz, 1
H), 4.20–4.13 (m, 1 H), 2.09 (dd, J = 13.5, 2.0 Hz, 1 H), 1.84–1.73 (m, 1
H), 1.68–1.52 (m, 3 H), 1.52–1.29 (m, 10 H), 1.27 (d, J = 2.5 Hz, 12 H),
75 °C for 48 h. The mixture was cooled to r.t. Once cooled, the reaction
was passed through a 2-cm plug of Celite in a pipette using EtOAc. The
chroman was purified by flash column chromatography (hex-
anes/EtOAc 3:1) to give 3a (35 mg, 0.146 mmol, 45%) as an off-white
solid; mp 173–174 °C.
0.99–0.91 (m, 3 H).
13
C NMR (126 MHz, CDCl ): δ = 153.57, 133.03, 126.74, 126.62,
3
1
2
19.86, 116.70, 82.91, 72.21, 42.50, 35.86, 32.86, 31.81, 29.51, 24.89,
4.81, 24.79, 22.63, 14.02.
IR (neat): 3414, 3322, 3063, 3032, 2965, 2926, 1640, 1578, 1534,
11
–1
B NMR (128 MHz, CDCl ): δ = 33.10.
1487, 1447, 1295, 1229, 1119, 1063 cm
.
3
1
HRMS (DART): m/z [M + H] calcd for C22H36BO : 359.27575; found:
H NMR (500 MHz, CDCl ): δ = 7.80–7.72 (m, 2 H), 7.55–7.48 (m, 3 H),
3
3
359.27579.
7.48–7.42 (m, 2 H), 7.42–7.35 (m, 2 H), 7.35–7.28 (m, 2 H), 7.24–7.18
(m, 1 H), 7.03–6.95 (m, 2 H), 5.39 (dd, J = 12.0, 2.0 Hz, 1 H), 4.14 (dd,
(
2R,4S)-4-Methyl-2-phenyl-4-[(4,4,5,5-tetramethyl-1,3,2-dioxa-
J = 14.0, 8.0 Hz, 1 H), 3.47 (ddd, J = 14.0, 5.5, 1.0 Hz, 1 H), 2.17 (dd, J =
14.0, 2.0 Hz, 1 H), 1.86 (ddd, J = 14.0, 12.0, 1.0 Hz, 1 H), 1.40 (s, 3 H).
borolan-2-yl)methyl]-3,4-dihydro-2H-pyrano[3,2-b]pyridine (2l)
13
Column chromatography (hexanes/EtOAc 6:1) gave 2l (32 mg, 0.088
C NMR (126 MHz, CDCl ): δ = 167.88, 154.77, 141.69, 134.55,
3
mmol, 44%) as an off white solid; mp 75–77 °C.
131.62, 128.70, 128.48, 128.16, 127.73, 127.19, 126.86, 126.83,
25.98, 120.74, 117.75, 74.47, 49.66, 41.63, 36.50, 26.08.
HRMS (DART): m/z [M + H] calcd for C24H24NO : 358.18070; found:
1
IR (neat): 3063, 2978, 2930, 1570, 1441, 1356, 1329, 1285, 1267,
–1
1
231, 1144, 1113, 1094, 1067, 1007 cm .
2
358.18011.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 1483–1490

1
489
Synthesis
H. Yoon et al.
Paper
Oxidation: [(2R,4S)-4-Methyl-2-phenylchroman-4-yl]methanol
3b)
To a 2-dram vial, 2a (72.8 mg, 0.2 mmol, 1 equiv) was added. THF
0.133 M) was added and the vial was cooled to 0 °C. Aq NaOH (0.8
mL, 3 M) and 30% H O (0.4 mL) were added dropwise. A Teflon-lined
Supporting Information
(
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561567.
S
u
p
p
ortioIgnfmr oaitn
S
u
p
p
o
nrtogI
i
f
rm oaitn
(
2
2
screw cap was fitted on the 2-dram vial, sealed with Teflon tape and
stirred at r.t. for 30 min. Once TLC analysis confirmed full conversion,
References
the reaction was extracted with EtOAc/H O (3 ×) and the combined
2
(
1) Boronic Acids: Prepartion and Applications in Organic Synthesis
and Medicine, 2nd ed., Hall, D. G., Ed.; Wiley-VCH: Weinheim,
011.
extracts were dried (Na SO ) and passed through a 2-cm plug of silica
2
4
gel in a pipette using EtOAc. The chroman was purified by flash col-
umn chromatography (hexanes/EtOAc 3:1) to give 3b (50.4 mg, 0.198
mmol, 99%) as an off-white solid; mp 82–84 °C.
2
(
2) For selected reviews, see: (a) Ishiyama, T.; Miyaura, N. Chem.
Rec. 2004, 3, 271. (b) Chow, W. K.; Yuen, O. Y.; Choy, P. Y.; So, C.
M.; Lau, C. P.; Wing, T. W.; Kwong, F. K. RSC Adv. 2013, 3, 12518;
and references therein.
IR (neat): 3521, 2966, 2929, 2874, 1578, 1487, 1455, 1372, 1291,
–1
1
214, 1120, 1088, 1001 cm .
1
(3) For selected examples: (a) Brown, H. C.; Cole, T. E. Organometal-
lics 1983, 2, 1316. (b) Li, W.; Nelson, D. P.; Jenson, M. S.;
Hoerrner, R. S.; Cai, D.; Larsen, R. D.; Reider, P. J. J. Org. Chem.
H NMR (500 MHz, CDCl ): δ = 7.51–7.45 (m, 2 H), 7.45–7.38 (m, 2 H),
3
7
.36–7.32 (m, 1 H), 7.32–7.28 (m, 1 H), 7.19 (ddd, J = 8.2, 7.3, 1.7 Hz, 1
H), 6.99–6.94 (m, 2 H), 5.25 (dd, J = 12.0, 2.0 Hz, 1 H), 3.85 (d, J = 11.0
Hz, 1 H), 3.71 (d, J = 11.0 Hz, 1 H), 2.27 (dd, J = 14.0, 2.5 Hz, 1 H), 1.91
2002, 67, 5394. (c) Huang, S.; Petersen, T. B.; Lipshutz, B. H.
J. Am. Chem. Soc. 2010, 132, 14021. (d) Demory, E.; Blandin, V.;
Einhorn, J.; Chavant, P. Y. Org. Process Res. Dev. 2011, 15, 710.
(dd, J = 14.0, 12.0 Hz, 1 H), 1.66 (s, 1 H), 1.35 (s, 3 H).
13
C NMR (126 MHz, CDCl ): δ = 155.09, 141.62, 128.49, 127.95,
3
(e) Leerman, T.; Leroux, F. R.; Colobert, F. Org. Lett. 2011, 13,
1
3
27.87, 127.16, 126.57, 126.05, 120.67, 117.43, 74.67, 71.75, 40.94,
6.84, 25.07.
4479.
(
4) For selected reviews and examples, see: (a) Hartwig, J. F. J. Am.
Chem. Soc. 2016, 138, 2. (b) Mkhalid, I. A. I.; Barnard, J. H.;
Marder, T. B.; Murphy, J. M.; Hartwig, J. F. Chem. Rev. 2010, 110,
HRMS (DART): m/z [M + H] calcd for C17H19O : 255.13850; found:
2
2
55.13796.
890. (c) Dai, H.-X.; Yu, J.-Q. J. Am. Chem. Soc. 2012, 134, 134.
Suzuki Coupling: (2R,4S)-4-Benzyl-4-methyl-2-phenylchroman
3c)
To a flame-dried or oven-dried 2-dram vial cooled under argon, 2a
36.4 mg, 0.1 mmol, 1 equiv), Pd(OAc)2 (2.26 mg, 0.01 mmol, 10
mol%), t-BuOK (33.7 mg, 0.3 mmol, 3 equiv), and 1,3,5,7-tetramethyl-
-phenyl-2,4,8-trioxa-6-phosphaadamantane (4.7 mg, 0.01 mmol, 10
mol%) were added and allowed to purge for 10 min. Toluene (0.1 M)
and iodobenzene (17 μL, 0.15 mmol, 1.5 equiv) were added. A Teflon-
lined screw cap was fitted on the 2-dram vial, which was sealed with
Teflon tape and place in a preheated oil bath at 100 °C for 12 h. The
mixture was cooled to r.t. Once cooled, the reaction was passed
through a 2-cm plug of silica gel in a pipette using EtOAc. The chro-
man was purified by flash column chromatography (hexanes/EtOAc
(5) For reviews on the Pd-catalyzed intramolecular Heck reaction,
(
see: (a) Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106, 4644.
(b) Shibasaki, M.; Vogl, E. M.; Ohshima, T. Adv. Synth. Catal.
2004, 346, 1533.
(
(
6) For reviews on total syntheses using the Pd-catalyzed intramo-
lecular Heck reaction, see: (a) Nicolaou, K. C.; Bulger, P. G.;
Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 4442. (b) Dounay, A.
B.; Overman, L. E. Chem. Rev. 2003, 103, 2945.
6
(
(
7) Grigg, R.; Sridharan, V. J. Organomet. Chem. 1999, 576, 65.
8) For a review, see: Vlaar, T.; Ruijter, E.; Orru, R. V. A. Adv. Synth.
Catal. 2011, 353, 809; and references therein.
(
9) For recent selected examples: (a) Liu, Z.; Xia, Y.; Zhou, S.; Wang,
L.; Zhang, Y.; Wang, J. Org. Lett. 2013, 15, 5032. (b) Liu, X.; Ma,
X.; Huang, Y.; Gu, Z. Org. Lett. 2013, 15, 4814. (c) Yoon, H.;
Petrone, D. A.; Lautens, M. Org. Lett. 2014, 16, 6420. (d) Zhou,
M.-B.; Huang, X.-C.; Liu, Y.-Y.; Song, R.-J.; Li, J.-H. Chem. Eur. J.
10:1) to give 3c (13.2 mg, 0.042 mmol, 44%) as a clear colorless oil.
IR (neat): 3062, 3028, 2961, 2929, 1578, 1484, 1448, 1297, 1278,
–1
1
225, 1119, 1083, 1066, 1009 cm .
2014, 20, 1843. (e) Petrone, D. A.; Yen, A.; Zeidan, N.; Lautens,
1
H NMR (500 MHz, CDCl ): δ = 7.45–7.39 (m, 4 H), 7.38–7.22 (m, 4 H),
3
M. Org. Lett. 2015, 17, 4838. (f) Sharma, U. K.; Sharma, N.;
Kumar, Y.; Singh, B. K.; Van der Eycken, E. V. Chem. Eur. J. 2016,
7.21–7.16 (m, 1 H), 7.12–7.07 (m, 2 H), 7.00–6.93 (m, 2 H), 4.94 (dd,
J = 12.0, 2.0 Hz, 1 H), 3.20 (d, J = 13.5 Hz, 1 H), 2.99 (d, J = 13.5 Hz, 1 H),
22, 481.
2.12 (dd, J = 14.0, 2.0 Hz, 1 H), 1.88 (dd, J = 14.0, 12.0 Hz, 1 H), 1.37 (s,
(
10) For selected examples: (a) Marco-Martínez, J.; López-Carrillo,
V.; Buñuel, E.; Simancas, R.; Cárdenas, D. J. J. Am. Chem. Soc.
2007, 129, 1874. (b) Marco-Martínez, J.; Buñuel, E.; Muñoz-
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3
H).
13
C NMR (126 MHz, CDCl ): δ = 154.27, 141.84, 138.09, 130.70,
3
1
1
29.86, 128.55, 128.06, 127.86, 127.49, 127.47, 126.56, 125.96,
20.52, 117.31, 74.26, 49.61, 42.81, 35.95, 28.65.
HRMS (DART): m/z [M + H] calcd for C23H23O: 315.17489; found:
15.17435.
3
10517. (e) Martos-Redruejo, A.; López-Durán, R.; Buñuel, E.;
Cárdenas, D. J. Chem. Commun. 2014, 50, 10094. (f) Camelio, A.
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Acknowledgment
1517. (g) Persson, A. K. Å.; Jiang, T.; Johnson, M. T.; Bäckvall, J.-E.
Angew. Chem. Int. Ed. 2011, 50, 6155. (h) Deng, Y.;
Bartholomeyzik, T.; Bäckvall, J.-E. Angew. Chem. Int. Ed. 2013,
The work was financially supported by Natural Sciences and Engi-
neering Research Council of Canada (NSERC), the University of Toron-
to, and Alphora Research Inc. Dr. Alan Lough (University of Toronto) is
thanked for the X-ray structural analysis of 2a. David Petrone is
thanked for helpful discussions.
5
2, 6283. (i) Jiang, T.; Bartholomeyzik, T.; Mazuela, J.;
Willersinn, J.; Bäckvall, J.-E. Angew. Chem. Int. Ed. 2015, 54,
024.
6
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