Synthesis of P-Chiral Dihydrobenzooxaphospholes Through Negishi Cross-Coupling

Article abstract of DOI:10.1021/acs.joc.5b02649

An efficient Negishi cross-coupling was developed for the synthesis of the biaryl axes present in useful P-chiral dihydrobenzooxaphosphole ligands. This approach has allowed for the synthesis of new derivatives of these ligands that were not accessible by the previous route employing Suzuki-Miyaura cross-coupling. The use of Pd₂(dba)₃/BI-DIME as the catalyst system affords the desired biaryl compounds in good yields with excellent rates and with catalyst loadings as low as 0.25 mol %.

Full text of DOI:10.1021/acs.joc.5b02649

Note
pubs.acs.org/joc
Synthesis of P‑Chiral Dihydrobenzooxaphospholes Through Negishi
Cross-Coupling
́
Joshua D. Sieber,* Bo Qu, Sonia Rodrıguez, Nizar Haddad, Nelu Grinberg, Heewon Lee, Jinhua J. Song,
Nathan K. Yee, and Chris H. Senanayake
Chemical Development, Boehringer Ingelheim Pharmaceuticals, Incorporated, 900 Ridgebury Road, Ridgefield, Connecticut 06877,
United States
S
* Supporting Information
ABSTRACT: An efficient Negishi cross-coupling was developed for the synthesis of the biaryl axes present in useful P-chiral
dihydrobenzooxaphosphole ligands. This approach has allowed for the synthesis of new derivatives of these ligands that were not
accessible by the previous route employing Suzuki−Miyaura cross-coupling. The use of Pd2(dba)3/BI-DIME as the catalyst
system affords the desired biaryl compounds in good yields with excellent rates and with catalyst loadings as low as 0.25 mol %.
igand accelerated catalysis1 is a valuable tool for the
reagent 7 is easily prepared by deprotonation of 1,3-
Lstraightforward synthesis of complex molecular frame- dimethoxybenzene followed by addition of ZnBr2. Gratifyingly,
works.2 Over the years, many privileged ligand3 structures have
the Negishi cross-coupling employing Pd/BI-DIME as the
catalyst was highly effective in forming the desired biaryl moiety.
In this note, we describe the generality of the Pd/BI-DIME
catalyzed Negishi cross-coupling reaction for the synthesis of
BI-DIME analogues.
been developed and applied to useful reactions. In the continual
effort to identify new ligand architectures for valuable organic
transformations, our laboratories have recently reported a
privileged class of P-chiral dihydrobenzooxaphosphole-derived
ligands (4, Scheme 1), whereby this common core structure can
be used for ligands suitable for both standard4 and asymmetric5
Suzuki−Miyaura6 cross-coupling reactions, asymmetric hydro-
genations of functionalized7 and unfunctionalized8 alkenes,
Buchwald−Hartwig9 amination10 reactions, asymmetric prop-
argylation11 reactions, and asymmetric boronic acid addition
reactions.12 In particular, the monophosphine BI-DIME and
derivatives are highly effective in Suzuki−Miyaura cross-
coupling chemistry.4,5 As such, the introduction of the biaryl
axis found in this family of ligands is installed using a Suzuki−
Miyaura cross-coupling reaction between triflate 1a and boronic
acid 2 employing Pd/BI-DIME as the catalyst.4a Because of the
extreme utility of this family of ligands, we have been interested
in preparing derivatives of this class of ligands by varying the
substituent on phosphorus (5) to determine if these changes
could have significant impact and utility on catalytic reactions.
For example, the triflate containing a ferrocenyl (Fc) substituent
on phosphorus (1b) was prepared to generate the P-Fc analogue
of BI-DIME. However, under the standard Suzuki cross-
coupling conditions used to install the biaryl axis, poor yield of
the desired cross-coupling product 3b was obtained, resulting in
mostly hydrolysis of the triflate. A survey of other catalysts did
not improve the yield of the desired coupling. At this point, we
decided to attempt the biaryl synthesis employing a Negishi
cross-coupling process.13 The dimethoxyphenyl zinc bromide
The substrate scope for the Negishi cross-coupling reaction is
given in Table 1. The coupling utilizing triflate 1a can be
employed to prepare the BI-DIME derivatives that were
previously prepared using Suzuki−Miyaura cross-coupling
chemistry (entries 1, 3, and 4). Notably, the Negishi coupling
was superior to the Suzuki−Miyaura reaction for the synthesis of
3c and 3e; 3c could not be prepared using a Suzuki reaction, and
3e is achieved in only 30% yield under Suzuki conditions.14
Additionally, reaction times were typically significantly reduced
with many of the cross-coupling reactions complete in <1 h.
When the P-t-Bu substituent of the triflate electrophile was
replaced with smaller groups (i.e., R = Fc, 1b or R = Ph, 1c),
catalyst loadings and reaction times could be reduced as
compared with triflate 1a (entries 6−13 vs entries 1−4).
However, reactions of triflates 1b or 1c with more hindered aryl
zinc reagents did require longer reaction times to reach
completion at 1−2 mol % Pd-loadings (entries 9, 11, and 13).
Because the Negishi cross-coupling reaction with triflate 1a to
prepare 3a was observed to be very fast employing only 1 mol %
Pd loading (Table 1, entry 1), we examined the reaction rate for
this process at reduced catalyst loadings (Scheme 2). Notably,
the catalyst loading could be reduced to 0.25 mol % Pd loading
Received: November 21, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b02649
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 1. BI-DIME Ligand and Derivatives
a
Table 1. Pd/BI-DIME Catalyzed Negishi Cross-Coupling
Scheme 2. (a) Effect of Catalyst Loading in the Negishi
Coupling with Triflate 1a and (b) Reaction Yields
a
entry
R
Ar
x
time
1 h
% yield
b
1
tBu
tBu
2,6-(MeO)2C6H3
2,6-(iPrO)2C6H3
0.5
2.0
1.0
0.5
2.0
2.0
0.5
2.0
0.5
1.0
0.5
0.5
2.0
0.5
0.5
3a, 87
3c, 75
3c, 50
3d, 54
3e, 79
3f, 37
3b, 92
3g, 83
3h, 75
3i, 83
3j, 84
3k, 65
3k, 78
3l, 73
3m, 74
2
5 h
20 h
2 h
3
tBu
tBu
tBu
Fc
2,6-(PhO)2C6H3
9-anthracenyl
c
4
d
10 h
2 h
5
mesityl
6
7
8
2,6-(MeO)2C6H3
2,6-(iPrO)2C6H3
2,6-(PhO)2C6H3
9-anthracenyl
0.4 h
1.5 h
2 h
Fc
Fc
c
9
Fc
10 h
0.25 h
20 h
0.4 h
0.4 h
20 h
10
11
Ph
Ph
2,6-(MeO)2C6H3
2,6-(iPrO)2C6H3
2,6-(iPrO)2C6H3
2,6-(PhO)2C6H3
9-anthracenyl
12
Ph
Ph
c
13
a
Reaction conditions: triflate 1 (0.40−1.40 mmol), arene (2.1−2.2
equiv), n-BuLi (2.0 equiv), ZnBr2 (2.4 equiv), Pd2(dba)3 (0.5−2.0 mol
%), rac-BI-DIME (2−8 mol %), 70 °C. (S)-BI-DIME was used as
a
b
Reaction conditions: triflate 1a (0.500 g, 1.40 mmol), 1,3-
dimethoxybenzne (0.38 mL g, 2.9 mmol), n-BuLi (2.55M, 1.1 mL,
2.8 mmol), ZnBr2 (0.754 g, 3.35 mmol), Pd2(dba)3 (0.125−0.5 mol
%), rac-BI-DIME (0.5−2 mol %), THF (4.7 mL), 70 °C. Conversion
to the desired product was measured by UPLC at 220 nm.
ligand to avoid potential contamination of the product with racemic 3a
derived from oxidation of rac-BI-DIME during the workup. A control
experiment utilizing rac-BI-DIME as the ligand gave identical reaction
rate and yields compared to (S)-BI-DIME, indicating no catalytic
c
nonlinear effects in the cross-coupling. Aryllithium prepared by Li-
halogen exchange between 9-bromoanthracene (1.75−2.05 equiv) and
of the active catalyst that is generated in situ. Because Pd(0) is
used as the precatalyst, the induction period observed for the
formation of the catalytically active species is likely related to
ligand exchange by the phosphine ligand.
d
t-BuLi (3.4−4.0 equiv). Aryllithium prepared by Li-halogen exchange
between 2-bromomesitylene (2.05 equiv) and t-BuLi (4.0 equiv).
giving full conversion in ∼7 h. Reaction yield was slightly
reduced at lower catalyst loadings due to increased amounts of
byproduct formation at lower Pd loadings (see also Table 1,
entry 2). Finally, initial rates demonstrated an increase in
reaction rate with respect to time that is indicative of formation
Reduction of the BI-DIME derivatives containing P-Fc (3b)
and P-Ph (3j) substituents was performed employing HSiCl3/
TEA (Scheme 3). Ligand 5c containing bis(ortho-methyl)
substitution on the lower aryl ring (i.e., mesityl) in place of
bis(ortho-methoxy) substitution was also prepared for compar-
B
DOI: 10.1021/acs.joc.5b02649
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The Journal of Organic Chemistry
Note
In summary, a convenient and efficient Negishi cross-
coupling method employing Pd/BI-DIME as catalyst for the
synthesis of BI-DIME analogues was disclosed. In many
instances, the Negishi coupling enabled the synthesis of
derivatives that were previously either inaccessible or provided
in poor yields when employing a Suzuki−Miyaura coupling to
install the desired biaryl axis. New BI-DIME analogues bearing
alternate substitution on phosphorus were prepared and
demonstrated to have similar effectiveness to BI-DIME in
Suzuki−Miyaura cross-coupling to generate hindered biaryls.
The ability to further tune the reactivity of catalysts derived from
a transition metal and BI-DIME through the variation of the
substitution on phosphorus may lead to catalysts with unique
reactivity/selectivity in desirable catalytic transformations.
Scheme 3. Phosphine Oxide Reduction of New BI-DIME
Analogues
ison. These three new BI-DIME derivatives were then
compared against BI-DIME in a standard Suzuki−Miyaura
cross-coupling reaction to form hindered biaryls (Scheme 4).
EXPERIMENTAL SECTION
■
General Methods. Unless otherwise stated, all reactions were
carried out using oven- or flame-dried glassware under an inert
atmosphere of N2 or Ar. Anhydrous solvents (THF, toluene) were
purchased from commercial vendors and degassed by Ar sparge before
use. Triflates were prepared according to our previously published
procedures.4a,12 ZnBr2 was dried under high vacuum (∼1 Torr) at 135
°C overnight and then stored and dispensed in a N2-filled glovebox. 1H
NMR spectra were recorded on 400 or 500 MHz spectrometers.
Chemical shifts are reported in ppm from tetramethylsilane with the
solvent resonance as an internal standard (CDCl3: 7.26 ppm, CD2Cl2:
5.32). Data are reported as follows: chemical shift, integration,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, p =
pentet, h = hextet, hept = heptet, br = broad, m = multiplet), and
coupling constants (Hz). 13C NMR was recorded using 125 or 100
MHz instruments with complete proton decoupling. Chemical shifts
are reported in ppm with the solvent as the internal standard (CDCl3:
77.0 ppm, CD2Cl2: 53.84). 31P NMR spectra were recorded using 202
or 161 MHz instruments with complete proton decoupling. Chemical
shifts are reported relative to 85% H3PO4. High-resolution mass
spectroscopy was performed on a TOF instrument with ESI and
positive and negative ionization modes. Flash chromatography was
performed using columns packed with silica gel.
Scheme 4. (a) Ligand Activity in Hindered Suzuki−Miyaura
Cross-Coupling and (b) NMR Yields Determined Using
a
Dimethyl Fumarate as Standard
(R)-3-(tert-Butyl)-4-(2,6-dimethoxyphenyl)-2H-benzo[d][1,3]-
oxaphosphole 3-Oxide (3a).4a A crimp-cap vial with a magnetic stir-
bar was sealed with a crimp-cap septum and inerted with N2 using
vacuum-purge cycles (3×). To the vial was charged 0.38 mL (2.9
mmol) of 1,3-dimethoxybenzene followed by 2.5 mL of THF. The
mixture was cooled in an ice-bath, and 1.25 mL (2.2 M, 2.8 mmol) of n-
BuLi was charged dropwise over 5 min. The mixture was then warmed
to rt and allowed to stir for 2 h. In a second crimp-cap vial was prepared
a slurry of ZnBr2 (754 mg, 3.35 mmol) in 1.2 mL of THF. To the ZnBr2
mixture cooled in an ice-bath was charged the aryllithium solution by
canula transfer. The resulting mixture was then warmed to rt and
allowed to stir for 15 min before use. In a third crimp-cap vial with stir-
bar were charged triflate 1a (500 mg, 1.40 mmol), Pd2(dba)3 (6.4 mg,
0.0070 mmol), and (S)-BI-DIME (9.2 mg, 0.028 mmol). The mixture
was inerted with N2 using vacuum-purge cycles (3×). THF (1.0 mL)
was then added, and the mixture was allowed to stir for 10 min. The
ArZnBr solution was then transferred to the catalyst/triflate solution
using cannula transfer. The final mixture was then immersed in an oil
bath at 70 °C and monitored by UPLC. After the time given in Table 1,
the reaction was cooled to rt and quenched with 8 mL of 2 M HCl.
THF was removed in vacuo, and CH2Cl2 (10 mL) was then added. The
layers were separated, and the aqueous phase was extracted with
CH2Cl2 (1 × 10 mL). Combined organics were washed with 20% citric
acid (2 × 8 mL), dried with Na2SO4, and concentrated in vacuo.
Purification of the crude mixture by flash chromatography (gradient,
50−100% EtOAc in hexanes to 3% MeOH in EtOAc) afforded 420 mg
(87%) of 3a as a white solid. Spectral data was in complete agreement
with the published data.4a Mp 120−123 °C.
a
Bromide 8 (127 μL, 0.500 mmol), boronic acid 9 (148 mg, 0.750
mmol), K3PO4 (318 mg, 1.50 mmol), Pd2(dba)3 (2.3 mg, 0.0025
mmol, 0.5 mol %), ligand (2 mol %), toluene (1.0 mL), 100 °C.
Conversion to the desired product was measured by UPLC at 220 nm.
Interestingly, all three ligands containing bis(ortho-methoxy)
substitution gave comparable reaction rates and yields in the
cross-coupling to form 10 (Scheme 4, BI-DIME vs 5a vs 5b). It
is surprising that the phosphorus substituent seems to have little
impact on the coupling. This observation suggests that
analogues of this family of ligand with P-substituents other
than t-Bu may be useful in other reactions where BI-DIME and
its derivatives have been applied.4,5,7,8,10−12,14 Ligand 5c was not
as effective in the coupling studied. The better activity of Pd
catalysts derived from similar ligands bearing bis(ortho-
methoxyphenyl) substitution compared to those with bis-
(ortho-alkylphenyl) substitution for very hindered Suzuki−
Miyaura cross coupling reactions has been previously noted by
Buchwald.15
(R)-4-(2,6-Dimethoxyphenyl)-3-(ferrocenyl)-2H-benzo[d][1,3]-
oxaphosphole 3-Oxide (3b). A crimp-cap vial with magnetic stir-bar
C
DOI: 10.1021/acs.joc.5b02649
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The Journal of Organic Chemistry
Note
was sealed with a crimp-cap septum and inerted with N2 using vacuum-
purge cycles (3×). To the vial was charged 0.11 mL (0.83 mmol) of 1,3-
dimethoxybenzene followed by 1.0 mL of THF. The mixture was
cooled in an ice-bath, and 0.31 mL (2.55 M, 0.79 mmol) of n-BuLi was
charged dropwise over 5 min. The mixture was then warmed to rt and
allowed to stir for 2 h. In a second crimp-cap vial with stir-bar was
charged solid ZnBr2 (214 mg, 0.952 mmol) under N2. To the agitated
ZnBr2 in an ice-bath was charged the aryllithium solution by canula
transfer. The resulting mixture was then warmed to rt and allowed to
stir for 15 min before use. In a third crimp-cap vial with stir-bar were
charged triflate 1b (193 mg, 0.397 mmol), Pd2(dba)3 (1.8 mg, 0.0020
mmol), and rac-BI-DIME (2.6 mg, 0.0079 mmol). The mixture was
inerted with N2 using vacuum-purge cycles (3×). THF (1.0 mL) was
then added, and the mixture was allowed to stir for 10 min. The ArZnBr
solution was then transferred to the catalyst/triflate solution using
cannula transfer. The final mixture was then immersed in an oil bath at
70 °C and monitored by UPLC. After the time given in Table 1, the
reaction was cooled to rt and quenched with 5 mL of 2 M HCl. THF
was removed in vacuo, and CH2Cl2 (5 mL) was then added. The layers
were separated, and the aqueous phase was extracted with CH2Cl2 (1 ×
5 mL). Combined organics were washed with 20% citric acid (2 × 5
mL), dried with Na2SO4, and concentrated in vacuo. Purification of the
crude mixture by flash chromatography (gradient, 50−90% EtOAc in
hexanes) afforded 173 mg (92%) of 3b as an orange solid. Mp 230−233
°C; Rf = 0.22 (75% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ
7.48 (t, J = 7.8 Hz, 1H), 7.22 (t, J = 8.4 Hz, 1H), 6.95 (dd, J = 8.3 Hz, J
= 3.8 Hz, 1H), 6.80 (dd, J = 7.2 Hz, J = 3.4 Hz, 1H), 6.64 (d, J = 8.4 Hz,
1H), 6.25 (d, J = 8.4 Hz, 1H), 4.66 (dd, J = 14 Hz, J = 11 Hz, 1H), 4.57
(dd, J = 14 Hz, J = 0.9 Hz, 1H), 4.34 (s, 1H), 4.30 (s, 1H), 4.23 (s, 5H),
4.05 (s, 1H), 3.98 (s, 1H), 3.79 (s, 3H), 3.14 (s, 3H); 31P{1H}NMR
(202 MHz, CDCl3) δ 40.5 ppm; 13C{1H}NMR (100 MHz, CDCl3) δ
164.0 (d, JC−P = 22.1 Hz), 158.6, 157.1, 138.0 (d, JC−P = 6.0 Hz), 134.5
(d, JC−P = 1.5 Hz), 129.5, 123.9 (d, JC−P = 8.4 Hz), 118.9 (d, JC−P = 108
Hz), 116.1 (d, JC−P = 3.0 Hz), 112.4 (d, JC−P = 6.0 Hz), 104.1, 102.8,
(d, J = 13 Hz, 1H), 4.30 (dd, J = 14 Hz, J = 11 Hz, 1H), 1.30 (d, J = 3.1
Hz, 3H), 1.22 (d, J = 6.1 Hz, 3H), 1.16 (d, J = 6.1 Hz, 6H), 0.92 (d, J =
16 Hz, 9H); 31P{1H}NMR (162 MHz, CDCl3) δ 62.5 ppm; 13C{1H}-
NMR (126 MHz, CDCl3) δ 164.8 (d, JC−P = 19.5 Hz), 157.7, 156.0,
139.4 (d, JC−P = 5.62 Hz), 133.5 (d, JC−P = 1.7 Hz), 129.4, 125.4 (d,
JC−P = 8.6 Hz), 118.6 (d, JC−P = 2.4 Hz), 114.6 (d, JC−P = 92.4 Hz),
111.7 (d, JC−P = 5.6 Hz), 105.2, 103.8, 70.63, 69.38, 65.28 (d, JC−P
=
61.2 Hz), 33.68 (d, JC−P = 71.8 Hz), 23.79, 23.32, 22.23, 22.02, 21.94;
HRMS(EI) m/z calcd for C23H32O4P [M + H]+ 403.2038, found
403.2047.
(R)-3-(tert-Butyl)-4-(2,6-diphenoxyphenyl)-2H-benzo[d][1,3]-
oxaphosphole 3-Oxide (3d).16 A crimp-cap vial with magnetic stir-bar
was charged with 805 mg (3.07 mmol) of 1,3-diphenoxybenzene. The
vial was sealed with a crimp-cap septum and inerted with N2 using
vacuum-purge cycles (3×). To the vial was sequentially charged 1.5 mL
of hexanes and 1.35 mL (2.1M, 2.8 mmol) of n-BuLi. The mixture then
immersed in an oil bath at 70 °C and allowed to stir for 2.5 h to afford a
white slurry. The mixture was then cooled to rt, and 2.2 mL of THF was
charged to afford a homogeneous solution. In a second crimp-cap vial
with stir-bar was charged solid ZnBr2 (754 mg, 3.35 mmol) under N2.
To the agitated ZnBr2 at rt was charged the aryllithium solution by
canula transfer. The resulting mixture was allowed to stir for 15 min
before use. To a 1-dram vial with stir-bar were charged triflate 1a (500
mg, 1.40 mmol), Pd2(dba)3 (6.4 mg, 0.0070 mmol), and rac-BI-DIME
(9.2 mg, 0.028 mmol). The vial was capped with a septum cap and
inerted with N2 using vacuum-purge cycles (3×). THF (1.0 mL) was
then added, and the mixture was allowed to stir for 10 min. The
catalyst/triflate solution was then transferred to the ArZnBr solution
using cannula transfer. The residue in the vial was rinsed with an
additional 0.4 mL of THF. The final mixture was then immersed in an
oil bath at 70 °C and monitored by UPLC. After the time given in
Table 1, the reaction was cooled to rt and quenched with 8 mL of 2 M
HCl. THF was removed in vacuo, and CH2Cl2 (10 mL) was then
added. The layers were separated, and the aqueous phase was extracted
with CH2Cl2 (1 × 10 mL). Combined organics were washed with 20%
citric acid (2 × 8 mL), dried with Na2SO4, and concentrated in vacuo.
Purification of the crude mixture by flash chromatography (gradient, 30
to 70 to 90% EtOAc in hexanes) afforded 357 mg (54%) of 3d as a
white solid. Spectral data was in complete agreement with the published
data.15 Mp 90−95 °C (lit.16 mp 97−99 °C).
(R)-4-(Anthracen-9-yl)-3-(tert-butyl)-2H-benzo[d][1,3]-
oxaphosphole 3-Oxide (3e).14 To a 25 mL 2-neck round-bottom flask
with magnetic stir-bar and fitted with a reflux condenser with a short-
path distillation head at the top of the condenser was charged 527 mg
(2.05 mmol) of 9-bromoanthracene. The second neck of the flask was
capped with a septum, and the system was inerted with N2 using
vacuum-purge cycles (3×). THF (2.5 mL) was then charged, and the
solution was cooled to −78 °C in a dry ice acetone bath. t-BuLi (1.5 M
in pentane, 2.67 mL, 4.0 mmol) was then added dropwise over 10 min.
The resulting yellow slurry was stirred at −78 °C for 5 min and then
allowed to warm to rt and stirred for an additional 10 min before use. In
a separate flask was prepared a solution of ZnBr2 (540 mg, 2.4 mmol) in
1.8 mL of THF. This solution was then transferred by cannula to the
aryllithium reagent at rt, and the mixture was allowed to stir for an
additional 15 min. To a 1-dram vial with stir-bar were charged triflate 1a
(358 mg, 1.00 mmol), Pd2(dba)3 (18.3 mg, 0.0200 mmol), and rac-BI-
DIME (26.4 mg, 0.0800 mmol). The vial was capped with a septum cap
and inerted with N2 using vacuum-purge cycles (3×). THF (1.0 mL)
was then added, and the mixture was allowed to stir for 10 min. The
catalyst/triflate solution was then transferred to the ArZnBr solution
using cannula transfer. The residue in the vial was rinsed with an
additional 0.25 mL of THF. The final mixture was then immersed in an
oil bath at 70 °C and monitored by UPLC. Note that during the
reaction pentane was distilled off via the short-path distillation head.
After the time given in Table 1, the reaction was cooled to rt and
quenched with 5 mL of 2 M HCl. THF was removed in vacuo, and
CH2Cl2 (5 mL) was then added. The layers were separated, and the
aqueous phase was extracted with CH2Cl2 (1 × 5 mL). Combined
organics were washed with 20% citric acid (2 × 5 mL), dried with
Na2SO4, and concentrated in vacuo. Purification of the crude mixture
73.05 (d, JC−P = 11.6 Hz), 72.03 (d, JC−P = 11.3 Hz), 71.22 (d, JC−P
=
11.1 Hz), 69.88 (d, JC−P = 16.4 Hz), 69.39, 69.28 (d, JC−P = 73 Hz),
69.17 (d, JC−P = 190 Hz), 56.21, 55.03; HRMS(EI) m/z calcd for
C25H24FeO4P [M + H]+ 475.0762, found 475.0759.
(R)-3-(tert-Butyl)-4-(2,6-diisopropoxyphenyl)-2H-benzo[d][1,3]-
oxaphosphole 3-Oxide (3c). A crimp-cap vial with magnetic stir-bar
was sealed with a crimp-cap septum and inerted with N2 using vacuum-
purge cycles (3×). The vial was sequentially charged with 0.62 mL (3.1
mmol) of 1,3-diisopropoxybenzene, 1.5 mL of hexanes, and 1.1 mL
(2.55M, 2.8 mmol) of n-BuLi. The mixture was then immersed in an oil
bath at 70 °C and allowed to stir for 2.5 h to afford a white slurry. The
mixture was then cooled to rt, and 2.2 mL of THF was charged to afford
a homogeneous solution. In a second crimp-cap vial with stir-bar was
charged solid ZnBr2 (754 mg, 3.35 mmol) under N2. To the agitated
ZnBr2 at rt was charged the aryllithium solution by canula transfer. The
resulting mixture was allowed to stir for 15 min before use. To a 1-dram
vial with stir-bar were charged triflate 1a (500 mg, 1.40 mmol),
Pd2(dba)3 (25.6 mg, 0.0280 mmol), and rac-BI-DIME (36.9 mg, 0.112
mmol). The vial was capped with a septum cap and inerted with N2
using vacuum-purge cycles (3×). THF (1.0 mL) was then added, and
the mixture was allowed to stir for 10 min. The catalyst/triflate solution
was then transferred to the ArZnBr solution using cannula transfer. The
residue in the vial was rinsed with an additional 0.4 mL of THF. The
final mixture was then immersed in an oil bath at 70 °C and monitored
by UPLC. After the time given in Table 1, the reaction was cooled to rt
and quenched with 8 mL of 2 M HCl. THF was removed in vacuo, and
CH2Cl2 (10 mL) was then added. The layers were separated, and the
aqueous phase was extracted with CH2Cl2 (1 × 10 mL). Combined
organics were washed with 20% citric acid (2 × 8 mL), dried with
Na2SO4, and concentrated in vacuo. Purification of the crude mixture
by flash chromatography (gradient, 30 to 70 to 90% EtOAc in hexanes)
afforded 423 mg (75%) of 3c as a white solid. Mp 77−80 °C; Rf = 0.33
1
(100% EtOAc); H NMR (500 MHz, CDCl3) δ 7.43 (t, J = 7.9 Hz,
1H), 7.20 (t, J = 8.4 Hz, 1H), 6.85 (dd, J = 8.3 Hz, J = 3.4 Hz, 1H), 6.83
(dd, J = 7.6 Hz, J = 3.3 Hz, 1H), 6.56 (d, J = 8.4 Hz, 1H), 6.47 (d, J = 8.4
Hz, 1H), 4.50 (sept, J = 6.1 Hz, 1H), 4.47 (sept, J = 6.1 Hz, 1H), 4.48
D
DOI: 10.1021/acs.joc.5b02649
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The Journal of Organic Chemistry
Note
by flash chromatography (gradient, 50% to 100% EtOAc in hexanes)
afforded 304 mg (75%) of 3e as a white solid. Spectral data was in
complete agreement with the published data.14 Mp 217−219 °C.
(R)-3-(tert-Butyl)-4-mesityl-2H-benzo[d][1,3]oxaphosphole 3-
Oxide (3f). To a 25 mL 2-neck round-bottom flask with magnetic
stir-bar and fitted with a reflux condenser with a short-path distillation
head at the top of the condenser under N2 was charged 0.31 mL (408
mg, 2.05 mmol) of 2-bromomesitylene. THF (2.5 mL) was then
charged, and the solution was cooled to −78 °C in a dry ice acetone
bath. t-BuLi (1.5 M in pentane, 2.67 mL, 4.0 mmol) was then added
dropwise over 10 min. The resulting yellow slurry was stirred at −78 °C
for 5 min and then allowed to warm to rt and stirred for an additional
10 min before use. In a separate flask was prepared a solution of ZnBr2
(540 mg, 2.4 mmol) in 1.8 mL of THF. This solution was then
transferred by cannula to the aryllithium reagent at rt, and the mixture
was allowed to stir for an additional 15 min. To a 1-dram vial with stir-
bar were charged triflate 1a (358 mg, 1.00 mmol), Pd2(dba)3 (18.3 mg,
0.0200 mmol), and rac-BI-DIME (26.4 mg, 0.0800 mmol). The vial
was capped with a septum cap and inerted with N2 using vacuum-purge
cycles (3×). THF (1.0 mL) was then added, and the mixture was
allowed to stir for 10 min. The catalyst/triflate solution was then
transferred to the ArZnBr solution using cannula transfer. The residue
in the vial was rinsed with an additional 0.25 mL of THF. The final
mixture was then immersed in an oil bath at 70 °C and monitored by
UPLC. Note that during the reaction pentane was distilled off via the
short-path distillation head. After the time given in Table 1, the reaction
was cooled to rt and quenched with 5 mL of 2 M HCl. THF was
removed in vacuo, and CH2Cl2 (5 mL) was then added. The layers
were separated, and the aqueous phase was extracted with CH2Cl2 (1 ×
5 mL). Combined organics were washed with 20% citric acid (2 × 5
mL), dried with Na2SO4, and concentrated in vacuo. Purification of the
crude mixture by flash chromatography (gradient, 30 to 70 to 90%
EtOAc in hexanes) afforded 122 mg (37%) of 3f as an off-white solid.
with 20% citric acid (2 × 5 mL), dried with Na2SO4, and concentrated
in vacuo. Purification of the crude mixture by flash chromatography
(gradient, 20−50% EtOAc in hexanes) afforded 174 mg (83%) of 3g as
an orange solid. Mp 140−143 °C; Rf = 0.21 (50% EtOAc/hexanes); 1H
NMR (500 MHz, CDCl3) δ 7.42 (t, J = 8.0 Hz, 1H), 7.137 (t, J = 8.5
Hz, 1H), 6.90 (dd, J = 8.3 Hz, J = 3.9 Hz, 1H), 6.75 (dd, J = 7.2 Hz, J =
3.3 Hz, 1H), 6.58 (d, J = 8.3 Hz, 1H), 6.22 (d, J = 8.3 Hz, 1H), 4.63 (dd,
J = 14 Hz, J = 11 Hz, 1H), 4.55 (d, J = 14 Hz, 1H), 4.47 (sept, J = 6.1
Hz, 1H), 4.29 (m, 1H), 4.26 (m, 1H), 4.22 (s, 5H), 4.09 (m, 1H), 3.98
(m, 1H), 3.89 (sept, J = 6.1 Hz, 1H), 1.23 (d, J = 6.1 Hz, 3H), 1.18 (d, J
= 6.1 Hz, 3H), 0.95 (d, J = 6.1 Hz, 3H), 0.75 (d, J = 3H); 31P{1H}NMR
(202 MHz, CDCl3) δ 40.1 ppm; 13C{1H}NMR (100 MHz, CDCl3) δ
163.6 (d, JC−P = 22.1 Hz), 157.6, 156.0, 139.0 (d, JC−P = 6.0 Hz), 133.8
(d, JC−P = 1.2 Hz), 128.9, 124.2 (d, JC−P = 8.7 Hz), 118.9 (d, JC−P = 108
Hz), 118.6 (d, JC−P = 3.2 Hz), 111.7 (d, JC−P = 6.2 Hz), 106.0, 105.3,
73.16 (d, JC−P = 12.1 Hz), 71.80 (d, JC−P = 11.1 Hz), 71.24, 71.18 (d,
JC−P = 13.1 Hz), 70.05 (d, JC−P = 17.1 Hz), 69.68, 69.42 (d, JC−P = 123
Hz), 69.31, 69.12 (d, JC−P = 73 Hz), 22.57, 22.54, 22.16, 21.52;
HRMS(EI) m/z calcd for C29H32FeO4P [M + H]+ 531.1388, found
531.1388.
(R)-4-(2,6-Diphenoxyphenyl)-3-(ferrocenyl)-2H-benzo[d][1,3]-
oxaphosphole 3-Oxide (3h). A crimp-cap vial with magnetic stir-bar
was charged with 237 mg (0.905 mmol) of 1,3-diphenoxybenzene. The
vial was sealed with a crimp-cap septum and inerted with N2 using
vacuum-purge cycles (3×). To the vial was sequentially charged 0.45
mL of hexanes and 0.32 mL (2.55M, 0.82 mmol) of n-BuLi. The
mixture then immersed in an oil bath at 70 °C and allowed to stir for
2.5 h to afford a white slurry. The mixture was then cooled to rt, and 0.6
mL of THF was charged to afford a homogeneous solution. In a second
crimp-cap vial with stir-bar was charged solid ZnBr2 (222 mg, 0.987
mmol) under N2. To the agitated ZnBr2 at rt was charged the
aryllithium solution by canula transfer. The resulting mixture was
allowed to stir for 15 min before use. To a 1-dram vial with stir-bar were
charged triflate 1b (200 mg, 0.411 mmol), Pd2(dba)3 (1.9 mg, 0.0020
mmol), and rac-BI-DIME (2.7 mg, 0.0080 mmol). The vial was capped
with a septum cap and inerted with N2 using vacuum-purge cycles
(3×). THF (1.0 mL) was then added, and the mixture was sonicated for
2 min and then allowed to stir for 10 min. The catalyst/triflate slurry
was then transferred to the ArZnBr solution using cannula transfer. The
residue in the vial was rinsed with an additional 0.5 mL of THF. The
final mixture was then immersed in an oil bath at 70 °C and monitored
by UPLC. After the time given in Table 1, the reaction was cooled to rt
and quenched with 5 mL of 2 M HCl. THF was removed in vacuo, and
CH2Cl2 (5 mL) was then added. The layers were separated, and the
aqueous phase was extracted with CH2Cl2 (1 × 5 mL). Combined
organics were washed with 20% citric acid (2 × 5 mL), dried with
Na2SO4, and concentrated in vacuo. Purification of the crude mixture
by flash chromatography (gradient, 20−50% EtOAc in hexanes)
afforded 186 mg (75%) of 3h as an orange solid. Mp 225−228 °C; Rf =
0.23 (50% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.29−7.35
(m, 3H), 7.22−7.27 (m, 2H), 7.15 (t, J = 8.1 Hz, 2H), 7.05−7.12 (m,
2H), 6.96 (t, J = 7.3 Hz, 1H), 6.90 (dd, J = 8.3 Hz, J = 3.5 Hz, 1H), 6.80
(dd, J = 7.6 Hz, J = 3.7 Hz, 1H), 6.58 (d, J = 7.8 Hz, 2H), 6.52 (d, J = 8.1
Hz, 1H), 6.30 (d, J = 8.2 Hz, 1H), 4.72 (dd, J = 14 Hz, J = 11 Hz, 1H),
4.66 (d, J = 14 Hz, 1H), 4.49 (m, 1H), 4.42 (m, 1H), 4.30 (m, 1H), 4.29
(s, 5H), 4.16 (m, 1H); 31P{1H}NMR (202 MHz, CDCl3) δ 40.6 ppm;
13C{1H}NMR (100 MHz, CDCl3) δ 163.9 (d, JC−P = 22.1 Hz), 157.9,
1
Mp 135−138 °C; Rf = 0.22 (70% EtOAc/hexanes); H NMR (500
MHz, CDCl3) δ 7.49 (t, J = 8.0 Hz, 1H), 6.97 (s, 1H), 6.94 (dd, J = 8.2
Hz, J = 3.3 Hz, 1H), 6.88 (s, 1H), 6.80 (dd, J = 7.1 Hz, J = 3.3 Hz, 1H),
4.51 (dd, J = 14 Hz, J = 2.7 Hz, 1H), 4.38 (dd, J = 14 Hz, J = 11 Hz,
1H), 2.29 (s, 3H), 2.21 (s, 3H), 2.05 (s, 3H), 0.90 (d, J = 16 Hz, 9H);
31P{1H}NMR (162 MHz, CDCl3) δ 62.6 ppm; 13C{1H}NMR (100
MHz, CDCl3) δ 166.1 (d, JC−P = 19.3 Hz), 144.3 (d, JC−P = 6.5 Hz),
137.7, 137.6, 136.7 (d, JC−P = 1.9 Hz), 135.1, 134.6 (d, JC−P = 1.7 Hz),
128.9, 127.9, 124.2 (d, JC−P = 8.5 Hz), 113.7 (d, JC−P = 89.4 Hz), 112.6
(d, JC−P = 5.3 Hz), 65.73 (d, JC−P = 61.0 Hz), 33.41 (d, JC−P = 71.9 Hz),
23.94, 21.08, 21.01, 20.94; HRMS(EI) m/z calcd for C20H26O2P [M +
H]+ 329.1670, found 329.1670.
(R)-4-(2,6-Diisopropoxyphenyl)-3-(ferrocenyl)-2H-benzo[d][1,3]-
oxaphosphole 3-Oxide (3g). A crimp-cap vial with magnetic stir-bar
was sealed with a crimp-cap septum and inerted with N2 using vacuum-
purge cycles (3×). The vial was sequentially charged with 0.18 mL
(0.87 mmol) of 1,3-diisopropoxybenzene, 0.45 mL of hexanes, and 0.31
mL (2.55M, 0.79 mmol) of n-BuLi. The mixture then immersed in an
oil bath at 70 °C and allowed to stir for 2.5 h to afford a white slurry.
The mixture was then cooled to rt, and 0.6 mL of THF was charged to
afford a homogeneous solution. In a second crimp-cap vial with stir-bar
was charged solid ZnBr2 (214 mg, 0.952 mmol) under N2. To the
agitated ZnBr2 at rt was charged the aryllithium solution by canula
transfer. The resulting mixture was allowed to stir for 15 min before
use. To a 1-dram vial with stir-bar were charged triflate 1b (193 mg,
0.397 mmol), Pd2(dba)3 (7.3 mg, 0.0080 mmol), and rac-BI-DIME
(10.5 mg, 0.0318 mmol). The vial was capped with a septum cap and
inerted with N2 using vacuum-purge cycles (3×). THF (1.0 mL) was
then added, and the mixture was sonicated for 2 min and then allowed
to stir for 10 min. The catalyst/triflate slurry was then transferred to the
ArZnBr solution using cannula transfer. The residue in the vial was
rinsed with an additional 0.5 mL of THF. The final mixture was then
immersed in an oil bath at 70 °C and monitored by UPLC. After the
time given in Table 1, the reaction was cooled to rt and quenched with
5 mL of 2 M HCl. THF was removed in vacuo, and CH2Cl2 (5 mL) was
then added. The layers were separated, and the aqueous phase was
extracted with CH2Cl2 (1 × 5 mL). Combined organics were washed
156.9, 156.3, 155.6, 136.2 (d, JC−P = 5.8 Hz), 134.2 (d, JC−P = 1.2 Hz),
129.6, 129.3, 129.2, 123.94, 123.93 (d, JC−P = 8.2 Hz), 123.0, 121.2,
120.9 (d, JC−P = 3.2 Hz), 119.1, 119.0 (d, JC−P = 107 Hz), 113.0 (d, JC−P
= 6.0 Hz), 111.5, 110.9, 73.47 (d, JC−P = 11.7 Hz), 72.39 (d, JC−P = 11.4
Hz), 71.57 (d, JC−P = 11.1 Hz), 70.31 (d, JC−P = 16.3 Hz), 69.46, 69.41
(d, JC−P = 73 Hz), 69.28 (d, JC−P = 122 Hz); HRMS(EI) m/z calcd for
C35H28FeO4P [M + H]+ 599.1075, found 599.1077.
(R)-4-(Anthracen-9-yl)-3-(ferrocenyl)-2H-benzo[d][1,3]-
oxaphosphole 3-Oxide (3i). To a 15 mL 2-neck round-bottom flask
with magnetic stir-bar fitted with a reflux condenser with a short-path
distillation head at the top of the condenser was charged 209 mg (0.813
mmol) of 9-bromoanthracene. The second neck of the flask was capped
with a septum, and the system was inerted with N2 using vacuum-purge
E
DOI: 10.1021/acs.joc.5b02649
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The Journal of Organic Chemistry
Note
cycles (3×). THF (1.0 mL) was then charged, and the solution was
cooled to −78 °C in a dry ice acetone bath. t-BuLi (1.5 M in pentane,
1.1 mL, 1.6 mmol) was then added dropwise over 10 min. The resulting
yellow slurry was stirred at −78 °C for 5 min and then allowed to warm
to rt and stirred for an additional 10 min before use. In a separate flask
was prepared a solution of ZnBr2 (214 mg, 0.952 mmol) in 0.72 mL of
THF. This solution was then transferred by cannula to the aryllithium
reagent at rt, and the mixture was allowed to stir for an additional 15
min. To a 1-dram vial with stir-bar were charged triflate 1b (193 mg,
0.397 mmol), Pd2(dba)3 (3.6 mg, 0.0039 mmol), and rac-BI-DIME
(5.2 mg, 0.016 mmol). The vial was capped with a septum cap and
inerted with N2 using vacuum-purge cycles (3×). THF (1.0 mL) was
then added, and the mixture was sonicated for 2 min and then allowed
to stir for 10 min. The catalyst/triflate slurry was then transferred to the
ArZnBr solution using cannula transfer. The residue in the vial was
rinsed with an additional 0.5 mL of THF. The final mixture was then
immersed in an oil bath at 70 °C and monitored by UPLC. Note that
during the reaction pentane was distilled off via the short-path
distillation head. After the time given in Table 1, the reaction was
cooled to rt and quenched with 5 mL of 2 M HCl. THF was removed in
vacuo, and CH2Cl2 (5 mL) was then added. The layers were separated,
and the aqueous phase was extracted with CH2Cl2 (1 × 5 mL).
Combined organics were washed with 20% citric acid (2 × 5 mL), dried
with Na2SO4, and concentrated in vacuo. Purification of the crude
mixture by flash chromatography (gradient, 20−50% EtOAc in
hexanes) afforded 130 mg (64%) of 3i as an orange solid. Mp > 300
°C; Rf = 0.35 (75% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ
8.44 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.61−
7.67 (m, 2H), 7.38−7.49 (m, 2H), 7.17−7.22 (m, 1H), 7.16 (dd, J = 8.2
Hz, J = 3.6 Hz, 1H), 6.99 (dd, J = 7.2 Hz, J = 3.5 Hz, 1H), 6.77−6.86
(m, 2H), 4.64 (dd, J = 14 Hz, J = 12 Hz, 1H), 4.53 (dd, J = 14 Hz, J =
1.7 Hz, 1H), 4.04 (s, 5H), 4.03 (m, 1H), 3.83 (m, 1H), 3.69 (m, 1H),
2.94 (m, 1H); 31P{1H}NMR (202 MHz, CDCl3) δ 39.8 ppm;
13C{1H}NMR (100 MHz, CDCl3) δ 164.0 (d, JC−P = 21.9 Hz), 141.6
3.8 Hz, 1H), 6.86 (dd, J = 7.2 Hz, J = 3.5 Hz, 1H), 6.61 (d, J = 8.4 Hz,
1H), 6.08 (d, J = 8.4 Hz, 1H), 4.66 (dd, J = 14 Hz, J = 11 Hz, 1H), 4.48
(d, J = 14 Hz, 1H), 3.80 (s, 3H), 2.99 (s, 3H); 31P{1H}NMR (202
MHz, CDCl3) δ 38.4 ppm; 13C{1H}NMR (100 MHz, CDCl3) δ 165.6
(d, JC−P = 21.7 Hz), 158.5, 156.6, 138.7 (d, JC−P = 6.2 Hz), 135.1 (d,
JC−P = 1.4 Hz), 131.4 (d, JC−P = 3.0 Hz), 131.2 (d, JC−P = 107 Hz),
131.1 (d, JC−P = 10.8 Hz), 129.7, 128.0 (d, JC−P = 13.0 Hz), 124.5 (d,
JC−P = 8.6 Hz), 116.8 (d, JC−P = 106 Hz), 112.4 (d, JC−P = 6.2 Hz),
104.0, 102.3, 70.24 (d, JC−P = 69 Hz), 56.17, 54.64; HRMS(EI) m/z
calcd for C21H20O4P [M + H]+ 367.1099, found 367.1101.
(R)-4-(2,6-Diisopropoxyphenyl)-3-(phenyl)-2H-benzo[d][1,3]-
oxaphosphole 3-Oxide (3k). A crimp-cap vial with magnetic stir-bar
was sealed with a crimp-cap septum and inerted with N2 using vacuum-
purge cycles (3×). The vial was sequentially charged with 0.44 mL (2.2
mmol) of 1,3-diisopropoxybenzene, 1.1 mL of hexanes, and 0.78 mL
(2.55M, 2.0 mmol) of n-BuLi. The mixture was then immersed in an oil
bath at 70 °C and allowed to stir for 2.5 h to afford a white slurry. The
mixture was then cooled to rt, and 1.6 mL of THF was charged to afford
a homogeneous solution. In a second crimp-cap vial with stir-bar was
charged solid ZnBr2 (540 mg, 2.40 mmol) under N2. To the agitated
ZnBr2 at rt was charged the aryllithium solution by canula transfer. The
resulting mixture was allowed to stir for 15 min before use. To a 1-dram
vial with stir-bar were charged triflate 1c (378 mg, 1.00 mmol),
Pd2(dba)3 (18.3 mg, 0.0200 mmol), and rac-BI-DIME (26.4 mg,
0.0800 mmol). The vial was capped with a septum cap and inerted with
N2 using vacuum-purge cycles (3×). THF (0.71 mL) was then added,
and the mixture was allowed to stir for 10 min. The catalyst/triflate
solution was then transferred to the ArZnBr solution using cannula
transfer. The residue in the vial was rinsed with an additional 0.3 mL of
THF. The final mixture was then immersed in an oil bath at 70 °C and
monitored by UPLC. After the time given in Table 1, the reaction was
cooled to rt and quenched with 5 mL of 2 M HCl. THF was removed in
vacuo, and CH2Cl2 (5 mL) was then added. The layers were separated,
and the aqueous phase was extracted with CH2Cl2 (1 × 5 mL). The
combined organics were washed with 20% citric acid (2 × 5 mL), dried
with Na2SO4, and concentrated in vacuo. Purification of the crude
mixture by flash chromatography (gradient, 20−50% EtOAc in
hexanes) afforded 330 mg (78%) of 3k as a clear glass. Rf = 0.20
(50% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.50 (t, J = 7.9
Hz, 1H), 7.31−7.41 (m, 3H), 7.24−7.29 (m, 2H), 7.07 (t, J = 8.4 Hz,
1H), 6.98 (dd, J = 8.4 Hz, J = 3.8 Hz, 1H), 6.81 (dd, J = 7.4 Hz, J = 3.6
Hz, 1H), 6.55 (d, J = 8.4 Hz, 1H), 6.07 (d, J = 8.4 Hz, 1H), 4.61 (dd, J =
14 Hz, J = 11 Hz, 1H), 4.47 (sept, J = 6.1 Hz, 1H) 4.46 (d, J = 14 Hz,
1H), 3.88 (sept, J = 6.1 Hz, 1H), 1.30 (d, J = 6.1 Hz, 3H), 1.19 (d, J =
6.1 Hz, 3H), 0.95 (d, J = 6.1 Hz, 3H), 0.71 (d, J = 6.1 Hz, 3H);
31P{1H}NMR (202 MHz, CDCl3) δ 37.9 ppm; 13C{1H}NMR (100
(d, JC−P = 6.3 Hz), 134.8 (d, JC−P = 1.2 Hz), 132.4 (d, JC−P = 3.1 Hz),
131.1, 130.7, 129.7, 128.0, 127.8, 127.2, 127.1, 126.1, 125.7, 125.6,
125.0, 124.6 (d, JC−P = 8.3 Hz), 124.5, 119.9 (d, JC−P = 106 Hz), 113.3
(d, JC−P = 5.8 Hz), 72.06 (d, JC−P = 11.8 Hz), 71.95 (d, JC−P = 11.8 Hz),
71.63 (d, JC−P = 11.3 Hz), 69.40 (d, JC−P = 16.7 Hz), 69.08, 69.03 (d,
JC−P = 73 Hz), 67.41 (d, JC−P = 124 Hz); HRMS(EI) m/z calcd for
C31H24FeO2P [M + H]+ 515.0863, found 515.0864.
(R)-4-(2,6-Dimethoxyphenyl)-3-(phenyl)-2H-benzo[d][1,3]-
oxaphosphole 3-Oxide (3j). A crimp-cap vial with magnetic stir-bar
was sealed with a crimp-cap septum and inerted with N2 using vacuum-
purge cycles (3×). To the vial was charged 0.28 mL (2.1 mmol) of 1,3-
dimethoxybenzene followed by 1.8 mL of THF. The mixture was
cooled in an ice-bath, and 0.78 mL (2.55 M, 2.0 mmol) of n-BuLi was
charged dropwise over 5 min. The mixture was then warmed to rt and
allowed to stir for 2 h. In a second crimp-cap vial was prepared a slurry
of ZnBr2 (540 mg, 2.40 mmol) in 0.89 mL of THF. To the ZnBr2
mixture cooled in an ice-bath was charged the aryllithium solution by
canula transfer. The resulting mixture was then warmed to rt and
allowed to stir for 15 min before use. In a third crimp-cap vial with stir-
bar were charged triflate 1c (378 mg, 1.00 mmol), Pd2(dba)3 (4.6 mg,
0.0050 mmol), and rac-BI-DIME (6.6 mg, 0.020 mmol). The mixture
was inerted with N2 using vacuum-purge cycles (3×). THF (0.71 mL)
was then added, and the mixture was allowed to stir for 10 min. The
ArZnBr solution was then transferred to the catalyst/triflate solution
using cannula transfer. The final mixture was then immersed in an oil
bath at 70 °C and monitored by UPLC. After the time given in Table 1,
the reaction was cooled to rt and quenched with 5 mL of 2 M HCl.
THF was removed in vacuo, and CH2Cl2 (5 mL) was then added. The
layers were separated, and the aqueous phase was extracted with
CH2Cl2 (1 × 5 mL). Combined organics were washed with 20% citric
acid (2 × 5 mL), dried with Na2SO4, and concentrated in vacuo.
Purification of the crude mixture by flash chromatography (gradient,
50−80% EtOAc in hexanes) afforded 308 mg (84%) of 3j as a white
MHz, CDCl3) δ 165.1 (d, JC−P = 21.7 Hz), 157.4, 155.7, 139.8 (d, JC−P
= 6.1 Hz), 134.4 (d, JC−P = 1.4 Hz), 131.6 (d, JC−P = 74.1 Hz), 131.4 (d,
JC−P = 3.0 Hz), 131.0 (d, JC−P = 10.7 Hz), 129.1, 127.9 (d, JC−P = 12.9
Hz), 124.8 (d, JC−P = 8.7 Hz), 118.2 (d, JC−P = 3.2 Hz), 116.7 (d, JC−P
107 Hz), 111.7 (d, JC−P = 6.2 Hz), 105.8, 104.9, 77.16, 69.95 (d, JC−P
=
=
69 Hz), 69.64, 22.30, 22.18, 22.13, 21.60; HRMS(EI) m/z calcd for
C25H28O4P [M + H]+ 423.1725, found 423.1722.
(R)-4-(2,6-Diphenoxyphenyl)-3-(phenyl)-2H-benzo[d][1,3]-
oxaphosphole 3-Oxide (3l). A crimp-cap vial with magnetic stir-bar
was charged with 577 mg (2.20 mmol) of 1,3-diphenoxybenzene. The
vial was sealed with a crimp-cap septum and inerted with N2 using
vacuum-purge cycles (3×). To the vial were sequentially charged 1.1
mL of hexanes and 0.78 mL (2.55M, 2.0 mmol) of n-BuLi. The mixture
then immersed in an oil bath at 70 °C and allowed to stir for 2.5 h to
afford a white slurry. The mixture was then cooled to rt, and 1.6 mL of
THF was charged to afford a homogeneous solution. In a second
crimp-cap vial with stir-bar was charged solid ZnBr2 (754 mg, 3.35
mmol) under N2. To the agitated ZnBr2 at rt was charged the
aryllithium solution by canula transfer. The resulting mixture was
allowed to stir for 15 min before use. To a 1-dram vial with stir-bar were
charged triflate 1c (378 mg, 1.00 mmol), Pd2(dba)3 (4.6 mg, 0.0050
mmol), and rac-BI-DIME (6.6 mg, 0.020 mmol). The vial was capped
with a septum cap and inerted with N2 using vacuum-purge cycles
(3×). THF (0.71 mL) was then added, and the mixture was allowed to
1
solid. Mp 175−177 °C; Rf = 0.20 (80% EtOAc/hexanes); H NMR
(500 MHz, CDCl3) δ 7.55 (t, J = 7.9 Hz, 1H), 7.42 (t, J = 7.1 Hz, 1H),
7.27−7.39 (m, 4H), 7.16 (t, J = 8.4 Hz, 1H), 7.03 (dd, J = 8.5 Hz, J =
F
DOI: 10.1021/acs.joc.5b02649
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The Journal of Organic Chemistry
Note
stir for 10 min. The catalyst/triflate solution was then transferred to the
ArZnBr solution using cannula transfer. The residue in the vial was
rinsed with an additional 0.3 mL of THF. The final mixture was then
immersed in an oil bath at 70 °C and monitored by UPLC. After the
time given in Table 1, the reaction was cooled to rt and quenched with
5 mL of 2 M HCl. THF was removed in vacuo, and CH2Cl2 (5 mL) was
then added. The layers were separated, and the aqueous phase was
extracted with CH2Cl2 (1 × 5 mL). The combined organics were
washed with 20% citric acid (2 × 5 mL), dried with Na2SO4, and
concentrated in vacuo. Purification of the crude mixture by flash
chromatography (gradient, 20−50% EtOAc in hexanes) afforded 357
mg (73%) of 3l as a white solid. Mp 215−225 °C; Rf = 0.27 (50%
EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.47−7.57 (m, 3H),
7.44 (t, J = 7.9 Hz, 1H), 7.38 (td, J = 7.7 Hz, J = 3.2 Hz, 2H), 7.29−7.35
(m, 4H), 7.08−7.17 (m, 3H), 6.94−7.05 (m, 3H), 6.90 (dd, J = 7.2 Hz,
J = 3.4 Hz, 1H), 6.49 (dd, J = 8.9 Hz, J = 0.7 Hz, 1H), 6.41 (d, J = 8.3
Hz, 2H), 6.14 (dd, J = 8.2 Hz, J = 0.6 Hz, 1H), 4.69 (dd, J = 14 Hz, J =
11 Hz, 1H), 4.53 (dd, J = 14 Hz, J = 0.7 Hz, 1H); 31P{1H}NMR (202
MHz, CDCl3) δ 38.7 ppm; 13C{1H}NMR (100 MHz, CDCl3) δ 165.5
(d, JC−P = 21.6 Hz), 157.9, 156.7, 156.2, 155.3, 137.2 (d, JC−P = 6.0 Hz),
134.9 (d, JC−P = 1.3 Hz), 131.9 (d, JC−P = 2.9 Hz), 131.5 (d, JC−P = 106
Hz), 69.74 (d, JC−P = 69 Hz); HRMS(EI) m/z calcd for C27H20O2P [M
+ H]+ 407.1201, found 407.1205.
(S)-4-(2,6-Dimethoxyphenyl)-3-(ferrocenyl)-2,3-dihydrobenzo[d]-
[1,3]oxaphosphole (5a). To a 5 mL Schlenk flask with magnetic stir-
bar was charged 275 mg (0.580 mmol) of oxide 3b. A reflux condenser
was added, and the reaction was inerted with Ar using vacuum-purge
cycles. Toluene (1.6 mL) was charged followed by triethylamine (0.16
mL, 1.2 mmol) and HSiCl3 (0.088 mL, 0.87 mmol). The mixture was
then immersed in an oil bath at 55 °C and monitored by 31P NMR
spectroscopy. After 2 h, the reaction was cooled to rt and quenched
with 2 mL of degassed (Ar sparge) 30% NaOH. The mixture was then
allowed to vigorously stir at rt for 1 h. The aqueous layer was removed
and subsequently extracted under Ar with MeTHF (2 × 2 mL)
followed by CH2Cl2 (2 × 2 mL). The combined organics were dried
with MgSO4, filtered quickly through a pad of Celite, and immediately
concentrated in vacuo. The crude residue was chromatographed on the
bench by dissolving the crude solid in CH2Cl2 and loading the mixture
onto a short pad of silica gel and eluting with degassed (Ar sparge)
hexanes/EtOAc (10−50%) using Ar to pressurize the flash column.
The product fractions were immediately collected and concentrated in
vacuo to afford 135 mg (51%) of 5a as a yellow-orange solid. Mp 195−
197 °C; Rf = 0.34 (20% EtOAc/hexanes); 1H NMR (500 MHz,
CD2Cl2) δ 7.33 (t, J = 8.4 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 6.87 (d, J =
8.1 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.67 (dd, J = 7.3 Hz, J = 3.2 Hz,
1H), 6.54 (d, J = 8.4 Hz, 1H), 5.19 (dd, J = 12 Hz, J = 3.1 Hz, 1H), 4.79
(dd, J = 31 Hz, J = 12 Hz, 1H), 4.20 (s, 1H), 4.16 (s, 1H), 4.13 (s, 1H),
4.08 (s, 5H), 3.79 (s, 3H), 3.68 (s, 1H), 3.35 (s, 3H); 31P{1H}NMR
(202 MHz, CD2Cl2) δ −42.4 ppm; 13C{1H}NMR (126 MHz, CD2Cl2)
δ 162.8, 158.8, 158.1, 138.7 (d, JC−P = 19.2 Hz), 131.1, 129.9, 129.4 (d,
JC−P = 6.8 Hz), 123.8 (d, JC−P = 3.7 Hz), 119.7, 110.7 (d, JC−P = 1.0
Hz), 104.7, 104.4, 78.44 (d, JC−P = 22.4 Hz), 74.97 (d, JC−P = 31.8 Hz),
74.77 (d, JC−P = 20.6 Hz), 71.32, 70.73 (d, JC−P = 7.2 Hz), 69.72 (d,
JC−P = 2.8 Hz), 69.42 (d, JC−P = 0.9 Hz), 56.67 (d, JC−P = 1.0 Hz),
56.09; HRMS(EI) m/z calcd for C25H24FeO4P [M + O + H]+
475.0762, found 475.0785.
Hz), 131.3 (d, JC−P = 10.8 Hz), 129.6, 129.4, 129.3, 128.4 (d, JC−P
13.0 Hz), 124.5 (d, JC−P = 8.5 Hz), 124.1, 123.1, 121.4, 120.3 (d, JC−P
=
=
3.2 Hz), 119.0, 116.5 (d, JC−P = 105 Hz), 113.0 (d, JC−P = 6.1 Hz),
111.0, 110.6, 70.14 (d, JC−P = 69 Hz); HRMS(EI) m/z calcd for
C31H24O4P [M + H]+ 491.1412, found 491.1417.
(R)-4-(Anthracen-9-yl)-3-(phenyl)-2H-benzo[d][1,3]oxaphosphole
3-Oxide (3m). To a 25 mL 2-neck round-bottom flask with magnetic
stir-bar fitted with a reflux condenser with a short-path distillation head
at the top of the condenser was charged 450 mg (1.75 mmol) of 9-
bromoanthracene. The second neck of the flask was capped with a
septum, and the system was inerted with N2 using vacuum-purge cycles
(3×). THF (1.6 mL) was then charged, and the solution was cooled to
−78 °C in a dry ice acetone bath. t-BuLi (1.5 M in pentane, 2.27 mL,
3.4 mmol) was then added dropwise over 10 min. The resulting yellow
slurry was stirred at −78 °C for 5 min and then allowed to warm to rt
and stirred for an additional 10 min before use. In a separate flask was
prepared a solution of ZnBr2 (450 mg, 2.0 mmol) in 1.5 mL of THF.
This solution was then transferred by cannula to the aryllithium reagent
at rt, and the mixture was allowed to stir for an additional 15 min. To a
1-dram vial with stir-bar were charged triflate 1c (378 mg, 1.00 mmol),
Pd2(dba)3 (4.6 mg, 0.0050 mmol), and rac-BI-DIME (6.6 mg, 0.020
mmol). The vial was capped with a septum cap and inerted with N2
using vacuum-purge cycles (3×). THF (0.5 mL) was then added, and
the mixture was allowed to stir for 10 min. The catalyst/triflate solution
was then transferred to the ArZnBr solution using cannula transfer. The
residue in the vial was rinsed with an additional 0.25 mL of THF. The
final mixture was then immersed in an oil bath at 70 °C and monitored
by UPLC. Note that during the reaction pentane was distilled off via the
short-path distillation head. After the time given in Table 1, the reaction
was cooled to rt and quenched with 5 mL of 2 M HCl. THF was
removed in vacuo, and CH2Cl2 (5 mL) was then added. The layers
were separated, and the aqueous phase was extracted with CH2Cl2 (1 ×
5 mL). Combined organics were washed with 20% citric acid (2 × 5
mL), dried with Na2SO4, and concentrated in vacuo. Purification of the
crude mixture by flash chromatography (gradient, 20−50% EtOAc in
hexanes) afforded 300 mg (74%) of 3m as an off-white solid. Mp 205−
208 °C; Rf = 0.31 (75% EtOAc/hexanes); 1H NMR (500 MHz,
CDCl3) δ 8.39 (s, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 8.5 Hz,
1H), 7.70 (t, J = 8.1 Hz, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.42−7.51 (m,
2H), 7.22−7.26 (m, 1H), 7.00−7.16 (m, 3H), 6.79−6.90 (m, 4H),
6.71−6.77 (m, 2H), 4.68 (dd, J = 14 Hz, J = 11 Hz, 1H), 4.60 (dd, J =
14 Hz, J = 2.0 Hz, 1H); 31P{1H}NMR (202 MHz, CDCl3) δ 37.4 ppm;
13C{1H}NMR (100 MHz, CDCl3) δ 165.3 (d, JC−P = 21.4 Hz), 142.2
(S)-4-(2,6-Dimethoxyphenyl)-3-(phenyl)-2,3-dihydrobenzo[d]-
[1,3]oxaphosphole (5b). To a 5 mL Schlenk flask with magnetic stir-
bar was charged 200 mg (0.546 mmol) of oxide 3i. A reflux condenser
was added, and the reaction was inerted with Ar using vacuum-purge
cycles. Toluene (1.5 mL) was charged followed by triethylamine (0.15
mL, 1.1 mmol) and HSiCl3 (0.083 mL, 0.82 mmol). The mixture was
then immersed in an oil bath at 55 °C and monitored by 31P NMR
spectroscopy. After 2 h, the reaction was cooled to rt and quenched
with 2 mL of degassed (Ar sparge) 30% NaOH. The mixture was then
allowed to vigorously stir at rt for 30 min. The aqueous layer was
removed and subsequently extracted under Ar with MTBE (3 × 2 mL).
The combined organics were dried with MgSO4, filtered quickly
through a pad of Celite, and immediately concentrated in vacuo. The
crude residue was chromatographed on the bench by dissolving the
crude solid in CH2Cl2 and loading the mixture onto a short pad of silica
gel and eluting with degassed (Ar sparge) hexanes/EtOAc (10% to
30%) using Ar to pressurize the flash column. The product fractions
were immediately collected and concentrated in vacuo to afford 171 mg
(89%) of 5b as a white solid. Mp 80−82 °C; Rf = 0.56 (30% EtOAc/
1
hexanes); H NMR (500 MHz, CDCl3) δ 7.40 (t, J = 7.9 Hz, 1H),
7.13−7.26 (m, 6H), 7.02 (d, J = 31 Hz, 1H), 6.87 (dd, J = 7.0 Hz, J =
3.2 Hz, 1H), 6.64 (d, J = 8.3 Hz, 1H), 6.37 (d, J = 8.4 Hz, 1H), 4.65−
4.78 (m, 2H), 3.79 (s, 3H), 3.02 (s, 3H); 31P{1H}NMR (202 MHz,
CDCl3) δ −33.7 ppm; 13C{1H}NMR (100 MHz, CDCl3) δ 163.2,
157.6, 157.3, 139.0 (d, JC−P = 19.7 Hz), 138.3 (d, JC−P = 23.0 Hz), 132.3
(d, JC−P = 20.0 Hz), 131.2, 129.2, 128.8, 128.0 (d, JC−P = 7.1 Hz), 125.4
(d, JC−P = 3.6 Hz), 123.7 (d, JC−P = 4.1 Hz), 118.9 (d, JC−P = 2.2 Hz),
110.1, 104.0, 103.4, 75.46 (d, JC−P = 22.3 Hz), 56.06, 54.67; HRMS(EI)
m/z calcd for C21H20O3P [M + H]+ 351.1150, found 351.1141.
(S)-3-(tert-Butyl)-4-mesityl-2,3-dihydrobenzo[d][1,3]-
oxaphosphole (5c). To a 5 mL Schlenk flask with magnetic stir-bar was
charged 128 mg (0.390 mmol) of oxide 3f. A reflux condenser was
added, and the reaction was inerted with Ar using vacuum-purge cycles.
Toluene (1.5 mL) was charged followed by triethylamine (0.22 mL, 1.6
mmol) and HSiCl3 (0.12 mL, 1.2 mmol). The mixture was then
(d, JC−P = 6.6 Hz), 135.3 (d, JC−P = 1.2 Hz), 132.0 (d, JC−P = 3.1 Hz),
131.4 (d, JC−P = 3.1 Hz), 131.73 (d, JC−P = 56 Hz), 131.70, 130.2 (d,
JC−P = 10.7 Hz), 130.1, 129.1 (d, JC−P = 8.1 Hz), 128.0 (d, JC−P = 8.3
Hz), 127.82, 127.80, 127.4, 127.1, 125.8, 125.52, 125.48, 125.0 (d, JC−P
= 8.4 Hz), 124.9, 124.3, 118.3 (d, JC−P = 104 Hz), 113.3 (d, JC−P = 5.9
G
DOI: 10.1021/acs.joc.5b02649
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
immersed in an oil bath at 65 °C and monitored by 31P NMR
spectroscopy. After 3 h, the reaction was cooled to rt and quenched
with 2 mL of degassed (Ar sparge) 30% NaOH. The mixture was then
allowed to vigorously stir at rt for 1 h. The aqueous layer was removed
and subsequently extracted under Ar with MTBE (3 × 2 mL). The
combined organics were dried with MgSO4, filtered quickly through a
pad of Celite, and immediately concentrated in vacuo. The crude
residue was chromatographed on the bench by dissolving the crude in
hexanes and loading the mixture onto a short pad of silica gel and
eluting with degassed (Ar sparge) hexanes/EtOAc (neat hexane to 10%
EtOAc/hexanes) using Ar to pressurize the flash column. The product
fractions were immediately collected and concentrated in vacuo to
afford 108 mg (88%) of 5c as an off-white solid. Mp 65−67 °C; Rf =
0.64 (10% EtOAc/hexanes); 1H NMR (500 MHz, CD2Cl2) δ 7.22 (t, J
= 7.8 Hz, 1H), 6.84 (s, 1H), 6.81 (s, 1H), 6.79 (d, J = 8.5 Hz, 1H), 6.62
(dd, J = 7.5 Hz, J = 3.3 Hz, 1H), 4.77 (dd, J = 13 Hz, J = 2.1 Hz, 1H),
4.41 (dd, J = 26 Hz, J = 13 Hz, 1H), 2.22 (s, 3H), 2.05 (s, 3H), 2.02 (s,
3H), 0.67 (d, J = 12 Hz, 9H); 31P{1H}NMR (202 MHz, CD2Cl2) δ
(4) (a) Tang, W.; Capacci, A. G.; Wei, X.; Li, W.; White, A.; Patel, N.
D.; Savoie, J.; Gao, J. J.; Rodriguez, S.; Qu, B.; Haddad, N.; Lu, B. Z.;
Krishnamurthy, D.; Yee, N. K.; Senanayake, C. H. Angew. Chem., Int. Ed.
2010, 49, 5879. (b) Zhao, Q.; Li, C.; Senanayake, C. H.; Tang, W.
Chem. - Eur. J. 2013, 19, 2261−2265.
(5) (a) Tang, W.; Patel, N. D.; Xu, G.; Xu, X.; Savoie, J.; Ma, S.; Hao,
M.-H.; Keshipeddy, S.; Capacci, A. G.; Wei, X.; Zhang, Y.; Gao, J.; Li,
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W. J. Am. Chem. Soc. 2014, 136, 570. (c) Fandrick, K. R.; Li, W.; Zhang,
Y.; Tang, W.; Gao, J.; Rodriguez, S.; Patel, N. D.; Reeves, D. C.; Wu, J.
− P.; Sanyal, S.; Gonnella, N.; Qu, B.; Haddad, N.; Lorenz, J. C.; Sidhu,
K.; Wang, J.; Ma, S.; Grinberg, N.; Lee, H.; Tsantrizos, Y.; Poupart, M.
− A.; Busacca, C. A.; Yee, N. K.; Lu, B. Z.; Senanayake, C. H. Angew.
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(6) Reviews: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457−
2483. (b) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58,
9633−9695. (c) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011,
111, 1417−1492.
−8.3 ppm; 13C{1H}NMR (100 MHz, CD2Cl2) δ 164.2, 145.6 (d, JC−P
=
17.7 Hz), 138.5, 136.8, 135.8, 135.2, 130.9, 128.5, 128.3, 124.0 (d, JC−P
= 15.2 Hz), 123.0 (d, JC−P = 4.2 Hz), 109.4, 70.36 (d, JC−P = 26.0 Hz),
30.85 (d, JC−P = 19.4 Hz), 26.74 (d, JC−P = 14.2 Hz), 21.04, 20.75 (d,
JC−P = 11.3 Hz), 20.73; HRMS(EI) m/z calcd for C20H26OP [M + H]+
313.1721, found 313.1715.
(7) (a) Tang, W.; Qu, B.; Capacci, A. G.; Rodriguez, S.; Wei, X.;
Haddad, N.; Narayanan, B.; Ma, S.; Grinberg, N.; Yee, N. K.;
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General Procedure for Suzuki−Miyaura Cross Coupling
(Scheme 4). In a N2-filled glovebox, to a microwave vial with
magnetic stir-bar were charged 2.3 mg (0.0025 mmol) of Pd2(dba)3,
0.010 mmol of ligand, 318 mg (1.50 mmol) of K3PO4, and 149 mg
(0.750 mmol) of 2-bipheny boronic acid 9. The vial was sealed with a
crimp-cap septum and removed from the glovebox. Degassed (Ar
sparge) toluene (1.0 mL) and 0.127 mL (0.500 mmol) of bromide 8
were charged, and the vial was inserted into an oil bath at 100 °C.
Aliquots were removed by syringe and quenched in MeOH and
analyzed by UPLC. After complete consumption of the starting aryl
bromide, the reaction was cooled to rt and partitioned between water
and CH2Cl2. The organic layer was collected, dried with Na2SO4, and
concentrated in vacuo. The yield of the crude mixture was determined
by 1HNMR spectroscopy using dimethylfumarate as the analytical
standard.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02649.
1
Copies of H and 13C NMR spectra of the compounds
(PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: joshua.sieber@boehringer-ingelheim.com.
■
(14) Tang, W.; Keshipeddy, S.; Zhang, Y.; Wei, X.; Savoie, J.; Patel, N.
D.; Yee, N. K.; Senanayake, C. H. Org. Lett. 2011, 13, 1366−1369.
(15) (a) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461−
1473. (b) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L.
J. Am. Chem. Soc. 2005, 127, 4685−4696. (c) Walker, S. D.; Barder, T.
E.; Martinelli, J. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2004, 43,
1871−1876.
Notes
The authors declare no competing financial interest.
DEDICATION
■
This work is dedicated to the life and memory of Richard Joseph
Sieber and Mary Marcella “Chumly” Sieber.
(16) Li, K.; Hu, N.; Luo, R.; Yuan, W.; Tang, W. J. Org. Chem. 2013,
78, 6350−6355.
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H
DOI: 10.1021/acs.joc.5b02649
J. Org. Chem. XXXX, XXX, XXX−XXX