Nickel-catalyzed C-P cross-coupling of diphenylphosphine oxide with aryl chlorides

Article abstract of DOI:10.1039/c2ob26874d

A novel protocol for the preparation of various diarylphosphine oxide compounds via a Ni-catalyzed cross-coupling of aryl chlorides with R ₂P(O)H has been developed. Notably, this process exhibits the following very attractive features: (i) the process is simpler and operates under mild reaction conditions; (ii) the process is generally cheaper in part because the more accessible aryl chloride is used to form the C-P bond; (iii) the process avoids the need for simultaneous preparation and use of Ar ₂P(O)M. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2ob26874d

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Organic &
Biomolecular
Chemistry
PAPER
Nickel-catalyzed C–P cross-coupling of
diphenylphosphine oxide with aryl chlorides†
Hong-Yu Zhang,a Meng Sun,a Yan-Na Ma,a Qiu-Ping Tiana and Shang-Dong Yang*a,b
Cite this: Org. Biomol. Chem., 2012, 10,
9627
A novel protocol for the preparation of various diarylphosphine oxide compounds via a Ni-catalyzed
cross-coupling of aryl chlorides with R2P(O)H has been developed. Notably, this process exhibits the
following very attractive features: (i) the process is simpler and operates under mild reaction conditions;
(ii) the process is generally cheaper in part because the more accessible aryl chloride is used to form the
C–P bond; (iii) the process avoids the need for simultaneous preparation and use of Ar2P(O)M.
Received 28th July 2012,
Accepted 23rd October 2012
DOI: 10.1039/c2ob26874d
www.rsc.org/obc
more concise, efficient method for the C–P cross-coupling of
aryl chloride is highly desirable and presents a considerable
Introduction
Transition metal-catalyzed phosphination of aryl halides or challenge. Herein, we describe a versatile method of construct-
triflates has evolved as one of the most powerful methods for ing a C–P bond by Ni-catalyzed cross-coupling of aryl chlorides
the synthesis of aromatic organophosphorus compounds,1 with R2P(O)H compounds (Scheme 1, Path B). Importantly,
which play important roles in organic synthesis as well as the this process is simple, operates under mild reaction con-
pharmaceutical and life sciences.2 Since the pioneering work ditions, and is generally cheaper because the accessible and
of the Hirao group in this area,3 researchers have developed inexpensive compound aryl chloride is used. Moreover, the
the palladium-, nickel-, and copper-catalyzed phosphination of process avoids the simultaneous preparation and use of
aryl halides with phosphorus-based nucleophiles.4 In general, Ar2P(O)M. In addition, use of our method allows for the easy
however, only highly reactive aryl iodides or bromides and synthesis of different N,P-ligands such as (S)-phosphine
triflates can be used as coupling partners (Scheme 1, Path A). oxazoline and 3-arylphosphoindole (API), which are novel non-
To date, very few examples of palladium-catalyzed phosphina- nucleoside reverse transcriptase inhibitors (NNRTIs) for the
tion of inactive aryl chloride have been reported. In 2001, treatment of HIV-1 infections.2i,j During the preparation of
Montchamp reported the Pd-catalyzed reaction between anili- this manuscript, a similar catalytic system was reported by the
nium hypophosphite and various aromatic electrophiles group of Han et al., they disclosed NiCl2(dppp)-catalyzed C–P
applied to the synthesis of monosubstituted phosphinic acids. bond formation through the cross-coupling of aryl halides
With this catalyst system, the relative activated 4-chlorobenzo- with a dialkyl phosphite, diphenylphosphine oxide, and di-
nitrile also proceeds smoothly and affords the corresponding phenylphosphane.8 Although their investigation mainly focuses
product in good yield.5 Recently, there have been significant on aryl bromides, part of their work also involves use of aryl
advances in this field of research, a general palladium- chlorides.
catalyzed cross-coupling to synthesize disubstituted phosphi-
nates between H-phosphinates and aryl chlorides has been
performed.6 Moreover, Buchwald unveiled the only current
example of synthesis of dialkylphosphine by palladium-
catalyzed cross-coupling with aryl chloride in 2004.7 Neither
nickel nor copper-catalyzed phosphination of aryl chloride,
however, has been reported. Therefore, the development of a
aState Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou
730000, P.R. China. E-mail: yangshd@lzu.edu.cn; Fax: (+)86-931-8912859;
Tel: (+)86-931-8912859
bState Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute
of Chemical Physics, Chinese Academy of Sciences, Lanzhou, 730000, P.R. China
†Electronic supplementary information (ESI)
available. See DOI:
10.1039/c2ob26874d
Scheme 1 Pathway for the synthesis of diphenylphosphine oxides.
Org. Biomol. Chem., 2012, 10, 9627–9633 | 9627
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Table 1 Cross-coupling of 8-chloroquinoline with Ph2P(O)H under different
conditionsa
Results and discussion
In the past several years, we have focused our efforts on the
development of new and efficient methods for transition
metal-catalyzed C–P bond formation. We have made consider-
able advances in this regard.9 Recently, we reported a highly
efficient protocol for the preparation of various diphenylpho-
sphoryl ligands via nickel-catalyzed C–CN bond cleavage.9b In
light of the above results, we hypothesize that the C–Cl bond
might show cleavage under a similar catalytic system because
the bond-dissociation energy (BDE) of the C–Cl bond (79 kcal
mol−1) is very close to the C–CN bond (83 kcal mol−1).10 In par-
ticular, activating the C–Cl bond is not only cheaper, but also
more easily accessible. Furthermore, it also presents a funda-
mental challenge of considerable scientific interest. In an
initial study, we chose 8-chloroquinoline 1a and Ph2P(O)H as
the model substrates with which to begin our test with 5 mol%
Ni(PPh3)2Cl2 and 1.5 equiv. t-BuOK in dioxane at 120 °C, the
expected product of 2a was obtained in 36% yield (Table 1,
entry 1). Encouraged by this result, we further optimized the
reaction conditions. Screening of different bases in this trans-
formation was carried out and results indicated that the base
plays a crucial role in this reaction system; t-BuOLi, NaH,
Cs2CO3, and K2CO3 were also promising. K2CO3 gave the best
yield with 64% (Table 1, entries 2–5). Investigation of different
solvents showed that DMF was the best suitable solvent for
this procedure and that 2a was afforded in a 69% yield
(Table 1, entries 6–8). Over time we found that depression of
the reaction temperature is beneficial for the reaction, as the
yield of 2a improved to 89% at 50 °C (Table 1, entries 9–11).
Finally, the loading of Ni(PPh3)2Cl2 was also evaluated and
2 mol% Ni(PPh3)2Cl2 is sufficient to afford a smooth reaction,
without a significant decrease in reaction yield (Table 1,
entries 12–14). We would like to stress that the control experi-
ment clearly shows that the catalyst of Ni(PPh3)2Cl2 is essential
for the reactions (Table 1, entry 15).
As our comprehensive experimental results show, we
selected 2 mol% Ni(PPh3)2Cl2 and 1.5 equiv. K2CO3 as the
base in DMF at 50 °C as our optimization reaction conditions
(Table 1, entry 13). The scope of substrates was first examined
by varying the N-heteroaromatic chloride compounds for the
N,P-based ligands, which are key to many metal-catalyzed
organic transformations, including chiral reactions (Table 2).11
In this way our method provided mild and efficient ways
to construct these ligands. Different quinoline chlorides
and 4-methyl-2-chloropyridine are also suitable substrates,
affording the corresponding N,P-products in good to high
yields (Table 2, entries 1a–1e). The 2-oxazoline chlorobenzene
(1f) and 2-tetrazole chlorobenzene (1g) reactions occurred
smoothly, yielding products of 2f and 2g, with 71% and
63% yields, respectively (Table 2, entries 1f–1g). The ethyl
4-chloroquinoline-3-carboxylate (1h) was investigated as a
potential N,O-ligand; this reaction afforded 2h in 83% yield.
Under the same conditions, we wished to extend the
methodology to chlorobenzene and its derivatives. We selected
4-methyl chlorobenzene (1g) as a substrate to react with
Entry NiCl2(PPh3)2 Base
Solvent t [°C] Yieldb [%]
1
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
3 mol%
2 mol%
1 mol%
—
t-BuOK 1.5 equiv. Dioxane 120 36
2
t-BuOLi 1.5 equiv. Dioxane 120 31
3
Cs2CO3 1.5 equiv. Dioxane 120 58
4
NaH 1.5 equiv.
Dioxane 120 55
5
K2CO3 1.5 equiv. Dioxane 120 64
6
K2CO3 1.5 equiv. DMF
K2CO3 1.5 equiv. NMP
120 69
120 47
7
8
K2CO3 1.5 equiv. MeOH 120 50
9
K2CO3 1.5 equiv. DMF
K2CO3 1.5 equiv. DMF
K2CO3 1.5 equiv. DMF
K2CO3 1.5 equiv. DMF
K2CO3 1.5 equiv. DMF
K2CO3 1.5 equiv. DMF
K2CO3 1.5 equiv. DMF
90
70
50
50
50
50
50
78
86
89
87
86
65
n.r.
10
11
12
13
14
15
a All the reactions were carried out in the presence of 0.5 mmol of
1a in 3 mL of different solvents. b Isolated yield.
Ph2P(O)H under the former reaction conditions. Disappoint-
ingly, however, the results indicated that the reaction failed
entirely (Table 3, entry 1). This prompted us to reconsider
our screening, which had concentrated on different bases
and temperatures because the activity of chlorobenzene was
generally lower than heteroaromatic chloride compounds.
After extensive experimentation, we found that the use of
NiCl2(PPh3)2 as a catalyst and t-BuONa or t-BuOK as a base at
70 °C was critical for obtaining the desired aromatic diphenyl-
phosphine oxides in 40% and 37% yields, respectively
(Table 3, entries 2 and 3). Increasing the temperature to 90 °C
improved the yield of 2g to 46% (Table 3, entry 4). However,
continuing to raise the temperature accelerated the decompo-
sition of Ph2P(O)H and led to decreases in yield. A survey
showed that all the various nickel catalysts were able to
catalyze this reaction, but NiCl2(DME) gave the highest yield of
51% (Table 3, entries 5–14). A screening of solvents further
indicated that DMF was the best choice. Similarly, the control
experiment showed that the catalyst of NiCl2(DME) was
essential for the reactions (Table 3, entry 15).
Having established optimized reaction conditions (Table 3,
entry 5), we moved on to investigate the cross-coupling of
different chlorobenzene derivatives with Ph2P(O)H. The results
illustrate that steric and electronic effects play key roles in this
reaction. For example, the electron-deficient 4-chlorobenzoni-
trile reacted very well with Ph2P(O)H and the product of 2j was
obtained in 85% yield (Table 4, entry 1j). The reaction of elec-
tron-neutral 4-chlorotoluene, electron-rich 4-chloroanisole,
and electron-deficient 3-chlorobenzonitrile with Ph2P(O)H
resulted in lower yields (Table 4, entries 1i, 1n and 1k). Never-
theless, 4-trifluoromethyl chlorobenzene also afforded the
product of 2m in 46% yield. Although the electron-deficient or
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Table 2 Cross-coupling with different N-heteroaromatic chloridesa
Entry
R–Cl
Products
Yieldb [%]
86
Entry
R–Cl
Products
Yieldb [%]
70
1a
1e
1b
1c
87
84
1f
71
63
1g
1d
85
1h
83
a All the reactions were carried out in the presence of 0.5 mmol of 1a–1f in 3 mL of DMF at 50 °C. b Isolated yields.
To our delight, some heteroaromatic chloride compounds that
failed under former reaction conditions such as 2-chloropyri-
midine, 3-chloride-N-methylindole, 10-chlorobenzoquinoline,
2-chlorobenzothiazole, and 2-chloro-4-methylquinoline could
be successfully carried out using our new reaction conditions.
Indeed, these compounds afforded the corresponding pro-
ducts in good yield (Table 4, entries 1p and 1r–1v).
In the course of exploring the scope of this method, we dis-
covered a new catalytic transformation. As a substrate, (E)-2-
chlorobenzaldehyde O-methyl oxime (1t) reacted with Ph2P(O)
H under optimal reaction conditions. To our surprise the
2-diphenylphosphoryl-benzonitrile (2t) was obtained in 74%
yield (Scheme 2). Simultaneously, the conversion of oxime
ether to nitrile also occurred by elimination of methanol. As
illustrated, this finding will provide us with a novel and
efficient pathway for the synthesis of 2-diphenylphosphoryl-
benzonitrile and its derivatives by domino processes.
Table 3 Cross-coupling of 4-methyl chlorobenzene with Ph2P(O)H under
different conditionsa
Yieldb
t [°C] [%]
Entry [M]
Base
1
NiCl2(PPh3)2 5 mol% K2CO3 1.5 equiv.
NiCl2(PPh3)2 5 mol% t-BuONa 1.5 equiv. 70
NiCl2(PPh3)2 5 mol% t-BuOK 1.5 equiv. 70
50
n.r.
40
37
46
51
29
26
25
38
47
24
41
40
38
n.r.
2
3
4
NiCl2(PPh3)2 5 mol% t-BuONa 1.5 equiv. 90
NiCl2(DME) 5 mol% t-BuONa 1.5 equiv. 90
NiBr2(DME) 5 mol% t-BuONa 1.5 equiv. 90
5
6
7
NiCl2(dppe) 5 mol%
t-BuONa 1.5 equiv. 90
8
NiCl2(dppp) 5 mol% t-BuONa 1.5 equiv. 90
NiCl2(PCy3)2 5 mol% t-BuONa 1.5 equiv. 90
NiBr2(PPh3)2 5 mol% t-BuONa 1.5 equiv. 90
9
10
11
12
13
14
15
Ni(acac)2 5 mol%
NiCl2 5 mol%
NiBr2 5 mol%
Ni(OTf)2 5 mol%
—
t-BuONa 1.5 equiv. 90
t-BuONa 1.5 equiv. 90
t-BuONa 1.5 equiv. 90
t-BuONa 1.5 equiv. 90
t-BuONa 1.5 equiv. 90
a All the reactions were carried out in the presence of 0.5 mmol of
1g in 3 mL of DMF. b Isolated yield.
electron-rich group lies in the ortho-position of chlorobenzene,
the steric hindrance is nevertheless apparent and the products
of 2l and 2o were obtained in 56% and 51% yields, respectively
(Table 4, entries 1l and 1o). It is worth noting that the C–Cl
bond cleavage precedes the C–CN bond in this transformation
and the cyano group is retained. In addition, the coupling of
1-chloronaphthalene was accomplished and 2q was obtained
Scheme 2 Phosphination and elimination of 2-chlorobenzaldehyde O-methyl
oxime.
Conclusions
in 71% yield (Table 4, entry 1q). Furthermore, this reaction dis- In summary, we have developed a protocol for the preparation
plays good functional group tolerance and the acetamide was of various diphenylphosphoryl compounds through nickel-cat-
also compatible with this transformation (Table 4, entry 1o). alyzed cross-coupling reactions of Ph2P(O)H with aromatic
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Table 4 Cross-coupling with different aromatic chloridesa,b
Entry
R–Cl
Products
Yieldb [%]
51
Entry
1q
R–Cl
Products
Yieldb [%]
71
1i
1j
85
49
1r
1s
53
51
1k
1l
56
46
1t
48
76
1m
1u
1n
47
1v
76
1o
1p
51
79
a All the reactions were carried out in the presence of 0.5 mmol of 1g–1s in 3 mL of DMF at 90 °C. b Isolated yield.
chlorides. Notably, the process is simple and operates under reported as follows: chemical shift, multiplicity (s = singlet,
mild reaction conditions. Moreover, the process is generally d = doublet, t = triplet, q = quartet, m = multiplet), coupling
cheaper in part because the more accessible aryl chloride constants, J, are reported in hertz. Mass data were measured
is used to form the C–P bond. Use of the Ph2P(O)H also with a Thermo Scientific DSQ II mass spectrometer. IR spectra
avoids the need to simultaneously prepare Ar2P(O)M. Further were recorded on an FT-IR spectrometer and only major peaks
application of this approach to the synthesis of chiral ligands are reported in cm−1
is ongoing.
.
Typical procedure for the preparation of diphenylphosphine
oxides of 2a–2h
Experimental section
General details
An oven-dried 10 mL screw-capped vial was charged with aryl
All reactions involving air- or moisture-sensitive reagents were chloride (0.5 mmol, 1.0 equiv.), NiCl2(PPh3)2 (0.01 mmol,
carried out under an argon atmosphere. Toluene, DMF, 1,2- 2 mol%), K2CO3 (0.75 mmol, 1.5 equiv.), and Ph2P(O)H
dichloroethane, DMSO, 1,4-dioxide, and CH3CN were distilled (0.6 mmol, 1.2 equiv.). Then, the vial was purged and filled
from appropriate drying agents prior to use. All chemicals with Ar three times. After DMF (3.0 mL) was added with a
were purchased from Aldrich and J&K Chemical and used syringe, the reaction mixture was stirred at 50 °C for about 8 to
without further purification. Thin-layer chromatography (TLC) 10 hours. After completion of the reaction, the mixture was
was performed using 60 mesh silica gel plates visualized cooled to room temperature and CHCl3 (50 mL) and water
with short-wavelength UV light (254 nm). Silica gel 60 (50 mL) were added. The organic layer was isolated and the
(230–400 mesh) was used for column chromatography. remaining aqueous phase was further extracted with CHCl3
1H NMR and 13C NMR spectra were recorded on a 400 instru- (50.0 mL × 3). The combined organic extracts were washed
1
ment (400 MHz for H and 100 MHz for 13C). Chemical shifts with saturated brine (50.0 mL × 3) and dried over Na2SO4. The
1
(δ) were measured in ppm relative to TMS = 0.0 for H, or to desired products of 2a–2f were obtained in corresponding
chloroform = 77.0 for 13C as the internal standard. Data were yields after purification by flash chromatography on silica gel.
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2a, White solid, 86% yield, mp 194–196 °C; 31P NMR 3.77–3.81 (t, J = 4.8 Hz, 1 H), 3.64–3.68 (t, J = 8.4 Hz, 1 H),
1
(CDCl3, 162 MHz): δ = 28.78; H NMR (CDCl3, 400 MHz): δ = 3.47–3.54 (q, J = 8.8 Hz, 1 H), 3.77–3.81 (dt, J = 6.8 Hz, 1 H),
8.72–8.73 (d, J = 4.0 Hz, 1 H), 8.34–8.39 (q, J = 7.2 Hz, 1 H), 3. 0.86–0.87 (d, J = 6.8 Hz, 1 H), 0.75–0.77 (d, J = 6.8 Hz, 1 H);
8.13–8.15 (d, J = 8.4 Hz, 1 H), 8.00–8.02 (d, J = 8.0 Hz, 1 H), 13C NMR (CDCl3, 100 MHz): δ = 163.19, 134.86, 134.75, 134.05,
7.82–7.87 (m, 4 H), 7.62–7.66 (t, J = 7.6 Hz, 1 H), 7.44–7.48 (m, 133.82, 132.99, 132.76, 132.55, 132.49, 132.21, 131.78, 131.74,
1 H), 7.32–7.40 (m, 5 H); 13C NMR (CDCl3, 100 MHz): δ = 131.64, 131.40, 131.34, 131.30, 131.25, 131.22, 130.81, 130.72,
149.78, 148.03, 147.98, 137.35, 137.27, 136.04, 134.23, 133.16, 130.20, 130.08, 128.52, 128.29, 128.16, 77.32, 77.00, 76.68,
132.77, 132.74, 132.23, 132.12, 131.82, 131.22, 131.19, 130.81, 72.73, 70.71, 32.61, 19.09, 18.50; IR (neat, cm−1): 3424.4,
128.25, 128.18, 127.95, 127.82, 126.0, 125.89, 121.45; IR (neat, 3053.1, 1590.8, 1436.7, 1128.9, 726.4, 695.0; MS (ESI): [M + H]+,
cm−1): 3429.9, 3058.4, 1461.7, 1173.5, 1119.4, 725.1, 563.1; MS 390.3.
(ESI): [M + H]+, 330.2.
2g, The reaction was carried out at 70 °C. White solid, 61%
2b, White solid, 87% yield, mp 111–113 °C; 31P NMR yield, mp 181–183 °C; 31P NMR (CDCl3, 162 MHz): δ = 28.94;
(CDCl3, 162 MHz): δ = 20.37; H NMR (CDCl3, 400 MHz): δ = 1H NMR (CDCl3, 400 MHz): δ = 7.82–7.85 (m, 1 H), 7.63–7.75
1
8.33–8.36 (m, 1 H), 8.27–8.30 (m, 1 H), 8.15–8.27 (d, J = 7.2 Hz, (m, 6 H), 7.53–7.56 (t, J = 7.6 Hz, 1 H), 7.45–7.49 (t, J = 7.2 Hz,
1 H), 7.98–8.13 (m, 4 H), 7.82–7.84 (d, J = 8.4 Hz, 1 H), 2 H), 7.37–7.41 (m, 4 H), 4.06 (s, 3 H); 13C NMR (CDCl3,
7.70–7.72 (m, 1 H), 7.57–8.59 (d, J = 7.2 Hz, 1 H), 7.41–7.56 (m, 100 MHz): δ = 163.88, 134.88, 134.78, 133.56, 132.99, 132.50,
6 H); 13C NMR (CDCl3, 100 MHz): δ = 157.63, 156.34, 148.09, 132.00, 131.92, 131.90, 131.76, 131.66, 131.42, 131.39, 131.36,
147.88, 136.05, 135.96, 132.89, 132.10, 132.01, 131.86, 131.80, 131.33, 131.30, 131.23, 129.65, 129.53, 128.14, 128.02, 39.06,
131.77, 131.68, 131.65, 130.15, 129.90, 128.41, 128.29, 128.21, 39.04; IR (neat, cm−1): 3433.6, 3055.2, 1438.4, 1190.2, 1116.6,
128.09, 128.02, 127.73, 123.29, 123.07; IR (neat, cm−1): 3430.4, 752.8, 704.4, 545.1; MS (ESI): [M + H]+, 361.3.
3055.2, 1585.3, 1436.7, 1191.7, 1118.5, 723.2, 564.9; MS (ESI):
[M + H]+, 330.2.
2h, White solid, 83% yield, mp 162–164 °C; 31P NMR
1
(CDCl3, 162 MHz): δ = 30.57; H NMR (CDCl3, 400 MHz): δ =
2c, White solid, 84% yield, mp 192–193 °C; 31P NMR 9.01–9.02 (d, J = 4.4 Hz, 1 H), 8.58–8.61 (d, J = 8.8 Hz, 1 H),
1
(CDCl3, 162 MHz): δ = 28.40; H NMR (CDCl3, 400 MHz): δ = 3.70–3.76 (q, J = 7.2 Hz, 2 H), 1.10–1.04 (t, J = 7.2 Hz, 3 H); 13C
9.42–9.44 (d, J = 8.8 Hz, 1 H), 8.61–8.63 (d, J = 5.6 Hz, 1 H), NMR (CDCl3, 100 MHz): δ = 167.03, 166.97, 148.88, 148.82,
7.83–7.88 (m, 5 H), 7.68–7.74 (m, 2 H), 7.61–7.65 (t, J = 7.2 Hz, 147.93, 147.85, 137.94, 137.06, 132.46, 132.37, 132.34, 132.19,
1 H), 7.50–7.53 (m, 2 H), 7.42–7.47 (m, 4 H); 13C NMR (CDCl3, 132.08, 131.96, 131.89, 131.40, 131.35, 130.64, 130.30, 130.29,
100 MHz): δ = 156.46, 155.17, 141.75, 141.53, 136.15, 136.08, 128.59, 128.46, 128.37, 128.31, 128.26, 127.94, 127.46, 127.39,
133.54, 132.50, 132.24, 132.15, 132.03, 131.92, 131.71, 131.68, 62.10, 13.55; IR (neat, cm−1): 3424.7, 1726.3, 1568.1, 1488.5,
131.49, 130.56, 128.53, 128.41, 128.28, 128.16, 127.29, 127.20, 1437.7, 1187.4, 1113.2, 793.8, 696.5; MS (ESI): [M + H]+, 402.3.
127.19, 122.97, 122.94; IR (neat, cm−1): 3054.4, 1435.5, 1174.5,
Typical procedure for the preparation of diphenylphosphine
oxides of 2i–2v
1117.0, 752.4, 697.9; MS (ESI): [M + H]+, 330.2.
2d, White solid, 85% yield, mp 98–100 °C; 31P NMR (CDCl3,
1
162 MHz): δ = 18.71; H NMR (CDCl3, 400 MHz): δ = 8.31–8.34 An oven-dried 10 mL screw-capped vial was charged with aryl
(m, 1 H), 8.21–8.23 (m, 1 H), 8.09–8.13 (m, 4 H), 7.42–7.46 (m, chloride (0.5 mmol, 1.0 equiv.), Ni(DME)2Cl2 (0.025 mmol,
7 H), 7.34–7.37 (d, J = 8.0 Hz, 1 H); 13C NMR (CDCl3, 5 mol%), NaOtBu (0.75 mmol, 1.5 equiv.), and Ph2P(O)H
100 MHz): δ = 156.08, 155.96, 154.64, 140.44, 140.23, 135.84, (0.6 mmol, 1.2 equiv.). Then the vial was purged and filled
135.75, 133.12, 132.47, 132.15, 132.09, 132.06, 131.88, 131.55, with Ar three times. After DMF (3.0 mL) was added by a
131.52, 130.61, 130.49, 129.26, 129.23, 128.84, 128.71, 128.48, syringe, the reaction mixture was stirred at 90 °C for about 8 to
128.31, 128.19, 128.07, 123.64, 123.43, 119.44, 108.97, 56.38, 10 hours. After completion of the reaction, the mixture was
56.34; IR (neat, cm−1): 3426.8, 2927.8, 1725.9, 1554.2, 1460.2, cooled to room temperature and CHCl3 (50 mL) and water
1437.3, 1197.7, 1104.8, 725.4, 579.0; MS (ESI): [M + H]+, 360.2.
(50 mL) were added. The organic layer was isolated and the
2e, White solid, 70% yield, mp 150–152 °C; 31P NMR remaining aqueous phase was further extracted with CHCl3
1
(CDCl3, 162 MHz): δ = 20.98; H NMR (CDCl3, 400 MHz): δ = (50.0 mL × 3). The combined organic extracts were washed
8.61–8.63 (d, J = 4.8 Hz, 1 H), 8.17–8.19 (d, J = 6.4 Hz, 1 H), with saturated brine (50.0 mL × 3) and dried over Na2SO4. The
7.86–7.91 (m, 4 H), 7.49–7.53 (m, 2 H), 7.41–7.46 (m, 4 H), desired products of 2g–2t were obtained in the corresponding
7.18–7.19 (m, 1 H); 13C NMR (CDCl3, 100 MHz): δ = 156.41, yields after purification by flash chromatography on silica gel.
155.10, 150.02, 149.82, 147.67, 147.58, 132.80, 132.09, 131.99,
2i, White solid, 51% yield, mp 128–130 °C; 31P NMR
1
131.78, 131.76, 129.38, 129.18, 128.50, 128.38, 128.31, 128.19, (CDCl3, 162 MHz): δ = 29.05; H NMR (CDCl3, 400 MHz): δ =
127.29, 127.20, 127.19, 126.04, 126.02, 122.97, 122.94, 21.02; 7.64–7.69 (m, 4 H), 7.51–7.58 (m, 4 H), 7.43–7.47 (m, 4 H),
IR (neat, cm−1): 3440.1, 3056.6, 1589.2, 1433.3, 1193.0, 1154.9, 7.26–7.27 (d, J = 4.4 Hz 2 H), 2.40 (s, 3 H); 13C NMR (CDCl3,
723.5, 693.5, 563.6; MS (ESI): [M + H]+, 294.2.
100 MHz): δ = 142.42, 142.39, 133.38, 132.35, 132.16, 132.10,
2f, The reaction was carried out at 70 °C. White solid, 71% 132.06, 132.00, 131.88, 131.79, 131.76, 129.73, 129.29, 129.16,
yield; recovery start material: 17%; 31P NMR (CDCl3, 162 MHz): 128.67, 128.52, 128.47, 128.40, 128.35, 21.57; IR (neat, cm−1):
1
δ = 20.98; H NMR (CDCl3, 400 MHz): δ = 7.89–7.91 (m, 1 H), 3431.8, 3051.5, 1600.4, 1438.2, 1185.7, 1118.7, 752.1, 698.3,
7.67–7.75 (m, 4 H), 7.56–7.61 (m, 2 H), 7.44–7.52 (m, 7H), 542.0; MS (ESI): [M + H]+, 293.2.
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2j, White solid, 85% yield, mp 137–139 °C; 31P NMR 100 MHz): δ = 168.32, 166.73, 156.80, 156.66, 131.99, 131.89,
1
(CDCl3, 162 MHz): δ = 27.70; H NMR (CDCl3, 400 MHz): δ = 131.32, 130.28, 128.16, 128.04, 121.59; IR (neat, cm−1): 3430.6,
7.74–7.83 (m, 4 H), 7.58–7.68 (m, 6 H), 7.48–7.52 (m, 4 H); 13C 3053.0, 1554.6, 1391.3, 1183.2, 724.3, 697.4, 536.3; MS (ESI):
NMR (CDCl3, 100 MHz): δ = 138.90, 137.92, 132.60, 132.50, [M + H]+, 281.2.
132.46, 131.98, 131.88, 131.64, 130.59, 128.82, 128.70, 117.80,
2q, White solid, 71% yield, mp 174–176 °C; 31P NMR
1
115.58, 115.55; IR (neat, cm−1): 3430.3, 3045.1, 2230.2, 1434.3, (CDCl3, 162 MHz): δ = 32.43; H NMR (CDCl3, 400 MHz): δ =
1198.6, 1115.5, 751.8, 696.9, 564.1; MS (ESI): [M + H]+, 304.2.
8.58–8.60 (d, J = 8.0 Hz, 1 H), 8.00–8.02 (d, J = 8.0 Hz, 1 H),
2k, White solid, 49% yield, mp 108–109 °C; 31P NMR 7.87–7.89 (d, J = 8.0 Hz, 1 H), 7.66–7.71 (m, 4 H), 7.51–7.56 (m,
1
(CDCl3, 162 MHz): δ = 27.70; H NMR (CDCl3, 400 MHz): δ = 2 H), 7.41–7.49 (m, 6 H), 7.35–7.40 (m, 1 H), 7.27–7.32 (m,
7.74–7.83 (m, 4 H), 7.58–7.68 (m, 6 H), 7.48–7.52 (m, 4 H); 13C 1 H); 13C NMR (CDCl3, 100 MHz): δ = 133.84, 133.75, 133.64,
NMR (CDCl3, 100 MHz): δ = 135.98, 135.89, 135.75, 135.40, 133.57, 133.23, 133.20, 132.16, 132.03, 131.93, 131.85, 131.82,
135.29, 135.05, 135.02, 134.75, 132.52, 132.50, 132.05, 131.96, 129.30, 128.70, 128.58, 128.46, 128.29, 127.53, 127.47, 127.29,
131.86, 131.59, 130.54, 129.44, 129.33, 128.85, 128.72, 128.48, 126.42, 124.14, 124.00; IR (neat, cm−1): 3429.9, 3055.8, 1433.5,
128.35, 117.78, 113.09, 112.96; IR (neat, cm−1): 3433.5, 3054.9, 1188.3, 1145.4, 777.0, 696.0, 54 539; MS (ESI): [M + H]+, 329.2.
2228.2, 1436.0, 1196.5, 1115.9, 752.8, 695.3, 542.6; MS (ESI):
[M + H]+, 304.2.
2r, White solid, 53% yield, recovery start material: 28%; mp
205–206 °C; 31P NMR (CDCl3, 162 MHz): δ = 21.42; 1H NMR
2l, White solid, 56% yield, mp 194–196 °C; 31P NMR (CDCl3, 400 MHz): δ = 7.75–7.80 (m, 4 H), 7.50–7.52 (m, 2 H),
1
(CDCl3, 162 MHz): δ = 26.76; H NMR (CDCl3, 400 MHz): δ = 7.42–7.46 (m, 8 H) 7.35–7.37 (d, J = 8.4 Hz, 2 H), 7.23–7.29 (m,
7.74–7.78 (m, 1 H), 7.64–7.69 (m, 5 H), 7.48–7.61 (m, 4 H), 2 H), 7.05–7.09 (t, J = 4.8 Hz 1 H); 13C NMR (CDCl3, 100 MHz):
7.39–7.44 (m, 4 H); 13C NMR (CDCl3, 100 MHz): δ = 136.85, δ = 138.32, 138.22, 137.45, 137.26, 134.51, 133.44, 131.81,
135.90, 135.02, 134.94, 134.06, 133.98, 132.48, 132.45, 132.21, 131.70, 131.60, 131.57, 128.81, 128.72, 128.43, 128.31, 122.81,
132.09, 131.98, 131.94, 131.81, 130.95, 130.54, 130.43, 129.88, 121.40, 121.18, 109.86, 105.34, 104.06, 33.30; IR (neat, cm−1):
128.79, 128.65, 128.53; IR (neat, cm−1): 3421.8, 3054.8, 2224.3, 3434.6, 3051.7, 1512.4, 1463.5, 1172.1, 1117.8, 761.7, 547.9; MS
1463.8, 1195.3, 1119.4, 752.7, 699.0, 545.7; MS (ESI): [M + H]+, (ESI): [M + H]+, 332.2.
304.2.
2s, White solid, 51% yield, recovery start material: 42%; mp
2m, White solid, 46% yield, mp 89–90 °C; 31P NMR (CDCl3, 240–246 °C; 31P NMR (CDCl3, 162 MHz): δ = 33.14; 1H NMR
1
162 MHz): δ = 27.98; H NMR (CDCl3, 400 MHz): δ = 7.80–7.85 (CDCl3, 400 MHz): δ = 8.34–8.36 (d, J = 7.2 Hz, 1 H), 8.20–8.21
(dd, J = 7.6 Hz, 2H), 7.64–7.74 (m, 6 H), 7.56–7.61 (m, 2 H), (d, J = 4.0 Hz, 1 H), 8.20–8.17 (d, J = 8.0 Hz, 1 H), 8.02–8.05 (m,
7.74–7.51 (m, 4 H); 13C NMR (CDCl3, 100 MHz): δ = 137.26, 1 H), 7.89–7.91 (m, 1 H), 7.70–7.75 (m, 6 H), 7.25–7.39 (m,
136.27, 133.41, 133.12, 133.09, 132.19, 132.09, 131.97, 131.95, 7 H); 13C NMR (CDCl3, 100 MHz): δ = 145.20, 143.55, 137.85,
131.74, 131.67, 131.57, 130.70, 128.38, 128.26, 125.01, 124.98, 137.61, 137.50, 136.71, 134.81, 134.51, 134.43, 133.39, 133.35,
124.93, 124.89, 124.86, 124.50; IR (neat, cm−1): 3435.1, 3053.8, 132.82, 132.80, 130.54, 130.44, 129.90, 129.87, 129.27, 128.25,
1437.7, 1398.0, 1329.1, 1198.1, 1118.9, 739.7, 535.9; MS (ESI): 128.10, 127.97, 127.85, 127.36, 127.22, 127.04, 126.07, 122.00;
[M + H]+, 347.2.
IR (neat, cm−1): 3428.9, 3042.1, 1434.1, 1190.9, 719.7, 696.8,
2n, White solid, 47% yield, mp 106–108 °C; 31P NMR 560.7, 538.9; MS (ESI): [M + H]+, 380.3.
1
(CDCl3, 162 MHz): δ = 29.02; H NMR (CDCl3, 400 MHz): δ =
2t, White solid, 48% yield, mp 154–156 °C; 31P NMR
1
7.63–7.69 (m, 4 H), 7.51–7.61 (m, 4 H), 7.43–7.47 (m, 4 H), (CDCl3, 162 MHz): δ = 20.03; H NMR (CDCl3, 400 MHz): δ =
6.95–6.98 (m, 2 H), 3.84 (s, 3 H); 13C NMR (CDCl3, 100 MHz): δ 8.19–8.21 (d, J = 8.0 Hz, 1 H), 7.94–8.03 (m, 5 H), 7.48–7.60 (m,
= 162.48, 162.45, 133.99, 133.93, 133.87, 133.82, 133.48, 8 H); 13C NMR (CDCl3, 100 MHz): δ = 167.41, 166.15, 155.45,
132.44, 132.06, 131.96, 131.76, 131.73, 128.46, 128.40, 128.33, 155.23, 136.78, 132.62, 132.60, 131.97, 131.87, 131.49, 130.41,
124.11, 123.01, 55.30; IR (neat, cm−1): 3433.3, 3067.6, 1461.7, 128.69, 128.56, 126.64, 126.59, 124.74, 122.08; IR (neat, cm−1):
1437.8, 1258.7, 1182.2, 1118.7, 756.0, 697.7, 536.4; MS (ESI): 3433.8, 3051.3, 1465.0, 1198.7, 696.1, 536.1; MS (ESI): [M + H]+,
[M + H]+, 309.2.
336.2.
2u, Yellow solid, 76% yield; 31P NMR (CDCl3, 162 MHz): δ =
2o, White solid, 51% yield, mp 133–135 °C; 31P NMR
1
1
(CDCl3, 162 MHz): δ = 37.01; H NMR (CDCl3, 400 MHz): δ = 30.14; H NMR (CDCl3, 400 MHz): δ = 8.62–8.60 (d, J = 9.2 Hz,
10.99 (s, 1 H), 8.52–8.55 (m, 1 H), 7.57–7.66 (m, 6 H), 7.47–7.53 1 H), 8.28–8.30 (d, J = 8.8 Hz, 1 H), 7.69–7.74 (m, 6 H),
(m, 5 H), 6.94–7.04 (m, 2 H), 2.09 (s, 3 H); 13C NMR (CDCl3, 7.54–7.58 (dt, J = 1.2 Hz, 7.2 Hz, 2 H), 7.43–7.48 (m, 4 H),
100 MHz): δ = 168.93, 144.22, 144.19, 133.31, 133.29, 132.67, 7.31–7.35 (m, 2 H); 13C NMR (CDCl3, 100 MHz): δ = 148.57,
132.56, 132.44, 132.41, 131.98, 131.94, 131.88, 130.89, 128.74, 148.49, 134.91, 133.87, 132.21, 132.19, 131.52, 131.42, 130.53,
128.62, 122.59, 122.46, 121.99, 121.92, 117.55, 116.55, 24.92; 129.60, 129.02, 128.90, 128.29, 128.22, 127.09, 127.02, 126.66;
IR (neat, cm−1): 3438.4, 3307.7, 3107.4, 1694.5, 1458.7, 1436.0, IR (neat, cm−1): 3436.1, 3056.1, 1458.3, 1169.0, 1115.3, 743.7,
752.7, 697.7, 542.2; MS (ESI): [M + H]+, 336.3.
697.0, 528.4; MS (ESI): [M + H]+, 380.2.
2p, White solid, 79% yield, mp 164–166 °C; 31P NMR
2v, White solid, 76% yield, mp 145–147 °C; 31P NMR
1
1
(CDCl3, 162 MHz): δ = 19.73; H NMR (CDCl3, 400 MHz): δ = (CDCl3, 162 MHz): δ = 20.36; H NMR (CDCl3, 400 MHz): δ =
8.88–8.90 (d, J = 4.8 Hz, 2 H), 7.90–7.94 (m, 4 H), 7.52–7.54 (m, 8.21–8.22 (d, J = 4.4 Hz, 1 H), 8.13–8.16 (d, J = 8.4 Hz, 1 H),
2 H), 7.46–7.47 (m, 4 H), 7.37–7.39 (m, 1 H); 13C NMR (CDCl3, 7.97–8.04 (m, 5 H), 7.71–7.75 (m, 1 H), 7.60–7.64 (m, 1 H),
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7.41–7.48 (m, 2 H), 7.41–7.46 (m, 4 H), 2.76 (s, 3 H); 13C NMR
(CDCl3, 100 MHz): δ = 157.16, 155.87, 147.99, 147.77, 144.87,
144.78, 133.09, 132.23, 132.14, 132.06, 131.72, 131.69, 130.96,
130.84, 129.56, 128.27, 128.22, 128.15, 127.85, 124.08, 123.87,
18.71; IR (neat, cm−1): 3439.5, 3056.6, 1733.3, 1584.8, 1438.1,
1193.0, 1116.5, 726.4, 696.6; MS (ESI): [M + H]+, 344.3.
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Acknowledgements
We are grateful to the NSFC (No. 21072079), International
Cooperation and Exchanges NSFC (No. 20921120404) and
Research Fund for the Doctoral Program of Higher Education
of China (No. 20100211120014) for financial support.
S.F. Reichard, MA contributed to the editing of the
manuscript.
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