Autoxidative C(sp2)-P Formation: Direct Phosphorylation of Heteroarenes under Oxygen, Metal-Free, and Solvent-Free Conditions

Article abstract of DOI:10.1021/acs.joc.6b00592

We reveal here a direct autoxidative phosphorylation of heteroarenes induced by oxygen under metal-free and solvent-free conditions. This new methodology provides an economical, operationally simple, and environmentally friendly approach toward (Het)C(sp²)-P formation with medium to excellent yields. Heteroarenes including thiazole and quinoxaline derivatives are applicable under standard conditions, which is testified via a radical mechanism.

Full text of DOI:10.1021/acs.joc.6b00592

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Article
Autoxidative C(sp2)-P Formation: Direct Phosphorylation of
Heteroarenes under Oxygen, Metal-free and Solvent-free Conditions
Kai Luo, Yao-Zhong Chen, Li-Xian Chen, and Lei Wu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00592 • Publication Date (Web): 11 May 2016
Downloaded from http://pubs.acs.org on May 15, 2016
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Autoxidative C(sp2)ꢀP Formation: Direct Phosphorylation of Heteroarenes under
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Oxygen, Metalꢀfree and Solventꢀfree Conditions
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, ,§
,
,§
,∫,
‡
Kai Luo, † ‡ YaoꢀZhong Chen, † LiꢀXian Chen † AND Lei Wu †
*
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†Jiangsu Key Laboratory of Pesticide Science and Department of Chemistry, College of Sciences, Nanjing
Agricultural University, Nanjing 210095, China.
‡College of Plant Protection, Nanjing Agricultural University, Nanjing 210095, P. R. China.
∫Beijing National Laboratory for Molecular Sciences and Institute of Chemistry, Chinese Academy of
Sciences, Beijing 100190, P. R. China.
ABSTRACT: We reveal here a direct autoxidative phosphorylation of heteroarenes induced by oxygen
under metalꢀfree and solventꢀfree conditions. This new methodology provides an economical,
operational simple and environmental friendly approach toward (Het)C(sp2)ꢀP formation with medium
to excellent yields. Heteroarenes including thiazole and quinoxaline derivatives are applicable under
standard condition, which is testified via a radical mechanism.
O
N
S
O
O2 balloon
N
S
PAr2
R
R
+
+
H
R
R
H-PAr2
Sovlent-free
65 oC, 18 h
O
N
PAr2
N
H
O
O2 balloon
H-PAr2
Sovlent-free
65 oC, 1 h
N
R'
N
R'
The first C(sp2)-P formation by autoxidative coupling
Sovent-free, Metal-free, Additive-free
The first direct C-H phosphorylation of quinoxaline derivatives
■
INTRODUCTION
The development of direct CꢀH bond functionalization facilitates the build of useful molecular
architecture, which attracts high interest to academic and industrial chemists.1 Many achievements have been
made, but special activating, directing or leaving groups are indispensable for most of them. From the aspect
of “green chemistry”, oxidative coupling reactions between two CꢀH bonds would avoid unwanted waste
and extra synthetic steps, along with hydrogen as “leaving group” and in the ideal case water as the only
waste.2 Cross dehydrogenative coupling (CDC) and autoxidative coupling reactions have emerged as a
flourishing research area to generate CꢀC bonds. Leading scientists such as Li,2a,3 Klussmann,2c,4 Lei,5 Jiao,6
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Jiang7 and others 8 have contributed various carbonꢀcarbon formations directly from two different CꢀH bonds
under oxidative conditions, which have shown versatility and generality of these protocols. Generally, CDC
reactions were mostly catalyzed by copper, iron, or palladium salts in combination with stoichiometric
amount of synthetic oxidants including TBHP, TEMPO, DDQ etc.2a Nevertheless, autoxidative couplings
presented a more environmental benign strategy using only molecular oxygen without metal catalysts.2c In
terms of these criteria, several achievements have been extended to construct CꢀX (X = N, O, S etc) bonds as
well,9 intriguingly, CꢀN bond cleavage was also revealed under the autoxidation process.10 However, to be
noted, C(sp2)ꢀP formation as a hot research area has not been realized by autoxidative couplings.11
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It’s wellꢀknown that organophosphorus compounds play key roles in catalysis, organic synthesis,
biochemistry and materials chemistry,12 where phosphorus substituents regulate important biological,
medicinal and material functions, and perform as ligands or directing group for transition metal catalysis. As
such, the introduction of organophosphorus functionalities in convenient means continues to motivate
methods for their synthesis. Of these methods, the transition metals catalyzed/ mediated coupling of
phosphonate esters or phosphine oxides with electrophiles has been widely recognized as an efficient and
promising approach for C(sp2)ꢀP bond formation. The phosphorylation of alkynes,13 propargylic
derivatives,14 styrenes,15 arylboronic acids,16 aryl(pseudo) halides,17 and (hetero)arenes11 were extensively
enabled by palladium, nickel, copper, rhodium and silver etc. Among which, the direct CꢀH functionalization
of benzothiazoles with diarylphosphine oxides are extremely rare. One was reported by Zhang et al., they
demonstrated a silver nitrateꢀmediated phosphorylation of benzothiazoles and thiazoles in refluxing
acetonitrile (Scheme 1, a).11h Chen et al. revealed another oxidative coupling of benzothiazoles and
o
diarylphosphine oxides by heating with diꢀtertꢀbutyl peroxide (DTBP) in acetonitrile at 80 C (Scheme 1,
b).18 It’s worthy to mention that these transformations and the aforementioned transition metals catalyzed
C(sp2)ꢀP formations are associated with one or more limitations such as expensive, toxic or stoichiometric
transition metals, airꢀsensitive ligands, synthetic oxidants, elevated temperatures. Thus, the potential
development of such a synthesis with economical, operational simple and environmental friendly approach is
highly demanded.
Recently, our group developed a novel crossꢀcoupling hydrogen evolution of thiazoles derivatives with
diarylphosphine oxides by organic dyesꢀsensitized photoredox catalysis without metal, oxidant or additive
(Scheme 1, c).19 In sharp contrast with traditional oxidative couplings, this photoredox catalytic reaction
proceed worse under air or oxygen atmosphere, however, controlling experiments showed that a certain
amount of target adduct formed under molecular oxygen without photocatalyst. This preliminary result spurs
a potential C(sp2)ꢀP formations by autoxidative coupling. In continuing research on synthesis and application
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of organophosphorous chemistry,
herein we report, for the first time, the autoxidative coupling of
heteroarenes (thiazole and quinoxaline derivatives) with diarylphosphine oxides under oxygen, metalꢀfree
and solventꢀfree conditions (Scheme 1, d).
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Scheme 1. Previous direct CꢀH functionalization of
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benzothiazoles with diarylphosphine oxides and this work.
a. 1 eq. AgNO3
Previous work:
CH3CN, 90 oC, 24 h
O
O
b. di-tert-butyl peroxide
N
S
N
S
PAr2
H
R
R
H
PAr2
+
CH3CN, 80 oC, 30 h
c. 5 mol % Eosin B
11 W LED, CHCl3, rt
(Our Work)
a. Chem. Commun. 2015, 51, 3450-3453;
b. J. Org. Chem. 2014, 79, 8407-8416;
c. Org. Lett. 2016, 18, 452-455.
This work (Autoxidative coupling)
O
N
S
O
O2 balloon
N
S
PAr2
R
R
+
+
H
R
R
H-PAr2
Sovlent-free
65 oC, 18 h
O
N
PAr2
N
O
O2 balloon
H-PAr2
Sovlent-free
65 oC, 1 h
N
R'
N
R'
■
RESULTS AND DISCUSSION
The Table 1 depicts the optimized conditions after systematic screening, where the parameters alter in
solvent, temperature, atmosphere and reaction time. Initially, as the aforementioned result, 9% isolated yield
of 2ꢀ(diphenylphosphine oxide)benzo[d]thiazole (3aa) was detected in the coupling of benzothiazole (1a)
with diphenylphosphine oxide (2a) in refluxing chloroform under oxygen atmosphere (entry 1). A series of
solvents including 1,2ꢀdichloroethane, THF, dioxane, DMF, DME, EtOH, and toluene were then screened to
improve the yields. However, the couplings in common organic solvents only afforded low yields, albeit
21% yield of adduct were isolated in 1,1ꢀdichloroethane (entry 2). Quite interestingly, the couplings under
o
solventꢀfree conditions dramatically improved the yield to 97% when heated to 65 C (entry 11). Higher
reaction temperature of 100 oC led to lower yield (entry 13), which might be contributed to the
decomposition of substrates. Notably, the oxygen content significantly affected the coupling; only 37% of
product 3aa was detected under solventꢀfree and air with heating (entry 14), and the substrates remained
intact under the oxygenꢀfree condition (entry 18). Moreover, the ratios of substrates impacted the results as
well. The excess of diphenylphosphine oxide (2a) is necessary to obtain satisfactory yields. These results
indicate that oxygen atmosphere, solventꢀfree, appropriate temperature and substrate ratios are essential to
achieve the reaction efficiently.
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Table 1. Reaction condition optimizations: autoxidative
coupling of benzothiazoles and diphenylphosphine oxides.a
O
N
O2 balloon
O
N
S
PPh2
H
H
PPh2
+
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Sovlent-free
65 oC, 18 h
S
1a
2a
3aa
entry
variations
yield of 3aab
(based on standard conditions)
CHCl3, reflux, 24 h
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1,2ꢀdichloroethane, 65 oC, 24 h 21
THF, reflux, 24 h
dioxane, , 65 oC, 24 h
DMF, 65 oC, 24 h
DME, 65 oC, 24 h
EtOH, 65 oC, 24 h
toluene, 65 oC, 24 h
20oC
trace
trace
N.R.
17
trace
trace
33
91
97
85
52
9
10
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12
13
14
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16
17c
18d
50oC
None
80oC
100oC
air
N2
1a:2a=1:1
1a:2a=3:1
None
37
0
69
37
97
a0.2 mmol benzothiazole, 1 mmol diphenylphosphine oxide,
o
b
oxygen balloon, 65 C, 18 h; Isolated yield based on benzoꢀ
thiazole(1a). cIsolated yield based on diphenylphosphine oxide
(2a).dIn dark under standard conditions.
On the basis of this optimized conditions, we further evaluated the scope of thiazole derivatives and
diarylphosphine oxides that could participate in the autoxidative coupling. In general, the reactions were
remarkably sensitive to the electronic properties of substitutions on thiazole derivatives and phosphine
oxides. As shown in Scheme 2, diarylphosphine oxides bearing electronꢀdonating or withdrawing groups at
their paraꢀ and metaꢀpositions, including methoxy, and methyl, were applicable to the coupling with yields
up to 85% (compounds 3ab, 3ac, 3ae, 3af). Methyl substitutions on orthoꢀpositions of phosphine oxide
moieties led to the failure of coupling due to steric hindrance (compound 3ad). This effect was found to be
extremely detrimental for di(2,4,6ꢀtrimethylphenyl)phosphine oxide, the coupling ceased to afford couple of
decompositions. In addition, dialkylphosphine oxides and dialkylphosphites (3ag, 3ah) exhibited no
reactivity according to the standard conditions. Arylthiazoles with electronꢀwithdrawing groups, such as Brꢀ
and Clꢀ, were coupled with diarylphosphine oxides to afford the corresponding adducts in excellent yields
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(3faꢀ3ia). Substrates with strong electronꢀdonating methoxy (3ba) and strong electronꢀwithdrawing nitro
groups (3ea) gave comparable lower yields, which might be ascribed to the relatively unstable radical
intermediates. Notably, ethyl 4ꢀmethyl thiazoleꢀ5ꢀcarboxylate and methyl 4ꢀmethyl thiazoleꢀ5ꢀcarboxylate
could also react under the standard conditions affording the products 3ka, 3la, in yields of 78% and 70%,
respectively. Unfortunately, 4,5ꢀdimethylthiazole (3ma) was left intact even after systematic screening, in
part because of the less of conjugation on substrates to stabilize the radical intermediate. An attempt to
couple benzoxazole with diphenylphosphine oxide under standard conditions was found to be sluggish as
well.
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Scheme 2. Autoxidative coupling of thiazole derivatives
and diarylphosphine oxides.a,b
R1
R2
R1
R2
O
O
N
O2 balloon
N
S
H
H
PAr2
PAr2
+
Sovlent-free
65 oC, 18 h
S
1a-1h
2a-2h
3aa-3ha
O
O
O
S
N
S
N
S
PPh2
P(p-MeC6H4)2
P(m-MeC6H4)2
N
3aa, 97%
3ab, 85%
3ac, 21%
O
O
S
N
S
N
O
S
P(o-MeC6H4)2
P(p-F-C6H4)2
P(m-F-C6H4)2
N
3ad, trace
3ae, 56%
3af, 67%
O
O
S
S
MeO
O
S
PPh2
N
PCy2
P(OEt)2
N
N
3ag, 0%
3ah, trace
3ba, 62%
Me
N
O2N
O
O
Me
O
S
N
S
PPh2
PPh2
PPh2
S
N
3ca, 41%
3da, 61%
3ea, 55%
O
O
S
N
S
Br
O
S
PPh2
PPh2
PPh2
N
3ha, 91%
N
Br
Cl
N
3fa, 95%
3ga, 97%
O
O
S
N
F
O
S
N
PPh2
PPh2
O
PPh2
S
O
Cl
3ia, 90%
3ja, 57%
3ka, 78%
O
PPh2
N
S
O
O
N
O
S
N
PPh2
O
PPh2
O
3la, 70%
3ma, 0%
3na, trace
a 0.2 mmol thiazole derivatives, 1 mmol diarylphosphine oxide,
o
b
oxygen balloon, 65 C, 18 h; Isolated yield based on thiazole
derivatives.
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Further efforts were devoted to apply this autoxidative coupling to other heterocycles. Benzothiophene,
benzofuran, indole, quinoline and quinazoline derivatives were investigated with diarylphosphine oxides
affording negative results, where quinoline and quinazoline derivatives formed C(sp3)ꢀP bonds leading to
reductive addition products (see details in experimental section).21 To be noted, quinoxalines exhibited
similar reactivity to benzothiazoles while subjected to the above conditions. It’s well known that phosphinyl
functionalized quinoxaline are versatile intermediates in medicinal chemistry, coordination chemistry and
catalysis. However, the syntheses of diarylphosphinyl quinoxalines are rather trivial and limited.22 For an
elegant example, in 2015, Han et al. disclosed a nickel catalyzed CꢀO/P(O)ꢀH coupling of quinoxalinꢀ3ꢀyl
pivalate with diphenylphosphine oxide to access the 2ꢀ(diphenylphosphino) quinoxaline with 42% yield.22c
To the best of our knowledge, the direct CꢀH phosphorylation of quinoxaline derivatives has not been
established yet.
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The optimized conditions for thiazole derivatives were applied here directly (oxygen balloon, 65 oC,
solventꢀfree), with a ratio of 1.1:1 for quinoxaline (4aꢀh) and diarylphosphine oxides (2aꢀi). Quite
interestingly, while the mixtures solidified within 1 h, the coupling of diphenylphosphine oxide (2a) with
quinoxaline (4a) underwent completely to afford the adduct 5aa with 58% yield. Subsequently, varieties of
diarylphosphine oxides and quinoxaline derivatives were allowed to react. As shown in Scheme 3, all kinds
of diarylphosphine oxides bearing electronꢀdonating and withdrawing groups gave medium to good yields
(5abꢀ5ai), where electronꢀwithdrawing groups slightly impaired the reaction. Substituents on quinoxaline
moiety also proceeded with acceptable yields. When 5ꢀmethylꢀquinoxaline (4d) was used, the coupling
reaction run smoothly to produce 5da in 42% combined yield with a ratio of 1:2.8. In regard to the
5,6,7,8ꢀtetrahydroquinoxaline and 2,3ꢀdimethylpyrazine, no reactions were observed, which further indicated
the larger conjugation on heteroarenes is crucial to enable the autoxidative coupling.
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Scheme 3. Autoxidative coupling of quinoxaline
derivatives and diarylphosphine oxides.a,b
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O
N
PAr2
N
O
O2 balloon
R
+
R
H-PAr2
Sovlent-free
65 oC, 1 h
N
R'
N
R'
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4a-4h
2a-2i
5aa-5ha
O
O
O
N
N
PPh2
N
N
P(p-MeC6H4)2
N
N
P(m-MeC6H4)2
5aa, 58%
5ab, 80%
5ac, 60%
O
O
O
N
P(o-MeC6H4)2
N
N
P(p-MeO-C6H4)2
N
N
P(3,5-dimethyl-C6H3)2
N
5ad, 55%
5ae, 48% (85 oC)
5af, 60%
O
O
O
N
P(p-F-C6H4)2
N
N
P(m-F-C6H4)2
N
N
P(p-CF3-C6H4)2
N
5ag, 45%
5ah, 36%
5ai, 42%
O
O
O
N
N
PPh2
N
PPh2
N
N
PPh2
N
N
Me
N
Cl
PPh2
O
Me
Me
5ba, 57%
Me
5ca, 26%
5da, 42% (1:2.8 mixture)
O
O
O
N
N
PPh2
Me
Me
N
P(p-F-C6H4)2
Me
Me
N
P(m-Me-C6H4)2
Me
N
N
5ea, 30%
5fc, 54%
5fg, 40%
O
O
O
Me
Me
N
N
P(m-F-C6H4)2
Me
Me
N
PPh2
N
N
PPh2
N
5fh, 35%
5ga, 0%
5ha, 0%
a0.22 mmol quinoxaline derivatives, 0.2 mmol diarylphosphine
oxide, oxygen balloon, 65 oC, 1 h; bIsolated yield based on
diarylphosphine oxide.
In order to gain an understanding of the reaction mechanisms of this C(sp2)ꢀP formation, we performed
some controlling and deuterium experiments. Initially, 4 equivalents of TEMPO (2,2,6,6ꢀtetramethylꢀ1ꢀ
piperidinyloxy) was found to suppress the reaction completely, thus, a radical mechanism might occur in the
process (Scheme 4, eq. a). The isolation of deuterium exchange product 2aꢀD and TEMPO captured adduct 6
testified the initiation of coupling from Pꢀradical (eq. b and c, see details in supporting information). Next, a
rapid color change of FeCl2/KSCN solution toward reaction mixtures indicated the generation of peroxide
from diphenylphosphine oxide. Finally, the utility of common radical initiators, AIBN and diꢀtertꢀbutyl
peroxide (DTBP), dramatically accelerated the coupling reactions while combining with molecular oxygen
under solventꢀfree conditions, which further confirmed the radical mechanism of this reaction (eq. d). The
above results coupled with previous reports on oxidative couplings,2c,18 collectively point to a proposed
mechanism in Scheme 4. The oxygen excite the diphenylphosphine oxide under heat to generate a Pꢀradical
2’a, along with a peroxide radical. The peroxide radical undergoes hydrogen atom abstraction of the
2ꢀposition of C(sp2)ꢀH of benzothiazole to form intermediate 1’a, with H2O and oxygen released as well.
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Eventually, two radicals 1’a and 2’a combine to give the coupling product 3aa.
4
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6
7
8
9
Scheme 4. Tentative mechanism for the autoxidative
coupling of heteroarenes with diphenylphosphine oxide.
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O
Ph
P
H
O2
Ph
2a
O
Ph
P
O OH
Ph
S
N
N
N
H
H
OOH
1a
4a
O
O
P
S
N
N
Ph
P
Ph
-H2O,
-1/2O2
Ph
2'a
N
Ph
2'a
1'a
4'a
O
N
N
PPh2
O
S
PPh2
N
3aa
5aa
■
CONCLUSIONS
In conclusion, a direct autoxidative phosphorylation of heteroarenes induced by oxygen under metalꢀfree
and solventꢀfree conditions was disclosed. Thiazole and quinoxaline derivatives were enabled to coupling
with various diarylphosphine oxides by this novel economical, operational simple and environmental
friendly approach toward (Het)C(sp2)ꢀP formation. Mechanistic studies verified this coupling undergoes
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through a radical pathway initiated by diarylphosphine oxide.
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■
EXPERIMENTAL SECTION
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General Methods. Solvents and reagents were reagent grade and used without purification unless
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otherwise noted. Anhydrous solvents were obtained as follows: THF, 1,4ꢀdioxane and toluene were dried by
distillation from sodium and benzophenone; CHCl3, DMF were redistilled over CaH2. All reactions were
carried out in oven dried glassware under oxygen unless otherwise specified. Column chromatography was
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performed using silica gel (300ꢀ400 mesh). H NMR, 13C NMR and 31P NMR spectra were recorded in
CDCl3 operating at 400, 100 and 162 MHz in the presence of tetramethylsilane (TMS) as an internal
standard and are reported in ppm (δ). Coupling constants are reported in Hertz (Hz). Spectral splitting
patterns are designated as s, singlet; d, doublet; t, triplet; q, quartet; p, pentet; m, multiplet; and br, broad.
Synthetic Procedures. General Procedure for the Autoxidative coupling of thiazole derivatives with
diarylphosphine oxides to Access compounds (3): 2-(diphenylphosphine oxide)benzo[d]thiazole (3aa)19. To a
5 mL vial equipped with oxygen balloon was added benzo[d]thiazole (1a, 27.0 mg, 0.2 mmol) and
diphenylphosphine oxide (2a, 202.1 mg, 1 mmol). The reaction was then heated to 65 0C for 18 hours until
the complete consuming of starting materials monitored by TLC. After being cooling down, the mixtures
were quenched by adding water, and then extracted with ethyl acetate (3 mL×2). The crude product was
purified on flash chromatography, with ethyl acetate/petroleum ether (1:1) as eluents to afford product 3aa as
white solid (67 mg, 97% yield). 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 7.8 Hz, 1H), 8.05ꢀ8.01 (m, 1H),
8.01ꢀ7.93 (m, 4H), 7.65ꢀ7.43 (m, 8H). 13C NMR (100 MHz, CDCl3) δ 166.6 (d, J = 127.0 Hz), 155.2 (d, J =
21.6 Hz), 136.6, 132.5 (d, J = 2.9 Hz), 131.8 (d, J = 10.2 Hz), 130.8 (d, J = 109.0 Hz), 128.5 (d, J = 12.8 Hz),
126.5 (d, J = 4.3 Hz), 124.6, 121.9. 31P NMR (162 MHz, CDCl3) δ 20.07 (s).
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benzo[d]thiazol-2-yldi-p-tolylphosphine oxide(3ab).19 A yellow liquid (60 mg, 85% yield). H NMR (400
MHz, CDCl3) δ 8.18 (d, J = 8.2 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.84 (dd, J = 12.5, 8.1 Hz, 4H), 7.49 (tdd,
J = 15.1, 10.8, 4.2 Hz, 2H), 7.29 (dd, J = 8.1, 2.8 Hz, 4H), 2.38 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 167.2
(d, J = 126.3 Hz), 155.2 (d, J = 21.4 Hz), 143.1 (d, J = 2.9 Hz), 136.6, 131.8 (d, J = 10.6 Hz), 129.2 (d, J =
13.2 Hz), 127.6 (d, J = 111.6 Hz), 126.4 (d, J = 6.6 Hz), 124.5, 121.9, 21.5. 31P NMR (162 MHz, CDCl3) δ
20.80 (s).
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benzo[d]thiazol-2-yldi-m-tolylphosphine oxide(3ac).19 A white solid (15 mg, 21% yield). H NMR (400
MHz, CDCl3) δ 8.21 (d, J = 8.2 Hz, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.76 (m, 4H), 7.53 (m, 2H), 7.44ꢀ7.31 (m,
4H), 2.39 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 167.0 (d, J = 126.0 Hz), 155.3 (d, J = 21.4 Hz), 138.5 (d, J
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= 12.7 Hz), 136.8, 133.4 (d, J = 2.9 Hz), 132.2 (d, J = 10.0 Hz), 130.6 (d, J = 108.5 Hz), 129.0 (d, J = 10.5
Hz), 128.5 (d, J = 13.6 Hz), 126.5 (d, J = 6.3 Hz), 124.7, 122.0, 21.4 . 31P NMR (162 MHz, CDCl3) δ 20.75
(s).
benzo[d]thiazol-2-ylbis(4-fluorophenyl)phosphine oxide(3ae).19 A white solid (44 mg, 56% yield). 1H
NMR (400 MHz, CDCl3) δ 8.19 (d, J = 8.1 Hz, 1H), 8.03ꢀ7.96 (m, 5H), 7.52 (dt, J = 15.0, 7.2 Hz, 2H), 7.20
(td, J = 8.6, 1.9 Hz, 4H). 13C NMR (100 MHz, CDCl3) δ 166.9ꢀ166.0 (m), 165.4 (s), 164.1 (d, J = 3.4 Hz),
155.1 (d, J = 21.9 Hz), 136.5, 134.3 (dd, J = 11.7, 9.1 Hz), 126.7 (dd, J = 113.1, 3.0 Hz), 126.7, 124.5, 122.0,
116.0 (dd, J = 21.6, 14.1 Hz). 31P NMR (162 MHz, CDCl3) δ 18.29 (s).
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benzo[d]thiazol-2-ylbis(3-fluorophenyl)phosphine oxide(3af).19 A white solid (50 mg, 67% yield). 1H
NMR (400 MHz, CDCl3) δ 8.22 (d, J = 8.0 Hz, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.86ꢀ7.66 (m, 4H), 7.63ꢀ7.39
(m, 4H), 7.35ꢀ7.20 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 165.0 (d, J = 131.3 Hz), 163.6 (d, J = 18.2 Hz),
161.1 (d, J = 18.2 Hz), 155.1 (d, J = 22.2 Hz), 136.6 (s), 133.0 (dd, J = 108.8, 5.9 Hz), 130.7 (dd, J = 15.0,
7.4 Hz), 127.5 (dd, J = 9.5, 3.3 Hz), 126.9 (d, J = 3.1 Hz), 124.8, 122.05, 120.0 (dd, J = 21.2, 2.6 Hz), 118.6
(dd, J = 22.9, 11.2 Hz). 31P NMR (162 MHz, CDCl3) δ 16.78 (t, J = 6.3 Hz).
(6-methoxybenzo[d]thiazol-2-yl)diphenylphosphine oxide(3ba).19 A yellow liquid (49 mg, 62% yield). 1H
NMR (400 MHz, CDCl3) δ 8.06 (d, J = 9.1 Hz, 1H), 8.00ꢀ7.91 (m, 4H), 7.57 (td, J = 7.3, 1.4 Hz, 2H), 7.53ꢀ
7.45 (m, 4H), 7.41 (d, J = 2.4 Hz, 1H), 7.15 (dd, J = 9.1, 2.5 Hz, 1H), 3.88 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 163.2 (d, J = 130.0 Hz), 158.8, 150.0 (d, J = 22.0 Hz), 138.5, 132.5 (d, J = 2.9 Hz), 131.8 (d, J =
10.2 Hz), 131.1 (d, J = 109.0 Hz), 128.5 (d, J = 12.8 Hz), 125.2, 117.1, 103.3, 55.8. 31P NMR (122 MHz,
CDCl3) δ 20.07 (s).
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(4-methylbenzo[d]thiazol-2-yl)diphenylphosphine oxide(3ca).19 A white solid (29 mg, 41% yield). H
NMR (400 MHz, CDCl3) δ 8.06ꢀ7.94 (m, 4H), 7.82 (d, J = 7.9 Hz, 1H), 7.56 (dd, J = 10.4, 4.3 Hz, 2H), 7.49
(td, J = 7.4, 3.2 Hz, 4H), 7.36 (dt, J = 14.8, 7.3 Hz, 2H), 2.78 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 164.7
(d, J = 129.0 Hz), 154.8 (d, J = 21.1 Hz), 136.5, 134.7, 132.4 (d, J = 2.8 Hz), 131.8 (d, J = 10.1 Hz), 130.6,
128.4 (d, J = 12.8 Hz), 126.9, 126.5, 119.3, 18.3. 31P NMR (162 MHz, CDCl3) δ 19.39 (s).
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(6-methylbenzo[d]thiazol-2-yl)diphenylphosphine oxide(3da).19 A white solid (43 mg, 61% yield). H
NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.5 Hz, 1H), 7.95 (dd, J = 12.6, 7.2 Hz, 4H), 7.78 (s, 1H), 7.60 –
7.52 (m, 2H), 7.48 (td, J = 7.4, 3.0 Hz, 4H), 7.35 (d, J = 8.4 Hz, 1H), 2.50 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 165.1 (d, J = 128.4 Hz), 153.5 (d, J = 21.9 Hz), 137.0 (d, J = 5.4 Hz), 132.5 (d, J = 2.8 Hz), 131.8
(d, J = 10.2 Hz), 131.0 (d, J = 109.0 Hz), 128.6 (d, J = 12.8 Hz), 128.4, 124.1, 121.5, 21.6. 31P NMR (162
MHz, CDCl3) δ 20.12 (s).
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(6-nitrobenzo[d]thiazol-2-yl)diphenylphosphine oxide(3ea).19 A yellow solid (43 mg, 55% yield). 1H NMR
(400 MHz, CDCl3) δ 8.97 (d, J = 2.2 Hz, 1H), 8.42 (dd, J = 9.1, 2.2 Hz, 1H), 8.30 (d, J = 9.1 Hz, 1H), 8.09ꢀ
7.88 (m, 4H), 7.63 (td, J = 7.3, 1.4 Hz, 2H), 7.59ꢀ7.48 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 174.2 (d, J =
119.5 Hz), 158.4 (d, J = 20.8 Hz), 145.8, 137.0, 133.0 (d, J = 2.9 Hz), 131.9 (d, J = 10.3 Hz), 130.0 (d, J =
109.5 Hz), 128.8 (d, J = 13.0 Hz), 125.2, 121.9, 118.8. 31P NMR (162 MHz, CDCl3) δ 19.90 (s).
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(5-bromobenzo[d]thiazol-2-yl)diphenylphosphine oxide(3fa).19 A white solid (92 mg, 95% yield). 1H
NMR (400 MHz, CDCl3) δ 8.34 (d, J = 1.1 Hz, 1H), 7.97 (dd, J = 12.6, 7.4 Hz, 4H), 7.85 (d, J = 8.6 Hz, 1H),
7.58 (t, J = 7.2 Hz, 3H), 7.50 (td, J = 7.4, 3.1 Hz, 4H). 13C NMR (100 MHz, CDCl3) δ 169.0 (d, J = 124.2
Hz), 156.4 (d, J = 21.4 Hz), 135.5, 132.7 (d, J = 2.9 Hz), 131.8 (d, J = 10.2 Hz), 130.6 (d, J = 109.1 Hz),
129.8, 128.7 (d, J = 12.9 Hz), 127.4, 123.1, 120.4. 31P NMR (162 MHz, CDCl3) δ 19.77 (s).
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(6-bromobenzo[d]thiazol-2-yl)diphenylphosphine oxide(3ga).19 A white solid (80 mg, 97% yield). H
NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.96 (dd, J = 12.6, 7.6 Hz, 4H), 7.63 (d, J
= 8.8 Hz, 1H), 7.58 (t, J = 7.2 Hz, 2H), 7.51 (dt, J = 7.0, 3.5 Hz, 4H). 13C NMR (100 MHz, CDCl3) δ 167.5
(d, J = 125.1 Hz), 154.1 (d, J = 21.4 Hz), 138.3, 132.7 (d, J = 2.8 Hz), 131.8 (d, J = 10.3 Hz), 130.5 (d, J =
109.1 Hz), 130.3, 128.6 (d, J = 12.9 Hz), 125.7, 124.5, 120.7. 31P NMR (162 MHz, CDCl3) δ 19.97 (s).
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(5-chlorobenzo[d]thiazol-2-yl)diphenylphosphine oxide(3ha).19 A white solid (68 mg, 91% yield). H
NMR (400 MHz, CDCl3) δ 8.18 (d, J = 1.9 Hz, 1H), 8.02ꢀ7.93 (m, 4H), 7.91 (d, J = 8.6 Hz, 1H), 7.63ꢀ7.55
(m, 2H), 7.51 (tdd, J = 8.2, 3.2, 1.2 Hz, 4H), 7.45 (dd, J = 8.6, 1.7 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ
169.1 (d, J = 124.3 Hz), 156.0 (d, J = 21.5 Hz), 135.0, 132.8, 132.7 (d, J = 2.9 Hz), 131.8 (d, J = 10.3 Hz),
130.6 (d, J = 109.2 Hz), 128.7 (d, J = 12.9 Hz), 127.2, 124.3, 122.8. 31P NMR (162 MHz, CDCl3) δ 19.86 (s).
(4-chlorobenzo[d]thiazol-2-yl)diphenylphosphine oxide(3ia).19 A white solid (66 mg, 90% yield). 1H NMR
(400 MHz, CDCl3) δ 8.07 – 8.02 (m, 4H), 7.87 (d, J = 8.1 Hz, 1H), 7.58 – 7.56 (m, 1H), 7.54 – 7.47 (m, 6H),
7.37 (t, J = 7.9 Hz, 1H).13C NMR (100MHz, CDCl3) δ 167.8 (d, J = 124.7 Hz), 152.3 (d, J = 21.5 Hz), 138.1,
132.6 (d, J = 2.9 Hz), 131.8(d, J = 10.2 Hz), 131.2, 130.1, 129.5, 128.6 (d, J = 12.9 Hz), 126.9 (d, J = 24.1
Hz), 120.5. 31P NMR (162 MHz, CDCl3) δ 19.00 (s).
(6-fluorobenzo[d]thiazol-2-yl)diphenylphosphine oxide(3ja).19 A white solid (40 mg, 57% yield). 1H NMR
(400 MHz, CDCl3) δ 8.12 (dd, J = 9.0, 4.8 Hz, 1H), 7.96 (dd, J = 12.6, 7.3 Hz, 4H), 7.66 (dd, J = 8.0, 2.3 Hz,
1H), 7.59ꢀ7.55 (m, 2H), 7.49 (td, J = 7.4, 3.1 Hz, 4H), 7.30ꢀ7.25 (m, 1H). 13C NMR (100 MHz, CDCl3) δ
166.5 (dd, J = 126.5, 3.6 Hz), 161.1 (d, J = 249.0 Hz),151.9 (d, J = 21.8 Hz), 137.8 (d, J = 11.4 Hz), 132.6 (d,
J = 2.9 Hz), 131.7 (d, J = 10.3 Hz), 130.6 (d, J = 109.2 Hz), 128.6 (d, J = 12.9 Hz), 125.7 (d, J = 9.7 Hz),
115.8 (d, J = 25.3 Hz), 107.9 (d, J = 26.8 Hz). 31P NMR (162 MHz, CDCl3) δ 19.91 (s).
ethyl 2-(diphenylphosphoryl)-4-methylthiazole-5-carboxylate(3ka).19 A white solid (59 mg, 78% yield). 1H
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NMR (400 MHz, CDCl3) δ 7.97ꢀ7.86 (m, 4H), 7.65ꢀ7.56 (m, 2H), 7.51 (tdd, J = 8.2, 3.2, 1.2 Hz, 4H), 4.36
(q, J = 7.1 Hz, 2H), 2.82 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 167.6 (d, J = 125.8
Hz), 163.0 (d, J = 19.0 Hz), 161.6, 132.6 (d, J = 2.9 Hz), 131.8 (d, J = 10.3 Hz), 130.8 (d, J = 109.4 Hz),
128.6 (d, J = 12.8 Hz), 127.4, 61.7, 17.6, 14.2. 31P NMR (162 MHz, CDCl3) δ 18.80 (s).
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methyl 2-(diphenylphosphoryl)-4-methylthiazole-5-carboxylate(3la).19 A white solid (48 mg, 70% yield).
1H NMR (400 MHz, CDCl3) δ 7.96ꢀ7.90 (m, 4H), 7.63ꢀ7.58 (m, 2H), 7.55ꢀ7.50 (m, 4H), 3.91 (s, 3H), 2.83 (s,
3H). 13C NMR (100 MHz, CDCl3) δ 167.8 (d, J = 125.6 Hz), 163.2 (d, J = 19.0 Hz), 162.1, 132.7 (d, J = 2.9
Hz), 131.8 (d, J = 10.3 Hz), 130.7 (d, J = 109.5 Hz), 128.7 (d, J = 12.9 Hz), 126.9, 52.5, 17.6. 31P NMR (162
MHz, CDCl3) δ 18.78 (s).
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General Procedure for the Autoxidative coupling of quinoxaline derivatives with diarylphosphine oxides
to Access compounds (5): diphenyl(quinoxalin-2-yl)phosphine oxide(5aa).22c To a 5 mL vial equipped with
oxygen balloon was added quinoxaline (4a, 28.6 mg, 0.22 mmol) and diphenylphosphine oxide (2a, 40.4 mg,
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0.2 mmol). The reaction was then heated to 65 C for 1 hour until the complete consuming of starting
materials monitored by TLC. After being cooling down, the mixtures were quenched by adding water, and
then extracted with ethyl acetate (3 mL×2). The crude product was purified on flash chromatography, with
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ethyl acetate/petroleum ether (1:1) as eluents to afford product 5aa as yellow solids (38 mg, 58% yield). H
NMR (400 MHz, CDCl3) δ 9.64 (s, 1H), 8.18ꢀ8.14 (m, 2H), 7.99ꢀ7.94 (m, 4H), 7.86ꢀ7.81 (m, 2H), 7.56ꢀ
7.53 (m, 2H), 7.48 (tdd, J = 8.3, 3.1, 1.3 Hz, 4H). 13C NMR (100 MHz, CDCl3) δ 152.3 (d, J = 124.2 Hz),
146.5 (d, J = 22.1 Hz), 142.7 (d, J = 2.3 Hz), 142.2 (d, J = 17.1 Hz), 132.3 (d, J = 2.8 Hz), 132.1 (d, J = 9.6
Hz), 131.9 , 131.5 (d, J = 104.2 Hz), 130.7, 130.20, 129.7 (d, J = 1.8 Hz), 128.6 (d, J = 12.3 Hz). 31P NMR
(162 MHz, CDCl3) δ 20.40 (s).
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quinoxalin-2-yldi-p-tolylphosphine oxide(5ab). A brown solid, m.p.: 178.7ꢀ180.1 C (85 mg, 80% yield).
1H NMR (400 MHz, CDCl3) δ 9.61 (s, 1H), 8.15 (dd, J = 11.0, 4.2 Hz, 2H), 7.86ꢀ7.79 (m, 6H), 7.29 (dd, J =
8.1, 2.6 Hz, 4H), 2.40 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 152.6 (d, J = 123.9 Hz), 146.3 (d, J = 22.1 Hz),
142.8 (d, J = 2.8 Hz), 142.5 (d, J = 2.3 Hz), 142.1 (d, J = 16.9 Hz), 132.1 (d, J = 10.0 Hz), 131.1 (d, J =
120.9 Hz), 130.1, 129.5, 129.2 (d, J = 12.8 Hz), 128.1 (d, J = 107.4 Hz), 21.6. 31P NMR (162 MHz, CDCl3) δ
21.33 (s). HRꢀMS m/z (ESI): C22H20N2OP (calcd.: 359.1313), found: 359.1307 ([M+H]+). IR (film)
2907, 2856, 1599, 1485, 1360, 1321, 1216, 1192, 1116, 1091, 1017, 967, 812, 769.
v 3031,
quinoxalin-2-yldi-m-tolylphosphine oxide(5ac). A yellow solid, m.p.: 143.8ꢀ144.4 oC (63 mg, 60% yield).
1H NMR (400 MHz, CDCl3) δ 9.63 (s, 1H), 8.17 (dd, J = 8.2, 1.5 Hz, 2H), 7.88ꢀ7.78 (m, 4H), 7.73 (dd, J =
12.7, 4.9 Hz, 2H), 7.39ꢀ7.36 (m, 4H), 2.37 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 152.3 (d, J = 123.6 Hz),
146.3 (d, J = 22.1 Hz), 142.5 (d, J = 2.3 Hz), 142.1 (d, J = 17.1 Hz), 138.4 (d, J = 12.2 Hz), 133.0 (d, J = 2.9
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Hz), 132.3 (d, J = 9.4 Hz), 131.8, 131.6, 130.6, 129.8 (dd, J = 62.3, 1.4 Hz), 129.1 (d, J = 9.8 Hz), 128.3 (d,
J = 13.1 Hz), 21.3. 31P NMR (162 MHz, CDCl3) δ 20.98 (s). HRꢀMS m/z (ESI): C22H19N2OPNa (calcd.:
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381.1133), found: 381.1125 ([M+Na]+). IR (film)
1120, 1060, 1027, 872, 766, 668.
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quinoxalin-2-yldi-o-tolylphosphine oxide(5ad). A yellow solid, m.p.: 146.2ꢀ147.5 C (45 mg, 55% yield).
1H NMR (400 MHz, CDCl3) δ 9.58 (s, 1H), 8.22 (d, J = 7.6 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.93 – 7.88 (m,
1H), 7.86ꢀ7.82 (m, 1H), 7.46 (td, J = 14.5, 7.6 Hz, 4H), 7.33 (dd, J = 7.4, 4.6 Hz, 2H), 7.23 (t, J = 6.6 Hz,
2H), 2.50 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 152.7 (d, J = 122.9 Hz), 147.2 (d, J = 22.6 Hz), 143.1 (d, J
= 8.5 Hz), 142.5, 142.0 (d, J = 16.9 Hz), 133.1 (d, J = 12.1 Hz), 132.4, 132.2ꢀ131.6 (m), 130.5 (d, J = 34.5
Hz), 129.6 (d, J = 102.5 Hz), 129.6, 125.6 (d, J = 12.9 Hz), 21.9.31P NMR (162 MHz, CDCl3) δ 29.77 (s).
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HRꢀMS m/z (ESI): C22H20N2OP (calcd.:359.1313)，found: 359.1301（[M+H]+）. IR (film)
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bis(3,5-dimethylphenyl)(quinoxalin-2-yl)phosphine oxide(5ae). A yellow red solid, m.p.: 144.6ꢀ146.3 C
(56 mg, 48% yield). 1H NMR (400 MHz, CDCl3) δ 9.61 (s, 1H), 8.19 (dd, J = 6.1, 1.9 Hz, 2H), 7.90ꢀ7.82 (m,
2H), 7.55 (d, J = 12.4 Hz, 4H), 7.19 (s, 2H), 2.35 (s, 12H). 13C NMR (100 MHz, CDCl3) δ 152.7 (d, J =
123.0 Hz), 146.5 (d, J = 22.1 Hz), 142.6 (d, J = 2.3 Hz), 142.3 (d, J = 17.0 Hz), 138.3 (d, J = 13.0 Hz), 134.1
(d, J = 2.9 Hz), 131.2 (d, J = 120.6 Hz), 131.1 (d, J = 103.3 Hz), 130.3, 129.7, 129.6, 21.4. 31P NMR (162
MHz, CDCl3) δ 21.87 (s). HRꢀMS m/z (ESI): C24H24N2OP (calcd.: 387.1626), Found: 387.1620 ([M+H]+).
IR (film) v 3047, 2911, 2851, 1529, 1485, 1441, 1362, 1317, 1265, 1190, 1130, 1099, 1033, 966, 848, 769.
bis(4-methoxyphenyl)(quinoxalin-2-yl)phosphine oxide(5af). A white solid, m.p.:182.5ꢀ184.1 oC (67 mg,
60% yield ). 1H NMR (400 MHz, CDCl3) δ 9.61 (s, 1H), 8.16ꢀ8.12 (m, 2H), 7.87ꢀ7.79 (m, 6H), 6.97 (dd, J =
8.8, 2.2 Hz, 4H), 3.81 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 162.8 (d, J = 2.9 Hz), 152.9 (d, J = 124.8 Hz),
146.4 (d, J = 22.1 Hz), 142.5 (d, J = 2.3 Hz), 142.2 (d, J = 17.0 Hz), 134.1 (d, J = 11.0 Hz), 131.8, 130.6,
129.9 (d, J = 57.9 Hz), 122.7 (d, J = 112.0 Hz), 114.2 (d, J = 13.4 Hz), 55.4. 31P NMR (162 MHz, CDCl3) δ
21.32 (s). HRꢀMS m/z (ESI): C22H19N2O3PNa (calcd.: 413.1031 ), found: 413.1024 ([M+Na]+). IR (film)
3100, 2978, 2852, 1597, 1505, 1405, 1259, 1177, 1121, 1059, 1024, 965, 869, 765.
v
bis(4-fluorophenyl)(quinoxalin-2-yl)phosphine oxide(5ag). A yellow solid, m.p.: 178.3ꢀ179.5 oC (50 mg,
45% yield). 1H NMR (400 MHz, CDCl3) δ 9.67 (s, 1H), 8.19 (dd, J = 17.0, 7.8 Hz, 2H), 7.99 (ddd, J = 11.7,
8.5, 5.6 Hz, 4H), 7.93ꢀ7.87 (m, 2H), 7.21 (td, J = 8.7, 2.2 Hz, 4H). 13C NMR (100 MHz, CDCl3) δ 165.4 (d,
J = 257.8 Hz), 151.7 (d, J = 126.5 Hz), 146.3 (d, J = 22.2 Hz), 142.8, 142.1 (d, J = 17.4 Hz), 134.7 (dd, J =
11.0, 9.0 Hz), 131.6 (d, J = 124.7 Hz), 129.9 (d, J = 31.3 Hz), 127.3 (d, J = 108.4 Hz), 116.1 (dd, J = 21.5,
13.5 Hz). 31P NMR (162 MHz, CDCl3) δ 18.86 (s). HRꢀMS m/z (ESI): C20H14F2N2OP (calcd.: 367.0812),
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found: 367.0806 ([M+H]+). IR (film)
1116, 1090, 963, 815, 760.
v 3067, 2911, 2843, 1584, 1500, 1486, 1397, 1361, 1320, 1234, 1194,
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7
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bis(3-fluorophenyl)(quinoxalin-2-yl)phosphine oxide(5ah). An orange solid, m.p.: 143.6ꢀ144.7 oC (37 mg,
36% yield). 1H NMR (400 MHz, CDCl3) δ 9.66 (s, 1H), 8.20 (d, J = 8.2 Hz, 2H), 7.89 (dq, J = 7.0, 5.6 Hz,
2H), 7.79 (dd, J = 11.7, 7.7 Hz, 2H), 7.74ꢀ7.68 (m, 2H), 7.53ꢀ7.47 (m, 2H), 7.29ꢀ7.24 (m, 2H). 13C NMR
(100 MHz, CDCl3) δ 163.7 (d, J = 17.5 Hz), 161.2 (d, J = 17.5 Hz), 151.0 (d, J = 127.2 Hz), 146.3 (d, J =
22.4 Hz), 142.9, 142.1 (d, J = 17.5 Hz), 134.2 (d, J = 5.8 Hz), 133.1 (d, J = 5.8 Hz), 131.7 (d, J = 129.7 Hz),
130.7 (dd, J = 14.4, 7.5 Hz), 130.2ꢀ129.7 (m), 127.8 (dd, J = 8.9, 3.3 Hz), 119.8 (dd, J = 21.2, 2.6 Hz), 118.9
(dd, J = 22.8, 10.5 Hz). 31P NMR (162 MHz, CDCl3) δ 17.09 (t, J = 6.2 Hz). HRꢀMS m/z (ESI):
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C20H13F2N2OPNa (calcd.: 389.0631), found: 389.0622 ([M+Na]+). IR (film)
1418, 1363, 1323, 1226, 1193, 1127, 1093, 966, 879, 764.
v 3047, 2919, 2843, 1583, 1472,
quinoxalin-2-ylbis(4-(trifluoromethyl)phenyl)phosphine oxide(5ai). A yellow solid, m.p.: 136.8ꢀ138.3 oC
(41 mg, 42% yield). 1H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 8.19 (td, J = 12.1, 8.5 Hz, 6H), 7.92 (dt, J =
15.0, 6.2 Hz, 2H), 7.78 (d, J = 6.4 Hz, 4H). 13C NMR (100 MHz, CDCl3) δ 150.5 (d, J = 127.4 Hz), 146.3 (d,
J = 22.4 Hz), 143.0 (d, J = 2.3 Hz), 142.1 (d, J = 17.5 Hz), 135.3 (d, J = 103.0 Hz), 134.3 (dd, J = 32.9, 3.0
Hz), 132.5 (d, J = 9.7 Hz), 131.3, 130.1, 129.9 (d, J = 1.9 Hz), 125.7ꢀ125.5 (m), 123.4 (d, J = 273.4 Hz). 31
P
NMR (162 MHz, CDCl3) δ 16.79. HRꢀMS m/z (ESI): C22H14F6N2OP (calcd.: 467.0748), found: 467.0740
([M+H]+). IR (film)
963, 865.
v 3019, 2939, 2835, 1587, 1502, 1397, 1363, 1321, 1217, 1192, 1117, 1101, 1062, 1023,
(3-methylquinoxalin-2-yl)diphenylphosphine oxide(5ba).22a A dark red solid. m.p.: 159.1ꢀ160.3 oC (58 mg,
1
57% yield). H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.83 (dt, J =
14.8, 7.5 Hz, 5H), 7.71 (t, J = 7.6 Hz, 1H), 7.58 (t, J = 7.4 Hz, 2H), 7.50 (td, J = 7.7, 2.7 Hz, 4H), 3.01 (s,
3H). 13C NMR (100 MHz, CDCl3) δ 156.7 (d, J = 22.1 Hz), 151.5 (d, J = 124.2 Hz), 141.7, 139.9 (d, J =
17.5 Hz), 132.2 (d, J = 9.4 Hz), 132.0 (d, J = 15.4 Hz), 131.1, 130.0, 129.4, 128.5 (d, J = 2.2 Hz), 128.4 (d, J
= 12.3 Hz), 23.7. 31P NMR (162 MHz, CDCl3) δ 27.28.
(3-chloroquinoxalin-2-yl)diphenylphosphine oxide(5ca). A yellow solid, m.p.: 198.8ꢀ199.5 oC (29 mg,
1
26% yield). H NMR (400 MHz, CDCl3 ) δ 8.05 (d, J = 8.4 Hz,1H), 7.97 (d, J = 8.4 Hz,1H), 7.90ꢀ7.75 (m,
6H), 7.60 (td, J = 7.3, 1.3 Hz,2H), 7.54ꢀ7.49 (m,4H). 13C NMR (100 MHz, CDCl3) δ 150.8 (d, J = 127.1 Hz),
148.7 (d, J = 21.6 Hz), 141.8, 139.9 (d, J = 15.3 Hz), 133.2, 132.4 (d, J = 2.7 Hz), 132.1 (d, J = 9.7 Hz),
130.5 (d, J = 108.3 Hz), 130.4 (d, J = 54.3 Hz), 128.5 (d, J = 12.7 Hz), 128.3. 31P NMR (162 MHz, CDCl3) δ
27.61. HRꢀMS m/z (ESI): C20H14ClN2OPNa (calcd.: 387.0430), found: 387.0421 ([M+Na]+). IR (film)
v
3059, 2923, 2839, 1554, 1477, 1437, 1369, 1333, 1252, 1175, 1115, 1099, 1009, 772, 754, 725, 707, 694.
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o
(5-methylquinoxalin-2-yl)diphenylphosphine oxide(5da-1). A brown solid, m.p.: 155.2ꢀ156.3 C (23 mg,
11% yield). 1H NMR (400 MHz, CDCl3) δ 9.60 (s, 1H), 8.00ꢀ7.98 (m, 2H), 7.96 (d, J = 1.4 Hz, 1H), 7.95 (s,
1H), 7.93 (d, J = 1.3 Hz, 1H), 7.70 (dd, J = 9.5, 4.7 Hz, 2H), 7.57ꢀ7.53 (m, 2H), 7.48 (ddd, J = 7.1, 5.4, 2.5
Hz, 4H), 2.82 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 151.6 (d, J = 124.8 Hz), 145.2 (d, J = 22.3 Hz), 142.4
(d, J = 17.0 Hz), 141.9 (d, J = 2.3 Hz), 138.1, 132.2 (d, J = 2.8 Hz), 132.1 (d, J = 9.6 Hz), 131.1 (d, J = 131.8
Hz), 131.1, 128.5 (d, J = 12.3 Hz), 128.0, 17.3. 31P NMR (162 MHz, CDCl3) δ 20.49. HRꢀMS m/z (ESI):
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C21H18N2OP (calcd.: 345.1157), found: 345.1151 ([M+H]+). IR(film)
1360, 1313, 1192, 1120, 1098, 997, 920, 847, 751, 705.
v
3055, 2920, 2843, 1526, 1483, 1435,
o
(8-methylquinoxalin-2-yl)diphenylphosphine oxide(5da-2). A brown solid, m.p.:206.8ꢀ207.1 C (63 mg,
1
31% yield). H NMR (400 MHz, CDCl3) δ 9.62 (s, 1H), 7.99ꢀ7.96 (m, 4H), 7.94 (d, J = 1.4 Hz, 1H), 7.75ꢀ
7.71 (m, 1H), 7.63 (d, J = 7.0 Hz, 1H), 7.53 (dd, J = 7.4, 1.4 Hz, 1H), 7.51 (t, J = 2.5 Hz, 1H), 7.45 (ddd, J =
7.1, 5.4, 2.4 Hz, 4H), 2.71 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 150.6 (d, J = 125.9 Hz), 146.1 (d, J = 22.3
Hz), 142.9, 141.3 (d, J = 16.5 Hz), 138.4, 132.2 (d, J = 2.9 Hz), 132.1 (d, J = 9.4 Hz), 131.3 (d, J = 128.0
Hz), 131.2, 128.5 (d, J = 12.2 Hz), 127.5 (d, J = 2.0 Hz), 17.2. 31P NMR (162 MHz, CDCl3) δ 20.13. HRꢀMS
m/z (ESI): C21H18N2OP (calcd.: 345.1157), found: 345.1151 ([M+H]+). IR(film)
1480, 1435, 1329, 1257, 1192, 1158, 1120, 1100, 1050, 927, 829, 782, 748, 689.
v 3047, 2915, 2843, 1569,
(6,7-dimethylquinoxalin-2-yl)diphenylphosphine oxide(5ea). A yellow solid, m.p.: 124.1ꢀ125.6 oC (31 mg,
30% yield). 1H NMR (400 MHz, CDCl3) δ 9.53 (s, 1H), 7.98ꢀ7.93 (m, 4H), 7.89 (s, 2H), 7.56ꢀ7.52 (m, 2H),
7.47 (ddd, J = 7.1, 5.3, 2.3 Hz, 4H), 2.49 (d, J = 9.7 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 150.6 (d, J =
126.2 Hz), 145.6 (d, J = 22.4 Hz), 143.1, 141.6 (d, J = 2.3 Hz), 141.5, 141.19 (d, J = 17.3 Hz), 132.0, 131.9,
131.62 (d, J = 104.5 Hz), 128.9, 128.4 (d, J = 12.3 Hz), 20.5, 20.2. 31P NMR (162 MHz, CDCl3) δ 20.54.
HRꢀMS m/z (ESI): C22H19N2OPNa (calcd.: 381.1133), found: 381.1125 ([M+Na]+). IR (film)
2847, 1622, 1482, 1434, 1354, 1197, 1175, 1110, 866, 750, 721, 695.
v 3051, 2920,
(6,7-dimethylquinoxalin-2-yl)di-m-tolylphosphine oxide(5fc). A yellow solid, m.p.: 132.8ꢀ134.6 oC (61 mg,
54% yield). 1H NMR (400 MHz, CDCl3) δ 9.50 (s, 1H), 7.89 (s, 2H), 7.78 (d, J = 12.5 Hz, 2H), 7.71 (dd, J =
12.5, 5.0 Hz, 2H), 7.38 – 7.35 (m, 4H), 2.49 (d, J = 9.2 Hz, 6H), 2.37 (s, 6H). 13C NMR (101 MHz, CDCl3) δ
150.9 (d, J = 125.6 Hz), 145.7 (d, J = 22.3 Hz), 143.1, 141.7 (d, J = 2.3 Hz), 141.5, 141.33 (d, J = 17.2 Hz),
138.4 (d, J = 12.2 Hz), 133.0 (d, J = 2.9 Hz), 132.4 (d, J = 9.4 Hz), 131.5 (d, J = 104.1 Hz), 129.3 (d, J = 9.8
Hz), 129.0, 128.4, 128.3, 21.5, 20.6, 20.3. 31P NMR (162 MHz, CDCl3) δ 21.19. HRꢀMS m/z (ESI):
C24H23N2OPNa (calcd.: 409.1446), found: 409.1437 ([M+Na]+). IR (film)
1355, 1189, 1171, 1108, 1000, 869, 783, 693.
v 3043, 2919, 2851, 1618, 1481,
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(6,7-dimethylquinoxalin-2-yl)bis(4-fluorophenyl)phosphine oxide(5fg). A yellow solid, m.p.: 134.1ꢀ135.6
4
5
1
oC (46 mg, 40% yield). H NMR (400 MHz, CDCl3) δ 9.54 (s, 1H), 7.97 (ddd, J = 11.6, 8.6, 5.6 Hz, 4H),
6
7
8
9
7.91 (d, J = 7.8 Hz, 2H), 7.18 (dd, J = 11.7, 4.8 Hz, 4H), 2.52 (d, J = 7.5 Hz, 6H). 13C NMR (101 MHz,
CDCl3) δ 165.3 (dd, J = 254.2, 3.3 Hz), 150.1 (d, J = 128.6 Hz), 145.5 (d, J = 22.5 Hz), 142.7 (d, J = 157.1
Hz), 141.8 (d, J = 2.3 Hz), 141.2 (d, J = 17.4 Hz), 134.6 (dd, J = 11.0, 8.9 Hz), 128.9 (d, J = 0.9 Hz), 128.5
(d, J = 1.9 Hz), 127.6 (dd, J = 108.2, 3.4 Hz), 116.0 (dd, J = 21.4, 13.5 Hz), 20.6, 20.4. 31P NMR (162 MHz,
CDCl3) δ 19.07. HRꢀMS m/z (ESI): C22H17F2N2OPNa (calcd.: 417.0944), found: 417.0935 ([M+Na]+). IR
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(film) v 3055, 2931, 2847, 1593, 1500, 1357, 1237, 1162, 1118, 1061, 830.
(6,7-dimethylquinoxalin-2-yl)bis(3-fluorophenyl)phosphine oxide(5fh). A yellow solid, m.p.: 132.6ꢀ133.5
1
oC (32 mg, 35% yield). H NMR (400 MHz, CDCl3) δ 9.53 (s, 1H), 7.92 (d, J = 2.4 Hz, 2H), 7.77 (dd, J =
11.5, 7.7 Hz, 2H), 7.69 (dd, J = 15.1, 6.0 Hz, 2H), 7.51ꢀ7.45 (m, 2H), 7.26 (dd, J = 15.4, 7.0 Hz, 2H), 2.52 (d,
J = 6.2 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 162.4 (dd, J = 250.4, 17.4 Hz), 149.4 (d, J = 129.2 Hz),
145.5 (d, J = 22.6 Hz), 143.7 , 142.1 , 142.0 (d, J = 2.3 Hz), 141.2 (d, J = 17.7 Hz), 134.0 (dd, J = 104.2, 5.8
Hz), 130.6 (dd, J = 14.3, 7.4 Hz), 128.7 (d, J = 42.3 Hz), 127.7 (dd, J = 8.8, 3.3 Hz), 119.6 (dd, J = 21.2, 2.5
Hz), 118.9 (dd, J = 22.8, 10.4 Hz), 20.7, 20.4. 31P NMR (162 MHz, CDCl3) δ 17.18 (t, J = 6.0 Hz). HRꢀMS
m/z (ESI): C22H17F2N2OPNa (calcd.: 417.0944), found: 417.0936 ([M+Na]+). IR (film)
2843,1581, 1477, 1420, 1356, 1269, 1220, 1174, 1094, 866, 793, 686.
v 3055, 2911,
General Procedure for the reductive addition of diarylphosphine oxides with quinoline to Access
compounds (8): (1,2,3,4-tetrahydroquinoline-2,4-diyl)bis(diphenylphosphine oxide) (8aa). To a 5 mL vial
equipped with oxygen balloon was added quinoline (7a, 25.8 mg, 0.2 mmol) and diphenylphosphine oxide
(2a, 80.8 mg, 0.4 mmol). The reaction was then heated to 65 0C for 18 hours until the complete consuming
of starting materials monitored by TLC. After being cooling down, the mixtures were quenched by adding
water, and then extracted with ethyl acetate (3 mL×2). The crude product was purified on flash
chromatography, with ethyl acetate/petroleum ether (1:1) as eluents to afford product 8aa as a white solid
(85 mg, 80% yield). 1HꢀNMR (400 MHz, CDCl3) δ 7.84 (dd, J = 13.9, 4.9 Hz, 4H), 7.72ꢀ7.65 (m, 2H),
7.61ꢀ7.33 (m, 14H), 6.93 (t, J = 7.7 Hz, 1H), 6.49 (d, J = 8.0 Hz, 1H), 6.29 (t, J = 7.4 Hz, 1H), 6.08 (d, J =
7.6 Hz, 1H), 4.93 (d, J = 12.3 Hz, 1H), 4.11 (s, 1H), 3.77ꢀ3.74 (m, 1H), 2.48 (t, J = 11.1 Hz, 1H), 2.21ꢀ2.04
(m, 1H). 31PꢀNMR (162 MHz, CDCl3) δ 31.88, 30.56. HRꢀMS m/z (ESI): C33H29NO2P2Na (calcd.: 556.1571),
found: 556.1579 ([M+Na]+).
General Procedure for the reductive addition of diarylphosphine oxides with quinazoline to Access
compounds (10): (1,2-dihydroquinazolin-2-yl)diphenylphosphine oxide(10aa). To a 5 mL vial equipped with
oxygen balloon was added quinazoline (9a, 26.0 mg, 0.2 mmol) and diphenylphosphine oxide (2a, 80.8 mg,
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0.4 mmol). The reaction was then heated to 65 0C for 18 hours until the complete consuming of starting
materials monitored by TLC. After being cooling down, the mixtures were quenched by adding water, and
then extracted with ethyl acetate (3 mL×2). The crude product was purified on flash chromatography, with
1
ethyl acetate as eluent to afford product 10aa as awhite solid (62 mg, 93% yield). HꢀNMR (400 MHz,
9
CDCl3) δ 7.92 (dd, J = 9.8, 8.4 Hz, 2H), 7.71ꢀ7.66 (m, 2H), 7.52ꢀ7.40 (m, 6H), 7.07 (s, 1H), 6.95 (t, J = 7.6
Hz, 1H), 6.65 (t, J = 7.5 Hz, 1H), 6.55 (d, J = 7.9 Hz, 1H), 6.20 (d, J = 7.4 Hz, 1H), 5.66 (d, J = 5.0 Hz, 1H).
31PꢀNMR (162 MHz, CDCl3) δ 29.61. HRꢀMS m/z (ESI): C20H18N2OP (calcd.: 333.1157), found: 333.1151
([M+H]+).
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■
AUTHOR INFORMATION
§ These authors contributed equally to this work.
Corresponding Author
*EMAIL: rickywu@njau.edu.cn
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGEMENTS
This project is supported by the Foundation Research Project of Jiangsu Province (The Natural Science Found
No. BK20141359), and “333 high level talent project” of JiangSu Province.
■
SUPPORTING INFORMATION
1
Supporting Information: [Experimental details and procedures, compound characterization data, and copies of H,
13C, 31P NMR and HRꢀMS for all new compounds]. This material is available free of charge via the Internet at
http://pubs.acs.org/.
■
REFERENCES
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Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624ꢀ655; (e) Sun, C.ꢀL.; Li, B.ꢀJ.; Shi, Z.ꢀJ.
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