Rhodium-catalyzed oxidative coupling through C-H activation and annulation directed by phosphonamide and phosphinamide groups

Article abstract of DOI:10.1039/c3cc44995e

Rhodium-catalyzed oxidative coupling reactions via C-H activation and annulation directed by phosphonamide and phosphinamide groups were developed under aerobic conditions, which produced benzazaphosphole 1-oxides and phosphaisoquinolin-1-oxides.

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Rhodium-Catalyzed Oxidative Coupling through C H Activation and
Annulation Directed by Phosphonamide and Phosphinamide Group‡,
†
Sangjune Park,† Boram Seo,† Seohyun Shin, Jeong-Yu Son and Phil Ho Lee*
Received (in XXX, XXX) XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
45 solvents tested, xylene gave 4a in 23% yield (entry 6). After
surveying a wide array of bases (See the SI), we observed
CsOPiv gave the best reactivity (entries 7ꢀ9). Next, a variety
of oxidants were examined in the presence of CsOPiv in
xylene. The reaction was relatively sensitive to the choice of
50 oxidants used, and AgOAc and Na2S2O8were not effective
(entries 11 and 12). The oxidants, Ag2O and TEMPO, gave
moderate conversion of the starting 1a (entries 10 and 13). To
our delight, TEMPO (2 equiv) and CsOPiv (0.75 equiv) in
xylene turned out to be the most effective and resulted in the
55 complete consumption of 1a to produce selectively
benzazaphosphole 1ꢀoxide 4a in 88% yield (entry 14). When
CsOPiv was not used (entry 15), the reaction did not proceed
because deprotonation of 1a could occur to give the
corresponding salt which trigger C−H activation in a similar
60 manner to that of benzoic acid substrates.12
Rhodium-catalyzed oxidative couplings via C H activation
and annulation directed by phosphonamide and
phophinamide group were developed under aerobic
conditions, which produced benzazaphosphole 1-oxides and
10 phosphaisoquinolin-1-oxides with high selectivity, a wide
substrate scope and an excellent functional group tolerance.
Transitionꢀmetalꢀcatalyzed C H bond activations have been
established to be a very efficient process for the formation of
C C and C heteroatom bonds.1 In general, ortho C H bond
15 activation can be achieved by the application of a multitude of
directing groups with the assitance of coordination of
transition metals. In a variety of directing groups for C H
bond activations,2 carboxyl and hydroxyl compounds3 and
nitrogenꢀcontaining ones4,5 have been extensively explored.
20 We have recently interested in development of new
phosphorylꢀrelated directing groups6 in the C H bond
activations and its application to synthesis of phosphorus
heterocyclic compounds.6a,7 Although the oragnophosphorus
compounds have been recognized as crucial compounds in the
25 area of pharmaceutical and agricultural chemistry,8 their
employment in transitionꢀmetalꢀcatalyzed C H bond
activations has been barely studied.9 Therefore, development
of efficient C–H activation using phosphorusꢀrelated directing
group is stimulating. Herein, we report Rhꢀcatalyzed
Table 1 Reaction optimizationa
Yieldb (%)
3a 4a
Entry Oxidant (equiv) Base (equiv)
Solvent
1
2
3
4
5
6
7
8
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2O (2)
AgOAc (2)
Na2S2O8 (2)
TEMPO (2)
TEMPO (2)
TEMPO (2)
none
none
none
none
none
none
NaOAC (0.5)
Na2CO3 (0.5)
CsOPiv (0.5)
CsOPiv (0.5)
CsOPiv (0.5)
CsOPiv (0.5)
CsOPiv (0.5)
CsOPiv (0.75)
none
MeCN
tꢀBuOH
toluene
PhCl
0
2
4
0
0
2
2
8
30 annulation
reaction
through
C H
activation
of
phosphonamides and phosphinamides under aerobic
conditions, thus producing benzazaphosphole 1ꢀoxides and
phosphaisoquinolinꢀ1ꢀoxides (Scheme 1).10
dioxane 18 13
xylene
xylene
xylene
xylene
xylene
xylene
xylene
xylene
xylene
xylene
0
8
8
0
0
0
0
0
0
0
23
39
17
42
43
14
6
59 (60)
84 (88)c
0
9
10
11
12
13
14
15
35
Scheme 1 Rhꢀcatalyzed CꢀH activation and annulations.
To search the usefulness of the phosphonamideꢀbased
a 1a (0.2 mmol), 2a (0.4 mmol), [Cp*RhCl2]2 (4 mol %), solvent (0.8 mL)
b
at 110 oC for 20 h. Yield were determined by 1H NMR intergration
directing groups in the C–H activation, we embarked on our
studies with ethyl Nꢀphenyl phenylphosphonamidate (1a) as 65 methods with CH2Br2 as an internal standard. c Isolated yield.
shown in Table 1. First, when [Cp*RhCl2]2 (4 mol %) and
40 Ag2CO3 (2 equiv) in acetonitrile (110 °C, 20 h) under air11
were applied to cyclization of 1a, the reaction did not proceed
(entry 1). Use of tꢀBuOH and toluene gave orthoꢀalkenylated
product 3a and orthoꢀalkenylation followed by azaꢀMichael
reaction product 4a in trace (entries 2 and 3). Among the
With these results in hand, various phosphonamides (1)
were investigated under the standard conditions using methyl
acrylate (Scheme 2). Substrate having 2ꢀmethyl group on the
Pꢀphenyl ring underwent orthoꢀalkenylation followed by azaꢀ
70 Michael reaction, thus providing benzazaphosphole 1ꢀoxide
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4b in 87% yield (dr = 1:2.5). Rhꢀcatalyzed oxidative
cyclization of 3-methyl substrate with 2a took place
regioselectively at the sterically less hindered position to
provide 4c (95%) possessing methyl group on 6ꢀposition.
Phosphonamide bearing electron donating 4ꢀmethoxy group
gave the cyclic compound 4d in 50% yield. Functional groups
commonly used in organic synthesis were tolerated. When 4ꢀ
fluoro and 3ꢀtrifluoromethyl substituted phosphonamides were
used, the corresponding cyclized products (4e and 4g) were
10 obtained in 82% yield, respectively. Substrates having 4ꢀ
chloro and 4ꢀacetyl group was oxidatively cyclized to give 4f
and 4i in high yields. The tolerance of fluoro and ketone
group on the phenyl ring is especially valuable, affording an
opportunity for further functionalization. The cyclized product
15 4h was obtained in 53% yield albeit the presence of strong
electronꢀwithdrawing nitro group. When substrate possessing
2,3ꢀdimethyl group was subjected to the standard conditions,
the desired tandem product 4j was isolated in 98% yield.
However, 2,4ꢀdifluoro substituted phosphonamide was less
20 reactive due to electronic effect, thus providing the cyclized
product 4k in 55% yield. 2ꢀNaphthalenylphosphonamide
worked well too. When N,P,Pꢀtriphenylphosphinamide (5a)
was treated with rhodium catalyst, the cyclized product 6a
was obtained in 97% yield (dr = 1:2.9). Also, substrates
25 having 4ꢀmethoxy and 4ꢀfluoro group were smoothly
converted to benzazaphosphole 1ꢀoxides 6b and 6c in 90%
and 94% yields, respectively.
5
a
1a or 5a (0.2 mmol), 2 (0.4 mmol), [Cp*RhCl2]2 (4 mol %), TEMPO
o
(0.4 mmol), CsOPiv (0.15 mmol), xylene (0.8 mL) at 110 C for 20 h.
Ratios in parentheses indicate diastereomeic ratios by 1H NMR.
b
50 Diastereomeric ratio after isolation.
Scheme 3 Activated alkenes scope.a
amide (7a) was treated with 2a under the optimum conditions, the
corresponding product 8a was obtained in 54% yield through
tandem orthoꢀalkenylation and azaꢀMichael reaction. Electronic
55 variation of substituents on the arene moiety of 7 had a little
affected on the reaction efficiency. Although 7c having electronꢀ
withdrawing chloro group on the phenyl ring was cyclized to
provide 8c in 53% yield, substrate 7b bearing electronꢀdonating
methyl group underwent the cyclization with 2a, producing
60 azaphosphole 1ꢀoxide 8b in 71% yield.
O
P
NPh
O
R2
R2
2
1
6
P
cat. [Cp*RhCl2]2
R1
R1 3
4
H
NHPh
+
CO2Me
TEMPO, CsOPiv
under air
a
7 (0.2 mmol), 2a (0.8 mmol), [Cp*RhCl2]2 (4 mol %), Cu(OAc)2 (0.2
H
5
CO2Me
(R = OEt), (R2 = R1-C6H4)
2
o
1
5
2a
1 = H, 88% (1:2.8)
4, 6
mmol), Cs2CO3 (0.4 mmol), DCE (0.8 mL) at 80 C for 30 h. Ratios in
4g
4h
7
4
R
R
R
R
1 = 6-CF3, 82% (1:2.5)
1 = 5-NO2, 53% (1:2.2)
parentheses indicate diastereomeric ratios by 1H NMR.
O
4a
4b
1P
OEt
1 = 7-Me, 87% (1:2.5)
R16
5
NPh
2
65
Scheme 4 Alkenylphosphonamides scope.a
4c R1 = 6-Me, 95% (1:2.2)
4i R1 = 5-Ac, 88% (1:2.9)
1 = 5-MeO, 50% (1:1.6)
R1 = 6,7-(Me)2, 98% (1:2.2)
3
4d
4e
4f
4j
4k
R
R
1 = 5-F, 82% (1:2.5)
R
1 = 5,7-(F)2, 55% (1:3)
In contrast to activated alkenes, when nonꢀactivated alkenes
CO2Me
R1 = 5-Cl, 98% (1:2.9)
were employed in Rhꢀcatalyzed C H activation, only orthoꢀ
alkenylation occurred to give the corresponding products 10
(Scheme 5). For example, exposure of 5a to 4ꢀtꢀbutylstyrene 9a
O
P
NPh
O
P
NPh
O
P
NPh
O
OEt
4-MeO-C6H4
4-F-C6H4
Ph
P
NPh
MeO
F
70 in the presence of Rh catalyst, TEMPO and CsOPiv in toluene
under aerobic conditions provided 10a in 59% yield. Likewise,
the use of 3ꢀmethylꢀ and 4ꢀchlorostyrene furnished the orthoꢀ
alkenylated products (10b and 10c) in good yields.
CO2Me
6a
CO2Me
90% (1:5.2)
CO2Me
6c
94% (1:5)
CO2Me
4l
6b
73% (1:2.5)
97% (1:2.9)
a 1 or 5 (0.2 mmol), 2a (0.4 mmol), [Cp*RhCl2]2 (4 mol %), TEMPO (0.4
o
30 mmol), CsOPiv (0.15 mmol), xylene (0.8 mL) at 110 C for 20 h. Ratios
in parentheses indicate diastereomeric ratios by 1H NMR.
Scheme 2 Arylphosphonamides and arylphosphinamides scope.a
As shown in Scheme 3, the scope of the oxidative
cyclization is extensive and various electronꢀdeficient alkenes
35 could be successfully employed in the tandem orthoꢀ
alkenylation and azaꢀMichael reaction. Methyl vinyl ketone
and N,Nꢀdimethylacrylamide reacted with 1a to furnish the
corresponding benzazaphosphole 1ꢀoxide 4o and 4p in 87%
and 72% yields, respectively. Similarly, acrylonitrile and
40 vinyl sulfone also worked well with 5a producing 6g and 6h
in excellent yields.
We also examined Rhꢀcatalyzed oxidative cyclization of
alkenylphosphonamides 7 with methyl acrylate (Scheme 4).
The use of DCE as the solvent was necessary to obtain
45 acceptable yields with substrates 7. When αꢀstyrylphosphonꢀ
a
75 5a (0.2 mmol), 9 (1.8 mmol), [Cp*RhCl2]2 (4 mol %), AgSbF6 (16
mol %), TEMPO (0.4 mmol), CsOPiv (0.15 mmol), toluene (0.8 mL) at
110 oC for 20 h.
Scheme 5. Nonꢀactivated alkenes scope.a
Next, Rhꢀcatalyzed oxidative couplings via C H activation
80 and annulation from 5a and various alkynes were investigated
(Scheme 6). When 5a was treated with various alkynes 11 under
the optimum conditions, the phosphaisoquinolinꢀ1ꢀones 12 were
obtained in good to excellent yields through Rhꢀcatalyzed
cyclization. Dialkylacetylenes such as hexꢀ3ꢀyne and decꢀ5ꢀyne
2
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DOI: 10.1039/C3CC44995E
turned out to be compatible with the reaction conditions. We
Notes and references
were please to observe that 5a was readily reacted with electronꢀ
rich and electronꢀdeficient diarylacetylenes as well. The tolerance
of chloro and bromo group is especially important, as following
Department of Chemistry, Kangwon National University, Chuncheon
40 200-701, Republic of Korea; Fax: (+)-82-33-253-7582; E-mail:
phlee@kangwon.ac.kr
†These authors contributed equally to this work.
5
catalytic
crossꢀcouplings
are
promising.
Electronꢀrich
†This paper is dedicated to Professor Nakcheol Jeong on the occasion of
arylphosphinamide 5 having methyl, methoxy, fluoro and
trifluoromethyl group on the Pꢀphenyl ring were cyclized to
afford the corresponding phosphaisoquinolinꢀ1ꢀones in good to
excellent yields. Substrate having 3,5ꢀdimethyl group was
his 60th birthday.
45 ‡Electronic Supplementary Information (ESI) available: [Experimental
1
procedures, characterization data, and H and 13C NMR spectra for new
compounds.]. See DOI: 10.1039/b000000x/
1
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10 smoothly activated and annulated to furnish 12n in 60% yield.
Phosphinamide bearing 1ꢀthiophenyl group underwent the
oxidative cyclization in reasonable yield.
50
55
60
65
70
75
80
85
90
95
100
2
3
4
a
5 (0.15 mmol), 11 (0.3 mmol), [Cp*RhCl2]2 (4 mol %), Ag2CO3 (0.3
15 mmol), KH2PO4 (0.15 mmol), tꢀBuOH (1.5 mL) at 110 oC for 16 h.
b
Reaction time: 30 h. c Reaction temperature: 130 oC.
Scheme 6 Scope of arylphosphinamides and alkynes. a
5
To obtain insight into the reaction mechanism, a catalytic C H
bond transformation in the presence of D2O performed, thereby
20 affording a remarkable D/H exchange in the orthoꢀposition of the
recovered starting material 1a-[D1] (eq 1, Scheme 7). A
significant kinetic isotope effect (KIE) was detected (kH/kD = 4.8),
suggesting that the C H bond cleavage at the orthoꢀposition of
phosphonamide is most likely involved in the rateꢀdetermining
25 step (eq 2).
6
7
(a) J. Seo, Y. Park, I. Jeon, T. Ryu, S. Park and P. H. Lee, Org. Lett.,
2013, 15, 3358; (b) B. C. Chary, S. Kim, Y. Park, J. Kim and P. H.
Lee, Org. Lett., 2013, 15, 2692; (c) L. Y. Chan, S. Kim, T. Ryu and
P. H. Lee, Chem. Commun., 2013, 49, 4682.
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8
9
Scheme 7 Studies with isotopically labeled compounds.
10 (a) M. J. P. Harger and P. A. Shimmin, J. Chem. Soc., Chem.
Commun., 1991, 1187; (b) J. A. Miles, R. C. Grabiak and M. T.
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Tetrahedron, 2008, 64, 10507.
In summary, we have developed an efficient rhodiumꢀ
catalyzed oxidative couplings via C H activation and annulation
30 using arylphosphonamides and arylphosphinamides under aerobic
conditions, which produced benzazaphosphole 1ꢀoxides and
phosphaisoquinolinꢀ1ꢀoxides with high selectivity,
substrate scope and an excellent functional group tolerance.
This work was supported by the National Research Foundation
35 of Korea (NRF) grant funded by the Korea government (MSIP)
(No. 2011ꢀ0018355) and BRL (2009ꢀ0087013). P.H. thanks Prof.
E. J. Yoo (KNU) for helpful discussions.
a wide
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