Metal-free azaphosphaannulation of phosphonamides through intramolecular oxidative C-N bond formation

Article abstract of DOI:10.1021/ol501207w

We report an efficient metal-free azaphosphaannulation of a myriad of phosphonamides through intramolecular oxidative C-N bond formation using PhI(OAc)₂ and iodine in acetonitrile under air, thus leading to the formation of benzazaphosphol-3-on

Full text of DOI:10.1021/ol501207w

Letter
pubs.acs.org/OrgLett
Metal-Free Azaphosphaannulation of Phosphonamides through
Intramolecular Oxidative C−N Bond Formation
Yea Rin Kim, Seungyoon Cho, and Phil Ho Lee*
Department of Chemistry, Kangwon National University, Chuncheon 200-701, Republic of Korea
S
* Supporting Information
ABSTRACT: We report an efficient metal-free azaphosphaannulation of a myriad of phosphonamides through intramolecular
oxidative C−N bond formation using PhI(OAc)2 and iodine in acetonitrile under air, thus leading to the formation of
benzazaphosphol-3-one 1-oxides, which are novel phosphorus heterocyclic privileged structures.
Scheme 1. Azaphosphaannulations through Phosphoryl-
Group-Directed C−H Activation
elective C−H activation using a variety of transition metal
catalysts with the aid of directing groups has become one of
S
the most efficient synthetic methods for carbon−heteroatom
(O and N) bond formation due to its step and atom-
economical advantages, avoiding prefunctionalization of start-
ing materials.1 Accordingly, development of a new and efficient
directing group represents an ongoing pivotal subject of
research in C−H activation. Although a wide range of directing
groups to facilitate position-selective C−H activation have been
reported,2 directing groups possessing phosphorus have been
less exploited.3 However, because organophosphorus com-
pounds have been broadly used in agricultural and pharma-
ceutical chemistry and material science,4 development of an
efficient synthetic method for these compounds has been
continuously required. In this regard, we recently investigated
phosphoryl-group-directed C−H activation and demonstrated
a series of C−O bond formations.5 Encouraged by these re-
sults, we were next interested in transition-metal-catalyzed C−H
activation/C−N bond formation and developed a Rh-catalyzed
C(sp2)−H activation/annulation (eq 1, Scheme 1) and
oxidative alkenylation/aza-Michael reaction (eq 2, Scheme 1)
directed by phosphonamide and phophinamide groups.6 These
results prompted us to examine the possibility of transition-
metal-catalyzed C(sp3)−H activation/C−N bond formation
because C(sp3)−H activation is more challenging and attractive
than C(sp2)−H. Herein, we report a streamlined metal-free
azaphosphaannulation of a multitude of phosphonamides
through intramolecular oxidative C−N bond formation for
the synthesis of benzazaphosphol-3-one 1-oxides, which are novel
phosphorus heterocyclic scaffolds and a kind of bioisosters of
imide and acid anhydride (eq 3, Scheme 1).
C(sp3)−N bonded product 3a was not observed. Thus, synthetic
methods of previously reported transition-metal-catalyzed C−N
bond formation were applied to construction of the intra-
molecular C−N bond of 1a (see Supporting Information).
However, Rh and Cu catalysts and additives such as bases and
oxidants were totally ineffective (see Supporting Information).
Because there is still a great need for metal-free synthetic
methods in organic synthesis,7 we next changed our strategy for
intramolecular C−N bond formation from transition metal
catalysis to metal-free conditions.
First, under metal-free conditions, treatment of 1a with
PhI(OAc)2 in ethyl acetate at 50 °C for 12 h unexpectedly
produced the azaphosphaannulated product 2a through
oxidative C−N bond formation instead of a C−N bond, albeit
in low yield (entry 1). The structure of 2a was unambiguously
determined by X-ray crystallography and HRMS (see
Supporting Information). The use of additives such as NIS
We initiated our investigation by examining intramolecular
C−N bond formation of ethyl 2,6-dimethylphenylphosphon-
amide (1a) (Table 1). Although we first used the optimum
reaction conditions [Pd(OAc)2, (4-MeO-C6H4)3P, Ag2CO3,
K2HPO4 in chlorobenzene]5e for C(sp3)−H activation/C−O
cyclization of phosphonic acids to cyclization of 1a, the expected
Received: April 28, 2014
© XXXX American Chemical Society
A
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Letter
Table 1. Optimization of Azaphosphaannulation
a
entry
oxidant (equiv)
additive (equiv)
solvent
temp (°C)
time (h)
yield (%)
1
PhI(OAc)2 (3)
PhI(OAc)2 (3)
PhI(OAc)2 (3)
PhI(OAc)2 (3)
PhI(OAc)2 (3)
PhI(OAc)2 (3)
PhI(OAc)2 (2)
none
none
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
CH3CN
CH3CN
CH3CN
50
50
50
50
50
50
50
50
50
80
100
12
12
12
12
12
12
12
12
6
7
2
NIS (0.5)
Br2 (0.5)
I2 (0.5)
I2 (0.1)
I2 (1.0)
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
16
21
58
24
60
41
0
3
4
5
6
7
8
9
PhI(OAc)2 (3)
PhI(OAc)2 (3)
PhI(OAc)2 (3)
60
b
10
1
75 (73)
11
1
65
a
b
1H NMR yields of 2a using CH2Br2 as an internal standard. Isolated yield of 2a.
and Br2 (0.5 equiv) slightly increased the yield (entries 2 and 3).
However, in the case of the combination of PhI(OAc)2 (3 equiv)
and iodine (0.5 equiv), yield of the desired oxidative C−N
bonded product 2a improved up to 58% (entry 4). Iodine (0.1
equiv) afforded 2a in 24% yield (entry 5), while 1.0 equiv of
iodine gave the similar result (60%) as 0.5 equiv (entries 4 vs 6).
The use of PhI(OAc)2 (2 equiv) gave an inferior result
(entry 7). Control reactions without PhI(OAc)2 or iodine did
not proceed, indicating that these reagents are essential for
oxidative C−N bond formation (entries 1 and 8). Screening of
temperature gave the best result at 80 °C (entries 9−11, see
Supporting Information). Acetonitrile was found to be the
solvent of choice (see Supporting Information). The best result
for oxidative C−N bond formation was obtained, using
PhI(OAc)2 (3 equiv) and iodine (0.5 equiv) in acetonitrile at
80 °C, after 1 h, which gave rise to 2a in 75% yield (isolated
yield 73%) (entry 10).
to the desired product 2b in 65% yield (entry 5; see Supporting
Information for X-ray of 2b). However, ethyl 2-methylphenyl-
phosphonamide (1f′) was totally ineffective, indicating that 2,6-
disubstituents are essential for the oxidative azaphosphoaannu-
lation (entry 6). P-2,6-Dimethylphenyl-P-phenylphosphinamide
1g′ was not azaphosphaannulated (entry 7). These results suggest
that the oxidative azaphosphaannulation is very sensitive to the
nature of substituents attached to the phosphorus and nitrogen
atoms.
Next, a number of phosphonamides 1 were examined to
demonstrate the scope and limitations of metal-free azaphos-
phaannulation through the intramolecular oxidative C−N bond
formation (Scheme 2). Reaction of ethyl 2,4,6-trimethylphenyl
and ethyl 4-tert-butyl-2,6-dimethylphenylphosphonamides 1c
and 1d with PhI(OAc)2 and iodine produced the desired
azaphosaphaannulation products 2c and 2d in 70% and 66%
yields, respectively. Phosphonamides having 4-methoxy (1e)
and 4-phenoxy (1f) groups on the phenyl ring underwent the
intramolecular oxidative C−N bond formation to afford
benzazaphosphol-3-one 1-oxides 2e and 2f in good yields.
This transformation was chemoselective in that the phenyl-
sulfenyl group (1g), a reacting site for oxidant, was inert.
Substrate 1h bearing a 4-triisopropylsilyloxy group on the
phenyl ring was azaphosphaannulated to afford 2h in 60% yield.
The reaction turned out to be compatible with the labile
4-trimethylsilyl group (1i), thus leading to the formation of 2i
in 71% yield. In addition, functional groups frequently
employed in synthetic chemistry were completely tolerated.
For example, phosphonamides having aldehyde, ketone, or
bromo groups were all smoothly azaphosphaannulated in
moderate to good yields. Subjecting 3-acetyl-2,4,6-trimethyl-
phenylphosphonamide (1m) to PhI(OAc)2 and iodine gave rise
to benzazaphosphol-3-one 1-oxide in 70% yield (2ma:2mb =
1:1.8; also see NOE in Supporting Information). We reasoned
that 2mb might be produced as the major product due to
adjacent trisubstituents on the phenyl ring. Likewise, the
oxidative azaphosphaannulation occurred efficiently with 3-
bromo-2,4,6-trimethylphenylphosphonamide (1n) to deliver
2na (26%) and 2nb (46%). The structure of the isomers
was unambiguously determined by NOE (see Supporting
Information).
On the basis of these results, we screened a variety of
phosphonamides and phosphinamides 1 under the metal-
free conditions (Table 2). When ethyl N-methyl, -phenyl,
a
Table 2. Scope of Phosphoamide Directing Groups
b
entry
R1
R2
R3
1
2
yield (%)
1
2
3
4
5
6
7
Me
Me
Me
Me
Me
H
OEt
OEt
OEt
OEt
OMe
OEt
Ph
H
1a
2a
73
Me
Ph
Ts
H
1c′
1d′
1e′
1b
NR
NR
NR
65
2b
H
1f′
1g′
NR
NR
Me
H
a
Reaction conditions: 1 (0.2 mmol, 1 equiv), PhI(OAc)2 (3 equiv), I2
b
(0.5 equiv), and CH3CN (2.0 mL), 80 °C, 1 h under air. Isolated yields.
and -tosyl-2,6-dimethylphenylphosphonamides (1c′, 1d′, and 1e′)
were treated with PhI(OAc)2 (3 equiv) and iodine (0.5 equiv),
the corresponding oxidative C−N bonded products 2 were not
obtained (entries 2−4). Under the optimum conditions, methyl
2,6-dimethylphenylphosphonamide 1b was smoothly converted
As an extension of this work, a wide range of phos-
phonamides 1 bearing biaryl moieties were employed for the
B
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Organic Letters
Letter
a
Scheme 2. Scope of Azaphosphaannulation of Phosphonamides
a
b
Reaction conditions: 1 (0.2 mmol, 1 equiv), PhI(OAc)2 (3 equiv), I2 (0.5 equiv), and CH3CN (2.0 mL), 80 °C, 1 h. I2 (1 equiv), 50 °C.
optimal azaphosphaannulation. Ethyl 2,6-dimethyl-4-phenyl-
phenylphosphonamide (1o) was reacted with PhI(OAc)2
(3 equiv) and I2 (0.5 equiv) in acetonitrile, thus producing
the desired product 2o in 63% yield. Biaryl phosphonamides
1p, 1q, and 1r having an electron-donating methyl group on
the 4-phenyl ring turned out to be compatible with the reaction
conditions. Electron-withdrawing 4-chloro (1s) and 2,4-
difluoro (1t) groups were tolerated on the substituted aryl
ring, thus enabling a possibility for further functionalization.
We were pleased to obtain 2u from biaryl phosphonamide 1u
having a 2-naphthalenyl group at the 4-position.
(16) and 2a-[O18] (100) in 71% yield (eq 7). 2a-[O18] was
detected by HRMS (see Supporting Information).
Ethyl phosphonamides having different substituents at the
2,6-position worked equally well. For example, the desired
product 5a was obtained in 81% yield when 2-bromo and 4,6-
dimethyl groups were substituted on the phenyl ring of
phosphonamide (eq 4). Substrate 4b bearing 2,4-dimethyl as
well as 6-methoxy groups underwent the intramolecular
oxidative azaphosphaannulation, producing 5b in good yield
(eq 5). The structure of 5b was determined by NOE (see
Supporting Information). Under the reaction conditions, an
iodo group was introduced into the phenyl group due to the
electron-rich phenyl ring.
Because the conversion of ethyl 2,6-dimethylphenylphospho-
namide 1a to the corresponding benzazaphosphol-3-one 1-oxide 2a
could be quenched in the presence of TEMPO as a free radical
scavenger, a mechanism of the intramolecular oxidative C−N bond
formation with PhI(OAc)2 and iodine is proposed to involve a
radical intermediate (eq 6). Reaction of 1a with PhI(OAc)2 and I2
in CH3CN (1.9 mL) and H2O18 (72 μL, 20 equiv) produced 2a
On the basis of these results and generation of sulfonamidyl
radicals,8 a plausible mechanism for the azaphosphaannulation
is shown in Scheme 3. First, reaction of PhI(OAc)2 with iodine
provided phenyl iodide and acetyl hypoiodite (AcOI). Then,
phosphonamides 1 were reacted with acetyl hypoiodite to
C
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Scheme 3. A Plausible Mechanism
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afford phosphonamidyl radicals II, which underwent a 1,5-H
shift to give benzyl radicals III. Treatment of III with I2
produced intermediates IV, V, and the cyclized VI. However,
these intermediates were not observed in an NMR study
in CD3CN due to their instability. Hydrolysis of diiodide
intermediates VI eventually produced benzazaphosphol-3-one
1-oxides 2. The possibility of an initial cyclization of IV to VII
and then benzylic oxidation to the desired product 2 cannot be
completely ruled out at the present stage. The elucidation of
the detailed mechanism of the azaphosphaannulation must wait
for further study.
In summary, we have developed an efficient metal-free
azaphosphaannulation of a myriad of phosphonamides through
the intramolecular oxidative C−N bond formation, thus leading
to the production of benzazaphosphol-3-one 1-oxides, which
are novel phosphorus heterocyclic scaffolds.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization data, X-ray crystallo-
1
graphic data for 2a and 2b (CIF), and H and 13C NMR
spectra for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: phlee@kangwon.ac.kr.
Notes
The authors declare no competing financial interest.
DEDICATION
■
Dedicated to Professor Chan-Mo Yu, Sungkyunkwan Uni-
versity, on the occasion of his 60th birthday.
ACKNOWLEDGMENTS
■
This work was supported by a National Research Foundation of
Korea (NRF) grant funded by the Korea government (MSIP)
(No. 2014001403).
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