Direct oxidative phosphonylation of amines under metal-free conditions

Article abstract of DOI:10.1016/j.tetlet.2011.11.120

Direct oxidation coupling of tertiary amines and dialkyl- or diphenyl-substituted phosphonates was developed. The reaction was mediated by DDQ under room temperature. Various phosphonates and N-aryl tetrahydroisoquinolines were tolerated in this reaction,

Full text of DOI:10.1016/j.tetlet.2011.11.120

Tetrahedron Letters 53 (2012) 681–683
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Direct oxidative phosphonylation of amines under metal-free conditions
⇑
Haolong Wang, Xincheng Li, Fan Wu, Boshun Wan
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Direct oxidation coupling of tertiary amines and dialkyl- or diphenyl-substituted phosphonates was
Received 19 September 2011
Revised 18 November 2011
Accepted 25 November 2011
Available online 2 December 2011
developed. The reaction was mediated by DDQ under room temperature. Various phosphonates and N-
aryl tetrahydroisoquinolines were tolerated in this reaction, and
a
-aminophosphonates were obtained
with up to 99% yield.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Phosphonation
DDQ
Oxidative coupling
Tertiary amine
a
-Aminophosphonates and related
were studied as the analogous of -amino acids in which the car-
boxylic acid moieties were replaced by phosphonates or phosphonic
a
-aminophophonic acids
reported by Rueping15 and König16 respectively, which proceeded
under the irradition of visible light.
a
The work reported by Genies revealed that the amines were
converted into intermediate iminium ions by anodic oxidation,
and then reacted with dialkyl phosphonates to afford products11.
On the other hand, in Li’s13 and Ofial’s14 opinions, iminium ions
were proposed to be the intermediates involved in the transi-
tion-metal catalyzed oxidation of amines, which was also reported
by Rueping15 and König.16 The intermediate iminium ions can also
be afforded through direct oxidation using simple oxidants, includ-
acid groups.1
a-Aminophosphonates were also investigated in the
biological applications such as enzyme inhibitors,2 antibacterial
agents,3 antitumor agents,4 antibody generation,5 anti-HIV agents,6
and antifungals.7 A traditional method for the synthesis of
a-amin-
ophophonates was the one-pot three-component Kabachnik-Fields
reaction8 which involved dialkyl phosphonates, amines, and
aldehydes. Another operative method was the addition of phospho-
nates to imines, known as the Pudovik reaction.9 The enatioselective
ing DDQ,17 PhI(OAc)2, and oxoammonium salts,19 under metal-
18
synthesis of
a
-aminophosphonates catalyzed by metal or organo-
free conditions. Inspired by these achievements, we surmised that
a-aminophosphonates can be synthesized from tetrahydroquino-
line and dialkyl phosphonates and mediated by oxidant without
molecular was also developed.10
A different method to afford
a-aminophosphonates especially
from the tertiary amines is the cross-dehydrogenative-coupling
(CDC) reaction between a sp3 C–H bond adjacent to a nitrogen
atom and a P–H bond. In 1981, Genies and co-workers11 reported
a CDC reaction of dialkyl phosphonates with tertiary amines
through electrical oxidation albeit with moderate yields. In 2001,
Tilley and co-workers12 reported an intramolecular C–H/P–H dehy-
drogenative coupling catalyzed by Rh complex. Recently, Li and
co-workers13 developed the Cu-catalyzed CDC reaction of dialkyl
phosphonates with 1,2,3,4-tetrahydroisoquiline oxidized by
oxygen. At the same time, Ofial and co-workers14 explored the
Fe-catalyzed CDC reaction of dialkyl phosphonates with dialkyl
anilines ultilizing t-BuOOH (TBHP) as the oxidant. More recently,
the photoredox-catalyzed phosphonations of tertiary amines were
metal catalysis (Scheme 1). Herein, we report our efforts to explore
a new CDC reaction to afford
a
-aminophosphonates only oxidized
Phot oredox-Cat alyzed
Oxidat ion
Met al-Free
Ar
Direct
Ar
R'
Anodic
Ar
Oxidat ion
N
Oxidat ion
N
N
R'
this
R'
work
R
R
R
TM-Cat alyzed
Oxidat ion
O
HP OR''
OR''
O
Ar
N
P
R''O
R'
R''O
R
⇑
Corresponding author. Tel.: +86 0411 84379260; fax: +86 0411 84379223.
E-mail address: bswan@dicp.ac.cn (B. Wan).
Scheme 1. The intermediate involved in the phosphonation of tertiary amine.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.120

682
H. Wang et al. / Tetrahedron Letters 53 (2012) 681–683
Table 2
by 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) at room
temperature.
DDQ mediated phosphonation of N-aryl tetrahydroisoquinolinea
At the outset of our studies, several oxidants were tested in the
model reaction, which involved N-phenyltetrahydroisoquinoline
1a and diethyl phosphonate 2a. To our delight, DDQ was an effec-
tive oxidant for the reaction, and the product was obtained in a
quantitative yield (Table 1, entry 1).20 Nevertheless, significantly
O
DDQ
N
O
+
Ar
N
PH(OR)2
Ar
CH3CN RO P
RO
rt
2
1
3
lower yield of a-aminophosphonate 3a was observed when using
Entry
Ar
R
3
Yieldb (%)
the similar oxidant 1,4-BQ (21% yield, Table 1, entry 2). PhI(OAc)2
proved to be an effective oxidant albeit with lower yield (76% yield,
Table 1, entry 3) compared with DDQ. However, only trace
amounts of the product 3a could be separated either in the pres-
ence of aqueous solution/decane solution of TBHP (Table 1, entries
4 and 5), or under the influence of a metal oxidant AgOAc (Table 1,
entry 6). Unfortunately, the environmental friendly oxidant air and
hydrogen peroxide were totally ineffective for this reaction (Table
1, entries 7 and 8). Furthermore, the effects of solvents were also
investigated, and the reaction proceeded smoothly in almost all or-
ganic solvents tested (Table 1, entries 9–14). Either in low polarity
solvents (Table 1, entries 10 and 11) or high polarity solvents
(Table 1, entries 13 and 14), the product could be obtained in
excellent yields, yet only moderate yields of the product were
obtained when dichloromethane and acetone were used (Table 1,
entries 9 and 12). However, the reaction failed to afford the prod-
uct when water was used as the solvent (Table 1, entry 15).
Under the optimized conditions, we investigated the scope of
the reaction by employing different N-aryl isoquinolines and phos-
phonates, and the results were summarized in Table 2. Various
dialkyl phosphonates including methyl, ethyl, iso-propyl, and ben-
zyl phosphonates were effective substrates to afford the coupling
products in good to excellent yields. In previous work, diphenyl
phosphonate was an ineffective substrate to provide the desired
product. We were pleased to find that diphenyl phosphonate 2e re-
acted with tetrahydroquinoline successfully under the influence of
DDQ (Table 2, entries 5, 10, 15 and 20). Both electron-donating
groups and electron-withdrawing groups on N-aryl were tolerated
in the reaction, and the products were obtained in good to excel-
1
2
3
4
5
6
7
8
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
4-MeOC6H4 (1b)
4-MeOC6H4 (1b)
4-MeOC6H4 (1b)
4-MeOC6H4 (1b)
4-MeOC6H4 (1b)
4-MeO2CC6H4 (1c)
4-MeO2CC6H4 (1c)
4-MeO2CC6H4 (1c)
4-MeO2CC6H4 (1c)
4-MeO2CC6H4 (1c)
2-MeC6H4 (1d)
Me (2b)
Et (2a)
iPr (2c)
Bn (2d)
Ph (2e)
Me (2b)
Et (2a)
iPr (2c)
Bn (2d)
Ph (2e)
Me (2b)
Et (2a)
iPr (2c)
Bn (2d)
Ph (2e)
Me (2b)
Et (2a)
iPr (2c)
Bn (2d)
Ph (2e)
3b
3a
3c
3d
3e
3f
3g
3h
3i
95
99
87
95
95
88
91
87
99
80
94
91
82
88
75
86
87
86
83
51
9
10
11
12
13
14
15
16
17
18
19
20
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
2-MeC6H4 (1d)
2-MeC6H4 (1d)
2-MeC6H4 (1d)
2-MeC6H4 (1d)
a
Reaction conditions: tetrahydroquinoline 1 (0.2 mmol), diethyl phosphonate 2
(0.4 mmol), DDQ (0.22 mmol), 1 mL solvent.
b
Isolated yields.
lent yields. When the protecting phenyl group was replaced by
sterically hindered 2-methylphenyl (Table 2, entries 16–20), the
coupling products were obtained in good yields, except the reac-
tion with diphenyl phosphonate (Table 2, entry 20).
NC
O
CN
N
O
Ar
H
Table 1
1
Optimization of reaction conditionsa
Cl
Cl
CN
Ar
NC
O
Oxidant
N
O
OEt
OEt
N
+
Ph
HP
N
Solvent
O
O
Ph
EtO P
EtO
H
rt
OR
OR
Cl
fast
Cl
Cl
H P
O
1a
2a
3a
Yieldsb (%)
2
Entry
Oxidant
Solvent
Cl
1
2
3
4
5
6
7
8
DDQ
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
THF
99
21
76
Trace
Trace
Trace
NRf
NR
78
92
94
85
1,4-BQc
OH
O
N
OR
PhI(OAc)2
Ar
4
P
TBHP (in H2O)d
OR
NC
CN
OH
TBHP (in decane)e
5
AgOAc
H2O2
Air
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
NC
CN
9
10
11
12
13
14
15
OH
HO
Cl
O
Toluene
Acetone
MeOH
EtOH
NC
NC
Cl
Cl
Cl
N
7
93
91
NR
Ar
RO
RO
P
OH
H2O
OH
N
a
Reaction conditions: tetrahydroquinoline 1a (0.2 mmol), diethyl phosphonate
Ar
6
RO
RO
2a (0.4 mmol), oxidant (0.22 mmol), 1 mL solvent at room temperature.
P
O
b
Isolated yields.
1,4-BQ = 1,4-benzoquinone.
65% weight.
5.0–6.0 M.
c
3
d
e
Scheme 2. The mechanism of DDQ mediated phosphonation of N-aryl tetrahydro-
isoquinoline.
f
No reaction.

H. Wang et al. / Tetrahedron Letters 53 (2012) 681–683
683
The regioselectivity of the products shows that probably the
References and notes
intermediate is radical or iminium ion. To confirm the intermediate
of the reaction, the radical inhibitor 2,6-di-tert-butyl-4-methylphe-
nol (BHT) was added to the reaction of 1a and 2a, and the product 3a
was obtained in a 79% yield (vs 99% yield in Table 2, entry 2). This re-
sult indicated that a radical intermediate is involved in the reaction
process, and quickly converts into another intermediate which
reacts with phosphonates. Such procedure was also proposed by
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Ofial and co-workers in the Fe-catalyzed a-phosphonation of N,N-
dialkylanilines.14 In previous works on the oxidation process of
DDQ, a charge–transfer complex was believed to be formed.17a,21
In addition, it is also well known that nucleophilic phosphite 5 is
an equivalent to phosphonate 2 in the reaction.22 Based on these
considerations, a most probable mechanism was proposed in
Scheme 2 to elucidate the reaction process. At the first stage of this
reaction, tetrahydronquinoline is oxidized by DDQ to form complex
4, in which a radical intermediate might be involved. Following
addition of phosphonate to the iminium ion part of 4 affords the
intermediate complex 6. Finally, the product 3 is obtained after
the leaving of diphenol 7.
5. Smith, A. B., III; Taylor, C. M.; Bencovic, S. J.; Hirschmann, R. Tetrahedron Lett.
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In summary, a new method for the
a-phosphonation of N-aryl
protected tetrahydroisoquinoline mediated by DDQ at room tem-
perature was developed. This method proceeded efficiently with-
out involving transition-metal and visible light. Diphenyl- and
various dialkyl-substituted phophonates were effective substrates
under the reaction conditions. Electronic and sterical groups on
the N-protected phenyl group of tetrahydroisoquinoline have little
influence on the reaction results. Further investigation on other
nucleophiles reacting with the tertiary amines mediated by DDQ
is in process.
19. Richter, H.; Mancheño, O. G. Eur. J. Org. Chem. 2010, 4460.
20. General procedure for direct oxidative phosphonylation of amines: N-Aryl
tetrahydroquinoline 1 (0.2 mmol) and DDQ (0.22 mmol) were added in a
reaction tube, and 1.0 mL CH3CN used as solvent. Dialkyl phosphonate 2
(0.4 mmol) was added through syringe. After stirred at room temperature over
night, the reaction mixture was diluted with CH2Cl2, and then concentrated
under vacuum. The product was purified by the chromatographic column on
aluminium oxide with petroleum ether/ethyl acetate (5/1 to 3/1) as eluant.
21. Hagen, T. J.; Narayanan, K.; Names, J.; Cook, J. M. J. Org. Chem. 1989, 54, 2170.
22. Akiyama, T.; Morita, H.; Itoh, J.; Fuchibe, K. Org. Lett. 2005, 7, 2583.
Acknowledgment
We are grateful for the financial support from the National Basic
Research Program of China (2010CB833300).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.11.120.