Molybdenum trioxide catalyzed oxidative cross-dehydrogenative coupling of benzylic sp3 C-H bonds: Synthesis of α-aminophosphonates under aerobic conditions

Article abstract of DOI:10.1016/j.tetlet.2012.01.031

Molybdenum trioxide (MoO₃) catalyzed efficient oxidative cross-dehydrogenative-coupling (CDC) method for C-H functionalization of N-aryl tetrahydroisoquinolines has been explored. This user-friendly method of synthesizing α-aminophosphonates employs 1.1 equiv of dialkyl-H- phosphonate under aerobic condition. Formation of new C-P bonds from unfunctionalized starting materials under environmentally benign conditions provides an excellent avenue for the synthesis of biologically active α-aminophosphonates.

Full text of DOI:10.1016/j.tetlet.2012.01.031

Tetrahedron Letters 53 (2012) 1456–1459
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Molybdenum trioxide catalyzed oxidative cross-dehydrogenative coupling
of benzylic sp3 C–H bonds: synthesis of
aerobic conditions
a-aminophosphonates under
⇑
Kaliyamoorthy Alagiri, Pradeep Devadig, Kandikere R. Prabhu
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, Karnataka, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Molybdenum trioxide (MoO3) catalyzed efficient oxidative cross-dehydrogenative-coupling (CDC)
Received 6 December 2011
Revised 5 January 2012
Accepted 7 January 2012
Available online 17 January 2012
method for C–H functionalization of N-aryl tetrahydroisoquinolines has been explored. This user-friendly
method of synthesizing
a-aminophosphonates employs 1.1 equiv of dialkyl-H-phosphonate under
aerobic condition. Formation of new C–P bonds from unfunctionalized starting materials under environ-
mentally benign conditions provides an excellent avenue for the synthesis of biologically active
a
-aminophosphonates.
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
CDC reaction
Aerobic oxidation
C–H functionalization
Molybdenum
Hydrophosphorylation
Transition metal catalyzed activation of sp3 C–H bonds has
gained tremendous importance in recent years due to their utility
in user-friendly methods under green reaction conditions.1 As a
result, a number of nucleophiles have been reacted with a variety
of activated systems.1–6 Although significant efforts have been
made toward the formation of C–C bonds,1–6 there are considerable
efforts to exploit the CDC reactions for the formation of C-hetero
bonds to accomplish heterocyclic compounds,3–6 which are impor-
tant pharmaceuticals, and agrochemicals.7–9 Generally, metal
catalysts such as Cu,1a,2f,3a Fe,2b,e,3b Ru,2a,g V,2c,4a etc. are used for
the C–H functionalization of sp3 C–H bonds adjacent to tertiary
nitrogen to achieve CDC reactions.
the preparation of
nes,12 synthesis of
amines is less known. Recently, metal catalysts such as copper or
iron are used effectively to activate sp3 C–H bond adjacent to
tertiary nitrogen.13,14 Basle and Li have reported Cu-catalyzed
a
-aminophosphonates from preformed imi-
a
-aminophosphonates directly from the tertiary
a
-phosphonation of N-phenyl tetrahydroisoquinoline to produce
C-P bonds by the CDC method.13a In their work on hydrophosph-
orylation, they have utilized a copper catalyst with excess dialkyl
H-phosphonates in the presence of molecular oxygen. Other than
this report,
a-phosphonation of N-aryl tetrahydroisoquinolines,
has been recently demonstrated by employing Ir or Ru com-
plexes,13b and eosin Y catalyst.13c Both of these reactions use
visible light and require a large excess of dialkyl H-phosphonates
(3–4 equiv). Notably, these two reactions13b,c use either DMF or
toluene/water as the solvent and are not suitable with dimethyl
phosphite (2b), as dimethyl phosphite undergoes hydrolysis in
the presence of water.13b Additionally, the phosphonation cata-
lyzed by Ir or Ru needs longer time and results in lesser yields,
particularly with sterically hindered phosphonates.13b
Moreover, CDC reactions have advantages over the traditional
methods of coupling reactions, as CDC reactions do not require pre-
functionalization of the starting material. Therefore, CDC reactions
may provide shorter synthetic routes to the required product. In
this context,
tions is attractive, as they provide an efficient and easy access to
-aminophosphonates and their derivatives, which are biologically
active compounds and useful precursors for Wittig reactions9b. The
traditional methods employed to synthesize -aminophospho-
a-phosphonation of tertiary amines using CDC reac-
a
Further, Ofial and coworkers14 reported the
tertiary amines, which is particularly useful for the
nation of N, N-dimethylanilines. This iron catalyzed CDC reaction
employs excess TBHP and is not useful for the -phosphonation
of N-aryl tetrahydroisoquinolines as it furnishes the corresponding
lactam as the major product.14b The advantages offered by the CDC
reactions such as not requiring prefunctionalized precursors, and
compatibility of the reaction with water and molecular oxygen
a-phosphonation of
a
a-phospho-
nates are hydrophosphorylation of aldehydes in the presence of
amine (Kabachnik-Field reaction),10 and hydrophosphorylation of
imines (Pudovik reaction).11 Despite a wide range of reports for
a
⇑
Corresponding author. Tel.: +91 80 229321887; fax: +91 80 23600683.
E-mail address: prabhu@orgchem.iisc.ernet.in (K.R. Prabhu).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.031

K. Alagiri et al. / Tetrahedron Letters 53 (2012) 1456–1459
1457
has prompted several groups to be actively involved in this field.15
To take the complete advantage of the CDC reactions, it is impor-
tant to develop simple, high-yielding, and using user-friendly pro-
tocols that are compatible with a variety of nucleophiles by
employing inexpensive reagents and oxidants. In pursuit of our
interest in CDC reactions to form C–C bonds16 and the utility of
molybdenum catalysts in organic synthesis under green chemistry
conditions,17 herein we report a molybdenum catalyzed CDC reac-
amount of MoO3 (5 mol %) in MeOH at 60 °C in the presence of
molecular oxygen.18 With this optimization study, we continued
our investigation on the reaction of a variety of N-protected tetra-
hydroisoquinoline derivatives with dialkyl H-phosphonates. As can
be seen in Table 2, N-phenyl tetrahydroisoquinoline 1a reacted
well with diethyl phosphite 2a smoothly to furnish the corre-
sponding
a-aminophosphonate 3a in excellent yield (94%, Table
2, entry 1). The formation of product 3a was confirmed by 1H,
13C, and 31P NMR spectral analyses. Similarly, tetrahydroisoquino-
line with p-methoxyphenyl (PMP) protecting group on nitrogen
(1b), reacted smoothly to afford the corresponding phosphonate
3b in excellent yield (90%, entry 2, Table 2). Next, we continued
our exploration with N-phenyl tetrahydroisoquinoline derivatives
bearing substitution on the aromatic ring. Hence, N-phenyl tetra-
hydroisoquinoline derived from veratraldehyde 1c reacted well
with 2a to yield the product 3c in excellent yield (92%, Table 2, en-
try 3). Similarly, N-phenyl tetrahydroisoquinoline derived from
heliotropin 1d reacted well with 2a to furnish an excellent yield
of the product 3d (95%, Table 2, entry 4). As expected dimethyl
phosphite 2b reacted well with N-aryl tetrahydroisoquinoline
tion. In this context, this is the first report on
a-phosphonation of
sp3 C–H bonds using molybdenum catalysts.
For the optimization studies, we chose N-phenyl tetrahydroiso-
quinoline (1a) as the model substrate and diethyl phosphite (2a) as
the phosphonate source. As can be seen in Table 1, reaction of 1a
with 2a (2 equiv) in MeOH using TBHP (1.5 equiv, 5 M solution in
decane) as the oxidant at room temperature with a variety of cat-
alysts (10 mol %) such as VO(acac)2, Ti(OiPr)4, MoO2(acac)2, or
MoO3 produced moderate yields of 3a (entries 1–4). Further inves-
tigation was continued with MoO3, as it is inexpensive and readily
available. The reaction of 1a and 2a (2 equiv) with MoO3 (10 mol %)
using O2 as the oxidant at room temperature furnished a trace
amount of 3a in 24 h (entry 5). Nevertheless, the reaction of 1a
with 2a (2 equiv) in the presence of 10 mol % MoO3 at 60 °C pro-
duced a remarkable result, affording 3a in 94% (16 h, entry 6). Fur-
ther, reducing the catalyst loading to 5 mol % did not lead to any
appreciable change in the yield of the phosphonated product 2a
(93%, entry 7). Finally, the optimal reaction condition was reached
by using an almost stoichiometric amounts of 1a (1 equiv) and 2a
(1.1 equiv), in MeOH under oxygen atmosphere at 60 °C to obtain
3a in a 94% yield (entry 8). The use of different solvents such as
THF, CHCl3, EtOAc, CH3CN under the similar reaction condition
resulted in lowering the yield of the product 3a (entries 9–12).
Interestingly, phosphonation of 1a with 2a in toluene required
100 °C to produce 3a in almost quantitative yield (entry 13). On
the other hand, the reaction of 1a and 2a in 5 mol % of MoO3 under
oxygen in water failed to furnish 3a at reflux temperature (entry
14). The same reaction in the absence of oxidants (O2 or TBHP)
afforded only trace amounts of 3a (entry 15).
derivatives 1a, 1b, 1c, or 1d to furnish the corresponding a-phos-
phonated products 3e, 3f, 3g, or 3h in excellent yields (Table 2,
entries 5–8). As can be seen from Table 2, the scope of the present
reaction appears to be good as
a-phosphonation works well with
diisopropyl phosphite 2c and dibenzyl phosphite 2d. Hence, 2c re-
acted well with a variety of N-aryl tetrahydroisoquinoline deriva-
tives (1a, 1b, 1c, or 1d) to furnish the corresponding
a-
phosphonated products 3i, 3j, 3k, or 3l in very good yields (Table
2, entries 9–12). Under similar reaction conditions, 2d reacted well
with N-aryl tetrahydroisoquinoline derivatives (1a, 1b, 1c, or 1d) to
afford the products 3m, 3n, 3o, or 3p (Table 2, entries 13–16).
However, the aliphatic tertiary amines, such as N,N-dialkyl
anilines, turned out to be poor substrates for this CDC reaction.
The exact mechanism of the reaction is not clear at this stage,
however the reaction proceeds in the presence of radical scavenger
BHT (2,6-bis(1,1-dimethylethyl)-4-methylphenol), suggesting that
the reaction may not be proceeding through a radical pathway.
We believe that N-aryl tetrahydroisoquinoline (1a) is oxidized to
iminium ion intermediate (II), which further reacts with nucleo-
phile to furnish the desired coupled product 3a (Scheme 1). Further
With these detailed screening experiments, it was established
that the
a-phosphonation of N-phenyl tetrahydroisoquinoline
requires reacting 2a (1.1 equiv), 1a (1 equiv), and a catalytic
Table 1
Optimization of reaction conditions
catalyst
oxidant
N
Ph
H
N
Ph
+
P(OEt)2
2a
3a
P(OEt)2
O
solvent
O
1a
Entry
Catalyst (mol %)
2a (equiv)
Oxidant (equiv)
Solvent
Time (h)
Temp (°C)
Yeilda (%)
1
2
3
4
5
6
7
8
VO(acac)2 (10)
Ti(iOPr)4 (10)b
MoO2(acac)2 (10)
MoO3 (10)
MoO3 (10)
MoO3 (10)
MoO3 (5)
MoO3 (5)
MoO3 (5)
MoO3 (5)
MoO3 (5)
2
2
2
2
2
2
2
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
TBHP (1.5)
TBHP (1.5)
TBHP (1.5)
TBHP (1.5)
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
THF
CHCl3
EtOAc
CH3CN
Toulene
H2O
16
72
16
24
24
16
16
24
24
24
24
24
24
24
24
rt
rt
rt
rt
52
48
78
66c
Tracec
94
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
none
rt
60
60
60
60
60
60
60
100
100
60
93
94
9
71c
38c
20c
42c
100c
Tracec
Trace
10
11
12
13
14
15
MoO3 (5)
MoO3 (5)
MoO3 (5)
MoO3 (5)
MeOH
a
b
c
Isolated yields.
MS 4 Å was used as additive.
NMR conversion based on starting material.

1458
K. Alagiri et al. / Tetrahedron Letters 53 (2012) 1456–1459
Table 2
Molybdenum catalyzed
a
-phosphonation of N-Aryl tetrahydroisoquinolinesa
O
O
O
1a
Ph
1b
1c
1d
Ph
N
N
N
N
PMP
O
H
Ph
H
H
H
P(OEt)2
O
P(OMe)2
O
P(OiPr)2
O
P(OCH2Ph)2
O
2a
2b
2c
2d
Entry
1
Precursors
Product
Yield (%)b
Entry
9
Precursors
Product
Yield (%)b
N
N
Ph
Ph
3a
3b
3i
1a+2a
1b+2a
94
1a+2c
92
P(OEt)2
P(OiPr)2
O
O
N
N
PMP
PMP
3j
2
3
90
92
10
11
1b+2c
1c+2c
93
89
P(OEt)2
P(OiPr)2
O
O
O
O
O
O
N
N
Ph
Ph
3c
3d
3k
1c+2a
1d+2a
P(OiPr)2
O
P(OEt)2
O
O
O
O
O
N
N
Ph
Ph
3l
4
95
12
1d+2c
88
i
P(OEt)2
P(O Pr)2
O
O
N
N
Ph
Ph
3e
3m
5
6
1a+2b
1b+2b
87
93
13
14
1a+2d
1b+2d
88
91
P(OMe)2
P(OCH2Ph)2
O
O
N
N
PMP
PMP
3n
3f
P(OMe)2
P(OCH2Ph)2
O
O
O
O
O
O
N
N
Ph
Ph
3g
3o
7
8
1c+2b
1d+2b
95
91
15
16
1c+2d
1d+2d
89
86
P(OMe)2
P(OCH2Ph)2
O
O
O
O
O
O
N
N
Ph
Ph
3h
3p
P(OMe)2
P(OCH2Ph)2
O
O
a
Standard reaction condition: 1a (1 mmol), 2a (1.1 mmol), MoO3 (5 mol %), MeOH (2 mL), O2 (1 atm), 60 °C, 24 h.
Isolated yields.
b
work to extend this methodology to other nucleophiles is under-
way in our laboratory.
H-phosphonates for a-phosphonation and furnishes the products
in excellent yields. Moreover, this method uses molecular oxygen
as an oxidant and compatible with a variety of phosphonates.
Further, using a readily available, inexpensive catalyst such as
molybdenum trioxide for the formation of new C–P bonds from
unfunctionalized starting materials to access biologically active
In summary,
a-phosphonation of N-aryl tertrahydroisoquino-
line derivatives is efficiently accomplished using CDC reactions
under aerobic conditions. Unlike other methods,13,14 this molyb-
denum mediated strategy uses a stoichiometric amount of dialkyl

K. Alagiri et al. / Tetrahedron Letters 53 (2012) 1456–1459
1459
Commun. 2009, 2371–2372; (d) Murahashi, S.-I.; Komiya, N.; Terai, H. Angew.
Chem. Int. Ed. 2005, 44, 6931–6933; (e) Han, W.; Ofial, A. R. Chem. Commun.
2009, 5024–5026; (f) Li, Z.; Li, C.-J. Eur. J. Org. Chem. 2005, 3173–3176; (g)
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H P(OR)2
O
Ph
N
O
O
Mo
O
H
I
P(OR)2
OH
3. Indolation by CDC (a) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 6968–6969; (b)
Liu, P.; Zhou, C.-Y.; Xiang, S.; Che, C.-M. Chem. Commun. 2010, 46, 2739–2741;
(c) Ghobrial, M.; Harhammer, K.; Mihovilovic, M. D.; Schnurch, M. Chem.
Commun. 2010, 46, 8836–8838.
4. Mannich like reaction by CDC (a) Sud, A.; Sureshkumar, D.; Klussmann, M.
Chem. Commun. 2009, 3169–3171; (b) Shen, Y.; Li, M.; Wang, S.; Zhan, T.; Tan,
Z.; Guo, C.-C. Chem. Commun. 2009, 953–955; (c) Yang, F.; Li, J.; Xie, J.; Huang,
Z.-Z. Org. Lett. 2010, 12, 5214–5217.
5. Aza-Henry reaction by CDC (a) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 3672–
3673; (b) Condie, A. G.; Gonzalez-Gomez, J. C.; Stephenson, C. R. J. J. Am. Chem.
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1050; (d) Tsang, A. S.-K.; Todd, M. H. Tetrahedron Lett. 2009, 50, 1199–1202.
6. Zhao, L.; Li, C.-J. Angew. Chem., Int. Ed. 2008, 47, 7075–7078.
N
N
N
Ph
O
Ph
Ph
II
1a
+
O
Mo O
O
P(OR)2
O
+
OH
Mo
O
H2O
O2
Scheme 1. Plausible mechanism for the
a-phosphonation of N-aryl
tetrahydroisoquinolines.
7. Edmundson, S. In The Chemistry of Organophosphorus Compounds; Hartley, F. R.,
Ed.; John Wiley & Sons: New York, 1996; p 147. Vol. 4.
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a
-aminophosphonates is the major strength of the present
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Acknowledgments
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This work is supported by the Indian Institute of Science, CSIR,
New-Delhi (no. 01(2415)/10/EMR-II) and RL Fine Chem. We are
thankful to Dr. A. R. Ramesha and Prof. S. Chandrasekhar for
encouragement. One of the authors (KA) thanks the CSIR, New-Del-
hi for a senior research fellowship.
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Supplementary data (experimental procedure 1H and 13C NMR
spectral data for all new compounds) associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2012.01.031.
References and notes
1. CDC reviews (a) Li, C.-J. Acc. Chem. Res. 2009, 42, 335–344; (b) Scheuermann, C.
J. Chem. Asian J. 2010, 5, 436–451; (c) Murahashi, S.-I.; Zhang, D. Chem. Soc. Rev.
2008, 37, 1490–1501; (d) Li, Z.; Bohle, D. S.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A.
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2. Cyanation by CDC (a) Murahashi, S.-I.; Nakae, T.; Terai, H.; Komiya, N. J. Am.
Chem. Soc. 2008, 130, 11005–11012; (b) Singhal, S.; Jain, S. L.; Sain, B. Adv.
Synth. Catal. 2010, 352, 1338–1344; (c) Singhal, S.; Jain, S. L.; Sain, B. Chem.
18. Typical experimental procedure: A mixture of 5 mol % of MoO3 (6.8 mg,
0.048 mmol), N-phenyl tetrahydroisoquinoline 1a (200 mg, 0.95 mmol) and
diethyl phosphite 2a (0.13 mL, 1.05 mmol) in MeOH (2 mL) was heated at 60 °C
under oxygen atmosphere (oxygen balloon) for 24 h. The solvent was removed
under vacuo, added water and extracted with DCM. The combined organic
layer was dried over Na2SO4, concentrated under reduced pressure, and
purified by column chromatography on silica gel using ethyl acetate/hexane
(1:4) to afford desired product 3a as pale yellow liquid (310 mg, 94%).