Synthesis of phosphorus containing medium ring heterocycles by sequential Claisen rearrangement and ring closing metathesis

Article abstract of DOI:10.1016/j.tetlet.2014.01.008

An efficient method for the synthesis of novel medium ring phosphorus containing heterocycles starting from phenol derivatives by ruthenium catalyzed ring closing metathesis is described. This work deals with a sequential aromatic Claisen-rearrangement, coupling of an allyl/vinyl phosphonate, and ring closing metathesis reaction. All of these reactions were carried out at ambient temperature to afford the medium-sized phosphorus heterocycles in excellent yields.

Full text of DOI:10.1016/j.tetlet.2014.01.008

Tetrahedron Letters 55 (2014) 1247–1250
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of phosphorus containing medium ring heterocycles
by sequential Claisen rearrangement and ring closing metathesis
⇑
K. C. Majumdar , Raj Kumar Nandi, Sintu Ganai
Department of Chemistry, University of Kalyani, Kalyani 741235, W.B, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method for the synthesis of novel medium ring phosphorus containing heterocycles starting
from phenol derivatives by ruthenium catalyzed ring closing metathesis is described. This work deals
with a sequential aromatic Claisen-rearrangement, coupling of an allyl/vinyl phosphonate, and ring clos-
ing metathesis reaction. All of these reactions were carried out at ambient temperature to afford the med-
ium-sized phosphorus heterocycles in excellent yields.
Received 8 October 2013
Revised 30 December 2013
Accepted 3 January 2014
Available online 10 January 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Phosphorus heterocycles
Medium-sized ring
Claisen rearrangement
Grubb’s I catalyst
Ring closing metathesis
Due to their ubiquity in biological systems1 and potential to
serve as novel pharmaceuticals and agrochemicals,2 phosphorus
containing heterocyclic compounds continue to receive wide-
spread attention by the synthetic organic chemists. Catalytic anti-
body developer Haptens and anti-cancer agent cyclophosphamide
are well known examples of phosphorus containing compounds.3
1,4-Dihydropyridine-5-cyclic phosphonate derivatives (such as
compound A) are known to be an anti-hypertensive agent,4a
besides these, several phosphorus analogues of sugars (as for
example B) are also known for their different bioactivities.4b–d
Addition to their bioactivities nowadays different P-heterocycles
(as for example C) are used as catalyst5 for asymmetric synthesis,
Lewis bases,6 and also as chiral auxiliaries ligand.7 As a part of
our continuing effort toward the development of new protocols
for the expeditious synthesis of biologically relevant heterocyclic
compounds,8 we became interested to explore newer methodolo-
gies for the synthesis of phosphorus containing heterocycles.
Considering their broad spectrum of bio-activity synthetic organic
chemists have provided different protocols including different me-
tal-catalyzed synthesis of phosphorus heterocycles.9 Nevertheless
these methods worked nicely but having some drawbacks. During
the last two decades, after the discovery of Grubbs’ catalyst,10 RCM
protocol has been used enormously in the construction of structur-
ally diverse phosphorus containing heterocycles viz.; small ring
and regular ring phosphorus heterocycles.11
However, synthesis of phosphorus containing medium ring
heterocycles especially benzo-fused heterocycles has largely
remained unexplored, this might, in part, be due to the lack of
general methods for their synthesis. This has prompted us to inves-
tigate for an effective and compatible synthetic methodology to
achieve the synthesis of some hitherto unreported benzo-fused
oxophosphocine and oxophosphopine derivatives of biological
interest.
In continuation with our work on the synthesis of medium ring
by the implementation of sequential Claisen rearrangement
followed by ring closing metathesis reaction,8a,b we have
undertook
a study to synthesize the hitherto unreported
benzo-fused oxophosphocine and oxophosphopine derivatives
from the substrates containing unsymmetrical alkenyl groups
directly linked to the phosphorus atom. Herein, we report the
results of our investigation.
Unsymmetrical alkenyl derivatives 4a–j were used as metathet-
ic precursors. For the synthesis of starting materials we have used
the century old thermal Claisen rearrangement12 of O-allylated
derivatives of 1a–j as one of the steps to access C-allylated phenol
derivatives 2a–j according to the published procedure.13 The syn-
thesis of unsymmetrical allyl arylphosphonate derivatives 4a–j
was accomplished according to Scheme 1.
The phosphonate derivatives 4a–j were prepared in 72–93%
yields by coupling of C-allylated phenol derivatives 2a–j and the
corresponding allylphosphonochloridate 3.
For the synthesis of benzo-oxophosphocin derivatives the cor-
responding metathetic precursors 6a–d were derived by the SN
displacement of chloride anion of vinylphosphonochloridate 4 by
⇑
Corresponding author. Tel.: +91 33 2582 7521; fax: +91 33 2582 8282.
E-mail addresses: kcmklyuniv@gmail.com, kcm_ku@yahoo.co.in, kcm@klyuniv.
2
ac.in (K.C. Majumdar).
0040-4039/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2014.01.008

1248
K. C. Majumdar et al. / Tetrahedron Letters 55 (2014) 1247–1250
: R1 = R3 = R4 = H, R2 = Br (76%)
4a
O
P
4b: R1 = R3 = R4 = H, R2 = Me (81%)
4c: R1 = R3 = R4 = H, R2 = OMe (84%)
4d: R1 = R3 = R4 = H, R2 = tBu (90%)
4e: R1 = R3 = R4 = H, R2 = NO2 (72%)
4f: R1 = R2 = H, R3 = R4 = benzo (84%)
EtO
O
OH
OH
O
P
EtO
Cl
R4
R3
R4
R3
R4
R3
(i)
3
R1
(iii)
(ii)
R1
R1
R2
2a-h
R2
1a-h
: R1 = R2 = benzo, R3 = R4 = H, (83%)
4g
4h
R2
4a-h
1
: R = R2 = R3 = R4 = H (79%)
OEt
O
O
O
P
O
O
OEt
Cl
P
O
OH
OH
EtN
3
EtN
EtN
O
(i)
(iii)
O
N
(ii)
O
N
N
Et
4i
Et
Et
(82%)
O
1i
2i
EtO
O
O
P
3
P
OH
OH
OEt
Cl
(i)
(iii)
(ii)
O
73%)
O
O
O
O
O
4j
2j
1j
O
P
EtO
O
OH
O
R4
R3
EtO
: R1 = R3 = R4 = H, R2 = Br (79%)
6a
: R1 = R3 = R4 = H, R2 = Me (81%)
6b
R4
R3
P
4
(iv)
Cl
R1
6c: R1 = R3 = R4 = H, R2 = OMe (84%)
6d: R1 = R3 = R4 = H, R2 = tBu (81%)
R1
6a-d
R2
2a-d
R2
Scheme 1. Synthesis of unsymmetrical phosphorus tethered metathetic precursor. Reagents and conditions: (i) allyl bromide, K2CO3, dry acetone, reflux, 8 h;
(ii) Dichlorobenzene, reflux 6 h; (iii) Dry Et2O, Et3N, 0 °C, 4 h; (iv) Dry Et2O, Et3N, 0 °C, 9 h.
EtO
O
O
the phenoxide anion of C-allylated aromatic precursors 2a–d. The
allylphosphonochloridate 3 and vinylphosphonochloridate 4 were
prepared according to the published procedure13 (scheme 1).
Finally, the ring closing metathesis was adopted for the synthe-
sis of the target phosphorus containing medium ring heterocycles
from the substrate 4a–j and 6a–d. Grubbs’ first generation catalyst
(D; Fig. 1) was used in the metathesis step for the formation of
medium ring containing phosphorus.
EtO
O
O
P
P
(i)
Br
Br
7a
4a
EtO
O
EtO
O
O
O
P
P
When unsymmetrical alkenyl derivative, substrate 4a was al-
lowed to react in the presence of 5 mol % Grubbs’ first generation
catalyst under a nitrogen atmosphere at room temperature (rt) in
dichloromethane for 5 h, the corresponding 8-membered cyclized
product 7a was obtained in excellent yield without any contamina-
tion of the product (Scheme 2).
For the synthesis of benzo-oxophosphocine derivatives the met-
athetic precursor 6a was subjected to the same protocol with
Grubbs’ catalyst I, but the reaction resulted in giving a poor yield
(23%) at room temperature, the rest of the starting material re-
mained unchanged. The seven-membered product 8a was obtained
in 79% yield under refluxing condition for 8 h.
(ii)
Br
8a
Br
6a
Scheme 2. Synthesis of phosphorus containing heterocycles by RCM. Reagents and
conditions: (i) Grubbs’ Cat I, 5 mol %, rt, DCM, 5 h, 92%; (ii) Grubbs’ Cat I, 5 mol %,
reflux, DCM, 8 h, 79%.
Encouraged by this result, other substrates 4b–j and 6b–d were
similarly treated with Grubbs’ catalyst I in dichloromethane to
afford the corresponding oxophosphocine (7b–j) and oxophospho-
pine (8b–d) derivatives in 67–93% and 65–79% yields, respectively.
PCy3
Ru
PCy3
Ar
O
Cl
Cl
O
O
O
O
O
P
O
P
OH
OH
Ph
P
O
o-C6H4NO2
OH
O
HO
HN
Grubbs' 1st generation
catalyst (Grubbs' Cat. I)
COOMe
Ar
OH
Me
C
A
D
B
Figure 1. Some important phosphorus containing heterocycles and Grubbs’ catalyst-I.

K. C. Majumdar et al. / Tetrahedron Letters 55 (2014) 1247–1250
1249
All oxophosphocine derivatives 8a–d were obtained in improved
EtO
O
EtO
O
O
O
P
P
yields (Table 1) under refluxing condition rather than room tem-
perature. Variation has been done by introducing different types
of electron demanding group. All structurally varied metathetic
precursors gave the corresponding cyclized products by Grubbs’
first generation catalyst, but the presence of electron withdrawing
group (such as 4e, 4i, 4j) gave comparable low yields than corre-
sponding electron rich precursors.
The medium ring heterocycles obtained by ring closing metath-
esis reaction can further be easily converted to the corresponding
saturated analogues by hydrogenation in the presence of
10 mol % Pd/C and. Seven-membered heterocycles 7d gave the
saturated analogue 9 in 98% yield. Other two eight-membered
compounds 8d and 7f also gave the corresponding saturated
analogue 10 and 11, respectively under same reaction condition
in almost quantitative yield (Scheme 3).
n
n
(i)
9 (n = 0, 98%)
10 (n = 1, 96%)
7d (n = 0)
8d (n = 1)
O
P
O
O
P
O
EtO
EtO
(i)
11
7f
(99%)
Scheme 3. Synthesis of saturated analogue of phosphorous containing heterocycles
by hydrogenation. Reagent and condition: 10 mol % Pd–C, H2, 2 h.
In conclusion, we have demonstrated
a straightforward
may find this process complementary to those that exist in the
literature.
synthetic approach for a series of novel phosphorus containing
medium ring heterocycles by applying the sequential Claisen rear-
rangement and RCM protocol. The methodology is simple, avoids
hazardous steps, and uses easily available starting materials. The
methodology is sufficiently flexible to permit the preparation of
various ring sizes. This type of ring closing metathesis and its tol-
erance to both electron releasing and electron withdrawing groups
Acknowledgments
One of us (K.C.M.) is thankful to UGC (New Delhi) for
UGC-Emeritus Fellowship. Two of us (R.K.N. and S.G.) are grateful
Table 1
Reaction condition, yield (%) of products (7a–8d)
Entry
Substrate
Product
Time
Yielda (%)
92
Entry
8
Substrate
Product
EtO
Time
Yielda (%)
87
EtO
O
O
O
P
O
P
1
4a
5h (rt)
4h
6h (rt)
Br
7a
EtO
O
7h
O
O
O
EtO
O
P
P
EtN
2
3
4b
4c
4.5h (rt)
4.5h (rt)
89
93
9
4i
4j
4h (rt)
6h (rt)
82
73
O
N
7b
Et
7i
O
EtO
O
O
P
EtO
P
O
10
MeO
7c
O
O
7j
EtO
O
EtO
O
O
O
P
P
23b
79c
4
5
4d
4e
5.5h (rt)
82
67
11
12
6a
6b
8h (reflux)
Br
8a
EtO
7d
EtO
O
O
O
P
O
P
19b
71c
8h (rt)
8.5h (reflux)
O2N
8b
7e
O
EtO
O
O
EtO
O
P
P
16b
73c
6
7
4f
6h (rt)
87
84
13
14
6c
8h (reflux)
MeO
8c
7f
EtO
O
O
OEt
O
P
18b
65c
P
4g
5.5h (rt)
6d
12h (reflux)
O
7g
8d
a
b
c
Isolated yield.
Isolated yield in room temperature.
Isolated yield under refluxing condition.

1250
K. C. Majumdar et al. / Tetrahedron Letters 55 (2014) 1247–1250
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