A concise synthesis of ortho-substituted aryl-acrylamides - Potent activators of soluble guanylyl cyclase

Article abstract of DOI:10.1016/j.tetlet.2003.09.161

Horner-Emmons reaction of phosphonate amides with aldehydes leads to generation of o-substituted aryl-acrylamides. These compounds have been shown to be useful to quickly establish structure-activity relationships (SAR) for soluble guanylyl cyclase (sGC)

Full text of DOI:10.1016/j.tetlet.2003.09.161

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8661–8663
A concise synthesis of ortho-substituted aryl-acrylamides—potent
activators of soluble guanylyl cyclase
Henry Q. Zhang,* Zhiren Xia, Teodozyj Kolasa and Jurgen Dinges
Department of Medicinal Chemistry Technologies (R-4CP), Global Pharmaceutical Research and Development,
Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA
Received 26 August 2003; revised 17 September 2003; accepted 18 September 2003
Abstract—Horner–Emmons reaction of phosphonate amides with aldehydes leads to generation of o-substituted aryl-acrylamides.
These compounds have been shown to be useful to quickly establish structure–activity relationships (SAR) for soluble guanylyl
cyclase (sGC) activator drug discovery.
© 2003 Elsevier Ltd. All rights reserved.
Nitric oxide (NO) plays an important role in a number
of physiological processes, acting as an inter- and intra-
cellular mediator. NO stimulates soluble guanylyl
cyclase (sGC) to convert guanosine 5%-trisphosphate
(GTP) to cyclic guanosine 3%,5%-monophosphate
(cGMP) which results in smooth muscle relaxation,
inhibition of platelet aggregation and neurotransmis-
sion.1,2 The increase of the cGMP level reduces Ca2+
concentration, resulting in cavernosal smooth muscle
relaxation and, ultimately, in penile erection. Therefore,
activation of sGC provides an alternate treatment of
sexual dysfuction.3 A-350619 has been reported as an
novel sGC activator, which can activate sGC in the
presence or absence of NO.4,5
Scheme 1. Reagents and conditions: (a) K2CO3, DMF, 50–80°C, 12–16 h (80–100%); (b) NaH, THF, rt, 8–16 h (90–98%); (c)
NaOH, EtOH–dioxane, rt, 24 h (95–99%); (d) EDCI, HOBt, CH3Cl or CH2Cl2, rt, 6–8 h (26–50%); (e) N-cyclohexylcarbodimide,
N%-methyl polystyrene (DCC resin), HOBT, DMA/CH2Cl2, rt, 18 h, tris-(2-aminoethyl)-amine polystyrene (PS-trisamine); (f)
LDA, THF, rt, 1 h (44–82% for two steps).
* Corresponding author. Tel.: +1-847-935-5250; fax: +1-847-935-5466; e-mail: henry.zhang@abbott.com
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.161

8662
H. Q. Zhang et al. / Tetrahedron Letters 44 (2003) 8661–8663
Table 1. Yields of products 4 from benzaldehydes 2
Entry
R1
4a (Yield %)
4b (Yield %)
In this paper, we report a three-step convergent synthe-
sis of o-substituted aryl-acrylamides from o-nitrobenz-
aldehyde or o-fluorobenzaldehyde (Scheme 1, Route
A). The chemistry exploits the Horner–Emmons reac-
tion with phosphonate amides instead of conventional
phosphonate esters (Scheme 1, Route B). This route
obviates the need for extra steps to convert the esters
into amides. Recently, there has been reports of
Horner–Emmons olefination for preparing a,b-unsatu-
rated N-methyl-N-methoxyamide (Weinreb amide).6
There has also been several reports of using phospho-
nate amides to provide a,b-unsaturated amides as syn-
thetic precursors in natural product synthesis.7
However, generation of phosphonate amides under
standard Arbuzov reaction6–8 does not allow for ade-
quate diversity of the amide side chains, mainly due to
the limited availability of the starting material. Our
approach took advantage of commercially available
diethylphosphonoacetic acid to generate phosphonate
amides in almost quantitative yield by a simple
modified solid phase peptide coupling procedure. The
chemistry is versatile and results in highly efficient
generation of o-substituted aryl-acrylamide libraries
when a large number of aldehydes and amines are
employed to quickly establish structure–activity rela-
tionships (SAR) for our sGC project.
1
2
3
4
5
6
7
8
Ph
69
44
53
54
54
69
75
80
82
68
66
56
75
81
56
60
69
76
64
58
56
69
71
65
3,5-diCl-Ph
2,6-diCl-Ph
3-Cl-Ph
4-Br-Ph
4-F-Ph
4-Me-Ph
3-Me-Ph
2-Me-Ph
2-iso-Pr-Ph
4-tert-Bu-Ph
3,4-diMeO-Ph
2-MeO-Ph
3-MeO-Ph
4-MeO-Ph
4-MeS-Ph
2-CF3-Ph
3,5-diCF3-Ph
2-Naphthyl
Cyclopentyl
Cyclohexyl
iso-Butyl
n/a*
n/a*
60
n/a*
49
n/a*
74
73
n/a*
n/a*
n/a*
n/a*
73
54
50
n/a*
n/a*
54
51
45
49
52
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
iso-Propyl
* Compounds were synthesized from Route B (Scheme 1).
room temperature.12 Only 2.5 equiv. of LDA was
required when the reaction was performed on a 1 mmol
scale. The reaction was typically carried out on a 0.1
mmol scale for our project. Amides 4a and 4b were
isolated in 44–82% overall yield in two steps starting
from diethylphosphonoacetic acid (Table 1).
o-Alkylsulfanylbenzaldehydes and o-arylsulfanylbenz-
aldehydes 2 were synthesized from commercially avail-
able 2-nitrobenzaldehyde or 2-fluorobenzaldehyde
following the literature procedure.9 A mixture of 1
equiv. of o-fluorobenzaldehyde, 1.1 equiv. of potassium
carbonate and 1.1 equiv. of thiol in DMF was heated at
80°C for 16 h. Product 2 was obtained by simple
filtration and removal of the solvent. In general, the
yields were high (80–100%). The products were easily
purified by recrystallization from methanol or used
without purification. Phosphonate amides 3a and 3b
were synthesized from commercially available
diethylphosphonoacetic acid by modifying conventional
solid phase peptide coupling procedure.10 2.5–3.5 equiv.
of N-cyclohexylcarbodimide, N%-methyl polystyrene
(DCC resin from Novabiochem) was required to com-
plete the amide formation. Trisamine resin (4–6 equiv.
from Argonaut Technology) was used as a scavenger to
remove HOBt after the reaction was completed.11 Prod-
ucts 3a and 3b were isolated by simple filtration and
were used without further purification.
In conclusion, we report a short convergent synthesis of
o-substituted aryl-acrylamides 4 from o-nitrobenzalde-
hyde or o-fluorobenzaldehyde in good overall yield.
Compounds in Table 1 have shown biological activities
(EC50=2.9–100 mM) as sGC activators.4 The most
potent activator (Table 1, entry 21, 4b) was identified
with EC50=2.9 mM. Libraries with different R1, R2, R3
and R4 groups (5) were synthesized. Identification of
more potent soluble guanylyl cyclase (sGC) activators
is in progress, and these results will be reported in the
near future.
In the final step, phosphonate amide 3 was treated with
5 equiv. of LDA. After 30 minutes, aldehyde 2 was
added and the reaction was completed in 1 hour at

H. Q. Zhang et al. / Tetrahedron Letters 44 (2003) 8661–8663
8663
Acknowledgements
polystyrene (5.0 g, 9.6 mmol) and HOBt (450 mg, 3.3
mmol) in N,N-dimethylacetamide/dichloromethane (1:1,
60 mL) was shaken at room temperature for 15 min.
4-(Dimethylamino)butyl amine (570 mg, 4.9 mmol) in
N,N-dimethylacetamide/dichloromethane (1:1, 10 mL)
was added and the resulting mixture was shaken at room
temperature for 18 h. Trisamine polystyrene (5.0 g, 20
mmol) was added and the resulting mixture was shaken
at room temperature for 6 h. The reaction solution was
collected by filtration. The resin was washed with
dichloromethane (2×10 mL). The combined filtrate was
concentrated in vacuo. The residue 0.89 g (100%) was
We thank Dr. Stevan W. Djuric (Medicinal Chemistry
Technologies, Abbott Laboratories) for many valuable
suggestions.
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12. Typical prodedure: To amide 3a (28 mg, 0.1 mmol) in
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