N-Arylation of a hindered indoline as a route to 2-(2-methyl-1-(4-oxo-3,4- dihydrophthalazin-1-yl)-1H-indol-3-yl)acetic acid derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.08.169

A convenient synthesis of 2-(2-methyl-1-(4-oxo-3,4-dihydrophthalazin-1-yl)- 1H-indol-3-yl)acetic acid derivatives is described using a microwave-promoted multi-step S_NAr reaction. The desired products were found to exhibit atropisomerism.

Full text of DOI:10.1016/j.tetlet.2011.08.169

Tetrahedron Letters 52 (2011) 6317–6320
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Tetrahedron Letters
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N-Arylation of a hindered indoline as a route to
2-(2-methyl-1-(4-oxo-3,4-dihydrophthalazin-1-yl)-1H-indol-3-yl)acetic acid
derivatives
Nikolaos Papaioannou a, , Vasilios Marathias b, Zhao-Kui Wan a, Neelu Kaila a, Zahid Ali b, Eddine Saiah a
⇑
a Pfizer Global Research & Development, Inflamation & Immunology Chemistry, Cambridge, MA, USA
b Pfizer Global Research & Development, Analytical Chemistry, Cambridge, MA, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient synthesis of 2-(2-methyl-1-(4-oxo-3,4-dihydrophthalazin-1-yl)-1H-indol-3-yl)acetic acid
derivatives is described using a microwave-promoted multi-step SNAr reaction. The desired products
were found to exhibit atropisomerism.
Received 19 May 2011
Revised 24 August 2011
Accepted 29 August 2011
Available online 10 September 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Indoline
Microwave-assisted
Atropisomer
CRTh2
Indole acetic acid
Prostaglandin D2 (PGD2) is involved in a wide variety of inflam-
matory conditions. Two receptors have been identified for PGD2,
DP1, and more recently DP2 (CRTh2).1–3 The recent discovery of
CRTh2 has prompted an enormous effort both in industry as well
as in academia for the identification of CRTh2 antagonists.4 Indole
acetic acids have found great prominence in this area of research.5
Our efforts in this particular area have led us to investigate struc-
tural motifs like 1 (Fig. 1) as antagonists for CRTh2.
this bond using a metal mediated coupling of an appropriately
functionalized substrate or a base promoted SNAr reaction.6 Preli-
minary experiments showed that 3,6-dichloropyridazine 5 could
be coupled to the desired indole 4, suggesting that 1,4-dichloroph-
thalazine 2 could also be a suitable coupling partner as well
(Scheme 2). Additionally, phthalazinones 3 could be used in the
event that 1,4-dichlorophthalazine failed to couple to 4. Strategy
A (Scheme 1) was preferred as structural diversity may be installed
at a later stage in the synthesis. Unfortunately, extensive efforts to
achieve this bond construction using both 2 as well as a variety of
Our initial retrosynthetic analysis of 1 led to the obvious discon-
nection between the two biaryl rings. We envisaged constructing
OH
N
O
Me
N
N
R
O
1a= Bn
1b= CH2CF3
Figure 1. Compounds with the indole acetic acid scaffold.
⇑
Corresponding author. Tel.: +1 617 665 5157; fax: +1 617 665 5682.
E-mail address: nikolaos.papaioannou@pfizer.com (N. Papaioannou).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.169

6318
N. Papaioannou et al. / Tetrahedron Letters 52 (2011) 6317–6320
OEt
OEt
O
OH
O
O
Strategy
Strategy
Me
R
Me
N
H
A
B
N
H
Me
N
X
Cl
N
N
N
N
Bn
N
N
O
O
3
Cl
2
1a
X= Cl and Br
R= alkyl and benzyl
Scheme 1. Initial synthetic strategy for the construction of indole acetic acids.
NHMe
OEt
N
O
NHMe
10 mol %
OEt
O
Cl
Cl
Me
CuI, K3PO4, toluene
100 oC
N
N
+
Me
N
N
N
H
30%
5
4
Cl
Scheme 2. Precedent for Buchwald coupling of 4.
We envisaged the desired product arising from an oxidation fol-
lowed by ester hydrolysis. N-Arylated indoline 7 would come from
hydrolysis of 8 followed by N-alkylation. The functionalized indo-
line 8 would be constructed from an SNAr reaction and the indoline
starting material 9 would be derived from reduction of the parent
indole 4 (Scheme 4).
OMe
Cl
Cl
iPrOH
Me
N
MeO
reflux, 2h
45%
N
N
+
N
N
Me
N
H
6
2
Cl
The synthesis commenced with the known reduction of com-
mercially available ethyl 2-(2-methyl-1H-indol-3-yl)acetate
4 using a mixture of Et3SiH and TFA. The reduction proceeded as
reported to afforded indoline 9 as an 8:1 cis:trans mixture.9 With
indoline 9 in hand, we were curious to try the SNAr reaction. We
selected a modified version of the conditions for the coupling of
aniline 7 with 1,4-dichlorophthalazine (Scheme 3). As a starting
point, we decided to use microwave heating as these conditions
would allow for rapid evaluation of the reaction at a larger range
of temperatures. To our delight, the initial experiment revealed
that microwave heating of indoline 9 along with 1,4-dichloroph-
thalazine 2 in iPrOH at 110 °C produced the desired functionalized
product 8 in 90% yield. Treatment of 8 with NaOH in AcOH at 70 °C
for 2 h afforded 10 in 61% yield (Scheme 5).
Scheme 3. Precedent for the synthetic strategy.
functionalized phthalazinones 3 were unsuccessful. This required
us to reevaluate our approach.
We surmised that both the substitution at the 2-position of the
indole as well as the electron withdrawing nature of the ester
served to decrease the nucleophilicity of the indole nitrogen. De-
aromatization of the indole should, in principle, increase the nucle-
ophilicity of the nitrogen while retaining the desired molecular
framework. Indeed, such a strategy has been previously utilized.7
However, details regarding the yields and efficiency of these reac-
tions were not disclosed. Additionally, indoline intermediates
could be valuable compounds in our medicinal chemistry endea-
vor. Since we had a large amount of intermediate 4 available and
literature precedent for using indolines, this strategy was deter-
mined to be a worthy pursuit.8
Upon evaluating the by-products of the microwave promoted
SNAr reaction, we found a small amount of 10 present in the crude
reaction mixture. We pondered whether this finding could be
exploited to drive the reaction directly to 10 obviating the need
OEt
O
OEt
N
OH
N
OEt
N
O
O
O
Me
N
H
Me
Me
Me
9
Cl
N
N
N
N
N
N
N
N
Bn
Bn
Cl
O
O
Cl
1a
8
3
7a
Scheme 4. Retrosynthetic analysis of 1a.

N. Papaioannou et al. / Tetrahedron Letters 52 (2011) 6317–6320
6319
OEt
OEt
N
Cl
O
O
OEt
N
N
O
Me
AcOH, NaOH
70 oC, 2h
Me
2
Cl
N
Me
N
N
N
NH
N
H
i PrOH, 110 o
10 Min, uW
90%
C
61%
9
Cl
O
8
(+/-) Cis:Trans > 8:1
10
Cl
i PrOH, 110 o
30 Min, uW
81%
C
N
N
2
Cl
Scheme 5. Microwave promoted coupling.
for the moderately yielding hydrolysis step. By simply extending
the microwave heating times from 10 min to 30 min, we were able
to drive the reaction to 10 with an isolated yield of 81% (Scheme 5).
At this stage, we chose to functionalize 10 because it provided the
best opportunity to introduce the greatest structural diversity into
the desired compounds. This also gave us the opportunity to inves-
tigate the indoline acetic acids for activity against CRTh2 by simply
converting the indoline esters to acids.
Treatment of 10 with benzyl bromide in the presence of K2CO3
and DMF at 70 °C, led to the desired indoline 7a as a mixture of cis
and trans isomers. A variety of electrophiles may be used in this
step. Isolation and stereochemical assignment of each of the iso-
mers was straight-forward at this point. Treatment of the indoline
7 with DDQ in toluene at 110 °C (11) followed by saponification
with LiOH afforded the desired compound 1 (Scheme 6).
OH
N
OH
N
O
O
Me
Me
N
N
N
N
Bn
Bn
O
O
1
1
Figure 2. Atropisomerism of 1.
ments utilizing liquid crystal alignment media showed that 1a
exists in two conformations at ambient temperature (Fig. 2). To
further investigate the atropisomeric nature of these molecules,
1a was separated using chiral LC chromatography. The absolute
stereochemistry was not determined for each enantiomer. Racemi-
zation of 1 was observed to be slow and by definition, 1a is a class 2
atropisomeric compound.10 More specifically, a solution of ent-1a
racemized to 90% ee, at ambient temperature after 20 h. The race-
mization half-life was calculated to be 19 days at 25 °C. Interest-
ingly, appropriate modifications to 1 may lead to axially chiral
ligands for asymmetric catalysis.
In summary, we report for the first time, the synthesis of 2-(2-
methyl-1-(4-oxo-3,4-dihydrophthalazin-1-yl)-1H-indol-3-yl)ace-
tic acid derivatives. The key features are the utilization of an ind-
oline as a masked indole, a microwave promoted, multi-step SNAr
reaction and late-stage oxidation to the desired compounds. More-
over, 1 was found to be a class 2 atropisomeric compound.
With the desired compounds in hand, we wanted to determine
if these compounds exhibited atropisomerism. Similar but more
sterically congested compounds have been reported to have re-
stricted rotation about the axial bond. Indeed, 13C NMR experi-
OEt
N
OEt
N
BnBr
or
O
O
CF3CH2I
K2CO3, DMF
70 o
C
Me
Me
N
N
NH
N
R
O
O
10
7a
7b
R= Bn 45%
R= CH2CF3 58%
DDQ
Acknowledgments
Toluene
110 o
C
The authors would like to thank Dr. Bruce Follows for materials
and helpful discussions.
OH
N
OEt
O
O
References and notes
LiOH(aq)
THF, MeOH
Me
Me
N
1. (a) Coleman, R. A. Prostanoid Receptors. In The IUPHAR Compendium of Receptor
Characterization and Classification; Girdlestone, D., Ed.; The Burlington Press:
N
N
Cambridge, 1998;
Pharmacol. Rev. 1994, 46, 205.
p 229; (b) Coleman, R. A.; Smith, W. L.; Narumiya, S.
N
N
Bn
Bn
2. Hirai, H.; Tanaka, K.; Yoshie, O.; Ogawa, K.; Kenmotsu, K.; Takamori, Y.;
Ichimasa, M.; Sugamora, K.; Nakamura, M.; Takano, S.; Nagata, K. J. Exp. Med.
2001, 193, 255.
3. Monneret, G.; Gravel, S.; Diamond, M.; Rokach, J.; Powell, W. Blood 2001, 98,
1942.
O
O
1a
1b
R= Bn 89%
R= CH2CF3 95%
11a
11b
R= Bn 85%
R= CH2CF3 21%
4. Norman, P. Exp. Opin. Therapeutic Patent 2005, 15(12), 1817.
5. Norman, P. Exp. Opin. Invest. Drugs 2010, 19, 947.
Scheme 6. DDQ mediated oxidation.

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N. Papaioannou et al. / Tetrahedron Letters 52 (2011) 6317–6320
6. Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 11684.
7. Birchall, G. R.; Hepworth, W.; Smith, S. C. Ger Pat Appl DE 2253927 1973.
8. Cai, S. X.; Anderson, M. B.; Willardsen, A.; Jiang, S.; Halter, R. J.; Slade, R.;
Klimova, Y. WO 2006074223 A2.
9. Forest, O. A.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 14264.
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