Synthesis of isoindolinones via inverse-electron demand Diels-Alder cycloadditions

Article abstract of DOI:10.1016/j.tetlet.2014.02.093

A new synthetic method has been developed for the synthesis of 2,4,5-substituted isoindolinones by means of intramolecular inverse-electron demand Diels-Alder cycloaddition reactions of substituted pyridazines. By taking advantage of the inherent reactivity of an intermediate chloropyridazine, a diverse set of analogues were prepared from common reagents and intermediates.

Full text of DOI:10.1016/j.tetlet.2014.02.093

Tetrahedron Letters 55 (2014) 2286–2289
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of isoindolinones via inverse-electron demand Diels–Alder
cycloadditions
⇑
Raymond J. Huntley, Mahender Gurram, Joel R. Walker , David M. Jenkins, Emmanuel J. Robé,
Feryan Ahmed
Medicinal Chemistry Department, AMRI, 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A new synthetic method has been developed for the synthesis of 2,4,5-substituted isoindolinones by
means of intramolecular inverse-electron demand Diels–Alder cycloaddition reactions of substituted
pyridazines. By taking advantage of the inherent reactivity of an intermediate chloropyridazine, a diverse
set of analogues were prepared from common reagents and intermediates.
Received 8 January 2014
Revised 19 February 2014
Accepted 24 February 2014
Available online 1 March 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Isoindolinones
Chloropyridazines
Diels–Alder cycloadditions
Inverse-electron demand cyclizations
Phthalimidine
Introduction
In recent years, a number of natural products have been found to
contain an isoindolinone (phthalimidine) core. The three examples
shown in Figure 1 include staurosporine,1 vitedeomamine,2 and len-
noxamine.3 In addition to the prevalence of this group in natural
product chemistry, the pharmaceutical industry has made exten-
sive use of this substructure in the development of biologically
relevant molecules. Two notable examples of marketed drugs
incorporating an isoindolinone nucleus include indoprofen4 and
lenalidomide5 (RevlimidÒ) (Fig. 1).
A number of synthetic strategies for the preparation of isoindoli-
nones have been developed in response to these needs.6 Our goal
was to develop a synthetic method that would allow for the rapid
construction of a diverse set of isoindolinone-containing molecules
with multiple points of diversity, thus facilitating the synthesis of
compound libraries for structure–activity studies. In particular,
we were intrigued by the possibility of constructing these libraries
by means of the inverse-electron demand Diels–Alder reaction of
appropriately substituted pyridazine carboxamides.
Synthetic strategy
The overall synthetic plan we chose to explore is shown in
Scheme 1. The key cyclization step draws inspiration on the
⇑
Corresponding author. Tel.: +1 518 512 2405.
E-mail address: joel.walker@amriglobal.com (J.R. Walker).
Figure 1. Natural products and marketed drugs containing an isoindolinone core.
http://dx.doi.org/10.1016/j.tetlet.2014.02.093
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

R. J. Huntley et al. / Tetrahedron Letters 55 (2014) 2286–2289
2287
amides 2. The enhanced reactivity of the chloropyridazine ring
toward nucleophilic substitution and metal-catalyzed cross-cou-
pling reactions would subsequently allow for the introduction of
a diverse set of R3 substituents. Similar to the syntheses of substi-
tuted indole9 and indoline substructures,10 we intended to then
perform an intramolecular inverse-electron demand Diels–Alder
cycloaddition/retrocycloaddition to arrive at the desired isoindoli-
nones 4.
Proof-of-concept and 2-position substitution
Our initial proof-of-concept studies are shown in Table 1. Con-
densation of propargyl amine with acid chloride 1 was effected to
give secondary amide 5a. For the cyclization step, we chose Dow-
thermTM A as a high boiling solvent. After prolonged heating at
220 °C only starting material 5a was seen, with no evidence of
isoindolinone 6 observed by MS. Hypothesizing that the desired
cyclization requires a secondary amide to adopt an unfavorable
s-cis conformation, the cyclization may be prohibited due to an
intramolecular hydrogen bond between the amide N–H and
pyridazine nitrogen.11,12
Scheme 1. General scheme for isoindolinone synthesis.
Although a minor modification to 5a, we elected to prepare the
tertiary, N-methyl amide 5b. We were delighted to find that after
heating for 1 h at 220 °C, the desired isoindolinone 7 could be iso-
lated in excellent yield.13
We decided to further explore the scope of N-substitution, and
found that benzyl and phenyl analogues all readily underwent
cyclization to the corresponding isoindolinones 8–10. The
2,4-DMB analogue 9 was of particular interest to us, due to the
well precedented conditions available for its removal from
isoindolinones.14
Scheme 2. Snyder’s approach to the staurosporine aglycone.
Variation of the 4- and 5-position substitution
Having demonstrated the feasibility of the Diels–Alder
approach to various N-substituted isoindolinones, we elected to
explore the synthesis of 4-substituted analogues, as shown in
Table 2. To that end, a variety of 2,4-DMB-substituted propargyl
amines 12a–e were prepared.15 Condensation with acid chloride
pioneering work of Snyder and co-workers wherein pyridazi-
no[4,5-b]indoles were employed under similar conditions for the
synthesis of a staurosporine aglycone analogue (Scheme 2).7
Condensation of 6-chloropyridazine-3-carbonyl chloride 18
with a series of propargyl amines would provide chloropyridazine
Table 1
Initial proof of concept/N-position substitution
Entry
R1
Acylation yield (%)
Cyclization yield (%)
5a
65
5b
74
6
1
2
No reaction
7
86
5c
85
8
65
3
4
5d
94
9
87
5e
68
10
67
5

2288
R. J. Huntley et al. / Tetrahedron Letters 55 (2014) 2286–2289
Table 2
4-Position substitution
Entry
1
R2
X
Amination yield (%)
Acylation yield (%)
Isoindolinone
Cyclization yield (%)
12a
72
13a
86
14
89
Br
12b
59
13b
89
15
78
2
3
Cl
Cl
12c
20
13c
53
16
36
12d
42
13d
90
17
71
4
5
Cl
12e
53
13e
79
18
78
OTs
1 gave amides 13a–e. These amides were subjected to the standard
cyclization conditions to yield isoindolinones 14–18.
With the diversely substituted amides 19a–g in hand, the
inverse-electron demand cyclization reactions were attempted.
We speculated that these reactions, which all employed strongly
electron donating and/or bulky substituents, would be the most
challenging to prepare via the inverse electron demand Diels–Alder
reaction. However, all the reactions proceeded smoothly to give
the corresponding isoindolinones. Of particular note is the prepa-
ration of the sterically congested analogue 26.
As shown in Table 2, the synthetic method tolerates a variety of
substituents at C(4). Alkyl and aryl substituents appeared to be
acceptable, as well as the silyl-protected hydroxymethyl analogue
17, which could be employed to introduce a wide range of function-
alities by further derivatization of the desilylated alcohol. The het-
eroatom substituted alkyne utilized was silyl derivative 13e, which
also underwent cyclization to afford the silyl isoindolinone 18.
While we were pleased that these initial examples proceeded
uneventfully, we were most intrigued by the possibility that chlo-
ropyridazines 13 could serve as useful substrates for introduction
of a range of C(5) substituents. Amides 13a and 13b were selected
for further functionalization, as shown in Table 3. These pyrida-
zines underwent facile SNAr reactions with a range of oxygen,
nitrogen, and sulfur nucleophiles to give amides 19a–c and
19e–f. Furthermore, the chloropyridazines 13a–b underwent
Suzuki reactions under mild conditions to give aryl substituted
pyridazines 19d and 19g.
Conclusion
The preparation of a variety of 2, 4 and 5-substituted isoindoli-
nones has been performed from the readily available acid chloride
1. This synthetic method allows for multiple points of divergence
at the 2, 4, and 5-positions and tolerates a variety of functional
groups, heteroatoms, and steric bulk. In particular, the highly
functionalized chloropyridazines 13a–e serve as excellent building
blocks for the synthesis of
isoindolinones.
a diverse range of substituted

R. J. Huntley et al. / Tetrahedron Letters 55 (2014) 2286–2289
2289
Table 3
Introduction of the 5-position substituents
Entry
1
R2
Conditions⁄
a
R3
Substitution yield (%)
Isoindolinone
Cyclization yield (%)
19a
96
20
68
21
88
19b
98
2
b
19c
78
22
86
3
4
5
6
7
c
d
a
b
d
19d
58
23
94
19e
73
24
83
19f
94
25
87
19g
76
26
82
*
Conditions: (a) CH3OH, K2CO3, rt; (b) R2NH, acetonitrile, reflux; (c) n-BuLi, dimethylsulfide, THF, À20 to 60 °C; (d) PhB(OH)2, PdCl2(dppf), Cs2CO3, dioxane, water, 70 °C.
10. Boger, D. L.; Coleman, R. S. J. Am. Chem. Soc. 1987, 109, 2717–2727.
References and notes
11. Ma, Z.; Ni, F.; Woo, G. H. C.; Lo, S.-M.; Roveto, P. M.; Schaus, S. E.; Snyder, J. K.
Beilstein J. Org. Chem. 2012, 8, 829–840.
12. In attempts to disrupt the intramolecular hydrogen bond, several high
temperature reactions (150–220 °C) in aprotic polar solvents (DMF, NMP,
polypropylene carbonate) were conducted. However, the cyclization of 5a to 6
did not take place.
1. Furusaki, A.; Hashiba, N.; Matsumoto, T.; Hirano, A.; Iwai, Y.; Omura, S. J. Chem.
Soc., Chem. Commun. 1978, 800–801.
2. Ono, M.; Nishida, Y.; Masuoko, C.; Li, J.-C.; Okawa, M.; Ikeda, T.; Nohara, T. J.
Nat. Prod. 2004, 67, 2073–2075.
3. Valencia, E.; Freyer, A. J.; Shamma, M.; Fajardo, V. Tetrahedron Lett. 1984, 25,
599–602.
4. Ventafridda, V.; Martino, G.; Mandelli, V.; Emanueli, A. Clin. Pharmacol. Ther.
1975, 17, 284–289.
5. Bartlett, J. B.; Dredge, K.; Dalgleish, A. G. Nat. Rev. Cancer 2004, 4, 314–322.
6. Reviews: (a) Stájer, G.; Csende, F. Curr. Org. Chem. 2005, 9, 1261–1276; (b)
Stájer, G.; Csende, F. Curr. Org. Chem. 2005, 9, 1277–1286; (c) Takahashi, I.;
Hatanaka, M. Heterocycles 1997, 45, 2475–2499. Other methods; (d) Tsuritani,
T.; Kii, S.; Akao, A.; Sato, K.; Nonoyama, N.; Mase, T.; Yasuda, N. Synlett 2006,
801–803; (e) Lamblin, M.; Couture, A.; Deniau, E.; Grandcloudon, P. Tetrahedron
2007, 63, 2664–2669; (f) Huang, X.; Xu, J. J. Org. Chem. 2009, 74, 8859–8861; (g)
Augner, D.; Gerbino, D. C.; Slalov, N.; Neudörfl, J.-M.; Schmalz, H.-G. Org. Lett.
2011, 13, 5374–5377; (h) Li, D.-D.; Yuan, T.-T.; Wang, G.-W. Chem. Commun.
2011, 12789–12791; (i) Yang, G.; Zhang, W. Org. Lett. 2012, 14, 268–271.
7. Nomak, R.; Snyder, J. K. Tetrahedron Lett. 2001, 42, 7929–7933. For the related
cycloaddition/retrocycloaddition reactions of pyrone carboxamides see:
Noguchi, M.; Kakimoto, S.; Kawakami, H.; Kajigaeshi, S. Bull. Chem. Soc. Jpn.
1986, 59, 1355–1362.
13.
A
representative
procedure
is
as
follows:
5-chloro-2-(2,4-
dimethoxybenzyl)isoindolin-1-one (9): To a 3-neck flask equipped with a
reflux condenser was added Dowtherm™ A (8 mL). The solution was heated to
220 °C with a sand bath. 6-Chloro-N-(2,4-dimethoxybenzyl)-N-(prop-2-yn-1-
yl)pyridazine-3-carboxamide 5d (100 mg, 0.29 mmol) in Dowtherm™ A (2 mL)
was added dropwise. The reaction was stirred at 220 °C for 1 h. After cooling to
ambient temperature, the crude product was purified by flash chromatography
(silica gel, hexanes to 50:50 hexanes/ethyl acetate) to give the desired product
9 (80 mg, 87%) as a light brown solid: 1H NMR (300 MHz, CDCl3) d 7.77 (d,
J = 8.1 Hz, 1H), 7.41 (dd, J = 1.8, 8.1 Hz, 1H), 7.36 (d, J = 1.8 Hz, 1H), 7.21 (d,
J = 8.1 Hz, 1H), 6.47–6.42 (m, 2H), 4.74 (s, 2H), 4.26 (s, 2H), 3.84 (s, 3H), 3.79 (s,
3H); 13C NMR (75 MHz, CDCl3)
d 167.30, 160.75, 158.56, 143.08, 137.37,
131.61, 131.21, 128.46, 124.86, 123.09, 117.44, 104.43, 98.58, 55.47, 55.42,
49.43, 40.69; HRMS [C17H16ClNO3+H]+ calcd 318.0897, found 318.0908.
14. (a)Protective Groups in Organic Synthesis; Greene, T. W., Wuts, P. G. M., Eds., 3rd
ed.; John Wiley and Sons: Hoboken, NJ, 1999; p 640; (b) Cai, Z. R.; Jabri, S. Y.;
Haolun, J.; Lansdown, R. A.; Metobo, S. E.; Mish, M. L.; Pastor, R. WO
2007136714, 2007.; (c) Chelliah, M. V.; Chackalamannil, S.; Greenlee, W. J.;
Eagen, K. A.; Zhuyan, G.; Clasby, M. C.; Xia, Y.; Jayne, C. L.; Dwyer, M.; Keertikar,
K. M.; Chan, T-Y.; Wang, L. WO 2011017296, 2011.
8. Abreo, M.; Chafeev, M.; Chakka, N.; Chowdhury, S.; Fu, J.-M.; Gschwend, H. W.;
Holladay, M. W.; Hou, D.; Kamboj, R.; Kodumuru, V.; Li, W.; Liu, S.; Raina, V.;
Sun, S.; Sun, S.; Sviridov, S.; Tu, C.; Winther, M. D.; Zhang, Z. WO 2005011655,
2005.
15. Cho, J. H.; Kim, B. M. Tetrahedron Lett. 2002, 43, 1273–1276.
9. (a) Boger, D. L.; Sakya, S. M. J. Org. Chem. 1988, 53, 1415–1423; (b) Boger, D. L.;
Zhang, M. J. Am. Chem. Soc. 1991, 113, 4230–4234.