Facile synthesis of 3,3-diallyl isoindolones via a indium-mediated double allylation of ortho-cyanobenzoates

Article abstract of DOI:10.1016/j.tetlet.2009.12.034

Various 3,3-diallyl isoindolones were synthesized via a indium-mediated Barbier type double allylation reaction of ortho-cyanobenzoates in good yields in short time. The reactivity of nitrile group toward allylindium is sufficient to form a cyclic compound when a suitable electrophilic center is present in the same molecule to trap the imine intermediate.

Full text of DOI:10.1016/j.tetlet.2009.12.034

Tetrahedron Letters 51 (2010) 860–862
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Facile synthesis of 3,3-diallyl isoindolones via a indium-mediated double
allylation of ortho-cyanobenzoates
*
Sung Hwan Kim, Se Hee Kim, Ko Hoon Kim, Jae Nyoung Kim
Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Various 3,3-diallyl isoindolones were synthesized via a indium-mediated Barbier type double allylation
reaction of ortho-cyanobenzoates in good yields in short time. The reactivity of nitrile group toward allyl-
indium is sufficient to form a cyclic compound when a suitable electrophilic center is present in the same
molecule to trap the imine intermediate.
Received 10 November 2009
Revised 1 December 2009
Accepted 7 December 2009
Available online 16 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Isoindolones
Indium
Barbier reaction
Double allylation
ortho-Cyanobenzoates
Allylindium reagents have been used extensively for the intro-
duction of allyl group in a Barbier type manner to various electro-
philes.1–3 Although many electrophiles including aldehydes,
ketones, imines, and N-tosylimines have been used in the in-
dium-mediated allylations,1 the reaction of a less reactive electro-
phile such as nitrile has not been used in organic synthesis. The
first successful results of indium-mediated allylation of nitriles
have been reported by Yamamoto and co-workers a decade ago
(vide infra, Scheme 1),2a,b although allylation of nitrile with allylin-
date instead of allylindium was reported by Butsugan and co-
workers in 1993.2c However, the allylation of nitrile with allylin-
dium was limited to substrates having an electron-withdrawing
aromatic nitrile can react with allylindium.3c In these contexts,
we envisioned that ortho-cyanobenzoates could afford 3,3-diallyl
isoindolone scaffold via indium-mediated double allylation strat-
egy, as shown in Scheme 1. The first results of Yamamoto in this
area2a,b and ours of
1 for comparison.
c
-cyanoesters3a are also depicted in Scheme
Hα
allylindium
R
R
C
N
Yamamoto2a,b
EWG
EWG
Ph
NH2
substituent and an
Very recently, we reported indium-mediated Barbier type ally-
lations of the nitrile group in -cyanoesters (vide infra, Scheme
1),3a -ketonitriles,3b and d-ketonitriles.3c The intrinsic reactivity
a
-proton.2a,b
O
COOEt
Ph
c
allylindium
Kim3a
NH
N
C
c
H
of the nitrile group toward allylindium species was sufficient to
form the corresponding imine or enamine intermediates, and the
corresponding d-valerolactams,3a pyrroles,3b and isoquinolines3c
were obtained in good to moderate yields via the subsequent cycli-
zation of the intermediates with an electrophilic moiety in the
same molecule. During the studies we have found that the nitrile
group can react with allylindium even in the absence of both an
COOMe
γ-cyanoester
COOMe
quencher
O
COOEt
allylindium
this work
NH
EWG and an a-proton when the intermediate can react with near-
by electrophile in the same molecule such as an ester3a or a steri-
cally hindered ketone.3b,c In addition, we also found that even
C
N
aromatic nitrile
ortho-cyanobenzoate
isoindolone
* Corresponding author. Tel.: +82 62 530 3381; fax: +82 62 530 3389.
E-mail address: kimjn@chonnam.ac.kr (J.N. Kim).
Scheme 1. Development of In-mediated allylation of nitrile.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.034

S. H. Kim et al. / Tetrahedron Letters 51 (2010) 860–862
861
Various isoindolone derivatives have been known to possess
O
interesting biological activities4–6 including MDM2-p53 interac-
tion inhibitory activity,4a mixed lineage kinase activity,4b CNS-re-
lated disorders treating activity,4c and HIV-1 integrase inhibitory
activity.4e Especially, various spiro-isoindolones have received
much attention due to their interesting biological activi-
ties.4c,f,6d,e,g,h Thus various synthetic approaches of isoindolone
scaffold have been developed.5,6 In some examples, a copper-cata-
Grubbs catalyst (3 mol%)
toluene, 50 ºC, 2 h
Mes
N
N
Mes
NH
2g
Cl
Ru
Cl
Ph
PCy3
3 (88%)
Scheme 2.
lyzed addition of nucleophile to carbonyl-ene-nitrile system,5a
a
palladium-catalyzed intramolecular C-arylation,5b and an addition
of transiently-generated methyl o-lithiobenzoate to imine5c have
been reported. Xu and co-workers reported the synthesis of 3-
monoallyl isoindolone derivatives via the In-mediated allylation
of N-tert-butanesulfinyl imines.7 The synthesis of Xu and co-work-
ers is the only paper describing the preparation of isoindolone scaf-
fold by using indium chemistry, to the best of our knowledge.
As the initial entry, we examined the reaction of ethyl 2-cya-
nobenzoate (1a) and allyl bromide in the presence of indium pow-
der in THF and obtained 3,3-diallyl isoindolone (2a) in 71% yield
(entry 1 in Table 1).8 The reaction was very fast (30 min) and clean.
Encouraged by the results, we prepared various ortho-cyanobenzo-
ates 1b–g9 and examined the syntheses of isoindolones 2b–h, as
summarized in Table 1. The mechanism for the reaction can be
proposed as follows: first allylation of 1 to produce the imine inter-
mediate (I), cyclization of (I) to form cyclic N-acylimine (II), and
second allylation of (II) to form 2, as shown in Table 1. As in entry
8, the reaction of 1a and methallyl bromide produced compound
During the studies we observed an interesting solvent effect.
The product 2a was formed in THF at refluxing temperature in
71% as described above; however, the reaction in DMF (70–80 °C)
was failed completely and 1a was recovered. Similarly, the reaction
failed in 1,4-dioxane, aqueous THF, PEG-3400, and DMSO, while 2a
was obtained in moderate yields both in dichloroethane (51%) and
ortho-dichlorobenzene (57%). From the results we could imagine
that the reaction is effective in a solvent which does not disrupt
the six-membered chelation transition state1,2,10 and a decisive
explanation deserved further studies.
As one of the synthetic applications of 3,3-diallylated isoindol-
ones, we examined the ring-closing metathesis (RCM) reaction of
2g with 2nd generation Grubbs catalyst (3 mol %) in toluene
(50 °C, 2 h) and obtained the corresponding spiro compound 3 in
88% yield, as shown in Scheme 2.
In summary, we synthesized various isoindolones via a indium-
mediated double Barbier type allylation of ortho-cyanobenzoate
derivatives in refluxing THF in moderate to good yields. We ex-
tended the scope of In-mediated allylation reaction toward ni-
trile-containing substrates which was hitherto regarded as un-
reactive.
2h in a similar yield (66%); however, the reaction with c-substi-
tuted allylic bromides such as cinnamyl bromide or crotyl bromide
did not produce appreciable amounts of the corresponding isoin-
dolone derivatives, presumably due to steric problems.10
Table 1
Synthesis of poly-substituted isoindolonesa
O
O
intramolecular
1st Barbier
allylation
2nd Barbier
allylation
COOMe
NH
COOMe
CN
quenching
Xn
N
Xn
NH
Xn
Xn
- MeOH
(II)
1
2
(I)
Entry
1
Substrate
Product (%)
Entry
Substrate
Product (%)
COOEt
CN
O
COOMe
CN
O
NH
NH
MeOOC
5
6
MeOOC
O
1a
1e
2a (71)
2e (67)
COOMe
CN
O
COOMe
CN
NH
NH
Me
N
1f
2
3
4
Me
N
1b
2b (73)
2f (73)
MeO
COOMe
O
COOMe
CN
O
MeO
NH
NH
CN
7
1c
1g
2c (70)
2g (65)
MeO
MeO
COOMe
CN
O
O
MeO
MeO
NH
NH
8b
1a
1d
2d (69)
2h (66)
a
Conditions: substrate (1.0 mmol), allyl bromide (4.0 mmol), In powder (2.0 mmol), THF, reflux, 30 min (60 min for entry 8).
Methallyl bromide was used.
b

862
S. H. Kim et al. / Tetrahedron Letters 51 (2010) 860–862
indium powder (228 mg, 2.0 mmol) in THF (1.5 mL) was heated to reflux for
Acknowledgements
30 min. After the usual aqueous workup and column chromatographic
purification process (hexanes/CH2Cl2/EtOAc, 5:1:1) we obtained compound
2a (151 mg, 71%) as a white solid. Other compounds were synthesized similarly
and the spectroscopic data of 2a, 2c, 2f, 2g, and RCM product 3 are as follows.
Compound 2a: 71%; white solid, mp 99–100 °C; IR (film) 3211, 1695, 1615,
This research was supported by Basic Science Research Program
through the National Research Foundation of Korea (NRF) funded
by the Ministry of Education, Science and Technology (2009-
0070633). Spectroscopic data was obtained from the Korea Basic
Science Institute, Gwangju branch.
1469 cmÀ1 1H NMR (CDCl3, 300 MHz) d 2.53–2.70 (m, 4H), 5.00–5.07 (m, 4H),
;
5.48–5.62 (m, 2H), 7.38 (dt, J = 7.5 and 0.9 Hz, 1H), 7.44 (td, J = 7.5 and 1.2 Hz,
1H), 7.56 (td, J = 7.5 and 1.2 Hz, 1H), 7.57 (br s, 1H), 7.82 (dq, J = 7.5 and 0.6 Hz,
1H); 13C NMR (CDCl3, 75 MHz) d 42.81, 64.07, 119.65, 121.63, 123.70, 128.07,
131.71, 131.74, 132.10, 149.66, 170.42; ESIMS m/z 236 (M++Na). Anal. Calcd for
C14H15NO: C, 78.84; H, 7.09; N, 6.57. Found: C, 78.92; H, 7.31; N, 6.44.
Compound 2c: 70%; white solid, mp 103–104 °C; IR (film) 3217, 1694, 1621,
References and notes
1. For the general review on indium-mediated reactions, see: (a) Auge, J.; Lubin-
Germain, N.; Uziel, J. Synthesis 2007, 1739–1764; (b) Kargbo, R. B.; Cook, G. R.
Curr. Org. Chem. 2007, 11, 1287–1309; (c) Lee, P. H. Bull. Korean Chem. Soc. 2007,
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Fujiwara, N.; Yamamoto, Y. J. Org. Chem. 1999, 64, 4095–4101; For diallylation
of benzonitrile with allylindate, see: (c) Jin, S.-J.; Araki, S.; Butsugan, Y. Bull.
Chem. Soc. Jpn. 1993, 66, 1528–1532; For the indium(I) iodide-promoted
1493, 1435 cmÀ1 1H NMR (CDCl3, 300 MHz) d 2.51–2.67 (m, 4H), 3.86 (s, 3H),
;
5.00–5.07 (m, 4H), 5.49–5.63 (m, 2H), 7.11 (dd, J = 8.4 and 2.4 Hz, 1H), 7.27 (dd,
J = 8.4 and 0.6 Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H), 7.69 (br s, 1H); 13C NMR (CDCl3,
75 MHz) d 42.87, 55.55, 63.73, 106.28, 119.48, 120.00, 122.53, 131.85, 133.45,
141.89, 159.88, 170,36; ESIMS m/z 266 (M++Na). Anal. Calcd for C15H17NO2: C,
74.05; H, 7.04; N, 5.76. Found: C, 74.40; H, 7.11; N, 5.49.
Compound 2f: 73%; white solid, mp 102–103 °C; IR (film) 3222, 1702, 1607,
1587, 1413 cmÀ1 1H NMR (CDCl3, 300 MHz) d 2.74 (d, J = 7.2 Hz, 4H), 4.96–5.06
;
(m, 4H), 5.46–5.60 (m, 2H), 7.38 (dd, J = 7.8 and 4.8 Hz, 1H), 7.77 (br s, 1H), 8.10
(dd, J = 7.8 and 1.5 Hz, 1H), 8.77 (dd, J = 8.1 and 1.5 Hz, 1H); 13C NMR (CDCl3,
75 MHz) d 41.46, 65.36, 119.79, 123.03, 125.99, 131.29, 131.79, 152.64, 168.50,
168.56; ESIMS m/z 237 (M++Na).
allylation of
Lett. 2004, 45, 6875–6877.
a,b-unsaturated nitrile, see: (d) Ranu, B. C.; Das, A. Tetrahedron
3. (a) Kim, S. H.; Lee, H. S.; Kim, K. H.; Kim, J. N. Tetrahedron Lett. 2009, 50, 1696–
1698; (b) Kim, S. H.; Kim, S. H.; Lee, K. Y.; Kim, J. N. Tetrahedron Lett. 2009, 50,
5744–5747; (c) Kim, S. H.; Lee, H. S.; Kim, K. H.; Kim, J. N. Tetrahedron Lett.
2009, 50, 6476–6479.
Compound 2g: 65%; white solid, mp 145–146 °C; IR (film) 3213, 1693, 1620,
1462, 1435, 1383 cmÀ1 1H NMR (CDCl3, 300 MHz) d 2.88–3.04 (m, 4H), 4.85–
;
5.01 (m, 4H), 5.33–5.47 (m, 2H), 7.55 (br s, 1H), 7.59–7.68 (m, 2H), 7.87 (d,
J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.99–8.02 (m, 1H), 8.08–8.11 (m, 1H);
13C NMR (CDCl3, 75 MHz) d 42.86, 65.73, 119.40, 119.79, 123.68, 126.98,
127.21, 127.46, 129.71, 129.85, 130.77, 131.35, 135.76, 146.43, 170.48; ESIMS
m/z 286 (M++Na).
4. For the biological activities of isoindolone derivatives, see: (a) Riedinger, C.;
Endicott, J. A.; Kemp, S. J.; Smyth, L. A.; Watson, A.; Valeur, E.; Golding, B. T.;
Griffin, R. J.; Hardcastle, I. R.; Noble, M. E.; McDonnell, J. M. J. Am. Chem. Soc.
2008, 130, 16038–16044; (b) Hudkins, R. L.; Johnson, N. W.; Angeles, T. S.;
Gessner, G. W.; Mallamo, J. P. J. Med. Chem. 2007, 50, 433–441; (c) Jitsuoka, M.;
Tsukahara, D.; Ito, S.; Tanaka, T.; Takenaga, N.; Tokita, S.; Sato, N. Bioorg. Med.
Chem. Lett. 2008, 18, 5101–5106; (d) Comins, D. L.; Schilling, S.; Zhang, Y. Org.
Lett. 2005, 7, 95–98. and further references cited therein; (e) Fardis, M.; Jin, H.;
Jabri, S.; Cai, R. Z.; Mish, M.; Tsiang, M.; Kim, C. U. Bioorg. Med. Chem. Lett. 2006,
16, 4031–4035; (f) Wrobel, J.; Dietrich, A.; Woolson, S. A.; Millen, J.; McCaleb,
M.; Harrison, M. C.; Hohman, T. C.; Sredy, J.; Sullivan, D. J. Med. Chem. 1992, 35,
4613–4627.
Compound 3: 88%; white solid, mp 160–161 °C; IR (film) 3211, 1693, 1620,
1462, 1383 cmÀ1 1H NMR (CDCl3, 300 MHz) d 2.86 (d, J = 16.2 Hz, 2H), 3.28 (d,
;
J = 16.2 Hz, 2H), 6.00–6.06 (m, 2H), 7.54–7.64 (m, 2H), 7.74–7.77 (m, 1H), 7.87
(d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.98–8.01 (m, 1H), 8.07 (br s, 1H); 13C
NMR (CDCl3, 125 MHz) d 45.74, 66.96, 119.66, 123.33, 126.92, 127.00, 127.28,
128.94, 129.00, 129.26, 129.65, 135.80, 148.99, 170.10; ESIMS m/z 258
(M++Na). Anal. Calcd for C16H13NO: C, 81.68; H, 5.57; N, 5.95. Found: C,
81.82; H, 5.63; N, 5.69.
5. For the synthesis of isoindolone derivatives, see: (a Murai, M.; Miki, K.; Ohe, K.
J. Org. Chem. 2008, 73, 9174–9176; (b) Salcedo, A.; Neuville, L.; Zhu, J. J. Org.
Chem. 2008, 73, 3600–3603; (c) Campbell, J. B.; Dedinas, R. F.; Trumbower-
Walsh, S. A. J. Org. Chem. 1996, 61, 6205–6211; (d) He, Z.; Yudin, A. K. Org. Lett.
2006, 8, 5829–5832; (e) Kobayashi, K.; Hase, M.; Hashimoto, K.; Fujita, S.;
Tanmatsu, M.; Morikawa, O.; Konishi, H. Synthesis 2006, 2493–2496; (f) Enders,
D.; Braig, V.; Raabe, G. Can. J. Chem. 2001, 79, 1528–1535; (g) Sun, C.; Xu, B. J.
Org. Chem. 2008, 73, 7361–7364; (h) Deville, J. P.; Behar, V. Org. Lett. 2002, 4,
1403–1405; (i) Araki, S.; Shimizu, T.; Johar, P. S.; Jin, S.-J.; Butsugan, Y. J. Org.
Chem. 1991, 56, 2538–2542.
6. For the synthesis of polycyclic- and spiro-isoindolone derivatives, see: (a
Medimagh, R.; Marque, S.; Prim, D.; Marrot, J.; Chatti, S. Org. Lett. 2009, 11,
1817–1820; (b) Osante, I.; Lete, E.; Sotomayor, N. Tetrahedron Lett. 2004, 45,
1253–1256; (c) Bahajaj, A. A.; Vernon, J. M.; Wilson, G. D. Tetrahedron 2004, 60,
1247–1253; (d) Kang, S. W.; Kim, S. H. Bull. Korean Chem. Soc. 2006, 27, 153–
154; (e) Kang, S. W.; Heo, E. Y.; Jun, J. G.; Kim, S. H. Bull. Korean Chem. Soc. 2004,
25, 1924–1928; (f) Majumdar, K. C.; Das, T. K.; Jana, M. Synth. Commun. 2005,
35, 1961–1969; (g) Bertus, P.; Menant, C.; Tanguy, C.; Szymoniak, J. Org. Lett.
2008, 10, 777–780; (h) Bertus, P.; Szymoniak, J. J. Org. Chem. 2003, 68, 7133–
7136.
9. Starting material 1a was purchased from the commercial source. Other
compounds (1b–g) were synthesized from the corresponding bromides or
chlorides via the Rosenmund-von Braun reaction with CuCN in DMF as
reported, see: (a) Powers, J. J.; Favor, D. A.; Rankin, T.; Sharma, R.; Pandit, C.;
Jeganathan, A.; Maiti, S. N. Tetrahedron Lett. 2009, 50, 1267–1269. (b) Wang, D.;
Kuang, L.; Li, Z.; Ding, K. Synlett 2008, 69–72. The spectroscopic data of
unknown compounds 1b and 1g are as follows.
Compound 1b: 85%; white solid, mp 65–66°C; IR (film) 2228, 1711, 1604,
1436 cmÀ1 1H NMR (CDCl3, 300 MHz) d 2.46 (s, 3H), 3.98 (s, 3H), 7.47 (ddd,
;
J = 8.1, 1.8, and 0.6 Hz, 1H), 7.60–7.61 (m, 1H), 8.03 (d, J = 8.1 Hz, 1H); 13C NMR
(CDCl3, 75 MHz) d 21.18, 52.61, 112.81, 117.64, 129.57, 131.14, 133.16, 135.23,
143.79, 164.51; ESIMS m/z 198 (M++Na).
Compound 1g: 85%; white solid, mp 109–110°C; IR (film) 2222, 1730, 1619,
1467 cmÀ1 1H NMR (CDCl3, 300 MHz) d 4.06 (s, 3H), 7.66–7.76 (m, 2H), 7.91–
;
7.95 (m, 1H), 8.07 (s, 2H), 8.39–8.42 (m, 1H); 13C NMR (CDCl3, 75 MHz) d 52.86,
111.25, 115.73, 125.35, 126.40, 128.34, 129.19 (2C), 131.99, 132.61 (2C),
134.30, 164.79; ESIMS m/z 234 (M++Na).
10. For the mechanistic study of In-mediated allylation, see: (a) Isaac, M. B.; Chan,
T.-H. Tetrahedron Lett. 1995, 36, 8957–8960; (b) Tan, K.-T.; Chng, S.-S.; Cheng,
H.-S.; Loh, T.-P. J. Am. Chem. Soc. 2003, 125, 2958–2963; (c) Loh, T.-P.; Tan, K.-T.;
Hu, Q.-Y. Tetrahedron Lett. 2001, 42, 8705–8708; (d) Loh, T.-P.; Tan, K.-T.; Yang,
J.-Y.; Xiang, C.-L. Tetrahedron Lett. 2001, 42, 8701–8703.
7. Sun, X.-W.; Liu, M.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2008, 10, 1259–1262.
8. Typical procedure for the synthesis of compound 2a:
A stirred mixture of
compound 1a (175 mg, 1.0 mmol), allyl bromide (484 mg, 4.0 mmol), and