The reaction of arynes with münchnones: Synthesis of isoindoles and azaisoindoles

Article abstract of DOI:10.1016/j.tetlet.2014.03.055

Arynes derived from silyltriflate precursors undergo a smooth 1,3-dipolar cycloaddition with münchnones to furnish isoindoles and azaisoindoles in moderate to high yields. Modification of the fluoride source, solvent, and temperature allows for the selective generation of either isoindoles or benzanthracenimines, the latter of which serve as precursors to polycyclic aromatic hydrocarbons.

Full text of DOI:10.1016/j.tetlet.2014.03.055

Tetrahedron Letters 55 (2014) 2809–2812
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Tetrahedron Letters
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The reaction of arynes with münchnones: synthesis of isoindoles
and azaisoindoles
⇑
Justin M. Lopchuk, Gordon W. Gribble
Department of Chemistry, Dartmouth College, Hanover, NH 03755-3564, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Arynes derived from silyltriflate precursors undergo a smooth 1,3-dipolar cycloaddition with münchnon-
es to furnish isoindoles and azaisoindoles in moderate to high yields. Modification of the fluoride source,
solvent, and temperature allows for the selective generation of either isoindoles or benzanthracenimines,
the latter of which serve as precursors to polycyclic aromatic hydrocarbons.
Received 19 February 2014
Revised 10 March 2014
Accepted 11 March 2014
Available online 25 March 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
1,3-Dipolar cycloaddition
Mesoionic heterocycles
Benzyne
Pyridyne
Isoindole
Modern methods for the mild generation of arynes have facili-
tated their resurgence as powerful synthetic intermediates capable
of engaging in a wide variety of chemistries.1 In particular, arynes
are willing partners in 1,3-dipolar cycloadditions with a variety of
dipoles including azides,2 sydnones,3 azomethine ylides,4 nitro-
nes,5 nitrile oxides,6 and nitrosoarenes.7 More recent efforts have
demonstrated their effectiveness in natural product synthesis.8
As a part of our ongoing interest in the chemistry of münchnon-
es,9 we began to investigate the possibility of using these mesoion-
ic heterocycles with arynes derived from silyltriflates as a mild
route to isoindoles. Such a method would provide a useful alterna-
tive to traditional preparations of isoindoles which often require
harsh conditions for their synthesis.10 Kato described an initial at-
tempt to generate isoindoles from arynes and münchnones
(Scheme 1); however, the arynes were generated via the oxidative
fragmentation of 1-aminobenzotriazole (1).3a These conditions
proved too harsh for the münchnones and resulted in only a trace
of desired isoindole 3 along with benzanthracenimine 4 and
biphenylene (5). It is notable that the researchers successfully con-
verted sydnones, a related and typically more stable mesoionic
heterocycle, to indazoles under the same oxidative conditions.
The successful development of this reaction between arynes
and münchnones is complicated by a number of factors: the
münchnones are sensitive to nucleophilic conditions (which are re-
quired to generate the aryne), the newly generated isoindole will
Ph
N
N
O
Pb(OAc)4
N
O
+
N
Me
1
NH2
Ph
2
Ph
Ph
N
Me
Me
+
+
N
5
3
Ph
4
Ph
(4%)
(7%)
(< 2%)
Scheme 1. Reaction of arynes with münchnones (Kato).3a
readily react with arynes, perhaps in preference to the münchnon-
es, and isoindoles are often unstable to isolation. Despite these per-
ceived difficulties, we now describe the successful reaction of
arynes with münchnones to afford a practical synthesis of isoin-
doles and azaisoindoles.
Münchnone precursors 6–9 were prepared as previously
described9 and cyclized in situ by treatment with N,N0-diisopropyl-
carbodiimide (DIPC) in dry THF or MeCN (Scheme 2).
We began our investigations by subjecting unsubstituted aryne
precursor 13 and münchnone 10 to n-Bu4NF (TBAF) at room tem-
perature. Unfortunately, after 24 h this resulted in a 1:1 mixture
of isoindole 15 and benzanthracenimine 16, along with unreacted
silyltriflate 13. A screen of fluoride sources identified CsF, TBAT,
and TAS-F as the most promising since they delivered isoindole
⇑
Corresponding author. Tel.: +1 603 646 3118; fax: +1 603 646 3946.
E-mail address: ggribble@dartmouth.edu (G.W. Gribble).
http://dx.doi.org/10.1016/j.tetlet.2014.03.055
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

2810
J. M. Lopchuk, G. W. Gribble / Tetrahedron Letters 55 (2014) 2809–2812
Me
Ph
N
Ph
Ph
N
O
R1
R2
O
Me
DIPC
O
Bn
Bn
N
R
R2
N
R3
CO2H
Bn
N
THF or MeCN
R3
R1
18
17
(88%)
Ph
(93%)
Ph
Ph
6: R1 = R2 = Ph, R3 = Bn
7: R1 = R2 = Ph, R3 = Me
10: R1 = R2 = Ph, R3 = Bn
2: R1 = R2 = Ph, R3 = Me
15
(91%)
3: R = Me (76%)
: R = Bn
8:
11:
R1 = Me, R2 = Ph, R3 = Bn
R1 = Me, R2 = Ph, R3 = Bn
Ph
9: R1 = Ph, R2 = Me, R3 = Bn
12: R1 = Ph, R2 = Me, R3 = Bn
OMe
Ph
N
Ph
N
N
Scheme 2. Cyclization of münchnone precursors 6–9.
N
Bn
Bn
Ph
Cl
19
20
(85%)
21
Ph
Ph
(87%)
(58%)
Bn
O
N
Ph
TMS
OTf
O
Ph
DIPC
F
O
O
Ph
+
N
Ph
N
Me
Bn
Ph
10
Ph
13
14
N
Bn
Bn
N
Bn
N
Bn
23
22 Ph
24
Me
Me
N
Ph
N
Ph
(41%)
generated in situ
unstable to air, difficult to isolate
Bn
+
- CO2
Figure 1. Scope of isoindole and azaisoindole synthesis.
15
Ph
16
Ph
benzanthracenimine
isoindole
adduct 27 (Scheme 4). Isoindoles 23 and 24 were generated
in situ, but decomposed rapidly upon any purification attempts.
As such, 23 was trapped with dimethyl acetylenedicarboxylate
(DMAD) to furnish 28 in 78% from münchnone 11 and 51% from
münchnone 12 (Scheme 5).
Scheme 3. Reaction of arynes with münchnones (this work).
15 in high yields with only minor amounts of benzanthracenimine
16 (Scheme 3).11
In summary, we have developed a mild synthesis of isoindoles
and azaindoles from the reaction of arynes and münchnones in
moderate to high yields. Despite the potential difficulties, the reac-
tion is made possible by the use of anhydrous conditions and a
mild nucleophile in fluoride which is both compatible with the
münchnone and able to generate the aryne; furthermore, an excess
of münchnone and room temperature conditions allow for the
selective formation and isolation of the labile isoindoles. It is also
noteworthy that the reaction conditions can be tuned to deliver
either the isoindole or benzanthracenimine by the choice of fluo-
ride source and solvent.
Conditions were also optimized to provide exclusive formation
of the benzanthracenimines (Table 1, entries 4 and 7); these com-
pounds are known to serve as useful precursors to polyaromatics
via deamination reactions.12
The reaction was successful for all arynes and münchnones
tested; isoindoles were obtained in high yields, while azaisoindoles
21 and 22 were synthesized in moderate yields from the corre-
sponding pyridyne precursors (Fig. 1).13
Since naphthalene derivative 19 was fairly unstable, it was
characterized by conversion to dione 26 under air or silica gel or
alternatively by trapping with a second equivalent of 25 to yield
Table 1
Optimization of the reaction between silyltriflate 13 and münchnone 1014–25
Bn
Ph
O
N
Ph
N
Ph
O
Bn
O
N
Bn
N
TMS
OTf
Ph
Bn
10
Ph
+
O
- CO2
DIPC, fluoride source
solvent, temperature, time
15
Ph
Ph
16
Ph
benzanthracenimine
13
14
isoindole
Time (h)
Entry
Münchnone (equiv)
Fluoridea
Solvent
Temp
Isoindoleb (%) Benzanthracenimineb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
3
3
3
3
3
3
0.7
0.7
3
3
1.5
3
3
3
TBAF (s)
TBAF (l)
CsF
TBAF (l)
CsF
KF/18-c-6
TBAF (l)
CsF
CsF
CsF
CsF
TBAF (l)
TBAT
THF
THF
THF
THF
THF
MeCN
THF
rt
rt
rt
70 °C
70 °C
rt
rt
rt
rt
70 °C
rt
70 °C
rt
rt
24
24
24
24
24
24
24
24
24
12
24
24
12
12
23
22
11
7
61
2
11
68
48
4
11
78
19
5
54
45
0
48
73
0
14
91
85
17
45
90
91
THF
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
TAS-F
3
a
TBAF = tetra-n-butylammonium fluoride; TBAT = tetrabutylammonium difluorotriphenylsilicate; TAS-F = tris(dimethylamino)sulfonium difluorotrimethylsilicate.
Yields based on isolated products after column chromatography.
b

J. M. Lopchuk, G. W. Gribble / Tetrahedron Letters 55 (2014) 2809–2812
2811
Ph
O
O
O
Ph
N
N
air and/or
silica gel
Bn
OTf
Ph
Ph
10
Ph
Bn
(87%)
CsF, MeCN
(3 equiv. münchnone)
TMS
26
25
Ph
19
O
Ph
O
NBn
O
Ph
Ph
N
Bn
OTf
10
Ph
N
Bn
(89%)
CsF, MeCN
(0.7 equiv. münchnone)
TMS
Ph
27
19
25
Ph
Scheme 4. Conversion of 19–26 and 27.
Ph
Bn
Me
O
O
i)
i)
O
O
N
N
12
Bn
Ph NBn
CO2Me
11
Me
Ph
OTf
OTf
CsF, MeCN
CsF, MeCN
ii) DMAD
(78%)
ii) DMAD
TMS
TMS
CO2Me
13
(51%)
13
Me
28
Scheme 5. Trapping of isoindole 23 with DMAD.
flash chromatography (silica gel, 0–10% ethyl acetate in pentane) to afford the
isoindole. Note the CsF was oven-dried overnight (>120 °C) prior to use.
15. 2-Benzyl-1,3-diphenyl-2H-isoindole (15): Orange solid (91%); 1H NMR
(300 MHz, CDCl3) d 7.55 (dd, 2H, J = 2.9, 6.6 Hz), 7.45–7.31 (m, 10H), 7.09–
7.07 (m, 3H), 6.98 (dd, 2H, J = 2.9, 6.6 Hz), 6.60–6.56 (m, 2H), 5.54 (s, 2H); 13C
NMR (75 MHz, CDCl3) d 138.8, 132.6, 130.7, 128.9, 128.6, 128.1, 127.4, 126.3,
Acknowledgements
J.M.L. acknowledges support from the Department of Education
GAANN fellowship. G.W.G. acknowledges support by the Donors of
the Petroleum Research Fund (PRF), and administered by the
American Chemical Society, and by Wyeth.
125.7, 123.4, 122.3, 119.9, 49.7; HRMS (ESI+) calcd for C27H22
N
(MH+)
360.1752, found 360.1755.
16. 11-Benzyl-9,10-diphenyl-9,10-dihydro-9,10-epimino-anthracene (16): White
solid (68%): 1H NMR (300 MHz, CDCl3) d 7.93 (d, 4H, J = 7.1 Hz), 7.43–7.30
(m, 10H), 7.10–7.04 (m, 4H), 6.83–6.78 (m, 3H), 6.58–6.55 (m, 2H), 3.53 (s, 2H);
13C NMR (75 MHz, CDCl3) d 151.8, 140.8, 134.4, 130.8, 128.6, 128.5, 128.0,
127.3, 125.6, 125.4, 123.5, 82.0, 48.5; HRMS (ESI+) calcd for C33H26N (MH+)
436.2065, found 436.2067.
References and notes
1. (a) Pellissier, H.; Santelli, M. Tetrahedron 2003, 59, 701; (b) Dyke, A. M.; Hester,
A. J.; Lloyd-Jones, G. C. Synthesis 2006, 4093; (c) Peña, D.; Pérez, D.; Guitián, E.
Heterocycles 2007, 74, 89; (d) Sanz, R. Org. Prep. Proced. Int. 2008, 40, 215.
2. (a) Campbell-Verduyn, L.; Elsinga, P. H.; Mirfeizi, L.; Dierckx, R. A.; Feringa, B. L.
Org. Biomol. Chem. 2008, 6, 3461; (b) Lin, Y.; Chen, Y.; Ma, X.; Xu, D.; Cao, W.;
Chen, J. Tetrahedron 2011, 67, 856.
17. 2-Methyl-1,3-diphenyl-2H-isoindole (3): Colorless oil (76%); 1H NMR (300 MHz,
CDCl3) d 7.74 (dd, 2H, J = 3.2, 6.6 Hz), 7.35 (d, 4H, J = 7.3 Hz), 7.22 (t, 4H,
J = 7.8 Hz), 7.12–7.07 (m, 2H), 7.03 (dd, 2H, J = 3.2, 6.6 Hz), 3.26 (s, 3H); known
compound.22
18. 2-Benzyl-4-methyl-1,3-diphenyl-2H-isoindole (17): Pale yellow oil (88%); 1H
NMR (300 MHz, CDCl3) d 7.57 (dd, 3H, J = 1.7, 8.3 Hz), 7.48 (t, 3H, J = 7.1 Hz),
7.44–7.36 (m, 6H), 7.17 (dd, 2H, J = 2.2, 4.9 Hz), 6.98 (dd, 1H, J = 6.6, 8.7 Hz),
6.80 (d, 1H, J = 6.6 Hz), 6.67–6.64 (m, 2H), 5.40 (s, 2H), 2.15 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 138.8, 134.9, 134.2, 134.1, 132.8, 130.8, 128.9, 128.5, 128.3,
127.8, 127.4, 127.3, 126.3, 124.6, 124.0, 123.3, 122.9, 122.1, 121.9, 117.8, 49.4,
21.2; HRMS (ESI+) calcd for C28H24N (MH+) 374.1909, found 374.1910.
19. 2-Benzyl-5-methyl-1,3-diphenyl-2H-isoindole (18): Pale yellow oil (93%); 1H
NMR (300 MHz, CDCl3) d 7.49–7.28 (m, 12H), 7.08–7.05 (m, 3H), 6.84 (d, 1H,
J = 8.8 Hz), 6.58–6.56 (m, 2H), 5.51 (s, 2H), 2.36 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 138.8, 136.4, 132.6, 131.5, 130.6, 130.5, 128.8, 128.5, 128.4, 127.3,
127.2, 127.1, 126.2, 125.2, 124.8, 123.9, 123.6, 122.6, 119.7, 117.7, 49.6, 22.2;
HRMS (ESI+) calcd for C28H24N (MH+) 374.1909, found 374.1909.
3. (a) Kato, H.; Nakazawa, S.; Kiyosawa, T.; Hirakawa, K. J. Chem. Soc., Perkin Trans.
1 1976, 672; (b) Wu, C.; Fang, Y.; Larock, R. C.; Shi, F. Org. Lett. 2010, 12, 2234;
(c) Fang, Y.; Wu, C.; Larock, R. C.; Shi, F. J. Org. Chem. 2011, 76, 8840.
4. Shi, F.; Mancuso, R.; Larock, R. C. Tetrahedron Lett. 2009, 50, 4067.
5. Wu, K.; Chen, Y.; Lin, Y.; Cao, W.; Zhang, M.; Chen, J.; Lee, A. W. M. Tetrahedron
2010, 66, 578.
6. Dubrovskiy, A. V.; Larock, R. C. Org. Lett. 2010, 12, 1180.
7. Chakrabarty, S.; Chatterjee, I.; Tebben, L.; Studer, A. Angew. Chem., Int. Ed. 2013,
52, 2968.
8. Tadross, P. M.; Stoltz, B. M. Chem. Rev. 2012, 112, 3550.
9. (a) Gribble, G. W.; Pelkey, E. T.; Simon, W. M.; Trujillo, H. A. Tetrahedron 2000,
56, 10133; (b) Lopchuk, J. M.; Gribble, G. W. Heterocycles 2011, 82, 1617; (c)
Lopchuk, J. M.; Gribble, G. W. Tetrahedron Lett. 2011, 52, 4106; (d) Lopchuk, J.
M.; Hughes, R. P.; Gribble, G. W. Org. Lett. 2013, 15, 5218.
10. (a) Kovtunenko, V. A.; Voitenko, Z. V. Russ. Chem. Rev. 1994, 63, 997; (b)
Heugebaert, T. S. A.; Roman, B. I.; Stevens, C. V. Chem. Soc. Rev. 2012, 41, 5626.
11. We elected to move forward with CsF as our fluoride source since it is
significantly more economical than TBAT or TAS-F.
12. (a) Gribble, G. W.; Allen, R. W.; LeHoullier, C. S.; Eaton, J. T.; Easton, N. R., Jr.;
Slayton, R. I.; Sibi, M. P. J. Org. Chem. 1981, 46, 1025; (b) LeHoullier, C. S.;
Gribble, G. W. J. Org. Chem. 1983, 48, 1682.
13. For the synthesis of pyridyne precursors, see: (a) Diaz, M.; Cobas, A.; Guitián,
E.; Castedo, L. Eur. J. Org. Chem. 2001, 4543; (b) Carroll, F. I.; Robinson, T. P.;
Brieaddy, L. E.; Atkinson, R. N.; Mascarella, S. W.; Damaj, M. I.; Martin, B. R.;
Navarro, H. A. J. Med. Chem. 2007, 50, 6383.
20. 2-Benzyl-4-methoxy-1,3-diphenyl-2H-isoindole (20): Pale yellow semisolid
(85%); 1H NMR (300 MHz, CDCl3)
d 7.45–7.27 (m, 11H), 7.15 (d, 1H,
J = 8.5 Hz), 7.06 (dd, 2H, J = 2.0, 5.0 Hz), 6.89 (t, 1H, J = 7.3 Hz), 6.54–6.51 (m,
2H), 6.23 (d, 1H, J = 7.3 Hz), 5.38 (s, 2H), 3.68 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 154.4, 138.7, 133.5, 132.7, 132.0, 130.7, 128.7, 128.4, 127.4, 127.3, 127.1,
126.2, 124.9, 124.7, 124.5, 122.2, 112.2, 109.9, 98.4, 55.1, 49.4; HRMS (ESI+)
calcd for C28H24NO (MH+) 390.1858, found 390.1850.
21. 2-Benzyl-4-chloro-1,3-diphenyl-2H-pyrrolo[3,4-c]pyridine (21): Yellow oil (58%);
1H NMR (300 MHz, CDCl3) d 7.70 (d, 1H, J = 6.1 Hz), 7.44–7.31 (m, 10H), 7.28 (d,
1H, J = 6.1 Hz), 7.14–7.12 (m, 3H), 6.55 (d, 2H, J = 7.1 Hz), 5.35 (s, 2H); 13C NMR
(75 MHz, CDCl3) d 146.2, 137.5, 136.1, 134.4, 132.9, 132.4, 130.6, 129.9, 129.1,
129.0, 128.9, 128.8, 128.7, 128.4, 128.3, 128.0, 127.6, 126.2, 113.1, 49.8; HRMS
(ESI+) calcd for C26H20N2Cl (MH+) 395.1315, found 395.1309.
14. General procedure for the synthesis of isoindoles: A round bottomed flask was
charged with the münchnone precursor 6–9 (3 equiv), silyltriflate (1 equiv),
and MeCN under nitrogen. DIPC (3 equiv) was added via syringe and the
mixture stirred 5–10 min. The fluoride source—all yields below use CsF—
(2.5 equiv) was added and the mixture stirred 12–24 h until the silyltriflate
was consumed. The reaction mixture was concentrated and purified directly by
22. 6-Benzyl-5,7-diphenyl-6H-pyrrolo[3,4-b]pyridine (22): Yellow oil (41%); 1H NMR
(300 MHz, CDCl3) d 7.84 (d, 1H, J = 7.3 Hz), 7.64–7.08 (m, 16H), 5.13 (s, 2H); 13
C
NMR (75 MHz, CDCl3) d 174.4, 149.0, 141.2, 137.6, 137.0, 132.9, 132.0, 129.9,
129.0, 129.0, 128.9, 128.8, 128.4, 127.9, 124.5, 115.5, 48.8; HRMS (ESI+) calcd
for C26H21N2 (MH+) 361.1705, found 361.1701.

2812
J. M. Lopchuk, G. W. Gribble / Tetrahedron Letters 55 (2014) 2809–2812
23. Naphthalene-2,3-diylbis(phenylmethanone) (26): White solid (87%); 1H NMR
(300 MHz, CDCl3) d 8.10 (s, 2H), 7.96–7.93 (m, 2H), 7.83–7.80 (m, 4H), 7.69–
7.65 (m, 2H), 7.55 (t, 2H, J = 7.3 Hz), 7.42 (t, 4H, J = 7.3 Hz). Known
compound.23
25. Dimethyl 9-benzyl-1-methyl-4-phenyl-1,4-dihydro-1,4-epiminonaphthalene-2,3-
dicarboxylate (28): After completion of isoindole formation, the reaction was
cooled to 0 °C and DMAD (10 equiv) was added via syringe. Stirred 1 h,
concentrated in vacuo, and directly purified by flash chromatography. Clear oil
(78% for münchnone 87; 51% for münchnone 88); 1H NMR (300 MHz, CDCl3) d
7.59–7.09 (m, 14H), 5.01 (s, 2H), 3.75 (s, 3H), 3.70 (s, 3H), 2.16 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 173.5, 137.5, 136.0, 132.7, 131.3, 129.8, 129.1, 129.0, 128.9,
128.8, 128.7, 128.6, 128.3, 128.2, 128.0, 127.7, 110.1, 78.8, 74.0, 52.4, 49.5,
26.7; HRMS (ESI+) calcd for C28H25NO4 (MH+) 440.1862, found 440.1860.
24. 15-Benzyl-6,13-diphenyl-6,13-dihydro-6,13-epiminopentacene (27): Pale orange
solid (89%); 1H NMR (300 MHz, CDCl3) d 8.17 (d, 4H, J = 7.3 Hz), 7.85 (s, 4H),
7.77 (dd, 4H, J = 3.2, 6.2 Hz), 7.51 (t, 4H, J = 7.8 Hz), 7.44 (dd, 6H, J = 3.2, 6.2 Hz),
6.86–6.84 (m, 3H), 6.65–6.63 (m, 2H), 3.63 (s, 2H); 13C NMR (75 MHz, CDCl3) d
147.5, 140.7, 137.8, 134.5, 132.5, 130.8, 128.8, 128.3, 128.0, 127.4, 126.3, 125.5,
N
122.1, 80.9, 48.6; HRMS (ESI+) calcd for C41H30 (MH+) 536.2378, found
536.2378.