Copper-catalyzed direct N-arylation of naphthalimides using diaryliodonium Salts

Article abstract of DOI:10.1055/s-0033-1339448

An effective copper-catalyzed N-arylation of naphthal-imides with diaryliodonium salts in toluene at 100 °C has been developed. This cross-coupling reaction gives the desired N-arylated 1,8-naphthalimides in moderate to good yields. The synthetic potentia

Full text of DOI:10.1055/s-0033-1339448

LETTER
▌1959
lCettoerpper-Catalyzed Direct N-Arylation of Naphthalimides Using Diaryliodoni-
um Salts
Direct N-Arylation of Naphthalimides
Song Mao,a Fenglou Guo,a Juan Li,a Xu Geng,a Jianjun Yu,a Jianwei Han,b Limin Wang*a,c
a
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology,
130 Meilong Road, Shanghai 200237, P. R. of China
Fax +86(21)64253881; E-mail: wanglimin@ecust.edu.cn
b
Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, The Chinese Academy of Sciences,
345 Ling Ling Road, Shanghai 200237, P. R. of China
c
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200032, P. R. of China
Received: 07.05.2013; Accepted after revision: 18.06.2013
terials,10 in solar energy collectors,11 as fluorescent tags
Abstract: An effective copper-catalyzed N-arylation of naphthal-
for use in molecular biology,12 for potential photosensitiz-
imides with diaryliodonium salts in toluene at 100 °C has been de-
ing biological activity,13 and in liquid-crystalline dis-
veloped. This cross-coupling reaction gives the desired N-arylated
1,8-naphthalimides in moderate to good yields. The synthetic po-
plays.14 Dehydrative condensation of 1,8-naphthalic
tential of this coupling is applied in functional materials based on N- anhydride with amines, the cyclization of N-substituted
arylated 1,8-naphthalimides, such as molecular probes.
amic acid in the presence of acidic reagents, direct N-al-
kylation under Mitsunobu conditions, and the condensa-
tion of iminophosphoranes with phthaloyl dichloride
followed by alkaline hydrolysis are available methods for
the synthesis of naphthalimides.15 Generally, N-arylated
1,8-naphthalimide derivatives can be synthesized by con-
densation of 1,8-naphthalic anhydride with aromatic
amines,15a,16 cross-coupling between 1,8-naphthalimides
and arylboronic esters,17 aminocarbonylation of 1,8-di-
iodonaphthalene,18 and direct N-arylation of 1,8-naph-
thalimides with arenes.19 Recently, we have been
interested in the use of diaryliodonium salts in organic
synthesis.20 Herein, we report a new approach to the syn-
thesis of N-arylated 1,8-naphthalimide derivatives
through copper-catalyzed direct N-arylation of naph-
thalimides with diaryliodonium salts, which are efficient,
mild, nontoxic and selective arylating reagents.
Key words: arylation, copper catalysis, diaryliodonium salts,
naphthalimides, C–N cross coupling
Reactions involving C–N cross-coupling have captured
considerable attention from organic chemists over several
decades because numerous pharmaceuticals, agrochemi-
cals, polymers, and biologically relevant molecules con-
tain the aryl nitrogen functionality.1 Transition-metal-
catalyzed C–N bond formation has revolutionized organic
synthesis during the past decades. Since the founding
work of Ullmann and Goldberg2 and the pioneering work
of Buchwald and Hartwig3 were reported, there have been
a number of recent advances in the field of transition-
metal-promoted C–N cross-coupling reactions.4
Hypervalent iodine reagents have been extensively used
in organic synthesis.5 As one of the most versatile hyper-
valent iodine compounds, diaryliodonium(III) salts have
been used as electrophilic arylating agents in various reac-
tions, such as nucleophilic substitution reactions with ni-
trogen nucleophiles,6 carbon nucleophiles,7 and others, 5b
as well as Cu- and Pd-catalyzed coupling reactions,5c,8 and
trapping reactions (in which they are used as benzyne pre-
cursors).9 Recently, Cu-promoted heteroatom coupling
reactions between various amines, amides6a and azoles6b
with diaryliodonium salts have been reported. However,
the use of imides as coupling partners in this process is
rare.
To test our N-arylation of naphthalimides, we treated 1,8-
naphthalimide (1a) with 1.2 equivalents diphenyliodoni-
um tetrafluoroborate (2a) and t-BuOK as base, in toluene
at 80 °C for 12 hours, which were the standard conditions
adopted in our previous study.20a We were pleased to find
that N-arylation proceeded to give 3a in 9% yield (Table
1, entry 1). Fortunately, in the presence of 10 mol% CuI,
the desired arylated product 3a was observed in 65% yield
after 30 minutes (Table 1, entry 2). Investigation of reac-
tion temperature revealed that 100 °C was the most effi-
cient temperature to generate 3a (80% yield; Table 1,
entries 2–4). Prolonging the reaction time, did not lead to
a better result (Table 1, entry 5). Decreasing the catalyst
loading to 5 mol% had a negative impact on yield (Table
1, entry 6). Modifying the nature of the copper source es-
tablished CuI as the most efficient catalyst (Table 1, en-
tries 3, 7, and 8). A range of bases including t-BuOK,
KOH, K2CO3, Et3N were screened (Table 1, entries 3 and
9–11), and t-BuOK was found to be the most suitable. The
influence of solvents was examined and toluene proved to
In recent years, 1,8-naphthalimide derivatives have been
the subject of numerous synthetic efforts, and they have
been applied in dyeing synthetic polymers and textile ma-
SYNLETT 21709013, 2415, 1959–1962
Advanced online publication: 07.08.2013
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DOI: 10.1055/s-0033-1339448; Art ID: ST-2013-W0427-L
© Georg Thieme Verlag Stuttgart · New York

1960
S. Mao et al.
LETTER
Table 1 Optimization of Cu-Catalyzed N-Arylation of Naphthalimide (1a)a
base, [Cu]
+
Ph2IX
O
N
O
solvent, temp, time
O
N
H
O
1a
2
3a
Entry
X
Base
[Cu] (mol%)
Solvent
Temp (°C)
Time (h)
Yield (%)b
1
BF4
BF4
BF4
BF4
BF4
BF4
BF4
BF4
BF4
BF4
BF4
BF4
BF4
Br
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
KOH
–
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
1,4-dioxane
DMF
80
12
9
2
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (5)
80
0.5
0.5
0.5
2
65
80
76
78
40
55
35
23
43
60
57
10
26
33
50
3
100
120
100
100
100
100
100
100
100
100
100
100
100
100
4
5
6
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
7
CuBr (10)
Cu(OTf)2 (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
8
9
10
11
12
13
14
15
16
K2CO3
Et3N
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
toluene
toluene
toluene
OTs
OTf
a Reaction conditions: 1,8-naphthalimide (0.4 mmol, 1 equiv), diphenyliodonium salt (0.48 mmol, 1.2 equiv), copper catalyst, base (0.8 mmol,
2 equiv), solvent (3 mL).
b Yield of isolated product.
be the most suitable; more polar solvents led to lower sired product (Table 2, entry 5). The presence of an ortho-
yields (Table 1, entries 3, 12, and 13). Furthermore, di- methyl group with steric hindrance gave a dramatically
aryliodonium salts 2, bearing different counteranions (Ta- decreased yield (Table 2, entry 6), however, no reaction
ble 1, entries 3, 14–16) were studied. Among all the tested was observed when the diaryliodonium salt was para-
reagents, tetrafluoroborate diaryliodonium furnished the methyl-substituted. It is worth mentioning that the unsym-
desired product 3a in good yield (80%; Table 1, entry 3), metrical salt 2g selectively transferred the phenyl group to
whereas bromide, p-toluenesulfonate, and triflate diaryl- the 1,8-naphthalimide in moderate yield (55%; Table 2,
iodonium salts gave only moderate yields (Table 1, entries entry 7). However, no desired products were obtained
14–16).
when (4-methylphenyl)(2,4,6-trimethylphenyl)iodonium
tetrafluoroborate or (4-ethoxycarbonyl)(2,4,6-trimethyl-
phenyl)iodonium tetrafluoroborate were employed. Fur-
ther exploration of the scope of the reaction was
conducted with various substituted naphthalimides. With
2a, substituted naphthalimides with 3-nitro, 4-bromo and
4-phenylethynyl were found to be compatible with the re-
action conditions, undergoing N-arylation to give the cor-
responding products in 42, 57 and 53% yields,
respectively (Table 2, entries 8–10). Use of 1,8-naph-
With the optimized conditions in hand, the scope of the N-
arylation of naphthalimides was explored by using a vari-
ety of symmetrical and unsymmetrical diaryliodonium
salts. First, various substituted diaryliodonium salts were
prepared and used for the direct coupling toward 1,8-
naphthalimide. As shown in Table 2, diaryliodonium salts
with halogen substituents gave the corresponding prod-
ucts in moderate yields (Table 2, entries 2–4), whereas the
carboxyl-substituted diaryliodonium salts afforded no de-
Synlett 2013, 24, 1959–1962
© Georg Thieme Verlag Stuttgart · New York

LETTER
Direct N-Arylation of Naphthalimides
1961
Table 2 Scope of the N-Arylation of Naphthalimidesa
R
R
BF4
I
t-BuOK (2 equiv), CuI
Ar1
Ar2
+
toluene, 100 °C
0.5–2 h
O
N
Ar2
O
O
N
H
O
(1.2 equiv)
3
2
1
Entry
1
R
2
Ar1
Ph
Ar2
Ph
t (h)
3
Yield (%)b
1
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1e
1e
H
2a
2b
2c
2d
2e
2f
0.5
2
3a
3b
3c
3d
n.d.
3e
3a
3f
80
75
45
64
n.d.
36
55
42
57
53
82
44
52
2
H
4-ClC6H4
4-ClC6H4
3
H
4-BrC6H4
4-FC6H4
3-HO2CC6H4
2-MeC6H4
Mesityl
Ph
4-BrC6H4
4-FC6H4
3-HO2CC6H4
2-MeC6H4
Ph
2
4
H
0.5
2
5
H
6
H
2
7
H
2g
2a
2a
2a
2a
2b
2f
2
8
3-NO2
4-Br
Ph
2
9
Ph
Ph
2
3g
3h
3i
10
11
12
13
4-phenylethynyl
4-morpholinyl
4-morpholinyl
4-morpholinyl
Ph
Ph
2
Ph
Ph
0.5
2
4-ClC6H4
2-MeC6H4
4-ClC6H4
2-MeC6H4
3j
2
3k
a Reaction conditions: naphthalimide (0.4 mmol, 1 equiv), iodonium salt (0.48 mmol, 1.2 equiv), CuI (10 mol%), t-BuOK (0.8 mmol, 2 equiv),
toluene (3 mL), 100 °C, 0.5–2 h.
b Yield of isolated product.
thalimide substituted with the strong electron-donating
morpholinyl group 1e gave a good yield of the desired
product (82%; Table 2, entry 11). In addition, use of 1e as
substrate gave moderate yields with 4-Cl- and 2-Me-sub-
stituted diaryliodonium salts (Table 2, entries 12 and 13).
References and Notes
(1) (a) Amino Group Chemistry, From Synthesis to the Life
Sciences; Ricci, A., Ed.; Wiley-VCH: Weinheim, 2008.
(b) Bellmann, E.; Shaheen, S. E.; Thayumanavan, S.;
Barlow, S.; Grubbs, R. H.; Marder, S. R.; Kippelen, B.;
Peyghambarian, N. Chem. Mater. 1998, 10, 1668.
In summary, we have developed a new protocol for the N-
arylation of naphthalimides using diaryliodonium salts as
the electrophilic coupling partners.21 The overall process
avoids extended periods of time and is easy to handle
without the need for an inert atmosphere. This metho-
dology provides an efficient way to prepare N-arylated
1,8-naphthalimides, which can be applied in functional
materials.
(2) (a) Ullmann, F.; Sponagel, P. Ber. Dtsch. Chem. Ges. 1905,
2211. (b) Goldberg, I. Ber. Dtsch. 1906, 1691.
(3) (a) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002,
219, 131. (b) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534.
(c) Zhang, M.; Zhang, A. Synthesis 2012, 44, 1. (d) Surry, D.
S.; Buchwald, S. L. Chem. Sci. 2011, 2, 27. (e) Sadig, J. E.
R.; Willis, M. C. Synthesis 2011, 1. (f) Surry, D. S.;
Buchwald, S. L. Angew. Chem. Int. Ed. 2008, 47, 6338.
(g) Hartwig, J. F. Nature 2008, 455, 314.
(4) (a) Morphy, R.; Rankovic, Z. J. Med. Chem. 2005, 48, 6523.
(b) Wexler, R. R.; Greenlee, W. J.; Irvin, J. D.; Goldberg, M.
R.; Prendergast, K.; Smith, R. D.; Timmermans, P. B. M. W.
M. J. Med. Chem. 1996, 39, 625. (c) Schnurch, M.; Flasik,
R.; Khan, A. F.; Spina, M.; Mihovilovic, M. D.; Stanetty, P.
Eur. J. Org. Chem. 2006, 15, 3283. (d) Surry, D. S.;
Buchwald, S. L. Angew. Chem. Int. Ed. 2008, 47, 6338.
(e) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534.
Acknowledgment
The work was supported by the National Nature Science Foundati-
on of China (NSFC, 21272069), the Fundamental Research Funds
for the Central Universities and Key Laboratory of Organofluorine
Chemistry, Shanghai Institute of Organic Chemistry, Chinese Aca-
demy of Sciences.
(f) Monnier, F.; Taillefer, M. Angew. Chem. Int. Ed. 2009,
48, 6954. (g) Corbet, J.-P.; Mignani, G. Chem. Rev. 2006,
106, 2651. (h) Evano, G.; Blanchard, N.; Toumi, M. Chem.
Rev. 2008, 108, 3054. (i) Meldal, M.; Tornoe, C. W. Chem.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1959–1962

1962
S. Mao et al.
LETTER
(9) (a) Kitamura, T.; Yamane, M.; Inoue, K.; Todaka, M.;
Rev. 2008, 108, 2952. (j) Patil, N. T.; Yamamoto, Y. Chem.
Rev. 2008, 108, 3395. (k) Wurtz, S.; Glorius, F. Acc. Chem.
Res. 2008, 41, 1523. (l) Ley, S. V.; Thomas, A. W. Angew.
Chem. Int. Ed. 2003, 42, 5400.
Fukatsu, N.; Meng, Z.; Fujiwara, Y. J. Am. Chem. Soc. 1999,
121, 11674. (b) Xue, J.; Huang, X. Synth. Commun. 2007,
37, 2179.
(5) (a) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102,
2523. (b) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008,
108, 5299. (c) Merritt, E. A.; Olofsson, B. Angew. Chem. Int.
Ed. 2009, 48, 9052; Angew. Chem. 2009, 121, 9214.
(d) Silva, L. F.; Olofsson, B. Nat. Prod. Rep. 2011, 28, 1722.
(e) Yusubov, M. S.; Zhdankin, V. V. Curr. Org. Synth. 2012,
9, 247.
(6) (a) Kang, S. K.; Lee, S. H.; Lee, D. Synlett 2000, 1022.
(b) Beletskaya, I. P.; Davydov, D. V.; Gorovoy, M. S.
Tetrahedron Lett. 2002, 43, 6221. (c) Zhou, T.; Chen, Z. C.
Synth. Commun. 2002, 32, 903. (d) Wang, F. Y.; Chen, Z.
C.; Zheng, Q. G. J. Chem. Res. 2004, 206. (e) Niu, H. Y.;
Xia, C.; Qu, G. R.; Zhang, Q.; Jiang, Y.; Mao, R. Z.; Li, D.
Y.; Guo, H. M. Org. Biomol. Chem. 2011, 9, 5039.
(f) Vaddula, B.; Leazer, J.; Varma, R. S. Adv. Synth. Catal.
2012, 354, 986.
(10) (a) Grabtchev, I.; Philipova, T. Dyes Pigments 1994, 27,
321. (b) Bojinov, V.; Konstantinova, T. Dyes Pigments
2002, 54, 239.
(11) Philipova, T. J. Prakt. Chem. 1994, 336, 587.
(12) Wolarz, E.; Moryson, H.; Bauman, D. Displays 1992, 13,
171.
(13) Chang, S. C.; Archer, B. J.; Utecht, R. E.; Lewis, D. E.; Judy,
M. M.; Matthews, J. L. Bioorg. Med. Chem. Lett. 1993, 3,
555.
(14) Qian, X.; Tang, J.; Zhang, J. Dyes Pigments 1994, 25, 109.
(15) (a) Walker, M. A. J. Org. Chem. 1995, 60, 5352. (b) Walker,
M. A. Tetrahedron Lett. 1994, 35, 665. (c) Corrie, J. E. T. J.
Chem. Soc., Perkin Trans. 1 1994, 2975. (d) Mehta, N. B.;
Phillips, A. P.; Lui, F. F.; Brooks, R. E. J. Org. Chem. 1960,
25, 1012. (e) Aubert, T.; Farnier, M.; Guilard, R.
Tetrahedron 1991, 47, 53.
(7) (a) Beringer, F. M.; Galton, S. A. J. Org. Chem. 1963, 28,
3417. (b) Hampton, K. G.; Harris, T. M.; Hauser, C. R.
J. Org. Chem. 1964, 29, 3511. (c) Chen, K.; Koser, G. F.
J. Org. Chem. 1991, 56, 5764. (d) Gao, P.; Portoghese, P. S.
J. Org. Chem. 1995, 60, 2276. (e) Ryan, J. H.; Stang, P. J.
Tetrahedron Lett. 1997, 38, 5061. (f) Iwama, T.; Birman, V.
B.; Kozmin, S. A.; Rawal, V. H. Org. Lett. 1999, 1, 673.
(g) Oh, C. H.; Kim, J. S.; Jung, H. H. J. Org. Chem. 1999,
64, 1338. For recent work, see: (h) Allen, A. E.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2011, 133, 4260. (i) Harvey, J.
S.; Simonovich, S. P.; Jamison, C. R.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2011, 133, 13782. (j) Bigot, A.;
Williamson, A. E.; Gaunt, M. J. J. Am. Chem. Soc. 2011,
133, 13778. (k) Skucas, E.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2012, 134, 9090.
(16) (a) Upadhyay, S. K.; Pingali, S. R. K.; Jursic, B. S.
Tetrahedron Lett. 2010, 51, 2215. (b) Machado, K. E.;
Oliveria, K. N.; Santos-Bubniak, L.; Licinio, M. A.; Nunes,
R. J.; Santos-Silva, M. C. Bioorg. Med. Chem. 2011, 19,
6285. (c) Zhang, Y.; Feng, S. B.; Wang, K.; Yi, X. H.;
Wang, H. S.; Pan, Y. M. Synth. Commun. 2012, 42, 3042.
(d) Cao, H.; Chang, V.; Hernandez, R.; Heagy, M. D. J. Org.
Chem. 2005, 70, 4929.
(17) Chernick, E. T.; Ahrens, M. J.; Scheidt, K. A.; Wasielewski,
M. R. J. Org. Chem. 2005, 70, 1486.
(18) Takács, A.; Ács, P.; Kollár, L. Tetrahedron 2008, 64, 983.
(19) (a) Kim, H. J.; Kim, J.; Cho, S. H.; Chang, S. J. Am. Chem.
Soc. 2011, 133, 16382. (b) Kantak, A. A.; Potavathri, S.;
Barham, R. A.; Romano, K. M.; DeBoef, B. J. Am. Chem.
Soc. 2011, 133, 19960.
(8) (a) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S.
J. Am. Chem. Soc. 2005, 127, 7330. (b) Deprez, N. R.;
Kalyani, D.; Krause, A.; Sanford, M. S. J. Am. Chem. Soc.
2006, 128, 4972. (c) Phipps, R. J.; Grimster, N. P.; Gaunt,
M. J. J. Am. Chem. Soc. 2008, 130, 8172. (d) Deprez, N. R.;
Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 11234.
(e) Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593.
(f) Xiao, B.; Fu, Y.; Xu, J.; Gong, J. J.; Dai, J. Y.; Liu, L.
J. Am. Chem. Soc. 2010, 132, 468. (g) Ciana, C. L.; Phipps,
R. J.; Brandt, J. R.; Meyer, F. M.; Gaunt, M. J. Angew.
Chem. Int. Ed. 2011, 50, 458; Angew. Chem. 2011, 123, 478.
(h) Duong, H. A.; Gilligan, R. E.; Cooke, M. L.; Phipps, R.
J.; Gaunt, M. J. Angew. Chem. Int. Ed. 2011, 50, 463;
Angew. Chem. 2011, 123, 483.
(20) (a) Guo, F. L.; Wang, L. M.; Wang, P. Q.; Yu, J. J.; Han, J.
W. Asian J. Org. Chem. 2012, 1, 218. (b) Guo, F. L.; Han, J.
W.; Mao, S.; Li, J.; Geng, X.; Yu, J. J.; Wang, L. M. RSC
Adv. 2013, 3, 6267.
(21) N-Arylation of Naphthalimides with Diaryliodonium
Salts; General Procedure: A mixture of 1,8-naphthalimide
(0.4 mmol), diaryliodonium salt (0.48 mmol), t-BuOK (2
equiv), CuI (10 mmol%) and toluene (3 mL) was taken in a
10 mL reaction tube and heated at 100 °C for 0.5–2 h under
vigorous stirring. After completion of the reaction, as
indicated by TLC, the reaction mixture was concentrated
under reduced pressure, and the crude compound was
purified by chromatography on a silica gel column (EtOAc–
petroleum ether) to afford the desired product.
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