Three-component coupling using arynes and aminosilanes for ortho-selective double functionalization of aromatic skeletons

Article abstract of DOI:10.1021/jo800761b

(Chemical Equation Presented) Arynes were found to couple with aminosilanes and carbonyl compounds in the presence of benzoic acid to provide 2-aminobenzhydrols. Sulfonylimines could also be applied to the reaction, enabling amino and aminomethyl moieties to be incorporated into contiguous positions of aromatic skeletons. Only a small amount of the three-component coupling product was obtained in the absence of benzoic acid, which confirms its vital role in the present reaction.

Full text of DOI:10.1021/jo800761b

Three-Component Coupling Using Arynes and Aminosilanes for
ortho-Selective Double Functionalization of Aromatic Skeletons
Takami Morishita, Hiroyuki Fukushima, Hiroto Yoshida,* Joji Ohshita, and Atsutaka Kunai
Department of Applied Chemistry, Graduate School of Engineering, Hiroshima UniVersity,
Higashi-Hiroshima 739-8527, Japan
yhiroto@hiroshima-u.ac.jp
ReceiVed April 4, 2008
Arynes were found to couple with aminosilanes and carbonyl compounds in the presence of benzoic
acid to provide 2-aminobenzhydrols. Sulfonylimines could also be applied to the reaction, enabling amino
and aminomethyl moieties to be incorporated into contiguous positions of aromatic skeletons. Only a
small amount of the three-component coupling product was obtained in the absence of benzoic acid,
which confirms its vital role in the present reaction.
1. Introduction
component coupling, in which the intramolecular cyclization
is impeded entirely (Scheme 1).5 We report herein new methods
for simultaneous introduction of two functionalities into neigh-
boring positions of aromatic skeletons based upon a three-
component coupling using arynes and aminosilanes.6 By
employing such carbon electrophiles as carbonyl compounds
or sulfonylimines, diverse multisubstituted arenes containing
Synthetic application of arynes to constructing polysubstituted
arenes and/or benzo-annulated cyclic compounds, which are
difficult to obtain by conventional methods, has attracted
considerable attention.1 Among these, multicomponent coupling
reactions would be very beneficial from a synthetic standpoint
for generating molecular complexity and diversity, and we have
already disclosed that iminoisobenzofuran,2a iminoiso-
indoline2b or benzoxazinone2c derivatives can directly be
synthesized based upon the three-component coupling using
arynes. The reaction proceeds through following three steps:
(1) formation of zwitterions resulting from nucleophilic attack
of such unsaturated nucleophiles as isocyanides or imines to
arynes, (2) capture of the resulting zwitterions by electrophiles,3
(3) intramolecular cyclization.4 The third step is triggered by
the unsaturation in the cationic site of intermediate A, and thus
we envisaged that the use of saturated nucleophiles in lieu of
unsaturated ones should result in a different type of three-
(3) Formation of monosubstituted arenes by proton abstraction: (a) Sato, Y.;
Toyooka, T.; Aoyama, T.; Shirai, H. J. Org. Chem. 1976, 41, 3559–3564. (b)
Nakayama, J.; Takeue, S.; Hoshino, M. Tetrahedron Lett. 1984, 25, 2679–2682.
(c) Hayashi, S.; Ishikawa, N. Bull. Chem. Soc. Jpn. 1972, 45, 642–644. (d)
Ramtohul, Y. K.; Chartrand, A. Org. Lett. 2007, 9, 1029–1032. (e) Kolomeitsev,
A. A.; Vorobyev, M.; Gillandt, H. Tetrahedron Lett. 2008, 49, 449-454. For a
review on insertion reactions of arynes into element-element σ-bond, see: Pen˜a,
D.; Pe´rez, D.; Guitia´n, E. Angew. Chem., Int. Ed. 2006, 45, 3578-3581. For
examples, see: (f) Yoshida, H.; Shirakawa, E.; Honda, Y.; Hiyama, T. Angew.
Chem., Int.Ed. 2002, 41, 3247–3249. (g) Liu, Z. J.; Larock, R. C. J. Am. Chem.
Soc. 2005, 127, 13112–13113. (h) Yoshida, H.; Terayama, T.; Ohshita, J.; Kunai,
A. Chem. Commun. 2004, 1980–1981. (i) Yoshida, H.; Minabe, T.; Ohshita, J.;
Kunai, A. Chem. Commun. 2005, 3454–3456. (j) Yoshida, H.; Watanabe, M.;
Ohshita, J.; Kunai, A. Chem. Commun. 2005, 3292–3294. (k) Yoshida, H.;
Watanabe, M.; Ohshita, J.; Kunai, A. Tetrahedron Lett. 2005, 46, 6729–6731.
(l) Yoshida, H.; Watanabe, M.; Morishita, T.; Ohshita, J.; Kunai, A. Chem.
Commun. 2007, 1505–1507. (m) Tamber, U. K.; Stoltz, B. M. J. Am. Chem.
Soc. 2005, 127, 5340–5341. (n) Tamber, U. K.; Ebner, D. C.; Stoltz, B. M.
J. Am. Chem. Soc. 2006, 128, 11752–11753. (o) Yoshida, H.; Watanabe, M.;
Ohshita, J.; Kunai, A. Chem. Lett. 2005, 34, 1538–1539. (p) Yoshida, H.; Mimura,
Y.; Ohshita, J.; Kunai, A. Chem. Commun. 2007, 2405–2407. (q) Beltra´n-Rodil,
S.; Pen˜a, D.; Guitia´n, E. Synlett 2007, 8, 1308–1310. (r) Toledo, F. T.; Margues,
H.; Comasseto, J. V.; Raminelli, C. Tetrahedron Lett. 2007, 48, 8125–8127.
(4) Other three-component couplings using neutral nucleophiles: (a) Yoshida,
H.; Watanabe, M.; Fukushima, H.; Ohshita, J.; Kunai, A. Org. Lett. 2004, 6,
4049–4051. (b) Jeganmohan, M.; Cheng, C.-H. Chem. Commun. 2006, 2454–
2456.
(1) For reviews, see: (a) Biehl, E. R.; Khanapure, S. P. Acc. Chem. Res.
1989, 22, 275–281. (b) Kessar,S. V. In ComprehensiVe Organic Synthesis
Trost,B. M. , Fleming,I. , Semmelhack,M. F. , Eds.; Pergamon: Oxford ,1991;
Vol. 4, pp 483-515. (c) Pellissier, H.; Santelli, M. Tetrahedon 2003, 59, 701–
730. (d) Dyke, A. M.; Hester, A. J.; Lloyd-Jones, G. C. Synthesis 2006, 4093–
4112. For recent examples, see: (e) Hamura, T.; Ibusuki, Y.; Uekusa, H.;
Matsumoto, T.; Siegel, J. S.; Baldridge, K. K.; Suzuki, K. J. Am. Chem. Soc.
2006, 128, 10032–11033. (f) Liu, Z.; Larock, R. C. J. Org. Chem. 2007, 72,
223–232. (g) Gilmore, C. D.; Allan, K. M.; Stoltz, B. M. J. Am. Chem. Soc.
2008, 130, 1558–1559.
(2) Aryne-isocyanide-aldehyde: (a) Yoshida, H.; Fukushima, H.; Ohshita,
J.; Kunai, A. Angew.Chem., Int. Ed. 2004, 43, 3935–3938. Aryne-isocyanide-
imine: (b) Yoshida, H.; Fukushima, H.; Ohshita, J.; Kunai, A. Tetrahedron Lett.
2004, 45, 8659–8662. Aryne-imine-CO2: (c) Yoshida, H.; Fukushima, H.;
Ohshita, J.; Kunai, A. J. Am. Chem. Soc. 2006, 128, 11040–11041. See also: (d)
Yoshida, H.; Fukushima, H.; Morishita, T.; Ohshita, J.; Kunai, A. Tetrahedron
2007, 63, 4793–4805.
(5) (a) Meyers, A. I.; Pansegrau, P. D. Tetrahedron Lett. 1983, 24, 4935–
4938. (b) Meyers, A. I.; Pansegrau, P. D. J Chem. Soc., Chem. Commun. 1985,
690–691. (c) Tripathy, S.; LeBlanc, R.; Durst, T. Org. Lett. 1999, 1, 1973–
1975.
5452 J. Org. Chem. 2008, 73, 5452–5457
10.1021/jo800761b CCC: $40.75 2008 American Chemical Society
Published on Web 06/21/2008

SCHEME 1
SCHEME 2. Three-Component Coupling of Arynes,
Aminosilanes and Aldehydes
SCHEME 3. Three-Component Coupling of Benzyne, 2a
and Ketones
amino and hydroxymethyl (or aminomethyl) moieties can be
synthesized all in one pot.7,8
2. Results and Discussion
2.1. Three-Component Coupling of Arynes, Aminosi-
lanes and Carbonyl Compounds. We previously reported on
a three-component coupling using aldehydes as electrophiles,
which gave 2-aminobenzyl alcohol (or phthalide) derivatives
of structural diversity in a straightforward manner (Scheme 2).9
On the basis of these results, we next conducted the three-
component coupling using other carbonyl compounds (Scheme
3). First we carried out the reaction of benzyne, prepared in
situ from 2-(trimethylsilyl)phenyl triflate (1a)10 and a fluoride
ion (KF/18-Crown-6), with [bis(2-methoxyethyl)amino]trim-
ethylsilane (2a) and acetophenone (3a) in the presence of a
substoichiometric amount of benzoic acid (10 mol %), in THF
at 0 °C, and observed that a three-component coupling product,
1-{2-[bis(2-methoxyethyl)amino]phenyl}-1-phenylethanol (4a),
SCHEME 4. Three-Component Coupling of Benzyne, 2a
and Methyl 8-Formylnaphthoate
was formed in 43% yield. In marked contrast, no trace of the
three-component coupling product was obtained with 2,2,2-
trifluoroacetophenone, regardless of its highly electrophilic
character. The present coupling was also applicable to 2,5-di-
tert-butylbenzoquinone (3b), affording a 47% yield of 4b. In
addition, methyl 8-formylnaphthoate (3c) could also be applied
to the present reaction to provide a 16% yield of (2-aminophe-
nyl)benzo[de]isocoumarin 5a, as were the cases with methyl
2-formylbenzoates (Scheme 4).9
2.2. Three-Component Coupling of Arynes, Aminosi-
lanes and Sulfonylimines. Simultaneous introduction of amino
and aminomethyl moieties into aromatic skeletons could also
be achieved by employing sulfonylimines as electrophiles. Under
reaction conditions similar to those described above, N-
tosylbenzaldimine (6a) was coupled with benzyne and dialky-
laminosilanes (2b-2d, 2g) to give the respective 2-aminoben-
zhydrylamine derivatives (Table 1, entries 2-4, 7), although
the yields were rather lower than those of 2-aminobenzhydrols
(6) The reaction of arynes with primary and secondary amines: (a) Snieckus,
V. Chem. ReV. 1990, 90, 879–933. (b) Wickham, P. P.; Hazen, K. H.; Guo, H.;
Jones, G.; Reuter, K. H.; Scott, W. J. J. Org. Chem. 1991, 56, 2045–2050.
(7) The reaction of benzyne with benzaldehyde was reported to produce
2-(dimethylamino)benzhydrol (12% yield), whose dimethylamino moiety was
derived from a benzyne precursor (1-(2-carboxyphenyl)-3,3-dimethyltriazene).
However, this reaction was not developed as a useful synthetic procedure, because
it required harsh conditions (160 °C) and excess aldehyde (∼39 equiv).
Nakayama, J.; Yoshida, M.; Shimamura, O. Chem. Lett. 1973, 451–454.
(8) Similar products can be synthesized by the direct ortho-lithiation of
anilides followed by reaction with an electrophile, although the highly basic
reaction conditions would limit the use of substrates bearing relatively sensitive
functional groups. (a) Fuhrer, W.; and Gschwend, H. W. J. Org. Chem. 1979,
44, 1133–1136. (b) Muchowski, J. M.; Venuti, M. C. J. Org. Chem. 1980, 45,
4798–4801.
(9) Yoshida, H.; Morishita, T.; Fukushima, H.; Ohshita, J.; Kunai, A. Org.
Lett. 2007, 9, 3367–3370.
(10) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 12, 1211–
1214.
J. Org. Chem. Vol. 73, No. 14, 2008 5453

TABLE 1. Three-Component Coupling of Benzyne, Aminosilanes and Sulfonyliminesa,b
a The reaction was carried out in DME (1 mL) at 80 °C using 1a (0.18 mmol), 2 (0.15 mmol), 6 (0.23 mmol), PhCOOH (0.015 mmol), KF (0.51
mmol) and 18-Crown-6 (0.36 mmol). b Isolated yield based on 2.
(cf. ref 9). Alkoxy-substituted aminosilanes (2a, 2e or 2f)
provided moderate yields of products 7a,7e or 7f (entries 1, 5
and 6), whereas the reaction using cyclic aminosilanes (2h-2j)
resulted in low yield (entries 8-10). In addition, sulfonylimines
bearing an electron-donating (6b) or electron-withdrawing (6c)
substituent at the para position underwent the reaction to give
7k or 7l in 55% or 59% yield, respectively (entries 11 and 12),
and the reaction of 1-naphthyl (6d) or 2-thienylsulfonylimine
(6e) afforded a 51% or 59% yield of the product as well (entries
13 and 14). Steric bulk around the imine carbon of 6f or 6g
inhibited the course of the reaction, leading to lowering the yield
(entries 15 and 16).
Variously substituted 2-aminobenzhydrylamine derivatives
were readily synthesized by the reaction of substituted arynes.
As shown in Table 2, such symmetrical arynes as 4,5-dialkylated
arynes (1b-1d) or 2,3-naphthalyne (1e) reacted with 2a and
6e to afford products 7q-7t in moderate yield (entries 1-4).
Sterically congested arynes (1f and 1g) could also participate
in the reaction, giving 7u or 7v in 56% or 39% yield,
respectively (entries 5 and 6). Furthermore, almost the same
regioselectivities as those with an aldehyde were observed in
the reaction using unsymmetrical arynes: 4-methoxybenzyne
(1h) produced equal amounts of regioisomers (7w and 7′w),
and 7x or 7y was obtained as the major product in the reaction
of 4-fluorobenzyne or 3-methylbenzyne (entries 7-9). Exclusive
formation of 7z, which bears the amino moiety at the meta
position of the methoxy group, was observed in the reaction of
3-methoxybenzyne (entry 10).
2.3. Reaction Pathway. We next investigated the reaction
pathway as depicted in Scheme 5. In the absence of benzoic
acid, the reaction of benzyne, 2a and benzaldehyde gave only
aminosilylated product 811 in place of the three-component
coupling product (9) (eq 1), and a similar reaction using
sulfonylimine 6a afforded a small amount of 7a (eq 2).
5454 J. Org. Chem. Vol. 73, No. 14, 2008

TABLE 2. Three-Component Coupling of Arynes, 2a and 6ea,b,c,d,e
a The reaction was carried out in DME (1 mL) at 80 °C using 1 (0.18 mmol), 2a (0.15 mmol), 6e (0.23 mmol), PhCOOH (0.015 mmol), KF (0.51
mmol) and 18-Crown-6 (0.36 mmol). b Isolated yield based on 2a. c 7w:7′w ) 1:1. d 7x:7′x ) 63:37. e 7y:7′y ) 62:38.
J. Org. Chem. Vol. 73, No. 14, 2008 5455

SCHEME 5. Mechanistic Studies
SCHEME 6. Plausible Pathway
Moreover, 9 was not formed at all in the reaction of benzal-
dehyde with 8 (eq 3), showing that the aminosilylated product
is not an intermediate in the three-component coupling. In
marked contrast to the cases of an aminosilane (eqs 1 and 2),
treatment of an amine (10a) with benzyne and 6a was found to
produce 7a without added benzoic acid (eq 4).12
These results prompted us to propose a plausible reaction
pathway, where in situ generated amine 10 (from aminosilane
2and benzoic acid)13 serves as an actual nucleophile to afford
zwitterion 11 through action with an aryne (Scheme 6).
Subsequent nucleophilic coupling of 11 with an electrophile
(carbonyl compound 3 or sulfonylimine 6),14 furnished 4 or 7,
which then reacts with 2 to give silylether 12 or silylamine 13
(11) The TMS group in aminosilylated product 8 was demonstrated to derive
not from 1 but from 2a. See ref 3i.
(12) A large amount of N,N-diethylaniline was formed as a byproduct in
this reaction, which demonstrates an advantage of the use of aminosilanes in
the three-component coupling. The existence of only a catalytic amount of amines,
generated from aminosilanes and benzoic acid, in the reaction mixture would
decrease aniline derivatives. For N-arylation of amines by the use of arynes,
see: (a) Liu, Z.; Larock, R. C. Org. Lett. 2003, 5, 4673–4675. (b) Liu, Z.; Larock,
R. C. J. Org. Chem. 2006, 71, 3198–3209.
with regeneration of amine 10.15 The resulting silylether (or
silylamine) would be transformed into 4 (or 7) via the workup
process.16
Owing to a strong electron-withdrawing inductive effect of
fluoro substituent, the negative charge at the meta position of
the fluoro moiety in the transition state would be stabilized for
the addition of amine to 4-fluorobenzyne, which results in the
preferential formation of 7x (Scheme 7).17 In contrast, a methoxy
substituent in 4-methoxybenzyne exerts little effect on the
(13) An amine and a silyl carboxylate are readily formed in the reaction of
an aminosilane and a carboxylic acid: (a) Wissner, A. Tetrahedron Lett. 1978,
19, 2749–2752. (b) Ruhlmann, K. Chem. Ber. 1961, 94, 1876–1878.
(14) A reviewer pointed out that there may be an attractive hydrogen bonding
between the amine H in 11 and an electrophile, which enhances the electrophi-
licity of 3 or 6.
(15) Various alcohols are readily transformed into the respective silyl ethers
via action with aminosilanes: (a) Shirini, F.; Mollarazi, E. Synth. Commun. 2006,
36, 1109–1115. (b) Gautret, P.; El-Ghammarti, S.; Legrand, A.; Couturier, D.;
Rigo, B. Synth. Commun. 1996, 26, 707–717.
(16) Because there was an excess of fluoride in the reaction mixture, three-
component coupling products would exist as silicates, amides or alkoxides before
a workup process. Therefore, we could only detect trace amounts of silyl ether
12 or silylamine 13 in crude products. For protodesilylation of silyl ethers with
a fluoride ion, see: Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999; Chapter 2, pp 113-
148.
(17) Preferential nucleophilic attack at a para position of a chlorine atom
also occurred in electrophilic coupling reactions of 4-chlorobenzyne: (a) Bunnett,
J. F.; Pyun, C. J. Org. Chem. 1969, 34, 2035–2037. (b) Bunnett, J. F.; Kim,
J. K. J. Am. Chem. Soc. 1973, 95, 2254–2259.
5456 J. Org. Chem. Vol. 73, No. 14, 2008

SCHEME 7. Regioselectivities in the Nucleophilic Addition
of Amine
(1 mL) of an aryne precursor (0.18 mmol), an aminosilane (0.15
mmol), a carbonyl compound (0.23 mmol), benzoic acid (1.8 mg,
0.015 mmol) and 18-crown-6 (0.095 g, 0.36 mmol), KF (0.030 g,
0.51 mmol) was added, and the resulting mixture was stirred at 0
°C for the period as specified in Schemes 3 and 4. The mixture
was diluted with ethyl acetate, filtered through a Celite plug, and
concentrated. After a hexane (or toluene) solution (5 mL) of the
residue was treated with aluminum oxide (2.5 g) containing a 75
µL of water at room temperature overnight,18 the resulting mixture
was filtered through a Celite plug. Evaporation of the solvent
followed by silica-gel column chromatography (dichloromethane/
ethyl acetate as an eluent) gave the corresponding product.
1-{2-[Bis(2-methoxyethyl)amino]phenyl}-1-phenylethanol (4a).
1
Isolated in 43% yield as a colorless oil: H NMR (CDCl3) δ 1.82
(s, 3 H), 2.28-2.48 (m, 2 H), 2.77-2.86 (m, 1 H), 2.92-3.01 (m,
1 H), 3.07 (s, 3 H), 3.18-3.46 (m, 7 H), 7.09-7.17 (m, 1 H),
7.18-7.39 (m, 7 H), 7.54 (d, J ) 7.7 Hz, 1 H), 8.14 (s, 1 H);13C
NMR (CDCl3) δ 32.5, 55.0, 55.4, 58.4, 58.8, 69.5, 69.8, 70.5, 125.2,
125.5, 125.7, 126.1, 127.8, 127.9, 128.1, 143.7, 149.3, 150.8; HRMS
Calcd for C20H27NO3: M+, 329.1991. Found: m/z 329.1989.
Three-Component Coupling of Arynes, Aminosilanes, and
Sulfonylimines: A General Procedure. To a DME solution (1
mL) of an aryne precursor (0.18 mmol), an aminosilane (0.15
mmol), a sulfonylimine (0.23 mmol), benzoic acid (1.8 mg, 0.015
mmol), 18-crown-6 (0.095 g, 0.36 mmol), and KF (0.030 g, 0.51
mmol) was added, and the resulting mixture was stirred at 80 °C
for the period as specified in Tables 1 and 2. The mixture was
diluted with ethyl acetate, filtered through a Celite plug, and
concentrated. Silica-gel column chromatography (hexane/ethyl
acetate as an eluent) followed by gel permeation chromatography
gave the corresponding product.
regioselectivity of the nucleophilic attack, resulting in equal
formation of two regioisomers. Exclusive production of 7z in
the reaction of 3-methoxybenzyne can be attributed to an
electron-withdrawing inductive effect of a methoxy moiety
together with a steric repulsion between the methoxy moiety
and an incoming nucleophile, both of which direct the nucleo-
philic attack toward the meta position of the methoxy moiety.
In the case of 3-methylbenzyne, the steric effect would be in
conflict with an electron-donating inductive effect which favors
the generation of the anion at the meta position, and a mixture
of regioisomers is yielded.
N-p-Tosyl-2-[bis(2-methoxyethyl)amino)benzhydrylamine (7a).
1
Isolated in 56% yield as a white solid: mp 77-78 °C; H NMR
(CDCl3) δ 2.30 (s, 3H), 2.45-2.57 (m, 2 H), 2.75-2.90 (m, 2 H),
2.97-3.14 (m, 4 H), 3.27 (s, 6 H), 5.62 (d, J ) 8.9 Hz, 1 H),
6.95-7.30 (m, 11 H), 7.55 (d, J ) 8.2 Hz, 2 H), 8.15 (d, J ) 8.9
Hz, 1 H); 13C NMR (CDCl3) δ 21.26, 21.31, 21.36, 21.41, 54.3,
58.49, 58.52, 60.1, 60.6, 60.7, 61.2, 70.1, 125.0, 126.2, 126.4, 126.5,
126.9, 128.0, 128.5, 128.8, 137.6, 138.5, 142.0, 142.1, 150.0; Anal.
Calcd for C26H32N2O4S: C, 66.64; H, 6.88; N, 5.98. Found: C,
66.58; H, 7.16; N, 5.82.
Acknowledgment. This work was financially supported by
Grants-in-Aid for Young Scientist (B) (19750080) from the
Ministry of Education, Culture, Sports, Science, and Technol-
ogy, Japan. We thank Dr. Yoshiaki Nakao, Prof. Tamejiro
Hiyama (Kyoto University) for measurement of HRMS, and
also the Central Glass Co Ltd. for a generous gift of trifluo-
romethanesulfonic anhydride.
3. Conclusion
We have developed a convenient and general method for
introducing nitrogen and carbon functional groups into adjacent
positions of aromatic rings. The ortho-selective double func-
tionalization procedure enables 2-aminobenzhydrols or 2-ami-
nobenzhydrylamines, which are hardly accessible by conven-
tional methods, to be assembled straightforwardly and, thus,
would have high synthetic significance.
Supporting Information Available: Experimental procedure
and characterization of products. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO800761B
Experimental Section
Three-Component Coupling of Arynes, Aminosilanes, and
Carbonyl Compounds: A General Procedure. To a THF solution
(18) Feixas, J.; Capdevila, A.; Guerero, A. Tetrahedron 1994, 50, 8539–
8550.
J. Org. Chem. Vol. 73, No. 14, 2008 5457