Addition of Alkyl and Aryl Isocyanides to Benzyne

Full text of DOI:10.1021/jo980929q

6742
J . Org. Chem. 1998, 63, 6742-6744
Ad d ition of Alk yl a n d Ar yl Isocya n id es to
Ben zyn e
F igu r e 1. Reactivity relationships between isocyanates and
isocyanides.
J ames H. Rigby* and Ste´phane Laurent
Department of Chemistry, Wayne State University,
Detroit, Michigan 48202-3489
Ta ble 1. Ad d ition of Isocya n id es to Ben zyn e
Received May 18, 1998
Isocyanates are known to react with a wide range of
nucleophilic partners to effect a net installation of a
carbamoyl moiety.1 In contrast to the electrophilic nature
of the isocyanate function, the well-known nucleophilicity
of isocyanides suggests that this group could serve as an
umpoled version of the former species when reacted
under certain circumstances with appropriate electro-
philes (Figure 1).
We have previously reported that alkyl isocyanides can
combine with vinyl isocyanates to afford highly function-
alized hydroindolone products2 and that vinyl isocyanates
can also participate in a [4 + 2] cycloaddition with
benzyne to provide phenanthridone adducts.3 We now
disclose the results of a study in which alkyl and aryl
isocyanides have been found to react with benzynes with
reasonable efficiency.4
a
b
Trapping with H2O. Trapping with isoamyl alcohol.
ester, which was obtained as a single isomer of undeter-
mined geometry (eq 2).
Treatment of anthranilic acid with excess cyclohexyl
isocyanide5 in the presence of tert-butyl nitrite and water
in refluxing 1,2-dichloroethane/dioxane afforded benza-
mide 16 in a serviceable 58% yield (eq 1). The transfor-
mation presumably proceeds via addition of the nucleo-
philic isocyanide to the electrophilic benzyne to afford a
zwitterionic intermediate 2 that is rapidly protonated by
the water present in the reaction mixture. The resultant
N-alkylnitrilium ion is then trapped with additional
water to provide the observed amide product.7 Alterna-
tively, the nitrilium ion can be intercepted with isoamyl
alcohol to afford the corresponding N-substituted imidate
Several other examples of these addition reactions that
reveal some of the characteristics of the process are
compiled in Table 1. The reaction can easily be extended
to employ aryl isocyanides as the nucleophile without
compromising chemical efficiency. The addition de-
scribed in entry 3 once again produces a single geometric
isomer of undetermined structure, paralleling the obser-
vation depicted in eq 2. A particularly noteworthy result
is presented in entry 4, in which an 8.6:1 ratio of para-
addition to meta-addition products were obtained. Nor-
mally, 4-substituted benzynes exhibit little regioselec-
tivity in their additions with reactive nucleophiles;
however, less reactive addends can frequently exhibit
substantial para/meta ratios due, presumably, to the
involvement of a transition state in which substantial
charge has already been transferred to the arene ring.
Consequently, these reactions can be more sensitive to
substituent effects than is typical of this series,8 and thus,
(1) Richter, R.; Ulrich, H. In The Chemistry of Cyanates and Their
Thio Derivatives; Patai, S., Ed.; Wiley: Chichester, 1977; Part 2, pp
619-792.
(2) Rigby, J . H.; Qabar, M. J . Am. Chem. Soc. 1991, 113, 8975.
(3) Rigby, J . H.; Holsworth, D. D.; J ames, K. J . Org. Chem. 1989,
54, 4019.
(4) One low-yielding example of this reaction has been reported
previously: Knorr, R. Chem. Ber. 1965, 98, 4014.
(5) Ugi, I.; Meyr, R.; Lipinski, M.; Bodesheim, F.; Rosendahl, F. Org.
Synth. 1973, 5, 300.
(6) Choudary, B. M.; Prasad, A. D.; Bhuma, V.; Swapna, V. J . Org.
Chem. 1992, 57, 5841.
(7) Fry, J . L.; Ott, R. A. J . Org. Chem. 1981, 46, 3333.
(8) Bunnett, J . F.; Kim, J . K. J . Am. Chem. Soc. 1973, 95, 2254.
S0022-3263(98)00929-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/25/1998

Notes
J . Org. Chem., Vol. 63, No. 19, 1998 6743
3,4-Dim et h oxy-N-cycloh exylb en za m id e. 2-Amino-4,5-
dimethoxybenzoic acid (197 mg) gave 3,4-dimethoxy-N-cyclo-
hexylbenzamide (161 mg, 61%) as a white solid after column
chromatography (4:1 hexane/ethyl acetate): mp ) 169 °C
(EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.40 (s, 1H), 7.23 (d, J )
8.5 Hz, 1H), 6.83 (d, J ) 8.5 Hz, 1H), 5.97 (br d, J ) 7 Hz, 1H),
3.92 (s, 4H), 3.90 (s, 3H), 2.00-2.02 (m, 2H), 1.73-1.75 (m, 2H),
1.63-1.66 (m, 1H), 1.37-1.45 (m, 2H), 1.17-1.25 (m, 3H); 13C
NMR (125 MHz, CDCl3) δ 166.2, 151.5, 148.9, 127.7, 119.0, 110.6,
the selectivity seen in entry 4 may be reflective of the
relatively mild nucleophilicity of the isocyanide species.
110.1, 56.0, 48.7, 33.3, 25.6, 25.0; IR (CHCl3) ν 2395, 1625 cm-1
;
MS m/e 263 (M+, 35), 181 (90), 165 (100); mass calcd for C15H21
-
NO3 263.1521, found 263.1526.
Gen er a l P r oced u r e for th e Rea ction of Ar yl Isocya n id es
w ith Ben zyn es. To a gently refluxing solution of the required
aryl isocyanide (8.00 mmol) and H2O (36 mg, 2.00 mmol) in 1,2-
dichloroethane (10 mL) was added simultaneously a solution of
isoamyl nitrite (176 mg, 1.5 mmol) in dioxane and a solution of
the desired anthranilic acid (1.00 mmol) in dioxane (2 mL) via
two addition funnels over a period of 1.5 h. When the addition
was completed, the reaction mixture was refluxed for 30 min,
at which time the solution was cooled to room temperature.
Water (20 mL) was then added, and the aqueous phase was
extracted with CH2Cl2 (3 × 20 mL). The organic extract was
washed with brine and dried over anhydrous MgSO4. The
solvent was removed under reduced pressure, and the residue
was purified by column chromatography to afford the product.
N-(2-Br om op h en yl)ben za m id e. Anthranilic acid (137 mg)
and 2-bromophenyl isocyanide (1.45 g) gave N-(2-bromophenyl)-
benzamide (127 mg, 46%) as a pale yellow solid after column
chromatography (20:1 hexanes/ethyl acetate): mp 115 °C (etha-
nol) (lit.14 mp 116 °C); 1H NMR (500 MHz, CDCl3) δ 8.56 (dd, J
) 1.5, 8.5 Hz, 1H), 8.47 (br s, 1H), 7.94 (d, J ) 7 Hz, 2H), 7.59
(t, J ) 7 Hz, 2H), 7.52 (t, J ) 8 Hz, 2H), 7.38 (dd, J ) 1, 7.5 Hz,
1H), 7.02 (dd, J ) 1, 8.5 Hz, 1H).
Postaddition manipulations of these adducts are pos-
sible when they are appropriately functionalized. For
example, the addition products derived from ortho-
functionalized aryl isocyanide nucleophiles (entries 1 and
6) are amenable to cyclization to afford phenanthridone
products. Equations 3 and 4 depict a palladium(0)-
mediated cyclization process9 to provide the phenanthri-
dones 510 and 711 in useful yields.
In summary, it has been demonstrated that isocyanides
can behave as charge-reversed equivalents to isocyanates
in reactions with benzyne electrophiles. Further exploi-
tation of this reactivity pattern with other electrophile
partners will be reported in due time.
N-(2-Br om op h en yl)-3,4-d im eth oxyben za m id e. 2-Amino-
4,5-dimethoxybenzoic acid (197 mg) and 2-bromophenyl isocya-
nide (1.45 g) gave N-(2-bromophenyl)-3,4-dimethoxybenzamide
(121 mg, 36%) as a yellow solid after column chromatography
(4:1 hexanes/ethyl acetate): mp 149-151 °C (ethanol) (lit.15 mp
Exp er im en ta l Section 12
Gen er a l P r oced u r e for th e Rea ction of Cycloh exyl
Isocya n id e w ith Ben zyn es. To a gently refluxing solution of
cyclohexyl isocyanide (873 mg, 8.00 mmol), tert-butyl nitrite (124
mg, 1.20 mmol), and H2O (36 mg, 2.00 mmol) in 1,2-dichloroet-
hane (10 mL) was added a solution of the required anthranilic
acid (1.00 mmol) dissolved in dioxane (2 mL) over a period of
1.5 h. When the addition was completed, the reaction mixture
was refluxed for 30 min, at which time the solution was cooled
to room temperature. Water (20 mL) was then added, and the
aqueous phase was extracted with CH2Cl2 (3 × 20 mL). The
organic extract was washed with brine and dried over anhydrous
MgSO4. The solvent was removed under reduced pressure, and
the residue was purified by column chromatography to afford
the product.
1
148.5-150 °C); H NMR (500 MHz, CDCl3) δ 8.54 (dd, J ) 1.5,
8.5 Hz, 1H), 8.43 (br s, 1H), 7.58 (dd, J ) 1.5, 8 Hz, 1H), 7.54 (d,
J ) 1.5 Hz, 1H), 7.48 (dd, J ) 2, 8 Hz, 1H), 7.37 (t, J ) 8.5 Hz,
1H), 7.01 (dd, J ) 1.5, 8 Hz, 1H), 6.95 (d, J ) 8.5 Hz, 1H), 3.98
(s, 3H), 3.96 (s, 3H).
N-(4-Meth oxyp h en yl)ben za m id e. Anthranilic acid (137
mg) and 4-methoxyphenyl isocyanide (1.06 g) gave N-(4-meth-
oxyphenyl)benzamide (109 mg, 48%) as a yellow solid after
column chromatography (4:1 hexanes/ethyl acetate): mp 156 °C
(benzene) (lit.16 mp 153 °C from iPr2O); 1H NMR (500 MHz,
CDCl3) δ 7.85 (d, J ) 7.5 Hz, 3H), 7.44-7.54 (m, 5H), 6.89 (d, J
) 9 Hz, 2H), 3.80 (s, 3H).
Gen er a l P r oced u r e for th e Syn th esis of Ar yl Isocya -
n id es.17 The required formanilide (50 mmol) was dissolved in
diisopropylamine (13.7 g, 135 mmol) and CH2Cl2 (50 mL). The
mixture was cooled to 0 °C, and POCl3 (8.4 g, 55 mmol) was
added dropwise. Stirring was continued at 0 °C for 1 h, after
which time sodium carbonate (10 g) in water (50 mL) was added
at a rate so that the temperature was maintained at 25-30 °C.
The mixture was stirred for 1 h at room temperature, and then
more water (50 mL) and CH2Cl2 (25 mL) were added. The
organic layer was washed with water (3 × 25 mL), dried over
anhydrous MgSO4, and evaporated under reduced pressure to
afford the crude product, which was then purified by distillation
or recrystallization.
N-Cycloh exylben za m id e. Anthranilic acid (137 mg) gave
N-cyclohexylbenzamide (118 mg, 58%) as a white solid after
column chromatography (10:1 hexane/ethyl acetate): mp 144-
1
6 °C (lit.6 mp 144-145 °C); H NMR (500 MHz, CDCl3) δ 7.74
(d, J ) 7 Hz, 2H), 7.46-7.49 (m, 1H), 7.41 (t, J ) 8 Hz, 2H),
5.97 (br s, 1H), 3.96-3.99 (m, 1H), 2.02-2.05 (m, 2H), 1.73-
1.77 (m, 2H), 1.19-1.65 (m, 6H).
4-Ch lor o-N-cycloh exylben za m id e. 2-Amino-4-chloroben-
zoic acid (171 mg) gave 4-chloro-N-cyclohexylbenzamide (121 mg,
51%) as a white solid after column chromatography (10:1
hexanes/ethyl acetate): mp 184-5 °C (benzene) (lit.13 mp 184
°C); 1H NMR (500 MHz, CDCl3) δ 7.68 (d, J ) 8.5 Hz, 2H), 7.38
(d, J ) 8.5 Hz, 2H), 5.98 (br s, 1H), 3.93-3.96 (m, 1H), 2.00-
2.03 (m, 2H), 1.64-1.76 (m, 3H), 1.37-1.45 (m, 2H), 1.18-1.26
(m, 3H).
2-Br om op h en yl Isocya n id e. N-(2-Bromophenyl)forma-
mide (10 g) gave 2-bromophenyl isocyanide (4.16 g, 45%) as white
needles after recrystallization (hexanes): mp 41 °C; 1H NMR
(500 MHz, CDCl3) δ 7.66 (d, J ) 8 Hz, 1H), 7.44 (d, J ) 8 Hz,
1H), 7.35 (t, J ) 8 Hz, 1H), 7.27 (t, J ) 8 Hz, 1H); 13C NMR
(9) Ames, D. E.; Opalko, A. Tetrahedron 1984, 40, 1919.
(10) Yang, N. C.; Shani, A.; Lenz, G. R. J . Am. Chem. Soc. 1966,
88, 5369.
(11) Narasimhan, N. S.; Chandrachood, P. S. Tetrahedron 1981, 37,
825.
(12) For general experimental details, see: Rigby, J . H.; Qabar, M.;
Ahmed, G.; Hughes, R. C. Tetrahedron 1993, 49, 10219.
(13) Ono, M.; Araya, I.; Todoriki, R.; Tamura, S. Chem. Pharm. Bull.
1990, 38, 1824.
(14) Bunnett, J . F. Hrutfiord, B. F. J . Am. Chem. Soc. 1961, 83,
1691.
(15) Kasum, B.; Prager, R. H. Aust. J . Chem. 1983, 36, 1455.
(16) Pocar, D.; Roversi, E.; Trimarco, P.; Valgattarri, G. J ustus
Liebigs Ann. Chem. 1995, 487.
(17) Obrecht, R.; Herrmann, R.; Ugi, I. Synthesis 1985, 400.

6744 J . Org. Chem., Vol. 63, No. 19, 1998
Notes
(125 MHz, CDCl3) δ 168.4, 133.3, 130.4, 128.2, 128.1, 119.9; IR
2H), 1.86 (m, 1H), 1.72 (q, J ) 7.2 Hz, 2H), 1.00 (d, J ) 7 Hz,
6H); 13C NMR (75 MHz, CDCl3) δ 148.6, 131.6, 129.7, 129.3,
128.8, 127.8, 122.4, 121.7, 65.2, 37.6, 25.3, 22.6; IR (neat) ν 2950,
1647, 1590, 1259, 1104, 682 cm-1; MS m/e 267 (M+, 3), 105 (100);
mass calcd for C18H21NO 267.1623, found 267.1618.
(CH2Cl2) ν 2138 cm-1
.
4-Meth oxyp h en yl Isocya n id e. N-(4-Methoxyphenyl)for-
mamide (7.55 g) gave 4-methoxyphenyl isocyanide (4.10 g, 62%)
as a pale yellow oil after distillation: bp 76 °C/1 mmHg.
Analytical data were identical to those reported in the litera-
ture.18
P h en yl Isocya n id e. Formanilide (6.05 g) gave phenyl
isocyanide (2.60 g, 50%) as a yellow oil after distillation: bp 62
°C/16 mmHg (lit.19 bp 50-51 °C/11 mmHg).
6(5H)-P h en a n th r id in on e. N-(2-Bromophenyl)benzamide
(50 mg, 0.18 mmol), palladium(II) acetate (4 mg, 0.018 mmol),
and anhydrous sodium carbonate (23 mg, 0.21 mmol) in N,N-
dimethylacetamide (2 mL) were heated together at 160 °C for
2.5 h. The resultant mixture was cooled to room temperature,
poured into water (5 mL), and extracted with EtOAc (3 × 5 mL).
The organic extract was dried over anhydrous MgSO4 and
evaporated under reduced pressure. Column chromatography
of the crude product (4:1 hexanes/ethyl acetate) gave a white
solid (18 mg, 50%): mp 289 °C (lit.10 mp 291-292 °C); 1H NMR
(500 MHz, DMSO-d6) δ 11.67 (br s, 1H), 8.49 (d, J ) 8 Hz, 1H),
8.37 (d, J ) 8 Hz, 1H), 8.30 (dd, J ) 1 Hz, J ) 8 Hz, 1H), 7.84
(dt, J ) 1, 8.5 Hz, 1H), 7.63 (t, J ) 7.5 Hz, 1H), 7.47 (dt, J ) 1,
8 Hz, 1H), 7.35 (d, J ) 7.5 Hz, 1H), 7.25 (dt, J ) 1, 8 Hz, 1H).
8,9-Dim eth oxy-5H-p h en a n th r id in -6-on e. N-(2-Bromophe-
nyl)-3,4-dimethoxybenzamide (41 mg, 0.122 mmol), palladium-
(II) acetate (5.4 mg, 0.024 mmol), and anhydrous sodium
carbonate (15 mg, 0.146 mmol) in N,N-dimethylacetamide (2 mL)
were heated at 160 °C for 2.5 h. The mixture was cooled to room
temperature, poured into water (5 mL), and extracted with
EtOAc (3 × 5 mL). The organic extract was dried over
anhydrous MgSO4 and evaporated under reduced pressure.
Column chromatography of the crude product (4:1 hexanes/ethyl
acetate) gave a pale yellow solid (12 mg, 39%): mp 296 °C
(ethanol) (lit.11 mp 296 °C); 1H NMR (500 MHz, DMSO-d6) δ
11.58 (br s, 1H), 8.37 (d, J ) 8 Hz, 1H), 7.86 (s, 1H), 7.67 (s,
1H), 7.41 (t, J ) 7.5 Hz, 1H), 7.31 (d, J ) 8 Hz, 1H), 7.22 (t, J
) 7.5 Hz, 1H), 4.00 (s, 3H), 3.88 (s, 3H).
Gen er a l P r oced u r e for th e Syn th esis of Im id a te Ester s.
To a gently refluxing solution of the required isocyanide (8.00
mmol), isoamyl nitrite (141 mg, 1.20 mmol), and isoamyl alcohol
(264 mg, 3.00 mmol) in 1,2-dichloroethane (10 mL) was added a
solution of anthranilic acid (137 mg, 1.00 mmol) in dioxane (2
mL) over a period of 1.5 h. When the addition was completed,
the reaction mixture was refluxed for 30 min, after which time
the solution was cooled to room temperature. The solvent was
removed under reduced pressure, and the residue was placed
under high vacuum (0.1 mmHg) for 45 min at 35 °C to remove
the bulk of unreacted isocyanide. The product was obtained by
filtration through a plug of silica gel (10:1 hexanes/ethyl acetate/
1% Et3N).
Isop en tyl N-Cycloh exylben zim id a te. Cyclohexyl isocya-
nide (873 mg) gave the product (118 mg, 43%) as a colorless oil:
1H NMR (300 MHz, CDCl3) δ 7.28-7.41 (m, 5H), 4.20 (t, J )
6.6 Hz, 2H), 3.1-3.2 (m, 1H), 1.18-1.80 (m, 13H), 0.95 (d, J )
6.9 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 159.1, 133.4, 128.9,
128.2, 127.6, 63.6, 57.6, 37.7, 35.0, 25.7, 25.2, 24.5, 22.7; IR (neat)
ν 2921, 2844, 1661, 1442, 1259, 1111, 1076 cm-1; MS m/e 273
(M+, 3), 105 (100); mass calcd for C18H27NO 273.2092, found
273.2088.
Isop en tyl N-P h en ylben zim id a te. Phenyl isocyanide (824
mg) gave the product (94 mg, 35%) as a greenish oil: 1H NMR
(300 MHz, CDCl3) δ 7.14-7.32 (m, 7H), 6.45 (tt, J ) 1.2 Hz, J
) 7.5 Hz, 1H), 6.72 (dd, J ) 1.2, 8.4 Hz, 2H), 4.38 (t, J ) 7.2 Hz,
Ack n ow led gm en t. The authors wish to thank the
National Science Foundation for their generous support
of this research.
(18) Casanova, J ., J r.; Werner, N. D.; Schuster, R. E. J . Org. Chem.
1966, 31, 3473.
(19) Ugi, I.; Fetzer, U.; Eholzer, U.; Knupfer, H.; Offermann, K.
Angew. Chem., Int. Ed. Engl. 1965, 4, 472.
J O980929Q