Copper-promoted C-N bond cross-coupling with phenylstannane

Article abstract of DOI:10.1016/S0040-4039(02)00356-8

Copper-promoted C-N bond cross-coupling of NH-containing substrates with phenylstannane at room temperature was accomplished with the addition of TBAF.

Full text of DOI:10.1016/S0040-4039(02)00356-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3091–3094
Copper-promoted CꢀN bond cross-coupling with phenylstannane
Patrick Y. S. Lam,* Guillaume Vincent, Damien Bonne and Charles G. Clark
Bristol-Myers Squibb Co., Experimental Station, PO Box 80500, Wilmington, DE 19880-0500, USA
Received 28 September 2001; accepted 6 February 2002
Abstract—Copper-promoted CꢀN bond cross-coupling of NH-containing substrates with phenylstannane at room temperature
was accomplished with the addition of TBAF. © 2002 Elsevier Science Ltd. All rights reserved.
Copper-promoted carbonꢀnitrogen (CꢀN) bond cross-
coupling reactions of NH-containing substrates with
organometalloids have emerged as a powerful synthetic
methodology since the initial reports.1 This novel
methodology is an important addition to the general
transition-metal promoted CꢀN bond cross-coupling
reactions1–11 useful for the synthesis of nitrogen-con-
taining compounds in pharmaceuticals, crop-protection
chemicals and material sciences. Many extensions and
applications of this new methodology have been
reported.2–7,10 Recently, this reaction has been rendered
catalytic by Lam,3 Buchwald6 and Collman.7 In addi-
tion to arylboronic acids, the scope of the cupric ace-
hypervalent aryl siloxanes3 and hypervalent diaryliodo-
nium salts.10
The use of aryltrialkylstannanes as coupling partners
could be valuable as a result of their availability, air
and moisture stability and compatibility with a variety
of functional groups. However, previous attempts1a to
use organostannanes gave poor or no yield of the
arylated products. It was hypothesized that the
transmetallation of the aryl group from stannane to
copper was inefficient. It is well known that, like sili-
con, tin is fluorophilic.12 We reasoned that, similarly to
arylsiloxanes,2 the addition of fluoride may form a
hypervalent stannane anion that can accelerate the
transmetallation step. In light of the fact that Stille
tate
(Cu(OAc)2)
methodology
includes
other
organometalloids such as arylbismuth,8 aryllead,9
Table 1. Evaluation of bases
N
NH
1.1 eq Cu(OAc)2 / Base
CH2Cl2 / RT / 48 h
SnMe3
N
+
N
O
O
2 eq
1
3
2
Entry
Base
Isolated yield (%)
1
2
3
4
5
6
7
8
9
TBAF (2 equiv.)
TBAF (2 equiv.)+TEA (2 equiv.)
CsF (2 equiv.)
TASF (2 equiv.)
TEA (2 equiv.)
Cs2CO3 (2 equiv.)
K2CO3 (2 equiv.)
Pyridinium fluoride (2 equiv.)
None
69
58
58
47
14
0
0
0
0
* Corresponding author. E-mail: patrick.lam@bms.com
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00356-8

3092
P. Y. S. Lam et al. / Tetrahedron Letters 43 (2002) 3091–3094
aryl–aryl (CꢀC) bond formation is accelerated with the
addition of fluoride,12 we investigated the effect of
different fluoride species on our CꢀN cross-coupling
reaction with phenylstannane.
stannane 1 (2 equiv.) and benzimidazolinone 2 (Table 1,
entry 1, 69%) in methylene chloride open to air.13 Other
fluoride sources such as CsF (entry 3, 58%) and tris-
(dimethylamino)sulfur (trimethylsilyl)difluoride (TASF,
entry 4, 47%) gave acceptable yields but are less effec-
tive. Other bases such as triethylamine (TEA, entry 5,
14%), Cs2CO3 (entry 6, 0%), K2CO3 (entry 7, 0%) and
pyridinium fluoride (entry 8, 0%) proved to be ineffec-
Indeed, we found that tetrabutylammonium fluoride
(TBAF, 2 equiv.) is a very effective additive for the
room temperature cross-coupling of trimethylphenyl-
Table 2. Evaluation of solvents
N
NH
O
1.1 eq Cu(OAc)2 / 2 eq TBAF
solvent / RT / 48 h
SnMe3
N
O
+
N
2 eq
1
3
2
Entry
Solvent
Isolated yield (%)
1
2
3
CH2Cl2
DMF
1,4-Dioxane
69
58
11
Table 3. CꢀN bond cross-coupling of trimethyl(phenyl)tin and NH-containing substrates

P. Y. S. Lam et al. / Tetrahedron Letters 43 (2002) 3091–3094
3093
tive. The active arylating agent is probably a stan-
nane fluoride anion by the fact that the yields are
very low without fluoride additive (entries 5, 6, 7, 9).
When using arylboronic acids, a base/ligand was
required for the reaction. In the case of hypervalent
stannanes, a base/ligand like TEA did not increase
the yield (entry 3, 58%), similar to our observations
for hypervalent arylsiloxanes.2b A brief screening of
solvents (Table 2) showed that methylene chloride
(entry 1, 69%) and DMF (entry 2, 58%) are preferred
over 1,4-dioxane (entry 3, 11%).
3. Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.;
Jadhav, J. K. Tetrahedron Lett. 2001, 42, 3415–3418.
4. For
a solid-phase version of N-arylation, see: (a)
Combs, A. P.; Tadesse, S.; Rafalski, M.; Lam, P. Y. S.
J. Combinatorial Chem. 2002, 4, 179–182; (b) Combs,
A. P.; Rafalski, M. J. Combinatorial Chem. 2000, 2,
29–32; (c) Combs, A. P.; Saubern, S.; Rafalski, M.;
Lam, P. Y. S. Tetrahedron Lett. 1999, 40, 1623–1626.
5. For S-arylation see: (a) Herradura, P. S.; Pendola, K.
A.; Guy, R. K. Org. Lett. 2000, 2, 2019–2022. For
O-arylation see: (b) Evans, D. A.; Katz, J. L.; Peter-
son, G. S.; Hintermann, T. J. Am. Chem. Soc. 2001,
123, 12411–12413; (c) Simon, J.; Salzbrunn, S.;
Prakash, G. K. S.; Petasis, N. A.; Olah, G. A. J. Org.
Chem. 2001, 66, 633–634; (d) Decicco, C. P.; Song, Y.;
Evans, D. A. Org. Lett. 2001, 3, 1029–1032; (e)
Petrassi, H. M.; Sharpless, K. B.; Kelly, J. W. Org.
Lett. 2001, 3, 139–142; (f) Jung, M. E.; Lazarova, T. I.
J. Org. Chem. 1999, 64, 2976–2977. For N-arylation
see: (g) Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron
Lett. 2000, 41, 9053–9057; (h) Mederski, W. W. K. R.;
Lefort, M.; Germann, M.; Kux, D. Tetrahedron 1999,
55, 12757–12770; (i) Cundy, D. J.; Forsyth, S. A. Tet-
rahedron Lett. 1998, 39, 7979–7982.
A number of other NH-containing substrates can be
arylated at room temperature (Table 3).14 4-tert-Butyl-
aniline (entry 2) 4 gave 80% yield of 5. Picolinamide
6 can be N-phenylated to 7 (entry 3, 72%) assisted by
an a-nitrogen activating effect.2a,15 2-Pyridinone 8
(entry 4, 77%) easily undergoes N-arylation to 9.16
Finally mono- and bis-arylation products 11a and 11b
(entry 5) were obtained from sulfonamide 10 in 48%
yield (5:1). Water does not interfere with the reaction
as the commercial solution of TBAF in THF contains
5% of water. An advantage of this method is that
phenols or biphenyl ethers were never detected as side
products, in contrast to the arylboronic acid cross-
coupling.1
6. Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3,
2077–2079.
7. (a) Collman, J. P.; Zhong, M.; Zheng, L.; Costanzo, S.
J. Org. Chem. 2001, 66, 1528–1531; (b) Collman, J. P.;
Zhong, M.; Zheng, L.; Costanzo, S. J. Org. Chem.
2001, 66, 7892–7897; (c) Collman, J. P.; Zhong, M.
Org. Lett. 2000, 2, 1233–1236.
8. (a) Arnauld, T.; Barton, D. H. R.; Doris, E. Tetra-
hedron 1997, 53, 4137–4144; (b) Fedorov, A. Y.; Finet,
J.-P. Tetrahedron Lett. 1998, 39, 7979–7982.
In summary, we have discovered the copper-promoted
CꢀN bond cross-coupling with hypervalent phenyl-
stannane at room temperature.17 The large number of
arylstannane reagents available commercially makes
this new arylating agent a good complement to aryl-
boronic acids, arylsiloxanes and other organometal-
loids. We continue to explore the scope and
mechanism of this powerful copper-promoted C-het-
eroatom cross-coupling with organometalloids.
9. Lopez-Alvarado, P.; Avendano, C.; Menendez, J. C. J.
Org. Chem. 1995, 60, 5678–5682.
10. Kang, S.-K.; Lee, S.-H.; Lee, D. Synlett 2000, 1022–
1024.
11. (a) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem.
1999, 576, 126–145; (b) Hartwig, J. F. Angew. Chem.,
Int. Ed. 1998, 37, 2046–2067.
Acknowledgements
We thank Dr. Paul S. Anderson and Dr. Ruth R.
Wexler for their support of this research and Dr.
Dominic M. T. Chan and Professor David A. Evans
for helpful discussions.
12. Grasa, G. A.; Nolan, S. P. Org. Lett. 2001, 3, 119–122.
13. Representative procedure for 1-ethyl-3-phenyl-2-benzim-
idazolinone 3: To a 20 mL vial was added in sequence:
3 mL of dry dichloromethane, trimethylphenylstannane
(121 mL, 0.667 mmol, 2.0 equiv.), 1-ethyl-2-benzimida-
zolinone (54 mg, 333 mmol, 1.0 equiv.), cupric acetate
(66.7 mg, 0.367 mmol, 1.1 equiv.) and TBAF (0.67 mL
of 1 M solution in THF, 0.667 mmol, 2.0 equiv.). The
reaction was allowed to stir under air at room tempera-
ture for 48 h. The reaction was quenched with a solu-
tion of 2 mL of NH3 in MeOH (2 M). The solvent was
evaporated under reduced pressure and the residue was
dissolved in 3 mL of dichloromethane and purified by
silica gel chromatography (eluent: 7% methanol/chloro-
form) to give 54.6 mg (69%) of 1-ethyl-3-phenyl-2-benz-
imidazolinone 3. MS (AP) m/z 239.4 (25%) (M+H)+,
477.3 (100%) (2M+H)+; 1H NMR (CDCl3) 7.54–7.49
(m, 4H), 7.39 (t, J=6 Hz, 1H), 7.17–7.03 (m, 4H), 6.96
(q, J=7.3 Hz, 2H), 1.41 (t, J=7.1 Hz) ppm; HRMS
calcd for C15H15N2O (M+H)+ m/e 239.1184, found m/e
239.1196.
References
1. (a) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams,
J.; Averill, K.; Chan, D. M. T.; Combs, A. P. Synlett
2000, 674–676; (b) Lam, P. Y. S.; Clark, C. G.;
Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M.
T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941–2944;
(c) For related O-arylation see: Evans, D. A.; Katz, J.
L.; West, T. R. Tetrahedron Lett. 1998, 39, 2937–2940;
(d) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.;
Winters, M. P. Tetrahedron Lett. 1998, 39, 2933–2936.
2. (a) Lam, P. Y. S.; Deudon, S.; Hauptman, E.; Clark,
C. G. Tetrahedron Lett. 2001, 42, 2427–2429; (b) Lam,
P. Y. S.; Deudon, S.; Kristin, M. A.; Li, R.; He, M.;
DeShong, P.; Clark, C. G. J. Am. Chem. Soc. 2000,
122, 7600–7601.

3094
P. Y. S. Lam et al. / Tetrahedron Letters 43 (2002) 3091–3094
unreacted benzamide recovered after 48 h.
16. For the lactam series under standard conditions the yields
were low: 2-azetidinone (8%), 2-pyrrolidinone (5%), 2-
piperdinone (0%).
17. We have attempted catalytic copper acetate with no
success.
14. In addition to the results in Table 3 arylation of the
following substrates was attempted with results as follows:
4-phenyl-piperidine (31%), indazole (28%), benzimidazole
(20%), isatin (<15%), phthalimide (10%), 3,5-di-tert-butyl-
phenol (0%), oxazolidin-2-one (0%), saccharin (0%).
15. Benzamide can be N-phenylated in 19% yield with 76%