4-trifluoromethylaniline, which cannot be stored for long periods of time. Unfortunately, torcetrapib was dropped during the late stages of development.
5 Conclusion
The field of Pd-catalyzed N-arylation reactions has expanded rapidly since the early
studies of Migita, Boger, Buchwald, and Hartwig. Advances in catalyst design have
led to significantly improved scope, utility, and applicability of these transformations
to numerous areas of chemistry. It is likely that continued research in this area will lead
to further enhancement of catalyst activity, expansion of generality, and continued
applications to important problems in synthetic chemistry.
References
1. Bolinger JD, Lindsley CW (2007) Curr Top Med Chem 7:1643
2. Weber J, Lyseng-Williamson KA, Scott LJ (2008) CNS Drugs 22:807–813
3. Frampton JE, Keating GM (2007) Drugs 67:2433–2472
4. Hartwig JF (1997) Synlett 329–340
5. Wolfe JP, Wagaw S, Marcoux J-F, Buchwald SL (1998) Acc Chem Res 31:805–818
6. Hartwig JF (1998) Angew Chem Int Ed 37:2046–2067
7. Yang BH, Buchwald SL (1999) J Organomet Chem 576:125–146
8. Hartwig JF (2002) Palladium-catalyzed amination of aryl halides and related reactions. In:
Negishi E-I (ed) Handbook of organopalladium chemistry for organic synthesis, vol 1. Wiley,
New York
9. Muci AR, Buchwald SL (2002) Top Curr Chem 219:131–209
10. Hartwig JF (2006) Synlett 1283–1294
11. Schlummer B, Scholz U (2004) Adv Synth Catal 346:1599–1626
12. Surry DS, Buchwald SL (2008) Angew Chem Int Ed 47:6338–6361
13. Hartwig JF (2008) Acc Chem Res 41:1534–1544
14. Janey JM (2007) Buchwald-Hartwig amination. In: Li JJ (ed) Name reactions for functional
group transformations. Wiley, Hoboken
15. Hartwig JF (2008) Nature 455:314–322
CN
NH 2
CF 3
Cl
+
1. Pd(OAc) 2 (0.8 mol %)
DavePhos (1.1 mol %)
PhB(OH) 2 (1.5 mol %)
Cs 2 CO 3 , toluene, 80 ºC
F 3 C
N
H
O
NH 2
Et
75–79%
N
F 3 C
O
Et
N
MeO
O
CF 3
CF 3
Torcetrapib
2. H 2 SO 4 , H 2 O
Scheme 13 Large-Scale Synthesis of Torcetrapib via Pd-Catalyzed N-Arylation
42
G.S. Lemen and J.P. Wolfe
5 Conclusion
The field of Pd-catalyzed N-arylation reactions has expanded rapidly since the early
studies of Migita, Boger, Buchwald, and Hartwig. Advances in catalyst design have
led to significantly improved scope, utility, and applicability of these transformations
to numerous areas of chemistry. It is likely that continued research in this area will lead
to further enhancement of catalyst activity, expansion of generality, and continued
applications to important problems in synthetic chemistry.
References
1. Bolinger JD, Lindsley CW (2007) Curr Top Med Chem 7:1643
2. Weber J, Lyseng-Williamson KA, Scott LJ (2008) CNS Drugs 22:807–813
3. Frampton JE, Keating GM (2007) Drugs 67:2433–2472
4. Hartwig JF (1997) Synlett 329–340
5. Wolfe JP, Wagaw S, Marcoux J-F, Buchwald SL (1998) Acc Chem Res 31:805–818
6. Hartwig JF (1998) Angew Chem Int Ed 37:2046–2067
7. Yang BH, Buchwald SL (1999) J Organomet Chem 576:125–146
8. Hartwig JF (2002) Palladium-catalyzed amination of aryl halides and related reactions. In:
Negishi E-I (ed) Handbook of organopalladium chemistry for organic synthesis, vol 1. Wiley,
New York
9. Muci AR, Buchwald SL (2002) Top Curr Chem 219:131–209
10. Hartwig JF (2006) Synlett 1283–1294
11. Schlummer B, Scholz U (2004) Adv Synth Catal 346:1599–1626
12. Surry DS, Buchwald SL (2008) Angew Chem Int Ed 47:6338–6361
13. Hartwig JF (2008) Acc Chem Res 41:1534–1544
14. Janey JM (2007) Buchwald-Hartwig amination. In: Li JJ (ed) Name reactions for functional
group transformations. Wiley, Hoboken
15. Hartwig JF (2008) Nature 455:314–322
CN
NH 2
CF 3
Cl
+
1. Pd(OAc) 2 (0.8 mol %)
DavePhos (1.1 mol %)
PhB(OH) 2 (1.5 mol %)
Cs 2 CO 3 , toluene, 80 ºC
F 3 C
N
H
O
NH 2
Et
75–79%
N
F 3 C
O
Et
N
MeO
O
CF 3
CF 3
Torcetrapib
2. H 2 SO 4 , H 2 O
Scheme 13 Large-Scale Synthesis of Torcetrapib via Pd-Catalyzed N-Arylation
42
G.S. Lemen and J.P. Wolfe