This document discusses palladium-catalyzed Buchwald-Hartwig C-N coupling reactions and their applications in medicinal chemistry. It provides an overview of the reaction mechanism and components of the catalytic system, including solvents, bases, palladium sources, and ligands. Common troubleshooting issues are also reviewed, such as low conversion or yield that can be addressed by optimizing reaction conditions like temperature, base selection, drying of reagents, and ligand choice to promote reductive elimination. Examples are given of applications in coupling secondary amines and functionalized substrates. In summary, Buchwald-Hartwig amination is a versatile method for C-N bond formation widely used in drug development.

1. Pd-Catalyzed Buchwald-Hartwig C−N
Coupling Reactions and its applications in
Medicinal Chemistry
1
-:Presented By:-
Anil Kumar Pujari
M.S. (Pharm.)
MEDICINAL CHEMISTRY

2. Flow of Presentation
2
Introduction
Current strategies for C-N bond Formation Reactions
General Reaction and Mechanism
Components of the Catalytic System
Troubleshooting guide for Pd-catalyzed amination
Applications of Palladium-Catalyzed C−N Cross-Coupling Reactions
Conclusions

3. 3
Introduction
 A carbon–nitrogen bond is a covalent bond that is one of the most
abundant bonds in organic chemistry and biochemistry
It is present in amino acids, DNA bases, and many other important biological
active molecules, include kinase inhibitors, antibiotics and CNS active agents
 Buchwald-Hartwig amination is a palladium-catalyzed cross-coupling
reaction of amines and aryl halides that results in formation of C-N bonds
 C-N bond forming reaction is used in the synthesis of many classes of
compound such as amines, carbamates, lactam, sulfonamide, guanidines etc
 In the past 20 years, the utility and versatility of this transformation has
been amply demonstrated through literature reports in many fields of chemical
research

4. 4
J. Med. Chem. 2011, 54, 3451 Org. Biomol. Chem. 2006, 4, 2337
Med Chem
• A survey of reactions used in Med Chem at
GSK, Pfizer and Astra Zeneca from 2008 to
2011
• 23.1% included heteroatom
alkylation/arylation (also largest class of
reactions).
29%
29%
34%
4%
3%
N-Substitution
Reductive Alkylation N-Alkylation with Alk-X
N-Arylation with Aryl-X Amide N-Alkylation
Heteroaryl N-Alkylation
73%
24%
3%
Alkylation/Arylation
N-substitution O-substitution
S-substitution
C-N bond Formation: Who needs it?

5. 5
J. Med. Chem. 2011, 54, 3451 Org. Biomol. Chem. 2006, 4, 2337
Process Chem
• A survey of reactions used in Process Chem at
GSK, Pfizer and Astra Zeneca.
• Out of small molecule drugs (<550 MW), 90%
contained nitrogen.
• Heteroatom alkylation/arylation represented the
largest class of reactions (19%)
57%
28%
8%
7%
Alkylation/Arylation
N-substitution O-substitution
S-substitution Other
36%
20%
17%
10%
10%
8%
N-Substitution
Alkylation with Alk-X Reductive Alkylation
Arylation with Aryl-X Amide Alkylation
Aniline alkylation Heteroaryl Alkylation
C-N bond Formation: Who needs it?

6. Current strategies for C-N bond
Formation Reactions
6
In early 1990, Buchwald and Hartwig developed C-N bond formation reaction using Pd and
Cu catalyst in presence of suitable ligands.
Chem. Soc. Rev., 2013,42, 9283

7. 7
• Early work by Migita in 1983.
• Limited scope, but conditions are mild
compared to other methods at the time.
• Sn toxicity problematic.
• Buchwald and Hartwig studied this reaction
in detail.
Chem. Lett. 1983, 927
J. Am. Chem. Soc.1994,116, 5969
J. Am. Chem. Soc.1994, 116, 7901
• Developed a tin-free methodology utilizing
a bulky base.
• Scope was limited to secondary amines
due to competing β-hydride elimination.
• Encouraged the development of novel
phosphine ligands to improve the reaction
generality.
J. Am. Chem. Soc.1996,118, 72
J. Am. Chem. Soc.1996,118, 7217.
• Since 1994, vast amount of
research devoted to extending the
reaction generality.
• Can now be applied to a vast array
of systems.
Chem. Sci. 2010, 2, 27
Buchwald-Hartwig Amination

8. General Reaction and Mechanism
8
Chem. Sci., 2011, 2, 27-50

9. Components of the Catalytic System
9

10. Solvents
Role of the solvent
 Dissolution of the coupling partners as well as parts of the
base
 Allowing for a respective temperature window for the reaction
 Stabilization of intermediates in the catalytic cycle
10
Tetrahedron 2002, 58, 2041–2075

11. • Buchwald–Hartwig aminations are usually run within an
organic solvent system
• Toluene and 1,4-dioxane are most commonly employed
• 1,4-dioxane has an unfavorable toxicity profile and can
typically be replaced with Bu2O
• THF and DME can also be used
• Toluene is particularly advantageous in the coupling of aryl
iodides due its weak ability to solubilize the inorganic iodide
salts
• Polar solvents DMF, DMSO and t-BuOH can also be used
11
Angew. Chem. .Int. Ed. 1998, 37, 2047

12. 12
Base
 Bases deprotonates the amine before or after coordination to palladium
 The most common bases for C-N couplings are: t-BuONa, t-BuOK, LHMDS,
Cs2CO3, K2CO3, K3PO4, NaOMe, NaOH, KOH
 The relative base strength determines the functional group tolerance
 Weak inorganic bases such as Cs2CO3, K3PO4 or K2CO3 can bring significant
benefits in the functional group tolerance of Pd-catalyzed amination reactions
Base strengths of typical bases used in Buchwald– Hartwig aminations
 LHMDS allows amination of aryl halides containing hydroxy, amide or
enolizable keto groups with dialkylbiaryl phosphine ligands
 Cs2CO3 is most effective when chelating bisphosphine ligands are used
Angew. Chem. Int. Ed. 1999, 38, 2413

13. 13
Base Advantages Disadvantages
NaOt-Bu Permits highest reaction rates and lowest
catalyst loadings
Incompatible with many
electrophilic functional
groups
LHMDS Allows utilization of substrates bearing
protic functional groups
Useful for low temperature amination
Solid base is air sensitive
Incompatible with some
functional groups at elevated
temperature
Cs2CO3 Provides excellent functional group
tolerance and often highest reaction rate
of weak bases
Expensive
Can be hard to stir on large
scale
K3PO4,
K2CO3
Excellent functional group tolerance
Often most efficient for the arylation of
amides
Economically attractive
Can require relatively high
catalyst loadings and long
reaction times
Comparison of bases typically used in Pd-catalyzed amination
Chem. Sci., 2011, 2, 27-50

14. 14
Palladium
 Typically, Pd(0) or Pd(II) precursors are used
 The most prominent Pd(0) precursors are Pd2(dba)3 and Pd(dba)2
 The most versatile Pd(II) precursor is Pd(OAc)2. [allPdCl]2 or Pd(acac)2 also
show remarkable activity in special cases
 One of the most abundant Pd(II) salts is PdCl2, efficient in the amination of
aryl bromides using diphosphines but not very promising with mono-
phosphines
 The palladium catalyst must be in the (0) oxidation state before the catalytic
cycle initiates, and therefore the palladium(II) in Pd(OAc)2 must be reduced
prior to catalysis initiation
Can. J. Chem. , 2001, 79(11), 1799-1805

15. Pd2(dba)3
 In the case of Pd2(dba)3 (dba = dibenzylideneacetone), the oxidation state
of palladium is already (0) and there is no need for reduction
 In this case reaction with phosphines L gives species of the type Pd(dba)L2
rather than Pd(0)Ln
15
Pd(OAc)2
 Pd(OAc)2 is usually reduced to palladium(0) complex [Pd(OAc)L2]- by
phosphines
 At least 3 equivalents of PPh3 is needed for the reduction of Pd(OAc)2
Chem. Sci., 2011, 2, 27-50

16. Ligands
16
 C-N coupling reactions are usually carried out with an added ligand
 A palladium precursor is typically stabilized in solution by an adequate ligand
that also raises the electron density at the metal to facilitate oxidative
addition and provides sufficient bulkiness to accelerate reductive elimination
 The first ligands to be used were P(o-Tol)3 and P(t-Bu)3
 The chelating bisphosphines BINAP, DPPF and DtBPF used by Buchwald and
Hartwig
 These bisphos-phines interestingly can act in a trans-chelating mode
 Buchwald developed a series of new monodentate phosphines exemplified
by DavePhos, XPhos, BrettPhos and RuPhos
 van Leeuwen developed XantPhos and DPEPhos (aryl ethers) that show
especially high activity for coupling of aryl halides with amides, hydra-zines,
oxazolidinones and ureas
J. Am. Chem. Soc. 2004, 126, 1, 82–83
J. Am. Chem. Soc. 2002, 124, 6043–6048

17. Ligands
17
Acc. Chem. Res., 1998, 31 (12), 805–818 Org. Lett. 2000, 2 (8), 1101− 1104

18. J. Am. Chem. Soc. 2003, 125, 6653–6655 Chem. Sci., 2011, 2, 27-50

19. 19
 BINAP and Xant-phos have become the most often used ligands
for N-arylation reactions
 BrettPhos first became famous because of its ability to effect
amination of aryl mesylates
 DavePhos with Pd2(dba)3 and Pd(OAc)2, it demonstrated good
results for arylation of both primary and secondary amines with
various aryl halides with low catalyst loading
 Hartwig explored the use of DPPF which improved on the
amination of primary amines by promoting reductive elimination
over β-hydride elimination because of its coordination geometry
and bite angle
Name BrettPhos RuPhos
Best nucleophiles Primary alkyl amines
Primary anilines
Secondary alkyl amines
Secondary anilines
Chem. Sci., 2011, 2, 27-50

20. 20
Chem. Sci., 2011, 2, 57
Cross-coupling reactions of functionalized aryl chlorides and simple primary aliphatic amines

21. 21
Chem. Sci., 2011, 2, 57
RuPhos as the ligand for Pd-catalyzed C–N coupling reactions of secondary amines and aryl
chlorides

22. 22
N-arylation of the chiral amine with the bromonaphthalene
J. Am. Chem. Soc., 2010, 132 (3), 1151–1158

23. 23
Problem Possible causes Solutions
Low conversion Inefficient formation of active catalyst
Low rate of reaction
Employ readily activatable precatalysts
Increase catalyst loading
Perform reaction at a higher temperature
Poor yield Incompatibility of base with functional groups in
substrate
Employ a weaker base with better functional
group tolerance (Cs2CO3 or K3PO4)
Formation of Catalyst decomposition
Inefficient reductive elimination
Perform reaction at a lower temperature
Use a ligand that gives faster reductive
elimination
Presence of adventitious water in reaction Dry reagents
Add activated molecular sieves
Presence of adventitious water in reaction Dry reagents
Add activated molecular sieves
Inefficient transmetallation
Unsuitable solvent for reaction
Use a ligand that is less sterically hindered or
more electron-deficient at P
Troubleshooting guide for Pd-catalyzed amination
Chem. Sci., 2011, 2, 27-50

24. 24
24
Nucleophile Ligand Typical condition Pd source
BrettPhos NaOt-Bu,dioxane
Or K2CO3, t-BuOH
90-110 ̊C
Pd2(dba)3
RuPhos NaOt-Bu, THF
Or Cs2CO3, t-BuOH
65-110 ̊C
Pd2(dba)3
tBuBrettPhos Pd(OAc)2, K3PO4
t-BuOH,110 ̊C Pd(OAc)2
DavePhos
or others
NaOt-Bu,
toluene,80-100 ̊C
Pd2(dba)3
tBuXPhos K3PO4,
DME, 30 ̊C
Or NaOt-Bu,
Toluene, 65 ̊C
Pd2(dba)3
Reaction conditions used for different classes of nucleophile
Chem. Sci., 2011, 2, 27-50

25. 25
Electrophile Ligand Typical condition
Aryl bromides and chlorides BrettPhos/
RuPhos/tBuBrettPhos
K2CO3, t-BuOH
110 ̊C
Aryl sulfonates XPhos NaOt-Bu, t-BuOH
K3PO4 , 110 oC
25
Reaction conditions used for different classes of electrophile
ArI> ArBr > ArCl > ArF
Chem. Sci., 2011, 2, 27-50

26. 26
Applications of Palladium-
Catalyzed C−N Cross-Coupling
Reactions

27. 27
Chem. - Eur. J. 2011, 17 (38), 10618−10627

28. 28
Chem. Commun. 2010, 46(14), 2450−2452

29. 29
Org. Lett., 2011, 13 (24), 6496–6499

30. 30
Org. Process Res. Dev. 2014, 18 (11), 1571−1574

31. 31
Org. Lett. 2011, 13 (10), 2564−2567 US Patent 20130224149, Aug 29, 2013

32. 32
Conclusions
 Nitrogen containing compounds are of great importance because of their interesting
and diverse biological activities
 The construction of the C–N bond is of significant importance as it opens avenues
for the introduction of nitrogen in organic molecules
 Nitrogen-based heterocycles are key building blocks in the area of medicinal
chemistry
 Methods for their preparation that utilize Pd-catalyzed C−N coupling chemistry
typically provide significant advantages over traditional ones
 These methods have become increasingly versatile as a result of innovations in
catalyst design and improvements in reaction conditions
 The applicability of Pd-catalyzed C-N cross-coupling reactions in medicinal
chemistry has rapidly grown in the past years

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Thank You….