Negishi E. 2002 Handbook of organopalladium chemistry for organic synthesis / 0995 105

III.3.1 Pd-CATALYZED HYDROGENOLYSIS

1035

The selective hydrogenolysis of N-benzylamine in the presence of a trityl ether was also carried out in 60% yield (Scheme 109).[170]

Benzhydryl group has been used for protecting alcohols as well as amines and amides. The protected imide was hydrogenolyzed at 65 °C in 75 min (Scheme 110).[171]

The imine derived from benzophenone was also hydrogenolyzed after the initial reduction of the C"N double bond (Scheme 111).[172]

Trityl,[173] 9-phenyl-9-fluorenyl,[174] and dibenzosubery[175] groups have also been used for amine protection and they can also be removed quite readily (Scheme 112).

N-Benzylamide is usually difficult to hydrogenolyze. Surprisingly, even the relatively more difficult to hydrogenolyze p-methoxybenzyl on an amide nitrogen was removed under acidic conditions and PdCl2 to give lactam 382 in excellent yield (Scheme 113).[176] N-Benzylpyridone 383[177] and N-benzylurea 385[178] were also hydrogenolyzed in

good yields using AcOH and Pd(OH)2/C (Scheme 114).

Dibenzylpyrimidine 387 was monodebenzylated under transfer hydrogenolysis conditions to give 388 in 60% yield (Scheme 115).[179] The imide benzyl group was slower to react but did get removed after 48 h at reflux and 300 wt % catalyst loading to give the completely debenzylated product in 78% yield.

Ph3CO

O

N

OMe

Ph 369

O Ph

N Ph

N

N O

H

371

	Ph		O
Ph	O		O Ph
Ph	O		O
			O
	N		O
			OMe
	Ph 373 Ph

1 atm H2				Ph3CO
12 wt % of
Pd(OH)2/C(20%)								O
MeOH							N
r.t., 4 h								OMe
							H
							370	60%
Scheme 109
	H2				O
	Pd/C(5%)						H
	EtOH
							N
	65 °C, 75 min
				N	N		O
					H
				372			95%
Scheme 110

				Ph	O
			Ph	O	O Ph
	H2
					O
	Pd/C(5%)		Ph	O
	MeOH, HCl
					O
	r.t., 2 h

O

H2N

OMe

374 96%

Scheme 111

1036

III Pd-CATALYZED CROSS-COUPLING

2.5 atm H2

O

O

10 wt % of

O

O

O

O

Pd black

O Ph

EtOAc/MeOH

O Ph

MeO

MeO

r.t., 4 h

+ t-BuO

O OBu-t

NHCPh3

HN OBu-t

MeO

O

MeO

O

375

O

376 97% O

		O				atm H2
Ph	O					21 wt % of
						Pd/C(10%)
		HN				THF/MeOH
						r.t., 26 h
		Ph
	377
		Ph			H2
					Pd/C
					MeOH
	N			OH	r.t., 1 h			H2N

H O

379

Scheme 112

				H			H2
O							PdCl2
		H					EtOAc, AcOH
							r.t.
O				N
		OH O
	381
						OMe
							Scheme 113
						Ph
							H2
				N		O Pd(OH)2/C
							AcOH
	O						r.t.

O 383

O

NH

O Ph

OH

378 98%

Ph

OH

O 380 100%

				H
O
		H
O				N
				H
	OH
		O
382		90%

H

NO O

O 384 80%

O

H2

O

t-BuO

NH

Ph

Pd(OH)2/C

NH H

MeOH/AcOH t-BuO

HO

N

NH2

r.t., 24 h

HO

N NH2

385

O

386 78% O

Scheme 114

III.3.1 Pd-CATALYZED HYDROGENOLYSIS 1037

HCO2NH4

O

150 wt % of

O

Pd/C(10%)

MeOH

Ph

N

Ph

N

reflux, 4.3 h

N

O

O

N

H

Ph

388 60%

387

Scheme 115

Benzylic C—N bonds of sulfonamides 389[180] and 391[181] are more readily hydrogenolyzed than N-benzylamide protecting group (Scheme 116). Hydrogenolysis of 389 under neutral conditions resulted in the opening of the -lactam ring. Both the benzhydryl and benzyl groups were removed in the hydrogenolysis of 391 to give the primary sulfonamide in excellent yield.

Nitrone 393,[182] oxazapyrrolidinone 395,[183] and dienone 397[184] were hydrogenolyzed to give primary amines (Scheme 117).

Nitrogen on heterocycles has frequently been protected as the N-benzyl derivative. Thus, 2-benzylimidazole 399 was successfully debenzylated to 400 in excellent yield (Scheme 118).[185] It should be noted that the benzylic ketone in 399 was not hydrogenated. Transfer hydrogenolysis with ammonium formate was also effective for the removal of the benzyl group in N-benzyl-2-methylimidazole.

The p-methoxybenzyl protecting group in tetrazole 401 was hydrogenolyzed without the cleavage of the hydroxy group (Scheme 119).[186]

Diazo compounds are also easily hydrogenolyzed (Scheme 120).[187]

	O	H	H2			O	H
			Pd/C
Ph	S				Ph	S
			EtOH
N	O	O	reflux, 12 h		HN	O	O
AcO	O				AcO	O
389					390	65%

1 atm H2

O

OH O

Ph

Pd(OH)2/C

O

OH O

MeOH/THF

Et3N

S

S

r.t., 18 h

t-BuO N

N

Ph

t-BuO N

NH2

O

O

O

O

Ph

391

392

92%

Scheme 116

1038 III Pd-CATALYZED CROSS-COUPLING

Ph

+

O−

atm H2

H

N

60 wt % of

H

NH2

OH

OH

Pd/C(10%)

AcOH

H

r.t., 6 h

H

393

394

85%

Cl

Cl

H2

25 wt % of

Pd/C(10%)

1 N HCl

MeOH

O

N

r.t.

H2N

396

100%

CO2H

CO2H

O 395

H

Ph N

O

t-Bu Bu-t

O 397

OMe

	atm H2
O	7 wt % of
N	Pd/C(10%)
	1 N HCl, MeOH
H	r.t., 4 h

OMe

O

N H2N H

O 398 88%

Scheme 117

O	atm H2			O
	18 wt % of
H2N	Pd/C(10%)		H2N
	conc. HCl			NH2
NH2	MeOH/H2O
Ph N N . 2 HCl	r.t., 16 h		HN	N . 2 HCl
399			400	96%

Scheme 118

OMe

		3.4 atm H2
N N		PdCl2, EtOH
		r.t., 3 h
R	N
N
OH
401

Scheme 119

HNN

N

R

N

OH

402

R = Ph 90%

R = Ph(CH2)2 91%

			III.3.1 Pd-CATALYZED HYDROGENOLYSIS							1039
O	CO2Me	O	CO2Me		OH	O	OH		O
				H2, Pd/C			O +			O
O	+ O
	N2		N2	MeOH
							HO
	OH		OH		HO
	403	404		405		77.5%	406	15.5%

Scheme 120

J. OTHER HYDROGENOLYSIS

The oxygen–oxygen bonds of peroxides and ozonides (resulting from the ozonolysis of alkenes) can easily be cleaved under Pd-catalyzed hydrogenation conditions

(Scheme 121).[188]–[190]

Interestingly, even carbon–tin[191] and oxygen–silicon bonds[192] can be hydrogenolyzed (Scheme 122). The Si—O bond can be hydrogenolyzed with interesting selectivity. The diethylisopropylsilyl group in 415 was selectively removed while the t-butyldiphenylsilyl was untouched. In a competitive hydrogenolysis experiment between benzyl ether and diethylisopropylsilyl ether in dioxane, only the benzyl group was hydrogenolyzed in 98%. Acylsilane 417 was hydrogenolyzed to aldehyde 418.[193] The phenyl substituent on silicon is crucial in the acceleration of the hydrogenolysis rate.

3.4 atm H2

75 wt % of

H

Pd/C(5%)

H

EtOH

O

r.t., 2 h

OH

H

O

H

OH

407

408

75%

H

H2

H

O

Pd/CaCO3

HO

EtOH

HO

O O

r.t., 22 h

H

O

H

H O

H

O

409

410

91%

O

atm H2

O

O

O

5 wt % of

H

H

O

Pd/C(10%)

EtOAc

O

H

NH

H

NH

O

O

411

412

100%

Scheme 121

1040 III Pd-CATALYZED CROSS-COUPLING

n-Bu3Sn

O

O

H

H2

H

N

Pd/C

N

H

H

N

O

H

O

413

414

85%

O

Si

H2

OH

Pd(OH)2/C

r.t., 1 h

O Ph

O

Ph

Si

Si

Ph

Ph

415

416

98%

atm H2

OCH2Ph

20 wt % of

OCH2Ph

Pd/C

PhMe2Si

H

EtOH

r.t., 10 h

O

O

417

418

80%

Scheme 122

K. SUMMARY

This section summarizes the different hydrogenolyzable functional groups discussed in previous sections.

Reaction Number	Substrates	Products
Sect. B Carbon–Carbon Bonds (Cyclopropane)

H

1.

Sect. C Nitrogen–Oxygen Bonds										H
2.	R2					R	2
	N		O
								N			H
	R2 H (R3)					R2

	III.3.1				Pd-CATALYZED HYDROGENOLYSIS 1041
	R2		R1
3.			+		_	R3		NH2
			N		O
		R3

R1

4.

N

R2 O H (R3)

O

N

5.

6.

R

ONO2

7.

R

N

OH

NH2

Sect. D Nitrogen–Nitrogen Bonds

8.

R1

R

N3

N

9.

R2

N

R3

H

N

10.

N

N NN

O

Sect. E Carbon–Oxygen Bonds (Epoxide)

11.

O

Sect. F Carbon–Nitrogen Bonds (Aziridine)

N

12.

H

R1

NH2

R2

O OH

R OH

NH

R

NH2

R NH2

R1

NH2 + R3 NH2

R2

NH2

N N

O

H OH

H NH2

1042	III Pd-CATALYZED CROSS-COUPLING

Sect. G Carbon–Halogen Bond (I, Br, Cl)

13.

14.

15.

16.

17.

18.

Sect. H

19.

20.

21.

22.

R

X

R

H

X

H

Ar

X

Ar

H

O

Cl

O

Cl

Cl

Cl

Cl

H

O

X

O

X

X

H

X

H

OMe

OMe

N

N

Carbon–Oxygen Bond (Benzylic and Others)

O

H(R)

O

+

H(R)

O

Ar

OH

HO Ar

O

Ar

R

H(R)

R

OH

OH

H

Ar

Ar

O

R

R

Ph

O

2 R

OH

	O	O
23.	Ph	Ph	OH OH
24.		OR	R OH

III.3.1 Pd-CATALYZED HYDROGENOLYSIS

1043

25.	Ar OSO2Me
	O
26.				OSO2CF3

O

27. RO P O CCl3

O CCl3

	O				NH
28.	Ar				NEt2
			Ph
	O				N N
29.					N N
	Ar

Ph

N N O N N

30. Ph

Sect. I Carbon–Nitrogen Bond (Benzylic)

			R1
31.			N		Ar
	R2
			R1
32.			N		Ar
	R2
				Ar
33.	R		NHCPh3

NHR

34.

Ph

35.

NHR

ArH

O

H

O

ROPOH

OH

Ar H

Ar H

Ph

R1

NH

R2

R1

NH

R2

R NH2

R NH2

R NH2

1044 III Pd-CATALYZED CROSS-COUPLING
	Ph	Ph
36.	O	N	R1
	O		R2

Ph NHR

37.

38.

39.

40.

Sect. J Other Bond Cleavage

41.

42.

43.

44.

45.

t-Bu Bu-t

O

N N Ph

N

N N Ph

N

R1 N2

R2

O R

R O

O

O

O

R1 R2

SnBu3-n

R1 R2

Si

O

R1 R2

O

R SiMe2Ph

R1

R2 NH2

R NH2

N NH

N

N NH

N

H

R1

H

R2

2 ROH

O

R1 R2

R1 R2

OH

R1 R2

O

R H