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

III.3.1 Pd-CATALYZED HYDROGENOLYSIS

1025

The hydrogenolysis of benzylic alcohols in many cases can benefit from the use of an acid to provide faster or more satisfactory reaction rates (Scheme 84).[121]

Commonly used acids include hydrochloric, sulfuric, perchloric, and acetic. Although aliphatic ketones are generally resistant to Pd-catalyzed hydrogenation, benzylic ketones readily hydrogenolyze to aryl alkanes via hydroxy intermediates (Scheme 85).[122]

3-Acyltetronic acids, which carry a nonbenzylic ketone function, can also be hydrogenolyzed to give 3-alkyltetronic acids (Scheme 86).[123]

Interestingly, in the presence of KOH and aliquat 336, the Pd-catalyzed hydrogenolysis of (4 -chlorophenyl)-1-propanol in hydrocarbon solvents gave propylbenzene in 96% yield along with 4% of 1-phenyl-1-propanol (Scheme 87).[124] With nonhalogenated aryl alcohols, such as 1-phenyl-1-propanol, the hydrogenolysis did not proceed unless an aryl halide was also added. Thus, in the presence of -dichlorobenzene even t-benzylic alcohol 278 was hydrogenolyzed quite rapidly. The reason for this selectivity is unknown at this time.

OH

N

MeO

SO2

OCH2Ph 270

MeO

H

H

O

272

O

HO R1

R2O O

274

3 atm H2

15 wt % of

	Pd/C(10%)
	MeOH			N
	aq. HCl
		MeO		SO2
			OH	271 98%
	Scheme 84
		MeO		H
	H2, Pd/C

EtOH

H

					273		97%
	Scheme 85
	1 atm H2				HO			CH2R1
	Pd/C (10%)
	EtOH
	r.t., 4−6 h			R	2		O	O
					275
					R2
R1				H				Me
CH 3			96%					95%
Et			86%					86%
n-Pr			84%					93%
Benzyl			93%

Scheme 86

1026	III Pd-CATALYZED CROSS-COUPLING

OH

Cl

Et

276

OH

278

atm H2

5% Pd/C Aq KOH isooctane aliquat 336 50 °C, 45 min

atm H2

5% Pd/C Aq KOH isooctane

o-dichlorobenzene aliquat 336

50 °C, 1 h

Scheme 87

Pr-n

277 96%

279 100%

Other commonly encountered hydrogenolyzable O-protecting groups are shown below. These include triphenylmethyl,[125] diphenylmethyl,[126] 9-fluorenyl,[127] and 9- fluorenylmethyl[128] (Scheme 88). The 9-fluorenylmethyl protecting group has also been hydrogenolyzed under transfer hydrogenolysis conditions using freshly precipitated Pd

O
H
	H
H
280	O CPh3
	OMe

O

HO Ph

OH O

282 Ph

2.5 atm H2

55 wt % of Pd/C(5%) EtOH

r.t., 14 h

atm H2

10 wt % of Pd/C(10%)

AcOH, EtOH r.t.,12 h

O						H		O
						N
PhCH2O N										O
		H		O				284
						Ph

O

H

H

H

281 80% OH

OMe

HOO OH OH

283 90%

H2
Pd/C(10%)				H		O
MeOH
r.t.	H2N			N				OH
		O
				Ph		285

O O

HNCO2H

286

atm H2

50 wt % of Pd/C(10%)

AcOH, MeOH
0 °C, 4 h	H2N CO2H

287

Scheme 88

III.3.1 Pd-CATALYZED HYDROGENOLYSIS

1027

[from Pd(OAc)2] on Pd/C and ammonium formate as the hydrogen source.[129] The catalyst prepared in this manner was more active in the hydrogenolysis reaction.

Several less commonly utilized protecting groups include 2-trimethylsilylpropenyl,[130] dimethylpicolinyl,[131] and 3-alkoxyisoxazole[132] (Scheme 89).

The frequently used protecting group for carbonyl protection is 1,2-bis(hydrox- ymethyl)benzene. It has been used for the protection of both aldehyde[133] and ketone[134] functional groups (Scheme 90).

This diol has also been used to protect boronic acids[135] and phosphates[136] (Scheme 91). Another protecting group for aliphatic aldo and keto carbonyl groups is

phenylethandiol (Scheme 92).[137]

O

atm H2

O

Pd/C(10%)

P

P

O

O

EtOH, r.t.

HO

OH

TMS

OEt

TMS

OEt

288

289

O

H

O

H2, Pd/C

O

H

N

DMF

N

t-BuO N

N

O

r.t., 1.5 h

t-BuO N

NH2

H

O

H

N

H

O

290

291

85%

n-C16H33

O

O

CPh3

4 atm H2,

n-C16H33

O

CPh3

Pd/C(10%)

O

O

EtOH/THF (9:1)

OH

292

r.t., 48 h

N

293 94%

O

Scheme 89

1 atm H2

1 mol % of

O

PdO

H

THF

O

r.t., 0.5 h

O

294

295 100%

H2, Pd/C(10%)

O

O

O

EtOH, CH2Cl2

cat. NaHCO3

r.t., 12 h

OAc

OAc

OAc

OAc

296

297 95%

Scheme 90

1028 III Pd-CATALYZED CROSS-COUPLING

H2

20 wt % of

O

Pd/C

OH

AcOH/MeOH

Br

B

r.t.

Br

B

O

OH

298

299

Ph

H2, Pd/C(10%)

Ph

O

O

aq. MeOH

O

OH

P

r.t., 24 h

P

O

O

OH

O

300

301

98%

Scheme 91

Ph

atm H2

8 wt % of

O

O O

Pd/C(10%)

THF

r.t., 6 h

CO2Me

302

CO2Me

303 80%

Scheme 92

Diols, on the other hand, can be protected as the benzaldehyde acetal or the benzophenone ketal, which are readily deprotected again under Pd-catalyzed hydrogenolysis condi-

tions (Scheme 93).[138],[139]

Although similar hydrogenolyzable groups are in the same molecule, the selective removal of one may sometimes be carried out (Scheme 94).[140],[141]

In a competitive hydrogenolysis reaction, the benzyl protecting group was selectively removed leaving the dimethylbenzyl ether intact (Scheme 95).[142] The dimethylbenzyl ether could be removed after 15 h under 4 atm of hydrogen.

The parent benzyl group was also selectively removed in the presence of the 4-methoxy-substituted benzyl (Scheme 96).[143]

n-C17H35CO2

304

Ph

PhO

O O

O

H2, Pd/C

Ph

O

OCH2Ph		atm H2
	OCH2Ph
		12 wt % of
		Pd/C(10%)
	OCH2Ph	EtOAc, r.t.

O

CO2Me 306

Scheme 93

			OH
n-C17H35CO2
	305		OH
			OH
	OH				OH
HO
	O				OH
	O
	CO2Me 307 95%

III.3.1 Pd-CATALYZED HYDROGENOLYSIS 1029

O

NHCH2Ph

40 psi H2

O

NHCH2Ph

5% Pd/C

MeOH

PhCH2O

CO2CH2Ph

r.t., 15 min

PhCH2O

CO2H

308

309

69%

PhCH2O

O

1 atm H2

PhCH2O

O

5% Pd/BaSO4

O

EtOAc

O

O

25 °C, 1 h

O

O H

O H

PhCH2O

HO

310

311

88%

Scheme 94

1 atm H2

10 wt % of

O

O

Pd/C (10%)

HO

O

THF/EtOH

r.t., 3 h

312

313

84%

Scheme 95

O

atm H2,

10 wt % of

O

Pd/C(5%)

H

pyridine

t-Bu

CO2Me

N

MeOH/dioxane

O

N

r.t., 24 h

H

O

314

O

OMe

OH

O

H

t-Bu

CO2Me

N

O

N

H

O

315 96%

O

OMe

Scheme 96

1030	III Pd-CATALYZED CROSS-COUPLING

As expected, certain hydrogenolyzable protecting groups are more readily removed than others. For example, the benzyl ether was removed faster than the trityl protecting group (Scheme 97).[144]

Similarly, the benzyl protected ester was selectively hydrogenolyzed in the presence of the 9-fluorenylmethyl protecting group,[145] but the benzyl group was slower to hydrogenolyze than the 9-fluorenyl protecting group[146] (Scheme 98).

Even though aliphatic mesylates are difficult to hydrogenolyze, no difficulty was encountered in the cleavage of benzylic mesylate 322 (Scheme 99).[147]

Marinating Pd/C with (1R,3S)-3-aminoborneol, (S)-2-hydroxymethylazetidine, and (1R,2S)-ephedrine produced useful chiral heterogeneous catalysts. These catalysts have been used for the asymmetric hydrogenolysis of benzyl -keto esters and benzyl enol carbonates to give chiral ketones in fair to good yield (ee) (Scheme 100).[148]–[151] These

		O		atm H2			O
PhCH2O		O		14 wt % of		HO	O
				Pd black
				EtOH
O				r.t., 30 h		O
	O	OCPh3					O
	316						317 75% OCPh3
			Scheme 97

O

O

t-BuO

O

2.7 atm H2

t-BuO

O

Pd/C(10%)

O N

O

Ph

MeOH, r.t.

O

N

OH

319 79%

H

O 318

H

O

OCH2Ph

OCH2Ph

atm H2

Pd/C(10%)

OH

AcOH/EtOH

OH

O

OH

r.t., 12 h

HO

OH

320

321

90%

Scheme 98

6 atm H2

CF3

10 wt % of

CF3

OSO2Me

Pd/C(10%)

H

R = NH2

90%

MeOH

R = OEt

75%

R

r.t., 5 h

323

R

322 O

O

Scheme 99

III.3.1 Pd-CATALYZED HYDROGENOLYSIS

1031

transformations have also been accomplished under homogeneous transfer hydrogenolysis conditions with phosphinated palladium complexes (see Sects. V.2.3.1 and V.2.3.2).

Hydrogenolysis of a nonbenzylic mesylate group on an sp3 carbon is generally sluggish, but the trifluoromethanesulfonate seems to be easier. Thus, the -triflate leaving group in lactone 330 was cleaved under mild hydrogenolysis conditions (Scheme 101).[152] Even enol triflate 332 was hydrogenolyzed along with the hydrogenation of the olefin, but very high loading of catalyst was used.[153]

Trichloroethyl phosphate and phosphonate esters are hydrogenolyzed to give phosphate and phosphonate acids, respectively (Scheme 102).[154],[155]

Phenolic hydroxy group can be hydrogenolyzed via the diethylisourea (Scheme 103).[156] Under either hydrogenation[157] or transfer hydrogenation[158] conditions, the 5-oxy-

tetrazole fragment can be hydrogenolyzed in fair to good yields (Scheme 104).

O

atm H2

Pd/C(5%)

aminobornane

324

OCH2Ph

CH3CN, 52 °C

O

O

O

atm H2

OCH2Ph

Pd/C(5%)

aminobornane

326

O

CH3CN, 43 °C

O

OCH2Ph

H2

Pd/C(5%)

aminoborneol

CH3CN

328

r.t., 0.7 h

Scheme 100

HO

OSO2CF3

4.4 atm H2

DIPEA

O

Pd/C(10%)

O

O

AcOEt

r.t., 4.5 h

O

330

H

276 wt %

Pd/C(10%)

atm H2

H

MeOH

CF3SO3

r.t., 2 h

H

332

Scheme 101

O

32586%

99% ee

O

32790%

63% ee

O

32990%

64% ee

	HO
	O	O
	O
	O 331 86%

H

H

H

333 62%

1032

III Pd-CATALYZED CROSS-COUPLING

OCH2CCl3

OH

Cl3CCH2O

P

O

atm H2

HO

P

O

75 wt % of

H

O

O

H

O

O

H

O

Pd/C(10%)

O

PhCH

O

EtOH/H2O

H

N

2

N

N

N

OEt

r.t., 24 h

2

N

N

OEt

O

H

O

Ph

H

O

Ph

334

335

90%

O

O

Ph

H2

Ph

N

10% Pd/C

N

OEt

EtOH

OEt

336 O

O

P

20 °C, 72 h

337

50% O

O

P

OCH2CCl3

OH

Scheme 102

O

5 atm H2

O

t-Bu

9 wt % of

t-Bu

Pd/C(10%)

EtOH

O

O

r.t., 8 h

339

O

N

NH

88%

338

Scheme 103

N

Ph

N

N

N

O

10 atm H2

OMe

OMe

Pd/C(5%)

dioxane

MeO

N

OMe

60 °C, 24 h

MeO

OMe

N 341

MeO

MeO

66%

340

CO

Et

Pd/C

CO2Et

H

Ph

2

N

HCO2NH4

Ph

O

N

N

EtOH

N

reflux, 0.2 h

N

N

O

N

N

H

344

N N

342

Ph

343 44%

HCO2H

H

Ph

benzene

Ph

reflux

+

+

Ph

+ Ph

H

345

H

H

347

348

346

Catalyst = Pd/C, 5 min

0%

0%

0%

100%

Catalyst = Pd/Pb/C, 15 min

81%

1%

8%

1%

Scheme 104

III.3.1 Pd-CATALYZED HYDROGENOLYSIS

1033

To preserve the olefin in 344, Pb-doped Pd/C was required. Some olefin isomerization products were also formed.

I. HYDROGENOLYSIS OF C—N BONDS

Many hydrogenolyzable protecting groups used for O-protection can also be used for N-protection. Again, benzyl is the most common protecting group used for N-protection. As shown by the examples in Scheme 105, many different reaction conditions and Pd catalysts have been used successfully to accomplish the hydrogenolysis of the N-benzyl

Ph

Ph

N

CF3

H2

H2N

CF3

Pd/C(10%)

EtOAc

N

r.t., 3 days

N

O

O

349

OMe

350 83%

OMe

2 atm H2

Ph

N

Pd/C

HN

MeOH

MeO

r.t., 4 h

MeO

OMe 352 60%

351 OMe

O

H2

8.5 wt % of

Pd/C(10%)

H

PhH2C

NMe2

AcOH

t-BuO

r.t., 10 h

N

353

N

H

H

O

CO2H

t-BuO

N

N

CO2H

354

O

1 atm H2

H2

Pd/BaSO4

OH

Pd black

OH Ph

conc. HCl

Ph

N

EtOH H2N

N

OH MeOH

r.t.

r.t., 45 min

Ph

355

356 80%

Ph

357 O

Ph

Ph

5 atm H2

N

H2N

Ph

N

Ph

Pd(OH)2/C

TFA

H2N

Ph

H

aq. MeOH

H

r.t., 45 min

O

O

HO

O

359

360

83%

Scheme 105

O

NMe2

H

PhNOH

358 O 70%

1034	III Pd-CATALYZED CROSS-COUPLING

group.[159]–[164] Acidic conditions in conjunction with Pd(OH)2/C (this catalyst has been used especially for hydrogenolysis reactions) are used favorably in many instances.

In some cases the selective monodebenzylation of N,N-dibenzylamine has been accomplished (Scheme 106).[165]

Chiral -methylbenzylamine has frequently been used as a chiral auxiliary for diastereoselective synthesis. This protecting group does not present any problem during its hydrogenolysis (Scheme 107).[166]

The N-methylbenzyl and N-benzyl protecting groups have been selectively removed in the presence of benzylic hydroxy[167] and N-nitrosoamine[168] functional groups, respectively (Scheme 108).

In a competitive hydrogenolysis reaction between O-benzyl ether and N-benzylamine groups, the latter was preferably hydrogenolyzed. Amines have been shown to have an inhibitory effect on the hydrogenolysis of benzyl ether.[111],[119],[169]

0.3 atm H2

O

H

40 wt % of

O

H

Pd/C(5%)

CH2Ph

N

conc. HCl

N

NHCH2Ph

MeO

MeO

N

EtOH, 2 h

361

CH2Ph

362

81%

Scheme 106

Ph

3.9 atm H2

HO

HO

H

25 wt % of

N

CO2K

Pd/C(10%)

Ph

N

CO2K

Ph

H2O

r.t., 2 h

363

OMe

364

91%

OMe

Scheme 107

OH

H2

OH

20 wt % of

Ph

Ph

Pd(OH)2/C

N

EtOAc

NBoc

Boc2O

H

H

365 Ph

366 93%

Ph

1 atm H2

Ph

N

Pd(OH)2/C

N

EtOAc

Ph

N

N O

BocHN

N O

r.t.

OH

OH

Ph

Boc2O

368

367

89%

Scheme 108