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

	III.3.1	Pd-CATALYZED HYDROGENOLYSIS	1015
N	1 atm H2
Ph	Pd/C	NH2
	AcOH

15−55 °C

	O	N	O	N
		178		179	90%
		Ph		Ph

Scheme 54

G. HYDROGENOLYSIS OF HALIDES

Pd-catalyzed hydrodehalogenation of halides is a useful method for the removal of halogen atoms. Since other metals are usually not as effective for this reaction (there are exceptions), Pd is therefore the metal of choice. In fact, in order to preserve halogen on a substrate, other metals such as Pt, Rh, and Raney nickel are used in the hydrogenation of other functional groups. In general, the order of reactivity for halide removal is F Cl Br I. Fluoride is usually not hydrogenolyzed except in a limited number of cases. Unless the substrate contains a basic functional group, it is beneficial to add one or more equivalents of a base to neutralize the hydrogen halide formed in order to minimize its poisonous effect on the catalyst. In the absence of a base, rapid slowing down of the reaction may sometimes occur, resulting in incomplete reaction. The following are common bases used in hydrodehalogenation reactions: MgO, carbonates, bicarbonates, hydroxides, acetates, alkoxides, R3N, and DABCO. The useful hydrodehalogenation of acyl halides to aldehydes, the Rosenmund reduction, will not be covered here but will be covered in Sect. VI.2.4.

Besides carrying out dehydrohalogenation in organic solvents, the reaction can also be carried out in water. 1°-Chloride 180 was dehalogenated in an aqueous bicarbonate solution in 94% yield (Scheme 55).[77] Reduction of the corresponding bromide gave an 81% yield.

3°-Chloride 182 was also removed to give 184 as the major diastereomeric product in 83% combined yield (Scheme 56).[78]

	OH	H2			OH
		20 wt % of
	O	Pd/C			O
	O	aq. NaHCO3		O
Cl	OH	50 °C, 32 h			OH
	HO 180 OH			HO	OH 181 94%
		Scheme 55

	S N		atm H2
	N		10 wt % of
		Cl	Pd/C(5%)
			EtOH, r.t.
N	Cl
	182

	S	N
	N
			N	N
		Cl
			+	S
	N		Cl	N
		8%	184	75%
	183
	Scheme 56

1016	III Pd-CATALYZED CROSS-COUPLING

The imino chloride in 185 was completely reduced but the bridgehead chloride was not touched. Surprisingly, when the bridgehead chloride was replaced with a methyl group, only 10% of the imino chloride reduced product was observed and the major product was the bislactam from hydrolysis (Scheme 57).[79]

The selective removal of the chloride in the presence of a readily hydrogenated aromatic nitro group was also reported (Scheme 58).[80] Acetonitrile was used as the solvent along with triethylamine as the base for the hydrogenolysis of the chloro group in chloronitrobenzene derivative 187. In EtOAc, however, the nitro group was concomitantly reduced to give aniline 189 in 80% yield.

It was interesting to note that in the process of removing the bromide in 190[81] and 193,[82] the hydroxy and acetoxy groups were also lost (Scheme 59). The primary bromide in 191 was removed in a separate step.

At 75% conversion, selectivity was observed in the reduction of bromoepoxysulfone 195 to give desbromo 196 in 79% yield with only 5% of the epoxide opened product 197 formed (Scheme 60).[83] On prolonged reaction time (15 h) hydroxysulfone 197 was obtained in 72% yield.

The multiple chloro-substituted substrate 198 underwent complete hydrodechlorination in good yield by passing the substrate over Pd/C at 250 °C and atmospheric hydrogen pressure (Scheme 61).[84]

In the hydrogenolysis of the Cbz group in 200, monodechlorination of the trichloroacetamide was also observed to give 201 in excellent yield (Scheme 62).[85]

				4 atm H2
		CH2Ph		30 wt % of		CH2Ph
				Pd/C(10%)
	N		O		N		O
				DABCO, THF
				r.t.
Cl	N		Cl		N		Cl
					H
	185				186		64%

Scheme 57

O2N

CO2H

		3 h,
		MeCN
O2N		CO2H
Cl		5 h
187		EtOAc

H2	188 70%
5−10 wt % of
Pd/C (5%)
Et3N
80	°C

H2N

CO2H

189 80%

Scheme 58

III.3.1 Pd-CATALYZED HYDROGENOLYSIS 1017

Br

OH

H2

Br

OH

H2

OH

O

O

Pd/C (5%)

O

Pd/C, Et3N

O

O

EtOH

O

EtOAc

H

H

H

OH Br

191

192

190

31% over 2 steps

AcO

N

atm H2

AcO

N

10 wt % of

O

N

NH2

AcO

Pd/C (10%)

O N

NH2

MgO, DMF

AcO

Br

N

N

r.t., 30 h

N

N

OAc

193

194

72%

Scheme 59

Br

		O	H2, BaCO3
			76 wt % of
PhCO2			OMe Pd/C(10%)
			2 h
	O2S
		O

	O				O
PhCO2		OMe	PhCO2		OMe
O2S		+	O2S		OH
	O

195

196

79%

197

5%

Scheme 60

F

Cl

atm H2

F

Pd/C(1%)

F

Cl

250 °C

F

F

F

198 Cl

199 65%

Scheme 61

O

O

O HO

Ph

O

O HO

4 atm H2

Ph

O

O

OCbz

12 wt % of

O

OH

O

Pd/C (10%)

O

H

H

EtOAc, MeOH

HN

r.t., 5 h

HN

Cl

OH

Cl

OH

O

O

Cl

Cl

Cl

200

201

94%

Scheme 62

1018	III Pd-CATALYZED CROSS-COUPLING

The selective monodebromination of geminal-substituted dibromopropane 202[86] was realized in only fair yield, whereas an excellent yield was obtained in the monodebromination of , -dibromolactam 205[87] (Scheme 63).

Dichlorolactam 207 behaved similarly to give the monochlorolactam in 98% yield (Scheme 64).[88]

More interestingly, 50% enantioselectivity was observed in the monodechlorination of, -dichlorolactam 209 using a cinchonine modified Pd catalyst (Scheme 65).[89]

In some cases alkenyl halides can be hydrodehalogenated without the reduction of the resulting olefins. Some examples are presented below (Scheme 66).[90]–[92] These olefinic products can and should eventually be reduced on prolonged reaction time or under more vigorous hydrogenation conditions.

Iodobutadiene 218 was also dehalogenated selectively (Scheme 67).[93]

Ph			50 psi H2
			50 wt % of
H			Pd/C(10%)
		CO2Et EtOAc, Et3N
Br			r.t., 9 days

Br

H N

PhCO

202

EtO2C		H2
		Pd/C(5%)
N	Br	AcOH, r.t.
		quinoline

Br

HN

O

205

Ph

Cl

Cl

N O

Ph

207

Cl

Cl

HN O

209

Ph

Ph

Br	H	CO2Et

H N

PhCO

203 29%

EtO2C

N

Br

HN

206 O 92%

Scheme 63

H2

20 wt % of Pd black benzene, 8 h

Scheme 64

3 atm H2

60 wt % of Pd/BaSO4(5%) THF, Bu3N cinchonine, r.t.

Scheme 65

H CO2Et

+

Br

H N

PhCO

204 23%

Ph

Cl

N O

Ph

208 98%

HN

Cl

O

21096%

50% ee

III.3.1 Pd-CATALYZED HYDROGENOLYSIS

1019

O O	O O
Br	+
O	O
Br	Br
211	212

O2S

I

214

atm H2

4.5 wt % of Pd/C (10%) EtOH, Et3N

atm H2

6 wt % of Pd/C(5%) NaOAc, MeOH quinoline

r.t., 2.5 h

		O				atm H2
	Ph					8 wt % of
						Pd/C(10%)
Ph						EtOH
						r.t., 3 h

Cl

216

I

FOH

OH

Scheme 66

atm H2 Pd/C(3%)

MeOH, NaOAc r.t., quinoline

218

Scheme 67

O O

O

213 56%

O2S

215 96%

O

Ph

Ph

217 85%

FOH

OH

219 75%

Under catalytic hydrogenolysis conditions, (Z)-N-methoxyarenecarboximidoyl halides 220 gave oximes 221 as the major if not exclusive product. The corresponding (E)-N- methoxyarenecarboximidoyl halides 223 gave nitriles 222 as the major or exclusive product instead (Scheme 68).[94]

With a variety of N-methoxyalkanimidoyl halides 225, good yields of oximes 226 were obtained exclusively.

Halogen-substituted aryl and heterocyclic compounds can also be hydrodehalogenated as easily. With NaOAc as the base, iodopyrrole was deiodinated in quantitative yield (Scheme 69).[95]

Chlorinated acetophenones and benzophenones were hydrodechlorinated selectively under phase transfer conditions without the hydrogenation of the ketone (Scheme 70).[96]

The hydrodehalogenation of -bromonitrobenzene with Pd and H2 to give nitrobenzene is usually unsatisfactory, but under transfer hydrogenation conditions with triethylammonium formate a 91% yield of nitrobenzene was obtained.[97]

Transfer hydrogenation with cyclohexene also removed the chloride in chlorodinitroaniline 233 but one of the two nitro groups was also reduced (Scheme 71).[98]

1020	III Pd-CATALYZED CROSS-COUPLING

Br

atm H2

H

3 wt % of

R1

OMe

Pd/C

R1

OMe R1

N

t-BuOH, Et3N

N

r.t., 1 h

+

R2

R2

R2

R3

R3

220

(a) R1 = R3 = H, R2 = OMe 221a 63%

(b) R1 = R2 = R3 = OMe

221b 70%

Br

H

R1

R1

R1

N

N

+

R2

OMe

R2

OMe

R2

R3

R3

223

(a) R1 = R3 = H, R2 = OMe

224a 11%

(b) R1 = R2 = R3 = OMe

224b

0%

X

H

R4

OMe

R4

OMe

225

N

226

N

(a) R = 2-naphthyl, X = Br

76%

(d) R = 4-MeOC6H4, X = Br

(b) R = PhCH2, X = Br

78%

(e) R = NC(CH2)9, X = Br

(c) R = 4-AcC6H4CH2, X = Br

84%

(f) R = PhCH2, X = Cl

N

R3

222a 8%

222b 0%

N

R3

222a 69%

222b 88%

85%

69%

64%

Scheme 68

Me

R

atm H2

Me

R

24 wt % of

R = p-CH3C6H4

Pd/C(5%)

MeOH, NaOAc

R = C6H5(CH2)2

Ts

N

I

r.t., 1 h

Ts

N

R = Et

R = t-Bu

H

H

227

228

100%

Scheme 69

atm H2

25 wt % of

Cl

Pd/C(5%)

aq. KOH, isooctane

Aliquat 336

50 °C, 2.25 h

229 Cl

230

O 81%

O

Cl

30 °C, 4.5 h

231

232

77%

Cl

O

O

Scheme 70

			III.3.1 Pd-CATALYZED HYDROGENOLYSIS 1021
		NH	cyclohexene		NH
			125 wt % pf
O2N		NO2	Pd/C(10%) O2N		NH2
			EtOH
			reflux, 0.5 h
233		Cl			234 85%
			Scheme 71

Although transfer hydrogenolysis conditions can be used to remove a 1°-chloride such as 235,[99] modification of the reaction conditions also allowed the selective removal of the aryl chloride in 237[100] while leaving the alkyl chloride untouched (Scheme 72).

Other monohalogen transfer hydrogenolysis was seen with trichloroanilide 239[101] and dibromo steroidal derivative 241[102] (Scheme 73).

The hydrogenation of benzaldehyde to the alcohol is usually facile with Pd, but even under the refluxing temperature of the transfer hydrogen conditions, hydrodehalogenation of bromoformylimidazole 243 still provided the formylimidazole in 70% yield (Scheme 74).[103]

Besides observing hydrodehalogenation of aryl bromides under transfer hydrogen conditions, in some cases biaryl coupling is observed. Bromopyridine 245 was homocoupled to give the bipyridyl 246 in 68% yield (Scheme 75).[104]

HCO2NH4 125 wt % of

HN

Cl

Pd/C, MeOH

HN

N

NH2

reflux

N

NH2

235

HCO2H

236

66%

30 wt % of

Pd/C(30%)

Cl

DMF

Cl

237

reflux, 5 h

Cl

238

85%

Scheme 72

O

O

HCO2H, Et3N

O

O

Pd

N

CH3CN, NaOAc

N

Cl

Cl

80 °C, 3.8 h

Cl

Cl

239

Cl

O

240

77.6%

O

HCO2H

Br

H

33 wt % of

H

Pd/C(10%)

H

H

reflux, 1.5 h

H H

DMF

HO

HO

241 Br

Br

242 70%

Scheme 73

1022 III Pd-CATALYZED CROSS-COUPLING

			HCO2NH4
		CHO	0.5 wt % of
	N		Pd/C(10%)
			MeOH
			reflux

N Br

243

Scheme 74

HCO2Na

Pd/C, EtOH

r.t., 6 h

N 245 Br

Scheme 75

CHO

N

N 244 70%

N

N

246 68%

H. HYDROGENOLYSIS OF BENZYLIC AND OTHER C—O BONDS

Of all the heterogeneous Pd-catalyzed C—O bond hydrogenolysis reactions, cleavage of benzyl esters is the most facile (Scheme 76).[105]

Benzyl carbonates[106] and carbamates[107] can be hydrogenolyzed as readily with the concomitant release of CO2 (Scheme 77).

O							O
O				H2		O
		OCH2Ph		Pd/C					OH
				MeOH
O HN O				r.t.		O	HN O
OBu-t						248	OBu-t
247							96%
			Scheme 76
O						O

O N

O

MeO			O
O	OMe
	O
O	249

		H2		O		NH
		12 wt % of
		Pd/C(10%)
		EtOAc, r.t.				O
			MeO			O
				HO		OMe
			O	250 98%
		O						NH2
			NH	H2, Pd/C		O
O				EtOH, Et3N
O						O
251						252		92%

Scheme 77

III.3.1 Pd-CATALYZED HYDROGENOLYSIS

1023

Debenzylation of esters has been carried out under transfer hydrogenation conditions with ammonium formate as the hydrogen source (Scheme 78).[108],[109] Under transfer hydrogenolysis conditions, the vinylogous carbamate 253 also underwent decarboxylation. The N-benzyl was also hydrogenolyzed.

Even 2-phenylethylcarbamate (“homobenzyloxycarbonyl”) can be hydrogenolyzed (Scheme 79).[110]

Although hydrogenolysis of benzyl ethers is slower than benzyloxycarbonyl derivatives, especially when an amine is used as an additive,[111] they are still readily reduced in a variety of solvents (Scheme 80).[112],[113]

In the case of binaphthyl ether 263, the secondary C—O bonds were hydrogenolyzed exclusively to provide the desired binaphthyl diol 264 (Scheme 81).[114]

				Pd/C(10%)
			O	NH4HCO2	t-BuO	O
t-BuO				MeOH
		O				O
				100 °C, 0.5 h
N					N
O PhCH	2	OCH2Ph			O	H
		O			254	97%
253

Scheme 78

H O N

O

100 wt % of
Pd(OAc)2
NH4HCO2
MeOH	H
r.t., 8 h

H N

255

256

90%

Scheme 79

atm H2

O

Ph

Pd/C(5%)

O

Ph

NH4OAc

t-BuO

O

t-BuO

O

MeOH, 16 h

HN

r.t.

HN

O

OH

O

Ph

O

257

258

96%

CH2Ph

H2, Pd/C

O

OH

O

O

MeOH

r.t., 12 h

P

N

P

N

EtO

EtO

OEt

OEt

259

260

95%

TBDMSO H H

H2, Pd/C

TBDMSO

H

H

EtOAc

r.t.

NH

O

O

NH

OH

O

CH2Ph

262

100%

261

Scheme 80

1024	III Pd-CATALYZED CROSS-COUPLING

O		5.1 atm H2
		Pd/C
		AcOH, r.t.

O

263

Scheme 81

OH

OH

264 90%

Benzyl ethers can be cleaved under hydrogen transfer conditions with many commonly used hydrogen donors such as ammonium formate,[115] 2-propanol,[116] and cyclohexene.[117]

Although the hydrogenolysis of benzyl protecting groups is faster than many other hydrogenolyzable groups, hydrogenolysis of benzyl ethers has been found to be inhibited by 2-methylnaphthalene. In the competitive hydrogenolysis of diether 265, only the naphthylmethyl ether group was cleaved to give the benzyloxy alcohol 266 (Scheme 82).[118] The 2-methylnaphthalene formed continued to inhibit the deprotection of the benzyl group. In fact, the addition of 2-methylnaphthalene alone inhibited the hydrogenolysis of benzyl ethers.

In addition, a catalytic amount of pyridine or ammonium acetate also suppresses the hydrogenolysis of aliphatic O-benzyl protective group.[111],[119] Cleavage of phenolic benzyl ethers, which are more labile than alkyl benzyl ethers, can also be prevented by the addition of 2,2 -dipyridyl (Scheme 83).[120]

The reduction of the stilbene olefin in 267 occurred selectively first while the aromatic nitro group was reduced with longer reaction time. Even prolonged reaction time did not further hydrogenolyze the phenolic benzyl ether.

1 atm H2

O

Pd/C(10%)

O

PhCH2

O

EtOH, r.t.

PhCH2

OH

265

266

96%

Scheme 82

atm H2

10 wt % of

Pd/C(5%)

PhCH2O

MeOH PhCH2O

NO2

r.t. 2 h

NO2

267

2,2′-dipyridyl

268

84%

24 h

PhCH2O

NH2

269

86%

Scheme 83