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Christa Gerlinger, Gaich Group Seminar, 19.07.2017 Isocyanate Chemistry

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Universität KonstanzChrista Gerlinger, Gaich Group Seminar, 19.07.2017

Isocyanate Chemistry

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Universität Konstanz

Isocyanate: History, physical- and chemical data

Isocyanate Chemistry2 19.07.2017

History Physical Properties

Chemical Properties

• versatile reactivity due to its electronic structure

• reaction with various nucleophiles; steric hindrance influences rate of reaction: primary > secondary > tertiary

• reaction with various electrophiles

• various addition, cycloaddition and insertion reactions along the N-C-bond

• first synthesis of an organic isocyanate reported in 1848 by Adolf Wurtz

A. von Wurtz, Justus Liebigs Ann. Chem. 1849, 71, 326–342

• commercially important synthesis by phosgenation of amines and amides discovered 1884 by W. Hentschel

• Since 1930 commercially polyurethane production discovered by O. Bayer at the I.G. Farben laboratories in Leverkusen

• Bhopal disaster 1984: Over half a million people exposed to MIC-Methly-Isocyanate. Over 5000 deaths, rest injured.

• colourless liquids or low melting solids

• IR: 2300 to 2250 cm-1

• 13C: 115-135 ppm

NC

O

RN

CO

RN

CO

R

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Syntheses of Isocyanates

Isocyanate Chemistry3 19.07.2017

1 Phosgenation reactions • Disadvantage: high toxicity• Advantage: very clean reaction, merely no side products

• Reaction with amines

2 Reaction of amines and amides

Application in the Total Synthesis of Welwitindolinone A- key step mechanism

Welwitindolinone A-Isonitrile

R NH2

O+ (COCl)2

R NCO

O

18 19

R NH2

O+ (COCl)2

R NH2

O

OO

Cl

- HCl

R NH

O

OO

Cl - HClO

NHR

O

O

R

O

NH

O

O

Cl

- CO- HCl

R NCO

OO

NH

if R = benzyl

Aryl

O

O∆T O

NRO

O

Cl

- HCl

20 21 22 23 24

25 26 19

proposed mechanism

O

O

NH2

H2N

Cl

Cl

2 (COCl)2

O

O

NCO

OCN

Cl

Cl N NCO

ClCl

Cl

Cl

Isocyanatoquinones

N

N

NCO

ClCl

Cl

N

N NCO

ClCl

1314

15 16 17

• Reaction of oxalyl chloride with amines

• Reaction of amides with oxalyl chloride to deliver acyl isocyanates

R NH2 + COCl2 - HCl NH

O

ClR

- HCl NC

O

R

NH

O

NH

RR + COCl2 - HCl NH

O

NR

RO

Cl∆T

- HClN

CO

R

2

SOCl2+-2 HCl

COCl2N

CO

RN

SO

R

SOCl2+R NH2

NH2

+ COCl2

−5 to 0 °C

NCO

12

3

1 4 3

5 6

7 83

NH2

MeMe

Me

ClMe

NH

H

O COCl2, NEt30 °C

N

MeMe

Me

ClMe

NC

C O

H

NR2

NH

Me

ClMe

H

MeO

NC

O

O

MeMe

LHMDS, THF−78 °C, 47%

9 10

11

12

• Reaction of primary amines with amine bases and CO2

R NH2 + NR3 + CO2MeCN N

H

O

OR

HNR3

POCl3NR3

NC

O

R

S. Ozaki Chem. Rev., 1972, 72 (5), pp 457–496

S. E. Reisman, J. M. Ready, A. Hasuoka, C. J. Smith, J. L. Wood, J. Am. Chem. Soc.2006, 128, 1448–1449.

S. Ozaki Chem. Rev., 1972, 72 (5), pp 457–496

A. J. Speziale, L. R. Smith, J. Org. Chem. 1963, 28, 1805–1811

T. E. Waldman, W. D. McGhee, J. Chem. Soc. Chem. Commun. 1994, 957

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Syntheses of Isocyanates

Isocyanate Chemistry4 19.07.2017

3 From isocyanic acid

3a Reaction with Olefins

3b Reaction with Carbonyls

3c Reaction with Acid Chlorides and Alkyl Chlorides

3d Reaction with Organometal Oxides

3e Reaction with Acid Anhydrides

R

O

Cl+ HNCO

R

O

NCO

Cl Cln + OCN NCOnHNCO

39 19

40 41

3f Reaction of Alkylhalides with Alkali Cyanates

• exo-Methylene most reactive• major drawback: harsh conditions, trimerization of isocyanicacid, polymerization of olefins• ionizable H-N bond makes HNCO behave like pseudo hydrogen halide

+HNCOH

+HNCOH

NCO29 30

NCO

31 32F3Cn(FC)

O

O (CF)nCF3

O

HNCO+ F3Cn(FC)

O

NCO+

44 45F3Cn(FC)

O

OH

O+HNCO

HO NCO

H H

O+HNCO HO NCO

THPTHPO NCO

O

O

+ HNCOBF3*OEt2

−22 °C, 16 h,0 °C, 144 h

95%

NH

O O

O

33 34

35 36

37 38

(Bu3Sn)2O + 2 HNCO 2 Bu3SnNCO H2O+70-80 °C

42 43

NH3 + COCl2H2N

O

ClNH4Cl HNCO HCl+ +

isocyanic acid27 28

MeO Cl + NaOCN MeO NCO + NaCl

Br Br + KOCN OCN NCO + KBr

RCl3 + NaOCN R(NCO)3

O

O Cl

Cl

+ 2 AgOCN

O

O NCO

NCO

R = P, Si, Ge

46 47 48

49 50 51

52 47 53

5455

56

H. S. Rothrock, 1964, 111, 3–5

S. Ozaki Chem. Rev., 1972, 72 (5), pp 457–496

S. Ozaki Chem. Rev., 1972, 72 (5), pp 457–496

S. Ozaki Chem. Rev., 1972, 72 (5), pp 457–496

S. Ozaki Chem. Rev., 1972, 72 (5), pp 457–496

H. S. Rothrock, 1964, 111, 3–5

H. S. Rothrock, 1964, 111, 3–5

H. S. Rothrock, 1964, 111, 3–5

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Syntheses of Isocyanates

Isocyanate Chemistry5 19.07.2017

4 Reduction of Nitrocompounds with “CO” 5 Oxidation of Isonitriles

Me

NO2

NO2

Me

NCO

NCO

Me

NH2

NH2

H2 COCl2

LnM(CO)

M = Pd, Fe, Mo, V

technical use

57 58

RN CI2 + NO RN CI

O N

I

NR NCO + + I2

R NC Pb(OAc)4 R NCO65 3

6667

6869

3

R NC + R N CX

XX2

X = Br, I

DMSO R NCO + DMS + X2

65 70 3

Proposed mechanism for the Oxidation of Isonitriles by Sulfoxides with TFAA:

R S RO

TFAA R S RO

COCF3

OCOCF3tBu N C R S R

CNtBu

OCOCF3

OCOCF3

R S RC

OCOCF3NtBu

OCOCF3

R S R

tBu N C OCF3

O

OCOCF3

tBu N C O + TFAA

71 72

73

74

757677

78

R N CDMSO

5 mol% TFAA,CH2Cl2

R N C O65 3LnM(CO)

ArNO2

LnMO N

O

O

Ar

LnMN

O

Ar

LnMN

O

O

Ar

LnM N Ar

LnMN

O

Ar

CO

CO2

CO2

CO

59

60

61

62

63

64

NC

O

Ar

CO

Proposed mechanism: S. Ozaki Chem. Rev., 1972, 72 (5), pp 457–496

A. M. Tafesh, J. Weiguny, Chem. Rev. 1996, 96, 2035–2052 H. V. Le, B. Ganem, Org. Lett. 2011, 13, 2584–2585

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Syntheses of Isocyanates

Isocyanate Chemistry6 19.07.2017

7 Rearrangement Reactions Application of the Hofmann rearrangement in the Total Synthesis of (+)-Dibromophakellstatin - key step mechanism

Application of the Curtius rearrangement in the Total Synthesis of Tamiflu - key step mechanism

N

N

O

OHH

12 steps

N

N

O

HNN

CO

N

N

O

NHN

OCBz

N

N

O

R2NH2N

OTHF/H2O (1:1),

23 °C

TiCl3, KOAc

2. NBS (2 eq),THF, 69%N

N

O

HN

HNO

Br Br

1. H2, Pd/C, MeOH, 50% o2s

CBz

88 89 90

9192

(+)-Dibromophakellstatin

OTMS

+ Cl

O

Cl

O

THF, rt; TMSN3, DMAP

1 N HCl aq., 55%

OH O

N3

O

N3

refluxN

N

OHC

O

CO

tBuOH

NHBoc

NHO

O

ONHAc

NH2EtO2C

10 steps

93 94 95 96

9798

Tamiflu

R

O

NH2

R

O

Cl

R

O

NHNH2

R

O

OH

R

O

NHOH

Br2

OH

NaN3

H2O

HNO2

H2O

HN3

H2O

1. Ac2O

2. NaOH

R

O

N Br

R

O

N N N

R

O

N OAc

[1,2]-rearr.

∆T

R N C O

(isolable in inertsolvents)

H2O

NH

O

OHR

- CO2

R NH2

79

80

81

82

83

84

85

86

87

1

Hoffmann

Curtius

Curtius

Schmidt

Lossen

Slocombe Chem. Rev., 1948, 43 (2), pp 203–218

D. Romo J. Am. Chem. Soc., 2003, 125 (21), pp 6344–6345

K. Yamatsugu, S. Kamijo, Y. Suto, M. Kanai, M. Shibasaki, Tetrahedron Lett. 2007, 48, 1403–1406

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Syntheses of Isocyanates

Isocyanate Chemistry7 19.07.2017

Application of the Schmidt rearrangement in the Total Synthesis of (+)-Aspidospermidine - key step mechanism

(+)-Aspidospermidine

Carbonyldiimidazole-mediated Lossen-rearrangement

NH

OOH N

N

O

N

N- imidazole

NH

OO N

O

N

- imidazoleN

OO

O

- CO2N

ON

CO

108

109

110111

112113

R

O

NH

OH CDIMeCN

O

NO

O

R- CO2

R NCO

R2R3NH

R4OH

NH

NR2R3

OR

NH

OR4

ORR = aryl, alkyl

72-99%83105

106

107

proposed mechanism:

O

9 steps

O

O

N3O

H TiCl4CH2Cl2, 53%

N

H

N2 O OTiCln

N

O OTiCln

OH

N

OH

O

O

4 steps

NH

N

H

H

99 100 101

102103104

O

R. Iyengar, K. Schildknegt, J. Aubé, Org. Lett. 2000, 2, 1625–7P. Dubé, N. F. Fine Nathel, M. Vetelino, M. Couturier, C. L. Aboussafy, S. Pichette, M. L. Jorgensen, M. Hardink, Org. Lett. 2009, 11, 5622–5625

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Syntheses of Isocyanates

Isocyanate Chemistry8 19.07.2017

8 More phosgene-free preparation methods8a Isocyanate formation using Mitsunobu Chemistry

2 RNH2 + CO2 NH

O

OR + RNH3 N

H

O

OHR

iPrO2CN

NCO2iPr

PPh3

O N

ORPh3P

H

+ iPrO2CN

NH

CO2iPrRNCO

Ph3P O+

1 114 115

116

117118

8c Mild phosgene free synthesis of isocyanates

Proposed Mechanism:

O O

O

O

OtButBu

DMAP+ N

OtBu

ON +

O OtBu

O

N OtBu

OHN

HNR+ RNH2

+

O OtBu

O

- tBuOH

NNNHR

O

O OtBu

O+NN

NHR

ODMAPH

NC

O

R

+

HO

O

OtBU CO2 + tBuOH

126127

128

129130

131

8b Alkyl isocyanates from Alcohol, Thiol, TMS-Ethers

R X PPh3, DDQ, Bu4NOCN R NCO

X = OH, SH, OSiMe3

R = prim., second., tert.- alkyl

54-98%

OH

OH

100%

0%

ConversionEntry

1

OH

OSiMe3

100%

0%2

OH

SH5

100%

0%

ConversionEntry

3

119

120

121

120

122

120

123

NH2R5

R4

R3R2

R1

Boc2O, DMAP

MeCN, 25 °C, 10min

R1 R2 R3 R4 R5 Yield [%]Me H Me H Me 96Me H H H Me 94iPr H H H iPr 99OMe H OMe H OMe 97Me H H H H 44OMe H H H H 86OMe H Me H H 88OMe H OMe H H 76Me H OMe H H 58Me Me OMe H H 89

OMe H H 42Ch ChH H OMe H H 41

NCOR5

R4

R3R2

R1

124 125

D. Saylik, M. J. Horvath, P. S. Elmes, W. R. Jackson, C. G. Lovel, K. Moody, J. Org. Chem.1999, 64, 3940–3946

B. Akhlaghinia, S. Samiei, Turkish J. Chem. 2007, 31, 35–43H. J. Knolker, T. Braxmeier, G. Schlechtingen, Angew. Chem. Int. Ed. Engl. 1995, 34, 2497–2500

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Syntheses of Isocyanates

Isocyanate Chemistry9 19.07.2017

9 The Staudinger-Aza-Wittig Reaction 9b Microwave assisted Staudinger-Aza-Wittig-Reaction

Main advantage: replacement of toxic phosgene by CO2(nontoxic, abundant, economical)

N PPh3RCX2

X = O,SN CR X

9a Aza-Wittig/intramolecular electrocyclic ring closure

Synthesis of ß-carbolines

Synthesis of 1,2,4-triazolo[5,1-b]quinazolin-9(3H)-ones

• polymer-bound diphenylphosphine (advantage: easily removable by filtration)

NMe

N

NHMeO

PPh3

NMe

N

NHMeO

CX

toluene, ∆T

NMe

N

ONHMe

XH

X = O (80%)X = S (90%)

CX2

X = O,S

132 133 134135

N

N

ON PPh3

NHAr

CX2

X = O,SN

N

ON

NHAr

C O

N

N

OHN

X

NArX = O (43%)X = S (83-87%)

136 137138139

R N3PPh2

CO2 (14 bar)

R NCO

R = Alkyl, Aryl, Arylether

140

141

F. Palacios, C. Alonso, D. Aparicio, G. Rubiales, J. M. de los Santos, Tetrahedron 2007, 63, 523–575

D. Carnaroglio, K. Martina, G. Palmisano, A. Penoni, C. Domini, G. Cravotto, Beilstein J. Org. Chem. 2013, 9, 2378–2386

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Reactions of Isocyanates

Isocyanate Chemistry10 19.07.2017

1a Reaction with Alcohols – Carbamate Formation

1c Reaction with Acetals

1d Reaction with ortho-Esters

1e Reaction with Epoxides

1f Reaction with Peroxy-compounds

R NCO + R´OHNR3

NH

OR´

OR

142 143

Ti-catalyzed reaction of highly hindered Isocyanates with Alcohols:

NCOR

RR

Ti(Ot-Bu)4 (10 mol%)

+ NH

OR´

O

R

RR

R´OHbenzole, 23 °C

144 142 145

Proposed mechanism:

O

CO

Ti

OH tBu

OtBu

OtBuOtBu

NR

R

NC

O

O

Ti

OtBuH

R

ROtBu

OtBuOtBu

OtBu TiOtBu

OtBuOtBu +

NH

O

ORR

146

147148 149

1b Reaction with tertiary Amines – Carbamoylation

NCO+ N H

RR

R

Et3B, air (O2)rt

HN

ON

RR

R

150 151 152

RO OR + Ph NCO N

O

ORPh

OR153 150

154

HC(OR)3+ Ph NCO N

H

O

C(OR)3Ph

155156

150

R1OOH + R2 NCO NH

OOR1

OR2 R NH

- CO2

+ OR2

R NH4 RN NR + RHN NHR

162 163 164 165

166 167 168

O

R

+ R´

NCO ON

O

Roxazolidones157

158

Synthesis of oxazetidinones:

NC

O

CCl3ClR

H2O HN

CCl3ClR

OH

O

- HCl

ONH

O

RCCl3159

160 161

S. Ozaki Chem. Rev., 1972, 72 (5), pp 457–496

C. Spino, M. A. Joly, C. Godbout, M. Arbour, J. Org. Chem. 2005, 70, 6118–6121

Tanaka Org. Lett., 2007, 9 (24), pp 5115–5118

S. Ozaki Chem. Rev., 1972, 72 (5), pp 457–496

S. Ozaki Chem. Rev., 1972, 72 (5), pp 457–496

A. Baba, M. Fujiwara, H. Matsuda, Tetrahedron Lett. 1986, 27, 77–80

S. Ozaki Chem. Rev., 1972, 72 (5), pp 457–496

S. Ozaki Chem. Rev., 1972, 72 (5), pp 457–496

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Reactions of Isocyanates

Isocyanate Chemistry11 19.07.2017

2a Reaction with Enamines 2b Reaction of Iodo Isocyanates with double bonds

R

R3 R2

R1

+ N C OI

R1

R2

NCOIR3

R MeOHR1

R2

HNIR3

R

O

OMe

R1

R2R3R

NH

OH

R1

R2

NH2HOR3

R

amino alcohol

aziridinecarbamate

OH

181 182 183184

185

186

R

R1

NMe2 +N

CO

N

O

R1RMe2N

O N +N

CO

HN

O N

O

HN O

-> formation of β-lactams

-> Quinoline derivatives

-> Pyridone derivatives

NC

O

+ N

ONH

N

NH

O

NCO

OMe

MeO

MeO+

N

-> Polycyclic Pyridone derivatives

NH

O

OMe

MeO

MeO

169 150 170

171 150 172

173

174 175 176 177

178179 180

Rigby J. Org. Chem., 1989, 54 (1), pp 224–228

S. Ozaki Chem. Rev., 1972, 72 (5), pp 457–496

3a [2+2]-Cycloaddition reaction

Synthesis of ß-Lactams (Azetidinones)

3 Cycloaddition Reactions – Formation of Heterocyclic Ring Systems

NC

O

R

CN

NO

O

R

R

187

189

188

190

F. P. Cossío, G. Roa, B. Lecea, J. M. Ugalde, J. Am. Chem. Soc. 1995, 117, 12306–12313

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Reactions of Isocyanates

Isocyanate Chemistry12 19.07.2017

3b Formal [4+2]-Cycloaddition

Proposed mechanism:

Enantioselective Synthesis of Pyrimidinones:

Synthesis of 4-alkylideneglutarimides:

N

R1

R2

+ NC

O

R3

[Rh(C2H4)2Cl]2 (5 mol%)

L2 (10 mol%)PhMe, 110 °C

N N

OR3R2

R1

OP

OO

ON

Ph Ph

Ph Ph

MeMe

L2 =205206

207

N N

OhexPh

PhN N

Ohex

Ph

N N

Ohex

Ph

N N

OhexPMB

Ph

N N

OhexBn

Ph

MeO

N N

Ohex

Ph

F3C

N N

Ohex

Ph

N N

OhexBn

MeO

N N

OhexBn

OMe

N N

OhexBn

NO2

N N

OhexBn

O

N N

OhexBn

Me

N N

OhexBn

Me

N N

OhexBn

Me

MeN N

OBn

Ph

N N

OBnBn

Ph

N N

OPhBn

Ph

56%, 90% ee 49%, 89% ee 65%, 91% ee 80%, 75% ee

69%, 94% ee 75%, 94% ee 67%, 93% ee

67%, 94% ee

69%, 92% ee 36%, 95% ee 82%, 94% ee 60%, 89% ee

38%, 77% ee 53%, 83% ee 53%, 91% ee 65%, 94% ee 42%, 84% ee

208 209 210 211

212 213 214215

216 217 218 219

220 221 222 223 224

R

NCOR

NR2OR

O

HN

RR

O

NH

NH

OR

R

O

OHR

R191 192193

194

NR2

H

O

R1R2

+ NC

O

R3

5% [Rh(cod)2]BF4/(S)-segphosCH2Cl2, RT,

20-46 h

NR3

O

O

HR1

R2

+

O

R1

R2

HO

O

O

O

PPh2PPh2

0.5 equiv.

R1 = nBu, Cy, 1-cyclohexenyl, PhR2 = nBu, Me, PhR3 = nBu, Cy, Bn, Ph

Yields up to 50%, ee up to 97%

Yields up to 38%, ee up to 98%

195 196197

198

[RhI]+

H

O

R1R2

Rh

O

R1R2

H

Rh

O

HR2 R1

O

HR2

R1

Rh

O

R1 HR2

NR3Rh

O

OR1

H

R2

NR3

O

O

HR1

R2

-[RhI]+

199

200

201 202203

204

196

NC

O

R3

J. H. Rigby, M. Qabar, G. Ahmed, R. C. Hughes, Tetrahedron 1993, 49, 10219–10228

K. Tanaka, Y. Hagiwara, M. Hirano, J. H. Rigby, D. D. Holsworth, K. James, K. M. Oberg, T. Rovis, J. Am. Chem. Soc. 2006, 133, 4019–4020

K. M. Oberg, T. Rovis, J. Am. Chem. Soc. 2011, 133, 4785–4787

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Reactions of Isocyanates

Isocyanate Chemistry13 19.07.2017

3c [2+2+2]-Cycloaddition

Cobalt-catalyzed:

R

R1

+N

CO

N

O

OO

TMS

n-Pr

CpCo(CO)2 (20 mol%)

m-xylene, hv, 139 °C, 3-5 h,yields 14-76%

X

R = TMS, nPr, tBu, Me, ketal, Ch2ORR1 = TMS, Et, CO2EtX = H2, ketal

NN

O

O

OHO

NC

OPr

TMS

+

OO

228 229 230

231 232 233

CO2Me

Ph

+ CN

Ph

O

Co PhPh

MeO2C CO2Me

Ph3P Cp

PhH, 135 °C, 19 h,40%

NPh

OPh

PhCO2Me

MeO2C

225 150

226

227

Rhodium-catalyzed:

XR

RCN

R1

O+

[Rh(cod)2]BF4/H8-BINAP

CH2Cl2, rt, 18 hyields 48-99%

NX

O

R1R

RR = H, Me, EtR1 = Bn, nBu, Ph, CyX = C(CO2Me)2, NTs, alkyl

234150

235

R1

+ NR2

C O [Rh(C2H4)2Cl]2 (2.5 mol%)

L (5.0 mol%)

PhMe, 110 °Cyields 34-92%

+

R1 = Ph, nHex, Bn, OEt, p/m/o-OMe-C6H4, m-F-C6H4R2 = Bn, PMB, Ph, nHex, Cy, p-F-C6H4, p-OMe-C6H4

L = OO

P NMe

Me

236 237238

239

N

N

O O

R1R1

R2R1 R1

R2

Proposed Mechanism:

R1

+ NR2

C ORhLn N

Rh

OR2

R1

Ln

COmigration N RhR2

R1

O

Ln

NN

O O

R1 R1

R2

R2

R1 R1

2-pyridone 4-pyridone

RhN

O

Ln

R2

R1

RhLn

R1

RhLn

RhLnRhLn

R1 R1240 241

242 243 244

236

camptothecin

Application in the Total Synthesis of Camptothecin:

R. A. Earl K. P. Vollhardt, 1983, 6991–6993

K. Tanaka, A. Wada, K. Noguchi, Agriculture 2005, 2117–2119

K. M. Oberg, E. E. Lee, T. Rovis, Tetrahedron 2009, 65, 5056–5061

Yamazaki, Tet. Lett. 1977, 18, 1333-1336.

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Reactions of Isocyanates

Isocyanate Chemistry14 19.07.2017

Rhodium-catalyzed:

R

+ NC

O [Rh(C2H4)2Cl]2 (5 mol%)

L (10 mol%)

PhMe, 110 °C46-99%, ee up to 95%

N N

R

O

O

R

+

lactam vinylogous amide

O

O

OP

OMeMe N

Ph

Ph

L:

H H236 246245 247

248

R = aryl, alkyl

+

OMeMeO

NC

O

N

OMeMeO

HOH

3 steps

255 256

257

(+)-lasubine II

Proposed Mechanism:

Application in the Total Synthesis of (+)-Lasubine II:

Ruthenium-catalyzed:

Nickel-catalyzed:

R

+ NC

O

pathway A N

RhO

H

R

H Ln

pathway B

COmigration

NRh

H

R

O

Ln

N

Rh

O LnH

R

N

O

R

RhN

O

Ln

H

R RhN

OR

H

Ln

NH

R

O

n n

nnn

n

nn

lactam vinylogous amide

Rpyridones

236 245 249 251

250

252

253 254246 247

X CN

R1

O+ N

XO

R1CpRu(cod)Cl (5 mol%)

DCE, reflux, 1-2 h

258 259

Ph

Ph

+ CN

Ph

ON

PhO

Ph

PhPh

Ph

Ni(COD)2 (5 mol%)

PCy3 (10 mol%)

PhMe, 23 °C, 24 h,84%

260 150 261

XR

RCN

R1

O+

N

O

R

R

XR1Ni(COD)2

(3-5 mol%)

SIPr (3-5 mol%)

R1 = Ph, p-OMe-C6H4, p-CF3, 2,6-dimethyl, Cy, Bu, BnR = H, Me, Et, iPrX = C(CO2Me)2, C2H4, NTs, O

yields 31-99%

262263

R. T. Yu, T. Rovis, J. Am. Chem. Soc. 2006, 12370–12371

Yamamoto Y, Itho K, Org.. Lett. 2001, 3, 2117.

H. A. Duong, M. J. Cross, J. Louie, J. Am. Chem. Soc. 2004, 126, 11438–11439

C

R1

NCO

R2

+ N N

O

OR2 R2

R1

Ni(cod)2 (10 mol%)

L (20 mol%)

THF, 80 °C, 12 h

FePPh2

NO iPr

L =

R1 = hex, CH2Cy, (CH)2Cy, Cy, (CH2)4OBn, (CH2)4OTBS, (CH2)2CH=CMe2, OctR2 = Tol, 4-Me2N-C6H4, 4-OMe-C6H4, Ph, 4-Cl-C6H4, 4-CO2Me-C6H4

,

4-MeCO-C6H4, 4-CF3-C6H4, 3-Me-C6H4, 2-Naphthyl, Bn

264265

266 T. Miura, M. Morimoto, M. Murakami, J. Am. Chem. Soc. 2010, 132, 15836–15838

H. Hoberg, B. W. Oster, Synthesis (Stuttg). 1982, 1982, 324–325

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Reactions of Isocyanates

Isocyanate Chemistry15 19.07.2017

3e [4+2+2]-Cycloaddition – Synthesis of Bicyclic AzocineRings

R1

NR2

CO

+[Rh(C2H4)2Cl]2

(5 mol%)

L2 (10 mol%)

PhMe, 110 °C, 12 h

N

O

R1

R2H

N

O

hex

H

N

O

H

Cl N

O

H

O

OMe

N

O

H

N

O

H

TIPSO N

O

H

N

O

O

N

O

H

N

O

HNBoc

N

O

H

Br

N

O

hex

HMe

N

O

H

TIPSO

Me

N

O

H

TIPSO

Me

74%, 99% ee 69%, 99% ee 70%, 99% ee

55%, 99% ee

82%, 99% ee65%, 97% ee

68%, 99% ee

57%, 97% ee

35%, 99% ee 62%, 99% ee

51%, 99% ee

54%, 99% ee

OP

OO

ON

Ar Ar

Ar Ar

L2 =

266267

268

269 270 271

272 273 274

275 276 277

278279

280

3g [4+1]-Cycloaddition of Isocyanates with various carbenes

• rapid entry to functionalized pyrrolidinone rings• well-suited for installation of quaternary stereocenters

Synthesis of functionalized Pyrrolinone derivatives:

Synthesis of functionalized hydroindolones:

Application in the Total Synthesis of Tazettine:

(+/-)-Tazettine:

RR

NC

O

+X

Y RR

N

O

Y

X HN

O

RR

YX

pyrrolinone281 282 283 284

Me

NH

NHCy

O

Me

NH

NHCy

O

HNO

ONH

OCyHN

NH

Ph O

O

75% 68% 82% 75%51%

RR

NC

O

+ C N Cy

NH

NHCy

ORT

MeCN

281285

286

287 288 289 290 291

NN

O

OMeOMeN

CO

+ xylenereflux N

R

O

MeO OMe

292 293 294

O

ON3

O

OTHP

OO N

NO

OMeOMe

relfux, 75%

O

ON

OTHP

CH(OMe)2

O

O

O

OMeOMe

10 steps

NMe

O

O

O

MeO

OH

295

293

296

297

R. T. Yu, R. K. Friedman, T. Rovis, Angew. Chem. Int. Ed. Engl. 2009, 13250–13251

J. H. Rigby, M. Qabar, G. Ahmed, R. C. Hughes, Tetrahedron 1993, 49, 10219–10228

J. H. Rigby, M. Qabar, G. Ahmed, R. C. Hughes, Tetrahedron 1993, 49, 10219–10228

Rigby J. Am. Chem. Soc., 1996, 118 (50), pp 12848–12849

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Reactions of Isocyanates

Isocyanate Chemistry16 19.07.2017

Application in the Total Synthesis of debromoflustramide/-amine:

[4+1]-Cycloaddition with cyclic carbenes

NN

O

SPrSPr

+N

O

SPrSPr

SPrPrS

PhHrefluxNCO

292 298299

NCO2H

DPPA, NEt3

NCON3

NN

O

SPrSPr

PhH, reflux,N

N

OSPr

SPr

NH2

4 steps

NN C O

heat

SPrPrS

NN O

SPrSPr

4 steps

NNMe

X

H

X = H, H debromoflustramine BX = O debromoflustramide B

300 301 302

291

304305306

307:308:

303

NCO

+PhN NPh

NH

O

PhNNHPh

NH

O

PhN

NHPh

NH

O

PhN

NHPh

NH

O

PhN

NHPh

NH

O

NPhPhN

NH

O

PhN

PhHN

NNPh

N

NPh

O

O

NNPh

N

NPh

O

O

Cl3C H

57% 55%52% 51%

65% 71% 70%

292309 310

311 312313 314

315 316 317

[4+1]-Cycloaddition with bis(alkylthio)carbenes

J. H. Rigby, S. Laurent, J. Org. Chem. 1999, 64, 1766–1767

S. De, J. H. Rigby, Tetrahedron Lett. 2013, 54, 4760–4762 J. H. Rigby, Z. Wang, Org. Lett. 2002, 22–24

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Reactions of Isocyanates

Isocyanate Chemistry17 19.07.2017

4 Insertion Reactions4a Insertion in Si-N bond

4b Insertion in B-N bond

4e Insertion in Metal-C/H/N/O bond

4c Insertion in labile Methoxy Derivatives

4d Insertion in Organotin Oxides

RN

BR2

RN

C

Ph

O+ R2N N

OBR2

Ph

322 323129

MeO NMe

O

OMeN

C

Ph

O+

MeO NMe

O

NPh

O

OMe

324 129 325

Me3SiHN

SiMe3

+N

C

Ph

OMe3Si

HN N

OSiMe3

Ph

RN

SiMe3

R+ N

C

R

OR

NR

N

OSiMe3

R

318 129 319

320 321

(Bu3Sn)2O + NC

O

RBu3Sn

NR

O

OSnBu3

326 129327

NC

O

R

Insertion in[M]-H-bond

Insertion in[M]-C-bond

Insertion in[M]-O-bond

Insertion in[M]-N-bond ∆T

[M]OR + R´NCONR

OR

O[M]

[M]= Nb, Zr

[M]NR2+

R´NCONR

NR2

O[M]

[M]= Ti, Zr, Hf

330

328

329

334

333

[M](CH3)3ClNR

Me

O[M]

Me Me

Cl

HFeCp(CO)2

Cp(CO)2Fe NH

OR

332

H transfer to C

H transfer to O H transfer

to N

(OC)3Os Os(CO)3

Os(CO)3

H

O NC RH

(OC)3Os Os(CO)3

Os(CO)3

H

C NHO R

331

C. Chang, J. Chen, B. Srinivas, M. Y. Chiang, G. Lee, S. Peng, G. J. C. Soc, D. Trans, J. A. A. Chem, I. E. Engl, et al., Organometallics 1997, 7333, 4980–4984

P. Braunstein, D. Nobel, Chem. Rev. 1989, 89, 1927–1945

S. Ozaki Chem. Rev., 1972, 72 (5), pp 457–496

S. Ozaki Chem. Rev., 1972, 72 (5), pp 457–496

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Reactions of Isocyanates

Isocyanate Chemistry18 19.07.2017

5 Chlorosulfonyl Isocyanate

SO3 + Cl C N NC

O

S OOCl

335 336337

• colorless liquid• mp -44 to -43 °C, bp 107-108 °C• thermally stable up to 300 °C• most reactive isocyanate species

5a Reaction with H-X

NC

O

S OOCl

H 2O

ROH, NR3

RNH2

or HNR2

Ar-H,AlCl3

R-XH,

X= O/S

HNXY, X,Y= H, alkyl

RCOOH

HO

O

NH

SO2Cl - CO2H2N SO2Cl

H2N SO

OOR

H2N S NR

R/H

O

O

Ar S NH2

O

O

RX

O

NH

SO2Cl

N NH

OX

Y

SO2Cl

R NH

OSO2Cl+CO2

+

+

+ HCl

HCl

HCl

ester of sulfamic acids

sulfamide derivatives

aromatic sulfonic acids

thioester/ester of N-chlorosulfonylcarbamic acid

N-chlorosulfonylureas

337

338

339a

340

341

342

343

344

Et3N S N

O

OMeO

O

Burgess reagent (MeOH, NEt3)

339b

5b Reaction with Olefines – Synthesis of ß-lactams

5c Various Reactions

5d Stereoselective amination of chiral benzylic ethers and its application in total synthesis

NC

O

S OOCl

C

N

Me

OClO2S

CH2

NClO2S O

NH

OSO2Cl

H

NOClO2S

H2OHN

OAzetidinon

NOClO2S

345346

347

348

349350

351

352 337

NC

O

S OOCl

H

O

R

NO

RH

OClO2S- CO2

N SO2ClH

R

azomethine-N-sulfonylchlorides

C OH

H

H2C N

O

O

SO2Cl ROH, ∆THO

O

OR

O

malonic acid derivatives

RO

ON N

diazoacetic ester

NN

NRO

O

OSO2Cl

DMSO

MeS

N

MeSO2Cl

MeO OMe

MeO N

OSO2Cl

MeO

HC(OMe)3

MeO

O

NMe

SO2Cl

ester of N-alkyl-N-chlorosulfonly-carbamic acid

353354

356

357

358

359360

361

362363

365

364

337

X

OR

Rn X

OR

n

1. CSI (150 mol%),Na2CO3

(300 mol%), CH2Cl2

2. sat. Na2CO3 X

HN

Rn X

HN

n

OR

O

OR

O

366 367 368 369

ClCl

NHMe

(+)-sertralineCl

Cl

OBnN

CO

S OOCl

ClCl

O

O

NClO2S Bn

ClCl

ON

O

BnClO2S

H

front side attackCl

Cl

HN

O

OBn

retention of theconfiguration

SNi 3 steps

370 371 372 373 374

Yields up to 89%, ee up to 99%

S. H. Lee, I. S. Kim, Q. R. Li, G. R. Dong, L. S. Jeong, Y. H. Jung, J. Org. Chem. 2011, 76, 10011–10019

S. Ozaki Chem. Rev., 1972, 72 (5), pp 457–496

S. Ozaki Chem. Rev., 1972, 72 (5), pp 457–496

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Reactions of Isocyanates

Isocyanate Chemistry19 19.07.2017

6 Catalytic C-H Amidation Reactions

H

DG[Rh]

NC

O

R

DG

O

NHR

NRX

O

or

H

R

R

R

NOMe

+ NC

O

RN

R

RO

R

R[Cp*Rh(CH3CN)2](SbF6)2, 5 mol%

CO2H+ N

CO

R

Cat. [Cp*RhCl2]2, NaOAcN

O

O

RR R

R1

NH

R2

HO

Me

+ NC

O

R3

[Cp*Rh(CH3CN)3](SbF6)2, 5 mol%

R1

NH

R2

O

Me

NHR3

O

N

t-BuO

H

RR

+ NC

O

R

[RhCp*Cl2]2 (2.5 mol%)

AgNTf2 (10 mol%)

Cu(OAc)2 (30 mol%)

DCE, 20 h, rt

N

t-BuO

RR

NR

O

O

RHN

yields 30-91%36 h, 100 °C

THF, 16 h, rtyields 44-96%

DCE, 100 °C, 12 hyields 47-93%

375 376 377

378 379

380 381

382 383

384 385

H

DG[Co, Re, Ru]

NC

O

R

DG

O

NHR

NN

+ NC

O

RR

NN

R

O

NH

R

[Cp*Co(C6H6)][PF6]2 (10 mol%)

KOAc (20 mol%)

H

Nt-Bu

+ NC

O

R

[ReBr(CO2(thf)]2 (3 mol%)

NR

O

HN t-Bu

RR

NRX

O

or

+ NC

O

R

[RuCl2(p-cymene)]2 (5 mol%)

AgSbF6 (20 mol%)

yields 40-96%

yields 47-90%

yields 52-82%

toluene, reflux, 24 h

DCE, 100 °C, 24 h

1,4-dioxane, 120 °C, 20 h

375 376 377

386 387

388 389

390 391

LG

O

R NR

O

O

R

W. Hou, B. Zhou, Y. Yang, H. Feng, Y. Li, Org. Lett. 2013, 2, 1–42

X. Y. Shi, A. Renzetti, S. Kundu, C. J. Li, Adv. Synth. Catal. 2014, 356, 723–728

J. A. Ellman, J. Am. Chem. Soc. 2011, 113, 11430-11433.

I. S. Kim, O. P. Zee, Y. H. Jung, Adv. Synth. Catal. 2017, 359, 1-9.

J. R. Hummel, J. A. Ellman, Org. Lett. 2015, 17, 2400–2403

Y. Kuninobu, Y. Tokunaga, A. Kawata, K. Takai, J. Am. Chem. Soc. 2006, 202–209

S. Desarkar, L. Ackermann, Chem. - A Eur. J. 2014, 20, 13932–13936

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Isocyanate Chemistry

Isocyanate Chemistry20 19.07.2017

Take Home Message

Synthesis of Isocyanates

• despite the high toxicity of phosgene, very clean reaction with merely no side products

• synthesis from isocyanic acid with a large amount of functional groups.

• a lot of mild, phosgene free methods available with various functional groups

Reactions of Isocyanates

• Isocyanate reacts with a huge amount of different functionalities

• Cycloaddition and C-H-Amidation reactions as very powerful reactions for the synthesis of heterocyclic systems

• Chlorosulfonyl isocyanate a very powerful and versatile applicable reagent!