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Universität KonstanzChrista Gerlinger, Gaich Group Seminar, 19.07.2017
Isocyanate Chemistry
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
Universität Konstanz
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
Universität Konstanz
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
Universität Konstanz
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
Universität Konstanz
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
Universität Konstanz
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
Universität Konstanz
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
Universität Konstanz
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
Universität Konstanz
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
R´
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
Universität Konstanz
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
Universität Konstanz
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
Universität Konstanz
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.
Universität Konstanz
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
Universität Konstanz
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
Universität Konstanz
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
Universität Konstanz
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
Universität Konstanz
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
Universität Konstanz
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
Universität Konstanz
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!