59
General Reactivity and Applications of Chlorosulfonyl Isocyanate (CSI) Daniel Tzvi Cohen Long Literature Presentation January 7, 2010 N C O S Cl O O
General Reactivity and Applications of
Chlorosulfonyl Isocyanate
(CSI)
Daniel Tzvi Cohen
Long Literature Presentation
January 7, 2010
NC
OS
Cl
OO
Overview
! Background/Discovery/Applications
! Basic Functional Groups Reactivity with CSI
! Total Synthesis of (+)-Blastmycinone
Discovery/Background
" CSI was discovered by Graf and coworkers in Germany in
the early 1950!s
" Liquid at room temperature
" Fumes in moist air and reacts violently with water
" Incompatible with protic solvents
" Thermally stable up to 300°C
ClCN + SO3 ClSO2NCO
" NCO lowest energy geometry is bent ( 118°) based on
microwave spectroscopic data
N C
O
ClO2S
Dihedral Angle Rational
" Positions 1 and 5 repulsion between C=N bond and lone pairs of O/Cl
S
OO
Cl
C O
1 2
3
4
5
6
7
Jo, O.L., et al., J. Mol. Spectros., 1992, 152, 261-273
" Positions 3 and 7 repulsion between nitrogen lone pairs and O/Cl lone pairs
" Position 2 the C=N bond is near the Cl lone pairs
" Position 6 the nitrogen lone pairs are near the Cl lone pairs
" Position 4 Dihedral angle of ~ 94° is preferred (confirmed by X-ray diff.)
Reactivity Pattern
" Complexity of this reactant allows for various products
" Reactivity is dependent on temp/solvent and other reactant(s)
" Isocyanate is the most reactive part of CSI
N
C
O
S
Cl
OO
+ !+
!-
!-/!+
!-
!-
!-
CSI Applications
CSI is used to produce many commercially available products
for agricultural, biological, and body ailments.
Increases leaf length in corn
NH
NHS
O O
OR
Phenylaminosulfonyl ureas
Pesticides for protecting crops
S
N
R O
R1
O O
Isothiazolidinones
Anti-inflammatory and
anti-metastatic agent
Useful in the treatment of leukemia
N
O
R2HN
R
O
NHSO2NHR3
Acylated !-Lactams, derived from ketenes
N
R1R
O
OPh
O
HN
Ph
Acylated !-Lactams
Antibacterial agents
SO2NH
R
NH
O
N
NN
NMe Me
ON
MeMe
Phenylsulfonyl ureidotriazoles
Reactivity of CSI with different Functional Groups
R
R4R2
R3R1
R1
R
R
H2N
R
N3
R
SH
R
OH
R(H)R1
O
R
XRO
X=O,S,N
CSI
R4
SiR1
R3R2
NOR1
R2 R3CH2n
Aromatics
1) Graf,R. Justus Liebigs Annalen der Chemie, 661, 111
2) Giger, R., et al. Tetrahedron, 29, 2392
X i) CSI, AlCl3 20-30°C
ii) hydroylsis
X
NH2
O
i) CSI, toluene 80°C
ii) hydroylsis
OH2N
CSI
CH2Cl240°CN
O
MeO2C CO2Me
Me
OMe
OMe
N
O
MeO2C CO2Me
Me
OMe
OMe
Cl
81%
Cycloalkanes
Moriconi, E.J., et al. JOC, 33, 3448 (1968)
CSIMe
Me
Me
Me
Me
Me
Me
Me
N
OClO2S
Me
MeMe
O
H2N
+
65% 22%
Me
Me
Me
Me
Mechanism
O C NSO2Cl
Me Me
Me
MeO
N
SO
O
Cl
[1,2] shift
- CSIMe
Me
Me
Me
O C NSO2Cl
Me
Me
MeO
N
SO
O
Cl
MeMe
Me
Me
Me
N
OClO2S
Rearrangement Rational
Moriconi, E.J., et al. JOC, 33, 3448 (1968)
xMe
Me
MeON
SO
O
Cl
Me
Me
Me
Me
ON
SO2Cl
Me
Me
H
Me
ON
SO2Cl
[1,2] shift
Me
Me
Me
-CSI
Me Me
Me Me
isomerization
[2+2]
CSI
CSI
N
MeMe
MeMe
OClO2S
Me
Me
H
Me
74%
Paquette, L.A., et al. J. Am. Chem. Soc., 93, 3448 (1971)
Cycloalkanes Continued
MeMe
H
Me
i) CSI, CH2Cl2, -78°C
ii) NaOH- aq. Acetone
HN O
Me
Me
Me
+
4%43%
O OMe
Me
Me
MeMe
O C NSO2Cl
MeMe
Me
MeC
O
NSO2Cl
Me Me
Me
C
O
NSO2Cl
HN O
Me
Me
Me
Mechanism
i) CSI, CH2Cl2, -78°C
ii) NaOH- aq. Acetone
NH
O
+
37%9%
NH
O
1) Eur. Pat. Appl. E.P. 53, 331, C.A. 97, 144359z (1982)
2) Mickel, S. J. et al. Org. Syn. 65, 135
3) Miyavdera, T., et al. Heterocycles 19, 1497
Monosubstituted Alkenes
R = H, Me, Et, Bu, ClCH2, Cl2CHCH2
N
O
CO2H
S
NH2
H3C
HOH
H
Thienamycin
AcO
H
H
H
CSI
Hydrolysis HN
AcO
H
O62%
IH2C
H
H
H
CSI
Hydrolysis HN
IH2C
H
O
HN
H
O
S
N
thienamycin intermediate
R
H
H
H
CSI, h! or 1R
H
Cl
H
H
SO2NCO
RO O
O
O
O
OR
1
60-90%
R
H
H
H
SO2NCO
1) Dunogues, J., et al., J. Organomet. Chem., 116, C45-C48
2)Gehanne, S., et al., Tet. Lett. Syn. 35, 2047
3) Kaluza, Z., et al. Tet. Asymm. 6, 1719
More Monosubstituted Alkenes
SiMe3
CSI, 0°C
CCl4 NSO2Cl
OSiMe3
CNPyridine
0 °C
Si Cl
Me Me CSI
HydrolysisNH
O
78%
Si
Me
MeCl
Me3Si
O
NSO2Cl
[1,5]-Brook rearrangement
CSI, -78°C
Hydrolysis
54% 46%
OR1
O
R2
OO
Me
Me
OR1
O
R2NH
OO
Me
Me
OR1
O
R2NH
O
O
Me
Me
OO
H H
1) Pasto, D.J., et al., Tet. Lett. 14, 713
2) Sarel, S., et al., Tet. Lett. 17, 451
1,1 Disubstituted Alkenes
(CH2)nCSI
HydrolysisNH
O
(CH2)n
Me
Ph
CSI, 0°CN
Me
O
SO2Cl
Ph
CSI, 0°CPh Ph
CONHSO2Cl
Pasto, D.J., et al., Tet. Lett. 14, 713
Mechanism to Explain Product Formation
CSI, 0°CPh Ph
CONHSO2Cl
Me
Ph
CSI, 0°CN
Me
O
SO2Cl
Ph
Ph
ONSO2Cl
HONSO2Cl
Me
Ph
O
NSO2Cl
Me
Ph
1) Imanieh, H., et al., Tet. Lett. 30, 2689
2) Doyle, T. W., Conway, T. T., Tet. Lett. 10, 1889
More 1,1-Disubstituted
CSI, -40 °C
HydrolysisClO2SN!
O
warm O!NSO2Cl
ClO2SN!
OClO2SN
O
NSO2Cl
O
Bu3Sn
PhS
CSI, -40 °C
Hydrolysis
Bu3Sn
PhS
NH2
O
Nakatsuka, T, et al., JCS Chem. Comm., 662 (1991)
1,2 Disubstituted Alkenes
Me
SPh
O
Me2tBuSi
CSI
NH NH
SPhSPhH H
OMe2
tBuSi
H HO
Me2tBuSi
O O
+65%
dr 3:1
Me Me
Me
SPh
ONH
O
Me2tBuSi
CSI
Me
SPh
O
Me2tBuSi
CSI
Me
SPh
O
Me2tBuSi
NSO2Cl
O
Me
SPh
ONH
O
Me2tBuSi
Mechanism Path B
1) Vorbruggen, H., et al., Tetrahedron. 50, 6549
2) Hall, R.H., et al., JCS Perkins Trans. I, 38 (1973)
More 1,2-Disubstituted
O
i) CSI
ii) Et3N, CH2Cl2 O
CN
CSI
O
AcO
OEtAcO
O
AcO
AcO
NHCO2Et
O
O
N
ClO2S
OH
N
ClO2S
C
O
OEt
1) Graf. R., Angew. Chem. Int. Ed. Engl. 7, 172
2) Rosenthal, S., Williams, R.V., Synthesis, 621(1988)
Tri-Substituted Alkenes
EtO
H
Me
Me
+ 2 CSIN N
O
Me Me
O
OEt
SO2ClClO2S
[O]
HN NH
O
Me Me
O
O
CSI
N
O
Me Me
OEt
ClO2S
N
O
SO2Cl
N
O
Me Me
OEt
ClO2S
CSI
EtO
Me3Si Alkyl 1) CSI, CHCl3
0°C
AlkylNH2
O
HCl, H2O, !48-52%
N
EtOAlkyl
SiMe3
O2S O
Cl
OCN
EtO Alkyl
Malpass, J.R., Tet. Lett., 13, 4951
More Tri-Substituted Alkenes
Me
Me Me
CSI
-70°C
Me
Me Me
NSO2Cl
OH
CSI
warm
Me
Me Me MeMe
N
OClO2S
MeMe
O
NSO2Cl
Me Me
50% 20%
Me
Me MeO
N SO2Cl1,2 shift
Me
Me MeO
N SO2Cl
Alkynes
C C RR'CSI
O!SO2
N
R
Cl
R'
O!SO2
N
R'
Cl
R
+
1) Kobelt, D., et al., Tet Lett. 12, 1211 and 3627
2) Moriconi, E. J. Shimakawas, Y., JOC, 37, 196
3) Kobrich, G.,et al., Chem. Ber., 105 1683
O!SO2
N
R
Cl
R'PhSH
pyridine O!SO2
N
R
PhS
R'
Ring manipulations
O!SO2
N
R
Cl
R'
LAH
O!SO2
NH
R
Cl
R'1) CH3I, K2CO3
2) Li, t-BuOH O!SO2
N
R
R' Me
C CRR'
N
OClO2S
C C
RR'
N C
OClO2S
C C
RR'
N CO
O2S Cl
1) Giering, W. P., et al., JACS, 94, 8251
2) Rosenthal, S., Williams, R.V., Synthesis, 621(1988)
3) Moriconi, E. J., Shimakawa, Y., JOC, 37 196
More Alkynes
RC[M]
H
H
CSIN
R
[M]
O
SO2Cl
SiMe3R1) CSI, CHCl3
0°C2) HCl, H2O, !
R
NH2
O
54-71%
PhPhCSI (2.0 eq.)
N
N
PhPh
OClO2S
O SO2Cl
57%
R
SiMe3
O
NSO2Cl
1) Graf, R., Chem. Ber., 96,56
2) Dewynter, G., et al., Tetrahedron, 52, 993
3) Tanino, H., et al., JACS, 99 2818
Alcohols/Thiols
Me
Me
Me
OHCSI
Me
Me
Me
O NHSO2Cl
OCO2Me
NH3+Cl-
R1)
2) Et3NMe
Me
Me
O NHS
O
NH
O
O
CO2Me
R
steps
NH
S
NH
O
O
O
R
HN
N NH
HN
H2N
NH2
HO
OH
OH
1) CSI
2) H2O
HN
N NH
HN
H2N
NH2
O
OH
OH
H2N
O
RCSI
RX NHSO2Cl
O
XH
X = S or O
Olah, G., Synthesis,(2) 141, (1980)
CSI as an Oxidant for Alcohols
OH
H
1) CSI-Me2SO, CH2Cl2
-78°C2) Et3N, 25°C, 0.5 hr
O
HO H
1) CSI-Me2SO, CH2Cl2
-78°C2) Et3N, 25°C, 0.5 hr
O69-90%
Me
S
Me
O + CSI
Me
S
Me
O N
O
SO2Cl
Mechanism
+ CR OH
H
H Me
S
Me
O NH
O
SO2ClO
H
H
R
Pyridine
C O
R
H+ S
Me
Me
+ CO2 + H2N S
O
O
Cl
Vicinal Diols
Joseph., S.P., Dhar, D.N., Synth. Comm.,18, 2295
R1
R2
HO OH
R3
R41) CSI 0°C
2) Heat
R1
O R2
R3
R4
R1
R2
O O
R3
R4
O
R1
R2
R3
R4
O
R1
R2
HO O
R3
R4
H2N
O
+ + +
Mechanism
R1
R2
HO O
R3
R4
ClO2SHN
O
R1
R2
O O
R3
R4
O
R1
R2
HO O
R3
R4
ClO2SHN
O
- CO2
R1
R2
OH
R3
R4
R1
O R2
R3
R4R1
R2
R3
R4
O
Epoxides
1) Keshava Murthy, K.S., Dhar, D.N., Synth. Comm.,14, 687
2) Keshava Murthy, K.S., Dhar, D.N., J. Heterocylc.chem.,21, 1721
3) Dhar, D.N., et al., Chem. Lett. 1575 (1992)
O
Ph
Ph Ph
Ph
CSIPh
O
Ph
PhPh
O
Ph
MeOC6H4
1) CSIPh
MeOC6H4 HN O2) H2ONH
O
Ph
MeOC6H4
O O
51% 48%
O
R2
R1 R4
R3
CSIO O
R2
R1
R3
R4
NSO2Cl
O N
R2
R1
R3
R4
O
SO2Cl
+
H2O
OH-
O O
R2
R1
R3
R4
O NH
R2
R1
R3
R4
O
+
O
61-74% 21-31%
Mechanism
R
R1N O
O
ClO2S
H2OH2O
R
R1HN O
ONH
O
R
R1
O Dhar, D.N., et al., Chem. Lett. 1575 (1992)
O
R
R1
O C NSO2Cl
R1O
ON
SO2Cl
R
R1O
ON
SO2Cl
R
N
O
R
R1
OSO2Cl
Ketenes/Thioketenes
1) Mundloss, E., Graf, R., Ann., 677, 108
2) Schaumann, E., et al., Tet. Lett. 21, 4247
3) Romming, C., Skatteboel, L., Acta Chem. Scand., 43, 819
H2C C OCSI, CH2Cl2
-10°C
N
O
O
ClO2S
C C S
CSI, 100-150°C
12-48 hrs
N
S
O
ClO2S
29-83%
R
R1
N MeC
Ph
Ph
CSI, Et2O
-30 °CN NH
N
O
CPh2Ph2C
Me
Me
84%
Aldehydes
Graf, R., Angew. Chem. Int. Ed. Engl., 7, 172
R H
O
CSI
> 0 °C R H
NSO2Cl
+ CO2
O
N
C
R
O
SO2Cl
R H
O
CSI
< 0 °C
2 O
O
N
O
SO2Cl
RR
O
R
O
NSO2Cl
R H
O
di-Aldehydes
Daniel, J., Dhar, D.N., Tetrahedron, 48, 4551
H
O
ArO
H
1) CSI (2.0 eq)
2) H2OO
HN
NH
O O
ArH
O
Ar = p-ClC6H4, p-BrC6H4, o-ClC6H4, p-MeC6H4
67-88%
N
O
O
HAr H
SO2Cl
O
[4+2]
[4+2]
N
O
O
HAr H
SO2Cl
ON
SO2Cl
O
H2O
H
O
ArO
H
1) CSI (2.0 eq)
2) H2O
S
N NH
O O
Ar
Ar = p-NO2C6H4
64%
O
O
N
O
O
HAr H
SO2Cl
O
[4+2]
[2+2] N
O
N
HAr H
SO2Cl
OSO2Cl H2O
OH-Product
Ketones
Rasmussen, J.K., Hassner, A., JOC, 38, 2114
R
O
R1O NH
S
R
R1
O
O O
CSI
CH2Cl2
O NH
R
R1
O
O
+
R
OH
R1CSI
R
O
R1
O
NH
ClO2S
CSI
R
O
R1
O
N
SO2Cl
NHSO2Cl
O
NH3
HN NH
R
R1
O
O
uracil derivative
O NH
R
R1
O
O
More Ketones
1) Rasmussen, J.K., Hassner, A., JOC, 38, 2114
2) (Hoechst, A.G.), German Patent, 2, 327, 804 C.A. 82, 171097 (1975)
Me O
O O
MeCSI
Me O
O O
Me!
CONHSO2Cl
Me
O
CONHSO2ClS
O
HNO
O
O
Me
R
O
R2 R1
1) CSI
2) H2O
HN
O
R1 R2
RO 39-54%
R
O
R1 CSI
DMFR2
R
O
R1
R2CN
69%
R
O
R2
R1
O
NClO2S
N
O
R1 R2
RO
ClO2S
Ketones…
1) Clauss, K., et al., Ann., 561 (1974)
2) Kamal, A., et al., Synth. Comm., 10, 799
3) Daniel, J., Dhar, D.N., Synth. Comm., 21, 1695
4) Dhar, D.N., Bag, A.K., Ind. J. Chem., 22B, 627
O
Ar
NH
Ar
1) CSI, Toluene
2) H2O, OH-
N
Ar
N
Ar
O 61-81%
OH
O
R
CSI
PhMe, Reflux
O
N
S
O
O
R
65-85%
Ph
O
CSI
then ! S
N
O
O
Ph
28%
NNH
Ar
RR
O O1) CSI, 0-25°C
2) H2O/OH-
NN
Ar
R
R
N OS
OO
NH
O
35-45%
…Ketones…
1) Black, H. T., et al., Synth. Comm., 22, 2729
2) Baker, W. R., et al., JOC, 53, 2340
3) Van Allan, J. A., et al., Heterocylc. Chem., 11, 195
O
Me
1) CH2I2, Zn, TiCl4
2) CSI, 23°CN
O
SO2ClMe
H
75%
O
O
Ph Ph
CSI, MeCN
23°C, 1 hrO
N
Ph Ph
SO2Cl
72-92%
O
O
O
Me
HO
Me
OMe
OR3
OR1Me
Me
Me
Me
Me CSI, CH2Cl2
- 5°C O
O
O
Me
O
Me
OMe
OR3
OR1
MeMe
Me
Me
MeNH
O
O
O
O
Me
O
Me
OMe
OR3
OR1
MeMe
Me
Me
MeNH
O+
6% 4%
… 2 more
1) Tripathi, M., Dhar, D. N., Ind. J. Chem., 26B, 1082
2) Clauss, K., et al., Ann, 561 (1974)
O
O
Ar
CSI (2.0 eq)
O
O
Ar
NH
O
O
Me
O
Me
O
CSI, -50°CO N
O
SO2Cl
O
MeMe
Me
O
O
NSO2Cl
Me
O
Carboxylic Acids
1) Graf. R., (Farbwke Hechst A.G.) German Patent, 931, 225, 1952
2) Keshava Murthy, K. S., et al., Synthesis, 506 (1982)
R OH
O
CSI, Et3N
R1 OH
O
R2OH
R3
NHR4
R OR2
O
R N
O
R O
O
R1
O
R3
R4
H OH
O
CSI
H O
O
NHSO2Cl
O
Esters/Thioesters
1) Wamhoof, H., Ertas, M., Synthesis, 190 (1985)
2) Iwakawa, T., et al., Chem. Pharm. Bull., 38, 1075, and 39, 1939
S
O
OR
NH
R1
1) CSI
2) 5% KOH S N
NH
O
O
R1
74%
N
XMe
Me
S
1) CSI, 0°C
2) warm to 23 °C3) AlCl3
N
XMe
Me
NS
OO
75%
X = S or O
[2+2]
NXMe
Me
S
N
O
SO2Cl-COS
N XMe
Me
NSO2Cl
FC
Amides
1) Olah, G., et al., Synthesis, 227 (1979)
2) Graf, R., et al., (Farbwke Hechst A.G.) German Patent, 1144718, Chem. Zbl., 20282 (1963)
3) Campbell, M. M., et al., JCS Pekin Trans. I, 817 (1978)
N
SN
O
O
O
Me
Me
CO2Me
1) CSI (Excess)
2) Na2S2O5 (aq.)
N
S
NO O
Me
Me
CO2Me
HN
O
O37%
R NH2
O
CSIR CN 74-87%
Et3N+ CO2 Cl S NH2
O
O
+
R NH
OH
Et3N
R NH
O
R N
O
H
N
O
SO2Cl
CSI
Amides Continued
1) Barbachyn, M.R., Tuominen, T. C., J. Antibiot., 43, 1199
2) Graf, R., et al., (Farbwke Hechst A.G.) German Patent, 1144718, Chem. Zbl., 20282 (1963)
3) Schossler, W., Regitz, M., Chem. Ber., 107 1931
S
N
HN
BoC
NH
O
NRO
NH
O
CSI, CH2Cl2
S
N
HN
BoC
NH
O
NRO
N
O
NHSO2Cl
O
R1—L
S
N
HN
BoC
NH
O
NRO
N
O
NHSO2
O
R1
R N
O
R1
R2
CSI
R N
N
R1
R2
ClO2S
H2O
R N
NH
R1
R2
N
N
Ph
Ph
N
O O
Ph
N
N
Ph
Ph
N
O O
Ph
CSI, CH2Cl2
71%O
N
SO2Cl
Amines
1) Hoechst. A. G., German Patent 2, 1855, 884. C.A. 94, 15413(1981)
2) Pasto, D. J., Chen, A. F. T., Tet. Lett, 14, 713
NH2
NO2
1) CSI
2) H2O
NH
NO2
NH2
O
Redn.
NH
HN
O
N
NN
HN
NH2
1) CSI
2) Hunig base
HN
NH
SO2
N3
O
!
H2ON
NN
HN
NH
NH2
O
79%
Mechanism
Pasto, D. J., Chen, A. F. T., Tet. Lett, 14, 713
N
NN
HN
NH2
1) CSI
2) Hunig base
HN
NH
SO2
N3
O
!
H2ON
NN
HN
NH
NH2
O
79%
N
NN
HN
NH
NSO2Cl
O
H+ transfer
N
NN
N
NH
NHSO2
O
Cl
N
NN
N
NH
NHO2S
O
N
NN
HN
NH
HN
SO3H
O
H2O
N
NN
N
NH
NHO2S
O
Amines
Hammer H., Winterfeldt, E., Tetrahedron 37, 3609
NN O
CO2Me
Et
H
ONH
NN
Et
H
ONH
aza-eburnamonine
NH
N O
CO2MeEt
H 1) CSI
2) H2ON
N O
CO2MeEt
H
ONH2
Na2CO3 NN O
CO2MeEt
H
ONH
Aziridines
Kehsava Murthy, K.S., Dhar, D.N., J. Heterocycl. Chem. 21, 1699
NPh
H
H
R
O
Ar
CSI
O O
N
H Ar
NSO2Cl
R
Ph
H
N N
O
H Ar
O
Ph
H
SO2ClR
Ar = Ph, p-Me-Ph
Ar = p-Cl-Ph, p-F-Ph
N
Ph
H
Ph
H
Ph
CSI, 0°C
Et2O:CHCl3(4:1)
H2O
KOH
N O
NSO2Cl
Ph
PhPh
HH
N O
O
Ph
PhPh
HH
66% 82%
Proposed Mechanism
Kehsava Murthy, K.S., Dhar, D.N., J. Heterocycl. Chem. 21, 1699
NPh
H
R
OAr
NSO2Cl
O
N N
O
H Ar
O
Ph
H
SO2ClRNPh
H
H
R
O
Ar
Ar = p-Cl-Ph, p-F-Ph
NPh
H
H
R
O
Ar
O
Ar
O
N
ClO2S
N
R
Ph
HO O
N
H Ar
NSO2Cl
R
Ph
H
Ar = Ph, p-Me-Ph
Nitrogen Heterocycles
1) Moddy, J. C., Swann, E., Tet. Lett., 34, 1987
2) Yasuyoshi, M., et al., Heterocylces, 38, 1881
3) Joseph, S. P., Dhar, D.N., Tetrahedron, 44, 5209
N
Me
1) CSI, Et2O
2) H2O
OBn
MeO
N
Me
OBn
MeO
ONH2
97%
NN
Ph1) CSI, MeCN
2) H2O or DMF
NN
Ph
R
H2O, R= CONH2DMF, R = CN
N
R2R4
R6
O
R1
R5 CSI, CH2Cl2
-10°CN
R2R4
R6 R1
R5
52-70%
[3+2]
N
R2R4
R6
O
R1R5
O
NSO2Cl
H
H+
N
R2R4
R6
O
R1R5
O
NH
SO2Cl
H
More Nitrogen Heterocycles
1) Joseph, S. P., Dhar, D.N., Tetrahedron, 44, 5209
2) Friedrichsen, W., et al., Heterocycles, 20, 845
N
NMe
R
Me
SiMe3 CSIN
NMe
R
Me
N
O2
S
O
N
Me
Me
O
H
Me CSI, CH2Cl2
-10°CNH
Me
Me O
Me
40%
MeMe
[3+2]
NMe
O
Me
O
NSO2Cl
MeMe
H
N
Me
Me O
Me
Me
H+
Nitrones for Ring Expansion
Joseph, S. P., Dhar, D. N., Tetrahedron, 44, 5209
RMe
Me
NMe
O
CSI, -15°C
RMe
Me
N
Me
O72%
then 23°C
N
O
Me N
O
Me 64%CSI, -15°C
then 23°C
N
Me
O[3+2] O
O N
Me
N
ClO2S
Mechanism
23°C
N
Me
O
Cyanides with Adjacent Heteroatom
1) Garcia, M. V., et al., Synthesis, 6978 (1991)
2) Reddy, A. V. N., et al., Synth. Comm., 18, 525
R
Me
OH
CN
1) CSI
2) H2O, H+
O
NH
Me
RO
O
43-78%
NH
R
CN
CSI, CH2Cl2
NH
N
R
O
NH
R
Me
O
C
NSO2Cl
O
N H+
O
N
Me
R
O
HN SO2Cl
Diazo Compounds
1) Steinbeisser, H., et al., Anorg. Allg. Chem., 406, 299
2) Graf, R., Angew. Chem. Int. Ed. Engl., 7, 172
C
F3C
F3C
N NCSI
10-60°C
O
SN
F3CCF3
O
O
Cl
RO
O
N NRO
O
N
N
N
SO2Cl
O
CSI
CF3C
F3C
N N
NO
S
O
O
Cl
CF3C
F3CN
N
NO
S
O
O
Cl
Azides
Vander Sarel, J-M., et al., JOC, 38, 675
R N3CSI
N
N N
N
O
SO2ClR 95%
R N N NR N N N
O C N
SO2Cl
N
N N
N
O
SO2ClR
[3+2]
Oxygen Heterocycles
1) Sampath Kumar, E., Dhar, D.N., Synth. Comm., 25, 1939
2) L!Abbe!, G.,Destexhe, R., Chem. Comm., 1614 (1985)
O
Ar
1) CSI, 15-30°C
2) H2OHN O
O
Ar
O
Ar O
N
SO2Cl
N O
O
Ar
ClO2S
H2O
N
OMe
Me
N
Ar
OEt
CSI, Benzene
70°C
N
O Me
Me
O
N
Ar
ClO2S
33%
N
OMe
Me
N
Ar
OEt
O
NClO2S
O
N
Ar
N
SO2Cl
Me Me
N
O
OEt
Organo-Silicon Compounds
1) Barton, T.J., Rogido, R.J., Chem. Comm., 878 (1972)
2) Barton, T.J., Rogido, R.J., JOC, 40, 582
N N
O
Me Me
SiMe3Me3Si CSI, CH2Cl2N
SO2
N
NO
Me
OSiMe3
Me
100%
Si PhPh
Me Me
CSI, Et2O
SiO
Me MePh
Ph
NSO2Cl
N N
O
Me
Me
SiMe3
Me3Si
O NSO2Cl
Silyl migration N N
O
Me
Me
SiMe3
O N
SiMe3
S
O
Cl
O
- Me3SiCl
Organo-Silicon Compounds Continued
1) Esch, P. M., et al., Tetrahedron, 48, 3445
2) Roberson C., Woerpel, K., JOC, 64, 1434
N
OO
PhPh
SiMe3 1) CSI, (1.7 eq)
2) HCl/H2O N
OO
PhPh
NH2
OH 61%
R
Si Me
Me
Me
Ph
98% ee
1) CSI, PhCH3, 23°C
2) Red-Al, -78°C to 23°CNH
PhMe2Si Me
R O
64%
> 95:5 dr
98% ee
N
OO
PhPh
SiMe3
N
O
SO2Cl
H
[1,5] Brook
rearrangement N
OO
PhPh N
O
SO2Cl
H
H2O/H+
SiMe3
Miscellaneous Reactions
Arnswald, M., Neumann, W.P., JOC, 58, 7022
SnR3
R1
CSI
- 20 °C
SO2NCO
R1
DMSO
SO2N
R1
S
Me
Me
O2S
R1
N
O
S O
MeMe
- CO2
SO2N
R1
C
DMF
O2S
R1
N
O
C O
NMe2H
- CO2
H
NMe2
Synthesis of (+)-Blastmycinone
1) Peng, Z. H., Woerpel, K. A., Org. Lett., 5, 675
2) Wasserman, H. H, Gambale, R. J., JACS, 107, 124
" Degradation product of the macrocyclic dilactone (+)-antimycin A3
" !-Butyrolactone an important core structure in many biological active
natural products
" Three contiguous stereogenic centers with a cis/trans/cis relationship
" Two major Challenges:
A) [3+2] cycloaddition C=O Vs. C=N
B) controlling the selectivity of the [1,2]-silyl shift
O
O
O
O n-Bu
Me
OOMe
n-BuOi-Bu
O
O
i-Bu
O
Me
HN
O
OH
NHCHO
(+)-Antimycin A3 (+)-Blastmycinone
[3+2] Cycloaddition Challenge
H R1
H
HR2
R3Si
O C NSO2Cl
H R1H
HR2
R3Si
ON
SO2Cl
[1,2]-Si shift
H R1H
H
R2O
N
SO2Cl
H R1H
H
R2
R3Si
NO
R3Si
SO2Cl
Favored R1 = large
R2 = smallN-Cyclization Favored R1 = small
R2 = largeO-Cyclization
NO
O
SO2Cl
NO2ClR2
R1R3Si
R1
R2
R3Si
Stepwise Synthesis of (+)-Blastmycinone
Peng, Z. H., Woerpel, K. A., Org. Lett., 5, 675
OTHP
1) BuLi, (Ph2CH)Me2SiCl p-TsOH, 94%
2) PCC; BuLi, 71%
3) PDC, 91%
Si
Me
Me
Ph
Ph
O
Me
i-PrOHNH
Ru
TsNPh
Ph
Me
Me Me(3 mol%) 99%
R3Si
OH
Me
97.4% ee
1) THP, CSA, 96%
2) Cy2BH;ACOH; p-TsOH, 90%3) PhNCO, 96%
Me
OCONHPhSiR3
Me
BuLi; CuI·2LiClPhMe2SiCh2MgCl 88%
R3Si
PhMe2Si
E:Z = 98:2
95% ee
Final Steps in the Synthesis (+)-Blastmycinone
Peng, Z. H., Woerpel, K. A., Org. Lett., 5, 675
Me
R3Si
PhMe2Si
1) CSI, CH2Cl2
2) HCl, THF-H2O 72%
O O
n-BuR3Si
PhMe2Si
d.r. = 97:3
94% ee
1) KBr, AcOOH, 73%
2) CBr4, PPh3; Bu3SnH, AIBN, 79%
O OMe
n-Bui-BuCOO
(+)-blastmycinone
1) CSF; H2O2, 81%
2) Me2CHCH2COCl, Et3N, DMAP, 89%
O O
n-Bui-BuCOO
PhMe2Si
Summary & Conclusions
" Powerful and versatile reagent
" Can be used to access valuable motifs for:
A) Biological
B) Pharmaceutical
C) Agricultural
Thank You!
