Post on 07-Feb-2018
Transition Metal-Catalyzed
1,2-Diamination of Alkenes
Group Meeting
Timothy Chang
04-27-10
Valuable 1,2-Diamine Motif
NH
Pt
HN
O
O O
O
Eloxatin(Anticaner)
H2N
AcHN
OCHEt2
O
OEt
Tamiflu(Antiviral)
NCl
CO2H
HN
O
Ph
O
Lorabid(Antibacterial)
Ph Ph
S
NHHN COOH
O
Biotin
For a review on various synthetic methods of vicinal diamines, see
Lucet, D.; Gall, T. L.; Mioskowski, C. Angew. Chem. Int. Ed. 1998, 37, 2580.
For a review on the transition-metal catalyzed diamination, see
Cardona, F.; Goti A. Nature Chemistry 2009, 1, 269.
N N
Ph PhMe Me
RuCl
PhPy
Cl Py
Metathesis Catalyst(Grubbs)
N N
O O t-Bu
t-But-Bu
t-BuMn
Cl
Epoxidation Catalyst(Jacobsen)
P
P
PhPh
PhPh
HN
RuNH
Ph
Ph
Cl
Cl
Hydrogenation Catalyst(Noyori)
Osmium Mediated Diamination
OOsO
Nt-Bu
Nt-BuOsO4 Ph3P Nt-Bu
2 equiv
+CH2Cl2
reflux, 48 h
OOsO
Nt-Bu
Nt Bu+
CO2Et NOsN
O
O
t-BuCO2Et
DCMrt, 5 h
63%
Chong, A. O.; Oshima, K. Sharpless, K. B. 1977 J. Am. Chem. Soc. 99, 3420.
For a review on osmium mediated diamination, see Muñiz, K. New J. Chem. 2005, 29, 1371.
O Nt-Bu EtO2C NO
t-BuCO2Et
rt, 5 h
1.5 equiv
84%
recovered unchanged frompreparative GLC at 250 oC
- Cis-disubstituted olefins react sluggishly.- Different amounts of hydroxyaminated products were observed for otherolefins such as styrene and 1-decene.
Palladium Mediated Diamination
2 equvMe2NH(9 equiv)-40oC45 min
THF, 0oC, 5 min
mCPBA(10 equiv)15 min
then rt, 3 h
1. KBH42. NaOH NH2
NH2
77%(based on Pd)
PdCl2(PhCN)2
Bäckvall, J.-E. C. Tet. Lett. 1978, 19, 163.
Ph
D Me2N NMe2
PhH D
H
PdCl2(PhCN)2
Proposed Mechanism:
Me2N
PhH
DH Me2N
PhH
DH
[PdIV][PdII]
Me2NH
[O]
Me2NH
Palladium Catalyzed Oxidative Intramolecular Diamination
Conditions:A: Pd(OAc)2 (5 mol %), PhI(OAc)2 (2.2 equiv), NMe4Cl/NaOAc (1 equiv), CH2Cl2, RT, 12 h.B: Pd(OAc)2 (25 mol%), PhI(OAc)2 (2.2 equiv), CH2Cl2, RT, 48 h.C: Pd(OAc)2 (10 mol%), PhI(OAc)2 (2.2 equiv), CH2Cl2, RT, 12 h.
NH
NH
O
RNN
O
R
( )n
( )n
Conditions
O O O OO
Streuff, J.; Hövelmann, C. H.; Nieger, M.; Muñiz, K. J. Am. Chem. Soc. 2005, 127, 14586.
NN
O
Tos
RR
R = Me, 92% (A)R = Ph, 95% (A)
NN
O
TosNN
O
Tos
91% (A) 86% (B)
NN
O
Tos
89% (C)
NN
O
Tos
MeMe Me
94% (A)
- Base is required (generated in situ from NMe4Cl/NaOAc) for reactivity (A).
- No reactivity difference by using Me4NOAc.
- Chlorinated intermediate may not be involved.
- Sulfamide substrates gave aminoacetoxylated product.
NN
Nt-Bu
Tos
95% (A)PhI(OAc)2 (2 equiv)
The Overall Stereochemistry of Diamination
The acetoxy intermediate is not involved.
Anti diamination
Conditions:
Pd(OAc)2 (5 mol%)
PhI(OAc)2 (2 equiv)
NMe4Cl/NaOAc (1 equiv)
CH2Cl2, RT, 12 h
Streuff, J.; Hövelmann, C. H.; Nieger, M.; Muñiz, K. J. Am. Chem. Soc. 2008, 130, 763.
Anti diamination
Anti diamination
Which step involves
the inversion of the
configuration?
Stereochemistry of Aminopalladation and Titration Experiment
Not isolable
Syn aminopalladation due
to geometric constraint of
the urea.
1b
Streuff, J.; Hövelmann, C. H.; Nieger, M.; Muñiz, K. J. Am. Chem. Soc. 2008, 130, 763.
Stereochemistry of Aminopalladation and Titration Experiment
Not isolable
Streuff, J.; Hövelmann, C. H.; Nieger, M.; Muñiz, K. J. Am. Chem. Soc. 2008, 130, 763.
Modes of Syn Aminopalladation
Streuff, J.; Hövelmann, C. H.; Nieger, M.; Muñiz, K. J. Am. Chem. Soc. 2008, 130, 763.
Rate Determining Step
NH
NH
O
Tos
X
X = H, t-Bu, Cl, Br, F, CN
Aminopalladation is the RDS.
Streuff, J.; Hövelmann, C. H.; Nieger, M.; Muñiz, K. J. Am. Chem. Soc. 2008, 130, 763.
EWGEDGNN
O
TosX
Pd(OAc)2 (5 mol%)PhI(OAc)2 (2 equiv)NMe4Cl/NaOAc (1 equiv)CH2Cl2, RT, 3 h
Proposed Mechanism for the Second C-N Bond Formation
Conditions: Pd(OAc)2 (5 mol%), PhI(OAc)2 (2 equiv), NMe4Cl/NaOAc (1 equiv), CH2Cl2, RT, 2 h
Streuff, J.; Hövelmann, C. H.; Nieger, M.; Muñiz, K. J. Am. Chem. Soc. 2008, 130, 763.
The second C-N bond formation is not the RDS.
Conditions: Pd(OAc)2 (5 mol%), PhI(OAc)2 (2 equiv), NMe4Cl/NaOAc (1 equiv), CH2Cl2, RT, 2 h
Ion pair
Electrophilicity of -CH2-[PdIV]+ is enhanced
SN2 type
reductive elimination
Proposed Catalytic Cycle
Streuff, J.; Hövelmann, C. H.; Nieger, M.; Muñiz, K. J. Am. Chem. Soc. 2008, 130, 763.
An Example of Syn Diamination
Conditions: Pd(OAc)2 (10 mol%), PhI(OAc)2 (1.4 equiv), NMe4Cl/NaOAc (1.1 equiv), DMF, RT, 14 h
Syn diamination
89% yield
R = Tol
Muñiz, K. J. Am. Chem. Soc. 2007, 129, 14542.
Nickel-Catalyzed Diamination Using Sulfamide
Muñiz, K.; Streuff, J.; Hövelmann, C. H.; Núñez, A. Angew. Chem. Int. Ed. 2007, 46, 7125.
Terminal alkenes are
good substrates.
Pd-Catalyzed Diamination of Terminal Alkenes Using NFBS
RO
Byproducts
Sibbald, P. A.; Michael, F. E. Org. Lett. 2009, 11, 1147.
NHMe
Me
R
Me4a
NMe
Me
O
R
OC(O)CF3
5a
Proposed Catalytic Cycle
Sibbald, P. A.; Michael, F. E. Org. Lett. 2009, 11, 1147.
The Overall Stereochemistry of Diamination
Mechanistic implications of the
Sibbald, P. A.; Rosewall C. F.; Swartz, R. D.; Michael, F. E. J. Am. Chem. Soc. 2009, 131, 15945.
Mechanistic implications of the
two C-N bond formations from
the overall syn diamination:
1. Anti aminopalladation
followed by SN2 displacement
of the C-Pd bond.
2. Syn aminopalladation
followed by C-N reductive
elimination (retentive).
Stereochemistry of the Aminopalladation (1st C-N Bond Formation)
Chelation from the acetamide minimizes
β-hydride elimination.
Sibbald, P. A.; Rosewall C. F.; Swartz, R. D.; Michael, F. E. J. Am. Chem. Soc. 2009, 131, 15945.
Inversion is required for the
2nd C-N bond formation for
the overall syn diamination.
Proposed Mechanism for the 2nd C-N Bond Formation
Sibbald, P. A.; Rosewall C. F.; Swartz, R. D.; Michael, F. E. J. Am. Chem. Soc. 2009, 131, 15945.
Challenges in the Palladium Catalyzed Alkene Diamination
Bar, G. L. J.; Lloyd-Jones, G. C.; Booker-Milburn, K. l. J. Am. Chem. Soc. 2005, 127, 7308.
Challenges:
1. Catalyst poisoning
2. Protonation of amine source 2
3. Oxidation of amine source 2
4. β-hydride elimination (route I)
5. Activation of Pd-C bond for a second attack by amine 2
Pd-Catalyzed Intermolecular 1,2-Diamination of Conjugated Dienes
Bar, G. L. J.; Lloyd-Jones, G. C.; Booker-Milburn, K. l.
J. Am. Chem. Soc. 2005, 127, 7308.
Pd-Catalyzed Diamination of Conjugated Alkenes
Du, H.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 762.
- Conjugated dienes are effective substrates.
- Highly stereoselective and regioselective at the internal double bond.
- Z isomers do not react.
Synthesis of Di-tert-butyldiaziridinone
Greene, F. D.; Stowell, J. C.; Bergmark, W. R. J. Org. Chem. 1969, 34, 2254.
Du, H.; Zhao, B.; Shi, Y. Org. Synth. 2009, 86, 315.
Properties of Diaziridinones
N
O
R N N
O
R R
O
C=O
R R
cyclopropanones aziridinones diaziridinones
amidesketones(saturated, aliphatic)
1813-1840 1837-1850 1855-1880
1650-1690~1710 1660-1695
ureas
C=O
cm-1
cm-1
Greene et. al. JOC 1969, 34, 2254.; JOC 1978, 43, 922.; JOC 1976 41 2813.
Heine, H. W. The Chemistry of Heterocyclic Compounds; Hassner, A., Ed; John Wiley & Sons, Inc: New York, 1983; pp 547.
N N
O
Me MeMeMe
Br Br
1.325 Å, typical amides (~1.33 Å)
F2N-NF2 (1.47 Å)H2N-NH2 (1.45 Å)
1.601 Å
The angle between the N-substituent andthe diaziridinone plane is 56o.
Proposed Catalytic Cycle
Pd(0)t-BuN Nt-Bu
O
O
Nt B
O
NN
O
t-But-Bu
R
Du, H.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 762.
t-BuN
Pd
Nt-Bu
R
t-BuN
Pd
Nt-Bu
O
Pd
Nt-But-BuN
R
R
Possible Reasons for High Stereoselectivity and Reactivity of E-Isomer
NMR Study of the Stoichiometric Reaction
1.36 ppm
1.32 ppm
1.59 ppm
177.3 (13C) 159.3 (13C)
58.1
33.6
59.327.2
19.8 (31P)
A is consumed in 1 min when
(E)-1-methoxybutadiene (6g)
was added at 85 min.
Zhao, B.; Du, H.; Cui, S.; Shi, Y. J. Am. Chem. Soc. 2010, 132, 3523.
Pd(PPh3)4 (0.03 mmol)
5 (0.02 mmol)
C6D6, 40oC
(0.04 mmol)1.05 ppm
Stoichiometric Reaction monitored by 1H NMRA is a possible intermediate.
Oxidative Addition is likely the RDS.
Kinetic Studies
MeOt-BuN Nt-Bu
O+
Pd(PPh3)4 (0.02 mmol)C6D6, 40
oCNN
O
t-But-Bu
E:Z = 15.7:10.24 mmol E
5
7g
6g
0.2 mmol
MeO
Zhao, B.; Du, H.; Cui, S.; Shi, Y. J. Am. Chem. Soc. 2010, 132, 3523.
1st order in diaziridinone 5.No induction period.
PPh3 dissociates rapidly.
Quantitative conversion . No side reaction. 1st order in Pd(PPh3)4 (not shown).
Kinetic Studies
Zhao, B.; Du, H.; Cui, S.; Shi, Y. J. Am. Chem. Soc. 2010, 132, 3523.
Inverse 1st-order in PPh3.Zero-order in diene 6g.
6g (0.12 mmol E isomer),
5 (0.1 mmol), Pd(PPh3)4 (0.01 mmol)
6g (0.12 mmol E isomer),
5 (0.1 mmol), Pd(PPh3)4 (0.01 mmol)
Kinetic Studies
+C6D6, 40
oCNN
O
t-But-Bu
7
6 MeO
RPd
NN
O
t-Bu t-Bu
Ph3P PPh3
A
Zhao, B.; Du, H.; Cui, S.; Shi, Y. J. Am. Chem. Soc. 2010, 132, 3523.
- A can be observed using 6i under catalytic reaction conditions ([A] is independent of PPh3).
C-N bond formation is slower for e-deficient dienes.
Refining the Catalytic Cycle
7-membered urea
was not observed
RDS for e-rich dienes.
- Rational for high regioselectivity?
- Why is cis-alkene unreactive?
Zhao, B.; Du, H.; Cui, S.; Shi, Y. J. Am. Chem. Soc. 2010, 132, 3523.
Associative displacement?
The olefin insertion into Pd-N is
slower for electron-deficient dienes.
Details of insertion?
Catalytic Asymmetric Diamination of Conjugated Alkenes
Du, H.; Yuan, W.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 11688.
Diamination at Allylic and Homoallylic Carbons
R2
R1
t-BuN Nt-Bu
O+
Pd(PPh3)4 (10 mol%)neat
65oC, 12 h55-93% yield
NN
O
t-But-Bu
R2
NN
O
t-But-Bu
2
NN
O
t-But-Bu NN
O
t-But-Bu
Et
2.75 equivslow addition R1
NN
O
t-But-Bu
Et
Du, H.; Yuan, W.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 7496.
R2
76%R2
PhEt
n-C6H13CH2OBn
CH2On-C6H13
Yield (%)90 (7 h)68749078
55%
Et
NN
O
t-But-Bu
PhMeO
NN
O
t-But-Bu
64%
MeO
n-Bu
92%
EtPh
93%
n-C6H13
- Highly stereoselective.
- No reactions for olefins with internal double bonds
(e.g. trans-5-decane and cis-cyclooctene).
Bisdiamination
A single diastereomer
Du, H.; Yuan, W.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 7496.
A single diastereomer
Using 5 mol% Pd(PPh3)4:
10a (14%) and
10b (20%) were isolated
after 12 h.
10a and 10b gave 11
under the diamination
reaction condition.
Proposed Catalytic Cycles
2 equiv
Du, H.; Yuan, W.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 7496.
Asymmetric Diamination at Allylic and Homoallylic Carbons
Rt-BuN Nt-Bu
O+
Pd2(dba)3 (5 mol%)L* (22 mol%)
neat65oC, 6 h50-85% yield89-94% ee
NN
O
t-But-Bu
R2.5 equivslow addition
O
OP N
Me Me
Me MeL*
REtn-C5H11CH2Ph
ee (%)909193
Yield (%)507167
NN
O
t-But-Bu NN
O
t-But-Bu
n-C6H13O
NN
O
t-But-Bu
Du, H.; Yuan, W.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 8590.
CH2Phi-PrPh
939490
675180 80% (92% ee)
6 3
85% (91% ee)
67% (92% ee)
NMeBn
NN
O
t-But-Bu
70% (97:3 dr)
NN
O
t-But-Bu
81% (90% ee)
n-C5H11
NN
O
t-But-Bu
69% (89% ee)
n-C5H11 MeOTMS
NN
O
t-But-Bu
66% (94:6 dr)
MeOTMS
Ligand control overrides substrate control
Diamination using Thiadiaziridine
Wang, B.; Du, .; Shi, Y. Angew. Chem. Int. Ed. 2008, 47, 8224.
Preliminary Studies on Mechanism
Diamination may not proceed Initial allylic amination is possible.
Wang, B.; Du, .; Shi, Y. Angew. Chem. Int. Ed. 2008, 47, 8224.
Diamination may not proceed
via a diene species
Initial allylic amination is possible.
No cyclization was observed
without 4.
Proposed Catalytic Cycle
Wang, B.; Du, .; Shi, Y. Angew. Chem. Int. Ed. 2008, 47, 8224.
Cu(I)-Catalyzed Diamination of Conjugated Dienes (1)
Yuan, W.; Du, H.; Zhao, B.; Shi, Y. Org. Lett. 2007, 9, 2589.
Cu(I)-Catalyzed Diamination of Conjugated Dienes (2)
Me+
t-BuN Nt-Bu
O CuCl (10 mol%)P(OPh)3 (10 mol%)C6D6, rt, 6 h Me
NN
O
MeN
N
Ot-Bu
t-Bu
t-Bu
t-Bu+
1:1.365%
+
t-BuN Nt-Bu
O CuCl (10 mol%)P(OPh)3 (10 mol%)C6D6, 65
oC, 6 h NN
Ot-Bu
t-Bu
MeMe
58%
1.5 equiv
1 5 equiv
Yuan, W.; Du, H.; Zhao, B.; Shi, Y. Org. Lett. 2007, 9, 2589.
+
t-BuN Nt-Bu
O CuCl (10 mol%)P(OPh)3 (10 mol%)C6D6, rt, 6 h N
N
Ot-Bu
t-Bu
PhPh Z/E = 3.3/1
76%
Ph+
t-BuN Nt-Bu
O CuCl (10 mol%)P(OPh)3 (10 mol%)C6D6, rt, 6 h
PhN
N
Ot-Bu
t-Bu
1.5 equiv
1.5 equiv
1.5 equiv
D
DD
DH
65:3573%
PhN
N
Ot-Bu
t-BuD
HD
+
Proposed Catalytic Cycle
Yuan, W.; Du, H.; Zhao, B.; Shi, Y. Org. Lett. 2007, 9, 2589.
Cu(I)-Catalyzed Asymmetric Diamination of Conjugated Dienes
Du, H.; Zhao, B.; Yuan, W.; Shi, Y. Org. Lett. 2008, 10, 4231.
Cu(I)-Catalyzed Diamination with Other Nitrogen Sources
R +t-BuN Nt-Bu
S
CuCl-P(n-Bu)3(10-20 mol%, 1:1)CDCl3, rt - 65
oC7-48 h R
NSN
t-Bu
t-Bu
R = arylheteroarylalkynealkylether
O O
1.2 equiv
OO
45-91% yield
- Electron-deficient olefin (ethyl acrylate) andaliphatic substituted olefin (1-octene) are not reactive.
Zhao, B.; Yuan, W.; Du, H.; Shi, Y. Org. Lett. 2007, 9, 4943.
Du, H.; Zhao, B.; Shi, Y. Org. Lett. 2008, 10, 1087.
R +t-BuN Nt-Bu
CuCl-P(n-Bu)3(10 mol%, 1:2)CDCl3, 50 - 65
oC24 h R
NN
t-Bu
t-Bu
R = arylheteroarylalkynealkenediene
1.2 equiv 48-86% yield
- No multiple diaminations with dienes or trienes.- Selective at the terminal olefin.- Electron-deficient olefin (ethyl acrylate) andaliphatic substituted olefin (1-octene) are not reactive.
NCN NCN
t-BuN Nt-Bu
Nt-Bu
No reaction
t-BuN Nt-Bu
NTs
Decomposed rapidly
Conclusions
- Transition-metal catalyzed 1,2-diamination allows rapid access to protected diamines
from alkenes. However, deprotection conditions are quite harsh (e.g. LAH, reflux con. HCl).
- High catalyst loadings are often required.
- Limited enantioselective approach available.
- The dinitrogen source has a strong influence on the reaction at the terminal or the - The dinitrogen source has a strong influence on the reaction at the terminal or the
internal alkene.
- Some mechanistic details are elucidated. More studies are required (e.g. nickel catalyzed
and copper catalyzed diaminations).
- Much work remained to be done to make this methodology general and practical.