transition metal-catalyzed 1,2-diamination of · pdf filepalladium catalyzed oxidative...

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


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


Stereochemistry of Aminopalladation and Titration Experiment

Not isolable


Modes of Syn Aminopalladation


Rate Determining Step

NH

NH

O

Tos

X

X = H, t-Bu, Cl, Br, F, CN

Aminopalladation is the RDS.


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


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


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


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.


Inversion is required for the

2nd C-N bond formation for

the overall syn diamination.

Proposed Mechanism for the 2nd C-N Bond Formation


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.


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


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


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


- 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?


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


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


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


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


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.


Diamination may not proceed

via a diene species

Initial allylic amination is possible.

No cyclization was observed

without 4.

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


+

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

+

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.

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