1 r3 2 h* 3 1 n 3 1 3 r o n ruthenium-hydride and n 2 n r ... · lansiumamide b fruits of clausena...

NH

O

Ru

PnBu

3

Ru

H

PnBu

3

N

O

PnBu

3

PnBu

3Ru

H

N

nBu

3P

PnBu

3

PnBu

3

O

Ru

H

NP

nBu

3

PnBu

3

O

nBu

3P

DMAPRu

H

N

DMAPP

nBu

3

PnBu

3

O

Ru

H

NP

nBu

3

PnBu

3

O

DMAP

DMAP

PnBu3

DMAP

toluene

T

[Ru0(PnBu3)xDMAPy]

ox. addition

red. ligandexchange ?

duplet/triplet quartet quartet triplet triplet

Literature and Further Reading (see also www.chemie.uni-kl.de/goossen)

(1) a) L. J. Gooßen, J. E. Rauhaus, D. Deng, Angew. Chem. Int. Ed. 2005, 44, 4042; b) L. J. Gooßen, K. S. M. Salih, M. Blanchot, Angew. Chem. Int. Ed. 2008, 47, 8492, c) L. J. Gooßen, M. Arndt, M.

Blanchot, F. Rudolphi, F. Menges, G. Niedner-Schatteburg, Adv. Synth. Cat. 2008, 350, 2701.

(2) L. J. Gooßen, M. Blanchot, M. Arndt, K. S. M. Salih, Synlett 2010, 1685.

(3) a) Yet, L. Chem. Rev. 2003, 103, 4283; b) Stefanuti, I.; Smith, S. A.; Taylor, R. J. K. Tetrahedron Lett. 2000, 41, 3735; c) Rao, M. R.; Faulkner, D. J. J. Nat. Prod. 2004, 67, 1064.

(4) a) L. J. Gooßen, M. Blanchot, C. Brinkmann, K. Gooßen, R. Karch, A. Rivas-Nass, J. Org. Chem. 2006, 71, 9506; b) L. J. Gooßen, M. Blanchot, K. S. M. Salih, K. Gooßen, Synthesis 2009, 2283; c) L. J.

Gooßen, M. Blanchot, K. S. M. Salih, R. Karch, A. Rivas-Nass, Org. Lett. 2008, 10, 4497; d) A. E. Buba, M. Arndt, L. J. Gooßen J. Organomet. Chem. 2010, in press.

(5) Unpublished results.

(6) M. Tokunaga, T. Suzuki, N. Koga, T. Fukushima, A. Horiuchi, Y. Wakatsuki, J. Am. Chem. Soc. 2001, 123, 11917.

(7) M. Oliván, E. Clot, O. Eisenstein, K. G. Caulton, Organometallics 1998, 17, 3091.

Ruthenium-Hydride and –Vinylidene

Species as key Intermediates

in Hydroamidation Reactions

Abstract: The enamide moiety is an important motif often encountered in biologically active compounds and synthetic drugs. We have previously developed ruthenium-

based complexes as effective catalysts for the anti-Markovnikov addition of amides, imides, and thioamides to terminal alkynes.1 This method proved to be suitable for

the synthesis of several natural products, namely botryllamides C and E, lansamide I, lansiumamides A and B. These new reaction pathways proceed in only one to

three steps and yield the products in 57 to 98%, starting from cheap and easily available compounds.2

Comprehensive mechanistic studies were performed with the goal of getting a better understanding of the catalytic cycle. In this context the reaction mixture was

investigated in situ by NMR (1H, 1H{P}, 2H, 31P, 31P{H}, PP-COSY, HP-HMQC), ESI-MS/ -MS-MS and IR spectroscopy. Complemental deuterium labelling experiments

and kinetic studies were carried out and lead to the conclusion that a redox neutral mechanism must be excluded for the hydroamidation. The new findings support a

catalytic cycle starting from a ruthenium(0) species. Oxidative addition of the N-H nucleophile results in the formation of a ruthenium-amide-hydride species. The alkyne

then inserts into the ruthenium-hydride bond generating a ruthenium-vinyl species, which in the rate-determining step rearranges to a ruthenium-vinylidene-hydride

intermediate. This mechanism explains the anti-Markovnikov selectivity of such hydroamidation reactions and their restriction to terminal alkyne substrates.

The Enamide Functionality

The enamide moiety is an important substructure often found in natural products and synthetic

drugs.3 Enamides and their derivatives are also versatile synthetic intermediates,

e. g. for the preparation of heterocycles, chiral amines or amino acids.

Matthias Arndt, Mathieu Blanchot, Kifah S. M. Salih, Annette E. Buba, Lukas J. Gooßen*

“Dream Reactions”: Addition of Amides, Imides and Thioamides to Terminal Alkynes1,4

Traditional syntheses of enamides require harsh conditions, lead to the formation of mixtures of

E/Z products or suffer from the limited availability of the starting materials.

A much more attractive synthetic access is the Ru-catalyzed addition of amides to alkynes:

Institut für Organische Chemie, TU Kaiserslautern, Erwin-Schrödinger-Straße-54, 67663 Kaiserslautern,

Tel.: (+49) 0631 205 2046, [email protected]

Synthesis of Natural Products via Hydroamidation2

Following the protocol for the addition of primary amides to terminal alkynes the natural

products botryllamides C and E, lansiumamides A and B, and lansamide I could be synthesized

in 1-3 steps and 57-98% overall yield.

Mechanistic Investigations5

NH

O

Ph

NH

O

N

O

nBu

EtO

N

O

O

nBu

NH

O

nBu

Ph

O

N

nBu

NO

OnBu

N

SnBu

N

O

SiMe3 N

OtBu

N

O

CO2Me

N

O

N

O

(CH2)OMe

80%, Z/E = 1:3

96%, E/Z = 1: 22

90%, E/Z = 2:1

96%, E/Z = 40: 1

93%, E/Z = 40: 1

98%, E/Z = 1: 8

94%, E/Z = 1: 18

97%, E/Z = 8:1

99%, E/Z = 24: 1

99%, E/Z = 40: 1

99%, E/Z = 40: 1

94% ,E/Z = 22: 1

Chondria atropurpurea

NH

NH

O

NH

Chondriamide C

N

O

Lansamide I

N

O

Lansiumamide A

N

O

Lansiumamide B

Fruits of Clausena Lansium Leaves of Clausena Lansium

3rd EuCheMS 2010 Chemistry Congress

29.08 – 02.09.2010 Nürnberg / Germany

Marine ascidian Botryllus Schlosseri

OHO

O

N

O

Br Botryllamide C

OHO

O

N

O

Botryllamide E

1.0

0

0.8

7

0.8

9

0.4

1

0.9

0

[ppm]5 0 - 5 - 10 - 15 - 20 [ppm]5 0 - 5 - 10 - 15 - 20

-8.4

1-8

.45

-8.5

0

-8.5

9-8

.63

-8.6

8

-18.5

9-1

8.6

3

-18.6

8-1

8.7

2

-22.7

0-2

2.7

4-2

2.7

9-2

2.8

3

-11.4

4-1

1.5

0-1

1.5

5

-12.4

7-1

2.5

1-1

2.5

4

-8.3

5

-8.5

5

-8.7

4

-11.5

1

-11.6

3

-12.5

2

-18.6

6

-22.7

7b)

a)

1H-NMR experiments with 2-pyrrolidinone after heating

to 100°C for 5 min. a) 1H-NMR (C6D6, 600 MHz, 298 K),

b) 1H{31P}-NMR (C6D6, .400 MHz, 298 K).

P,P-COSY and H,P-HMQC experiments with 2-pyrroli-

dinone; spectra measured at 298 K after 5 min at 100°C.

[ppm]100 50 0

1.0

3

2.2

6

2.2

2

1.0

0

-7.9

8-8

.42

13.8

613.7

713.6

8

19.3

719.2

619.1

5

52.7

552.6

3

a)

13.8

313.7

613.7

1

19.3

619.2

819.2

419.1

6

-7.9

2-8

.02

-8.1

8

-8.2

7-8

.22

52.8

752.7

552.6

4

b)

31P-NMR experiments: with 2-pyrrolidinone after heating

to 100°C for 5 min. a) 31P-NMR (C6D6, 243 MHz, 298

K), b) 31P{1H}-NMR (C6D6, 243 MHz, 298 K).

593.28675.38

716.38

757.48

798.46

833.53

921.71

1003.80

1085.92

0

2

4

6

8

x104

Intens.

400 500 600 700 800 900 1000 1100 1200 m/z

631.2

712.3792.4

0

1

2

3

x104

Intens.

400 500 600 700 800 900 1000 1100 1200m/z

675.3

691.3 757.4

839.5

921.6

0

50

100

150

200 Intens.

400 500 600 700 800 900 1000 1100 1200 m/z

501.1 549.2

596.2 716.4

757.5

798.5

833.5

880.5921.7

0

1

2

3

4

x105

Intens.

400 500 600 700 800 900 1000 1100 1200 m/z

a) b)

c) d)

ESI-MS spectra for the hydroamidation of 2-pyrolidinone and

1-hexyne. a) 100°C for 5 min without 1-hexyne; b) with

1-hexyne 5 min at 100°C; c) 40 min; d) 150 min.

M+H+ = 918.58

[Ru(PC12H27)2(C7H10N2)2(C4H6NO)1(C6H10)1H]

M+H+ = 751.45

[Ru(PC12H27)2(C7H10N2)2]

M+H+ = 836.50

[Ru(PC12H27)2(C7H10N2)2(C4H6NO)1H]

[Ru(PC12H27)2(C7H10N2)2(C6H10)1H]+

M+H+ = 877.50

[Ru(PC12H27)3(C4H6NO)2]

dimerisation species:

M+H+ = 798.45

[Ru(PC12H27)1(C7H10N2)2(C4H6NO)1(C6H10)2H]

827.53828.54 829.55

830.54

831.54

832.54

833.53

834.53

835.53

836.54

837.55 838.58

827.53828.54 829.53

830.53

831.53

832.53

833.53

834.53

835.53

836.53

837.54

828 830 832 834 836 838 m/z

792.47793.48 794.52

795.49

796.47

797.47

798.46

799.48

800.47

801.48

802.49

792.48793.48 794.48

795.48

796.48

797.48

798.48

799.48

800.48

801.48

802.48

792 794 796 798 800 802 m/z

[Ru(PC12H27)1(C7H10N2)2(C4H6NO)1(C6H10)1H]+H+

593.28675.38

716.38

757.48

798.46

833.53

1003.80

1085.92

0

2

4

6

8

4x10

Intens.

400 500 600 700 800 900 1000 1100 1200 m/z

921.71

successful assignment of 7 different Ru intermediates and

detection of [PnBu3C4H7+]-fragments (not displayed) →

evidence for PnBu3 mediated reductive ligand exchange

R1

R2

N

O

H*R

3

N

R1

R2

OH

H* LnRu

LnRu

H*

N R1

R2

O

H

R3

LnRu

NR

1

R2

O

H

R3

H*

Ln-1

Ru

H*

NR

1

R2

O

H

R3

Ln-1

Ru

H

NR

1

R2

O

R3

H*

LnRu

H

N

R3

H*

R2O

R1

L

L = phosphine and/or additive

LL

L

a

b

cd

e

f

In situ NMR-

experiments

Kinetic Isotope Effects via NMR

competition hydroamidation reactions:

In situ NMR-Experiments

In situ ESI-MS Experiments

kH/kD= 1.5-2.3 → primary KIE → cleavage

of the C(sp)-H bond of the alkyne in the

rate-determining step → involvement of Ru-

vinylidene species very likely → vinylidene

formation see Wakatsuki6 and Caulton7

a) oxidative addition of an amide

b) coordination of an alkyne

to the resulting Ru-H-amide

intermediate

c) insertion of the p-coordinated

alkyne into Ru-H bond

d) rearrangement to a Ru-H-

vinylidene species

e) selective attack of the amide in

a-C position

f) reductive elimination of the

product and regeneration of

the active Ru(0) species

Mechanism for the Ru-catalyzed Hydroamidation

• no 1,2-proton shifts → confirmed via deuterium-labeling experiments

• formation of E-enamides with sterically less hindered ligands (e.g.

PnBu3, PnOc3) → thermodynamically favored product

• formation of Z-enamides with bulky, bidentate ligands (e.g. dcypm,

dcypb) → repulsion of R3 and ligands (Ru-H-vinylidene species)

N

nBu

H

H

R1

O

R2

N

nBu

H

D

R1

O

R2

NR1

O

R2

H

H

nBu

D

nBu

2 eq.

2 eq.

+kH /kD = 1.5-2.3

1 eq.[Ru]-cat.

R1

N

O

R2

R3

R1

N

S

R3

R2

R1

N

S

R3

R2

R1

N

O

R3

R4

O

R1

N

O

R3

R4

O

R1

N

O

R3

H

R1

N

O

R3

H

R1

N

O

R2

R3

R1

N

O

R2

R3

R1

N

O

R2

R3

R1

N

X

R2

H

R3

enamide, X=O

thioenamide, X=S

sec. enamide, X=O

enimide, X=O(cod)Ru(met)2

(cod)Ru(met)2

PnBu3

Sc(OTf)3

PiPr3

Sc(OTf)3

NEt3

PnBu3/DMAP

K2CO3/H2O

PnOc3

3Å MS

dcypmKOtBu

up to 98% yield20/1 E/Z





up to 98% yield1/20 Z/E



dcypm, H2O


dcypb/Yb(OTf)3


PnBu3/DMAP

(cod)Ru(met)2

(cod)Ru(met)2

RuCl3.3 H2O

+

R2=C(O)R3

R2=H

dcypb, Yb(OTf)3

enamide, X=O

Assig

nm

en

t PhNH

O

Ph

Ph

N

O

Ph

Ph

NH2

O

Ph

N

O

PhPh

+

MeI, NaH, 85%

Lansiumamide A98%, E/Z = 1 : 20

Lansiumamide B, E/Z = 20 : 178% overall yield

Lansamide I, E/Z = 20 : 172% overall yield

Ru/Yb dcypb

1. Ru/Yb, dcypb2. MS, NEt3, 85%

3. MeI, NaH, 85%

OHOMe

O

NH

R

OMe

OHOMe

NH2

O OMe

R

R = Br: botryllamide C(59% overall yield)

R = H: botryllamide E(57% overall yield)

R = Br, 88%, E/Z = 20:1R = H, 85%, E/Z = 20:1

1. Ru/Yb dcypb2. MS, NEt3

accessible in 67% yield

F2 [ppm] 40 20 0 - -20 F1 [ppm] 5 0 -5 -15 -10

F1 [

pp

m]

40

20

0

-20

F1 [

pp

m]

40

20

0

- 20

Simulated pattern:

Simulated pattern:

http://www.chemie.uni-kl.de/goossen



1 r3 2 h* 3 1 n 3 1 3 r o n ruthenium-hydride and n 2 n r ... · lansiumamide b fruits of clausena...

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