Matthias Arndt, Mathieu Blanchot, Kifah S. M. Salih, Lukas ... · PDF fileMatthias Arndt,...
1
Literature and Further Reading (see also www.chemie.uni-kl.de/goossen ) (1) a) Gooßen, L. J.; Rauhaus, J. E.; Deng, D. Angew. Chem. Int. Ed. 2005, 44, 4042; b) Gooßen, L. J.; Blanchot, M.; Brinkmann, C.; Gooßen, K.; Karch, R.; Rivas-Nass, A. J. Org. Chem. 2006, 71, 9506; c) Gooßen, L. J.; Blanchot, M.; Salih, K. S. M.; Karch, R.; Rivas-Nass, A. Org. Lett. 2008, 10, 4497, d) Gooßen, L. J.; Salih, K. S. M.; Blanchot, M. Angew. Chem. Int. Ed. 2008, 47, 8492. (2) a) Arndt, M. diploma thesis, Technische Universität Kaiserslautern, 2008; b) Gooßen, L. J.;Arndt, M.; Blanchot, M.; Rudolphi, F.; Menges, F.; Niedner-Schatteburg, G. Adv. Synth. Cat. 2008, 350, 2701. (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) Wang, X.; Porco, Jr., J. A. J. Org. Chem. 2001, 66, 8215. (4) a) Doucet, H.; Kabouche, Z.; Bruneau, C.; Dixneuf, P. H. J. Organomet. Chem. 1997, 551, 151; b) Mitsudo, T.; Hori, Y.; Watanabe, Y. J. Org. Chem. 1985, 50, 1566; c) Gooßen, L. J.; Paetzold, J. Chem. Commun. 2003, 706. (5) a) Bassetti, M.; Floris, B. J. Chem. Soc. Perkin Trans. 2 1988, 227; b) Suzuki, T.; Makoto, T.; Wakatsuki, Y. Org. Lett. 2001,3, 735. (6) a) Pholki, F.; Doye, S. Chem. Soc. Rev. 2003, 32, 104; b) Beller, M.; Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem. 2004, 116, 3448. (7) Alonso, F.; Beletskaya, I. P. M. Yus, Chem. Rev. 2004, 104, 3079. (8) Unpublished results. Practical and Effective Catalyst Systems for the Regio- and Stereoselective Catalytic Hydroamidation of T erminal Alkynes 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 In an attempt to gain more insight about the mechanism we spectroscopically monitored in situ our catalytic system. The information thus obtained in combination with data provided by some complementary RuCp-complex catalyzed hydroamidation experiments allowed us to devise a new, second generation catalyst based on the inexpensive and easy-to-handle RuCl 3 . 2 After diligent optimization, the new protocol matched or even surpassed the yields and selectivities obtained with the first-generation catalyst at a fraction of the original cost. The hydroamidation method proved to be an extremely valuable tool for the synthesis of natural products. 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 chiral amines or amino acids. Catalyzed Addition of Amides, Imides and Thioamides to T erminal Alkynes 1 Recently, we developed new ruthenium-based catalyst systems for the anti-Markovnikov addition of secondary amides 1a , imides, 1b thioamides 1c or primary amides 1d to terminal alkynes. These systems proved to be generally applicable to a plethora of amides, imides and thioamides. Matthias Arndt , Mathieu Blanchot, Kifah S. M. Salih, Lukas J. Gooßen*, H. Sitzmann* 1 R N O R 1 R 2 R 3 R 2 N H O R 3 R 2 N O R 3 R 1 R 2 N O R 3 R 1 + up to 99%, E/Z 40:1 [Ru(cod)(met) 2 ] P( n Bu) 3 DMAP RuCl 3 · 3H 2 O [HP( n Bu) 3 ] [BF 4 ] DMAP K 2 CO 3 , H 2 O toluene, 100 °C toluene, 100 °C + up to 99%, E/Z 40:1 “Dream Reaction” 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 route would be a catalytic addition of amides to alkynes. However, while related addition reactions of carboxylates, 4 water, 5 and amines 6 are well- established, to the best of our knowledge no efficient catalyst for a hydroamidation reaction has been reported. 7 Institut für Organische Chemie, TU Kaiserslautern, Erwin-Schrödinger-Straße-54, 67663 Kaiserslautern, Tel (+49) 0631 205 2046, [email protected] , [email protected] R 2 R 3 N S R 1 Cat. R 1 R 2 R 3 N O R 1 R 2 R 3 N S R 1 R 2 R 3 N O R 1 R 3 N O O R 2 R 1 R 3 N O O R 2 R 1 R 3 NH O O R 2 R 3 NH O R 2 R 3 NH S R 2 R 2 NH 2 O R 2 N H O R 1 R 2 N H O R 1 Ru (II) toluene 100 °C toluene 100 °C DMF 60 °C P( n Bu) 3 DMAP dcypm KO t Bu P( n Oct) 3 3A MS dcypm H 2 O P( i Pr) 3 Sc(OTf) 3 P( n Bu) 3 Sc(OTf) 3 = + Cat. up to 98% Z/E > 1:30 up to 74% Z/E > 8:1 up to 99% Z/E > 1:30 up to 99% Z/E > 8:1 up to 75% Z/E > 1:15 up to 99% Z/E > 30:1 up to 99% Z/E = 40:1 dcypb Yb(OTf) 3 NEt 3 3A mol. sieves Same Pot up to 89% Z/E =1:20 DMF/ H 2 O 60 °C Synthesis of Natural Products via Hydroamidation 1d Following the protocol for the addition of primary amides to terminal alkynes the natural products Lansiumamide A and Alatamide could be synthesized in high yields and stereoselectivities. Development of a RuCl 3 ∙3H 2 O-based Protocol for the Catalytic Hydroamidation 2 In an attempt to reverse the regioselectivity of the hydroamidation in favour of the Markovnikov product, we synthesized sterically demanding and electron-rich RuCp-complexes and utilized them in hydroamidation reactions. Unfortunately no beneficial influence of the Cp-Ligand could be observed. Furthermore, the results matched those of the [Ru(cod)(met) 2 ]-based protocol. 8 The information thus obtained in combination with spectroscopic investigations led us to the discovery of a new RuCl 3 -based protocol. The key step is the selective reduction of Ru III to Ru II during the catalyst preformation, which is mediated by the employed phosphine, a process assisted by water. ● 90% reduction of the catalyst cost ● better fit for large-scale applications ● replacement of air-sensitive, liquid ● dramatic improvement of the P( n Bu) 3 by its tetrafluoroborate salt synthetic applicability Representative examples of the scope are illustrated below. N N O O n Bu n Bu N O N O (CH 2 ) 3 Cl N O SiMe 3 N O (CH 2 )OMe N O O OMe N O n Bu N O t Bu N O n Bu N O Ph O n Bu N N O O n Bu N O O n Bu N S n Bu N O n Bu EtO N O n Bu 71%, Z/E = 1:40 97%, Z/E = 1:8 99%, Z/E = 1:33 90%, Z/E = 1:2 99%, Z/E = 1:24 96%, Z/E = 1:40 99%, Z/E = 1:40 99%, Z/E = 1:32 97%, Z/E = 1:22 91%, Z/E = 1:40 99%, Z/E = 1:40 88%, Z/E = 1:30 94% 80%, Z/E = 1:3 93%, Z/E = 1:40 49%, Z/E = 1:40 ,Z/E = 1:22 Myxobacteria Chondromyces Seeds of Zizyphus vulgaris spinosus Bunge Chondria atropurpurea N O Lansamide I N O Lansiumamide A N O Lansiumamide B Fruits of Clausena Lansium OH O O O OH N H O Apicularen A NH O O N H O N H O N Frangufoline N H N H O N H Chondriamide C Leaves of Clausena Lansium O R 1 NH R 2 R 3 R 4 O R 1 N R 2 R 3 R 4 O R 1 N R 2 R 4 R 3 or [cat.] + O NH 2 N O Ph SiMe 3 O H O Ph SiMe 3 O N 3 Ph SiMe 3 N O Ph SiMe 3 N H O Ph Ph MgBr O NH 2 OMe N O OMe Lansiumamide A + [Ru.-cat.] 98%, Z/E = 20:1 DPPA, Et 3 N toluene RT, 0.5 h aq. THF, 85°C Et 2 O, -78°C 0°C Curtius- Rearrangement TBAF 4 steps: 7% Alatamide 79%, Z/E = 1:18 1.) [Ru.-cat.] 2.) Isomerization + Synthesis by Taylor et al. 1b Ru Cp R Cl Cl Ru Cp R Cl Cl n N H O n Bu N O n Bu Ru Cp R O Ru Cp R O n RuCl 3 ·3H 2 O Cp R H MeOH T, 6 h P( n Bu) 3 DMAP K 2 CO 3 , MeOH toluene 100 °C, 15 h K 2 CO 3 MeOH T, 6 h + Cp R H = 99%, E/Z = 40:1 Ru (II) O N R 3 R 2 R 1 O N H R 3 R 2 R 1 Ru (III) O N R 3 R 2 Ru (II) L n X HNR 2 C(O)R 3 P( n Bu) 3 , DMAP K 2 CO 3 , H 2 O L n = P( n Bu) 3 and/or DMAP X = NR 2 C(O)R 3 or Cl, ... toluene 100 °C 2 + HNR 2 C(O)R 3 P( n Bu) 3 , DMAP - OP( n Bu) 3 KCl, KHCO 3 up to 99% Z/E > 1:40 Cl 3 ·3H 2 O Main features
Transcript of Matthias Arndt, Mathieu Blanchot, Kifah S. M. Salih, Lukas ... · PDF fileMatthias Arndt,...
Literature and Further Reading (see also www.chemie.uni-kl.de/goossen)
(1) a) Gooßen, L. J.; Rauhaus, J. E.; Deng, D. Angew. Chem. Int. Ed. 2005, 44, 4042; b) Gooßen, L. J.; Blanchot, M.; Brinkmann, C.; Gooßen, K.; Karch, R.; Rivas-Nass, A. J. Org. Chem. 2006, 71, 9506;
c) Gooßen, L. J.; Blanchot, M.; Salih, K. S. M.; Karch, R.; Rivas-Nass, A. Org. Lett. 2008, 10, 4497, d) Gooßen, L. J.; Salih, K. S. M.; Blanchot, M. Angew. Chem. Int. Ed. 2008, 47, 8492.
(2) a) Arndt, M. diploma thesis, Technische Universität Kaiserslautern, 2008; b) Gooßen, L. J.; Arndt, M.; Blanchot, M.; Rudolphi, F.; Menges, F.; Niedner-Schatteburg, G. Adv. Synth. Cat. 2008, 350, 2701.
(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) Wang, X.; Porco, Jr., J. A. J. Org. Chem. 2001, 66, 8215.
(4) a) Doucet, H.; Kabouche, Z.; Bruneau, C.; Dixneuf, P. H. J. Organomet. Chem. 1997, 551, 151; b) Mitsudo, T.; Hori, Y.; Watanabe, Y. J. Org. Chem. 1985, 50, 1566; c) Gooßen, L. J.; Paetzold, J. Chem.
Commun. 2003, 706.
(5) a) Bassetti, M.; Floris, B. J. Chem. Soc. Perkin Trans. 2 1988, 227; b) Suzuki, T.; Makoto, T.; Wakatsuki, Y. Org. Lett. 2001, 3, 735.
(6) a) Pholki, F.; Doye, S. Chem. Soc. Rev. 2003, 32, 104; b) Beller, M.; Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem. 2004, 116, 3448.
(7) Alonso, F.; Beletskaya, I. P. M. Yus, Chem. Rev. 2004, 104, 3079.
(8) Unpublished results.
Practical and Effective Catalyst Systems
for the Regio- and Stereoselective Catalytic
Hydroamidation of Terminal Alkynes
Einleitung in 40 Pt:
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Beispiel der Druckerauswahl für gelungene Ausdrucke
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 In an attempt to gain more insight
about the mechanism we spectroscopically monitored in situ our catalytic system. The information thus obtained in combination with data provided by some
complementary RuCp-complex catalyzed hydroamidation experiments allowed us to devise a new, second generation catalyst based on the inexpensive and
easy-to-handle RuCl3.2 After diligent optimization, the new protocol matched or even surpassed the yields and selectivities obtained with the first-generation catalyst at
a fraction of the original cost. The hydroamidation method proved to be an extremely valuable tool for the synthesis of natural products.
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 chiral amines or amino acids.
Catalyzed Addition of Amides, Imides and Thioamides to Terminal Alkynes1
Recently, we developed new ruthenium-based catalyst systems for the anti-Markovnikov
addition of secondary amides1a, imides,1b thioamides1c or primary amides1d to terminal alkynes.
These systems proved to be generally applicable to a plethora of amides, imides and
thioamides.
Matthias Arndt, Mathieu Blanchot, Kifah S. M. Salih, Lukas J. Gooßen*, H. Sitzmann*
1R N
O
R1
R2
R3
R2
NH
O
R3
R2
N
O
R3
R1
R2
N
O
R3
R1
+
up to 99%, E/Z 40:1
[Ru(cod)(met)2]
P(nBu)3
DMAP
RuCl3· 3H2O
[HP(nBu)3][BF4]
DMAPK2CO3, H2O
toluene, 100 °C toluene, 100 °C+
up to 99%, E/Z 40:1
“Dream Reaction”
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 route would be a catalytic addition of amides to
alkynes.
However, while related addition reactions of carboxylates,4 water,5 and amines6 are well-
established, to the best of our knowledge no efficient catalyst for a hydroamidation reaction has
been reported.7
Institut für Organische Chemie, TU Kaiserslautern, Erwin-Schrödinger-Straße-54, 67663 Kaiserslautern,
Tel (+49) 0631 205 2046, [email protected] , [email protected]
R2
R3
N
S
R1
Cat.
R1
R2
R3
N
O
R1
R2
R3
N
S
R1
R2
R3
N
O
R1
R3
N
O
OR2
R1
R3
N
O
OR2 R
1
R3
NH
O
OR2
R3
NH
O
R2
R3
NH
S
R2
R2
NH2
O
R2
NH
O
R1
R2
NH
O
R1
Ru(II)
toluene100 °C
toluene100 °C
DMF60 °C
P(nBu)3
DMAP
dcypmKOtBu
P(nOct)3
3A MS
dcypmH2O
P(iPr)3
Sc(OTf)3
P(nBu)3
Sc(OTf)3
=
+ Cat.
up to 98%Z/E > 1:30
up to 74%Z/E > 8:1
up to 99%Z/E > 1:30
up to 99%Z/E > 8:1
up to 75%Z/E > 1:15
up to 99%Z/E > 30:1
up to 99%Z/E = 40:1
dcypbYb(OTf)3
NEt3
3A mol. sieves
Same Pot
up to 89%Z/E =1:20
DMF/ H2O
60 °C
Synthesis of Natural Products via Hydroamidation1d
Following the protocol for the addition of primary amides to terminal alkynes the natural products
Lansiumamide A and Alatamide could be synthesized in high yields and stereoselectivities.
Development of a RuCl3∙3H2O-based Protocol for the Catalytic Hydroamidation2
In an attempt to reverse the regioselectivity of the hydroamidation in favour of the Markovnikov
product, we synthesized sterically demanding and electron-rich RuCp-complexes and utilized
them in hydroamidation reactions.
Unfortunately no beneficial influence of the Cp-Ligand could be observed. Furthermore, the
results matched those of the [Ru(cod)(met)2]-based protocol.8
The information thus obtained in combination with spectroscopic investigations led us to the
discovery of a new RuCl3-based protocol. The key step is the selective reduction of RuIII to RuII
during the catalyst preformation, which is mediated by the employed phosphine, a process
assisted by water.
● 90% reduction of the catalyst cost ● better fit for large-scale applications
● replacement of air-sensitive, liquid ● dramatic improvement of the
P(nBu)3 by its tetrafluoroborate salt synthetic applicability
Representative examples of the scope are illustrated below.
N N
O
O
nBu
nBu
N
O
N
O(CH
2)3Cl
N
OSiMe
3
N
O(CH
2)OMe
N O
O OMe
N
OnBu
N
OtBu
N
OnBu
N
OPh
OnBu
N
NO
OnBu
NO
OnBu
N
SnBu
N
O
nBu
EtO
N
O
nBu
71%, Z/E = 1:4097%, Z/E = 1:8
99%, Z/E = 1:33
90%, Z/E = 1:2
99%, Z/E = 1:24 96%, Z/E = 1:4099%, Z/E = 1:40
99%, Z/E = 1:32 97%, Z/E = 1:22 91%, Z/E = 1:40
99%, Z/E = 1:40
88%, Z/E = 1:30
94% 80%, Z/E = 1:3
93%, Z/E = 1:40
49%, Z/E = 1:40 ,Z/E = 1:22
Myxobacteria Chondromyces
Seeds of Zizyphus vulgaris
spinosus Bunge
Chondria atropurpurea
N
O
Lansamide I
N
O
Lansiumamide A
N
O
Lansiumamide B
Fruits of Clausena Lansium
OH
O
O
O
OH
NH
O
Apicularen A
NHO
O
NH
O
NH
O
N
Frangufoline
NH
NH
O
NH
Chondriamide C
Leaves of Clausena Lansium
O
R1
NH
R2
R3
R4
O
R1
N
R2
R3
R4
O
R1
N
R2
R4
R3
or[cat.]
+
O
NH2
N
O
Ph
SiMe3
OH
O Ph
SiMe3
O
N3
Ph
SiMe3
N
OPh
SiMe3
NH
O
Ph
Ph
MgBr
O
NH2
OMe
N
OOMe
Lansiumamide A
+[Ru.-cat.]
98%, Z/E = 20:1
DPPA, Et3N
toluene RT, 0.5 h
aq. THF, 85°C Et2O, -78°C
0°C
Curtius-Rearrangement
TBAF
4 steps: 7%
Alatamide
79%,Z/E = 1:18
1.) [Ru.-cat.]2.) Isomerization
+ Synthesis by Taylor et al.1b
RuCpR
Cl Cl
Ru CpR
ClCln
NH
O
nBu N
OnBu
RuCpR
ORu Cp
R
O
n
RuCl3·3H2OCpRH
MeOH
T, 6 h
P(nBu)3
DMAPK2CO3, MeOH
toluene100 °C, 15 h
K2CO3
MeOH
T, 6 h
+
CpRH =
99%, E/Z = 40:1
Ru(II)
O
N R3
R2
R1
O
NH R3
R2R
1
Ru(III)
O
N
R3
R2
Ru(II)
LnX
HNR2C(O)R3
P(nBu)3, DMAP
K2CO3, H2O
Ln= P(nBu)3 and/or DMAP
X = NR2C(O)R3 or Cl, ...
toluene100 °C
2
+
HNR2C(O)R3
P(nBu)3, DMAP
- OP(nBu)3
KCl, KHCO3
up to 99%Z/E > 1:40
Cl3 ·3H2O
Main
features
