Recent Developments in Iron-Catalyzed Cross-Coupling
Jack Terrett MacMillan Group Meeting March 15th, 2016 Transition Metal-Catalyzed Cross-Coupling
■ One of the most fundamental class of reactions in organic synthesis for C–C bond formation
organometallic nucleophiles organometallic electrophiles
B(OH)2 I R N ZnCl Br Boc Cl SnBu3 BnO MgBr R R
■ 2010 Nobel Prize awarded in this area: Heck, Negishi, and Suzuki Metal-Catalyzed Cross-Coupling
■ One of the most fundamental reactions in organic synthesis for C–C bond formation
diverse nucleophile handles transition metal catalysts
Mg = Kumada Zn = Negishi B = Suzuki-Miyaura Sn = Stille Si = Hiyama
What about iron catalysis? Why Iron Catalysis?
■ Compared to palladium and nickel, iron has many beneficial characteristics
Iron is second most abundant metal in the Earth's crust
4.7 wt% vs. 1x10 –6 wt% for Pd
https://en.wikipedia.org/wiki/Abundance_of_the_chemical_elements Renner, H.; Schmuckler, G. Metals and their compounds in the environment., ed. E Merian, Wiley-VCH, Weinheim, 1991. Why Iron Catalysis?
■ Compared to palladium and nickel, iron has many beneficial characteristics
Iron is far more inexpensive than palladium
Nickel ($0.52 mol–1)
http://www.icmj.com/current-metal-prices.php Enthaler, S.; Junge, K.; Beller, M. Angew. Chem. Int. Ed. 2008, 47, 3317. Why Iron Catalysis?
■ Compared to palladium and nickel, iron has many beneficial characteristics
Iron is relatively non-toxic compared to palladium and nickel
Haemoglobin Cytochrome P450
Iron is present in a large number of biological systems, notably metalloproteins
https://en.wikipedia.org/wiki/Hemoglobin http://scottlab.info/illustration/human-cytochrome-p450-2a13/ Why Iron Catalysis?
■ Compared to palladium and nickel, iron has many beneficial characteristics
1) Abundance: Iron is second most abundant metal in the Earth's crust
2) Cost: Iron is far more inexpensive than palladium
3) Toxicity: Iron is relatively non-toxic compared to palladium and nickel
4) Reactivity!
Can we discover new reactivity that is unique to iron catalysis? Iron-Catalyzed Cross-Coupling
Fe
Kumada Coupling Negishi Coupling Suzuki Coupling
Mg Zn B
Me Me MgBr O Me ZnR Me B O Me
Grignard reagents organozincs organoboron Iron-Catalyzed Cross-Coupling
Fe
Kumada Coupling Negishi Coupling Suzuki Coupling
Mg Zn B
Me Me MgBr O Me ZnR Me B O Me
Grignard reagents organozincs organoboron Iron-Catalyzed Cross-Coupling
■ First report of iron-mediated cross-coupling came from Kharasch and Fields in 1941
MgBr Br 5 mol% FeCl3
Et2O
47% yield
■ Reactivity is observed in the presence of CoCl2, FeCl3, MnCl2, and NiCl2
■ Kharasch proposes that the metallic halide gets reduced to a lower oxidation state by the Grignard reagent
It was another 30 years until the field really got started.
Kharasch, M. S.; Fields, E. K. J. Am. Chem. Soc. 1941, 63, 2316. Iron-Catalyzed Cross-Coupling
■ Kochi reported the coupling of alkenyl halides with Grignard reagents in 1971
5 mol% FeCl3 R MgBr R2 R2 Br R THF
Me Me Me Me Me
>95% yield >95% yield 83% yield 64% yield
(trans reacts ~15 times faster than cis)
coupling of alkenyl halides occurs stereospecifically
Tamura, M.; Kochi, J. J. Am. Chem. Soc. 1971, 93, 1487. Tamura, M.; Kochi, J. Synthesis 1971, 1971, 303. Iron-Catalyzed Cross-Coupling
■ Kochi proposed an Fe(I)/(III) mechanistic cycle
iron(I)
Me I Me R Fe Br
R.E. O.A.
Me Me iron(III) R FeIII Br FeIII iron(III)
TM
MgBr2 R MgBr
active Fe(I) formed by reduction of Fe(III) precatalyst by Grignard reagent
Smith, R. S.; Kochi, J. K. J. Org. Chem. 1976, 41, 502. Iron-Catalyzed Cross-Coupling
■ Following Kochi's report, Fe-catalyzed couplings with alkenyl electrophiles developed rapidly
SO2R OTf
Julia, Tetrahedron Lett. 1982, 23, 2469. Fürstner, J. Org. Chem. 2004, 69, 3949.
Br SPh
Molander, Tetrahedron Lett. 1983, 24, 5449. Itami, Org. Lett. 2005, 7, 1219. Fe
Cl OTf
with various Cahiez, Pure & Appl. Chem. 1996, 68, 669. aryl and alkyl Knochel. Synlett 2006, 407. Grignard reagents
2 2 OPO(OEt)2 sp –sp OCOt-Bu sp3–sp3
Cahiez, Synthesis 1998, 1192. Shi, J. Am. Chem. Soc. 2009, 131, 14656. Iron-Catalyzed Cross-Coupling
■ Fürstner reported first coupling of aryl electrophiles with Grignard reagents in 2002
X 5 mol% Fe(acac)3 Me Me MgBr OMe OMe THF/NMP, 0 ºC → rt, 5 min O O
X = Cl, OTf, OTs
X Product ArH
I 27% 46% arene reduction possibly due to a Br 38% 50% radical decomposition pathway Cl >95% 0% OTf >95% 0% effectiveness of Ar–Cl is suggestive of Fe(–II) active catalyst for oxidative addition OTs >95% 0%
Fürstner, A.; Leitner, A. Angew. Chem. Int. Ed. 2002, 41, 609. Fürstner, A.; Leitner, A.; Mendez, M.; Krause, H. J. Am. Chem. Soc. 2002, 124, 13856. Iron-Catalyzed Cross-Coupling
■ Fürstner proposed a Fe(–II)/(0) mechanistic cycle
[Fe(MgX)2] active catalyst is prepared in situ from FeCl2 and 4 equiv. RMgBr
R H 0 FeCl2 TM Fe FeII FeII R R
2 MgBr R R Me R 2 MgBr2
–2
R 0 Fe TM (MgBr)2 [Fe(MgBr)2] Fe0 R
2 MgBr R R R Me
Fürstner, A.; Leitner, A. Angew. Chem. Int. Ed. 2002, 41, 609. Fürstner, A.; Leitner, A.; Mendez, M.; Krause, H. J. Am. Chem. Soc. 2002, 124, 13856. Iron-Catalyzed Cross-Coupling
■ Fürstner proposed a Fe(–II)/(0) mechanistic cycle
iron(–II)
Br R –II [Fe (MgBr)2]
O.A. R.E. MgBr2
0 iron(0) [ArFe (MgBr)2] ArFe0(MgBr) iron(0)
R
TM
R MgBr
Fürstner, A.; Leitner, A. Angew. Chem. Int. Ed. 2002, 41, 609. Fürstner, A.; Leitner, A.; Mendez, M.; Krause, H. J. Am. Chem. Soc. 2002, 124, 13856. Iron-Catalyzed Cross-Coupling
■ Cross-coupling shuts down in when MeMgBr is employed
MeMgBr
5 mol% Fe(acac)3 No cross coupling O yellow-golden mixture
OMe
Cl EtMgBr O
5 mol% Fe(acac)3 OMe Me dark brown/black mixture
> 95% yield
supports proposed active Fe(–II) catalyst as β-hydride elimination is required
in the presence of Fe(0), no reactivity is observed - restored upon addition of excess Grignard
Fürstner, A.; Leitner, A. Angew. Chem. Int. Ed. 2002, 41, 609. Fürstner, A.; Leitner, A.; Mendez, M.; Krause, H. J. Am. Chem. Soc. 2002, 124, 13856. Fürstner, A.; Martin, R.; Krause, H.; Seidel, G.; Goddard, R.; Lehmann, C. W. J. Am. Chem. Soc. 2008, 130, 8773. Iron-Catalyzed Cross-Coupling
■ In 2004, Nakamura, Hayashi, and Fürstner report coupling of alkyl halides with aryl Grignards
Nakamura 5 mol% FeCl3 Br BrMg additive (1.2 eq.)
THF, –78 ºC → 0 ºC, 30 min
1 2 3 4
bidentate TMEDA ligand suppressed competing β-hydride elimination
Me N Me TMEDA = Me N Me
Nakamura, M.; Matsuo, K.; Ito, S.; Nakamura, E. J. Am. Chem. Soc. 2004, 126, 3686. Nagano, T.; Hayashi, T. Org. Lett. 2004, 6, 1297. Fürstner, A.; Martin, R. Angew. Chem. Int. Ed. 2004, 43, 3955. Iron-Catalyzed Cross-Coupling
■ Nakamura and Fürstner propose a radical-based mechanism
Fürstner Me n-hexyl BrMg 5 mol% [Li(TMEDA)]2[Fe(C2H4)4] (1) Me n-hexyl 94% yield THF, –20 ºC racemate Br
98% ee
O O O Fe cat. 1 O cyclization suggests 85% yield intermediacy of radicals I PhMgBr Ph
O O O O Me Fe cat. 1 77% yield no cross-coupling observed Me from 3º radical I PhMgBr Me
Nakamura, M.; Matsuo, K.; Ito, S.; Nakamura, E. J. Am. Chem. Soc. 2004, 126, 3686. Fürstner, A.; Martin, R. Angew. Chem. Int. Ed. 2004, 43, 3955. Iron-Catalyzed Kumada Cross-Coupling
■ Chai demonstrated the first sp3–sp3 coupling using Fe catalysis
■ One of the greatest challenges is overcoming competing homocoupling and β-hydride elimination
8 1 mol% Fe(OAc)2 8 8 18 12 Br Me MgBr Me Me Me Me Me Me Me Me 1 mol% ligand A B C D Et2O, rt
A B C D Me Me 1 10% 62% 13% 5%
O O 2 2% 31% 10% 51%
PPh2 PPh2 PPh2 PPh2 1 2
use of Xantphos (2) reduced byproduct formation
Dongol, K. G.; Koh, H.; Sau, M.; Chai, C. L. L. Adv. Synth. Catal. 2007, 349, 1015. Iron-Catalyzed Kumada Cross-Coupling
■ Chai demonstrated the first sp3–sp3 coupling using Fe catalysis
■ A radical mechanism is proposed for this sp3–sp3 Kumada coupling
OPh 3 mol% Fe(OAc)2 PhO OPh MgBr 6 mol% Xantphos
3 Br 51% yield Ratio: 95 5
3 mol% Fe(OAc)2 PhO MgBr 6 mol% Xantphos PhO PhO
Br 48% yield Ratio: > 96 < 4
results suggest alkyl radicals are formed from the corresponding alkyl halides
Dongol, K. G.; Koh, H.; Sau, M.; Chai, C. L. L. Adv. Synth. Catal. 2007, 349, 1015. Iron-Catalyzed Cross-Coupling
■ Von Wangelin accomplished an iron-catalyzed cross electrophile coupling
■ Domino iron catalysis: iron-catalyzed Grignard formation followed by cross-coupling
1 mol% FeCl3 Br Br Mg 75% yield TMEDA Me Me 14% Ar–Ar 3b
4b = 4,4'-bitolyl
selectivity depends greatly on TMEDA loading, possibly stabilizes Fe and Mg complexes
increased TMEDA = slower formation of Grignard reagent
Czaplik, W. M.; Mayer, M.; von Wangelin, A. J. Angew. Chem. Int. Ed. 2009, 48, 607. Iron-Catalyzed Cross-Coupling
■ Von Wangelin accomplished an iron-catalyzed cross electrophile coupling
■ The intermediacy of both Grignard species (aryl and alkyl) is proposed
■ Formation of both Grignard species is accelerated in the presence of FeCl3
Czaplik, W. M.; Mayer, M.; von Wangelin, A. J. Angew. Chem. Int. Ed. 2009, 48, 607. Iron-Catalyzed Cross-Coupling
■ Von Wangelin accomplished an iron-catalyzed cross electrophile coupling
■ The intermediacy of both Grignard species (aryl and alkyl) is proposed
■ Formation of both Grignard species is accelerated in the presence of FeCl3
■ Bogdanovic has shown that [Fe(MgX)2] catalyzes formation of Grignards from aryl halides and Mg
ArCl
O.A.
[Fe(MgCl)2] [ArFe(MgCl)]MgCl2
TM
ArMgCl Mg
Bogdanovic, B.; Schwickardi, M. Angew. Chem. Int. Ed. 2000, 39, 4610. Czaplik, W. M.; Mayer, M.; von Wangelin, A. J. Angew. Chem. Int. Ed. 2009, 48, 607. Iron-Catalyzed Cross-Coupling
■ Von Wangelin accomplished an iron-catalyzed cross electrophile coupling
■ The intermediacy of both Grignard species (aryl and alkyl) is proposed
■ Formation of Grignard reagent appears to be rate-determining step
Czaplik, W. M.; Mayer, M.; von Wangelin, A. J. Angew. Chem. Int. Ed. 2009, 48, 607. Iron-Catalyzed Cross-Coupling
Fe
Kumada Coupling Negishi Coupling Suzuki Coupling
Mg Zn B
Me Me MgBr O Me ZnR Me B O Me
Grignard reagents organozincs organoboron Iron-Catalyzed Negishi Cross-Coupling
■ Nakamura extended iron-catalyzed cross coupling to organozincs for milder protocol
■ Diorganozinc nucleophile was effective, but still required a magnesium salt
5 mol% FeCl3 Br TMEDA (1.5 eq.) Zn 96% yield THF, 50 ºC, 30 min
organozinc is prepared in situ from aryl Grignard and ZnCl2
avoids the need for slow addition of Grignard reagent due to slower transmetallation of zinc to iron
5 mol% FeCl3 Br TMEDA (1.5 eq.) TMS Zn 95% yield THF, 50 ºC, 30 min
use of TMSCH 2 non-transferable ligand improves substrate economy
Nakamura, M.; Ito, S.; Matsuo, K.; Nakamura, E. Synlett 2005, 11 , 1794. Iron-Catalyzed Negishi Cross-Coupling
■ Nakamura extended iron-catalyzed cross coupling to organozincs for milder protocol
■ Diorganozinc nucleophile was effective, but still required a magnesium salt
5 mol% FeCl3 Br TMEDA (1.5 eq.) Zn 96% yield THF, 50 ºC, 30 min
■ Radical-based mechanisms are also proposed in this Negishi coupling
O 5 mol% FeCl Me Me Me O 3 O TMEDA (1.5 eq.) O Me n-BuO O O Zn I THF, 50 ºC, 30 min n-BuO 2 86% yield 2:1 d.r.
Nakamura, M.; Ito, S.; Matsuo, K.; Nakamura, E. Synlett 2005, 11 , 1794. Iron-Catalyzed Negishi Cross-Coupling
■ Bedford demonstrated iron-phosphine complexes as suitable Negishi catalysts
■ Benzyl halide and phosphate electrophiles couple with diarylzincs
5 mol% Fe cat. 1 Br Me Zn 92% yield toluene, 45 ºC Me OMe 2 OMe
organozinc reagents Fe cat. 1
Ph Ph 2 2 NMe2 P Cl P Me3Si Fe ArZnCl Zn Ar Zn Ar P Cl P Ph2 Ph2 50% yield 74% yield 89% yield
Bedford, R. B.; Huwe, M.; Wilkinson, M. C. Chem. Commun. 2009, 600. Iron-Catalyzed Negishi Cross-Coupling
■ Bedford proposed a cationic Fe(II) catalytic cycle with two possible pathways
1) σ-bond metathesis Ar P FeII 4 Ph 2) single-electron transfer Br
Ar II 1 2 P4Fe –X– X
Ar Iron Ar Ar P FeII II P FeIII Ph 4 Catalytic P4Fe Ph 4 Br X Cycle
Ar ArZnBr TM II P4Fe Zn Ar Ar Br II P4Fe stabilized resting state
Ar2Zn Ar Ph
Bedford, R. B.; Huwe, M.; Wilkinson, M. C. Chem. Commun. 2009, 600. Iron-Catalyzed Negishi Cross-Coupling
■ In 2009, Nakamura reported a stereospecific vinylation of alkyl halides with alkenyl zincs
Br Ph 5 mol% Fe cat. M Ph Ph Ph THF, 30 ºC 1a (M = ZnBr) 2 3 4 5 6
1b (M = ZnCH2SiMe3) 1c (M = MgBr)
excess TMEDA was necessary to ensure coordination of Fe in presence of Zn and Mg
Hatakeyama, T.; Nakagawa, N.; Nakamura, M. Org. Lett. 2009, 11 , 4496. Iron-Catalyzed Negishi Cross-Coupling
■ In 2009, Nakamura reported a stereospecific vinylation of alkyl halides with alkenyl zincs
■ Cross-coupling occurs with retention of olefin stereochemistry
5 mol% FeCl3 Br TMEDA (5 eq.) 87% yield EtO C EtO C 2 ZnR 2 THF, 30 ºC, 6h CN 96% Z 5 CN 5
R = CH2SiMe3
■ Experiments support existence of radical intermediates
Me 5 mol% FeCl Me 3 Br TMEDA (5 eq.) Br Br Zn Me 73% yield Me THF, 30 ºC, 6h 2
5 mol% FeCl3 Zn TMEDA (5 eq.) Br Ph 86% yield THF, 30 ºC, 6h
2
Hatakeyama, T.; Nakagawa, N.; Nakamura, M. Org. Lett. 2009, 11 , 4496. Iron-Catalyzed Cross-Coupling
Fe
Kumada Coupling Negishi Coupling Suzuki Coupling
Mg Zn B
Me Me MgBr O Me ZnR Me B O Me
Grignard reagents organozincs organoboron
"the iron-catalyzed Suzuki reaction...... represents something of a 'holy grail' in coupling chemistry"
- R. B. Bedford and M. Nakamura, 2009 Iron-Catalyzed Suzuki–Miyaura Cross-Coupling
■ First Fe-catalyzed Suzuki–Miyaura coupling was reported by Young in 2008
■ Elevated pressure (15 kBar) enables biaryl coupling
5 mol% FeCl3 10 mol% dppy
Br B(OH)2 KF/KOH 67% yield 15 kBar, 100 ºC Me Me THF
high pressure is presumably assisting reduction of FeCl3 down to low-valent active state
Guo, Y.; Young, D. J.; Hor, T. S. A. Tetrahedron Lett. 2008, 49, 5620.
■ Two additional publications proposed Fe-catalyzed Suzuki couplings to make biaryls (at ambient pressure)
Kylmala, T.; Valkonen, A.; Rissanen, K.; Xu., Y.; Franzen, R. Tetrahedron Lett. 2009, 50, 5692.
Bezier, D.; Darcel, C. Adv. Synth. Catal. 2010, 352, 1081.
both publications were later retracted due to irreproducibility issues Iron-Catalyzed Suzuki–Miyaura Cross-Coupling
■ Joint study by Bedford and Nakamura determined trace Pd responsible for reactivity
■ Biaryl coupling could not be reproduced with a range of iron catalysts
■ Coupling was observed with ppb levels of Pd, therefore Pd contamination likely
"the iron-catalyzed Suzuki biaryl coupling reaction appears to be, for the moment at least, out of reach"
Bedford, R. B.; Nakamura, M.; Gower, N. J.; Haddow, M. F.; Hall, M. A.; Huwe, M.; Hashimoto, T.; Okopie, R. A. Tetrahedron Lett. 2009, 50, 6110.
■ Buchwald and Bolm made similar observations in the Fe-catalyzed C–N coupling
■ Commercial Fe catalysts contained trace Cu, resulting in false activity
FeCl3 Yield
10 mol% FeCl3 I > 98% (Merck) 87% NH 10 mol% DMEDA N N > 99.99% (Aldrich) 9% N MeO K3PO4, toluene no Fe, 5 ppm Cu2O 77% MeO 135 ºC, 24 h
Buchwald, S. L.; Bolm, C. Angew. Chem. Int. Ed. 2009, 48, 5586. Iron-Catalyzed Suzuki–Miyaura Cross-Coupling
■ Bedford employed a mixed Fe–Zn catalytic system to access organoboron nucleophiles
Ph2 Ph2 P Cl P Br BXn 5 mol% Fe cat. Fe 10 mol% Zn(4-OMe-Ph)2 P Cl P Ph Ph OMe toluene, 85 ºC OMe 2 2
Me Me Me Ph B(OH)2 O BF3K Me B Ph Na+ Ph B O O O B O Me O O B B Me B Ph Ph Ph O Ph Na+ Ph
0% yield 0% yield 0% yield 0% yield 0% yield 96% yield
no incorporation of Zn aryl groups into product
diaryl zinc is likely consumed during reductive activation of Fe catalyst
Bedford, R. B.; Hall, M. A.; Hodges, G. R.; Huwe, M.; Wilkinson, M. C. Chem. Commun. 2009, 6430. Iron-Catalyzed Suzuki–Miyaura Cross-Coupling
■ Bedford employed a mixed Fe–Zn catalytic system to access organoboron nucleophiles
Ph2 Ph2 Br 5 mol% Fe cat. P Cl P B R Fe 10 mol% Zn(4-OMe-Ph)2 Na+ P Cl P R 4 Ph Ph toluene, 85 ºC 2 2
Limited nucleophile scope:
Na+ B Na+ B Me Na+ B Cl
4 4 4
91% yield 96% yield trace yield
Mechanistic Considerations:
Zn co-catalyst likely plays a role in boron transmetallation with Fe center via arylzinc intermediate
Bedford proposes an Fe(I) oxidation state for the active catalyst
Bedford, R. B.; Hall, M. A.; Hodges, G. R.; Huwe, M.; Wilkinson, M. C. Chem. Commun. 2009, 6430. Iron-Catalyzed Suzuki–Miyaura Cross-Coupling
■ Nakamura reported Suzuki coupling with aryl boronates using novel diphosphine ligands
Me 3 mol% Fe cat. Cl Bu O Me B additive Ph + O Me Li Me THF, 25 ºC, 4 h
prepared in situ from boronate ester and R–Li
R R
R R P P R Fe R
Cl Cl R R
1 (R = t-Bu) 2 (R = SiMe3)
bulky diphosphine ligand prevents formation of coordinatively saturated octahedral Fe complex
Hatakeyama, T.; Hashimoto, T.; Kondo, Y.; Fujiwara, Y.; Seike, H.; Takaya, H.; Tamada, Y.; Ono, T.; Nakamura, M. J. Am. Chem. Soc. 2010, 132, 10674. Iron-Catalyzed Suzuki–Miyaura Cross-Coupling
■ Nakamura reported Suzuki coupling with aryl boronates using novel diphosphine ligands
Me 3 mol% Fe cat. 2 O Me X t-Bu R B 20 mol% MgBr2 Ar + O Me Li Me THF, 25 ºC
(1.5–2 eq.)
Cl CO i-Pr O Me NC 2 AcO OPiv 5 N Ph N 4 Me 96% yield 83% yield 86% yield 65% yield
Br 99% yield
Hatakeyama, T.; Hashimoto, T.; Kondo, Y.; Fujiwara, Y.; Seike, H.; Takaya, H.; Tamada, Y.; Ono, T.; Nakamura, M. J. Am. Chem. Soc. 2010, 132, 10674. Iron-Catalyzed Suzuki–Miyaura Cross-Coupling
■ Nakamura proposes an Fe(II)/(III) cycle
R X P Ar FeIII P Ar
X R borate P Cl Iron FeII P Ar II Catalytic P Cl Fe Ar R P Ar Cycle
Me P X FeII O Me P Ar Bu B MgBr2 O Me Me
Me LiX Bu O Me B Ar + O Me Li Me
Hatakeyama, T.; Hashimoto, T.; Kondo, Y.; Fujiwara, Y.; Seike, H.; Takaya, H.; Tamada, Y.; Ono, T.; Nakamura, M. J. Am. Chem. Soc. 2010, 132, 10674. Iron-Catalyzed Suzuki–Miyaura Cross-Coupling
■ Nakamura extended this catalytic platform to vinylation
R R Me 3 mol% Fe cat. 1 Cl t-Bu O Me R R 20 mol% MgBr R' B 2 P P R' Li+ O Me R Fe R Me THF, –20 to 40 ºC Cl Cl 24 h R R prepared in situ from boronate ester and t-Bu–Li 1 (R = t-Bu) 2 (R = SiMe3)
Ph Pr Pr OTBS N N 4 Cbz Cbz
85% yield 77% yield 58% yield 93% yield >99% E >99% E >99% Z
vinylation proceeds with retention of olefin stereochemistry
Hashimoto, T.; Hatakeyama, T.; Nakamura, M. J. Org. Chem. 2012, 77, 1168. Iron-Catalyzed Suzuki–Miyaura Cross-Coupling
■ Nakamura extended this catalytic platform to vinylation
R R Me 3 mol% Fe cat. 1 Cl t-Bu O Me R R 20 mol% MgBr R' B 2 P P R' Li+ O Me R Fe R Me THF, –20 to 40 ºC Cl Cl 24 h R R prepared in situ from boronate ester and t-Bu–Li 1 (R = t-Bu) 2 (R = SiMe3)
Br reaction OTBS
conditions 3
N N N N 56% yield >99% E Ts Ts Ts Ts Me Me
Fe(II) abstracts Br•resulting in 5-exo cyclization and coupling N N N Ts Ts Ts 25% 3% 10%
Hashimoto, T.; Hatakeyama, T.; Nakamura, M. J. Org. Chem. 2012, 77, 1168. Iron-Catalyzed Suzuki–Miyaura Cross-Coupling
■ In 2012, Nakamura reported the first iron-catalyzed sp3–sp3 Suzuki-Miyaura cross-coupling
Me Me Br 3 mol% Fe(acac)3 R BXn 6 mol% Xantphos R RMgX or RLi activator CN CN O THF, 25 ºC PPh2 PPh2 Xantphos
Me OH Me Bu O Nucleophile B Me B Bu OH B Me Bu Bu Bu O
Activator both RMgX and RLi n-BuMgCl n-BuLi t-BuMgCl MeMgBr i-PrMgCl
0% yield 0% yield 85% yield 0% yield 0% yield 8% yield* 82% yield
*competing Me group transmetallation = 73% methylated product
rate of alkyl group transfer in transmetallation: Me > 1º alkyl > 2º alkyl
Hatakeyama, T.; Hashimoto, T.; Kathriarachchi, K. K. A. D. S.; Zenmyo, T.; Seike, H.; Nakamura, M. Angew. Chem. Int. Ed. 2012, 51, 8834. Iron-Catalyzed Suzuki–Miyaura Cross-Coupling
■ To expand nucleophile scope, Nakamura prepared tetraalkylborates in situ via hydroboration
Br
3 mol% Fe(acac)3 R BH •SMe 1) THF, 60 ºC 3 2 R 6 mol% Xantphos [(RCH2CH2)3i-PrB][MgCl] 2) i-PrMgCl (2 eq.) (6.3 eq.) THF, 25 ºC tetraalkylborate prepared in situ
Br CO2Et CO2Et 7 68% yield 7 AcO AcO 2:1 trans:cis
Br CO2Et CO2Et 9 56% yield 7 Br Br single regioisomer
a radical mechanism is proposed
Hatakeyama, T.; Hashimoto, T.; Kathriarachchi, K. K. A. D. S.; Zenmyo, T.; Seike, H.; Nakamura, M. Angew. Chem. Int. Ed. 2012, 51, 8834. Iron-Catalyzed Suzuki–Miyaura Cross-Coupling
■ Nakamura proposes radical-based mechanism
R2 Br P R1 Fen+1 P X
Br R2
1 [R 4B][MgCl] Iron Br P X P R1 P R2 FeII Fen Catalytic Fen+2 P X P X P R1 Cycle X
1 R.E. R 3B TM MgClBr
P Br R1 R2 Fen P X
1 [R 4B][MgCl] n = +2, +1, or lower oxidation state
Hatakeyama, T.; Hashimoto, T.; Kathriarachchi, K. K. A. D. S.; Zenmyo, T.; Seike, H.; Nakamura, M. Angew. Chem. Int. Ed. 2012, 51, 8834. Iron-Catalyzed Suzuki–Miyaura Cross-Coupling
■ Nakamura has also reported Fe-catalyzed Suzuki alkynylation
Cl 5 mol% FeCl2(SciOPP) Si(i-Pr)3 80% yield THF/hexane, 80 ºC
(i-Pr)3Si B(OMe)3Li
Nakagawa, N.; Hatakeyama, T.; Nakamura, M. Chem. Lett. 2015, 44, 486.
■ Han reported an Fe-catalyzed carbonylative Suzuki coupling to make bisaryl ketones
4 mol% FeCl2 O F I B(OH) 6 mol% FeCl3 2 F 82% yield Me NaHCO3, KOAc PEG-400 Me CO, 100 ºC
Fem(CO)n generated in situ is active catalyst
Zhong, Y.; Han, W. Chem. Commun. 2014, 50, 3874. Iron-Catalyzed Cross-Coupling
Fe
Kumada Coupling Negishi Coupling Suzuki Coupling
Mg Zn B
Me Me MgBr O Me ZnR Me B O Me
Grignard reagents organozincs organoboron
What about asymmetric catalysis? Asymmetric Iron-Catalyzed Cross-Coupling
■ In 2015, Nakamura reported the first asymmetric Fe-catalyzed cross-coupling reaction
3 mol% Fe(acac) Me 3 Me MgBr 6 mol% L1 OR OR Me t-Bu Cl P P t-Bu Me O THF, 0 ºC O
racemic 2 eq. L1 (R,R)-BenzP*
R = t-Bu 91% yield, 87:13 er
R = i-Pr 75% yield, 83:17 er
R = Et 40% yield, 82:18 er
R = theptyl 82% yield, 90:10 er
t-Bu Me Me
slow addition of Grignard and avoiding strongly coordinating solvents (DMPU, NMP) improved er
this helped to ensure the Fe catalyst was constantly ligated to the chiral ligand
Jin, M.; Adak, L.; Nakamura, M. J. Am. Chem. Soc. 2015, 137, 7128. Asymmetric Iron-Catalyzed Cross-Coupling
■ In 2015, Nakamura reported the first asymmetric Fe-catalyzed cross-coupling reaction
3 mol% Fe(acac) Me 3 Me MgBr 6 mol% L1 O t-Bu O t-Bu Me t-Bu Cl P P Me Me t-Bu Me O Me Me THF, 0 ºC O
racemic 2 eq. L1 (R,R)-BenzP* (slow addition)
no coupling until 0.12 eq. PhMgBr has been added no kinetic resolution of substrate PhMgBr reduces Fe catalyst to Fe(II) state C–C bond formation is selectivity-determining step
Jin, M.; Adak, L.; Nakamura, M. J. Am. Chem. Soc. 2015, 137, 7128. Asymmetric Iron-Catalyzed Cross-Coupling
■ In 2015, Nakamura reported the first asymmetric Fe-catalyzed cross-coupling reaction
3 mol% Fe(acac) Me 3 Me MgBr 6 mol% L1 O t-Bu O t-Bu Me t-Bu Cl P P Me Me t-Bu Me O Me Me THF, 0 ºC O
racemic 2 eq. L1 (R,R)-BenzP* (slow addition)
ee of product directly proportional to ee of chiral ligand enantioselectivity determined by chiral phosphine–iron complex
Jin, M.; Adak, L.; Nakamura, M. J. Am. Chem. Soc. 2015, 137, 7128. Asymmetric Iron-Catalyzed Cross-Coupling
■ In 2015, Nakamura reported the first asymmetric Fe-catalyzed cross-coupling reaction
3 mol% Fe(acac) Me 3 Me MgBr 6 mol% L1 O t-Bu O t-Bu Me t-Bu Cl P P Me Me t-Bu Me O Me Me THF, 0 ºC O
racemic 2 eq. L1 (R,R)-BenzP* (slow addition)
Radical probe experiment:
12% yield OR OR OR Cl Ph 85:15 er O O O
OR OR 40% yield racemic O Ph O
Jin, M.; Adak, L.; Nakamura, M. J. Am. Chem. Soc. 2015, 137, 7128. Asymmetric Iron-Catalyzed Cross-Coupling
■ In 2015, Nakamura reported the first asymmetric Fe-catalyzed cross-coupling reaction
3 mol% Fe(acac) Me 3 Me MgBr 6 mol% L1 O t-Bu O t-Bu Me t-Bu Cl P P Me Me t-Bu Me O Me Me THF, 0 ºC O
racemic 2 eq. L1 (R,R)-BenzP* (slow addition)
OR OR Ph O Ph O 5 6
1 st order relationship between ratio of 5/6 and catalyst loading alkyl radical intermediate escapes solvent cage, cyclizes, and then undergoes arylation with 2nd iron catalyst
Jin, M.; Adak, L.; Nakamura, M. J. Am. Chem. Soc. 2015, 137, 7128. Asymmetric Iron-Catalyzed Cross-Coupling
■ Nakamura proposes a bimetallic out-of-cage mechanism
R CO2R'
Cl Cl P* X P* X III II Fe Fe R CO2R' P* Ar P* Ar R CO2R'
1st Iron 2nd Iron P* X FeII Catalytic Catalytic P* Ar Cycle Cycle
MgClBr TM P* X II P* Fe I Ar P* Cl Fe X P* R CO2R'
ArMgBr enantioenriched product
Jin, M.; Adak, L.; Nakamura, M. J. Am. Chem. Soc. 2015, 137, 7128. Iron-Catalyzed Cross-Coupling Fe Fe
Kumada Coupling Negishi Coupling Suzuki Coupling
Mg Zn B
Me Me MgBr O Me ZnR Me B O Me
Grignard reagents organozincs organoboron
Useful Reviews
Sherry, B. D.; Fürstner, A. Acc. Chem. Res. 2008, 41, 1500. Czaplik, W. M.; Mayer, M.; Cvengros, J.; von Wangelin, A. J. ChemSusChem 2009, 2, 396. Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111 , 1417. Bauer, I.; Knölker, H.-J.. Chem. Rev. 2015, 115 , 3170. Bedford, R. B. Acc. Chem. Res. 2015, 48, 1485. Cassani, C.; Bergonzini, G.; Wallentin, C.-J. ACS Catal. 2016, 6, 1640.