Tetrahedron Letters 55 (2014) 3727–3737
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Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Digest Paper
Recent progress in copper-catalyzed difunctionalization of unactivated carbonAcarbon multiple bonds Yohei Shimizu a,⇑, Motomu Kanai a,b,⇑ a b
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan Kanai Life Science Catalysis Project, ERATO, Japan Science and Technology Agency (JST), 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
a r t i c l e
i n f o
Article history: Received 12 April 2014 Revised 9 May 2014 Accepted 14 May 2014 Available online 26 May 2014
a b s t r a c t Copper-catalyzed difunctionalization of unactivated carbonAcarbon multiple bonds involving a carbonAcarbon bond formation process is reviewed. Carboamination, carbooxygenation, carboboration, and other difunctionalization reactions of alkenes, alkynes, and allenes are described. Ó 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
Keywords: Copper Catalyst Difunctionalization Multiple bond CAC bond formation
Contents Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Difunctionalization of alkenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nucleocupration of alkenes (type A reactions) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Electrophilic activation of alkenes (type B reactions) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Radical addition to alkenes (type C reactions) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Difunctionalization of alkynes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nucleocupration of alkynes (type A reactions) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Electrophilic activation of alkynes (type B reactions) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Difunctionalization of allenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nucleocupration of allenes (type A reactions). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction Difunctionalization of unactivated carbonAcarbon (CAC) multiple bonds, adding two distinct functional groups on each side of the CAC bond, in a single operation is one of the most attractive transformations in organic chemistry.1 Typically, insertion of a ⇑ Tel.: +81 3 5841 4830; fax: +81 3 5684 5206. E-mail addresses:
[email protected] (Y. Shimizu),
[email protected]. u-tokyo.ac.jp (M. Kanai).
3727 3728 3728 3730 3731 3733 3733 3734 3735 3735 3736 3736 3736
CAC multiple bond (reactant 1) into a metalAX bond (reactant 2) generates an organometallic species in situ, which reacts with a third reactant (reactant 3) to give a difunctionalized product. Products with wide structural diversity can be synthesized by changing the combination of reactants in this three-component reaction. Combining two different bond-forming processes in one pot contributes to both step-2 and atom-economy3, and reduces laborious isolation and purification operations, leading to rapid synthesis of the target molecules. In addition, the difunctionalization reaction can form unstable, reactive organometallic intermediates that are
http://dx.doi.org/10.1016/j.tetlet.2014.05.077 0040-4039/Ó 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
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otherwise difficult to generate. Such reactions should be designed with compatible consecutive bond-forming steps. Copper catalysts promote various reaction types due to multiple abilities of the copper atom acting as a Lewis acid, a p-acid, a single-electron mediator, and a two-electron mediator. In addition, CuAX species generated as reaction intermediates can act as either a nucleophile or an electrophile, depending on the reaction conditions and oxidation state of the copper atom. Such properties of copper species account for the high utility of copper catalysts in the difunctionalization of CAC multiple bonds. Although it is difficult to clarify the precise mechanism underlying a copper-catalyzed reaction, for convenience, we classified the copper-catalyzed difunctionalization of CAC multiple bonds into three types according to the expected role of the copper catalysts in the first bond-formation step (Scheme 1). Type A involves nucleocupration of CAC multiple bonds with a nucleophilic CuAX species (X = C, N, O, etc.) to generate organocopper intermediates A, which can act as either nucleophiles or radical precursors. Type B involves activation of CAC multiple bonds by organocopper(III) species, generating electrophilic carbocation-like species B or organocopper(III) species C. Type C involves the formation of radical species through single-electron transfer from a copper catalyst to a precursor (e.g., organohalides) and subsequent addition of the thus-generated radical species to CAC multiple bonds, generating elongated carbon radical D or organocopper species E after recombination with a copper catalyst. Historically, the first example of copper-mediated difunctionalization of unactivated CAC multiple bonds was reported by Normant’s group (Scheme 2).4 In their Letter, the stoichiometric addition of organocopper species 1 to unactivated terminal alkynes 2 (carbocupration) was followed by an electrophilic trap of the resulting alkenylcopper species 3. The difunctionalization occurred
in a syn Markovnikov fashion. This reaction is classified as type A in Scheme 1. Difunctionalization of alkenes is generally more difficult than that of alkynes due to the lower polarizability of alkenes. The first report of copper-mediated difunctionalization of alkenes was disclosed by Nakamura’s group in 1988, using strained cyclopropene acetals 7 (Scheme 3).5 Both alkyl and alkenyl organocuprates were applicable to the reaction. The cuprio cyclopropane intermediates 8 reacted with several carbon electrophiles to provide ciscyclopropanes 9. Since these seminal reports, copper-mediated and -catalyzed difunctionalization of CAC multiple bonds have been intensively investigated. In this review, we focus on recent advances in copper-catalyzed ‘carbofunctionalization’ of unactivated CAC multiple bonds, where a CAC bond and a CAX bond are formed simultaneously. The reaction is highly valuable because functional group introduction and carbon skeleton extension proceed in one pot from CAC multiple bonds, allowing for a rapid increase in molecular complexity. Difunctionalization reactions via sequential reagent addition, such as copper-catalyzed carbometalation followed by an electrophilic trap,6 are not discussed here. Cycloaddition reactions, such as the Diels-Alder reaction and 1,3-dipolar cycloaddition, are also not included in this review. Difunctionalization of alkenes Epoxidation, aziridination, dihydroxylation, aminohydroxylation, and cyclopropanation are commonly-used methods for difunctionalization of alkenes. The incorporation of two distinct functional groups into alkenes through CAC bond-formation in one step is, however, a difficult transformation (Scheme 4). Nucleocupration of alkenes (type A reactions) Chemler’s group developed Cu(OAc)2-mediated intramolecular oxidative carboamidation of alkenes, constructing a cyclic sultam
Type A: nucleocupration Cu n
Cun
A Type B: electrophilic activation R 1R 2Cu
B CuIII
O
or Cu
III
Type C: radical addition
Cun
O
CuR 2
O
R1
8
E 9
Scheme 3. Carbocupration of cyclopropene acetals followed by electrophilic trap reported by Nakamura.
D
or
E+
O
R1 7
C
Y
O
O
Cu n+2 Y
Y-Cun+1
E
R1 C
Scheme 1. Classification of copper-catalyzed difunctionalization of CAC multiple bonds.
R3
+
+ R2
C
Cu cat.
X
R4
X
R 1 R 2 R 3R 4
Scheme 4. General scheme of copper-catalyzed difunctionalization of alkenes involving CAC bond-formation. Br
R1 R2
R1 Cu·MgX2 1
R1
Cu·MgX2
I2
+ H 2
R
H
H
Cu(OTf) 2 (20 mol%)
I
2
R2
R2
4
R1
H
R R2
R1 H 6
Scheme 2. The first carbocupration of alkynes followed by electrophilic trap reported by Normant.
10
N
12 Ph Ph (20 mol%)
O2 S
R1 R2
O N
NH
5
3 O2
O
R1 1
R2
MnO2 (3 equiv) K2 CO3 (1 equiv) PhCF3 , 120 oC, 24 h
R1 R1 N O2S
R2 11
45-85% yield 80-94% ee
Scheme 5. Catalytic enantioselective intramolecular carboamidation of alkenes developed by Chemler.
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Y. Shimizu, M. Kanai / Tetrahedron Letters 55 (2014) 3727–3737 R2
R1 R
10
R1
1
N CuII O 2S
CuII
O
H
MnO2
R1
CuI homolytic cleavage
cyclization; aromatization
or R1 R3
R1
R2
R2
O 23 81-93%
Scheme 8. Intramolecular carboetherification developed by Chemler. R2
R2
16
OH 21
CuII
N O 2S
N O 2S
22 56-98% yield
K2CO3 (1 equiv) MnO 2 (3 equiv) PhCF3 , 100-120 o C 12-24 h
R3
14 sy n-amidocupration
R1
R1
R1
R2
R1
R1
or R1
N
O
N
24 (25 mol%)
20
Ph N Cu II Ph N H S O H O
R1
O N
OH
R2
13
Cu(OTf )2 (20 mol%)
R2
R1
15
O
11
R1
Scheme 6. Proposed mechanism of the copper-catalyzed intramolecular carboamidation of alkenes.
+ 25
Cu(OTf )2 (10 mol%) LiBr (30 mol%) NaOAc (1 equiv)
Ac 2O or (EtCO) 2O
O R2
R1 26
120 oC, O 2, 12 h
R 2 = H or Me
solvent amount
71-93% yield
skeleton.7 The same group extended the reaction to provide the first example of a catalytic asymmetric variant (Scheme 5).8 The use of Cu(OTf)2/(R,R)-Ph-Box 12 as a catalyst afforded products 11 in good yield and high enantioselectivity in the presence of MnO2 and K2CO3 as an oxidant and a base, respectively. The proposed reaction mechanism was as follows9 (Scheme 6): (1) intramolecular enantioselective syn-amidocupration of the CAC double bond proceeds from in situ-generated copper amide 13, and (2) the thus-formed unstable CACu(II) bond undergoes homolytic cleavage to generate copper(I) species and carbon radical species 16, which is trapped by the tethered aromatic group. Oxidation of the copper(I) species by MnO2 regenerates the active copper(II) catalyst. The copper catalyst has two consecutive distinct roles in this reaction: that as a p-acid to facilitate the intramolecular syn-amidocupration step (14) and that as a singleelectron oxidant to generate a nucleophilic carbon radical (15–16). Chemler’s group further explored a copper(II)-catalyzed carboamidation reaction of alkenes involving intermolecular radical addition to olefins (vinyl arenes) as the CAC bond-forming step (Scheme 7).10 The putative radical intermediate 16 preferentially reacted with vinyl arenes rather than with the tethered sulfonyl benzene (in the cases when R = Ts and Ns). The copper catalysis was also applicable to intramolecular carboetherification of alkenes (Scheme 8).11,12 Jiang’s group developed a copper-catalyzed carbooxygenation of alkenes using acid anhydrides as carbon and oxygen sources (Scheme 9).13 Lactones 26 were obtained in one step from simple alkenes 25 through formal [3+2]-cycloaddition. Although its precise role was not discussed, the addition of a bromide salt, espe-
Scheme 9. Carbooxygenation of alkenes developed by Jiang.
cially LiBr, was crucial to promote the reaction. Using a solvent amount of acid anhydrides, the reaction proceeded in good yield with various terminal alkenes, including an aliphatic alkene, 1-octene. Because radical trapping agent TEMPO or BHT hardly affected the yield, radical intermediates are not likely involved. The reaction proceeded through syn-oxycupration, based on the product’s stereochemistry using an (E)-monodeuterated styrene as the substrate. A proposed mechanism that can explain these experimental observations is as follows (Scheme 10): (1) an alkene is activated by coordination to the cationic copper(II) catalyst (28), and syn-oxycupration proceeds with an enolate oxygen atom of anhydride 27 acting as a nucleophile: (2) insertion of the electron-rich CAC double bond proceeds to form a cyclized intermediate 30: (3) reaction between 30 and molecular oxygen followed by elimination of peroxide (R2CH2CO3H) affords product 26. In contrast to Chemler’s carboamidation reaction, a migratory insertion mechanism was proposed rather than carbon radical addition for the CAC bond-forming step. Although the radical trapping experiment partially supports the migratory insertion mechanism, further investigation is required to clarify the exact reaction pathway. In addition to amido- and oxycupration of alkenes, carbocupration is another possible approach to generate active organocopper species. In 2011, copper-mediated formation of 3-azabicy-
O
R2 O
R2
TfO
R2
O 27 R1
NHR 17 R = Ms, Ts, Ns R1
+
Ar R2
18 (3 equiv)
R1
Cu(OTf)2 (20 mol%) 12 (25 mol%) MnO 2 (3 equiv) K2CO3 (1 equiv), MS 4A PhCF3, 105-120 o C 8-24 h
NMs
Scheme 7. Intramolecular amidation/intermolecular Heck-type reaction cascade developed by Chemler.
R2 Cu(OTf)
R1 29
25 Cu(OTf)2 R2
19 64% yield 71% ee
O O
28
Ar R2
O Cu(OTf)2
O
O
26
Cu(OTf)
O O2 Tf O
R
R2
1
30
Scheme 10. Proposed mechanism of carbooxygenation.
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Y. Shimizu, M. Kanai / Tetrahedron Letters 55 (2014) 3727–3737 CuBr· SMe2 (1.1 equiv) 2,2'-bipyridine (1.1 equiv) DMSO, 60 oC, O2 1.5-4 h R5
R2
CO2Et
R1
condition B
31
O CO2Et
H CO2 Et
R1
N
42
O
HN
Cu(OAc) 2 (20 mol%) DABCO (50 mol%) K2CO3 (2 equiv) DMSO, 80 oC, O2 3h
N
H
Ph CO 2Et 41
O O [Cun ]
N [Cu n+1 ] Ph O Et2 OC O 39'
31-56% yield N Ph CO2Et 40
N
31
II
[Cu ] Ph Et 2 OC 35
CO2Et
Ph 34
N 32
N
Ph [Cu0]
CuBr·SMe 2 + 2,2'-bipyridine
Ph
[CuII]
CO2 Et
CO2 Et 37 O O CuII or N Br N
38
O
O
Scheme 13. Postulated mechanism of copper-catalyzed synthesis of 4-formylpyrroles 33 from 31.
room temperature and high selectivity for syn-addition was observed when trans- and cis-stylbene were used as substrates. In 2008, Ito and Sawamura’s group realized a copper-catalyzed carboboration of c-silylated allylic carbonates 45 (Scheme 15).18 The reaction proceeded through borylcupration of alkenylsilanes with borylcopper species generated via transmetalation from diboronate, and subsequent intramolecular substitution (cyclization). The regioselectivity of borylcupration is determined by the a-stabilization effects of the silyl group.19 Chiral ligands, especially (R,R)-QuinoxP⁄ (53) and (R)-Segphos (54), induced high enantioselectivity to afford chiral trans-cyclopropane derivatives 46. Like the silyl group in 45, an aromatic substituent on the CAC double bond also controlled the regioselectivity of borylcupration when allylic phosphates 47 were used as substrates.20 Moreover, the borylcupration-cyclization strategy was extended to diastereoselective cyclobutane- and cyclopentane-forming reactions using an OMs group as a leaving group (from 49 and 50 to 51 and 52, respectively).21 The same group further established a related reaction using simple terminal alkenes 56, 57 as substrates (Scheme 16).22 The use of Xantphos (60) as a ligand for copper atoms showed good reactivity, whereas monophosphine and NHC ligands produced far less satisfactory results. Although the diastereoselectivity was low in this reaction (1:1–1.4:1), three-, four-, and five-membered ring formation proceeded smoothly. Electrophilic activation of alkenes (type B reactions)
[CuII]
B(pin)
36 O Br N CuII CuII N Br O N N
[Cun+1 ]
A reaction between alkenes and organocopper(III) species was demonstrated by Gaunt’s group (Scheme 17).23 In contrast to the above-mentioned nucleocupration strategy, high oxidation state organocopper(III) species acted as electrophiles, while alkenes acted as nucleophiles. The combination of a copper catalyst and diaryliodonium salt 62 generated aryl-Cu(III) intermediate 65, which acted as highly activated aryl cation-like species 650 . An
N
[CuII]
CO2 Et 39
33
clo[3.1.0]hex-2-enes 32 and copper-catalyzed formation of 4-formylpyrrole 33 from N-allyl enamine carboxylates 31 were developed by Chiba’s group (Scheme 11).14,15 Although the detailed role remains unclear, the addition of K2CO3 dramatically switched the reaction pathway to form 4-formylpyrrole 33. Otherwise, 3-azabicyclo[3.1.0]hex-2-ene 32 was formed under similar conditions. Both reaction pathways started with the generation of copper azaenolate species (34 or 39), which underwent intramolecular carbocupration of the CAC double bond (Schemes 12 and 13). In condition A, a mononuclear 38 or a dinuclear copper-peroxo complex 380 was assumed as an active species to promote carbocupration step. Subsequent metallacyclobutane 37 formation followed by reductive elimination produced 3-azabicyclo[3.1.0]hex-2-ene 32. On the other hand, isomerization proceeded from copper-peroxo species 40 to peroxide intermediate 41. Subsequent elimination of [Cun]-OH and oxidation afforded 4-formylpyrrole 33 under condition B. Results indicated that slight modifications of the reaction conditions can dramatically switch the reaction pathway from in situ-generated transient CACu(II) species. Organoboron compounds are versatile in organic synthesis, and thus many approaches to prepare valuable organoboron compounds have been extensively studied. In 2000, groups of Hosomi and Miyaura independently reported copper-catalyzed conjugate addition of the B(pin) group to enones.16 Miyaura’s group also demonstrated copper-mediated addition of the B(pin) group to a,b-unsaturated esters, nitriles or a terminal alkyne and a coupling with an allyl chloride. The proposed active species was CuB(pin) generated through transmetalation from bis(pinacolato)diborane. More recently Sadighi’s group reported insertion of alkenes to IPrCuB(pin) complex 43 (Scheme 14).17 The reaction proceeded at
O O [Cun+1]
Ph
Scheme 11. Two reaction pathways of N-allyl enamine substrates through intramolecular carbocupration of alkenes reported by Chiba.
[CuII]
31
[Cun ]OH Ph
32 36-90% yield
NH
[Cun+1 ] O O
[O]
N
R3 CO2Et
R1
[O]
R5
N
condition A
R3
R4
33
R2 R4
Ph
B(pin) Cu [CuII]
38'
Ar N
N Ar
Ph
(1.1 equiv) Ar = 2,6-(iPr)2 -C 6H 3 43
Scheme 12. Postulated mechanism of copper-mediated synthesis of 3-azabicyclo[3.1.0]hex-2-enes 32 from 31.
+ Ph
Ph Cu
pentane rt, 15 h
Ar N
N Ar 44 81%
Scheme 14. Stoichiometric borylcupration of alkenes reported by Sadighi.
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alkene nucleophile 61 attacked the aromatic electrophile to form a CAC bond. Deprotonation from intermediate 66 regenerated a CAC double bond. Interestingly, the product ratio (63:64) was significantly different from that of a typical Heck reaction product. By applying this chemistry to allylic amides 67, anti-oxyarylation and -oxyvinylation proceeded to construct trans-oxazine scaffolds 69 (Scheme 18: R3 = aryl and vinyl).24 Putative carbocation intermediates, generated through the reaction between aryl-Cu(III) and alkenes, were trapped by the oxygen atom of the amide group. It is noteworthy that endo-cyclization proceeded selectively, and a variety of functional groups were tolerated. When allylic amide 70 bearing a phenyl group at the internal position of the CAC double bond was used as a substrate, however, exo-cyclization product 71 was obtained exclusively. In this case, the reaction should proceed through a stable tertiary carbocation intermediate.
R1 R2
R3 61
Ar1
I
TfO
+
CuCl or Cu(OTf)2 (10 mol%) 2,6-di-t Bu-pyridine (1.1-2 equiv)
Ar 2
R1 R2
R3 Ar 2 63
+ R1
solvent, 50-70 oC 62 Ar = C6 H 5 or 2,4,6-Me3 -C 6H 2
R2
1
R3 Ar 2 64
19-94% yield CuX R1
-H+
R2 TfO
Cu III
2
Ar
R3
R R2
61
X
R3
Ar2
65
1
H
H Ar 2
65'
66
Scheme 17. Electrophilic arylation of alkenes developed by Gaunt. CuOt Bu (5 mol%) ligand (5.5 mol%)
OCO2 Me + (pin)B B(pin)
SiR3
45
(2-2.2 equiv)
R3 Si = Me3 Si PhMe 2Si BnMe 2Si
THF, 30
oC
B(pin)
Radical addition to alkenes (type C reactions)
R3 Si
Copper-catalyzed three-component imidocyanation reactions, initiated with an aminyl radical addition to alkenes, were developed by Xiong, Li, and Zhang’s group (Scheme 19).25 The reac-
46
ligand = (R,R)-QuinoxP* 53 or (R)-Segphos 54
83-99% yield 91-98% ee
OP(O)(OR)2 CuCl (5 mol%) (R,R)-iPr-DuPhos 55 (6 mol%) KOtBu (1 equiv)
Ar
47 R = 2-ethylhexyl +
Ar
R1
B(pin) 48
toluene/THF, rt
(pin)B B(pin)
O
8-90% yield 64-94% ee
(1.2 equiv)
+
HN
TfO
R3 68 (2 equiv)
R2
67
R1
CuTC (10 mol%)
Ar
I
R2
O N
1,4-dioxane rt-70 o C, 2-15 h
R3 69
12-95 % yield
OMs n
R
49 or
+
(pin)B B(pin)
OMs
CuCl (5 mol%) dppp (5 mol%) KOtBu (1 equiv)
R
Me 3C
51 or R
R
O
Ph
HN
n
THF, rt
(2 equiv)
B(pin)
+
TfO
CuTC (10 mol%)
Ar
I
Me3 C
R3
1,4-dioxane rt-70 o C, 2-15 h
68 (2 equiv)
70
O
Ph
N
R3
71
B(pin)
95-97% yield
n
50
n
iPr
O Me tBu N P N P t Bu Me 53 (R,R)-QuinoxP*
Scheme 18. Electrophilic oxazine formation developed by Gaunt.
52 28-89% yield
R = Ar, R3 Si n = 1, 2
O O
R1
P
PPh2 PPh2
iPr iPr P
O
R2
72 + + TMSCN (1.4 equiv)
CN
SO2 Ph
CuBr (10 mol%) phen (10 mol%)
F N
R
SO2 Ph 73 CH2 Cl2 , 70 oC, 1 h (1.4 equiv)
R2 74 20-92% yield
iPr
54 (R)-Segphos
55 (R,R)-iPr-DuPhos
N(SO2Ph)2
1
Scheme 19. Three-component imidocyanation of alkenes developed by Xiong, Li, and Zhang.
Scheme 15. Carboboration of alkenes developed by Ito and Sawamura.
74 73
Br R1 56 or
+
(pin)B B(pin) (1.2 equiv)
Br
CuCl (5 mol%) 60 (5 mol%) KOt Bu (1.2 equiv)
(pin)B
R2
R n = 1, 2 57
2
(pin)B O PPh 3
PPh3
60 Xantphos
R
2
F
CuIII N(SO 2Ph) 2 75
F Br
CuII
CuIII
Br N(SO 2Ph) 2
R1
N(SO 2Ph) 2 75' 72
2 77 R
N(SO 2Ph) 2
R1 CuBrF
Scheme 16. Carboboration of simple terminal alkenes developed by Ito and Sawamura.
Br
78
TMSCN
n
59 74-95% yield
F
N(SO2 Ph) 2
1
TMSF
R3
R3 n
R
or THF, 30 oC
CuIII
R1 58
CuBr
Br
NC
R2
CuBrF
76
Scheme 20. Proposed mechanism of three-component imidocyanation of alkenes.
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Y. Shimizu, M. Kanai / Tetrahedron Letters 55 (2014) 3727–3737
SO2 Ph
R1 R
2
+
F N SO2 Ph
79
F3 C
Cu(CH 3 CN)4 BF4 (2.5 mol%) 81 (1.6 mol%)
73 (1.5 equiv)
o
PhCN, 60 C
SO 2 N SO2 Ph
1
R
R
CF3
N
O
[Cu ]
83
R2 80 44-91% yield
OH O
I O
I
86
81
Scheme 21. Catalytic intermolecular carboimidation of alkenes developed by Matsunaga and Kanai.
tion utilized NFSI (73) and TMSCN as nitrogen and cyanide sources, respectively. A plausible catalytic cycle begins with oxidation of CuBr with NFSI, producing Cu(III) complex 75, which can generate Cu(II)-stabilized aminyl radical 750 through an equilibrium (Scheme 20). The addition of the aminyl radical to alkenes generates carbon radical 76, which is recombined with Cu(II) to afford organocopper(III) intermediate 77. A radical clock experiment supported the generation of a carbon radical intermediate. Subsequent transmetalation and reductive elimination afford imidocyanation product 74. The use of other cyanide sources dramatically retards the reaction, indicating that the interaction between the silicon atom and fluoride plays an important role. Matsunaga and Kanai’s group developed copper-catalyzed intermolecular carboimidation of aliphatic alkenes utilizing NFSI (73) as an oxidant as well as a nitrogen source (Scheme 21).26 The catalyst loading was as low as 2.5 mol % and the reaction yield was increased by the addition of a weakly coordinating additive 81. Various functional groups such as Br, NO2, OH, and OAc were tolerated, providing rapid access to functionalized sultams. In contrast to the above-mentioned imidocyanation reaction, a carbon radical intermediate, generated through the addition of the aminyl radical to alkene, reacts with an electron-deficient aromatic group intramolecularly. In 2011, the Buchwald,27 Liu,28 and Wang29 groups independently disclosed a copper-catalyzed trifluoromethylation of unactivated alkenes. Sodeoka’s group also reported trifluoromethylation of allyl silanes in 2012 (Scheme 22).30 All the groups utilized a combination of copper(I) salt and either Togni’s reagent 86 or Umemoto’s reagent 87. Buchwald’s group later conducted radical clock experiments and a TEMPO trap experiment to reveal that the reaction proceeded via trifluoromethyl radical addition to alkenes 82, giving 89 (Scheme 23).31 The mechanism of the subsequent CAC double bond-generation step from 89, however, remains unclear. Two possible pathways are; (a) single-electron oxidation of 89 by Cu(II) to carbocation species, followed by deprotonation, and (b) recombination of 89 with Cu(II) to afford organocopper(III) species, which undergoes b-hydride elimination to generate a CAC double bond.
R
O CF3
+ 88
CF3
R
89
82
Scheme 23. Plausible mechanism of trifluoromethylation of alkenes.
After these seminal works, many groups have actively investigated trapping of the reactive intermediate 89 or its derivatives by various reactants. The Szabó32 and Sodeoka33 groups independently realized copper-catalyzed carboxytrifluoromethylation of alkenes, which are conjugated with aromatic, silyl, or sulfur groups (Scheme 24). Togni’s reagent 86 was utilized both as a trifluoromethyl and a carboxylate sources. The same conditions were also applicable to arylacetylenes. A successful example of copper-catalyzed oxytrifluoromethylation utilizing aliphatic alkenes was reported by Buchwald’s group (Scheme 25).34 When terminal alkenes tethered with oxygenbased nucleophiles 92 were subjected to a Cu(I)/2,20 -biquinoline 96 catalyst in the presence of Togni’s reagent 86, oxytrifluoromethylation proceeded efficiently. Carboxylic acids, alcohols, and phenols could be used as oxygen-based nucleophiles to trap the radical intermediate. Because ligand 96 was essential to promote the oxytrifluoromethylation reaction, Buchwald’s group further developed an asym-
Cu(I) cat 86 R
OCOAr CF 3
R 90
91
R = Ar, PhMe2 Si, PhS
Ar = o-I-C6 H4
Szabó: CuI, CHCl3, 60-120 oC Sodeoka: [Cu(CH 3 CN)4 ]PF6 , CH2 Cl2, 23 oC
Scheme 24. Carboxytrifluoromethylation of styrenes developed by Szabó and Sodeoka.
[Cu(CH 3 CN)4 ]PF6 (10 mol%) 96 (20 mol%) 86 (1.1 equiv)
R
R
n
OH
R 82
n
R
CF 3
F 3C
R2
Cu cat. CF3 source
84
[Cu(CH 3 CN)4 ]PF6 (7.5 mol%) 97 (7.5 mol%) 86 (1 equiv)
n
I O O
83
R1
93 35-94% yield
Ar
Buchwald: [Cu(CH 3CN) 4]PF6, 86, MeOH, rt Wang: CuCl, 86, MeOH, 70-90 oC Liu: CuTC, 87, DMAc, 40 oC
[Si]
CF3 O
MeCN, 55 o C, 16 h
92 n = 1-3 Cu cat. CF3 source
O
I [Cu II]
O 94
86
85
CF3
n
95 44-88% yield 74-83% ee
n = 1, 2
O S CF3 87
OTf
CF3
O
MTBE, rt, 16 h
R1 R2
Ar O
HO
N 96
O N
N tBu
N 97
tBu
Sodeoka: CuI, 86, MeOH, rt
Scheme 22. Trifluoromethylation of unactivated alkenes.
Scheme 25. Oxytrifluoromethylation of unactivated alkenes and extension to an asymmetric reaction reported by Buchwald.
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Y. Shimizu, M. Kanai / Tetrahedron Letters 55 (2014) 3727–3737
metric variant using a chiral ligand, (S,S)-tBu-Box (97), in MTBE solvent.31 Significant enantioselectivity was induced, indicating that the copper catalyst is relevant to the cyclization step. Based on these pioneering works, carbon- and nitrogen-based trapping agents have also been applied extensively by several groups.35 Although terminal alkenes were used in most of the examples, difunctionalization of internal alkenes35b,d,h and dienes35a was also amenable.
CuF2 (20 mol%) MnO2 (2.0 equiv) phen (2.0 equiv) K3PO 4 (3.0 equiv)
+ N N
OH 100
Difunctionalization of alkynes
O
O
DMF, rt, air 8-12 h
R O 101
R
N N
102 R = Ph: 57% R = 1-naphthyl: 53%
CuF2
In contrast to difunctionalization of alkenes, difunctionalization of alkynes preserves a CAC unsaturated bond (i.e., double bond) after the reaction (Scheme 26). Therefore, the transformation is effective for the synthesis of poly-substituted alkenes or aromatized products. In addition, the generated CAC double bonds can be utilized for further transformations.
OH 100
N N Cu
FCu
Ph
R
O
R
O
N N O
103
104
Scheme 28. Intramolecular oxycupration of alkynes followed by biaryl coupling developed by Hirano and Miura.
Nucleocupration of alkynes (type A reactions) In 2002, Hiroya’s group reported a successful copper-mediated carboamidation reaction (Scheme 27).36 They found that Cu(OTf)2 or Cu(OAc)2 was especially effective for the endo-dig cyclization of 98 to form indolylcopper species through intramolecular amidocupration. Although the indolylcopper intermediate was protonated in the absence of any additives, deprotonation of the sulfonamide group by KH facilitated the subsequent CAC bondformation, producing cyclization product 99 in moderate yield. The scope was limited to five- and six-membered ring constructions, and the reaction involving intramolecular addition to a formyl group was not successful under the same reaction conditions. Hirano and Miura’s group extended the nucleocupration strategy to dehydrogenative coupling between o-alkynylphenols 100 with oxadiazoles 101 (Scheme 28).37 A postulated mechanism involves CAH cupration of oxadiazoles by CuF2 to give arylcopper species 103, intramolecular oxycupration to give benzofurylcopper 104, and reductive elimination to form coupling product 102. Although most of the reported examples employed a stoichiometric amount of the CuF2/1,10-phenanthroline (2/1) complex, two examples of catalytic reactions using MnO2 as an oxidant were demonstrated. The redox property of copper atoms played a key role in the CAC bond-forming step, in contrast to Hiroya’s report. Difunctionalization of alkynes was triggered by amido- or oxycupration of CAC triple bonds in the above two reports. The reverse sequence, that is, carbocupration-triggered difunctionalization of alkynes, was reported by Li’s group in 2011 (Scheme 29).38 They
C + R1
R2 +
Cu cat.
C
X
R1
R2
developed CuCl2-catalyzed oxidative cyclization of 1,6-enyn3-ones 105. 1,4-Addition of H2O to the enone moiety generated copper enolate 108, which attacked the CAC triple bond in an intramolecular manner (Scheme 30). Finally, the CACu bond was oxygenated through copper-peroxo species 110, giving product 1,4-naphthoquinone 106. Although additive oxidant Ce(SO4)2 was not essential, it markedly enhanced the reactivity. 18O-labeling experiments showed that incorporated oxygen atoms were derived from both water and molecular oxygen, consistent with the proposed catalytic cycle. Chiba’s group also developed carbocupration-initiated alkyne carbooxygenation to construct aza-heterocycles (Scheme 31).39 Under CuBr/1,10-phenanthroline catalysis, enamine carboxylates 112 and O2 were used as carbon nucleophiles and an oxygen
R3
R1
O
H 2O CuCl2 (10-50 mol%) Ce(SO4) 2· 4H 2O (1.5 equiv)
R2
R2 R3
R1
o
DMA, 80 C, O2
O 105
O
Scheme 29. Oxidative cyclization of 1,6-enyn-3-ones to produce benzoquinones developed by Li.
CuCl O O
X
[O] HCl
106 H 2O CuCl2
105
R2
R2 R3
Scheme 26. General scheme of copper-catalyzed difunctionalization of alkynes involving CAC bond-formation.
O O O
n
NH Ts 98
OTs
KH; Cu(OAc) 2 (50 mol%) 1,2-dichloroethane 70 oC, 48 h
CuCl2 R3
OH
111
O 107
CuCl R2
O
H2 O HCl R2
R3
n
N Ts 99 n=1: 67% n=2: 64% n=3: 0%
O
106 8-85% yield
OH
CuCl CuCl
R3
R2
110 O2
R3 O
O
OH
108
OH
109
Scheme 27. Indole formation via amidocupration followed by substitution developed by Hiroya.
Scheme 30. Proposed mechanism of oxidative cyclization of 1,6-enyn-3-ones.
3734
Y. Shimizu, M. Kanai / Tetrahedron Letters 55 (2014) 3727–3737 R2
R1
NH
CO 2Et
DMF, 60 oC, O2 1.5-3.5 h
CO2 Et
R3
R2
O
CuBr·SMe 2 (10 mol%) phen (30 mol%) MS 4A R1
N
R3
113 59-90% yield
112
Scheme 31. Carbooxygenation of alkynes to produce quinolines developed by Chiba.
source, respectively. The sequence produced highly substituted quinolines 113, which are difficult to obtain by other means. Ligand 1,10-phenanthroline improved the yield, and the addition of molecular sieves 4A made the reaction more reproducible. It is noteworthy that other metal sources such as Fe(III), Pd(II), and Co(II) afforded no product or an inferior yield, indicating that both the p-philic nature and the one-electron redox property of the copper catalyst are keys for the successful transformation. In 2012, Hou’s group and Tortosa’s group independently reported copper-catalyzed carboboration of alkynes. In both reactions, borylcopper species were first generated through metathesis between diborane and a copper alkoxide catalyst. Then, vinylcopper species, generated through borylcupration of alkynes, reacted in the subsequent CAC bond-forming step. Hou’s group used CO2 as an electrophile to trap the vinylcopper intermediate (Scheme 32).40 Use of bulky NHC ligand, IPr 116, produced product 115 in only a trace amount; however, less stericallydemanding and electron-rich SIMes 117 proved to be a suitable ligand, affording the product in high yield. The proposed catalytic cycle shown in Scheme 33 begins with CuOtBu formation from CuCl and LiOtBu. Reaction of the thus-generated CuOtBu and B2(pin)2 affords CuB(pin) through metathesis, to which insertion
(pin)B B(pin) (1 equiv) R' + +
R
THF, 80 oC, 14 h
CO2 (1 atm)
114
iPr
Li O O B O
SIMesCuCl (5 mol%) LiOtBu (1.1 equiv)
iPr
R R' 115 64-94% yield
Me
Me
N
N
N
iPr
Electrophilic activation of alkynes (type B reactions) Taking advantage of the highly electrophilic nature of organocopper(III) species, Gaunt’s group developed a novel strategy to construct tri- or tetra-substituted alkenes through an electrophilic syn-carbotriflation of alkynes (Scheme 35).43 The combined use of a CuCl catalyst and vinyl- or diaryliodonium triflates 127 generates highly electrophilic carbon species, possibly vinyl- or arylACu(III) species 129, which react with alkynes to give putative vinylACu(III) intermediates 131 (Scheme 36). Reductive elimination from 131 results in tri- and tetra-substituted vinyltriflates 128. This electrophilic carbofunctionalization approach can complement nucleometalation of alkynes. The reaction is applicable to both internal and terminal alkynes. Products 128 appear to be versatile precursors for cross coupling reactions.
R 2 + (pin)B B(pin)
R1
iPr
Me
Me 117
IPr
SIMes
THF or toluene rt-60 o C, 24 h
ligand = Xantphos (60) or P(p-tolyl)3 R3 X = MeI, allyl-I, BnBr
RO + (pin)B B(pin)
R'
116
CuCl (10 mol%) ligand (10 mol%) NaOtBu (1.1 equiv) R 3 X (1.1-4 equiv)
(1.1 equiv)
120 R 1 = aryl
Me
Me N
O
of alkyne 114 proceeds in a syn fashion, furnishing vinylcopper intermediate 118. Nucleophilic addition of the vinylcopper species 118 to CO2 gives b-boralactone derivatives 119, which upon reaction with LiOtBu regenerate CuOtBu and release product 115. They isolated the key intermediates (118 and 119) under stoichiometric conditions, and characterized the structure by X-ray analysis, which supports their proposed mechanism. On the other hand, Tortosa’s group exploited alkyl halides as electrophiles (Scheme 34).41,42 Investigation of the phosphine ligand effects in the presence of CuCl and NaOtBu revealed that Xantphos (60) was the best ligand for terminal alkynes, whereas P(p-tolyl)3 was the best ligand for internal alkynes. In addition to aryl-substituted alkynes, propargylic ethers 122 and 1,3-enynes 124 were applicable for the reaction.
R' 122
R3
CuCl (10 mol%) 60 (10 mol%) NaOt Bu (1.1 equiv) MeI (4 equiv)
(1.1 equiv)
B(pin)
R1 R2 121 42-83% yield
Me
B(pin)
RO R' R' 123 56-59% yield
THF
Scheme 32. Boracarboxylation of alkynes developed by Hou. CuCl (10 mol%) ligand (10 mol%) NaOt Bu (1.1 equiv) MeI (4 equiv)
R1 R2
LCuCl
R 4 + (pin)B B(pin)
LiOt Bu R3
LiCl 115
LCuOt Bu
(1.1 equiv)
Me
R4
THF
R2
124
B2(pin) 2
B(pin)
R1
ligand = 60 or PPh 3
R3 125
58-77% yield
(L = SIMes 117) LiOtBu
(pin)BOtBu
CuL O O B O R 119
Scheme 34. Carboboration of alkynes using alkyl halides as electrophiles developed by Tortosa.
LCuB(pin)
O
Me
R'
CO 2
OTf
CuCl (10 mol%)
B(pin)
CuL
R
114
R' 118
Scheme 33. Proposed catalytic cycle of boracarboxylation of alkynes.
R1
R2 +
126 4 equiv
TfO
I
127
o
solvent, 5-60 C 6-36 h
R1 R2 128 27-89% yield
Scheme 35. Tri- and tetra-substituted vinyltriflates synthesis developed by Gaunt.
3735
Y. Shimizu, M. Kanai / Tetrahedron Letters 55 (2014) 3727–3737
As an extension of this chemistry, Gaunt’s group reported copper-catalyzed carboarylation of aryl- or nitrogen-substituted alkynes 132 (Scheme 37).44 In contrast to aryltriflation of alkyl-substituted alkynes described in Scheme 35, vinyl cation intermediate 136 stabilized by adjacent aryl group (R1) was assumed to be the key intermediate rather than vinylACu(III) species 131. The putative vinyl cation 136 was intercepted by the tethered aryl group acting as a nucleophile to form cyclized product 134. The reaction tolerated various functional groups, and was applied to a streamlined synthesis of the anticancer agent nafoxidine 140 (Scheme 38). An intermolecular 3-component coupling variant also resulted, albeit in lower yield.
Cl Cl
+ MeO
Nucleocupration of allenes (type A reactions) In 2013, two groups reported the use of in situ-generated allylcopper species from allenes for asymmetric nucleophilic addition to carbonyl compounds. Regioselectivity was very high in these reports.
128
127 CuCl
reductive elimination
oxidative addition
Cl
Cl
CuIII TfO
R1 R2 131
129
electrophilic carbofunctionalization
MeO 139 N
2) pyrrolidine EtOH, 100 o C 4 h, 88%
Allenes possess unique structural features compared to alkenes and alkynes. Because allenes comprise three carbons, the formation of regioselective CAC and CAX bonds is more difficult than that of other CAC multiple bonds. Recent successful examples of regioselective difunctionalization of allenes are discussed in this section (Scheme 39).
Cu
rt, 16 h 84%
I 138
1) CuCl (2.5 mol%) Ph 2IOTf (2 equiv) 2,6-di-tBu-pyridine (2 equiv) DCE, 50 o C, 24 h 73% (5:1 regioisomer)
Difunctionalization of allenes
TfO
O
137
MeO 140 nafoxidine
Scheme 38. Streamlined synthesis of nafoxidine by Gaunt.
Hoveyda’s group revealed that borylcupration of allenes produced allylcopper species in situ, which could be utilized for enantioselective nucleophilic addition to aldehydes and ketones (Scheme 40).45 Both NHC 144 and diphosphine 145 ligands were effective for the racemic reaction, while chiral diphosphines (146 for aldehydes and 147 for ketones) were effective for the asymmetric reaction. The reaction was initiated by the catalytic generation of allylcopper species 148 through the insertion of allenes 141 to the reactive CuAB bond of an in situ-generated borylcopper species, with the B(pin) group selectively incorporated at the central carbon of the allenes (Scheme 41). The thus-generated allylcopper species 148 reacted with carbonyl compounds 142. Regio-, diastereo-, and enantioselectivity were quite high (>98% c-selective, 88:12 to >98:2 dr, 70–94% ee). The applicability of this reaction to ketone electrophiles is noteworthy because ketones are significantly less electrophilic than aldehydes. Products 143 are versatile, and were converted to b-hydroxyketones via oxidation with NaBO3, and vinyl bromides via bromination with CuBr2. Shimizu and Kanai’s group developed an oxycupration approach to generate organocopper species containing an iso-
TfO Cu C
R2
R1
R3
R2
R4
+
C Cu cat. +
X
Scheme 36. Plausible mechanism of tri- and tetra-substituted vinyltriflates synthesis.
+ TfO R2
I
CuCl (2.5 mol%) 2,6-di-tBu-pyridine (2 equiv)
Ar
DCE, 50 12-36 h
X 132
oC
R 1 = aryl, NRR' X = CH2 , O, NTs
(1.1-1.5 equiv) X
141
Friedel-Crafts vinylation 132
R1
CuIII
CuCl (4-5 mol%) ligand (4-5 mol%) NaOtBu (16 mol% or 1.5 equiv)
R3
OH B(pin)
R2
THF, 22 o C
R1 143
ligand
Cl BF4
AdN
NAd rac-BINAP
Ad = adamantyl
TfO
X
R2 R3 142 (1.1-1.5 equiv)
38-97% yield
CuCl
+ O
R1
134
Ar = C6 H 5 or 2,4,6-Me 3-C6 H2
Cl
(pin)B-B(pin) +
R2
R3 R4
Scheme 39. General scheme of copper-catalyzed difunctionalization of allenes involving CAC bond-formation.
R1
133 (2 equiv)
R1 R2
130
R1
O
126
Cl
R1
O
PdCl2(PPh 3) 2 (3 mol%) CuI (6 mol%) NEt3
PPh2 S
Ph2 P MeO
OMe PPh2
PPh2 Cl
R2 135
135'
144
X 136
Scheme 37. Carboarylation of alkynes developed by Gaunt.
145
for racemic reaction
146
147
for aldehydes
for ketones
Scheme 40. Regioselective carboboration of allenes developed by Hoveyda.
3736
Y. Shimizu, M. Kanai / Tetrahedron Letters 55 (2014) 3727–3737 mesitylene
NaCl NaOt Bu R'
(pin)B
LCuCl
LCuOt Bu O
R3 R2
153 or 157
B(pin)
P X Cu
(pin)B-B(pin) (pin)BOtBu
R1 150
158
LCuB(pin)
O
*
B(pin) X
R2
n
R1 149
LCu 1
R1
B(pin)
148
MesCu (10 mol%) 154 or 155 (11 mol%) Al(Ot Bu)3 (0-5 mol%)
O R2
152 (1.5-2 equiv)
R' R O
HMPA−THF (1:19) −20 o C-rt, 3-62 h
R2 R1 OH
153 60-99% yield 76-97% ee O
Ph
O
Ph P
PAr 2 PAr 2
O Ph
Ph 154 (S,S)-Ph-BPE
159 P
* P
*
P
* Cu
R'
P
Cu
155 (R)-DTBM-SEGPHOS (Ar = 3,5-tBu2 -4-MeO-C 6H 2)
MesCu (5 mol%) 154 (5 mol%) Mg(OiPr)2 (0-30 mol%) Dioxane, rt, 3.5 h;
+ 1 NH R R2 2 N NaOH, 12-48 h, rt COOMe 156 152 (1.5-2 equiv)
P
n 2
X
X
R P Cu O H 1 R R'
161 6-member ed TS
n
160
X n
160'
152
Scheme 44. Proposed mechanism of carbooxygenation and carboamidation of allenes.
rium through 1,3-metallotropic rearrangement, where chirality of starting 158 disappeared. We extended this strategy to the formation of enantio-enriched 2-(2-hydroxyethyl)indole derivatives starting from allenic anilides 156 (Scheme 43).47 Mg(OiPr)2 co-catalyst effectively increased the yield of reactions with aliphatic aldehydes and ketones. Conclusion Although miscellaneous reaction patterns have been reported, there remains much room for improvement in this field. First, the development of a three-component, convergent assembly method is still in its infancy despite its potential utility for constructing complex molecules. Second, beyond methodology development, the method should contribute to the facilitation of molecular synthesis by achieving high reactivity and functional group tolerance under mild reaction conditions. Enantiocontrol is a prerequisite in this sense. Finally, elucidation of the basic reaction mechanism (especially for reactions using unactivated alkenes and alkynes) is extremely important. An understanding of the basic mechanism and concept underlying the catalytic generation of active species would allow for the design of new reaction sequences. Acknowledgments
O
Scheme 42. Oxycupration followed by asymmetric addition of carbonyl compounds for construction of isochromene scaffold developed by Shimizu and Kanai.
O
* P
R' *
R'
R
Cu
n
P
chromene skeleton (such as 160 and 1600 ) from allenes (Schemes 42 and 44).46 Asymmetric addition of the thus-generated organocopper species to carbonyl compounds 152, including aldehydes and a ketone, produced a unique scaffold 153. Notably, CAC bond-formation of the reactive organocopper species proceeded preferentially to protonolysis by the OH groups of the substrates. The addition of Al(OtBu)3 co-catalyst improved product yield, especially in the reaction with aliphatic aldehydes. Because the Al(OtBu)3 co-catalyst did not affect enantioselectivity, it likely accelerated the catalyst turnover step (162–158) by liberating the copper catalyst from the product (Scheme 44). Enantioselectivity was generally high and regioselectivity was virtually perfect. Furthermore, the reaction was stereoconvergent when applied to racemic disubstituted allenes. This result indicates that putative two allylcopper species 160 and 1600 exist in equilib-
P
R
O
X
2
chir ality-det er mining
B(pin)
Scheme 41. Plausible catalytic cycle of regioselective carboboration of allenes.
151
P
R1
*
148'
142
R1
Cu
P 162
LCu
R
OH +
R'
R'
R3
R
X = O or NCO2 Me n = 0 or 1
151 or 156
141
(pin)B-B(pin) LCu
* P
n
MesCu + ligand + 151 or 156
R OH 2
R N R1 H 157 57-98% yield 77-99% ee
Scheme 43. Amidocupration followed by asymmetric addition of carbonyl compounds for construction of indole scaffold developed by Shimizu and Kanai.
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