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(Guanidine)copper Complex-Catalyzed Enantioselective Dynamic Kinetic Allylic Alkynylation Under Biphasic Condition Xi-Yang Cui, Yi-Cen Ge, Siu Min Tan, Huan Jiang, Davin Tan, Yunpeng Lu, Richmond Lee, and Choon-Hong Tan J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b12806 • Publication Date (Web): 12 Jun 2018 Downloaded from http://pubs.acs.org on June 13, 2018
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Journal of the American Chemical Society
(Guanidine)copper Complex-Catalyzed Enantioselective Dynamic Kinetic Allylic Alkynylation Under Biphasic Condition Xi-Yang Cui1, Yicen Ge1, Siu Min Tan2, Huan Jiang1, Davin Tan1,2, Yunpeng Lu1, Richmond Lee2*, Choon-Hong Tan1* 1 2
Division of Chemistry and Biological Chemistry, Nanyang Technological University, 21 Nanyang Link, Singapore 637371 Singapore University of Technology and Design, 8 Somapah Road, Singapore 487372
ABSTRACT: Highly enantioselective allylic alkynylation of racemic bromides under biphasic condition is furnished in this report. This approach employs functionalized terminal alkynes as pro-nucleophiles and provides 6- and 7-membered cyclic 1,4-enynes with high yields and excellent enantioselectivities (up to 96% ee) under mild conditions. Enantio-retentive derivatizations highlight the synthetic utility of this transformation. Cold-spray ionization mass spectrometry (CSI-MS) and X-ray crystallography were used to identify some catalytic intermediates, which include guanidinium cuprate ion pairs and a copper-alkynide complex. A linear correlation between the enantiopurity of the catalyst and reaction product indicates the presence of a copper complex bearing a single guanidine ligand at the enantio-determining step. Further experimental and computational studies supported that the alkynylation of allylic bromide underwent an anti-SN2’ pathway catalyzed by nucleophilic cuprate species. Moreover, metal-assisted racemization of allylic bromide allowed the reaction to proceed in a dynamic kinetic fashion to afford the major enantiomer in high yield.
■ INTRODUCTION
(a)
Enantioselective allylic substitutions are powerful synthetic methods to strategically install C-C bonds.1 There are two main approaches for catalytic enantioselective allylic substitutions: 1) a new stereogenic center is generated from a prochiral substrate via SN2’ pathway or 2) resolution from racemic chiral starting materials (maximum yield of 50%). The development of dynamic kinetic processes broke the yield limit for the resolution approach and the use of stabilized nucleophiles (Nuc-H pKa 25).4,5 Unlike reactions with stabilized nucleophiles, which add in an outer-sphere manner, the control of non-stabilized nucleophiles in allylic substitutions requires the metal catalyst to modulate the reactivity of both the allylic substrate and nucleophile.4c This is further complicated by the fact that during dynamic kinetic reactions, the enantiomers of the starting material may have different rates of addition, isomerization and elimination when interacting with the chiral metal complex.5h Due to the high pKa values of nonstabilized nucleophiles, the pro-nucleophiles used for such reactions are typically organometallic reagents, which are readily transmetallated to the metal catalyst. The functional group tolerance is generally low or moderate at room temperature towards these active organometallic reagents.4 Therefore, it is not surprising that it is only recently that Cu-catalyzed dynamic kinetic enantioselective allylic substitutions with non-stabilized nucleophiles, mainly to construct Csp3-Csp3 bonds, have been achieved through the efforts of Alexakis and Fletcher.5
OPO(OEt)2 Al(iBu)2
R1
R3
R2
CuCl2/L1 SN2' pathway
+ R2
Ph H O S N NAr O O Ar = 2,6-(iPr)2C6H3 AgAg
R1
L1
R3
O O
NAr
S N O
Sawamura (2014) OPO(OEt)2 H
R1
N
N
H
R2
R1
Ph
Ph
R2 CuCl/L2 SN2' pathway
+
H
Ph
OH
BF4 L2
Carreira (2013) BF3K
OH R1
(±)
Ir complex/L3 dynamic kinetic process
+ R2
R2
O PN O
R1
L3
H
(b) R
Br (±) CuCN/CG R
+
H
dynamic kinetic process
tBu
N
tBu N I N CG H H
.First guanidine-modulated allylic substitution . Mild condition .Detailed mechanistic insights
Figure 1. Csp3-Csp bond construction via enantioselective allylic substitution. a) Successful examples using alkynes or equivalents in enantioselective allylic substitutions. b) Guanidine(copper) complex-catalyzed dynamic kinetic enantioselective allylic alkynylation (this work). The formation of Csp3-Csp bond through asymmetric allylic alkynylation is challenging but rewarding, as it leads to highly functionalized 1,4-enynes (skipped enynes)6 and to date, there are only three successful examples (Figure 1a).7 Using a mix of Cu/NHC-Ag catalyst system, Hoveyda reported the first example of allylic alkynylation employing organoaluminium reagents.7a The reaction proceeded via the SN2’ pathway with a variety of allylic phosphates. A significant improvement was subsequently reported by
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Sawamura who demonstrated that terminal alkyne pronucleophiles can be activated directly using a Cu-carbene catalyst and high enantioselectivities were achieved with triisopropylsilylacetylenes.7b In both examples, chiral Nheterocyclic carbene ligands played key roles to modulate reactivity and selectivity. The only example of allylic alkynylation using racemic chiral substrates, through a dynamic kinetic process, is the direct displacement of linear allylic alcohols with alkynyltrifluoroborates, utilizing an Irphosphoramidite catalyst.7c The enantioselective formation of Csp3-Csp bond through dynamic kinetic allylic alkynylation with Cu-catalyst is still unexplored until this work. Guanidine is known to coordinate with various metals in different modes.8 However, successful examples using chiral guanidine as ligands in metal-catalyzed asymmetric reactions are scarce and are only emerging recently.9 Reported reactions are limited to X-H (X = N or C) insertion with carbene precursor,9a,9b nucleophilic addition9c and Ullman reaction9d,9e. In the past decade, our group has developed guanidine, conjugate-guanidinium (pentanidium) and bis-guanidinium as organocatalyst, phase transfer catalyst and ion-pairing catalyst respectively.10 Herein, we present our efforts to expand the chemistry of guanidine to include the use of (guanidine)copper complexes to catalyze allylic alkynylation of racemic bromides (Figure 1b).
Enantioselective Alkynylation of Cyclic Allylic Bromides. We were initially motivated by examples in the literature demonstrating that Cu-catalyzed allylic substitutions can proceed at room temperature under biphasic conditions.11 Using the allylic alkynylation reaction between bromocyclohexene (1a) and phenylacetylene (2a) as the model reaction, we investigated several chiral cations developed in our laboratory under phase transfer conditions (Table 1). In the presence of copper(I) chloride, pentanidinium (PN)12 showed good reactivity but no enantioselective induction was detected (Table 1, entry 1). When 2 mol% of bisguanidinium (BG) was used, skipped enyne 3a was obtained in good yields with moderate enantioselectivity (entry 2). Cyclic-guanidinium (CG),13 previously prepared as a Brønsted base or phase transfer catalyst in our laboratory, gave the highest level of enantioselectivity after initial investigations (entry 3). It was found that a weaker base improved the enantioselectivity by suppressing background reaction and aqueous saturated K2CO3 was the most ideal (entries 4-8). It was also found that CuCN was the most suitable copper salt (entries 4-8). Solvent studies, leaving group studies and detailed optimization data are provided in the supporting information (see SI, Table S1-S2). Scheme 1. Enantioselective Alkynylation of Cyclic Allylic Bromides.a
Table 1. Chiral Cation/Cuprate-Catalyzed Enantioselective Alkynylationa Br +
H
Ph 2a
(±)-1a Ph
N
Ph
N
CH2Cl2, base, 23 oC
N
Ph
N
Ph
N Cl
tBu
Pentanidium (PN) R R Ph N N N N N N Ph R R 2ClBisguanidinium (BG)
n (±)-1 R1
catalyst (x mol %) CuX (y mol %)
Br +
R2
N H I
N H
Cyclicguanidium (CG) Ph R=
aq. sat. K2CO3 CH2Cl2, 23 oC
n 3
R1
R2 n = 1-3
Me 3b (pMe): yield 95%, ee 89% 3d:b,c yield 91 %, ee 89% 3c (mMe): yield 92%, ee 88% Cl
3a: yield 93%, ee 91%
tBu
CG (2.0 mol%) CuCN (15 mol%)
2
n = 1-3
OMe 3e:b,c
tBu
yield 90%, ee 89%
F 3f:b,d
yield 93%, ee 85%
3g:b,d
yield 92%, ee 88%
Ph tBu S 3h: yield 94%, ee 89%
catalyst/ x mol%
CuX/ y mol%
1
PN (2)
CuCl (20)
50 wt% NaOH
92
0
2
BG (2)
CuCl (20)
50 wt% NaOH
90
17
3n: yield 90%, ee 92%
3
CG (2)
CuCl (20)
50 wt% NaOH
90
25
N Ts
4
CG (2)
CuCl (20)
aq. sat. K2CO3
76
79
5
CG (2)
CuBr (20)
aq. sat. K2CO3
75
76
6
CG (2)
CuI (20)
aq. sat. K2CO3
72
60
7
CG (2)
CuCN (20)
aq. sat. K2CO3
80
89
8d
CG (2)
CuCN (15)
aq. sat. K2CO3
85
91
entry
H
3a N
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base
yield (%)b
ee (%)c
a Reaction was carried out with 1a (0.05 mmol) and 2a (0.05 mmol) in CH2Cl2 (1 mL) and base (0.5 mL) for 12 h under N2 atmosphere. b GC yield, 1,1'-biphenyl used as an internal standard. cDetermined by GC-MS analysis with a chiral column. d1.6 equiv. allylic bromide was used, ee of the recovered 1a was 0%.
■ RESULTS AND DISCUSSION
3i: yield 93%, ee 91%
n-Hex 3k: yield 95%, ee 92%
3j: yield 94%, ee 93% OH
COOMe 3l: yield 86%, ee 94%
3m: yield 93%, ee 94% Nphth
TMS
TBS 3o: yield 93%, ee 92%
3p:b yield 88%, ee 89% TMS
SPh 3q:b yield 85%, ee 88% OH
3r: yield 91%, ee 89% nHex
Me 3t: yield 94%, ee 92% OH
Me 3u: yield 95%, ee 90%
Me 3s: yield 90%, ee 91% TMS Ph 3v: yield 91%, ee 93% OH
Si Ph 3w: yield 87%, ee 93%
3x: yield 92%, ee 93%
3y: yield 90%, ee 89%
3z: yield 93%, ee 96%
3aa: yield 90%, ee 91%
3ab:e yield 52%, ee 81%
a Reactions were carried out with alkynes (0.4 mmol) and allylic bromides (0.64 mmol) in CH2Cl2 (7.0 mL) and sat. K2CO3 (3.5 mL) for 24 h under N2 atmosphere; yields refer to isolated yields
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Journal of the American Chemical Society and ee values were determined using chiral GC or HPLC. b4 mol % of guanidinium salt and 10 mol % of CuCN were used. cReaction time is 36 h. dReaction time is 16 h. e Reaction time is 48 h.
With the optimized reaction conditions in hand, the substrate scope of the reaction was examined (Scheme 1). Various aryl-substituted terminal alkynes were useful with this methodology (Scheme 1, 3a-h) including aromatic heterocycles such as 3-thienyl-substituted alkyne (3h). Benzyl-, cyclohexyl- and nhexyl-substituted terminal alkynes also gave good yields and high ee values (3i-3k). Alkynes containing ester (3l), tertiary hydroxyl (3m), silyl (3n, 3o), imide (3p, NPhth = phthalimido), sulfonamide (3q) and thioether (3r) are generally well tolerated and provides good yields and ee values of the skipped enynes. β-Substituted cyclic allylbromides show no negative effect on yields and enantioselectivities (3s-3w). 3Bromocyclopentenes were unstable under the reaction condition; thus, no desired product was observed. On the other hand, seven-membered allylbromides were suitable and provided good results for the asymmetric allylic alkynylation (3x-3aa). The reactivity for eight-membered cyclic allylic bromides was low; although a good level of enantioselectivity was obtained (3ab). We were able to scale up the reaction yielding 3a (1.02 g) in gram quantity (see SI, Page S13). Scheme 2. Enantio-retentive Derivatizations of Enantiopure Cyclic 1,4-Enynes. DIBAL-H cyclohexane 40 oC, 3 h
E Z 4, yield 93%, ee 89%
Na/NH3
Rh-catalyzed AAA,14 yield 67%, ee 96%
-78 oC, 10 min 5, yield 90%, ee 88% 3a, ee 91%
TBD (20 mol%) THF, 25 oC, 48 h
H Ph 6: yield 85%, ee 89% •
■ MECHANISTIC STUDIES
Identification of Reaction Intermediates and Mechanistic Studies. It was proposed by Alper that quaternary ammonium alkynylcuprate complex was a key intermediate in copper-catalyzed allylation reaction of alkynes.11b We found that commercially available ammonium cuprate ion-pair (Sigma-Aldrich, Inc.),18 which is soluble in CH2Cl2, catalyzed alkynylation successfully under biphasic conditions (Scheme 3, eqn. 1). As tetra-butyl ammonium (Bu4N+) is unlikely to act as a ligand to copper, it is most reasonable to propose that tetra-butyl ammonium alkynylcuprate19 ion-pair is the active catalyst in this reaction. During our initial investigations, we found that a variety of chiral cations including cyclic-guanidinium (CG) can ‘carry’ copper salts into the non-polar solvents (Table 1). Indeed, guanidinium cuprate 10 was isolated as yellow solid when CuCl was mixed with CG+Cl- in CH2Cl2 and a single crystal suitable X-ray diffraction was grown by vapor diffusion of Et2O into a CH2Cl2 solution (Scheme 3, eqn. 2). The dichlorocuprate anion is shown to form dual hydrogen bonds with the cyclic-guanidinium cation. When this ion pair 10 was added to the reaction, asymmetric alkylation proceeded with good reactivity and stereocontrol (Scheme 3, eqn. 3), indicating that this ion pair is an intermediate or catalyst precursor in (guanidine)copper-catalyzed enantioselective allylic alkynylation. Scheme 3. Identification of Guanidinium Cuprate Ion Pair as Catalyst Precursor.
I
TMS
by comparing with literature value of optical rotation of alkene 5.5e Enantiospecific base-catalyzed 1,3-proton isomerization reaction was conducted using triazabicyclodecene (TBD) and provided allene 6.15 The stability of the skipped enyne’s chirality encouraged us to be adventurous and we successfully used 3l in Larock annulation, obtaining indole 7 after removal of the silyl group.16 After deprotection of the silyl group in skipped enyne 3s, alkyne 8 underwent a Cu-catalyzed alkyne-azide cycloaddition (CuAAC) smoothly to afford triazole 9.17
NHMe
2(Bu4N)+ I Cu
(1) Pd(OAC)2, PPh3 N Na2CO3, LiCl (1 equiv.), DMF, 100 oC Me (2) 37% HCl, MeCN, 90 oC 3l, ee 92% 7: yield 88%, ee 89% TMS
N3
TBAF o PhTHF, 0 C
3s, ee 93%
Br
Br
H
CuSO4.5H2O sodium ascorbate H2O:tBuOH = 2:1 8, yield 71%, ee 93%
Br + H
N N N
Ph
Ph
(±)-1a N
tBu
N N H Cl- H 1 equiv.
2-
(20 mol%)
Ph
CH2Cl2, aq. sat. K2CO3 23 oC, under Ar, 16h
2a (1 equiv.)
tBu
I Cu I I
+ CuCl 1.2 equiv.
CH2Cl2, 23 oC under Ar, 4h
tBu
(±)-3a yield 90%
Ph (1)
N tBu N N H 10 H [CuCl2]- yield 85%
(2)
9, yield 85%, ee 93%
Enantiopure cyclic 1,4-enynes are versatile building blocks in organic synthesis (Scheme 2) and we demonstrate it through a series of reactions that retain their enantiopurity. When treated with diisobutylaluminium hydride (DIBAL-H), skipped enyne 3a was smoothly converted into Z,Z-1,4-diene 4 in excellent yields. The other geometric isomer, Z,E-1,4-diene, can be directly prepared from Rh-catalyzed asymmetric allylic substitution.14 When we reduced skipped enyne 3a in Na/NH3 at -78 oC, the alkyne was directly reduced to the alkane with the benzene unscathed, providing alkene 5 with retention of chirality. The absolute configuration of 1,4-enynes 3 were determined
Br + H (±)-1a
Ph
2a (1 equiv.)
10 (20 mol%) CH2Cl2, aq. sat. K2CO3
Ph 3a yield 88%, ee 80%
(3)
Using cold-spray ionization mass spectrometry (CSIMS),20 we observed a new species at m/z = 509.354 (positive mode) when adding 10 into the basic condition and it was assigned to be dimeric (guanidine)copper complex 11 (Scheme 4a). The anion of this complex should be [CuCl2]-, similar to a complex reported by Coles.8b We found that (guanidine)copper complex 11 can also be observed when
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Recently, copper-catalyzed coupling reactions with racemic substrates through enantioconvergent radical pathways were reported by Fu.23 In order to study the possibility of an inner-sphere radical intermediate, we tested radical-probe 16 and we did not observe any 5-exo-trig cyclization product. Only skipped enynes 17 was obtained in 82% yield and 88% ee and this result demonstrated that the radical processes are unlikely involved in (guanidine)copper-catalyzed allylic alkynylation (Scheme 5).
CuCl is treated with the corresponding cyclic-guanidine (free base) directly. We further postulate the presence of a neutral monomeric (guanidine)copper complex 12 through ligand exchange with 11.8a After the addition of alkyne 2a to (guanidine)copper complex 10, a cationic peak corresponding to copper alkynide intermediate 13 (Scheme 4b) was observed at m/z = 673.308 (positive mode). We also postulate that intermediate 13 is the source of active, monomeric copper alkynide 14 since copper alkynides are liable to polymerization21 and we found that polymeric copper alkynides poly-15 is an insoluble solid side product in our reaction (
