From Aryl Bromides to Enantioenriched Benzylic Alcohols in a Single Flask: Catalytic Asymmetric Arylation of Aldehydes*
We thank the National Institutes of Health (National Institute of General Medical Sciences) and the National Science Foundation for support of this research.
Abstract
Stop that achiral catalyst! Chiral Lewis acid catalyzed aryl additions to aldehydes that originate from aryl halides generate products with very low ee values (see scheme, left), because the achiral metal halide by‐products are much more efficient catalysts than those derived from chiral amino alcohols. A LiCl‐selective inhibitor is introduced that enables a highly enantioselective one‐pot arylation of aldehydes that begins with aryl bromides (right).
The catalytic asymmetric addition of aryl groups to aldehydes has generated an enormous amount of attention.1 The resulting diarylmethanols are important constituents of biologically active compounds, such as clemastine,2 orphenadrine,3, 4 neobenodine,3, 4 chloropheniramine,5, 6 cizolirtine,7 and carbinoxamine.8 Although the majority of enantioselective aldehyde arylation reactions rely on the use of costly diphenylzinc ($55–75 g−1), important advances in the use of other aryl transfer reagents, such as arylboronic acids9, 10 and Ph2Si(OMe)2,11 have been reported. Although a limited number of aryl boronic acids are commercially available, they are quite expensive as well (e.g., PhB(OH)2 $225.00 mol−1 from Aldrich). A more practical and versatile method would begin with aryl bromides, many of which are commercially available and inexpensive (compare PhBr $2.50 mol−1 from Aldrich). There are no reports, however, of successful catalytic asymmetric aryl additions to aldehydes that begin with aryl bromides.12, 13 Herein, we disclose a one‐pot method that begins with aryl bromides for the in situ generation of aryl zinc intermediates and their catalytic asymmetric addition to aldehydes to afford highly enantioenriched diarylmethanols and benzylic alcohols.
We chose to examine the amino alcohol ligand MIB developed by Nugent14, 15 in the asymmetric addition of commercial ZnPh2 to 2‐naphthylaldehyde [Eq. (1)]. We were pleased to find that phenylation proceeded in toluene with 94 % enantioselectivity (Table 1, entry 1). Unfortunately, transmetalation of phenyllithium with ZnCl2 in toluene was unsuccessful because of the insolubility of ZnCl2 in this medium. In contrast, ethereal solvents are known to promote transmetalation reactions. The asymmetric addition in diethyl ether, however, gave a low enantioselectivity (60 %; Table 1, entry 2). In an attempt to balance both the solvating properties of diethyl ether, needed for the transmetalation, and the low polarity of toluene, we examined tert‐butyl methyl ether (tBuOMe). A reaction mixture of commercial ZnPh2, (−)‐MIB, and 2‐naphthylaldehyde in tBuOMe furnished the product in 88 % ee (Table 1, entry 3). A solvent system of tBuOMe and hexanes (1:3) exhibited about the same enantioselectivity as tBuOMe alone (89 %; Table 1, entry 4). Having identified a suitable solvent for the asymmetric addition, we focused on the in situ generation of diphenylzinc.
(1)|
Entry |
ZnPh2 |
Solvent |
ee [%] |
|---|---|---|---|
|
1 |
commercial |
toluene |
94 |
|
2 |
commercial |
Et2O |
60 |
|
3 |
commercial |
tBuOMe |
88 |
|
4 |
commercial |
tBuOMe/Hex (1:3) |
89 |
|
5 |
in situ |
tBuOMe/Hex (1:3) |
2 |
The preparation of ZnPh2 was performed by metalation of 4.5 equivalents bromobenzene in tBuOMe with 4 equivalents of a freshly titrated solution of nBuLi (2.5 M in hexanes), transmetalation of the resultant PhLi with 2.1 equivalents of ZnCl2, and the addition of hexanes to precipitate LiCl. The use of solutions prepared as described in the asymmetric addition to 2‐naphthylaldehyde in the presence of 5 mol % of (−)‐MIB resulted in the formation of the product with 2 % enantioselectivity (Table 1, entry 5). We hypothesized that the LiCl, generated en route to ZnPh2, likely promoted the addition faster than the amino alcohol based catalyst promotes the asymmetric addition. Similar proposals were advanced by Seebach12 and Bolm16 in reactions that began with Grignard reagents or PhLi. Based on their observations, we set out to design an inhibitor to reduce the undesired LiCl promoted addition.
To develop a selective inhibitor for lithium chloride we took advantage of the differences in coordination chemistry between the lithium salts and the zinc‐based catalyst. It is proposed that three coordinate amino alcohol based catalysts possess a single open coordination site [Eq. (1)].17 In contrast, the lithium salts likely have at least two available coordination sites. Structures of [tmeda⋅LiCl]n (TMEDA = N,N,N′,N′‐tetramethylethylene diamine) contain four‐coordinate lithium centers with bridging chlorides.18, 19 Furthermore, we expected that the zinc catalyst is more sterically saturated than the lithium salts. Based on these points, we chose to examine bulky multidentate diamines as inhibitors that would chelate to lithium, but bind to the zinc catalyst in a monodentate fashion.
A series of chelating diamines was evaluated as LiCl inhibitors in the asymmetric addition with ZnPh2 prepared in situ under the conditions employed in Table 1, entry 5. In this study, it was found that addition of toluene (or hexanes) after transmetalation aided the precipitation of the lithium salts. Subsequent injection of tetraethylethylene diamine (TEEDA, 0.8 equiv) resulted in addition with 89 % enantioselectivity, the same value obtained under salt‐free conditions with commercially available diphenylzinc [Eq. (2) and Table 1, entry 4]. Achieving of the same enantioselectivity in the absence or presence of LiCl indicates that the diamine effectively inhibits the LiCl‐promoted addition pathway.
(2)Under the conditions outlined above, unfunctionalized aryl bromides (bromobenzene, 2‐bromotoluene, and 2‐bromonaphthalene) were employed to prepare diarylzinc reagents [Eq. (2)]. TEEDA was then added followed by MIB and the aldehyde. In this fashion, aryl aldehydes gave addition products with high enantioselectivities (80–92 %) and yields (78–99 %). trans‐Cinnamaldehyde and cyclohexanecarboxaldehyde underwent addition with 84 and 85 % enantioselectivities (Table 2, entries 12 and 13, respectively).
|
Entry |
ArBr |
Aldehyde |
ee [%] |
Yield [%] |
|---|---|---|---|---|
|
1 |
phenyl |
|
92 |
99 |
|
2 |
2‐tolyl |
92 |
90 |
|
|
3 |
2‐naphthyl |
|
89 |
96 |
|
4 |
phenyl |
|
84 |
89 |
|
5 |
2‐tolyl |
80 |
92 |
|
|
6 |
phenyl |
|
90 |
85 (S)[a] |
|
7 |
2‐tolyl |
80 |
86 |
|
|
8 |
2‐naphthyl |
87 |
96 |
|
|
9 |
phenyl |
|
90 |
90 (S)[a] |
|
10 |
2‐tolyl |
87 |
78 |
|
|
11 |
2‐naphthyl |
91 |
99 |
|
|
12 |
phenyl |
|
84 |
91 |
|
13 |
phenyl |
|
85 |
92 |
|
14 |
2‐naphthyl |
82 |
92 |
- [a] Absolute configuration.
During early investigations of phenyl additions with ZnPh2, it was realized that the uncatalyzed addition was fast and competitive with the catalyzed reaction pathway, thus resulting in low enantioselectivity.20–22 To circumvent this problem, Bolm and co‐workers introduced the mixed zinc reagent Et/Zn/Ph formed from combination of ZnEt2 and ZnPh2.22–28 Enantioselectivities with Et/Zn/Ph and planar chiral catalyst were up to 38 % higher than those that employed the same catalyst with ZnPh2 alone.
Based on the successful application by Bolm of mixed alkyl aryl zinc reagents,9 we wished to develop an in situ route to these species to increase the levels of enantioselectivity in the aryl addition reactions. In our strategy to prepare the mixed alkyl aryl zinc intermediates in situ, we chose to avoid the use of dialkyl zinc reagents and focused on the more readily available alkyl lithium reagents instead. Thus, 2.0 equivalents of aryl bromide and 2.1 equivalents of ZnCl2 were employed. Metalation of PhBr with nBuLi and addition to ZnCl2 resulted in the generation of Ph/Zn/Cl. A second equivalent of nBuLi was then added to produce Ph/Zn/Bu, which was used in situ in the asymmetric addition reaction after the addition of 0.8 equivalents of TEEDA [Eq. (3)]. We were pleased to find that the enantioselectivity observed with the Ph/Zn/Bu generated in situ was higher than that with Ph2Zn and equal to that of Ph/Zn/Et (generated from commercial Ph2Zn and Et2Zn), despite the 4 equivalents of LiCl formed in the preparation of Ph/Zn/Bu.
(3)A variety of substituted and functionalized aryl bromides underwent enantioselective addition to benzaldehyde derivatives under the conditions in Equation (3) with enantioselectivities around 95 % (Table 3, entries 2–9). These include 2‐bromotoluene, 2‐bromonaphthylene, 4‐bromoanisole, 4‐bromofluorobenzene, and 4‐bromochlorobenzene. α,β‐Unsaturated aldehydes underwent addition with enantioselectivities between 81 and 88 %, whereas cyclohexanecarboxaldehyde again gave slightly lower enantioselectivities (78 and 82 %). The results in Table 3 indicate that various aryl bromides can now be employed as starting materials in the catalytic asymmetric arylation of aldehydes.
|
Entry |
ArBr |
Aldehyde |
ee [%] |
Yield [%] |
|---|---|---|---|---|
|
1 |
Ph2Zn + Et2Zn |
|
97 |
98 |
|
2 |
phenyl |
97 |
90 |
|
|
3 |
4‐methoxyphenyl |
93 |
96 |
|
|
4 |
4‐fluorophenyl |
|
97 |
75 |
|
5 |
4‐chlorophenyl |
95 |
78 |
|
|
6 |
phenyl |
|
96 |
80 |
|
7 |
4‐methoxyphenyl |
93 |
84 |
|
|
8 |
2‐tolyl |
|
95 |
73 |
|
9 |
2‐naphthyl |
96 |
79 |
|
|
10 |
4‐methoxyphenyl |
|
83 |
82 |
|
11 |
4‐fluorophenyl |
88 |
64 |
|
|
12 |
4‐chlorophenyl |
87 |
55 |
|
|
13 |
phenyl |
|
88 |
95 |
|
14 |
4‐fluorophenyl |
84 |
74 |
|
|
15 |
4‐chlorophenyl |
81 |
68 |
|
|
16 |
2‐naphthyl |
|
82 |
76 |
|
17 |
4‐methoxyphenyl |
78 |
84 |
To demonstrate the utility of our method, we chose to prepare the precursor to BMS 184394 (1, Scheme 1), an retinoic acid receptor (RAR) γ‐selective retinoid with activity against various skin diseases and cancers, in particular breast cancer and acute promyelocytic leukemia.29–31 Although both (R)‐ and (S)‐BMS 184394 are RAR γ‐selective, the S enantiomer is significantly more potent than the R enantiomer.30 Enantioselective synthesis of this compound proved difficult. Currently, the only enantioselective route to this drug candidate employed two sequential enzymatic kinetic resolutions that required 2 and 3.5 days (43 % yield and 95 % ee).30 As with any kinetic resolution, the maximum yield is 50 % and the desired compound must be separated from the undesired derivatized product. In principle, secondary diarylmethanols could be prepared enantioselectively by asymmetric reduction of diaryl ketones. This approach has proven quite challenging, however, because it is difficult for catalysts to differentiate between the lone pairs on the carbonyl oxygen atom when the aryl groups are similar in size, thus resulting in low enantioselectivities.32–36

Formal synthesis of (S)‐BMS 184394.
Using our method, 3.0 equivalents aryl bromide (2, Scheme 1) were combined with nBuLi followed by ZnCl2 to generate the mixed aryl butyl zinc reagent. TEEDA (1.5 equiv) in hexanes was added followed by (+)‐MIB (5 mol %) and the aldehyde 3. The addition product 4 was produced with 87 % enantioselectivity in 88 % yield (Scheme 1). Conversion into (S)‐BMS 184394 can be accomplished by saponification of the ester.30 The one‐pot enantioselective arylation of 3 demonstrates the potential utility of our method for the synthesis of enantioenriched biologically active benzylic alcohols.
In summary, we have developed a versatile method to generate secondary benzylic alcohols with high levels of enantioselectivity and yields. The importance of this method is that one can now begin the asymmetric arylation of aldehydes with aryl bromides, many of which are readily available. In contrast, previous methods employed preformed aryl boron reagents to generate salt‐free aryl zinc intermediates or began with diphenylzinc. The introduction of a diamine, such as TEEDA, was the key to the success of this method. In the absence of TEEDA, the addition reaction is promoted by LiCl, thus generating racemic products. TEEDA prohibits the LiCl by‐product from promoting the addition reaction, thus allowing the addition to proceed through the chiral zinc catalyst. Importantly, it is not necessary to filter,16 centrifuge,13 or isolate the pyrophoric aryl zinc reagents, as required with previous methods, in the presence of the diamine, thus increasing the attractiveness of our method for large‐scale applications. This method enables the synthesis of a variety of benzylic alcohols that were previously difficult to access in enantioenriched form.
Experimental Section
Preparation of (4‐fluorophenyl‐4‐methoxyphenyl)methanol (Table 3, entry 7): A nitrogen‐purged Schlenk flask was charged with 4‐bromoanisole (100.1 μL, 0.8 mmol) and tBuOMe (1 mL) and cooled to −78 °C. Freshly titrated nBuLi (0.32 mL, 2.5 M in hexanes, 0.8 mmol) was added dropwise, and the solution was stirred for 1 h. The dry‐ice bath was replaced with an ice bath, ZnCl2 (114.5 mg, 0.84 mmol) was added, and the reaction mixture was stirred for 30 min. Additional nBuLi (0.32 mL, 2.5 M in hexanes, 0.8 mmol) was added to the reaction mixture, which was then stirred for 4.5 h at room temperature. Toluene (5 mL) and TEEDA (68 μL, 0.32 mmol) were added, and the solution was stirred for 1 h. After the addition of (−)‐MIB (4.8 mg, 0.02 mmol, 5 mol %), the reaction cooled to 0 °C for 30 min, and p‐fluorobenzaldehyde (43 μL, 0.4 mmol) was added. The reaction was stirred at 0 °C and monitored by TLC. After completion (18 h), the reaction mixture was quenched with H2O (20 mL) and extracted with ethyl acetate (3×20 mL). The organic layer was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel (hexanes/EtOAc, 95:5) to give the product (77.7 mg, 84 % yield, 93 % ee) as a white solid. M.p. 52 °C; [α]${{{20\hfill \atop {\rm D}\hfill}}}$
=(+)13.846 (c=0.195, THF); 1H NMR (C6D6, 300 MHz): δ=2.17 (s, 1 H), 3.38 (s, 3 H), 5.50 (s, 1 H), 6.81–6.95 (m, 4 H), 7.17–7.29 (m, 4 H) ppm; 13C{1H} NMR (C6D6, 75 MHz): 55.0, 75.3, 114.3, 115.4 (d, J=21.2 Hz), 128.4, 128.7 (d, J=8.0 Hz), 136.9, 141.0 (d, J=3.0 Hz), 159.7, 162.6 ppm (d, J=243 Hz); IR (neat): $\tilde \nu $
=3421, 2957, 2837, 1609, 1504, 1248, 1033, 831 cm−1; HRMS calcd for C13H13FO2 [M]+: 232.0900, found: 232.0900; determination conditions for the ee: Chiralpak AS‐H, hexanes/isopropylamine (95:5), flow rate=0.5 mL min−1, t=20.0 min, 22.1 min.
Dedicated to Professor Madeleine Joullié
Notes :
- 1 We thank the National Institutes of Health (National Institute of General Medical Sciences) and the National Science Foundation for support of this research.
- [a] Absolute configuration.
Number of times cited: 94
- Richard C. Larock and Cristiano Raminelli, Formation of Alcohols and Phenols by Alkylation of Carbonyl Compounds, Comprehensive Organic Transformations, (1-97), (2018).
- Junichiro Akai, Satoshi Watanabe, Kumiko Michikawa and Toshiro Harada, Application of a Heterogeneous Chiral Titanium Catalyst Derived from Silica-Supported 3-Aryl H 8 -BINOL to Enantioselective Alkylation and Arylation of Aldehydes , Organic Letters, 10.1021/acs.orglett.7b01625, 19, 13, (3632-3635), (2017).
- Ji-Cai Zhou, Lei Zhao, Yuan Li, Ding-Qiang Fu, Zi-Cheng Li and Wen-Cai Huang, Alkynylation of aldehydes mediated by zinc and allyl bromide: a practical synthesis of propargylic alcohols, Research on Chemical Intermediates, 10.1007/s11164-016-2859-2, 43, 7, (4283-4294), (2017).
- Pei Wang, Yue Liu, Ya‐Lun Zhang and Chao‐Shan Da, The inexpensive additive N‐methylmorpholine effectively decreases the equivalents of nucleophiles in the catalytic highly enantioselective arylation of aryl aldehydes, Chirality, 29, 8, (443-450), (2017).
- Manabu Hatano and Kazuaki Ishihara, Bifunctional Lewis Base Catalysis with Dual Activation of R–M and C=O (n → σ*), Lewis Base Catalysis in Organic Synthesis, (339-386), (2016).
- Kazuki Fujii, Koichi Mitsudo, Hiroki Mandai and Seiji Suga, Kinetic Resolution of Secondary Carbinols by a Chiral N , N -4-Dimethylaminopyridine Derivative Containing a 1,1′-Binaphthyl Unit: Hydrogen Bonding Affects Catalytic Activity and Enantioselectivity , Bulletin of the Chemical Society of Japan, 10.1246/bcsj.20160135, 89, 9, (1081-1092), (2016).
- Melike Kalkan and Ender Erdik, Reactivity of mixed organozinc and mixed organocopper reagents: 14. Phosphine-nickel catalyzed aryl-allyl coupling of (n-butyl)(aryl)zincs. Ligand and substrate control on the group selectivity and regioselectivity, Journal of Organometallic Chemistry, 10.1016/j.jorganchem.2016.05.014, 818, (28-36), (2016).
- Toshiro Harada, Development of Highly Active Chiral Titanium Catalysts for the Enantioselective Addition of Various Organometallic Reagents to Aldehydes, The Chemical Record, 16, 3, (1256-1273), (2016).
- Özgen Ömür Pekel, Reactivities of mixed organozinc and mixed organocopper reagents. Part 13 Kinetic study for phosphine‐catalyzed acylation of alkylarylzincs and effect of residual group on the transfer rate of alkyl group, Journal of Physical Organic Chemistry, 29, 4, (190-195), (2016).
- Andressa M.M. Carlos, Maria Eduarda Contreira, Bruna S. Martins, Maira F. Immich, Angélica V. Moro and Diogo S. Lüdtke, Catalytic asymmetric arylation of aliphatic aldehydes using a B/Zn exchange reaction, Tetrahedron, 71, 8, (1202), (2015).
- Chris Nottingham, Robert Benson, Helge Müller-Bunz and Patrick J. Guiry, Synthesis of Ferrocene Oxazoline N,O ligands and Their Application in Asymmetric Ethyl- and Phenylzinc Additions to Aldehydes, The Journal of Organic Chemistry, 80, 20, (10163), (2015).
- Tomasz Bauer, Enantioselective dialkylzinc-mediated alkynylation, arylation and alkenylation of carbonyl groups, Coordination Chemistry Reviews, 10.1016/j.ccr.2015.03.025, 299, (83-150), (2015).
- Shih-Ju Chang, Shuangliu Zhou and Han-Mou Gau, Enantioselective addition of ArTi(O i Pr) 3 to aldehydes catalyzed by a titanium complex of an N-sulfonylated amino alcohol , RSC Adv., 10.1039/C4RA14173C, 5, 13, (9368-9373), (2015).
- Duygu Özkan and Ender Erdik, Reactivity of mixed organozinc and mixed organocopper reagents: 12. Three component reaction of mixed (n-alkyl)(diaryl)zincates, chloroformates and phosphines for the synthesis of esters, Journal of Organometallic Chemistry, 10.1016/j.jorganchem.2015.08.012, 799-800, (75-81), (2015).
- Gaëlle Valot, Damien Mailhol, Christopher S. Regens, Daniel P. O'Malley, Edouard Godineau, Hiroshi Takikawa, Petra Philipps and Alois Fürstner, Concise Total Syntheses of Amphidinolides C and F, Chemistry – A European Journal, 21, 6, (2398-2408), (2014).
- Melike Kalkan, Reactivity of mixed organozinc and mixed organocopper reagents: 11. Nickel‐catalyzed atom‐economic aryl–allyl coupling of mixed (n‐alkyl)(aryl)zincs, Applied Organometallic Chemistry, 28, 9, (725-732), (2014).
- Lin Pu, Asymmetric Functional Organozinc Additions to Aldehydes Catalyzed by 1,1′-Bi-2-naphthols (BINOLs), Accounts of Chemical Research, 10.1021/ar500020k, 47, 5, (1523-1535), (2014).
- Chen Zheng and Fen-Er Chen, Asymmetric catalytic anhydride openings via carbon-based nucleophiles, Chinese Chemical Letters, 10.1016/j.cclet.2013.11.025, 25, 1, (1-8), (2014).
- T. Hirose and K. Kodama, 1.07 Recent Advances in Organozinc Reagents, Comprehensive Organic Synthesis II, 10.1016/B978-0-08-097742-3.00109-9, (204-266), (2014).
- Yong-Xin Yang, Yue Liu, Lei Zhang, Yan-E Jia, Pei Wang, Fang-Fang Zhuo, Xian-Tao An and Chao-Shan Da, Aryl Bromides as Inexpensive Starting Materials in the Catalytic Enantioselective Arylation of Aryl Aldehydes: The Additive TMEDA Enhances the Enantioselectivity, The Journal of Organic Chemistry, 79, 21, (10696), (2014).
- Özgen Ömür Pekel and Ender Erdik, Reactivity of mixed organozinc and mixed organocopper reagents: 10 Comparison of the transferability of the same group in acylation of mixed and homo halozinc diorganocuprates with benzoyl chloride. A kinetic study, Journal of Organometallic Chemistry, 10.1016/j.jorganchem.2013.10.030, 751, (644-653), (2014).
- Emilio Fernández‐Mateos, Beatriz Maciá and Miguel Yus, Catalytic Enantioselective Addition of Aryl Grignard Reagents to Ketones, European Journal of Organic Chemistry, 2014, 29, (6519-6526), (2014).
- Nusrah Hussain, Mahmud M. Hussain, Patrick J. Carroll and Patrick J. Walsh, Chemo- and diastereoselective tandem dual oxidation of B(pin)-substituted allylic alcohols: synthesis of B(pin)-substituted epoxy alcohols, 2-keto-anti-1,3-diols and dihydroxy-tetrahydrofuran-3-ones, Chemical Science, 10.1039/c3sc51616d, 4, 10, (3946), (2013).
- Ender Erdik, Fatma Eroğlu, Melike Kalkan, Özgen Ömür Pekel, Duygu Özkan and Ebru Z. Serdar, Reactivities of mixed organozinc and mixed organocopper reagents: 9. Solvent dependence of group transfer selectivity in sp3C coupling and acylation of mixed diorganocuprates and diorganozincs, Journal of Organometallic Chemistry, 10.1016/j.jorganchem.2013.07.037, 745-746, (235-241), (2013).
- Florence Mongin and Anne Harrison-Marchand, Mixed AggregAte (MAA): A Single Concept for All Dipolar Organometallic Aggregates. 2. Syntheses and Reactivities of Homo/HeteroMAAs, Chemical Reviews, 10.1021/cr3002966, 113, 10, (7563-7727), (2013).
- Melike Kalkan and Ender Erdik, Reactivities of mixed organozinc and mixed organocopper reagents. Part 7. Comparison of the transfer rate of the same group in allylation of mixed and homo diorganozinc reagents, Journal of Physical Organic Chemistry, 26, 3, (256-260), (2013).
- Ami Uenishi, Yuya Nakagawa, Hironobu Osumi and Toshiro Harada, Practical Enantioselective Arylation and Heteroarylation of Aldehydes with In Situ Prepared Organotitanium Reagents Catalyzed by 3‐Aryl‐H8‐BINOL‐Derived Titanium Complexes, Chemistry – A European Journal, 19, 15, (4896-4905), (2013).
- Genette I. McGrew, Corneliu Stanciu, Jiadi Zhang, Patrick J. Carroll, Spencer D. Dreher and Patrick J. Walsh, Asymmetric Cross‐Coupling of Aryl Triflates to the Benzylic Position of Benzylamines, Angewandte Chemie, 124, 46, (11678-11681), (2012).
- Vince Yeh and William A. Szabo, Asymmetric Cross‐Coupling Reactions, Applications of Transition Metal Catalysis in Drug Discovery and Development, (165-213), (2012).
- Ying‐Ni Cheng, Hsyueh‐Liang Wu, Ping‐Yu Wu, Ying‐Ying Shen and Biing‐Jiun Uang, Enantioselective Addition of Dialkylzincs to Aldehydes Catalyzed by (−)‐MITH, Chemistry – An Asian Journal, 7, 12, (2921-2924), (2012).
- Jinlong Zhang, Yuhong Yang, Mei Wang, Li Lin and Rui Wang, Asymmetric addition of benzothiazole to N-tert-butanesulfinyl imine for the synthesis of chiral α-branched heteroaryl amines, Tetrahedron Letters, 10.1016/j.tetlet.2012.09.131, 53, 51, (6893-6896), (2012).
- Yao‐Zong Sui, Xi‐Chang Zhang, Jun‐Wen Wu, Shijun Li, Ji‐Ning Zhou, Min Li, Wenjun Fang, Albert S. C. Chan and Jing Wu, CuII‐Catalyzed Asymmetric Hydrosilylation of Diaryl‐ and Aryl Heteroaryl Ketones: Application in the Enantioselective Synthesis of Orphenadrine and Neobenodine, Chemistry – A European Journal, 18, 24, (7486-7492), (2012).
- S. Suga and M. Kitamura, 4.17 Asymmetric 1,2-Addition of Organometallics to Carbonyl and Imine Groups, Comprehensive Chirality, 10.1016/B978-0-08-095167-6.00416-X, (328-342), (2012).
- A.B. Charette and M.-N. Roy, 3.25 Stoichiometric Auxiliary Ligands for Metals and Main Group Elements: Ligands for Zinc, Comprehensive Chirality, 10.1016/B978-0-08-095167-6.00325-6, (780-806), (2012).
- Genette I. McGrew, Corneliu Stanciu, Jiadi Zhang, Patrick J. Carroll, Spencer D. Dreher and Patrick J. Walsh, Asymmetric Cross‐Coupling of Aryl Triflates to the Benzylic Position of Benzylamines, Angewandte Chemie International Edition, 51, 46, (11510-11513), (2012).
- Hui Wei, Lu Yin, Haibin Luo, Xingshu Li and Albert S. C. Chan, Structural influence of chiral tertiary aminonaphthol ligands on the asymmetric phenyl transfer to aromatic aldehydes, Chirality, 23, 3, (222-227), (2010).
- David R. Armstrong, William Clegg, Pablo García‐Álvarez, Alan R. Kennedy, Matthew D. McCall, Luca Russo and Eva Hevia, Expanding Mg–Zn Hybrid Chemistry: Inorganic Salt Effects in Addition Reactions of Organozinc Reagents to Trifluoroacetophenone and the Implications for a Synergistic Lithium–Magnesium–Zinc Activation, Chemistry – A European Journal, 17, 30, (8333-8341), (2011).
- Mitsutaka Goto, Takahiro Konishi, Shinji Kawaguchi, Masatoshi Yamada, Toshiaki Nagata and Mitsuhisa Yamano, Process Research on the Asymmetric Hydrogenation of a Benzophenone for Developing the Manufacturing Process of the Squalene Synthase Inhibitor TAK-475, Organic Process Research & Development, 10.1021/op2001673, 15, 5, (1178-1184), (2011).
- Manabu Hatano, Riku Gouzu, Tomokazu Mizuno, Hitoshi Abe, Toshihide Yamada and Kazuaki Ishihara, Catalytic enantioselective alkyl and aryl addition to aldehydes and ketones with organozinc reagents derived from alkyl Grignard reagents or arylboronic acids, Catalysis Science & Technology, 1, 7, (1149), (2011).
- Özgen Ömür Pekel and Ender Erdik, Reactivity of mixed organozinc and mixed organocopper reagents: 6. Nickel-catalyzed coupling of methylarylzincs with primary alkyl halides; an atom-economic aryl–alkyl coupling, Tetrahedron Letters, 52, 52, (7087), (2011).
- Kuo-Hui Wu, Shuangliu Zhou, Chien-An Chen, Mao-Chi Yang, Ruei-Tang Chiang, Chi-Ren Chen and Han-Mou Gau, Instantaneous room-temperature and highly enantioselective ArTi(O-i-Pr)3 additions to aldehydes, Chemical Communications, 10.1039/c1cc15059f, 47, 42, (11668), (2011).
- R.S. Jagtap and N.N. Joshi, Bidentate ligand-catalyzed enantioselective addition of RZnX to benzaldehyde, Tetrahedron Letters, 10.1016/j.tetlet.2011.09.120, 52, 48, (6501-6503), (2011).
- Caitlin M. Binder and Bakthan Singaram, Asymmetric Addition of Diorganozinc Reagents to Aldehydes and Ketones, Organic Preparations and Procedures International, 10.1080/00304948.2011.564538, 43, 2, (139-208), (2011).
- Rebeca Infante, Javier Nieto and Celia Andrés, Asymmetric additive-free aryl addition to aldehydes using perhydrobenzoxazines as ligands and boroxins as aryl source, Organic & Biomolecular Chemistry, 9, 19, (6691), (2011).
- Sebastian Bernhardt, Georg Manolikakes, Thomas Kunz and Paul Knochel, Preparation of Solid Salt‐Stabilized Functionalized Organozinc Compounds and their Application to Cross‐Coupling and Carbonyl Addition Reactions, Angewandte Chemie International Edition, 50, 39, (9205-9209), (2011).
- Radovan Šebesta, Andrea Škvorcová and Branislav Horváth, Asymmetric allylic substitutions on symmetrical and non-symmetrical substrates using [5]ferrocenophane ligands, Tetrahedron: Asymmetry, 10.1016/j.tetasy.2010.05.054, 21, 15, (1910-1915), (2010).
- Hun Young Kim, Luca Salvi, Patrick J. Carroll and Patrick J. Walsh, One-Pot Catalytic Enantio- and Diastereoselective Syntheses of anti -, syn - cis -Disubstituted, and syn -Vinyl Cyclopropyl Alcohols , Journal of the American Chemical Society, 10.1021/ja907781t, 132, 1, (402-412), (2010).
- Hiroshi Naka, Keisuke Ito, Masahiro Ueno, Koji Kobayashi and Yoshinori Kondo, Generation of arylzinc reagents through an iodine–zinc exchange reaction promoted by a non-metallic organic superbase, New Journal of Chemistry, 10.1039/c0nj00202j, 34, 8, (1700), (2010).
- Yusuke Muramatsu, Shinichi Kanehira, Masato Tanigawa, Yuta Miyawaki and Toshiro Harada, Catalytic Enantioselective Alkylation and Arylation of Aldehydes by Using Grignard Reagents, Bulletin of the Chemical Society of Japan, 10.1246/bcsj.20090232, 83, 1, (19-32), (2010).
- Varsha R. Jumde, Sarah Facchetti and Anna Iuliano, A chiral Rh–phosphite complex displaying high activity in the enantioselective Rh-catalyzed addition of arylboronic acids to carbonyl compounds: when and why atropos is better than tropos, Tetrahedron: Asymmetry, 21, 23, (2775), (2010).
- Albrecht Metzger, Sebastian Bernhardt, Georg Manolikakes and Paul Knochel, MgCl2‐beschleunigte Additionen von funktionalisierten Organozinkreagentien an Aldehyde, Ketone und Kohlendioxid, Angewandte Chemie, 122, 27, (4769-4773), (2010).
- Xin‐Yuan Fan, Yong‐Xin Yang, Fang‐Fang Zhuo, Sheng‐Li Yu, Xiao Li, Qi‐Peng Guo, Zhi‐Xue Du and Chao‐Shan Da, AlCl3 and BDMAEE: A Pair of Potent Reactive Regulators of Aryl Grignard Reagents and Highly Catalytic Asymmetric Arylation of Aldehydes, Chemistry – A European Journal, 16, 27, (7988-7991), (2010).
- Daniel Glynn, Jonathan Shannon and Simon Woodward, On the Scope of Trimethylaluminium‐Promoted 1,2‐Additions of ArZnX Reagents to Aldehydes, Chemistry – A European Journal, 16, 3, (1053-1060), (2009).
- Albrecht Metzger, Sebastian Bernhardt, Georg Manolikakes and Paul Knochel, MgCl2‐Accelerated Addition of Functionalized Organozinc Reagents to Aldehydes, Ketones, and Carbon Dioxide, Angewandte Chemie International Edition, 49, 27, (4665-4668), (2010).
- Ricardo S. Schwab, Letiere C. Soares, Luciano Dornelles, Oscar E. D. Rodrigues, Márcio W. Paixão, Marcelo Godoi and Antonio L. Braga, Chiral Chalcogen Peptides as Ligands for the Catalytic Enantioselective Aryl Transfer Reaction to Aldehydes, European Journal of Organic Chemistry, 2010, 19, (3574-3578), (2010).
- Yuya Nakagawa, Yusuke Muramatsu and Toshiro Harada, Catalytic Enantioselective Synthesis of Diarylmethanols from Aryl Bromides and Aldehydes by Using Organolithium Reagents, European Journal of Organic Chemistry, 2010, 34, (6535-6538), (2010).
- Can Liu, Zong‐Liang Guo, Jiang Weng, Gui Lu and Albert S. C. Chan, Chiral 1,1′‐binaphthylazepine‐derived amino alcohol catalyzed asymmetric aryl transfer reactions with boroxine as aryl source, Chirality, 22, 1, (159-164), (2009).
- Manabu Hatano, Tomokazu Mizuno and Kazuaki Ishihara, Catalytic enantioselective synthesis of sterically demanding alcohols using di(2°-alkyl)zinc prepared by the refined Charette's method, Chemical Communications, 46, 30, (5443), (2010).
- Zhi-Long Wu, Hsyueh-Liang Wu, Ping-Yu Wu and Biing-Jiun Uang, Asymmetric addition of diethylzinc to aldehydes catalyzed by a camphor-derived β-amino alcohol, Tetrahedron: Asymmetry, 20, 13, (1556), (2009).
- Luca Salvi, Jeung Gon Kim and Patrick J. Walsh, Practical Catalytic Asymmetric Synthesis of Diaryl-, Aryl Heteroaryl-, and Diheteroarylmethanols, Journal of the American Chemical Society, 10.1021/ja9046747, 131, 34, (12483-12493), (2009).
- Ender Erdik and Özgen Ömür Pekel, Reactivities of mixed organozinc and mixed organocopper reagents, 2. Selective n-alkyl transfer in tri-n-butylphosphine-catalyzed acylation of n-alkyl phenylzincs; an atom economic synthesis of n-alkyl aryl ketones, Tetrahedron Letters, 50, 13, (1501), (2009).
- Takahiro Nakae, Recent Progress in Preparation of Functionalized Organometallics, Journal of Synthetic Organic Chemistry, Japan, 67, 4, (395), (2009).
- Jeffrey B. Johnson, Matthew J. Cook and Tomislav Rovis, Ligand differentiated complementary Rh-catalyst systems for the enantioselective desymmetrization of meso-cyclic anhydrides, Tetrahedron, 10.1016/j.tet.2008.10.075, 65, 16, (3202-3210), (2009).
- Michael H. Kerrigan, Sang-Jin Jeon, Young K. Chen, Luca Salvi, Patrick J. Carroll and Patrick J. Walsh, One-Pot Multicomponent Coupling Methods for the Synthesis of Diastereo- and Enantioenriched ( Z )-Trisubstituted Allylic Alcohols , Journal of the American Chemical Society, 10.1021/ja809821x, 131, 24, (8434-8445), (2009).
- Hongmei Li, Dunming Zhu, Ling Hua and Edward R. Biehl, Enantioselective Reduction of Diaryl Ketones Catalyzed by a Carbonyl Reductase from Sporobolomyces salmonicolor and its Mutant Enzymes, Advanced Synthesis & Catalysis, 351, 4, (583-588), (2009).
- Christian Defieber and Erick M. Carreira, Modern Arylations of Carbonyl Compounds, Modern Arylation Methods, (271-309), (2009).
- Ender Erdik, Özgen Ömür Pekel and Melike Kalkan, Reactivity of mixed organozinc and organocopper reagents. 3. Atom economic electrophilic amination of methyl arylzinc reagents, Applied Organometallic Chemistry, 23, 6, (245-248), (2009).
- Shuangliu Zhou, Da-Wei Chuang, Shih-Ju Chang and Han-Mou Gau, Synthesis, characterization, and structures of arylaluminum reagents and asymmetric arylation of aldehydes catalyzed by a titanium complex of an N-sulfonylated amino alcohol, Tetrahedron: Asymmetry, 10.1016/j.tetasy.2009.05.018, 20, 12, (1407-1412), (2009).
- Ciril Jimeno, Sonia Sayalero, Torstein Fjermestad, Gisela Colet, Feliu Maseras and Miquel A. Pericàs, Practical Implications of Boron-to-Zinc Transmetalation for the Catalytic Asymmetric Arylation of Aldehydes, Angewandte Chemie International Edition, 47, 6, (1098), (2008).
- Ender Erdik and Özgen Ömür Pekel, Reactivities of mixed organozinc and mixed organocopper reagents: 1 – Solvent controlled organic group transfer from mixed diorganozincs, Journal of Organometallic Chemistry, 693, 2, (338), (2008).
- Ciril Jimeno, Sonia Sayalero, Torstein Fjermestad, Gisela Colet, Feliu Maseras and Miquel A. Pericàs, Practical Implications of Boron-to-Zinc Transmetalation for the Catalytic Asymmetric Arylation of Aldehydes, Angewandte Chemie, 120, 6, (1114), (2008).
- Christine Hawner, Kangying Li, Virginie Cirriez and Alexandre Alexakis, Kupferkatalysierte asymmetrische konjugierte Addition von Arylaluminiumreagentien an cyclische Enone: Aufbau arylsubstituierter quartärer Stereozentren, Angewandte Chemie, 120, 43, (8334-8337), (2008).
- Christine Hawner, Kangying Li, Virginie Cirriez and Alexandre Alexakis, Copper‐Catalyzed Asymmetric Conjugate Addition of Aryl Aluminum Reagents to Trisubstituted Enones: Construction of Aryl‐Substituted Quaternary Centers, Angewandte Chemie International Edition, 47, 43, (8211-8214), (2008).
- Chien‐An Chen, Kuo‐Hui Wu and Han‐Mou Gau, A New Aspect of Magnesium Bromide‐Promoted Enantioselective Aryl Additions of Triaryl(tetrahydrofuran)aluminum to Ketones Catalyzed by a Titanium(IV) Catalyst of trans‐1,2‐Bis(hydroxycamphorsulfonylamino)cyclohexane, Advanced Synthesis & Catalysis, 350, 10, (1626-1634), (2008).
- Yusuke Muramatsu and Toshiro Harada, Catalytic Asymmetric Aryl Transfer Reactions to Aldehydes with Grignard Reagents as the Aryl Source, Chemistry – A European Journal, 14, 34, (10560-10563), (2008).
- Sheng‐Hsiang Hsieh, Chien‐An Chen, Da‐Wei Chuang, Mao‐Chih Yang, Hsu‐Tang Yang and Han‐Mou Gau, 1,3‐bis[N‐sulfonyl‐(1R,2S)‐1,3‐diphenyl‐2‐aminopropanol]benzene: An excellent ligand for titanium‐catalyzed asymmetric AlPh3(THF) additions to aldehydes, Chirality, 20, 8, (924-929), (2008).
- Jeffrey B. Johnson, Eric A. Bercot, Catherine M. Williams and Tomislav Rovis, A Concise Synthesis of Eupomatilones 4, 6, and 7 by Rhodium‐Catalyzed Enantioselective Desymmetrization of Cyclic meso Anhydrides with Organozinc Reagents Generated In Situ, Angewandte Chemie, 119, 24, (4598-4602), (2007).
- Frank Schmidt, Jens Rudolph and Carsten Bolm, Diarylmethanols by Catalyzed Asymmetric Aryl Transfer Reactions onto Aldehydes Using Boronic Acids as Aryl Source, Advanced Synthesis & Catalysis, 349, 4‐5, (703-708), (2007).
- M. Kevin Brown, Tricia L. May, Carl A. Baxter and Amir H. Hoveyda, All-Carbon Quaternary Stereogenic Centers by Enantioselective Cu-Catalyzed Conjugate Additions Promoted by a Chiral N-Heterocyclic Carbene, Angewandte Chemie, 119, 7, (1115), (2007).
- M. Kevin Brown, Tricia L. May, Carl A. Baxter and Amir H. Hoveyda, All-Carbon Quaternary Stereogenic Centers by Enantioselective Cu-Catalyzed Conjugate Additions Promoted by a Chiral N-Heterocyclic Carbene, Angewandte Chemie International Edition, 46, 7, (1097), (2007).
- Jeffrey B. Johnson, Eric A. Bercot, Catherine M. Williams and Tomislav Rovis, A Concise Synthesis of Eupomatilones 4, 6, and 7 by Rhodium‐Catalyzed Enantioselective Desymmetrization of Cyclic meso Anhydrides with Organozinc Reagents Generated In Situ, Angewandte Chemie International Edition, 46, 24, (4514-4518), (2007).
- Jonathan Shannon, David Bernier, Daniel Rawson and Simon Woodward, Direct asymmetric catalytic 1,2-addition of RZnX to aldehydes promoted by AlMe3 and reversal of expected stereochemistry, Chemical Communications, 10.1039/b710681e, 38, (3945), (2007).
- Zhuo Chai, Xin-Yuan Liu, Xiao-Yu Wu and Gang Zhao, Synthesis of modular thiophene-oxazoline ligands and their application in the asymmetric phenyl transfer reaction to aldehydes, Tetrahedron: Asymmetry, 17, 16, (2442), (2006).
- Tse‐Lok Ho, Mary Fieser and Louis Fieser, Chiral Auxiliaries and Catalysts, Fieser and Fieser's Reagents for Organic Synthesis, (123-200), (2011).
- Tse‐Lok Ho, Mary Fieser and Louis Fieser, Chiral auxiliaries and catalysts, Fieser and Fieser's Reagents for Organic Synthesis, (000-000), (2009).
- Jeffrey B. Johnson, Robert T. Yu, Paul Fink, Eric A. Bercot and Tomislav Rovis, Selective Substituent Transfer from Mixed Zinc Reagents in Ni-Catalyzed Anhydride Alkylation, Organic Letters, 10.1021/ol0616337, 8, 19, (4307-4310), (2006).
- Antonio Luiz Braga, Priscila Milani, Fabrício Vargas, Márcio W. Paixão and Jasquer A. Sehnem, Modular chiral thiazolidine catalysts in asymmetric aryl transfer reactions, Tetrahedron: Asymmetry, 17, 19, (2793), (2006).
- Tse‐Lok Ho, Mary Fieser and Louis Fieser, Chiral Auxiliaries and Catalysts, Fieser and Fieser's Reagents for Organic Synthesis, (95-160), (2013).
- Tse‐Lok Ho, Chiral auxiliaries and catalysts, Fieser and Fieser's Reagents for Organic Synthesis, (2017).
- Tse‐Lok Ho, Mary Fieser and Louis Fieser, Chiral auxiliaries and catalysts, Fieser and Fieser's Reagents for Organic Synthesis, (000-000), (2010).
- Jeung Gon Kim and Patrick J. Walsh, From Aryl Bromides to Enantioenriched Benzylic Alcohols in a Single Flask: Catalytic Asymmetric Arylation of Aldehydes., ChemInform, 37, 43, (2006).
- Albert M. DeBerardinis, Mark Turlington, Lin Pu, Kyle L. Kimmel and Jonathan A. Ellman, Catalytic Asymmetric Addition of an ‐ Prepared Arylzinc to Cyclohexanecarboxaldehyde: ()‐(+)‐α‐cyclohexyl‐3‐methoxy‐benzenemethanol, Organic Syntheses, (68-76), (2011).
- Mahmud M. Hussain, Patrick J. Walsh*, Y. K. Chen, S. ‐J Jeon, P. J. Walsh and W. A. Nugent, Discussion Addendum for: Applications of (2)‐(–)‐3‐exo‐Morpholinoisoborneol [(–)MIB] in Organic Synthesis, Organic Syntheses, (25-40), (2014).
- Willam Nugent, , (2003)., Encyclopedia of Reagents for Organic Synthesis













