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Enantioselective Atropisomeric Anilides Synthesis via Cu-Catalyzed Intramolecular Adjacent C-N Coupling Xiao Zhong Fan, Xue Zhang, Chunyu Li, and Zhenhua Gu ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b04789 • Publication Date (Web): 31 Jan 2019 Downloaded from http://pubs.acs.org on February 4, 2019
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ACS Catalysis
Enantioselective Atropisomeric Anilides Synthesis via Cu-Catalyzed Intramolecular Adjacent C-N Coupling Xiaozhong Fan, Xue Zhang, Chunyu Li and Zhenhua Gu* Department of Chemistry, Center for Excellence in Molecular Synthesis, and Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China 96 Jinzhai Road, Hefei, Anhui 230026, P. R. China ABSTRACT: Catalytically asymmetric synthesis of atropisomeric compounds is an important research area in organic synthesis. However, in comparison with C-C atropisomers, the atropisomers caused by the restricted rotation of C-N single bonds have been caught less attention due to the limited methods for accessing these compounds. Herein we report a Cu-catalyzed enantioselective intramolecular Ullmann-type amination reaction for the synthesis of C-N atropisomers. The C-N axial chirality was induced highly efficiently by the intramolecular adjacent C-N crosscoupling. The readily prepared N,N'-(cyclohexane-1,2-diyl)dipicolinamides showed high efficacy and stereo-induction (up to 99% ee).
KEYWORDS: Cu catalysis, atropisomer, C-N axial chirality, asymmetric catalysis, amides
INTRODUCTION Atropisomerism, which arises from the restricted rotation around a single bond, widely exists in bioactive natural products and privilege chiral organic catalysts or ligands. It is one of the key features in tridimensional molecules. The most representative examples are axially chiral biaryls, which are widely studied in the recent years.1-9 However, catalytically asymmetric synthesis of CN axially chiral compounds was less documented, which possibly attributed to the relatively lower atropo-stability of C-N bonds in comparison to the corresponding C-C bonds in biaryls. Through experimental and computational analysis, Schirok and co-workers pointed out that the aryl ring bending out the N-containing plane (deplanarization) reduced the rotational barrier of NC(aryl) bond.10 The growing findings of C-N atropisomers in natural products [biscarbazole alkaloid 1, ancisthrocladinium A (2)],11-13 medicinal chemistry (methaqualone 3)14 and chiral phosphine ligand 4, 15,16 compelled organic chemists to develop efficient methods for the synthesis of these molecules (Figure 1).17-19 The C-N axially chiral scaffolds were also applied to induce point chirality.20 Me
* N H
Me
MeO
N
OMe Me
Me O
N
OMe
Murrastifoline-F (1)
Me
N
N
OMe Me
OMe OMe
Ancistrocladinium A (2)
PPh2
F3C Me
Methaqualone (3)
(4)
Figure 1. Representative Examples of Atropisomeric C-N Bonds in Natural Products, Ligand and Drug Kamikawa, Uemura and Wencel-Delord, Colobert groups reported fruitful methods for direct C-N coupling for the synthesis of C-N atropisomers via diastereoselective induction. For example, chiral sulfoxide is a powerful directing group for induction of C-N
chirality (Scheme 1a).21-25 Jørgensen and Gong groups achieved efficient construction of non-biaryl C-N atropisomers via nucleophilic amination reaction between diazenes and naphthols or 2-(alkynyl)phenyl boronic acids. 26,27 However, the direct construction of atropisomeric C-N bonds was usually suffered from its harsh reaction conditions due to highly steric hindrance around the C-N bond. Thus, alternative methods have been developed by utilizing both transition-metalcatalysts and organocatalysts. 28,29 Miller, Sigman and Tan rapidly assembled densely functionalized C-N atropisomers via organo-catalyzed atroposelective functionalization of one of the aryl rings.30-32 The asymmetric construction of the aryl rings was also practical method for the synthesis of compounds with atropisomeric C-N bonds (Scheme 1b).33-35 In 2005, Taguchi and co-workers developed an elegant asymmetric N-arylation reaction of anilides for the creation of C-N axial chirality, where ortho t-butyl group in anilines and p-nitro group in arylhalides were necessary (Scheme 1c).36,37 Kitagawa and co-workers realized an elegant intramolecular version via palladium catalysis. However, the harsh reaction conditions resulted the products underwent racemization (up to 77% ee) at the same temperature, and a poor substrate scope was observed (Scheme 1c). 38,39 In 2011, the Maruoka group significantly broadened the substrates scope via chiral phase-transfercatalyzed N-alkylation of o-iodoanilides (Scheme 1d). 40,41 Albeit these valuable achievements, the methods are still limited to very specific substrates. Therefore, the development of new and efficient protocols to access C-N atropisomeric molecules with divergent motifs is highly appealing, yet still challenging. Recently, we realized a palladium-catalyzed biaryl axial chirality construction via the functionalization of the adjacent C-H bond of the axis.42 We speculated that the intramolecular C-N coupling would form a planar phenanthridin-6(5H)-one
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structure, and meantime the chirality of the adjacent C-N bond might be induced by chiral ligands. Thus, the direct construction of a steric hindered C-N bond can be avoided (Scheme 1e). a) Direct Atropselective C-N Bond Formation (Colobert and Wencel-Delord, ref.24) Mes MeO
I BF4 O S * pTol
(CuOTf)2 Tol Cs2CO3, Tol/DMSO
+
O S * pTol
N MeO
87%, dr 90:10
N H
OMe
OMe
b) Organo-Catalyzed C-N Axial Chirality Induction (Miller, Sigman, Tan, refs. 30-32) O N
OBr
NBS, peptide then TMSCHN2, MeOH
OH
N
86%, 94% ee
Me
N
N
Br OMe Br Me
O
O N N
N
bifunctional organocatalyst
+
N
Et2O, -78 C 51%, 94% ee
OH
tBu O
tBu
NH N
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diphenylethane-1,2-diamine and (1,1'-binaphthalene)-2,2'diamine derived ligands L5 and L6 had very low stereoinduction (entries 12-13), indicating that cyclohexanediamine moiety is shown to be crucial. The reaction with L7 as the ligand gave poor yield and low stereoselectivity, showcasing that the diamide is superior than monoamide (entry 14). Notwithstanding a relatively longer reaction time, the reaction was performed with 5.0 mol % copper catalyst without the loss of enantioselectivity (entry 15). Notably, under identical conditions the intermolecular C-N coupling between 6(5H)-phenantridinone and 2-halotoluene were unsuccessful (see the Supporting Information). Table 1. The Reaction Condition Optimizationa
OH
O tBu
Br
c) Pd-Catalyzed Adjacent C-N Bond Formation (Taguchi, Kitagawa, refs. 36-38) O X
X
R
+
+
chiral PTC KOH, iPr2O, -20 oC
Br
R1
O
O R
N
Me
I
80-95% ee
O Ar2
N H
X R
Ar1
CuTC Ligand
X R O R = alkyl, alkenyl, aryl, CF3, Br
§ High Enantioselectivity; Broad Functional Group Tolerance
O F
O NH HN
NH
+
Br
F
for
F
O
N
L5
NH
N
NH
N
On the basis of the excellent works of asymmetric Ullmann-type reactions by Cai and others,43-54 we chose copper as the catalyst. We commenced our initial studies with the amide 5a as model compound and CuI as the catalyst by following the pioneer work of Thasana (Table 1).55 It was found that N,N'-(cyclohexane-1,2diyl)dipicolinamide L1, 56,57 which was conveniently prepared from chiral diamines and picolinic acids, showed best stereocontrol in 1,4-dioxane among various solvents screened, such as MeCN, DMF and dimethoxyethane (DME) (entries 1-4). In comparison with CuI, CuBr and CuOTf·0.5PhH, copper(I)-thiophene-2carboxylate (CuTC) displayed good catalytic activity and the yield was improved to 88% (entries 4-7). Gratifyingly, NaOH was beneficial for both the yield and enantioselectivity (entry 8). Subsequent investigation focused on the catalytic activity of cyclohexane-1,2diamine derived picolinic amides L2-L4. meta-Methyl group at the pyridine ring (L2) influenced neither the yield nor the enantioselectivity (entry 9), while orthofluoro substituted ligand L3 significantly diminished the catalytic activity (entry 10). Pleasingly, the ee value of the product boosted to 96% when 3,5-difluoro substituted ligand L4 was employed (entry 11). Surprisingly, 1,2-
O O S NH HN
O
N Me
L6
L7
entry
[Cu] (mol%)
solvent
base
Ligand
Conv. /%
1
CuI (20)
MeCN
Cs2CO3
L1
99
11
2
CuI (20)
DMF
Cs2CO3
L1
99
13
3
CuI (20)
DME
Cs2CO3
L1
50
45
4
CuI (20)
dioxane
Cs2CO3
L1
50
88
5
CuBr (20)
dioxane
Cs2CO3
L1
60
88
6
CuOTf (20)
dioxane
Cs2CO3
L1
18
87
7
CuTC (20)
dioxane
Cs2CO3
L1
88
90
8
CuTC (10)
dioxane
NaOH
L1
99
93
9
CuTC (10)
dioxane
NaOH
L2
99
93
10
CuTC (10)
dioxane
NaOH
L3
10
80
11
CuTC (10)
dioxane
NaOH
L4
90
96
12
CuTC (10)
dioxane
NaOH
L5
90
3
13
CuTC (10)
dioxane
NaOH
L6
10
0
14
CuTC (10)
dioxane
NaOH
L7
15
48
15
CuTC (5)b
dioxane
NaOH
L4
99
97
C-N
RESULTS AND DISCUSSION
F L4
O
less efficient for intermolecular reaction
Strategies
F
N
O
Ph
N
N
L3
R
O
N
F
NH HN
§ Non-noble Metal; Readily Available Ligand
Scheme 1. Representative Atropisomer Synthesis
N R
Ar1
Ar2
O
L1, R = H L2, R = Me
O
N
Ar2
N
Ph
Atropisomeric Bond
O NH HN
R R'
Bond Formed Ar1
O NH HN
R1
N
R' e) This W ork: Cu-Catalyzed Adjacent C-N Bond Formation
Br
6a
R'
NH I
Me O
5a
R
R'
N
Me
N
O
d) PTC-catalyzed Adjacent C-N Bond Formation (Maruoka, Li, refs. 40, 41) O R Me
N H
X Pd(OAc)2 phosphine ligand
NH
[Cu], Chiral Ligand base, dioxane, 50 oC, 10 h
O
ee of 6a/%
Unless stated otherwise, the reaction was conducted with 5a (0.10 mmol), Cu catalyst (5-20 mol%), Ligand (1.1 equiv to Cu) in the indicated solvent (2.0 ml) at 50 ºC for 10 h. b The reaction was performed at 45 oC for 20 h. a
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ACS Catalysis With the optimum conditions in hand, we next evaluated the substrate scope (Table 2). The ortho alkyl group at the aniline moiety could be ethyl or isopropyl group, albeit the yields slightly decreased when isopropyl group was incorporated (6b and 6c). Additional groups (i.e., methyl, fluoro) adjacent to the 2-methyl group affected neither the yield nor the enantioselectivity (6d and 6e). The ortho groups at the aniline structure can be efficiently extended to phenyl, trifluoromethyl, vinyl, TBSOCH2 and naphthyl with exceptional good enantioselectivity, though there was no full conversions with phenyl or trifluoromethyl substituent (6f-6j). The reaction also tolerated some heterocycles. For example, 6fluoro-2-methylpyridin-3-amine or thiophene-2carboxylic acid derived substrates were also compatible for this transformation (6l and 6s). Further efforts were paid to test the substituent-loading capability at the (1,1'biphenyl)-2-carboxylic acid skeleton. They can be methyl, chloro, methoxyl groups at different positions, which had marginal effect on the enantioselectivity (6n-6r). The absolute configuration of 6k was unambiguously determined to be R by single-crystal X-ray diffraction analysis.58 The structures of other products were assigned by analogy to 6k, as well as the comparison the circular dichroism (CD) spectroscopies (see the Supporting Information). Table 2. Substrate Scopea
R1
R1
Br
O
Ar N H
R2
CuTC (5.0 mol%), L4 (5.5 mol%) NaOH, dioxane, 45 oC, 20 h
Ar
N
R2
O
R
5
R
6
N
N
N
O
O
Me O
6b, 93%, 98% ee
6c, 86%, 98% ee
6d, 94%, 99% ee
N
N Me O
F
O
N
N
O
O
6h, 91%, 95% ee
N
N Ph
F3C O
6f, 80%, 95% ee (84% conv.)
6e, 98%, 96% ee
6g, 57%, 99% ee (61% conv.)
N O
OTBS
6i, 91%, 98% ee
6j, 99%, 98% ee
N
Cl
Me O
Me O 6k, 98%, 95% ee
R 6m, R = Me, 94%, 96% ee 6n, R = Cl, 98%, 96% ee
N MeO
Me O
6o, 95%, 97% eeb
N
F
6l, 99%, 92% ee
structure of (R)-6k
N Me O
Me
N Cl
Me O 6p, 99%, 93% ee[b]
MeO
N MeO
Me O
MeO 6q, 99%, 99% ee
N
N Me O 6r, 99%, 94% ee
S
Me O
6s, 99%, 98% ee
The reaction was conducted with 5 (0.20 mmol), CuTC (0.010 mmol, 5.0 mol%), L4 (0.011 mmol, 5.5 mol%), NaOH (0.60 mmol, 3.0 equiv) in 1,4dixoane at 45 oC. b The reactions were performed at 0.10 mmol scale. a
The reaction conditions are mild and the differentiation of the two C(sp2)-Br bonds is achievable (Scheme 2). With an ortho C(sp2)-Br bond at the aniline structures, the reaction chemoselectively gave 6t-6v without the loss of yields. Notably, the reaction with 3.0 mmol scale of 5t worked uneventfully to give 6t in even better enantioselectivity, highlighting the potential utility in synthetic chemistry. Alternatively, the reaction of 5w afforded the desired product 6w in excellent ee value and quantity yield, with the less steric hindered C(sp2)-Br being unchanged.
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Br
CuTC (5.0 mol%), L4 (5.5 mol%) NaOH, dioxane
O N H
R Br
O
R = Me, 5u R = CF3, 5v
R
80%, 93% ee (45 oC, 48 h) 79%, 95% ee (3.0 mmol scale)
R = Me, 6u R = CF3, 6v
87%, 92% ee (55 oC, 16 h) 95%, 97% ee (55 oC, 16 h) Br
Br CuTC (5.0 mol%), L4 (5.5 mol%) NaOH, dioxane, 45 oC, 20 h
O N H 5w
Br
R = H, 6t
R = H, 5t
Br
N
Me
99%, 96% ee
N Me O 6w
Scheme 2. Selectivity for Different C(sp2)-Br Bonds Since the rotational barrier is an important property for these C-N axially chiral compounds and it is also crucial for further applications in organic synthesis, the studies of racemization vs time at different temperatures have been performed (Figure 2a and 2b). The ∆r≠ GƟm of 6t has been determined as 29.9 kcal/mol (80 ºC) by analysing the racemization plot at 80, 90 and 100 ºC, respectively. The rotational barrier of 6a is slightly lower than 6t (28.5 kcal/mol) according to the studies by Mintas and coworkers.59 These data suggested that these C-N atropisomers should be prepared at mild reaction conditions to avoid racemization (usually reaction temperature is below 60 ºC).
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(Scheme 3b). Furthermore, the treatment of 6i with TBAF gave free alcohol 7i. Mesylation, followed by nucleophilic attack of KPPh2 and treatment with BH3·THF furnished phosphine borane complex 8i without the loss of enantiopurity (Scheme 3c). Finally, a plausible catalytic cycle, as well as the stereoinduction model were proposed in Scheme 4.60 Initially, in the presence of NaOH, the Cu(I) complex A bonded to nitrogen anionic atom of 5 to give complex B. Subsequently, intramolecular oxidative addition of B delivered the Cu(III) complexes C or D. Alternatively, the complex A underwent oxidative addition with the bromide 5 to form Cu(III) complex F, which gave C or D via ligand substitution from bromide to amide. The ortho group in the aniline moiety of D has strongly steric repulsion with the upward picolinamide unit. On the contrast, less steric repulsion was generated in C due to the picolinamide group locating at the downward position. Finally, the reductive elimination of C formed a new C-N bond to afford 6 with R absolute configuration. a) Cross-coupling with zinc reagent
N O
+
H 3C
NiCp2, PPh3 THF, r.t., 24 h
ZnCl
N O
Br
Me 7t, 70%, 91% ee
6t (92% ee) b) Hydroboration and oxidation
9-BBN THF, 0 oC - r.t., 4 h
N
H2O2, NaOH 0 oC, 10 min
N O
O
HO
6h (96% ee)
7h, 95%, 96% ee
c) Synthesis of chiral phoshine TBAF (5.0 equiv) THF, r.t., 2 h
N
O
O
OTBS 6i, 94% ee
(a)
i) MsCl, Et3N, CH2Cl2, r.t.
N OH
N
ii) KPPh2, THF, r.t. then BH3·THF, r.t.
O Ph P·BH 2 3 8i, 72% 94% ee
7i, 91% 94% ee
Scheme 3. Synthetic Applications 2Br
HN
O
Ar O
O
F
N
N
F
CuI N ON Ar N
+ NaOH F
5
F
Br
strong steric repulsion
weak steric repulsion
B
R O F
O N
N CuI
N
F
F
6
F HN
Ar
N
N Br N CuIII
N
O O
N
N N
R ON N CuIII N
O
upward amide
C
D (fluoro atoms in the ligand were omitted)
O F N NaOH
O 5
(b)
N CuIII
downward amide O
Br
N N
A
F
O
N
O
F Ar
F
H N O F
Figure 2. (a) Plot of ee value vs time at various temperature. (b) Plot of ln(k/T) vs 1/T Brief synthetic studies were performed (Scheme 3). Compound 6t successfully underwent cross-coupling with aryl zinc reagent via the catalysis of nickel (Scheme 3a). Hydroboration with 9-BBN of 6h, followed by oxidation delivered the alcohol 7h in high yield and excellent ee
Scheme 4. Plausible Catalytic Cycle CONCLUSION In summary, we have developed a new Cu/N,N'(cyclohexane-1,2-diyl)dipicolinamide catalyst system for enantioselective Ullmann-type amination reaction for the construction of C-N atropisomers. This reaction
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ACS Catalysis proceeded through an intramolecular C-N coupling, and at the same time induced the axial chirality of the adjacent preformed C-N bond. A brief stereoinduction model was proposed and it was assumed that the steric repulsion between the ortho group of anilines and upward picolinamide group was the reason for excellent stereoselectivity.
AUTHOR INFORMATION Corresponding Author *
[email protected] Notes The authors declare no competing financial interests.
ASSOCIATED CONTENT Supporting Information. The Supporting Information is available free of charge via the internet at http://pubs.acs.org. Experimental procedures, characterization of products, and spectroscopic data (PDF). Crystallographic data for 6k (CIF)
ACKNOWLEDGMENT This work was supported by NSFC (21622206, 21871241), the '973' project from the MOST of China (2015CB856600) and Strategic Priority Research Program of the Chinese Academy of Sciences (XDB20000000), the Fundamental Research Funds for the Central Universities (WK2060190086).
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