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Superbase-Catalyzed anti-Markovnikov Alcohol Addition Reactions to Aryl Alkenes Chaosheng Luo, and Jeffrey S Bandar J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b00766 • Publication Date (Web): 27 Feb 2018 Downloaded from http://pubs.acs.org on February 27, 2018
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Journal of the American Chemical Society
Superbase-Catalyzed anti-Markovnikov Alcohol Addition Reactions to Aryl Alkenes Chaosheng Luo and Jeffrey S. Bandar* Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States
Supporting Information Placeholder ABSTRACT: The organic superbase P4-t-Bu catalyzes the
direct anti-Markovnikov addition of alcohols to aryl alkenes to access valuable β-phenethyl ethers. A diverse substrate scope of aryl alkenes and alcohols is demonstrated, including heterocyclic systems and unprotected aminoalcohols. Mechanistic studies reveal that the reaction is under equilibrium control, while extensive comparisons to common inorganic bases indicate that the broad reaction scope is uniquely enabled through the use of the organic superbase.
β-Phenethyl ethers constitute important structural features widely found in pharmaceuticals and natural products and are also useful synthetic intermediates.1 The most direct synthetic route to ethers of this type would be the antiMarkovnikov addition of alcohols to styrene derivatives, a process for which catalysts have long been desired (Figure 1).2 Typically, a three-step hydroboration/oxidation/substitution sequence must be followed in order to achieve the formal anti-Markovnikov addition of alcohols to olefins.3 Despite impressive developments of Brønsted acid-, metal- and photoredox-catalyzed alcohol addition methodologies,4-6 a general process for the preparation of β-phenethyl ethers remains undeveloped.7,8 In their pioneering work on photoredox-catalyzed alkenol cyclization, the Nicewicz group reported the anti-Markovnikov addition of methanol to trans-anethole, although this intermolecular variant has not been significantly generalized for other substrates.9 common ether unit in: pharmaceuticals
O
R
β-phenethyl ether
Scheme 1. P4-t-Bu (a) alcohol deprotonation, (b, c) ion pair properties and (d) proposed addition reaction. (a) P4-t-Bu superbase alcohol deprotonation equilibrium (pKa in DMSO) t-Bu
t-Bu
N
P P(NMe2)3 (Me2N)3P N + H OR N N P(NMe2)3
alkene
HO
R
alcohol
Figure 1. The ideal precursors to valuable β-phenethyl ethers.
In theory, the Brønsted base-catalyzed addition of alcohols to styrenes should proceed with anti-Markovnikov selectivity due to the inherent polarity of the olefin, although almost no
H
– OR
reactive alkoxide ion pair
pKa 28 to 32
P4-t-Bu 30.2 pKa’
N
P P(NMe2)3 (Me2N)3P N N N P(NMe2)3
(b) Relative size comparison to metal cations
(c) Comparison of ion pairs
metal coordination RO M
50 x
25-2
H
r
large
versus – RO H P4+
Cs+
K+
+ Li+ Na
+ P4-t-Bu
H-bonding (P4-t-Bu abbreviated to P4)
(d) Proposed superbase-catalyzed anti-Markovnikov alcohol addition to styrenes
ideal synthetic precursors: Ar
natural products synthetic intermediates
reports of this synthetic approach exist. The lack of reactivity of simple styrenes may be attributed to an unfavorable pairing of styrene electrophilicity and the nucleophilicity of common alkoxides.10 For example, the only reports of basecatalyzed alcohol additions to aryl alkenes involve highly activated systems such as conjugated vinyl N-heterocycles.11 The development of a general base-catalyzed approach has additional challenges, such as the reversibility of the proposed reaction and the propensity for styrene polymerization under basic conditions.12 We hypothesized that the identity of Brønsted base plays a crucial role in determining the activation energy for alcohol addition and herein report an organic superbase-catalyzed protocol for the anti-Markovnikov addition of alcohols to aryl alkenes.
Ar alkene
+
HO
R
alcohol
P4 catalytic P4-t-Bu
Ar
O
H P4+
R
β-phenethyl ether
OR
Ar via
We reasoned that the nature of the cation in an alkoxide ion pair, which is derived from the base used for alcohol deprotonation, plays a crucial role in dictating alkoxide reactivity. The commercially available neutral
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phosphazene base P4-t-Bu (pKa’ 30.2 in DMSO) is predicted to readily deprotonate alcohols (pKa 28 to 32 in DMSO) in organic solvents to form the alkoxide ion pair shown in Scheme 1a.13 This base, first reported by Schwesinger in 1987, derives its high basicity from extraordinary electronic donation to a central phosphazene by three flanking phosphazene units.14 In 2004, Kondo utilized P4-t-Bu to catalyze the addition of alcohols to aryl acetylenes15, a reaction that inorganic bases also catalyze.16 We wondered, however, if the unique properties of alkoxide ion pairs derived from P4-bases could enable other challenging addition reactions (Scheme 1b-d). The large size of the protonated P4-t-Bu cation (500 Å3, about 25 to 250 times larger volume than common metal cations)17 has been used to explain the observed “nakedness” and enhanced nucleophilicity of its counteranions.18 Furthermore, unlike inorganic bases that lead to metalcoordinated alkoxide anions, the P4-t-Bu conjugate acid participates in hydrogen bonding that could rapidly protonate alkoxide addition adducts in either a stepwise or concerted process. Based on this analysis, we hypothesized that the use of P4-t-Bu could overcome the challenges associated with a base-catalyzed approach for the nucleophilic addition of alcohols to aryl alkenes (Scheme 1d).
under a range of reaction conditions; out of the approximately 125 conditions examined with metal bases, only one gave greater than 20% yield (Scheme 2c).19 Similar observations to the reversibility experiments and base comparisons shown in Scheme 2 were found using other styrene substrates and are detailed in the Supporting Information. Overall, the comparison to inorganic bases suggests that P4-t-Bu is a more efficient and general catalyst for this transformation, although we cannot rule out that currently unidentified conditions could enable inorganic base catalysis. Table 1. Substrate scope for the anti-Markovnikov addition of alcohols to aryl alkenes.a
P4-t-Bu (10 mol%)
+
HO
1 (1 equiv)
n-Bu
2 (3 equiv)
m-xylene 70 °C
O
+
3a, 77% yield
O
Ar
3a (1 equiv)
+ n-Bu
P4-t-Bu (10 mol%)
Et HO
n-Bu
2 (2 equiv)
m-xylene 70 °C
O
O
N
Example solvents examined
O
n-Bu
3h, 110 °C 38% yield
n-Bu
3i, 95 °C 65% yieldb Et
N Me
O
n-Bu
Ar
O
O
9
Cl
n-Bu
Ar = 4-NO2-C6H4
3k, 90 °C 58% yieldb Me
O
N
3l, 45 °C 58% yield Et
Me Cl
O
O
n-Bu
9
Me
S
1, 23%
N
Me
3m, 35 °C 72% yieldb
(c) Common metal-containing bases give low yields (see Supporting Information) Example bases examined
Et
Et
Cl
Ar Br
n-BuLi, LDA, LiTMP, NaOH, m-xylene, DMSO, DMF, THF, NaOtBu, NaHMDS, NaH, KOH, MeCN, PhCN, NMP, dioxane KOtBu, Cs2CO3, CsOH
n-Bu
3f, 100 °C 69% yield
O
n-Bu
O
Et O
3e, 110 °C 57% yield
Et
Ar
I n-Bu
Et O
Me
Cl 3c, 100 °C 81% yield
O
n-Bu
OMe Me
Et
OCF3
OMe 3d, 90 °C 70% yield
O
Me
3b, 70 °C 82% yield
CF3
3j, 50 °C 91% yield
+
OMe Me
Et
Br
1, 23%
n-Bu
3a, 74% yield
Cl O
n-Bu
NO2 3a, 70 °C 80% yield
Et Ar
R1
Cl
Et
3g, 140 °C 22% yieldb
n-Bu
OR2
Ar
m-xylene, 24 h
(3 equiv)
O
(b) Addition process is under free energy equilibrium control Et
P4-t-Bu (10 mol%)
HO R2
a) Aryl alkene scope
Et Ar
+
(1 equiv)
(a) Optimized reaction conditions using P4-t-Bu superbase catalyst Et
R1
Ar
Scheme 2. (a) Optimized and (b) reversible alcohol addition reaction; (c) comparison to inorganic bases.a
O2N
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Me
Me
Cl 3o, 65 °C 73% yield
3n, 40 °C 74% yieldb
Best result 25% yield KOH + 18-crown-6 DMF, 70 °C
b) Alcohol scope alcohol substitution effects R = Me, 30% yieldc OR
a
Yields determined by 1H NMR analysis of crude reaction mixture, see Supporting Information for details; Ar = 3-NO2C6H4.
Using the addition of 2-ethyl-1-hexanol to 3-nitrostyrene as a model reaction for optimization, we discovered that P4-tBu (10 mol%) catalyzes alcohol addition in 77% yield at 70 °C in m-xylene, with 23% remaining alkene (Scheme 2a).19 We observed decreased yields at both lower and higher temperatures, suggesting the addition reaction may be under free energy equilibrium control.19 This was confirmed when the addition product 3a was subjected to identical reaction conditions as in Scheme 2a, resulting in a similar ratio of 3a to 3nitrostyrene (Scheme 2b). We tested a variety of common inorganic bases in catalytic and stoichiometric quantities
3p-t 80 to 90 °C
F3C
n-Bu, 51%
yieldd
i-Am, 54%
yieldd
Me
O Me
Cl
i-Pr, 24% yieldc
NO2
O
O
MeO
Me Me O O
Cl O
OMe
3v, 60 °C 71% yield
3w, 80 °C 60% yieldc
3x, 110 °C 92% yieldb
Ph Cl O Cl 3y, 120 °C 70% yieldb
Me N
Cl
MeO
OMe
Me
3u, 100 °C 96% yield
t-Bu, 7% yieldc Me
NO2
Cl
N
Ph
O N
Me
O
Cl O
N O
Cl 3z, 60 °C 65% yield
F
CF3
3aa, 80 °C 57% yield
a
All yields are isolated yields of runs performed with 0.5 to 1 mmol of alkene; b mesitylene used as solvent; c 1H NMR yield; d 5 equiv alcohol used; see Supporting Information for details.
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The substrate scope for P4-t-Bu-catalyzed antiMarkovnikov alcohol addition reactions is shown in Table 1. In line with our optimization studies, we found the temperature used for each substrate combination was crucial for obtaining optimal yield, with decreased yields occurring at higher temperatures. First, the scope of aryl alkene was explored using simple alcohols (Table 1a). In general, electronpoor to -neutral styrenes gave moderate to good yields, while highly electron rich styrenes provided trace product. The observed electronic trend is likely both a kinetic and thermodynamic consequence as more electron-rich styrenes require higher temperatures for addition to occur, at which point the equilibrium yield is significantly decreased. Diverse functional groups and substitution patterns were well-tolerated, including meta-nitro (3a), trifluoromethyl (3b) and -methoxy (3d) groups, as well as ortho-chloro, -bromo, -trifluoromethoxy and -iodo groups (3b-f). Styrene provided 22% product at 140 °C (3g), while 1-vinylnaphthalene and 9-vinylanthracene gave increased yields (3h,i; 38 and 65% yield, respectively). Heteroaryl alkenes, such as pyridines, quinolines, furans and thiazoles also delivered ethers in high yield (3j-n). In product 3j, the addition process selectively occurred over aromatic substitution at the 2-chloro position. β-substitution is also tolerated on the aryl alkene, yielding secondary ether products 3m-o. The aryl alkene scope indicates that the reaction does not require resonance-stabilizing functional groups (e.g. nitro, cyano or carbonyl groups) in the 2- or 4positions.20 The alcohol scope for this process is highlighted in Table 1b. First, using 4-(trifluoromethyl)styrene, we found that the alcohol addition equilibrium favors ether to a greater degree for longer chain primary alcohols compared to methanol (3p-r). Isopropanol (3s) and tert-butanol (3t) also provided product, albeit in decreased yields.21 A range of diverse and densely functionalized primary alcohols provided ethers in high yield. Geraniol (3u), solketal (3w), a paroxetine derivative (3x), and alcohols featuring olefin (3v), azetidine (3y) and phthalimide (3aa) functional groups were compatible with this protocol. A secondary homoallylic alcohol also coupled to 2-chloro-3-vinylpyridine in good yield (3z). Table 2. Highly selective anti-Markovnikov addition reactions of unprotected diols and aminoalcohols.a P4-t-Bu (10 mol%)
diol or aminoalcohol
+
Ar (1 equiv) NO2
Me MeO
O
NH2
OMe 4a, 70 °C 60% yield (>20:1 selectivity) Me
N
Cl
O
Me Cl
O
Me
Cl
OH
Me
NH2
4d, 60 °C 53% yield (>20:1 O:N)
NH2
Cl
4b, 100 °C 66% yield (3:1 O:N)b Cl
4c, 120 °C 68% yield (>20:1 O:N)b O
Yields represent isolated yields of shown product; selectivity determined by 1H NMR analysis of crude reaction mixture. b 1H NMR yield of O-addition product; 4b isolated as Boc-protected amine in 58% yield and 4c isolated as Fmoc-protected amine in 49% yield; see Supporting Information for details.
We sought to extend this protocol toward the selective functionalization of alcohols containing multiple nucleophilic heteroatoms, such as unprotected diols and aminoalcohols (Table 2).22 We found selective addition of primary alcohols occurred over a tertiary alcohol (4a), primary amines (4b-d) and an aniline (4e). This selectivity is promising for developing selective reactions of more complex molecules and leaves unprotected heteroatoms available for further functionalization. Finally, we show that the anti-Markovnikov addition reaction is scalable using low P4-t-Bu catalyst loadings. Thus, using 2.5 mol% catalyst, 7.2 g of ether product 3c was isolated from the 30 mmol scale reaction in Equation 1. Cl
Cl + Cl
Me HO
5 (30 mmol)
Me
O
P4-t-Bu (2.5 mol%)
OMe
m-xylene 115 °C, 40 h
6 (90 mmol)
OMe Me
Cl
Me
(1)
3c, 82% yield 7.2 g (25 mmol)
The described catalytic protocol dramatically streamlines the preparation of simple and complex β-phenethyl ethers through the direct anti-Markovnikov addition of alcohols to styrene derivatives. The addition reaction is governed by equilibrium control, and further mechanistic studies could reveal important thermodynamic parameters required to enable other challenging alcohol addition reactions.23 This work, and the development of other reactions enabled by organic superbases, are currently ongoing in our laboratory. ASSOCIATED CONTENT Supporting Information. The Supporting Information is available free of charge on the ACS Publications website. Experimental procedures and characterization data for all compounds (PDF).
AUTHOR INFORMATION Corresponding Author
*
[email protected] Notes The authors declare no competing financial interest.
ACKNOWLEDGMENT
4
1° OH selective addition Cl
O
OR
Ar
mesitylene, 24 h
(3 equiv)
a
We thank Colorado State University for startup funding used to support this work, and Professors Andrew McNally and Robert M. Williams (CSU) for sharing additional resources. We thank Dr. Michael Pirnot and Professor Andrew McNally for input on this manuscript. J.S.B. is grateful for invaluable mentorship from Professors Stephen L. Buchwald (MIT) and Tristan H. Lambert (Cornell).
NH2 Cl
4e, 110 °C 32% yield (>20:1 O:N)
REFERENCES
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F.; Lei, A. ACS Catal. 2017, 7, 1432. (d) Hammer, S. C.; Kubik, G.; Watkins, E.; Huang, S.; Minges, H.; Arnold, F. H. Science, 2017, 358, 215. (9) (a) Hamilton, D. S.; Nicewicz, D. A. J. Am. Chem. Soc. 2012, 134, 18577. (b) Romero, N. A.; Nicewicz, D. A. J. Am. Chem. Soc. 2014, 136, 17024. (c) Margrey, K. A.; Nicewicz, D. A. Acc. Chem. Res. 2016, 49, 1997. (d) See Reference 6b for an extension of this approach. (10) (a) Miller, S. I. J. Org. Chem. 1956, 21, 247. We also note that basecatalyzed anti-Markovnikov styrene hydroamination reactions are welldeveloped: (b) Seayad, J.; Tillack, A.; Hartung, C. G.; Beller, M. Adv. Synth. Catal. 2002, 344, 795. (c) Müller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795. (11) For selected examples, see: (a) Kharkar, P S.; Batman, A. M.; Zhen, J.; Beardsley, P. M.; Reith, M. E. A.; Dutta, A. K. ChemMedChem 2009, 4, 1075. (b) Alunni, S.; De Angelis, F.; Ottavi, L.; Papavasileiou, M.; Tarantelli, F. J. Am. Chem. Soc. 2005, 127, 15151. (c) White, K. A.; Warr, G. C. J. Colloid Interface Sci. 2009, 337, 304. (d) Otsuka, M.; Endo, K.; Shibata, T. Organometallics 2011, 30, 3683. (e) Chen, J. J.; Drach, J. C.; Townsend, L. B. J. Org. Chem. 2003, 68, 4170. (12) (a) Hadjichristidis, N.; Hirao, A. Anionic Polymerization: Principles, Practice, Strength, Consequences and Applications;
Springer: Tokyo, Japan, 2015. (b) Baskaran, D.; Müller, A. H. E. Anionic Vinyl Polymerization. In Controlled and Living Polymerization: From Mechanisms to Applications; Müller, A. H. E., Matyjaszewski, K., Eds.; Wiley-VCH Verlag GmbH & KGaA: Weinheim, 2009; pp 1−56. (c) Ntetsikas, K.; Alzahrany, Y.; Polymeropoulos, G.; Bilalis, P.; Gnanou, Y.; Hadjichristidis, N. Polymers 2017, 9, 538. (13) (a) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456. (b) Olmstead, W. N.; Margolin, Z.; Bordwell, F. G. J. Org. Chem. 1980, 45, 3295. (14) (a) Schwesinger, R.; Schlemper, H. Angew. Chem. Int. Ed. 1987, 26, 1167. (b) Schwesinger, R.; Hasenfratz, C.; Schlemper, H.; Walz, L.; Peters, E.-V.; Peters, K.; von Schnering, H. G. Angew. Chem. Int. Ed. 1993, 32, 1361. (c) Schwesinger, R.; Schlemper, H.; Hasenfratz, C.; Willaredt, J.; Dambacher, T.; Breuer, T.; Ottaway, C.; Fletschinger, M.; Boele, J.; Fritz, H.; Putzas, D.; Rotter, H. W.; Bordwell, F. G.; Satish, A. V.; Ji, G.-Z.; Peters, E.-M.; Peters, K.; von Schnering, H. G.; Walz, L. Liebigs Ann. 1996, 1055. (d) For a review, see: Superbases for Organic Synthesis: Guanidines, Amidines, Phosphazenes and Related Organocatalysts; Ishikawa, T., Ed.; John Wiley & Sons, Ltd: Chichester, UK, 2009. (15) Imahori, T.; Hori, C.; Kondo, Y. Adv. Synth. Catal. 2004, 346, 1090. (16) Selected examples: (a) Cuthbertson, J.; Wilden, J. D. Tetrahedron, 2015, 71, 4385. (b) Brinkmann, C.; Barrett, A. G. M.; Hill, M. S.; Procopiou, P. A.; Reid, S. Organometallics, 2012, 31, 7287. (c) Tzalis, D.; Koradin, C.; Knochel, P. Tetrahedron Lett. 1999, 40, 6193. (d) Bellucci, G.; Chiappe, C.; Lo Moro, G. Synlett, 1996, 9, 880. (e) Patel, M.; Saunthwal, R. K.; Dhaked, D. K.; Bharatam, P. V.; Verma, A. K. Asian J. Org. Chem. 2016, 5, 213. (17) (a) Seebach, D.; Beck, A. K.; Studer, A. In Modern Synthetic Methods 1995; Ernst, B.; Leumann, C., Eds.; VCH: Weinheim, 1995; Vol. 7, pp. 48–54. (b) Mamdani, H. T.; Hartley, R. C. Tetrahedron Lett. 2000, 41, 747. Metal cation radii from: (c) Shannon, R. D. Acta Cryst. A 1976, 32, 751. (18) For related discussions, see: (a) Fruchart, J.-S.; Gras-Masse, H.; Melnyk, O. Tetrahedron Lett. 2001, 42, 9153. (b) Solladié-Cavallo, A.; Liptaj, T.; Schmitt, M.; Solgadi, A. Tetrahedron Lett. 2002, 43, 415. (c) Kolonko, K. J.; Guzei, I. A.; Reich, H. J. J. Org. Chem. 2010, 75, 6163. (d) Kolonko, K. J.; Reich, H. J. J. Am. Chem. Soc. 2008, 130, 9668. (e) Kawai, H.; Yuan, Z.; Tokunaga, E.; Shibata, N. Org. Biomol. Chem. 2013, 11, 1446. (f) Schwesinger, R.; Link, R.; Wenzl, P.; Kossek, S.; Keller, M. Chem. Eur. J. 2006, 12, 429. (g) Jardel, D.; Davies, C.; Peruch, F.; Massip, S.; Bibal, B. Adv. Synth. Catal. 2016, 358, 1110. (h) Pietzonka, T.; Seebach, D. Chem. Ber. 1991, 124, 1837. For a discussion of these effects in polymerization catalysis, see: (i) Boileau, S.; Illy, N. Prog. Polym. Sci., 2011, 36, 1132. (j) Hong, M.; Chen, E. Y.-X. Angew. Chem. Int. Ed. 2016, 55, 4188. (19) See Supporting Information for details. (20) Activated aryl alkenes, such as 4-nitrostyrene and 4-vinylpyridine, undergo efficient addition, while electron-deficient α-substituted styrenes provide moderate yields; see Supporting Information.
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Journal of the American Chemical Society (21) Under the current reaction conditions, water and trimethylsilanol do not react to provide the desired β-phenethyl alcohol or protected alcohol, respectively.
(22) For a review on site-selective catalysis, see: Site-Selective Catalysis; Kawabata, T. Ed. Springer Publishing: Switzerland, 2016. (23) For a review of thermodynamic parameters determined using lanthanide catalysts, see: Lohr, T. L.; Li, Z.; Marks, T. J. Acc. Chem. Res. 2016, 49, 824.
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Ar alkene
+
HO
P4
R
alcohol
N O
58% yield
via
phenethyl ether
Ar
N
Cl
O
O Me
65% yield
H P4+ OR Me
Cl
O
Me 9
R
Ar
catalytic P4-t-Bu
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NH2
Cl 68% yield (>20:1 O:N selectivity)
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