Superbase-Catalyzed anti-Markovnikov Alcohol Addition Reactions to Aryl Alkenes

Article abstract of DOI:10.1021/jacs.8b00766

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 and extensive comparisons to common inorganic bases indicate that the broad reaction scope is uniquely enabled through the use of the organic superbase.

Full text of DOI:10.1021/jacs.8b00766

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Communication
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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Superbase-Catalyzed anti-Markovnikov Alcohol Addition Re-
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Chaosheng Luo and Jeffrey S. Bandar*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States
Supporting Information Placeholder
reports of this synthetic approach exist. The lack of reactivity
ABSTRACT: The organic superbase P4-t-Bu catalyzes the
direct anti-Markovnikov addition of alcohols to aryl alkenes
of simple styrenes may be attributed to an unfavorable pair-
ing of styrene electrophilicity and the nucleophilicity of
common alkoxides.10 For example, the only reports of base-
catalyzed 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 pro-
posed 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 acti-
vation energy for alcohol addition and herein report an or-
ganic superbase-catalyzed protocol for the 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. Mech-
anistic studies reveal that the reaction is under equilibrium
control, while extensive comparisons to common inorganic
bases indicate that the broad reaction scope is uniquely ena-
bled through the use of the organic superbase.
β-Phenethyl ethers constitute important structural fea-
tures 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 anti-
Markovnikov addition of alcohols to styrene derivatives, a
process for which catalysts have long been desired (Figure
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)
1).2
Typically,
a
three-step
hydrobora-
H
N
–
t-Bu
t-Bu
OR
N
P
N
P
tion/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 prepara-
tion of β-phenethyl ethers remains undeveloped.7,8 In their
pioneering work on photoredox-catalyzed alkenol cycliza-
tion, the Nicewicz group reported the anti-Markovnikov
addition of methanol to trans-anethole, although this inter-
molecular variant has not been significantly generalized for
other substrates.9
P(NMe2)3
P(NMe2)3
(Me2N)3P
(Me2N)3P
N
N
N
N
+
N
H
OR
P(NMe2)3
P(NMe2)3
reactive alkoxide ion pair
pKa 28 to 32
P4-t-Bu 30.2 pKa’
(b) Relative size comparison to metal cations
(c) Comparison of ion pairs
metal coordination
RO M
versus
H
P4+-t-Bu
–
+
RO
H
P4
25-250 x larger
K+
Cs+
Na+
H-bonding
Li+
(P4-t-Bu abbreviated to P4)
(d) Proposed superbase-catalyzed anti-Markovnikov alcohol addition to styrenes
common ether unit in:
ideal synthetic precursors:
+
H
P4
O
R
pharmaceuticals
O
R
+
P4
Ar
HO
R
Ar
Ar
HO
R
OR
natural products
Ar
catalytic
P4-t-Bu
synthetic intermediates
β-phenethyl ether
alkene
alcohol
alkene
alcohol
β-phenethyl ether
via
Figure 1. The ideal precursors to valuable β-phenethyl ethers.
We reasoned that the nature of the cation in an alkox-
ide ion pair, which is derived from the base used for al-
cohol deprotonation, plays a crucial role in dictating
alkoxide reactivity. The commercially available neutral
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
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phosphazene base P4-t-Bu (pKa’ 30.2 in DMSO) is predicted
Page 2 of 6
under a range of reaction conditions; out of the approximate-
ly 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, alt-
hough we cannot rule out that currently unidentified condi-
tions could enable inorganic base catalysis.
1
2
3
4
5
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7
8
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 phos-
phazene 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 Fur-
thermore, unlike inorganic bases that lead to metal-
coordinated alkoxide anions, the P4-t-Bu conjugate acid par-
ticipates 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 al-
cohols to aryl alkenes (Scheme 1d).
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Table 1. Substrate scope for the anti-Markovnikov addition of
alcohols to aryl alkenes.a
R1
P4-t-Bu (10 mol%)
+
OR2
R2
HO
Ar
Ar
m-xylene, 24 h
R1
O
(1 equiv)
(3 equiv)
a) Aryl alkene scope
Cl
Et
O
Cl
O
OMe
Me
OMe
Me
n-Bu
Me
Me
Cl
3a, 70 °C
CF3
3b, 70 °C
3c, 100 °C
NO2
80% yield
82% yield
O
81% yield
I
Et
Br
Et
OCF3
Et
O
O
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
OMe
3d, 90 °C
3e, 110 °C
3f, 100 °C
Scheme 2. (a) Optimized and (b) reversible alcohol addi-
tion reaction; (c) comparison to inorganic bases.a
70% yield
57% yield
69% yield
Et
Et
Et
O
O
O
n-Bu
n-Bu
(a) Optimized reaction conditions using P4-t-Bu superbase catalyst
3g, 140 °C
3h, 110 °C
3i, 95 °C
22% yieldb
38% yield
65% yieldb
P4-t-Bu
(10 mol%)
Et
Et
O2N
+
O
Et
+
Et
HO
Ar
n-Bu
Ar
N
n-Bu
m-xylene
70 °C
O
O
O
n-Bu
O
Me
Ar
Cl
(1 equiv)
3a, 77% yield
1, 23%
1
2 (3 equiv)
9
Ar = 4-NO2-C6H4
N
Cl
(b) Addition process is under free energy equilibrium control
3j, 50 °C
3k, 90 °C
58% yieldb
3l, 45 °C
91% yield
58% yield
P4-t-Bu
(10 mol%)
Et
Et
Et
+
Cl
Cl
Et
+
O
O
HO
Ar
n-Bu
Ar
n-Bu
Ar
O
Me
9
n-Bu
O
N
O
Me
Me
m-xylene
70 °C
n-Bu
Br
S
Me
Me
N
Me
(1 equiv)
3a, 74% yield
1, 23%
3a
(2 equiv)
2
3m, 35 °C
72% yieldb
3n, 40 °C
74% yieldb
3o, 65 °C
73% yield
(c) Common metal-containing bases give low yields (see Supporting Information)
Best result
Example bases examined
Example solvents examined
b) Alcohol scope
alcohol substitution effects
25% yield
KOH + 18-crown-6
DMF, 70 °C
n-BuLi, LDA, LiTMP, NaOH,
NaOtBu, NaHMDS, NaH, KOH,
KOtBu, Cs2CO3, CsOH
m-xylene, DMSO, DMF, THF,
MeCN, PhCN, NMP, dioxane
Cl
R = Me, 30% yieldc
O
Me
n-Bu, 51% yieldd
OR
Me
Me
i-Am, 54% yieldd
i-Pr, 24% yieldc
t-Bu, 7% yieldc
Cl
a
Yields determined by 1H NMR analysis of crude reaction
mixture, see Supporting Information for details; Ar = 3-NO2-
C6H4.
F3C
3u, 100 °C
96% yield
3p-t
80 to 90 °C
Me
N
Me
NO2
Me
Cl
Me
NO2
O
O
O
O
O
MeO
Cl
Using the addition of 2-ethyl-1-hexanol to 3-nitrostyrene
as a model reaction for optimization, we discovered that P4-t-
Bu (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 tem-
peratures, 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 con-
ditions as in Scheme 2a, resulting in a similar ratio of 3a to 3-
nitrostyrene (Scheme 2b). We tested a variety of common
inorganic bases in catalytic and stoichiometric quantities
MeO
OMe
OMe
3v, 60 °C
F
3w, 80 °C
60% yieldc
3x, 110 °C
92% yieldb
71% yield
Ph
Ph
O
Cl
Cl
N
O
Me
O
N
O
O
N
Cl
Cl
CF3
3y, 120 °C
70% yieldb
3z, 60 °C
3aa, 80 °C
65% yield
57% yield
a All yields are isolated yields of runs performed with 0.5 to 1
mmol of alkene; mesitylene used as solvent; c 1H NMR yield;
b
d
5 equiv alcohol used; see Supporting Information for details.
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a Yields represent isolated yields of shown product; selectivity
determined by 1H NMR analysis of crude reaction mixture. b 1
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.
The substrate scope for P4-t-Bu-catalyzed anti-
1
2
3
4
5
6
7
8
H
Markovnikov alcohol addition reactions is shown in Table 1.
In line with our optimization studies, we found the tempera-
ture used for each substrate combination was crucial for ob-
taining optimal yield, with decreased yields occurring at
higher temperatures. First, the scope of aryl alkene was ex-
plored using simple alcohols (Table 1a). In general, electron-
poor 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 sty-
renes require higher temperatures for addition to occur,
at which point the equilibrium yield is significantly de-
creased. Diverse functional groups and substitution patterns
We sought to extend this protocol toward the selective
functionalization of alcohols containing multiple nucleo-
philic heteroatoms, such as unprotected diols and aminoal-
cohols (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 promis-
ing for developing selective reactions of more complex mole-
cules and leaves unprotected heteroatoms available for fur-
ther functionalization.
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were well-tolerated, including meta-nitro (3a),
-
Finally, we show that the anti-Markovnikov addition reac-
tion is scalable using low P4-t-Bu catalyst loadings. Thus,
using 2.5 mol% catalyst, 7.2 g of ether product 3c was isolat-
ed from the 30 mmol scale reaction in Equation 1.
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 al-
kenes, such as pyridines, quinolines, furans and thiazoles also
delivered ethers in high yield (3j-n). In product 3j, the addi-
tion process selectively occurred over aromatic substitution
Cl
Cl
Me
Me
O
OMe
P4-t-Bu (2.5 mol%)
+
(1)
HO
OMe
Me
Me
m-xylene
115 °C, 40 h
Cl
Cl
5
(30 mmol)
6
(90 mmol)
3c, 82% yield
7.2 g (25 mmol)
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 4-
positions.20
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.
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 deriva-
tive (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).
ASSOCIATED CONTENT
Supporting Information. The Supporting Information is avail-
able free of charge on the ACS Publications website.
Experimental procedures and characterization data for all com-
pounds (PDF).
AUTHOR INFORMATION
Corresponding Author
Table 2. Highly selective anti-Markovnikov addition reactions
*jeff.bandar@colostate.edu
Notes
The authors declare no competing financial interest.
of unprotected diols and aminoalcohols.a
P4-t-Bu (10 mol%)
diol or
aminoalcohol
+
OR
Ar
4
ACKNOWLEDGMENT
Ar
mesitylene, 24 h
(1 equiv)
(3 equiv)
1° OH selective addition
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).
NO2
Cl
Cl
Me
NH2
O
OH
O
NH2
O
Me
Me
MeO
Cl
4b, 100 °C
Cl
OMe
4a, 70 °C
60% yield (>20:1 selectivity)
4c, 120 °C
68% yield (>20:1 O:N)b
66% yield (3:1 O:N)b
Me
Me
Cl
O
O
NH2
NH2
N
Cl
53% yield (>20:1 O:N)
4e, 110 °C
32% yield (>20:1 O:N)
4d, 60 °C
Cl
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(10) (a) Miller, S. I. J. Org. Chem. 1956, 21, 247. We also note that base-
catalyzed anti-Markovnikov styrene hydroamination reactions are well-
developed: (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.; Tarantel-
li, 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.; Polym-
eropoulos, 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, Ami-
dines, Phosphazenes and Related Organocatalysts; Ishikawa, T., Ed.; John
Wiley & Sons, Ltd: Chichester, UK, 2009.
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(16) Selected examples: (a) Cuthbertson, J.; Wilden, J. D. Tetrahedron,
2015, 71, 4385. (b) Brinkmann, C.; Barrett, A. G. M.; Hill, M. S.; Procopi-
ou, 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 Meth-
ods 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.
(7) For reviews on anti-Markovnikov oxidation and hydration reactions,
see: (a) Beller, M.; Seayad, J.; Tillack, A. Jiao, H. Angew. Chem. Int. Ed.
2004, 43, 3368. (b) Guo, J.; Teo, P. Dalton Trans. 2014, 43, 6952. (c)
Dong, J. J.; Browne, W. R.; Feringa, B. L. Angew. Chem. Int. Ed. 2015, 54,
734.
(8) For examples of styrene anti-Markovnikov hydration, see: (a) Dong,
G.; Teo, P.; Wickens, Z. K.; Grubbs, R. H. Science, 2011, 333, 1609. (b)
Wu, S.; Liu, J.; Li, Z. ACS Catal. 2017, 7, 5225. (c) Xu, H.; Zhang, G.; Bu,
(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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(22) For a review on site-selective catalysis, see: Site-Selective Catalysis;
(21) Under the current reaction conditions, water and trimethylsi-
lanol do not react to provide the desired β-phenethyl alcohol or pro-
tected alcohol, respectively.
Kawabata, T. Ed. Springer Publishing: Switzerland, 2016.
(23) For a review of thermodynamic parameters determined using lan-
thanide catalysts, see: Lohr, T. L.; Li, Z.; Marks, T. J. Acc. Chem. Res. 2016,
49, 824.
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via
O
R
+
P4
1
+
Ar
HO
R
Ar
H P4
2
3
catalytic
P4-t-Bu
OR
Ar
alkene
alcohol
phenethyl ether
4
5
6
7
8
9
Cl
Me
NH2
N
O
O
O
Me
Me
9
N
Cl
Cl
68% yield
(>20:1 O:N selectivity)
58% yield
65% yield
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