Double arylation of allyl alcohol via a one-pot heck arylation- isomerization-acylation cascade

Article abstract of DOI:10.1021/ol202144z

A one-pot, two-step catalytic protocol has been developed. A regioselective Heck coupling between aryl bromides and allyl alcohol leads to the generation of arylated allyl alcohols that in situ isomerize to give aldehydes, which then undergo an acylation reaction with a second aryl bromide. A variety of aryl bromides can be employed in both the initial Heck reaction and the acylation, providing easy access to a wide variety of substituted dihydrochalcones.

Full text of DOI:10.1021/ol202144z

ORGANIC
LETTERS
2011
Vol. 13, No. 20
5456–5459
Double Arylation of Allyl Alcohol via a
One-Pot Heck ArylationÀIsomerizationÀ
Acylation Cascade
Paul Colbon,† Jiwu Ruan,† Mark Purdie,‡ Keith Mulholland,‡ and Jianliang Xiao*,†
Department of Chemistry, Liverpool Centre for Materials and Catalysis,
University of Liverpool, Liverpool, L69 7ZD, U.K., and AstraZeneca, Silk Road
Business Park, Macclesfield, SK10 2NA, U.K.
j.xiao@liv.ac.uk
Received August 7, 2011
ABSTRACT
A one-pot, two-step catalytic protocol has been developed. A regioselective Heck coupling between aryl bromides and allyl alcohol leads to the
generation of arylated allyl alcohols that in situ isomerize to give aldehydes, which then undergo an acylation reaction with a second aryl bromide.
A variety of aryl bromides can be employed in both the initial Heck reaction and the acylation, providing easy access to a wide variety of
substituted dihydrochalcones.
The Heck reaction is one of the most widely used
methods for the construction of carbonÀcarbon bonds
in modern organic chemistry.1 Over the past few decades,
improved catalytic systems have been developed to
broaden its application, particularly toward electron-rich
olefins.2 In this context, our group recently disclosed a new
catalytic method that allows the direct acylation of aryl
halides with aliphatic aldehydes, which appears to occur
via a Heck-type mechanism (Scheme 1).3,4 In the presence
of molecular sieves, the aldehyde condenses with pyrroli-
dine to give an electron-rich enamine, which undergoes a
regioselective Heck coupling with aryl halides, most likely
via a cationic mechanism.5 During this work, some of the
aldehyde substratesweresynthesizedbya HeckarylationÀ
isomerization reaction of aryl halides withallylic alcohols.6
We envisioned that it might be possible to develop a single
palladium catalyst that is capable of generating aldehydes
from aryl halides and allyl alcohol and, in the same
reaction vessel, catalyzes the acylation of a second aryl
halide (Scheme 2). This would broaden the scope of
the acylation reaction beyond commercially available al-
dehydes, while circumventing the need for intermittent
isolation and purification. The products of this one-pot
† University of Liverpool.
‡ AstraZeneca.
(1) For recent reviews, see: (a) Ruan, J.; Xiao, J. Acc. Chem. Res.
2011, 44, 614. (b) Deagostino, A.; Prandi, C.; Tabasso, S.; Venturello, P.
Molecules 2010, 15, 2667. (c) The Mizoroki-Heck Reaction; Oestreich,
M., Ed.; Wiley: Chichester, U.K., 2009. (d) Nicolaou, K. C.; Bulger, P. G.;
Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4442. (e) Douney, A. B.;
Overman, L. E. Chem. Rev. 2003, 103, 2945.
(2) (a) Ruan, J.; Iggo, J. A.; Berry, N. G.; Xiao, J. J. Am. Chem. Soc.
2011, 132, 16689. (b) Gøgsig, T. M.; Lindhardt, A. T.; Dekhane, M.;
Grouleff, L.; Skrydstrup, T. Chem.;Eur. J. 2009, 15, 5950. (c) McConville,
M.; Saidi, O.; Blacker, J.; Xiao, J. J. Org. Chem. 2009, 74, 2692.
(d) Hyder, Z.; Ruan, J.; Xiao, J. Chem.;Eur. J. 2008, 14, 5555. (e) Mo,
J.; Xu, L.; Xiao, J. J. Am. Chem. Soc. 2005, 127, 751. (f) Andappan,
M. M. S.; Nilsson, P.; Schenck, H. V.; Larhed, M. J. Org. Chem. 2005, 69,
5212. (g) Hansen, A. L.; Skrydstrup, T. Org. Lett. 2005, 7, 5585.
(h) Nilsson, P.; Larhed, M.; Hallberg, A. J. Am. Chem. Soc. 2001, 123, 8217.
(3) (a) Colbon, P.; Ruan, J.; Purdie, M.; Xiao, J. Org. Lett. 2010, 12,
3670. (b) Ruan, J.; Saidi, O.; Iggo, J. A.; Xiao, J. J. Am. Chem. Soc. 2008,
130, 10510.
(5) (a) Amatore, C.; Godin, B.; Jutand, A.; Lemaıtre, F. Organome-
tallics 2007, 26, 1757. (b) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995,
28, 2.
(6) For examples of Heck reaction with allylic alcohols, see: (a) Stone,
ꢀ
M. T. Org. Lett. 2011, 13, 2326. (b) Alacid, E.; Najera, C. Adv. Synth.
Catal. 2007, 349, 2572. (c) Muzart, J. Tetrahedron 2005, 61, 4179.
(d) Larock, R. C.; Leung, W.-Y.; Stolz-Dunn, S. Tetrahedron Lett.
1989, 30, 6629.
(4) (a) Adak, L.; Bhadra, S.; Ranu, B. C. Tetrahedron Lett. 2010, 51,
3811. (b) Zanardi, A.; Mata, J. A.; Peris, E. Organometallics 2009, 28,
1480.
(7) For an alternative catalytic synthesis of DHCs, see: Briot, A.;
Baehr, C.; Brouillard, R.; Wagner, A.; Mioskowski, C. J. Org. Chem.
2004, 69, 1374.
r
10.1021/ol202144z
Published on Web 09/20/2011
2011 American Chemical Society

reaction would be substituted dihydrochalcones (DHCs),7
which have been reported to demonstrate antioxidant
properties8 and have received considerable attention as
food sweeteners.9
takes place in aqueous/organic media, which would be
incompatible with the molecular sieves needed for the
acylation reaction.3
Table 1. Optimizing Conditions for Heck ArylationÀ
Isomerization Reaction of 1a with 2aa
Scheme 1
entry
ligand
base
Et3N
yield (%)b
1
2
3
4
5
6
7
8
9
À
<2
<5
<2
37
59
62
<2
74
22
The acylation reaction necessiates a set of specific
conditions.3 We reasoned that, if the Heck arylationÀ
isomerization sequence could be catalyzed under condi-
tions suitable for the acylation, the one-pot process should
be feasible. For aryl iodides, the Heck arylation of allylic/
homoallylic alcohols is most commonly catalyzed by Pd-
(OAc)2 in the presence of tetraalkylammonium salts.6d,10
Such systems are particularly selective toward formation
of the carbonyl product due to the high levels of isomeri-
zation generally observed but would not be effective
toward aryl bromides. While the presence of a phosphine
ligand can promote the arylationÀisomerization reaction
ofaryl bromides, high temperatures are required toachieve
sufficient activity.11
PPh3
dpppc
Et3N
Et3N
P(t-Bu)3.HBF4
Et3N
L1
L2
L2
L2
L2
Et3N
Et3N
Pyrrolidine
Cy2NMe
K2CO3
a All reactions were carried out with 1a (1.0 mmol), 2a (1.1 mmol),
base (1.1 mmol), Pd(dba)2 (0.02 mmol), and ligand (0.06 mmol) in 4 mL
of DMF at 100 °C for 1 h. b Isolated yields. c 3 mol % of ligand was used.
Table 1 shows our attempt for the formation of hydro-
cinnamaldehyde 3a from a model reaction of bromo-
benzene 1a and allyl alcohol 2a. Commonly employed
phosphine ligands such as PPh3 and dppp resulted in poor
conversion, as did the ligand-free condition (entries 1À3).
However, the use of bulky, electron-rich monophosphines
P(t-Bu)3, L1, and L212 led to selective formation of the
desired aldehyde, with the latter two affording better yields
(entries 4À6); no internal arylation was observed. L1 was
previously demonstrated to be effective in the acylation of
aryl chlorides.3a The reaction conditions were further
optimized by changing the base (entries 7À9). The tertiary
amine Cy2NMe afforded the best result, with 3a being
isolated in 74% yield (entry 8). It was hoped that pyrroli-
dine would be a suitable base for the reaction, as its
presence is critical to the acylation step that follows in
the overall one-pot process.3 Unfortunately, use of pyrro-
lidine as the base yielded very little of the aldehyde product
(entry 7).
Scheme 2
More recent catalyst systems employ oxime-derived
palladacycles, which have proven to be highly active and
selective catalysts for the arylation of aryl halides with
a variety of allylic alcohols.6b However, the catalysis
(8) (a) Rezk, B. M.; Haenen, G. R. M. M.; Van der Vijgh, W. J. F.;
Bast, A. Biochem. Biophys. Res. Commun. 2002, 295, 9. (b) Silva,
D. H. S.; Davino, S. C.; Berlanga de Moraes Barros, S.; Yoshida, M.
J. Nat. Prod. 1999, 62, 1475. (c) Mathiesen, L.; Malterud, K. E.; Sund,
R. B. Free Radical Biol. Med. 1997, 22, 307.
(9) (a) Benavente- Garcia, O.; Castillo, J.; Del Bano, M. J.; Lorente,
J. J. Agric. Food Chem. 2001, 49, 189. (b) Whitelaw, M. L.; Chung, H.-J.;
Daniel, J. R. J. Agric. Food Chem. 1991, 39, 663. (c) Bakal, A. Alternative
Sweeteners, 2nd ed.; Dekker: New York, 1991.
To test the utility of the newly developed reaction
conditions, we examined the HeckÀisomerization reaction
of a range of aryl bromides with allylic/homoallylic alco-
hols (Table 2). Functional groups on the aryl bromides
were easily tolerated, posing no signifcant effect on the
isolated yield of the aldehyde products (entries 2À4).
(10) Jeffery, T. J. Chem. Soc., Chem. Commun. 1984, 1287.
(11) (a) Berthiol, F.; Doucet, H.; Santelli, M. Tetrahedron Lett. 2004,
ꢁ
45, 5633. (b) Calo, V.; Nacci, A.; Monopoli, A. J. Mol. Catal. A: Chem.
€
(12) Schulz, T.; Torborg, C.; Enthaler, S.; Schaffner, B.; Dumrath,
A.; Spannenberg, A.; Neumann, H.; Borner, A.; Beller, M. Chem.;Eur.
€
2004, 214, 45.
J. 2009, 15, 4528.
Org. Lett., Vol. 13, No. 20, 2011
5457

Table 2. ArylationÀIsomerization Reaction of Aryl Bromides
Table 3. One-Pot Arylation, Isomerization, and Acylation Re-
actions Varying the Initial Aryl Bromidesa
with Allylic Alcoholsa
a Reactions were carried out with 1aÀd (1.0 mmol), 2aÀd (1.1 mmol),
Cy2NMe (1.1 mmol), Pd(dba)2 (0.02 mmol), and L2 (0.06 mmol)
in 4 mL of DMF at 100 °C for 1 h. b Isolated yields. c Reaction time
was 2 h.
Internal substitution of the double bond of the allylic
alcohol was also tolerated (entry 5); however, the reaction
became sluggish and nonselective when terminally substi-
tuted allylic alcohols were employed. Secondary allylic
alcohol 2c was also a very effective substrate, giving access
to the corresponding ketone in high yield (entry 6). In
contrast, the homoallylic alcohol 2d furnished a lower
yield, due to incomplete isomerization (entry 7).
Armed with conditions that enable the facile formation
of aldehydes from aryl bromides and allyl alcohol, we
turned our attention to the one-pot synthesis of DHCs.
Bearing in mind that pyrrolidine is necessary for the
acylation but inhibits the arylationÀisomerization reac-
tion, an aryl bromide was first allowed to react with 1 equiv
of allyl alcohol at 100 °C for 30 min, at which point a
second aryl bromide was added together with pyrrolidine
and the reaction temperature was raised to 115 °C for 6 h.
The molecular sieves, another critical additive for the
acylation reaction, were present from the beginning and
did not impact the initial aldehyde formation.3b It was also
found that the presence of potassium carbonate accelerates
the acylation reaction, giving cleaner products and higher
yields. As can be seen in Table 3, the one-pot reaction
a Reactions were carried out with 1aÀc,eÀn (2.0 mmol), 2a (2.0 mmol),
Cy2NMe (2.0 mmol), K2CO3 (1.0 mmol), 4 A MS (1 g), Pd(dba)2 (0.02
mmol), and L2 (0.06 mmol) in 4 mL of DMF at 100 °C for 30 min, followed
by addition of 1e (1.0 mmol) and pyrrolidine (1.0 mmol) at
115 °C for 6 h. b Isolated yields based on 1e. c 0.04 mmol of Pd(dba)2
and 0.12 mmol of L2 were used.
proved capable of forming a variety of DHCs in moderate
to good isolated yields. In particular, functional groups on
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Org. Lett., Vol. 13, No. 20, 2011

the initial aryl bromides, such as ester, nitrile, and ketone,
were tolerated by the multistep catalysis (entries 3À9). In
steric terms, meta and para substitution did not pose any
significant problem, but unfortunately ortho substitution
with any group of steric bulk greater than that of methyl
(entry 11) dramatically inhibited the initial Heck coupling.
Furthermore, some heterocyclic aryl bromides were suc-
cessfully employed (entries 12 and 13).
Table 4. One-Pot Arylation, Isomerization, and Acylation Re-
actions Varying the Second Aryl Bromidesa
We next examined the efficiency of the one-pot process
by varying the second aryl bromide, which undergoes
the acylation reaction. The results are seen in Table 4.
We were happy to observe that the acylation step in the
one-pot process appears to behave in the same way as it
does in isolation.3 As such, the arylbromidecan bebroadly
functionalized in the meta and para positions and the
reaction runs smoothly, affording the DHCs in moderate
yields.
As a general trend, the arylation step appears to favor
aryl bromides bearing electron-withdrawing substituents,
while the acylation reaction works better with those having
electron-donating groups (Tables 3 and 4). This is prob-
ably because the oxidative addition in the arylation and the
insertion step in the acylation are facilitated by these
electron-withdrawing and -donating groups, respectively.
In addition, when 2a was replaced with 2b, the one-pot
reactionwas unsuccessful due tothe failureofthe acylation
with R-substituted aldehydes.3 Similarly, replacement of
2a with 2d gave poor results as a result of incomplete
isomerization.
In conclusion, a one-pot protocol has been developed,
which allows highly functionalized DHCs to be easily
synthesized from readily available substrates. The palla-
dium catalyzed Heck arylationÀisomerization reaction of
aryl bromides and allyl alcohol first leads to the formation
of aldehydes which, under the intervention of pyrrolidine
and the same palladium catalyst, undergo an acylation
reaction with an additional aryl bromide, affording the
DHCs.
Acknowledgment. Financial support from the EPSRC
(EP/F000316) and AstraZeneca is gratefully acknowl-
edged. We also thank the EPSRC National Mass Spectro-
metry Service Centre for analytical support.
a Reactions were carried out with 1b (2.0 mmol), 2a (2.0 mmol),
Cy2NMe (2.0 mmol), K2CO3 (1.0 mmol), 4 A MS (1 g), Pd(dba)2
(0.02 mmol), and L2 (0.06 mmol) in 4 mL of DMF at 100 °C for 30 min,
followed by addition of 1a,d,k,oÀu (1.0 mmol) and pyrrolidine (1.0 mmol)
at 115 °C for 6 h. b Isolated yields based on ArBr. c 0.04 mmol of Pd(dba)2
and 0.12 mmol of L2 were used.
Supporting Information Available. Experimental details
and analytical data (NMR, IR, MS). This material is
available free of charge via the Internet at http://pubs.acs.
org.
Org. Lett., Vol. 13, No. 20, 2011
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