Direct copper-catalyzed α-arylation of benzyl phenyl ketones with aryl iodides: Route towards tamoxifen

Article abstract of DOI:10.1002/anie.201206024

No activation needed: The first efficient method for direct α-arylation of non-activated or non-protected family of enolizable ketones with simple aryl iodides employs a catalytic copper system. The method shows potential for the easy and step-economical synthesis of tamoxifen, the most commonly administrated drug for the management of breast cancer. R, R′, R′′ = electron-donating or electron-withdrawing groups. Copyright

Full text of DOI:10.1002/anie.201206024

Angewandte
Chemie
DOI: 10.1002/anie.201206024
Synthetic Methods
Direct Copper-Catalyzed a-Arylation of Benzyl Phenyl Ketones with
Aryl Iodides: Route towards Tamoxifen**
Grꢀgory Danoun, Anis Tlili, Florian Monnier, and Marc Taillefer*
The direct and simple transition-metal-catalyzed a-arylation
of ketone enolates is the most general and efficient strategy to
access compounds possessing a benzylic carbonyl moiety. This
methodology thus constitutes an indispensable tool for the
organic chemist, as the molecules obtained are often struc-
tural motifs of prime importance in pharmaceutical, agro-
chemical, or fine chemistry. The first example of such direct a-
arylation was reported in the early 1970s by Semmelhack
et al., who described an intramolecular nickel-catalyzed a-
arylation serving as a key step of the total synthesis of the
cephalotaxinone.[1] Twenty years later there was a break-
through in this field with the independant discovery of
practical and efficient palladium-based catalysts by the
groups of Miura,[2] Buchwald,[3] and Hartwig.[4] These elegant
systems proved their efficiency in the intermolecular coupling
of aryl halides with enolates generated in situ from the
corresponding ketones in basic conditions. Since then, the a-
arylation of ketones based on palladium, mainly associated
with phosphines,[5] but also with other ligands such as N-
heterocyclic carbenes[6] or cyclic alkyl aminocarbenes,[7] has
been investigated.[8,9] Various types of ketones have been used
with palladium systems and among them are cyclic ketones,
dialkyl- or alkylaryl(or heteroayl) ketones, or aryl benzyl
ketones.[8,9] Notably, the challenge of the selective mono a-
arylation of acetone was recently performed by Stradiotto
et al.[10] and Ackermann et al.[11] in the presence of palladium/
phosphine systems. However, although palladium catalysis
remains the method of choice, it suffers from several short-
comings, particularly from the perspective of its use in
commercial syntheses because of the high cost, toxicity of
the metal, and the necessity of using expensive ligands.
As part of our studies on copper-catalyzed arylation of
nuclophiles,[12] we report herein the first efficient method for
which the direct a-arylation of a non-activated or non-
protected family of enolizable ketones (the deoxybenzoin
derivatives) with simple aryl iodides can also be achieved
using a copper-based catalytic system,[13] wherein the less
toxic and inexpensive metal is used together with 1,10-
phenanthroline or diketone-type ligands.[14] The potential of
the method is illustrated by its application in the total
synthesis of tamoxifen, the worldꢀs most-prescribed drug for
treatment of breast cancer.
First, a set of experiments was performed using 4-
iodotoluene and deoxybenzoin as model substrates. The
latter and its derivatives constitute the ketone family of
choice in this study, as their structure is present in numerous
bioactive compounds.[15,16] The preliminary survey, carried out
at 1108C with various solvents, bases, and copper sources,
helped us to evaluate the most efficient catalytic system for
the desired transformation (Table 1). When copper iodide
Table 1: Copper-catalyzed a-arylation of deoxybenzoin with 4-iodo-
toluene in the presence of 1,10-phenantroline (L1): parametric study.[a]
Entry Solvent
[Cu]
CuI
Base
Yield
[%][b]
1
DMF or
Cs2CO3
10
CH3CN
2
3
4
5
6
7
8
DMA
tBuOH
CuI
CuI
CuI
–
CuI
CuI
CuI
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Et3N or CsOH
KOAc or K3PO4
Rb2CO3 or
K2CO3
17
52
70
0
0
3
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
20
9
10
1,4-dioxane
1,4-dioxane
[Cu(acac)2]
Cu(OTf)2 or
Cu2O
Cs2CO3
Cs2CO3
30
44
11
1,4-dioxane
CuCl, Cu(OAc)2, Cs2CO3
CuBr2, or CuCN
50
[a] Reactions performed on 1 mmol scale (ketone/ArI=1.5:1).[b] Yield
determined by 1H NMR spectroscopy using 1,3-dimethoxybenzene as an
internal standard. acac=acetylacetonate, Tf=trifluoromethansulfonyl.
(10 mol%), 1,10-phenantroline (L1; 10 mol%), and Cs2CO3
were used in solvents such as N,N’-dimethylformamide
(DMF), acetonitrile (CH3CN), or dimethyacetamide
(DMA), we observed for the first time the expected a-
arylated product 1 in low yield (Table 1, entries 1 and 2). The
first significant result was obtained when the reaction was
performed in tert-butyl alcohol, as 52% of 1 was detected
under these reaction conditions (Table 1, entry 3). Moreover,
we were pleased to find that this yield could reach a satisfying
value (70%) when 1,4-dioxane was used instead of tBuOH
(Table 1, entry 4). Under these reaction conditions, replacing
Cs2CO3 by several organic and inorganic bases only led to
[*] Dr. G. Danoun,[+] Dr. A. Tlili,[+] Dr. F. Monnier, Dr. M. Taillefer
Institut Charles Gerhardt Montpellier, ENSCM
8 rue de l’Ecole Normale, 34296 Montpellier Cedex 5 (France)
E-mail: marc.taillefer@enscm.fr
[+] These authors contributed equally to this work.
[**] The CNRS, ENSCM, and ANR (grant ANR-07-CP2D-08,
H2OFERCAT) are thanked for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206024.
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Communications
disappointing results (Table 1, entries 6–8). Additionally,
several different copper sources (oxidation state I or II)
were screened but only low to modest conversions were
detected even in the most favorable cases (Table 1, entries 9–
11). It is worth noting that the blank experiments showed that
the presence of the copper catalyst is necessary in our
protocol (Table 1, entry 5).
We then examined, either in tBuOH or in 1,4-dioxane, the
influence of the ligand upon the course of the reaction
(Table 2). Diamine (L5, L6) and b-diketone (L7, L8, L9)
isolation (Table 3). Although the L4/tBuOH system used for
4-iodotoluene (Table 2) was applicable to all the substrates
tested, improved conversions were obtained using the L1/1,4-
dioxane couple highlighted in our preliminary studies
(Table 3, entries 3, 10, 13, 14, and 16–18). The ligand L1
(cheaper than L4) was also found to be efficient in combi-
nation with tBuOH for some examples (Table 3, entries 5, 7,
and 9). In the case of ortho-substituted aryl iodides, which are
traditionally poor substrates in copper-catalyzed arylation of
C, N, and O nucleophiles, low to fair amounts of the a-
arylated products were obtained.
Electron-poor aryl iodides were then considered
Table 2: Copper-catalyzed a-arylation of deoxybenzoin with 4-iodotoluene in
1,4-dioxane or tBuOH using the ligands L.[a]
and reacted with several deoxybenzoin derivatives
(Table 4, entries 1–14). Note that for a-arylation
catalytic systems based on other metals than copper,
this case has been less explored than those of
electron-rich aryl halides. Applying the conditions
of Table 3 led to poor yields of the coupling
L
Yield [%][b] in
L
Yield [%][b] in
products. For example, only 37% of the a-arylated
compound 23 (see Table 4, entry 1 for structure) was
obtained using the standard system CuI/L4/tBuOH
with 4-iodofluorobenzene (the main by-product was
the result of the homocoupling of deoxybenzoin).
However, a simple optimization led to an increase in
the yield to 52% by using the b-acetylcyclohexanone
ligand (L8) in tBuOH at 1108C (reaction conditions
previously employed for the a-arylation from 4-
iodotoluene). Finally the selectivity was improved
by lowering the reaction temperature to 708C, thus
producing 23 in 75% yield (Table 4, entry 1). By
using these reaction conditions, 15 differently sub-
stituted arylated deoxybenzoine derivatives were
obtained (Table 4) with yields ranging from low
(Table 4, entry 13) to excellent (Table 4, entry 14).
In some cases, the final compounds feature one or
two halides (Br, Cl, F) on the aromatic rings,
available for further functionalization at the corre-
sponding positions.
1,4-
dioxane
tBuOH
1,4-
dioxane
tBuOH
–
8
6
L5 29
5
8
L1 70
52
L6 23
L7 20
L2 27
46
17
L3
3
47
84
L8 24
L9 11
58
8
L4 68
[a] Reactions performed on 1 mmol scale (ketone/ArI=1.5:1). [b] Yields deter-
mined by 1H NMR spectroscopy using 1,3-dimethoxybenzene as an internal
standard.
ligands were ineffective, except for b-acetylcyclohexanone
(L8) in tBuOH (58% yield of 1). Finally, the 1,10-phenantro-
line-type ligands (L1, L2, L3, L4) offered the best solution,
with the use of bathophenantroline (L4) in tBuOH affording
1 in very good yield (84%). These reaction conditions were
used with bromobenzene but the cross-coupling failed (8% of
product and no reaction with PhCl). As it was the case for the
copper source, the presence of a ligand was necessary to
obtain satisfying results, as attested by the yields obtained
from PhI (6–8%) in its absence (Table 2). In addition, it
proved difficult to establish a relationship between the
structure or the solubility of the ligand and the reactivity
observed, even for the same structural family.
Next, the scope of the reaction with respect to various aryl
iodides and deoxybenzoin derivatives was investigated. Two
scenarios were observed, depending on the nature of the aryl
iodide substituents.
In the case of electron-rich aryl iodides bearing one or two
electron-donating groups (Me or OMe), a simple tuning of
the copper catalytic system allowed us to obtain numerous a-
arylated deoxybenzoins in good to excellent yields upon
The scope of this methodology was demonstrated by its
simple and efficient application to the synthesis of Tamoxifen
(TAM). Marketed under the trade name Nolvadex, this
molecule has for a long time been the worldꢀs most commonly
administrated drug for management of breast cancer.[15b,16]
We considered two new and original routes for the total
synthesis of this molecule, which belongs to the triphenyl-
ethylene class of compounds. In the first pathway, the
synthesis starts with the copper-catalyzed a-arylation of
deoxybenzoin with 4-Iodophenol (Scheme 1, Route A). The
latter is a suitable substrate as evidenced by the good yield
obtained for the a-arylated deoxybenzoin derivative 37. For
this step the most efficient catalytic system was CuI/L8.
tBuOH was preferred over 1,4-dioxane because of the greater
solubility of the phenolic reagent in alcohols. Compound 37
then underwent an alkylation/elimination/isomerization[17]
sequence and the resulting intermediate 38 was directly
reacted with 2-chloro-N,N-dimethylethylamine to give
tamoxifen in an overall yield of 70% (over 4 steps) upon
isolation.
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Table 3: Copper-catalyzed a-arylation of deoxybenzoin derivatives by aryl Table 4: Copper-catalyzed a-arylation of deoxybenzoin derivatives by aryl
iodides substituted by electron-donating groups.[a] iodides substituted by electron-withdrawing groups[a]
Entry Product
Yield
[%][b]
Entry Product
Yield
[%][b]
Entry Product
Yield
[%][b]
Entry Product
Yield
[%][b]
1
1
2
84[c]
12
12 60[c]
1
23 75
8
30 40[c]
2
3
99[c]
13
14
13 89[e]
2
3
4
24 60
25 57
26 48
9
31 90
3
4
48[d,e]
14 99[e]
10
11
32 75
33 33
4
99[c]
15
15 37[d,e]
5
6
5
6
74[f]
16
17
16 99[e]
5
27 60
12
34 49
75[c]
17 71[e]
6
7
28 57[c]
13
14
35 17
36 99
7
8
7
51[f]
18
19
18 74[e]
29 54[c]
[a] Reactions performed in tBuOH (1 mL) at 708C with 1 mmol of
iodoarene, 1.5 mmol of ketone, 2 mmol of Cs2CO3, 0.1 mmol of CuI and
0.1 mmol of L8. [b] Yield of isolated product. [c] Reaction performed at
908C.
8
9
70[c]
19 56[e]
9
56[f]
20
21
22
20 94[c]
21 81[d,c]
22 99[c]
We also developed a second route based on a reverse
strategy involving, in the first step, the iodoarene already
substituted by the dimethylethylamino substituent present on
tamoxifen (Scheme 1, Route B).[18] This electron-donating
group proved to be a suitable substituent. The coupling of the
corresponding aryl iodide with deoxybenzoin gave the
expected a-arylated intermediate 39 in good yield. For this
step the most efficient catalyst system was L1/CuI (10 mol%)
in 1,4-dioxane. The same alkylation/elimination/isomeriza-
tion sequence was used for 39 to yield tamoxifen in a satisfying
63% (3 steps). These two synthetic pathways show that our
method is easily applicable for the synthesis of major targets
and that it could constitute an efficient tool for the synthesis
of a library of tamoxifen derivatives.
10
11
10 21[d,e]
11 88[c]
[a] Reactions performed on 1 mmol scale (ketone/ArI: 1.5/1). [b] Yield of
isolated product. [c] tBuOH/L4. [d] Yields determined by 1H NMR spec-
troscopy. [e] 1,4-Dioxane/L1. [f] tBuOH/L1.
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Scheme 1. a) CuI (10 mol%), L8 (10 mol%), Cs2CO3 (4 equiv), tBuOH,
708C, 24 h; b) 1. EtMgBr (3 equiv), THF, 258C, 5 h, 2. HCl (37%),
MeOH, 658C, 15 h, 3. tBuOK (4 equiv), DMSO, 508C, 2 h; c) NaH
(3 equiv), ClC2H4NMe2 (2 equiv), DMF, 508C, 3 h. d) CuI (10 mol%),
L1 (10 mol%), Cs2CO3 (4 equiv), dioxane, 1108C, 24 h. e) 1. EtMgBr
(3 equiv), THF, 258C, 5 h, 2. HCl (37%), MeOH, 658C, 15 h, 3. tBuOK
(5 equiv), DMSO, 508C, 2 h.
À
À
À
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[13] For the synthesis of a-arylketones the copper has been involved
from other substrates than simple ketones or aryl halides. See for
example the copper-catalyzed arylation/decarbonylation of
diketones (one equivalent of KOAc is released and lost): a) C.
He, S. Guo, L. Huang, A. Lei, J. Am. Chem. Soc. 2010, 132, 8273.
21% of a phenylated deoxybenzoin has been observed in an
isolated example involving a copper system: b) S. L. Buchwald,
A. Klapars, J. C. Antilla, G. E. Job, M. Wolter, F. Y. Kwong, G.
Nordmann, E. J. Hennessy, US 7,115,784B2, 2006. The reaction
between diaryliodonium (one equivalent of aryl is lost) and
silylketene imides or silylketene acetals in the presence of chiral
copper bisoxazoline catalysts has also been reported. See: c) J. S.
Harvey, S. P. Simonovich, C. R. Jamison, D. W. C. MacMillan, J.
Am. Chem. Soc. 2011, 133, 13782; d) A. Bigot, A. E. Williamson,
M. J. Gaunt, J. Am. Chem. Soc. 2011, 133, 13778. Note that this
type of reaction is also known for metal-free conditions employ-
ing diaryliodonium triflates and either cyclic silyl enol ethers or
cyclic ketones, in racemic or enantioselective versions. See
respectively: e) K. Chen, G. F. Koser, J. Org. Chem. 1991, 56,
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such as keto esters, malonic acid derivatives, or diketone is also
known. See for example [8,12a – d] or g) X. Xie, G. Cai, D. Ma,
Org. Lett. 2005, 7, 4693.
In conclusion, we have discovered the first efficient
method in which the direct a-arylation with simple aryl
iodides of a non-activated or nonprotected family of enoliz-
able ketones (the deoxybenzoin derivatives) is possible by
using a copper catalyst system. The method is selective
towards other halides (Br, Cl or F) thus allowing further
functionalization of aromatic cycles without any protection/
deprotection sequence. This method is complementary to the
palladium systems which catalyze the reaction using aryl
chlorides. The use of copper in association with commercially
available and inexpensive phenanthroline or diketone-type
ligands is an advantage in line with sustainable develop-
ment.[14] Finally this method demonstrated its potential in the
easy and step-economical synthesis of tamoxifen, the most
commonly administrated drug for treatment of breast cancer.
Work is in progress to generalize its application field, to
understand the mechanism,[19] and to develop an asymmetric
version.
Received: July 27, 2012
Revised: September 12, 2012
Published online: November 9, 2012
Keywords: arenes · copper · homogeneous catalysis · ketones ·
.
synthetic methods
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sium Grignard reagent, leads to the corresponding tertiary
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37% in MeOH) to give two types of alkenes (two chemically
different protons are present at the a position of C-OH). After
isomerization of the latter by addition of tBuOK in DMSO, the
intermediate 38 is obtained with the unsaturation (Z/E = 1:1) at
the required position for the tamoxifen. For more details of this
sequence, see the Supporting Information.
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