Stereospecific copper-catalyzed C-H allylation of electron-deficient arenes with allyl phosphates

Article abstract of DOI:10.1002/anie.201007733

(Chemical Equation Presented) Rapid and concise: The title reaction proceeds via copper complexes in a highly stereospecific manner (see scheme; acac=acetylacetonate, phen=1,10-phenanthroline, TBS=tBuMe₂Si). The catalysis provides a rapid and c

Full text of DOI:10.1002/anie.201007733

Communications
DOI: 10.1002/anie.201007733
À
C H Functionalization
À
Stereospecific Copper-Catalyzed C H Allylation of Electron-Deficient
Arenes with Allyl Phosphates**
Tomoyuki Yao, Koji Hirano,* Tetsuya Satoh, and Masahiro Miura*
The allylation reaction is one of the most fundamental and
important transformations in organic synthesis because allyl
moieties are easily manipulated to access various versatile
functional groups. In particular, the metal-mediated allylation
of aryl metal compounds with allylic electrophiles ranks as a
powerful and reliable method for the introduction of allyl
units to aromatic rings. To date, various transition-metal
catalysts such as copper, palladium, rhodium, and iridium
have been developed to enable allyl coupling to several aryl
metal compounds, including magnesium, aluminum, zinc, and
boron reagents (Scheme 1a).[1] Although valuable, the major
erally restricted in substrate scope to electron-rich arenes.[3]
Thus, further developments to give more efficient and direct
access to allylated electron-deficient arenes are required
(Scheme 1c).
À
À
Recently, metal-mediated C C bond formation by C H
functionalization has grown rapidly as a potentially more
efficient and complementary process to the conventional
cross-coupling methodology, and direct arylations, alkenyla-
tions, alkynylations, and alkylations have been achieved.[4] On
the contrary, the corresponding allylation still remains largely
elusive despite its potential.[5] Herein, we report the copper-
À
catalyzed direct C H allylation with allyl phosphates. The
copper-based system provides a rapid and concise route to
allyl arenes that contain fluorinated aromatic cores of an
electron-deficient nature,[6] and are of importance in materials
and life science.[7] Moreover, the unique stereospecificity of
the reaction is also described.
On the basis of our recent studies on copper complexes in
[8,9]
À
C H functionalization chemistry,
we tested the copper-
based systems for the direct allylation of pentafluorobenzene
(1a; Table 1). After extensive screening of various reaction
parameters, we found that the treatment of 1a with allyl
phosphate (E)-2a in the presence of a catalytic amount of
[Cu(acac)2]/phen and LiOtBu as a base in 1,4-dioxane at room
temperature afforded 3aa in a 61% yield with high regio- and
stereoselectivity (linear/branched 98:2, E/Z 97:3; Table 1,
entry 1).[10] The choice of leaving group on the allyl electro-
phile was crucial; the reaction of the corresponding acetate or
carbonate instead of the phosphate resulted in no formation
of the allylated product. Alkyl-substituted allyl phosphates
bearing a silyl ether [(E)-2b] and the bulky iPr group [(E)-2c]
at the allylic position coupled with 1a effectively (entries 2
and 3, respectively). Cinnamyl phosphates (E)-2d–g also
underwent the reaction with regio- and stereoselectivities
similar to those of the aliphatic systems (E)-2a–c (entries 4–
7). Although both electron-rich and electron-deficient sub-
stituents on the benzene ring were tolerated, the methoxy-
substituted reagent gave a better yield (entries 5–7). More-
over, the cyclic framework of 2h was tolerated (entry 8).
By using the [Cu(acac)2]/phen catalyst, we subsequently
performed the allylation of an array of fluoroarenes (1;
(Scheme 2). Substituted tetrafluorobenzenes with electroni-
cally diverse substituents, which included methoxy, trifluoro-
methyl, and cyano groups, were all compatible with the
reaction conditions (3ba, 3bh, 3ca, 3ch, and 3dh). The
coupling of the pyridine analogue also proceeded without any
difficulties (3ec and 3eh). In the case of 1,2,4,5-tetrafluoro-
Scheme 1. Approaches to allylarenes with allylic electrophiles. EDG=
electron-donating group, EWG=electron-withdrawing group,
LG=leaving group.
drawback of these procedures is the inevitable preactivation
step of the arenes, that is the stoichiometric metalation of the
corresponding arenes or halogenated arenes. As an alterna-
tive and more straightforward approach, the Lewis acid
promoted Friedel–Crafts-type reaction (Scheme 1b) is useful
because it eliminates the prior preparation of the aryl metal
compounds.[2] However, this type of transformation is gen-
[*] T. Yao, Dr. K. Hirano, Prof. Dr. T. Satoh, Prof. Dr. M. Miura
Department of Applied Chemistry, Faculty of Engineering
Osaka University
Suita, Osaka 565-0871 (Japan)
Fax: (+81)6-6879-7362
E-mail: k_hirano@chem.eng.osaka-u.ac.jp
miura@chem.eng.osaka-u.ac.jp
[**] This work was partly supported by Grants-in-Aid from the Ministry
of Education, Culture, Sports, Science, and Technology (Japan).
À
benzene, the reaction occurred at both C H bonds to provide
a mixture of 3 fa and 3 fa’ in a ratio of 85:15. A similar result
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201007733.
was obtained in the reaction of 1,2,3,5-tetrafluorobenzene
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Table 1: Copper-catalyzed direct C H allylation of pentafluorobenzene
(1a) with various allyl phosphates 2.[a]
Entry
2
3[b]
1
2
(E)-2a
(E)-2b
3aa 61% (97:3)
3ab 82% (99:1)
3
4
(E)-2c
(E)-2d
3ac 77% (>99:1)
3ad 50% (>99:1)[c]
5
6
(E)-2e
(E)-2f
3ae 60% (>99:1)[c]
3af 76% (>99:1)
7
8
(E)-2g
(E)-2h
3ag 57% (>99:1)[c]
3ah 78% (>99:1)
[a] Reaction conditions: [Cu(acac)2] (0.050 mmol), phen (0.050 mmol),
LiOtBu (1.0 mmol), 1a (0.50 mmol), (0.60 mmol), 1,4-dioxane
2
À
Scheme 2. Copper-catalyzed direct C H allylation of various fluoro-
arenes 1 with allyl phosphates 2 performed using the reaction
(3.0 mL), RT, 4 h, N2. [b] The yields are of isolated products and the
1
E/Z ratios were determined by H NMR spectroscopy. In all cases the
À
conditions from Table 1. The new C C bond is illustrated with a bold
linear/branched ratios were >98:2. [c] Contaminated with 2–4% of
olefin isomerization product. acac=acetylacetonate, phen=1,10-phen-
anthroline, TBS=tert-butyldimethylsilyl.
line. The yields are of the isolated products and E/Z ratios were
1
determined by H NMR spectroscopy. The linear/branched ratios were
generally >95:5, except for 3ha. [a] With NaOtBu and toluene instead
of LiOtBu and 1,4-dioxane, respectively. [b] With toluene instead of 1,4-
dioxane. [c] With NaOtBu instead of LiOtBu.
(3ga and 3ga’). However, 1,2,4-trifluorobenzene reacted
differently than the above tetrafluorobenzenes: 1) it had a
comparatively moderate reactivity, 2) allylation occurred
isomer (3ha’) might be caused by an alternate catalytically
active copper intermediate.[12,13]
À
exclusively at the C H bond ortho to two fluorine atoms,
and 3) a significant amount of the branched isomer was
We then turned our attention to the stereospecificity of
the reaction when using Z-allyl phosphates. Pleasingly, the
products were obtained and the stereochemical information
of the starting materials was retained (Scheme 3). This
phenomenon is significant because the Z stereospecificity is
not trivial in the arylation of allylic electrophiles, although it is
sometimes observed in the reaction using alkyl and hetero-
formed (3ha and 3ha’). The moderate reactivity and selec-
À
tivity of this reaction indicate that the efficiency of the C H
cleavage process is highly dependent upon the acidity of the
C H.[11] Indeed, fluoroarenes bearing less than three fluorine
À
atoms, such as 1,3-difluorobenzene, completely failed to
couple with allyl phosphate. The formation of the branched
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Communications
Scheme 4. A plausible reaction mechanism. [Cu]=copper with appen-
dede ligands such as phen, acac, or OP(O)(OEt)2.
subsequent nucleophilic attack (oxidative addition) on (E)- or
(Z)-2a should proceed in an SN2’ manner followed by rapid s–
p conversion to give the
p-allyl copper species syn-6 or anti-6, respectively.[12] Finally,
reductive elimination at the less congested carbon center
provides the corresponding allylated products (E)- or (Z)-
3aa. The s–p conversion would need to be much faster than
rotation between s-allyl isomers 5 and 5’ for the stereochem-
ical information of the starting allyl phosphate to be
transferred into the product.[17] Given that the formation of
a p-allyl complex is not regiospecific, the putative 4 might be a
diarylcopper species rather than a monoaryl species.[13,18]
However, further investigations are essential to clarify the
effects of the ancillary ligands including phen, acac, and
phosphates, and these are currently underway in our labo-
ratory.
À
Scheme 3. Z-Specific copper-catalyzed C H allylation of polyfluoro-
arenes with Z-allyl phosphates. [a] Contaminated with a trace amount
of the olefin isomerization product. [b] With NaOtBu. Product con-
taminated with 2% of the olefin isomerization product and 2% of the
regioisomer. [c] With LiOtBu. Product contaminated with 1% of the
branched isomer. [d] Product contaminated with 6% of the olefin
isomerization product.
In conclusion, we have demonstrated an efficient copper
À
catalyst system for the direct C H allylation of polyfluoro-
arenes with allyl phosphates in a highly stereospecific manner.
The process could provide facile access to allylarenes of a
strongly electron-deficient nature. Investigations into the
application of this method to other arenes and to elucidate the
detailed mechanism are in progress.[19]
atom nucleophiles.[14] This unique stereospecificity was gen-
eral for various polyfluoroarenes. For 1b–e, the modification
of the base or solvent system was necessary for the
suppression of undesired olefin isomerization.
Experimental Section
À
Copper-catalyzed direct C H allylation of pentafluorobenzene (1a)
with allyl phosphate 2a (Table 1, entry 1): [Cu(acac)2] (13.1 mg,
0.050 mmol), 1,10-phenanthroline (9.0 mg, 0.050 mmol), and LiOtBu
(80 mg, 1.0 mmol) were placed in a 20 mL two-necked reaction flask,
which was filled with nitrogen by using the standard Schlenk
technique. 1,4-Dioxane (2.0 mL) was then added to the flask, and
the suspension was stirred for 10 min at ambient temperature. Finally,
a solution of pentafluorobenzene (1a, 84 mg, 0.50 mmol) and allyl
phosphate 2a (175 mg, 0.60 mmol) in 1,4-dioxane (1.0 mL) was added
dropwise. The solution was stirred at ambient temperature for 4 h and
the resulting mixture was quenched with water. The mixture was
extracted with n-hexane, and the combined organic layer was dried
over sodium sulfate. Concentration of the solution in vacuo and
subsequent silica gel column chromatography with n-hexane as an
eluent gave 1-(pentafluorophenyl)-2-decene (3aa, 93 mg, 0.31 mmol,
linear/branched 98:2, E/Z 97:3) in 61% yield.
Next, to investigate the regiospecificity of the reaction,
the regioisomeric allyl phosphate 2a’ was subjected to the
standard reaction conditions [Eq. (1)]. The reaction pro-
ceeded smoothly to furnish the linear allylated product 3aa
exclusively with moderate E/Z selectivity,[15] indicating that
the p-allyl copper intermediate is involved in the catalytic
cycle.
Received: December 9, 2010
Published online: February 25, 2011
On the basis of these results and literature precedent, we
are tempted to suggest the illustrated reaction mechanism
(Scheme 4) of the direct, stereospecific allylation of 1a with
(E)- and (Z)-2a. Initial LiOtBu-assisted direct cupration of
1a gives the pentafluorophenylcopper intermediate 4.[16] The
À
Keywords: allylation · C H functionalization · copper ·
fluoroarenes · stereospecificity
.
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[18] In our preliminary investigations of a multisubstituted system,
(Z)-2i, which has no steric and electronic biases, the competitive
formation of the SN2’ product 3ai’ with high E selectivity was
observed (see the following equation). For an addition/elimi-
nation pathway in the metal-catalyzed allylic substitution, see:
2994 www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 2990 –2994