Direct ortho cupration: A new route to regioselectively functionalized aromatics

Article abstract of DOI:10.1021/ja074669i

We have developed a direct regio- and chemoselective method for generating functionalized aromatic cuprate compounds through deprotonative directed ortho cupration using TMP(tetramethylpiperidino)-cuprates (R(TMP)Cu(CN)Li₂; R = alkyl, phenyl, o

Full text of DOI:10.1021/ja074669i

Published on Web 11/16/2007
Direct ortho Cupration: A New Route to Regioselectively Functionalized
Aromatics
Shinya Usui,†,‡ Yuichi Hashimoto, James V. Morey, Andrew E. H. Wheatley,* and
‡
§
,§
,
†
Masanobu Uchiyama*
AdVanced Elements Chemistry Laboratory, The Institute of Physical and Chemical Research, RIKEN, 2-1 Hirosawa,
Wako-shi, Saitama 351-0198, Japan, Institute of Molecular & Cellular Biosciences, The UniVersity of Tokyo,
1
-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan, and Department of Chemistry, UniVersity of Cambridge,
Lensfield Road, Cambridge, CB2 1EW, U.K.
Received June 26, 2007; E-mail: uchiyama@mol.f.u-tokyo.ac.jp; aehw2@cam.ac.uk
The use of organocuprate compounds has opened up new avenues
in organic and organometallic chemistry.1 Recently, increasing
Table 1. Screening of Cuprates for Directed ortho Cupration
-
attention has been devoted to heteroleptic cuprates ([R-Cu-R′] ),
-
as well as the large body of homoleptic cuprates ([R-Cu-R] ).
Organoamidocuprates are an important class of heteroleptic cuprate
2
by virtue of their structural features and unique reactivities: they
have many applications in organic transformations, especially in
stereoselective syntheses3 because the amido ligand can act not
only as a dummy (nontransferable) group but also as a chiral
auxiliary. The nontransferability of amido (heteroatom) ligands on
Cu-ates in carbon-carbon bond-forming reactions has also been
,4
a
TMP ) 2,2,6,6-tetramethylpiperidino. b Isolated yield.
5
theoretically clarified by DFT calculations. We present here new
uses of amidocuprates, wherein the amido ligand transfers (reacts)
first as a base for chemoselective directed ortho cupration (DoC)
and may also function as a switch in the successive C-C bond-
formation process.
To develop new applications of amidocuprates, we focused on
6
the deprotonative metalation of functionalized benzenes. Initial
studies used benzonitrile (2a) as a model aromatic compound with
an electron-withdrawing group to identify favorable reaction
conditions and indicated that a 2,2,6,6-tetramethylpiperidino (TMP)
group as the amido moiety and THF as solvent were suitable starting
points for the optimization of DoM reaction conditions (Table 1).
Attempts to use Gilman-type amidocuprates prepared from CuI
proved unsuccessful in terms of the reactivity (yields) and (DoC)
selectivity. On the other hand, Lipshutz-type7 amidocuprates
prepared from CuCN turned out to promote the DoC reaction of
2a, without any catalyst, in good yields at 0 °C. We found that
although in the latter case at least one TMP ligand, one of the
bulkiest available amido ligands, is crucial for good yield and
chemoselectivity, the scope for the other ligand on the Cu atom is
rather wide (various alkyl, phenyl, or even another TMP can be
utilized). This is in sharp contrast to the strict structural requirements
of recently reported zincate and aluminate bases in the DoM
reactions of functionalized aromatic compounds.
The structures of the amidocuprates were examined by X-ray
and DFT studies (Figure 1). After several attempts, we obtained
X-ray-grade crystals from a toluene solution of the complex
generated from CuCN and LTMP in a ratio of 1:2. The crystal
Figure 1. (1) The crystal structure of 1f shown at 40% probability; (2) the
asymmetric unit (monomer) in (1); and (3) the B3LYP/631SVP calculated
structure of (Me2N)2Cu(CN)Li2•OMe2. Hydrogen atoms and minor THF
disorder in the crystal structure are omitted for clarity. Figures represent
distances in Å.
8
9
Representative results from the DoM reactions of various func-
tionalized aromatic compounds with a model cuprate base 1g are
summarized in Table 2. Not only methoxy groups but also a variety
of polar functional groups including cyano, amide, and halogen,
as well as heteroaromatics, such as benzothiazole, pyridine, and
indole, are tolerated in the reaction. Functionalized aromatic iodides,
2 2
structure of (TMP) Cu(CN)Li (notwithstanding THF) (1f) is that
of a prototype Lipshutz-type cuprate (not a Gilman-type dimeric
structure) having a linear -Cu- geometry, and with the CN moiety
coordinated to two lithium atoms but not directly to copper. The
bond lengths and angles noted in the solid-state structure of 1f are
in good agreement with DFT calculation of the model cuprate
10
which are good substrates for iodine-copper exchange reactions,
also worked smoothly. The regioselectivity of deprotonation is very
high; while deprotonative metalation of meta-substituted benzenes
(2b-d and 2h), para-substituted benzenes (2f and 2g), and func-
tionalized heteroaromatics (2i-k) can take place in several posi-
tions, deprotonative cuprations proved to occur with complete
regioselectivity. In the reaction of meta-functionalized bromoben-
zene (2h) with 1g, the generation of benzyne was suppressed and
(Me
2
N)
2
Cu(CN)Li
2 2
•OMe .
†
RIKEN.
The University of Tokyo.
University of Cambridge.
‡
§
8b
only cupration occurred, again regio- and chemoselectively.
15102
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J. AM. CHEM. SOC. 2007, 129, 15102-15103
10.1021/ja074669i CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Deprotonative Cupration of Functionalized Aromaticsa
coupling biphenyl product 4ePh in 91% yield. Interestingly, the
deprotonation of 2e by homoleptic amidocuprate (TMP)
Li 1f followed by oxidation with PhNO gave the homocoupling
product 5e in quantitative yield.
2
Cu(CN)-
2
2
In summary, highly chemo- and regioselective deprotonative
cupration of functionalized aromatic and heteroaromatic compounds
was realized using newly developed Lipshutz-type TMP-Cu-ate
bases. In all cases, an amido ligand on the Cu-ates reacts first to
deprotonate the aromatic ring. This contrasts with the C-C bond-
forming reactions noted in the case of organoamidocuprates. Such
a result clearly indicates that the transfer aptitude of ligands on the
Cu-ates changes according to the reaction pattern. Functionalized
phenyl cuprate intermediates react with various electrophiles as aryl
anions with no additional catalyst. Furthermore, in the oxidation
-
of the [Ar-Cu(I)-R] intermediates, three types of reaction could
a
Deprotonative cupration was carried out using MeCu(TMP)(CN)Li2
be made to occur selectively on the aromatic ring by appropriately
changing the oxidants and cuprate bases, that is, the introduction
of an OH group, cross-coupling, and homocoupling. Further studies
to establish the scope and limitations of this directed ortho cupration
(
2.0 equiv) and substrate (1.0 equiv) in THF. b Isolated yield.
Chart 1. A Survey of the Electrophilic Trapping of Functionalized
Arylcuprate 3e
(DoC) reaction are underway, together with a mechanistic and
structural investigation of this novel metalation and the successive
oxidation.
Acknowledgment. We gratefully acknowledge financial support
from Hoansha (to M.U.), KAKENHI (Yong Scientist (A), Houga,
and Priority Area Nos. 452 and 459) (to M.U.), a JSPS Research
Fellowship for Young Scientists (to S.U.), and also the UK EPSRC
(
J.V.M). The calculations were performed by using the RIKEN
RSCC facility.
Supporting Information Available: Experimental procedures and
characterizations. This material is available free of charge via the
Internet at http://pubs.acs.org.
References
Table 3. Oxidation of Functionalized Phenyl Cuprate Intermediates
(
(
(
1) (a) Posner, G. H. Org. React. 1972, 19, 1-113. (b) Modern Organocopper
Chemistry; Krause, N., Ed.; Wiley-VCH: Weinheim, Germany, 2002.
2) For a recent example, see: Davies, R. P.; Hornauer, S.; Hitchcock, P. B.
Angew. Chem., Int. Ed. 2007, 46, 5191-5194.
3) (a) Rossiter, B. E.; Swingle, N. M. Chem. ReV. 1992, 92, 771-806. (b)
Krause, N.; Gerold, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 187-204.
(c) Dieter, R. K. In Modern Organocopper Chemistry; Krause, N., Ed.;
Wiley-VCH: Weinheim, Germany, 2002; pp 79-144.
4) For a recent example, see: Bertz, S. H.; Ogle, C. A.; Rastogi, A. J. Am.
Chem. Soc. 2005, 127, 1372-1373.
(
(
5) Yamanaka, M.; Nakamura, E. J. Am. Chem. Soc. 2005, 127, 4697-4706.
6) Review: Mulvey, R. E.; Mongin, F.; Uchiyama, M.; Kondo, Y. Angew.
Chem., Int. Ed. 2007, 46, 3802-3824.
(
(
7) (a) Lipshutz, B. H.; Wilhelm, R. S.; Floyd, D. M. J. Am. Chem. Soc.
1
981, 103, 7672-7674. (b) Lipshutz, B. H.; Wilhelm, R. S.; Kozlowski,
Having established a general preparative method for function-
alized aromatic copper compounds, we next demonstrated that the
J. A. Tetrahedron 1984, 40, 5005-5038. (c) Lipshutz, B. H.; Kozlowski,
J. A.; Wilhelm, R. S. J. Org. Chem. 1984, 49, 3943-3949. (d) Lipshutz,
B. H. Synthesis 1987, 325-341. (e) Lipshutz, B. H.; Sharma, S.; Ellsworth,
E. L. J. Am. Chem. Soc. 1990, 112, 4032-4034.
(
typical) functionalized arylcopper intermediate 3e can be utilized
as an aryl anion equivalent (Chart 1). Intermediate 3e, generated
from 2e using 1g, was treated with D O to give the corresponding
(
8) (a) Kondo, Y.; Shiai, M.; Uchiyama, M.; Sakamoto, T. J. Am. Chem.
Soc. 1999, 121, 3539-3540. (b) Uchiyama, M.; Miyoshi, T.; Kajihara,
Y.; Sakamoto, T.; Otani, Y.; Ohwada, T.; Kondo, Y. J. Am. Chem. Soc.
2
2002, 124, 8514-8515. (c) Uchiyama, M.; Matsumoto, Y.; Nobuto, D.;
ortho-deuterated product in a quantitative yield. Intermediate 3e
also undergoes C-C and C-Si bond-forming reactions, such as
methylation, allylation, benzoylation, and trimethylsilylation, in high
yields and with high chemo- and regioselectivities, without the
requirement for any cocatalyst. This contrasts with the documented
need for a copper or palladium catalyst to achieve comparable
Furuyama, T.; Yamaguchi, K.; Morokuma, K. J. Am. Chem. Soc. 2006,
128, 8748-8750. (d) Uchiyama, M.; Matsumoto, Y.; Usui, S.; Hashimoto,
Y.; Morokuma, K. Angew. Chem., Int. Ed. 2007, 46, 926-929. (e)
Uchiyama, M.; Kobayashi, Y.; Furuyama, T.; Nakamura, S.; Kajihara,
Y.; Miyoshi, T.; Sakamoto, T.; Kondo, Y.; Morokuma, K. J. Am. Chem.
Soc. 2007, 129, in press.
(
9) (a) Uchiyama, M.; Naka, H.; Matsumoto, Y.; Ohwada, T. J. Am. Chem.
Soc. 2004, 126, 10526-10527. (b) Naka, H.; Uchiyama, M.; Matsumoto,
Y.; Wheatley, A. E. H.; McPartlin, M.; Morey, J. V.; Kondo, Y. J. Am.
Chem. Soc. 2007, 129, 1921-1930.
8
9
chemistry using arylzinc or arylaluminum intermediates.
Finally, we examined the oxidation of intermediary aryl-Cu(I)-
(
10) (a) Kondo, Y.; Matsudaira, T.; Sato, J.; Murata, N.; Sakamoto, T. Angew.
Chem., Int. Ed. Engl. 1996, 35, 736-738. (b) Piazza, C.; Knochel, P.
Angew. Chem., Int. Ed. 2002, 41, 3263-3265.
11
ates with various oxidants (Table 3). When intermediate 3e was
exposed to molecular oxygen in the presence of 1.0 equiv of CuCN,
the corresponding phenol was obtained in 56% yield, realizing the
regioselective introduction of an OH group.12 On the other hand,
(
11) For an excellent review on the oxidation of organocuprates, see: Surry,
D. S.; Spring, D. R. Chem. Soc. ReV. 2006, 35, 218-225.
(12) For recent advances in meta-substituted phenol synthesis, see:
(a)
Maleczka, R. E., Jr.; Shi, F.; Holmes, D.; Smith, M. R., III. J. Am. Chem.
Soc. 2003, 125, 7792-7793. (b) Ishiyama, T.; Takagi, J.; Ishida, K.;
Miyaura, N.; Anastasi, N. R.; Hartwig, J. F. J. Am. Chem. Soc. 2002,
when PhNO
reaction of 3e proceeded smoothly and selectively to give ortho-
methylated product 4eMe. The use of PhCu(TMP)(CN)Li 1j instead
of 1g for the deprotonative cupration of 2e gave the desired cross-
2 2
was used in place of O , the oxidative ligand coupling
1
24, 390-391. However, the introduction of an OH group at the ortho
2
position with respect to various functional groups is still challenging.
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