C O M M U N I C A T I O N S
the initial electrostatic complex of 1c and iBu3Al(TMP)Li gradually
decreased, and the newly generated blue-shifted absorption (1600
cm-1) increased during the course of the metalation.13 The
mechanism of this ortho-alumination is considered to be more
complex than that of the conventional ortho-lithiation,14 complex-
induced proximity effects should play an important role,15 and the
(hetero)bimetallic system of iBu3Al(TMP)Li is considered to form
an effectively complexed transition state for efficient agostic
hydrogen activation.
Chart 1. Various Kinds of Electrophilic Trapping of the
Functionalized Phenyl Aluminate Intermediate (2c)
In summary, highly chemo- and regioselective deprotonative
alumination of functionalized aromatic and heteroaromatic com-
pounds was realized using iBu3Al(TMP)Li as a base. Further studies
to establish the scope and limitations of this alumination reaction
are under way, together with a structural study of iBu3Al(TMP)Li
and a mechanistic investigation of this novel metalation.
Acknowledgment. This research was partly supported by
Grants-in-Aid for Young Scientists (A) and for Scientific Research
on Priority Areas (A) from JSPS (to M. U.).
alumination with iBu3Al(TMP)Li, followed by electrophilic trapping
(with I2), proved to be a powerful tool for the preparation of 1,2,3-
trisubstituted aromatic compounds. π-Deficient and π-rich hetero-
cycles can be good substrates for this reaction, where the directed
alumination proceeded smoothly.
Note Added after ASAP Posting. Due to a production error,
Scheme 2 was incorrect as published on the Web July 29, 2004.
The corrected version was posted on August 3, 2004.
Supporting Information Available: Experimental procedures and
characterizations. This material is available free of charge via the
We next demonstrated, as shown in Chart 1, that the function-
alized arylaluminate intermediate 2c (as a typical intermediate) can
be utilized as an aryl anion equivalent. The intermediate 2c,
References
i
generated by the deprotonative alumination of 1c using Bu3Al-
(1) (a) Mole, T.; Jeffrey, E. A. Organoaluminum Compounds; Elsevier:
Amsterdam, 1972. (b) Hashimoto, S.; Kitagawa, Y.; Iemura, S.; Yama-
moto, H.; Nozaki, H. Tetrahedron Lett. 1976, 30, 2615-2616. (c) Negishi,
E. J. Organomet. Chem. Libr. 1976, 1, 93-125.
(TMP)Li, was treated with D2O to give the corresponding ortho-
deuterated product in a quantitative yield. The intermediate 2c also
undergoes copper- and palladium-catalyzed C-C bond-forming
reactions such as allylation, phenylation, and benzoylation in high
yields and with high chemo- and regioselectivities.
A preliminary result aimed at the regioselective introduction of
an OH moiety is also shown in Chart 1. When the intermediate 2c
was exposed to molecular oxygen in the presence of 0.5 equiv of
ZnCl2, the corresponding phenol was obtained in 56% yield. Since
regio- and chemoselective direct introduction of a hydroxyl group
on an aromatic ring is generally difficult,3 the present procedure
would provide a new, convenient one-pot synthesis of functionalized
phenols.11
Recently, we reported that chemo- and regioselective zincation
of meta-functionalized haloaromatics and generation of 3-substituted
benzynes could be controlled by utilizing the drastic ligand effects
in zincates.12 In this case, with the aluminum ate base, generation
of benzynes could be controlled by changing the reaction temper-
ature. The intermediate 2m generated by the deprotonative alumi-
nation of N,N-diisopropyl-3-bromo-2-iodobenzamide (1m) could
be trapped with an electrophile (I2) at low temperature (below 0
°C), whereas the generation of 3-functionalized benzyne proceeded
smoothly at room temperature, and the resulting benzyne reacted
with 1,3-diphenylisobenzofuran to give the corresponding Diels-
Alder adduct in a quantitative yield (Scheme 2).
(2) (a) Chen, E. Y.-X.; Cooney, M. J. J. Am. Chem. Soc. 2003, 125, 7150-
7151. (b) Ishikawa, T.; Ogawa, A.; Hirao, T. J. Am. Chem. Soc. 1998,
120, 5124-5125.
(3) Review: Eisch, J. J. In ComprehensiVe Organometallic Chemistry;
Wilkinson, G.; Stone, F. G. A.; Abel, E. W., Eds.; Pergamon Press:
Oxford, 1982; Vol. 6, Chapter 6 and references therein.
(4) Upton, C. J.; Beak, P. J. Org. Chem. 1975, 40, 1094-1098.
(5) Review: Eisch, J. J. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Ed.; Pergamon Press: Oxford, 1991; Vol. 8, Chapter 3.
(6) Excellent reviews on directed ortho metalation, see; (a) Snieckus, V. Chem.
ReV. 1990, 90, 879-933. (b) Gschwend, H. W.; Rodriguez, H. R.
Heteroatom Facilitated Lithiations; Dauben, W. G., Ed.; Organic Reac-
tions, Vol. 26; Wiley: New York, 1979; pp 1-360.
(7) Pioneering work on deprotonation of aliphatic acidic protons using
tricoordinated amide aluminum reagents, such as Et2Al(TMP), see:
Maruoka, K.; Oishi, M.; Yamamoto, H. J. Org. Chem. 1993, 58, 7638-
7639; however, these reagents were not effective for our purpose.
(8) From our preliminary 1H, 13C, 7Li, 15N, and 27Al NMR study, the complex
iBu3Al(TMP)Li showed different signals in the spectra from those of
LTMP or iBu3Al, suggesting the formation of the new ate complex
(Supporting Information). No decomposition was observed, judging from
the spectra after several weeks at 4 °C in THF, whereas LTMP itself is
known to react easily with THF to afford the lithium enolate of
acetaldehyde and ethylene gas. Bates, R. B.; Kroposki, L. M.; Potter, D.
E. J. Org. Chem. 1972, 37, 560-562. Such high stability should be also
i
a characteristic feature of the aluminum ate base, Bu3Al(TMP)Li.
(9) Kondo, Y.; Shilai, M.; Uchiyama, M.; Sakamoto, T. J. Am. Chem. Soc.
1999, 121, 3539-3540.
(10) (a) Gallagher, D. J.; Beak, P. J. Am. Chem. Soc. 1991, 113, 7984-7987.
(b) Beak, P.; Musick, T. J.; Chen, C. W.; J. Am. Chem. Soc. 1988, 110,
3538-3542.
(11) For recent advances in phenol synthesis via C-H activation/borylation-
oxidation process, 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, 124, 390-391. However, the ortho-selective direct
introduction of an oxygen atom has not been realized.
Finally, an in situ FT-IR study was performed by using 1c as
the substrate for monitoring this metalation (Supporting Informa-
tion). The absorption (1585 cm-1) due to the carbonyl group of
(12) Uchiyama, M.; Miyoshi, T.; Kajihara, Y.; Sakamoto, T.; Otani, Y.;
Ohwada, T.; Kondo, Y. J. Am. Chem. Soc. 2002, 124, 8514-8515.
(13) The ATR-IR spectrum of 1c itself in THF showed the C-O stretching
vibration band at 1636 cm-1 under the same measurement conditions.
(14) For recent studies on the mechanism of ortho-lithiation, see: (a) Zhao,
P.; Collum, D. B. J. Am. Chem. Soc. 2003, 125, 4008-4009. (b) Zhao,
P.; Collum, D. B. J. Am. Chem. Soc. 2003, 125, 14411-14424.
(15) (a) Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356-363. (b) Bauer,
W.; Schleyer, P. v. R. J. Am. Chem. Soc. 1989, 111, 7191-7198. (c)
Anderson, D. R.; Faibish, N. C.; Beak, P. J. Am. Chem. Soc. 1999, 121,
7553-7558.
Scheme 2. Generation and Suppression of 3-Functionalized
Benzyne
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