TMP-zincate as highly chemoselective base for directed ortho metalation [6]

Full text of DOI:10.1021/ja984263t

J. Am. Chem. Soc. 1999, 121, 3539-3540
3539
Lithium tetramethylpiperidine has been used for directed ortho
lithiation of arylcarboxylic esters; however, unwanted condensa-
tion reactions between the aryllithium and electrophilic directing
groups have been known to occur during the metalation.6 In situ
trapping of the aryllithium by electrophiles during the deproto-
nation of the arylcarboxylic esters has been reported; however,
the bulkiness of the ester group is essential for the successful
deprotonation-in situ trapping.7
TMP-Zincate as Highly Chemoselective Base for
Directed Ortho Metalation
Yoshinori Kondo,* Manabu Shilai, Masanobu Uchiyama, and
Takao Sakamoto
Graduate School of Pharmaceutical Sciences
Tohoku UniVersity
Aobayama, Aoba-ku, Sendai 980-8578, Japan
ReceiVed December 11, 1998
Since the pioneering work by Gilman and Wittig,1 the directed
ortho metalation reaction has been widely used as a powerful
and efficient method for regioselective functionalization of
aromatic compounds.2 Various directing groups have been
employed for facilitating the deprotonation of arenes, and various
strong bases such as alkyllithiums or lithium dialkylamides have
been employed. The ester group has been regarded as an important
and attractive directing group; however, use has been limited
because the deprotonation requires strictly controlled reaction
conditions due to the instability of intermediary aryllithium species
with the ester functionality. To develop a new chemoselective
deprotonation of functionalized arenes, we investigated the
chemoselective formation of arylzincates using newly developed
lithium di-tert-butyltetramethylpiperidinozincate (TMP-zincate)
as a base. The ortho metalation of alkyl benzoates and direct
R-metalation of π-deficient aza-aromatics proceeded smoothly at
room temperature to give the corresponding arylzincates and
heteroarylzincates which reacted with electrophiles.
Figure 1.
To develop a new chemoselective metalating reagent, we
investigated the novel deprotonative zincation of functionalized
aromatics and heteroaromatics using TMP-zincate. TMP-zincate
3 was prepared by adding di-tert-butylzinc 2 to the solution of
lithium tetramethylpiperidine 1 in THF at -78 °C, and the
complex solution was allowed to warm to room temperature
(Figure 1). From our preliminary 13C NMR study, the complex 3
showed different signals in the spectra from that of lithium
tetramethylpiperidide 1 or di-tert-butylzinc 2 (2tBuLi + ZnCl2),
suggesting the formation of the new ate complex.8 No decomposi-
tion was observed judging from the spectra after several hours at
room temperature.
Scheme 1
Among various organometallics, organozinc reagents have been
widely used as soft nucleophilic reagents in organic synthesis,
and organozinc reagents with functional groups were successfully
prepared by oxidative addition of organic halides to zinc metal
activated by various methods.3 We recently reported that lithium
trialkylzincates4 can be used as chemoselective metalating reagents
for the halogen-metal exchange reaction of aryl halides with
electrophilic functional groups.5 The arylzincates with ester groups
are considered to be more stable than ester-containing aryllithiums,
and self-condensation of the arylmetal species can be minimized.
Especially, lithium tri-tert-butylzincate was found to be the
practically useful metalating agent because the tert-butyl group
in the triorganozincates was found to be behind any other organic
groups in the migratory preference.5b
The ortho metalation of arenes with directed metalating groups
was examined using this complex solution. First, the reaction of
various alkyl benzoates with TMP-zincate 3 was investigated,
the metalation was found to proceed smoothly at room temper-
ature, and the arylzincates thus prepared were treated with I2 to
give iodobenzoates 6a-d in excellent yields respectively (Table
1, entry 1-4). Stepwise treatment of alkyl benzoates with lithium
tetramethylpiperidide 1 followed by the addition of di-tert-
butylzinc 2 was examined to be ineffective for the formation of
the arylzincates, and the precomplexation of the reactants 1 and
2 is essential for the successful metalation. N,N-Diisopropyl
benzamide 4e was also metalated, and the subsequent treatment
with I2 gave the iodide 6e (Table 1, entry 5). The cyano group
also worked well as an excellent directing group, and the
metalation proceeded smoothly. The arylzincate was trapped with
I2 or benzaldehyde to give iodide 6f or alcohol 6g in excellent
yield respectively (Table 1, entry 6,7).
(1) (a) Gilman, H.; Bebb, R. L. J. Am. Chem. Soc. 1939, 61, 109-112. (b)
Wittig, G.; Fuhrman, G. Chem. Ber. 1940, 73, 1197-1218. (c) Gilman, H.;
Morton, J. W., Jr. Org. React. 1954, 8, 258-304.
(2) (a) Snieckus, V. Chem. ReV. 1990, 90, 879-933. (b) Gschwend, H.
W.; Rodriguez, H. R. Heteroatom Facilitated Lithiations. Org. React. (N.Y.)
1979, 26, 1-360.
(3) (a) Knochel, P.; Singer, R. D. Chem. ReV. 1993, 93, 2117-2188. (b)
Erdik, E. Tetrahedron 1987, 43, 2203-2212. (c) Erdik, E. Tetrahedron 1992,
48, 9577-9648. (d) Knochel, P. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 1, pp 211-
229.
(4) For pioneering works using trialkylzincates in organic synthesis, see:
(a) Isobe, M.; Kondo, S.; Nagasawa, N.; Goto, T. Chem. Lett. 1977, 679-
682. (b) Tuckmantel, W.; Oshima, K.; Nozaki, H.Chem. Ber. 1986, 119, 1581-
1593. (c) Jansen, J. F. G. A.; Feringa, B. L. Tetrahedron Lett. 1988, 29, 3593-
3596; (d) Kjonaas, R. A.; Hoffer, R. K. J. Org. Chem. 1988, 53, 4133-4135.
(e) Harada, T.; Katsuhira, K.; Hattori, K.; Oku, A. J. Org. Chem. 1993, 58,
2958-2965. (f) Harada, T.; Katsuhira, K.; Hara, D.; Kotani, Y.; Maejima,
K.; Kaji, R.; Oku, A. J. Org. Chem. 1993, 58, 4897-4907.
(5) (a) Kondo, Y.; Takazawa, N.; Yamazaki, C.; Sakamoto,T. J. Org. Chem.
1994, 59, 4717-4718. (b) Kondo, Y.; Fujinami, M.; Uchiyama, M.; Sakamoto,
T. J. Chem. Soc., Perkin Trans. 1 1997, 799-800. (c) Uchiyama, M.; Koike,
M.; Kameda, M.; Kondo, Y.; Sakamoto, T. J. Am. Chem. Soc. 1996, 118,
8733-8734. (d) Uchiyama, M.; Kameda, M.; Mishima, O.; Yokoyama, N.;
Koike, M.; Kondo, Y.; Sakamoto, T. J. Am. Chem. Soc. 1998, 120, 4934-
4946. (e) Kondo, Y.; Komine, T.; Fujinami, M.; Uchiyama, M.; Sakamoto,
T. J. Comb. Chem. 1999, 1, 123-126.
The arylzincate derived from ethyl benzoate 4b and TMP-
zincate was reacted with iodobenzene and 3-iodopyridine in the
presence of Pd(PPh3)4 at room temperature for 24 h to give
biarylcarboxylates 7a,b respectively (Scheme 2).
(6) Upton, C. J.; Beak, P. J. Org. Chem. 1975, 40, 1094-1098. Relating
to the metalation of alkyl benzoates, the chemoselective magnesiation reaction
using magnesium amides has been known. See: (a) Eaton, P. E.; Lee, C.-H.;
Xiong, Y. J. Am. Chem. Soc. 1989, 111, 8016-8018. (b) Kondo, Y.; Yoshida,
A.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 1996, 2331-2332.
(7) (a) Krizan, T. D.; Martin, J. C. J. Am. Chem. Soc. 1983, 105, 6155-
6157. (b) Caron, S.; Hawkins, J. M. J. Org. Chem. 1998, 63, 2054-2055.
(8) 13C NMR spectrum of TMP-zincate 3 in THF showed the signal of
â-C (tBu) at 36.209 ppm, while the signal of tBu2Zn appeared at 31.908 ppm
(lit. δ â-C for tBu2Zn 31.03 ppm: Muller, H.; Rosch, L.; Erb, W. J. Organomet.
Chem. 1977, 140, C17-C20.). No shift of the signal was observed by changing
the ratio of the reactants.
10.1021/ja984263t CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/25/1999

3540 J. Am. Chem. Soc., Vol. 121, No. 14, 1999
Communications to the Editor
Table 1. Hydrogen-Zinc Exchange Reaction with TMP-ZntBu2Li
entry
substrate
DMG
TMP-ZntBu2Li (equiv)
electrophile
E
product
yield (%)
1
2
3
4
5
6
7
4a
4b
4c
4d
4e
4f
COOMe
COOEt
COOiPr
COOtBu
CONiPr2
CN
2.0
2.0
2.0
2.0
2.0
1.0
1.0
I2
I2
I2
I2
I2
I2
I
I
I
I
I
I
6a
6b
6c
6d
6e
6f
73
94
98
99
95
92
96
4f
CN
PhCHO
CH(OH)Ph
6g
Scheme 2
I2 to give 2-iodopyridine 11 in 76% yield. Interestingly, quinoline
was metalated preferentially at the 8-position, and the treatment
with I2 gave 8-iodoquinoline 13 in 61% yield together with
R-metalated 2-iodoquinoline 12 in 26% yield.12 Isoquinoline was
also easily metalated at the 1-position, and 1-iodoisoquinoline
14 was obtained in 93% yield (Figure 3). To the best of our
knowledge, no successful example for the direct R-lithiation of
isoquinoline has been reported due to the formation of the
isoquinoline dimer.10a
Intrigued by the high chemoselectivity of TMP-zincate 3, we
turned our focus to the metalation of various heteroaromatic
compounds at diverse positions. Ethyl 3-thiophenecarboxylate was
easily metalated at the 2-position with TMP-zincate at room
temperature, followed by treatment with I2 to give 2-iodo
derivative 8 in 89% yield, and the similar reaction using ethyl
2-thiophenecarboxylate gave 5-iodo derivative 9 in 62% yield.
Ethyl 2-furancarboxylate showed different regioselectivity from
that of ethyl 2-thiophenecarboxylate, and 3-iodo derivative 10
was obtained in 71% yield (Figure 2).
Figure 3.
An in situ FT-IR study was performed by using 4e as the
substrate for monitoring the metalation. The zincation of 4e using
TMP-zincate 3 and the lithiation of 4e using mesityllithium were
monitored, and in both cases the absorption due to the carbonyl
group gradually decreased and the newly generated red-shifted
absorption increased during the course of the metalation.13 The
two metalations showed the different red-shifted values in the
spectrum. 13C NMR data of the metalated benzamides suggest
the metal species formed by the deprotonation with TMP-zincate
to be the arylzincate.14 The mechanism for this ortho zincation
using TMP-zincate is considered to be more complex than that
of the conventional ortho lithiation;15 however, complex-induced
proximity effects16 should play an important role, and the
bimetallic system of TMP-zincate is considered to form an
effectively complexed transition state for efficient agostic hydro-
gen activation.
Figure 2.
R-Metalation of π-deficient heteroaromatic compounds has
been investigated in order to seek a more efficient, direct method
for introducing functionalities into heteroaromatic rings;9 however,
controlling the reactivity of metal species has been one of the
most important and essential issues in this approach.10 Thus, the
direct R-metalation of π-deficient heteroaromatics using TMP-
zincate 3 was considered to be a challenging subject.11 The
R-metalation of pyridine was found to proceed smoothly at room
temperature, and the resulting pyridinylzincate was treated with
In summary, the highly chemoselective deprotonative zincation
of functionalized aromatic and heteroaromatic compounds was
realized using TMP-zincate as a base. Further studies for
revealing the scope and limitation of the metalation using TMP-
zincate are underway, together with the structural study of TMP-
zincate and the mechanistic investigation of the novel metalation.
(9) (a) Comins, D. L.; O’Connor, S. AdV. Heterocycl. Chem. 1988, 44,
199-267. (b) Queguiner, G.; Marsais, F.; Snieckus, V.; Epsztajn, J. AdV.
Heterocycl. Chem. 1991, 52, 187-304. (c) Rewcastle, G. W.; Katritzky, A.
R. AdV. Heterocycl. Chem. 1993, 56, 155-302.
(10) (a) Clarke, A. J.; McNamara, S.; Meth-Cohn, O. Tetrahedron Lett.
1974, 2373-2376. (b) Verbeek, J.; Brandsma, L. J. Org. Chem. 1984, 49,
3857-3859. (c) Verbeek, J.; Brandsma, L. J. Org. Chem. 1984, 49, 3857-
3859.
Acknowledgment. This work was partly supported by Grant-in-Aid
for Scientific Research (No. 10671980) from the Ministry of Education,
Science, Sports and Culture, Japan. The authors thank Miss Mihoko
Shimada for technical assistance with spectroscopic experiments.
(11) Direct R-metalation of π-deficient aza-aromatics has been carried out
by the activation of substrates using in situ complexation. (a) Taylor, S. L.;
Lee, D. Y.; Martin, J. C. J. Org. Chem. 1983, 48, 4158-4159. (b) Kessar, S.
V.; Singh, P.; Singh, K. N.; Dutt, M. J. Chem. Soc., Chem. Commun. 1991,
570-571. (c) Kessar, S. V.; Singh, P. Chem. ReV. 1997, 97, 721-737. (d)
Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1996, 118, 1809-1810. (e) Vedejs,
E.; Monahan, S. J. Org. Chem. 1996, 61, 5192-5193.
Supporting Information Available: Representative experimental
procedure, spectral data and ATR FT-IR spectra (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
(12) For the preferential 8-position metalation, see: ref 1 (c) p 265 and ref
9 (b) p 232.
JA984263T
(13) See Supporting Information for in situ FT-IR spectrum of the
metalation of 4e using mesityllithium and TMP-zincate. 4e: ν (CdO) 1636
(15) For recent studies on the mechanism of ortho lithiation, see: (a)
Rennels, R. A.; Maliakal, A. J.; Collum, D. B. J. Am. Chem. Soc. 1998, 120,
421-422. (b) Saa, J. M.; Martorell, G.; Frontera, A. J. Org. Chem. 1996, 61,
5194-5195. (c) Saa, J. M.; Deya, P. M.; Guillem, A.; Suner, A.; Frontera, A.
J. Am. Chem. Soc. 1992, 114, 9093-9100. (d) Bauer, W.; Schleyer, P. v. R.
J. Am. Chem. Soc. 1989, 111, 7191-7198.
cm-1; Ar-Li: ν (CdO) 1578 cm-1; Ar-ZntBu2Li: ν (CdO) 1594 cm-1
.
(14) See Supporting Information for 13C NMR data of the metalated
benzamides. Deprotonative zincation of 4e using TMP-zincate 3 and the
halogen-metal exchange reaction of 2-iodo-N,N-diisopropylbenzamide using
tBu3ZnLi gave the similar 13C NMR spectra.
(16) Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356-363.