Highly functionalized benzene syntheses by directed mono or multiple magnesiations with TMPMgCl·LiCl

Article abstract of DOI:10.1021/ol0625536

The direct magnesiation of highly functionalized aromatics bearing an ester, a nitrile, or a ketone can be readily performed by using an OBoc as a directing group and TMPMgCl·LiCl as a base. It allows, for example, the preparation of a meta-magnesiated benzophenone in >95%. After quenching, highly functionalized and substituted benzenes are obtained.

Full text of DOI:10.1021/ol0625536

ORGANIC
LETTERS
2006
Vol. 8, No. 24
5673-5676
Highly Functionalized Benzene
Syntheses by Directed Mono or Multiple
Magnesiations with TMPMgCl‚LiCl
Wenwei Lin, Oliver Baron, and Paul Knochel*
Department Chemie und Biochemie, Ludwig-Maximilians-UniVersita¨t Mu¨nchen,
Butenandtstrasse 5-13, Haus F, 81377 Mu¨nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received October 17, 2006
ABSTRACT
The direct magnesiation of highly functionalized aromatics bearing an ester, a nitrile, or a ketone can be readily performed by using an OBoc
as a directing group and TMPMgCl LiCl as a base. It allows, for example, the preparation of a meta-magnesiated benzophenone in >95%. After
‚
quenching, highly functionalized and substituted benzenes are obtained.
The preparation of aryl organometallics by a directed
lithiation with use of a lithium base (such as sec-BuLi or
lithium tetramethylpiperidide (LiTMP)) has found broad
applications.1 However, the resulting aryllithiums have a high
reactivity, which precludes the presence of sensitive func-
tional groups like an ester or a ketone.2 Also, the nature of
the directing group is limited to functional groups which do
not react with strong lithium bases.3 Due to their moderate
solubility and low kinetic basicity, magnesium bases have
found fewer applications.4 However, there is a renewed
interest for these bases,5 since it has been shown that
arylmagnesium species are compatible with electrophilic
functional groups such as an ester, a nitrile, or even a ketone.6
Recently, we have developed a new class of magnesium
bases of type R2NMgCl‚LiCl that, due to the presence of
(2) Yus, M.; Foubelo, F. Handbook of Functionalized Organo-
metallics; Knochel, P., Ed.; Wiley-VCH: Weinheim, Germany, 2005; Vol.
1, p 7.
(3) (a) Clayden, J. Organolithiums: SelectiVity for Synthesis; Baldwin,
J. E., Williams, R. M., Eds.; Elsevier: London, UK, 2002. (b) Hartung, C.
G.; Snieckus, V. Modern Arene Chemistry; Astruc, D., Ed.; Wiley-VCH:
Weinheim, Germany, 2002; p 330. (c) Snieckus, V. Chem. ReV. 1990, 90,
879. (d) Clayden, J.; Stimson, C. C.; Keenan, M. Chem. Commun. 2006,
1393.
(4) (a) Bayh, O.; Awad, H.; Mongin, F.; Hoarau, C.; Bischoff, L.;
Tre´court, F.; Que´guiner, G.; Marsais, F.; Blanco, F.; Abarca, B.; Ballesteros,
R. J. Org. Chem. 2005, 70, 5190. (b) Bayh, O.; Awad, H.; Mongin, F.;
Hoarau, C.; Tre´court, F.; Que´guiner, G.; Marsais, F.; Blanco, F.; Abarca,
B.; Ballesteros, R. Tetrahedron 2005, 61, 4779. (c) Hevia, E.; Honeyman,
G. W.; Kennedy, A. R.; Mulvey, R. E.; Sherrington, D. C. Angew. Chem.,
Int. Ed. 2005, 44, 68. (d) Widhalm, M.; Mereiter, K. Bull. Chem. Soc. Jpn.
2003, 76, 1233.
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E.; Kennedy, A. R.; Mulvey, R. E.; O’Hara, C. T.; Talmard, C. Angew.
Chem., Int. Ed. 2005, 44, 3459. (b) Zhang, M.-X.; Eaton, P. E. Angew.
Chem., Int. Ed. 2002, 41, 2169. (c) Kondo, Y.; Akihiro, Y.; Sakamoto, T.
J. Chem. Soc., Perkin Trans. 1 1996, 2331. (d) Eaton, P. E.; Zhang, M.-X.;
Komiya, N.; Yang, C.-G.; Steele, I.; Gilardi, R. Synlett 2003, 9, 1275. (e)
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442.
(1) (a) Schlosser, M. Angew. Chem., Int. Ed. 2005, 44, 376. (b) Turck,
A.; Ple´, N.; Mongin, F.; Que´guiner, G. Tetrahedron 2001, 57, 4489. (c)
Mongin, F.; Que´guiner, G. Tetrahedron 2001, 57, 4059. (d) Schlosser, M.
Eur. J. Org. Chem. 2001, 21, 3975. (e) Hodgson, D. M.; Bray, C. D.;
Kindon, N. D. Org. Lett. 2005, 7, 2305. (f) Plaquevent, J.-C.; Perrard, T.;
Cahard, D. Chem. Eur. J. 2002, 8, 3300. (g) Chang, C.-C.; Ameerunisha,
M. S. Coord. Chem. ReV. 1999, 189, 199. (h) Leroux, F.; Schlosser, M.;
Zohar, E.; Marek, I. Chemistry of Organolithium Compounds; Rappoport,
Z., Marek, I., Eds.; Wiley: New York, 2004; Chapter 1, p 435. (i)
Henderson, K. W.; Kerr, W. J. Chem. Eur. J. 2001, 7, 3430. (j) Henderson,
K. W.; Kerr, W. J.; Moir, J. H. Tetrahedron 2002, 58, 4573. (k) Whisler,
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43, 2206. (l) Que´guiner, G.; Marsais, F.; Snieckus, V.; Epsztajn, J. AdV.
Heterocycl. Chem. 1991, 52, 187. (m) Veith, M.; Wieczorek, S.; Fries, K.;
Huch, V. Z. Anorg. Allg. Chem. 2000, 626, 1237. (n) Leroux, F.; Jeschke,
P.; Schlosser, M. Chem. ReV. 2005, 105, 827. (o) Kauch, M.; Hoppe, D.
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10.1021/ol0625536 CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/03/2006

Table 1. Generation of Magnesiated Polyfunctionalized Aryl Derivatives of Type 2 and Their Trapping with Electrophiles Leading to
Products of Type 3
a Reaction time for the deprotonation with TMPMgCl‚LiCl (1.1 equiv) at 0 °C. b Isolated yield of analytically pure product. c The reaction was performed
by using CuCN‚2LiCl (0.2 equiv).
LiCl, display an excellent solubility in THF (up to 1.2 M
for TMPMgCl‚LiCl) as well as an enhanced kinetic basicity
that has allowed a selective magnesiation of a broad range
of functionalized heterocycles.7 Herein, we wish to report
the use of these bases in combination with the appropriate
directing group for the preparation of highly functionalized
benzenes. Although the ortho-magnesiation of ethyl benzoate
with stoichiometric amounts of TMPMgCl‚LiCl proved to
be sluggish indicating that an ester group is only a moderately
active directing group,8 in the presence of a meta-chlorine
atom,1a a smooth magnesiation of ethyl 3-chlorobenzoate (1a)
took place at 0 °C within 6 h with TMPMgCl‚LiCl (1.2
equiv) as a base. The desired arylmagnesium species 2a was
obtained and furnished after iodolysis the expected aryl
iodide 3a in 76% yield (Table 1, entry 1). This experiment
indicates that the electron density of aromatic rings is also
of importance and that electron-poor benzenes are more
prone to magnesiation. Therefore, we have directed our
attention toward various derivatives of ethyl 3-hydroxyben-
(7) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem., Int.
Ed. 2006, 45, 2958.
(6) (a) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F.; Kopp,
F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed. 2003, 42,
4302. (b) Knochel, P.; Krasovskiy, A.; Sapountzis, I. Handbook of
Functionalized Organometallics; Knochel, P., Ed.; Wiley-VCH: Weinheim,
Germany, 2005; Vol. 1, p 109.
(8) (a) The conversion of the starting material is very slow even at 25
°C and no desired magnesiated product is observed. (b) Eaton, P. E.; Lee,
C.-H.; Xiong, Y. J. Am. Chem. Soc. 1989, 111, 8016. (c) Krizan, T. D.;
Martin, J. C. J. Am. Chem. Soc. 1983, 105, 6155. (d) Caron, S.; Hawkins,
J. M. J. Org. Chem. 1998, 63, 2054.
5674
Org. Lett., Vol. 8, No. 24, 2006

zoate such as the corresponding pivalate 1b, the N,N-
dimethylcarbamate 1c, and the Boc-derivative 1d. We have
submitted these aromatics to a magnesiation using TMPMgCl‚
LiCl (1.1 equiv) at 0 °C. The formation of the intermediate
arylmagnesium reagents 2b-d was monitored by GC
analysis of reaction aliquots. We have observed that the
pivalate 1b was only slowly metalated and led to the
formation of significant amounts of side products. After
iodine quenching, the expected aryl iodide 3b was detected
in only about 20% yield by GC analysis (Table 2, entry 1).
ketones 3e, 3h, 3l, 3n, 3q, and 3s in 82-93% yield (Table
1, entries 2, 5, 9, 11, 14, and 16). An ethyl carboxylation
could be readily realized by the reaction with EtOCOCN
(-40 to 25 °C, 0.5 h)12 leading to the di- and triester
derivatives 3f, 3i, 3m, and 3o in 78-88% yield (entries 3,
6, 10, and 12). The cyanation of the arylmagnesium species
2e with TsCN13 led to the aromatic nitrile 3j in 90% yield
(entry 7). A bromination was best performed by the reaction
with BrCl2CCCl2Br. With this method, the magnesium
derivative 2e was smoothly converted to the brominated ester
3k in 92% yield (entry 8). The reaction of Grignard reagents
2d, 2g, 2h, and 2i with benzaldehyde provided, after
spontaneous cyclization, the lactones 3g, 3p, 3r, and 3u in
77-91% yield (entries 4, 13, 15, and 18). A chlorination
could also be achieved by a reaction with PhSO2Cl.14 By
this method, the Grignard reagent 2i afforded the ester 3t in
78% yield (entry 17).
Table 2. Optimization of the Nature of the Protecting Group
for the Generation of Grignard Reagents 2b-d
We have found that products of type 3 can be magnesiated
again. Thus, the reaction of Boc-protected bromophenol 3k
with TMPMgCl‚LiCl (1.1 equiv, 0 °C, 1 h) provided the
Grignard reagent 4, which underwent a smooth benzoylation
with PhCOCl (2.0 equiv) in the presence of CuCN‚2LiCl
(0.2 equiv) affording the ketone 5 in 82% yield. Similarly,
the cyano-substituted diester 3j was converted to the corre-
sponding arylmagnesium derivative 6 with TMPMgCl‚LiCl
(1.1 equiv, 0 °C, 50 min). Its reaction with EtCOCl in the
presence of CuCN‚2LiCl provided the ketone 7 in 81% yield
(Scheme 1). The reaction of the Grignard reagent 6 with
TsCN led to the dinitrile 8 in 76% yield.
protecting
group
reaction
time (h)
product 3
entry
(yield %)a
1
2
3
tBuCO 1b
Me2NCO 1c
Boc 1d
20
3
3
3b, (20)b
3c, 50 (52)c
3d, 86
a Isolated yield of analytically pure compounds. b TMPMgCl‚LiCl (1.2
equiv) was used; there was less than 40% conversion and the desired product
was detected in ca. 20% by GC-analysis. c TMPMgCl‚LiCl (1.1 equiv) was
used; there was 52% conversion by GC analysis; the conversion did not
increase after 1 day reaction time and side products occurred by GC analysis.
Scheme 1. Boc-Directed Magnesiation of Polyfunctional
Bromoarene 3k and Benzonitrile 3j Followed by Trapping with
Electrophiles
The carbamate 1c was magnesiated much more readily, but
never led to a complete conversion. After iodolysis, the aryl
iodide 3c was obtained in 50% yield (entry 2). However, by
using the Boc-protected hydroxybenzoate 1d, a complete
magnesiation was obtained at 0 °C within 3 h and led cleanly
to the magnesium reagent 2d. After iodolysis, the aryl iodide
3d was isolated in 86% yield (entry 3). This preliminary
study indicates that a Boc-group is potentially an excellent
directing group for the magnesiation of benzenes with
TMPMgCl‚LiCl.9 Competitive studies show that the mag-
nesiation rate is also ca. 3 times faster with a Boc-directed
group as with Me2NCO.10
The excellent directing ability of the Boc-group was
confirmed by further studies summarized in Table 1 and
showed that various Boc-protected phenols can be magne-
siated leading to the polyfunctional arylmagnesium deriva-
tives 2d-i (Table 1, entries 2-18). In all cases, the
metalations were complete within a few hours at 0 °C with
TMPMgCl‚LiCl (1.1 equiv). The quenching with various
electrophiles proceeded with good yields. Thus, the benzoy-
lation of the copper derivatives of 2d-i (obtained by the
reaction with CuCN‚2LiCl)11 provided the corresponding
Interestingly, the functionalized benzophenone 3h was
readily magnesiated (-20 °C, 2 h) by using TMPMgCl‚LiCl
(1.1 equiv) leading to the keto-substituted arylmagnesium
reagent 9. This remarkable functional group compatibility
(12) Rho, T.; Abuh, Y. F. Synth. Commun. 1994, 24, 253.
(13) (a) Cox, J. M.; Ghosh, R. Tetrahedron Lett. 1969, 10, 3351. (b)
Kahne, D.; Collum, D. B. Tetrahedron Lett. 1981, 22, 5011. (c) Klement,
I.; Lennick, K.; Tucker, C. E.; Knochel, P. Tetrahedron Lett. 1993, 34,
4623. (d) Rutan, K. J.; Heldrich, F. J.; Bogers, L. F. J. Org. Chem. 1995,
60, 2948.
(9) Interestingly, a OBoc-group cannot be used to direct lithiation due
to its sensitivity toward organolithium reagents and various lithium bases.
(10) See the Supporting Information.
(11) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2390.
Org. Lett., Vol. 8, No. 24, 2006
5675

should be general and this magnesiation procedure may give
access to various arylketo-substituted arylmagnesium species.
After the Cu-catalyzed acylation of 9 with acid chlorides
followed by Boc-deprotection (TFA, 25 °C, 5 min), the
polyfunctional pentasubstituted phenols 10a,b were obtained
in 88-89% yield (Scheme 2).
Scheme 3. Successive Magnesiations of Ethyl
3-Chlorobenzoate (1a) Followed by Trapping with Electrophiles
Leading to Hexasubstituted Benzenes of Type 14
Scheme 2. Boc-Directed Magnesiation of a Polyfunctional
Benzophenone 3h Followed by Cu-Catalyzed Acylation and
Deprotection
TMPMgCl‚LiCl (1.2 equiv, -50 °C, 1.5 h) followed by the
addition of various acylating agents (EtOCOCN, PhCOCl,
TsCN, or EtCOCl) furnished the hexasubstituted benzenes
14a-d in 74-84% yield (Scheme 3).
In summary, we have shown that the magnesiation of
various Boc-substituted aromatics with TMPMgCl‚LiCl
allows the preparation of new highly functionalized aryl-
magnesium reagents of which some bear even a keto-func-
tion. The easy introduction and removal of a Boc-group make
this functionalization method of aromatics a useful comple-
ment to the well-known directed lithiation reaction.1k,r,3b,c
Further applications of this methodology in the synthesis of
polyfunctional unsaturated systems is currently underway in
our laboratories.
Finally, a multiple functionalization of ethyl 3-chloroben-
zoate (1a) can be achieved by successive magnesiations with
TMPMgCl‚LiCl and quenching with an electrophile leading
to a hexasubstituted benzene (Scheme 3). Thus, the meta-
lation of the ethyl ester 1a with TMPMgCl‚LiCl followed
by an electrophilic cyanation with TsCN provided the nitrile
11, which by a further regioselective magnesiation at the
R-position to the carboethoxy group afforded, after reaction
with EtOCOCN (1.7 equiv), the diester 12 in 60% yield.
The use of a solvent mixture THF/Et2O (1:2) was essential
for controlling the regioselectivity of the magnesiation
(>95% regioselectivity). By using only THF, a competitive
metalation at the R-position to the chlorine substituent of
11 was also observed (ca. 10% relative to 12 by GC analysis).
The treatment of 12 with TMPMgCl‚LiCl (1.2 equiv, -50
°C, 30 min) followed by a transmetalation with ZnCl2 and
Pd(0)-catalyzed acylation with EtOCOCl15 gave rise to the
triester 13 in 83% yield. The magnesiation of 13 with
Acknowledgment. We thank the Fonds der Chemischen
Industrie, the Deutsche Forschungsgemeinschaft (DFG), and
Merck Research Laboratories (MSD) for financial support.
We also thank Chemetall GmbH (Frankfurt) and BASF AG
(Ludwigshafen) for the generous gift of chemicals.
Supporting Information Available: Experimental pro-
cedures and analytical data. This material is available free
of charge via the Internet at http://pubs.acs.org.
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OL0625536
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