Preparation of functionalized organomanganese(II) reagents by direct insertion of manganese to aromatic and benzylic halides

Article abstract of DOI:10.1021/ol201109g

Functionalized arylmanganese compounds were prepared using commercial manganese powder in the presence of LiCl and catalytic amounts of both 2.5% InCl₃ and 2.5% PbCl₂ (THF, 0-50 °C). In addition, benzylic manganese reagents are obtained at 25 °C in ca. 70-80% yield (in the absence of LiCl) using commercial manganese powder and catalytic amounts of 2.5% InCl₃ and 2.5% PbCl₂. The resulting organomanganese reagents undergo smooth 1,2-addition, acylation, allylic substitution, Pd-catalyzed cross-coupling, and copper-catalyzed conjugate addition, affording the desired products in good yields.

Full text of DOI:10.1021/ol201109g

ORGANIC
LETTERS
2011
Vol. 13, No. 12
3198–3201
Preparation of Functionalized
Organomanganese(II) Reagents by Direct
Insertion of Manganese to Aromatic and
Benzylic Halides
Zhihua Peng and Paul Knochel*
€
Department Chemie, Ludwig-Maximilians-Universitat Munchen, Butenandtstrasse
€
5-13, Haus F, 81377 Mu€nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received April 27, 2011
ABSTRACT
Functionalized arylmanganese compounds were prepared using commercial manganese powder in the presence of LiCl and catalytic amounts of
both 2.5% InCl3 and 2.5% PbCl2 (THF, 0ꢀ50 °C). In addition, benzylic manganese reagents are obtained at 25 °C in ca. 70ꢀ80% yield (in the
absence of LiCl) using commercial manganese powder and catalytic amounts of 2.5% InCl3 and 2.5% PbCl2. The resulting organomanganese
reagents undergo smooth 1,2-addition, acylation, allylic substitution, Pd-catalyzed cross-coupling, and copper-catalyzed conjugate addition,
affording the desired products in good yields.
Functionalized organometallics are versatile reagents
for forming carbonꢀcarbon bonds reactions in organic
synthesis.1 Organomanganese reagents,2 because of their
excellent chemoselectivity, low toxicity, and good avail-
ability, havefound widespreadapplications forperforming
chemoselective 1,2-additions,3 acylations,4 cross-coupling
reactions,5 as well as copper-catalyzed conjugate
additions.6 Despite these advantages, the preparation
methods of organomanganese(II) reagents are limited.
Most organomanganese(II) reagents are prepared by
transmetalation from the corresponding organolithium
or organomagnesium reagents with manganese halides.7
Recently, a directed manganation using TMP2Mn 2LiCl
allowed the generation of the functionalized arylmanga-
nese compounds by a directed deprotonation.8 Moreover,
3
(1) (a) Knochel, P. In Handbook of Functionalized Organometallics;
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Alami, M.; Cahiez, G. J. Organomet. Chem. 2001, 624, 376. (d) Leleu, A.;
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r
10.1021/ol201109g
Published on Web 05/16/2011
2011 American Chemical Society

Table 1. Functionalized Arylmanganese(II) Halides Obtained by
Direct Insertion of Commercial Manganese Powder into Aro-
matic Halides and Subsequent Quenching with Electrophiles
Scheme 1. Preparation of (5-Cyano-2-fluorophenyl)
manganese(II) Bromide (2a) and Subsequent Reaction with
Electrophiles
organomanganese(II) reagents are difficult to generate by
an oxidative addition to organic halides using commercial
manganese powder because of the passivation exhibited by
commercial Mn. To date, commercial manganese powder
inserts only into reactive organic halides such as allylic
halides or R-halogenoesters.9,10 By using highly activated
Mn (Rieke-Mn), the insertion to aromatic and benzylic
halides can be achieved.11 Recently, we have reported that
LiCl facilitates the insertion of various metals (Zn,12 Mg,13
In14). By adding small amounts of a metallic salt like InCl3
and PbCl2 as pioneered by Takai,15 we wereabletoprepare
functionalized aromatic, benzylic, and allylic aluminum
reagents under mild conditions.16
Herein, we report a new preparation of aromatic and
benzylic manganese reagents by a direct insertion of
commercial manganese powder (99þ%, ∼325 mesh)17
into organic halides in the presence of PbCl2 (99.999%,
2.5 mol %)17 and InCl3 (anhydrous, 99.99%, 2.5 mol %).17
Thus, the reaction of 3-bromo-4-fluorobenzonitrile (1a) in
THF with manganese powder (3 equiv) in the presence
of LiCl (99%, 1.5 equiv), 2.5% InCl3, and 2.5% PbCl2 at
50 °C was complete within 24 h and led to the correspond-
ing arylmanganese reagent (2a) in 64% yield. Subsequent
Negishi cross-coupling18 with ethyl 4-iodobenzoate
(9) Hiyama, T.; Sawahata, M.; Obayashi, M. Chem. Lett. 1983, 8,
1237.
(10) (a) Cahiez, G.; Chavant, P.-Y. Tetrahedron Lett. 1989, 30, 7373.
(b) Takai, K.; Ueda, T.; Hayashi, T.; Moriwake, T. Tetrahedron Lett.
1996, 37, 7049.
(11) (a) Hiyama, T.; Obayashi, M.; Nakamura, A. Organometallics
€
1982, 1, 1249. (b) Furstner, A.; Brunner, H. Tetrahedron Lett. 1996, 37,
7009. (c) Kim, S.-H.; Hanson, M. V.; Rieke, R. D. Tetrahedron Lett.
1996, 37, 2197. (d) Kim, S.-H.; Rieke, R. D. Synth. Commun. 1998, 28,
1065. (e) Rieke, R. D.; Kim, S.-H.; Wu, X. J. Org. Chem. 1997, 62, 6921.
(f) Kakiya, H.; Nishimae, S.; Shinokubo, H.; Oshima, K. Tetrahedron
2001, 57, 8807.
(12) (a) Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel, P.
Angew. Chem., Int. Ed. 2006, 45, 6040. (b) Metzger, A.; Schade, M. A.;
Knochel, P. Org. Lett. 2008, 10, 1107.
(13) Piller, F. M.; Appukkuttan, P.; Gavryushin, A.; Helm, M.;
Knochel, P. Angew. Chem., Int. Ed. 2008, 47, 6802.
(14) (a) Chen, Y.-H.; Knochel, P. Angew. Chem., Int. Ed. 2008, 47,
7648. (b) Chen, Y.-H.; Sun, M.; Knochel, P. Angew. Chem., Int. Ed.
2009, 48, 2236.
(15) Takai, K.; Ikawa, Y. Org. Lett. 2002, 4, 1727.
a Isolated yield of analytically pure product. b 0.7 equiv of electro-
phile was used. c 0.6 equiv of electrophile was used. d Obtained after
cross-coupling18 with ethyl 3-bromobenzoate (3e) in the presence of Pd-
PEPPSI-i-Pr19 (5 mol %).
€
(16) (a) Blumke, T.; Chen, Y.-H.; Peng, Z.; Knochel, P. Nat. Chem.
€
2010, 2, 313. (b) Peng, Z.; Blumke, T. D.; Mayer, P.; Knochel., P. Angew.
Chem., Int. Ed. 2010, 49, 8516.
(17) The commercial suppliers are indicated in the Supporting
Information.
Org. Lett., Vol. 13, No. 12, 2011
3199

Table 2. Functionalized Benzylmanganese(II) Halides Obtained
by Direct Insertion of Commercial Manganese Powder into
Benzylic Halides and Subsequent Reaction with Electrophiles
Scheme 2. Preparation of (3-Chlorobenzyl)manganese(II)
Chloride (6a) and Its 1,4-Addition with Nitrostyrene (3j)
(3a, 0.6 equiv) in the presence of Pd-PEPPSI-i-Pr19
(5 mol %) afforded the biphenyl derivative 4a in 70%
yield. Additionally, a smooth allylic substitution of 2a with
ethyl (2-bromomethyl)acrylate (3b, 0.6 equiv) furnished
the acrylate 4b in 71% yield (Scheme 1). Both catalytic
amounts of InCl3 and PbCl2 and a stoichiometric amount
of LiCl are required for an efficient insertion reaction.
By using only InCl3 or only PbCl2, only a trace of the
arylmanganese species is formed. This salt combination
allows a unique activation of the Mn surface.
Similarly, 2-bromo-1-chloro-4-(trifluoromethyl)benzene
(1b) was converted to the corresponding organomanga-
nese reagent 2b (50 °C, 24 h, 72% yield). It readily under-
went a 1,2-addition to 3-formylbenzonitrile (3c), providing
thefunctionalizedalcohol4cin73%yield(entry1,Table1).
Manganese powder inserted into the functionalized
thiophene (1c) in the presence of LiCl (1.5 equiv), 2.5%
InCl3 and 2.5% PbCl2 between 0 and 25 °C within 12 h,
giving the arylmanganese reagent 2c (70% yield). It was
converted to the functionalized ketone derivative 4d (68%
yield) and the biaryl derivative 4e (77% yield), respectively,
byanacylation reactionwith4-chlorobenzoylchloride(3d,
0.6 equiv) and a Pd-catalyzed cross-coupling18 reaction
with ethyl 3-bromobenzoate (3e, 0.6 equiv) (entries 2ꢀ3).
In the same manner, various substituted aryl iodides such
as 1dꢀf, bearing substituents such as chloride or a trifluor-
omethyl group, were readily converted to the correspond-
ing arylmanganese reagents at 25 °C within 12ꢀ24 h.
Subsequent acylation and 1,2-addition afforded the
expected polyfunctionalized adducts 4fꢀh in 72ꢀ85%
yield (entries 4ꢀ6). Remarkably, manganese powder
chemoselectively inserted into ethyl 2,3,5-triiodobenzoate
(1g), yielding (2-(ethoxycarbonyl)-4,6-diiodophenyl)man-
ganese(II) iodide (2g). Its treatment with aldehyde 3c
(0.6 equiv) afforded the desired lactone 4i in 68% yield
(18) (a) Wang, J.-X.; McCubbin, J.; Jin, M.; Laufer, R.; Mao, Y.;
Crew, A.; Mulvihill, M.; Snieckus, V. Org. Lett. 2008, 10, 2923. (b) de
Meijere, A.; von Zezschwitz, P.; Braese, S. Acc. Chem. Res. 2005, 38, 413.
(c) Negishi, E.; King, A.; Okukado, N. J. Org. Chem. 1977, 42, 1821. (d)
Negishi, E. Acc. Chem. Res. 1982, 15, 340. (e) Zhao, Z.; Jaworski, A.;
Piel, I.; Snieckus, V. Org. Lett. 2008, 10, 2617. (f) Negishi, E.; Valente,
L. F.; Kobayashi, M. J. Am. Chem. Soc. 1980, 102, 3298. (g) Manoli-
kakes, G.; Schade, M.; Munoz Hernandez, C.; Mayr, H.; Knochel, P.
Org. Lett. 2008, 10, 2765. (h) Dong, Z.; Manolikakes, G.; Li, J.;
Knochel, P. Synthesis 2009, 681.
(19) (a) Brien, C. J. O.; Kantchev, E. A. B.; Hadei, N.; Chass, G. A.;
Lough, A.; Hopkinson, A. C.; Organ, M. G. Chem.;Eur. J. 2006, 12,
4743. (b) Organ, M. G.; Avola, S.; Dubovyk, I.; Hadei, N.; Kantchev,
E. A. B.; Brien, C. J. O.; Valente, C. Chem.;Eur. J. 2006, 12, 4749. (c)
Sase, S.; Jaric, M.; Metzger, A.; Malakhov, V.; Knochel, P. J. Org.
Chem. 2008, 73, 7380.
a Isolated yield of analytically pure product. b 0.7 equiv of electro-
phile was used. c Obtained after cross-coupling18 with 4-bromobenzoni-
trile (3m) in the presence of Pd(PPh3)4 (10 mol %). d Obtained after
cross-coupling18 with ethyl 4-iodobenzoate (3a) in the presence of Pd-
(PPh3)4 (10 mol %). e 0.6 equiv of electrophile was used. f Obtained after
cross-coupling18 with ethyl 4-bromobenzonitrile (3m) in the presence of
Pd-PEPPSI-iPr19 (5 mol %). g Obtained after cross-coupling18 with ethyl
4-iodobenzoate (3a) in the presence of Pd-PEPPSI-iPr19 (5 mol %).
3200
Org. Lett., Vol. 13, No. 12, 2011

(entry 7). Moreover, heterocyclic 4,5-diiodo-2,6-dimeth-
oxypyrimidine20 (1h) was converted selectively to the
organomanganese reagent (2h) which underwent acylation
and 1,2-addition, giving the functionalized benzophenone
derivative 4j and alcohol derivative 4k in 71ꢀ78% yield
(entries 8ꢀ9). This selective insertion of Mn powder was
triggered by a chelation to the neighboring functional
group.21
In the case of benzylic chlorides or bromides, a smooth
manganese insertion proceeds at 25 °C in the presence of
2.5% InCl3 and 2.5% PbCl2. These insertions proceed best
in the absence of LiCl since this salt favors extensive
homocoupling reactions. Thus, the reaction of 1-chloro-
3-(chloromethyl)benzene (5a) with Mn powder (3 equiv) in
the presence of 2.5% InCl3 and 2.5% PbCl2 afforded the
benzylic manganese reagent 6a within 14 h at 25 °C. A Cu-
catalyzed 1,4-addition reaction with nitrostyrene (3j, 0.7
equiv) provided the nitro derivative (7a) in 80% yield
(Scheme 2).
A smooth addition of the benzylic manganese reagent 6a
to the benzaldehyde 3h (0.7 equiv) generated the functiona-
lized alcohol derivative 7b in 73% yield (entry 1, Table 2).
In addition, the treatment of the benzylic manganese
reagent 6a with 4-chlorobenzoyl chloride (3d, 0.7 equiv)
produced the ketone derivative 7c in 75% yield (entry 2).
Several functionalized benzylic substrates (5bꢀf) readily
underwent a manganese insertion in the presence of 2.5%
InCl3 and 2.5% PbCl2 as catalysts, followed by quenching
with various electrophiles, affording the desired products
7dꢀk in 66ꢀ88% yield (entries 3ꢀ10). However, the
manganese insertion into benzylic chlorides bearing an
ester and a cyano group led to unsatisfactory yields. In
comparison, by using benzylic bromides, a smooth inser-
tion proceeds at 25 °C, allowing the direct preparation
of ester- or cyano-functionalized benzylmanganese bro-
mides. For instance, the reaction of butyl 3-(bromomethyl)
benzoate (5g) with Mn powder (3 equiv) in the presence of
2.5% InCl3 and 2.5% PbCl2 furnished the benzylic man-
ganese bromide 6g within 17 h at 25 °C. A Pd-catalyzed
cross-coupling18 with 4-bromobenzonitrile (3m, 0.6 equiv)
or ethyl 4-iodobenzoate (3a, 0.6 equiv) generated the
expected products 7lꢀm in 67ꢀ71% yield (entries
11ꢀ12). Similarly, 3-(bromomethyl)benzonitrile (5h) was
converted to the corresponding benzylic manganese re-
agent 6h, followed by an allylic substitution with ethyl
(2-bromomethyl)acrylate (3b, 0.6 equiv), producing the
allylated product 7n in 45% yield (entry 13).
In summary, we have developed a convenient method
for the preparation of functionalized arylmanganese ha-
lides and benzylic manganese halides by direct insertion of
commercial manganese powder into aromatic and benzylic
halides in the presence of 2.5% InCl3 and 2.5% PbCl2.
These organomanganese reagents smoothly undergo
1,2-addition, acylation, allylic substitution, Pd-catalyzed
cross-coupling, and copper-catalyzed conjugate addition
with various electrophiles affording the desired products in
good yields. Further studies of the substrate scope and on
the role of LiCl, InCl3, and PbCl2 are currently underway
in our laboratories.
Acknowledgment. The research leading to these results
has received funding from the European Research Council
under the European Community’s Seventh Framework
Programme (FP7/2007-2013) ERC grant agreement no.
227763. We also thank W. C. Heraeus (Hanau), Chemetall
(Frankfurt), and BASF AG (Ludwigshafen) for the gener-
ous gift of chemicals.
Supporting Information Available. Experimental pro-
cedures and characterization data of all compounds are
provided. This material is available free of charge via the
Internet at http://pubs.acs.org.
(20) Soorukram, D.; Boudet, N.; Malakhov, V.; Knochel, P. Synth-
esis 2007, 3915.
(21) For ortho-directed metalation, see: (a) Boudet, N.; Sase, S.;
Sinha, P.; Liu, C.-Y.; Krasovskiy, A.; Knochel, P. J. Am. Chem. Soc.
2007, 129, 12358. (b) See also ref 20.
Org. Lett., Vol. 13, No. 12, 2011
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