Silver-catalyzed, manganese-mediated allylation and benzylation reactions of aldehydes and ketones

Article abstract of DOI:10.1002/ejoc.200800898

Silver bromide catalyzes Barbier-type allylation of aldehydes and ketones using unactivated manganese powder. Aliphatic and aromatic aldehydes and ketones react, and aryl chlorides, nitriles, electron-donating and electron-withdrawing groups are tolerated. Benzylation using benzyl bromide also proceeds smoothly under these reaction conditions. Preliminary mechanistic studies are consistent with the formation a nucleophilic allylmetal intermediate. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800898

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200800898
Silver-Catalyzed, Manganese-Mediated Allylation and Benzylation Reactions
of Aldehydes and Ketones
Nicholas T. Barczak[a] and Elizabeth R. Jarvo*[a]
Keywords: Allylation reaction / Barbier reaction / Silver / Manganese / Radical trap
Silver bromide catalyzes Barbier-type allylation of aldehydes
and ketones using unactivated manganese powder. Aliphatic
and aromatic aldehydes and ketones react, and aryl chlo-
rides, nitriles, electron-donating and electron-withdrawing
groups are tolerated. Benzylation using benzyl bromide also
proceeds smoothly under these reaction conditions. Prelimi-
nary mechanistic studies are consistent with the formation a
nucleophilic allylmetal intermediate.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
using activated sources of Mn0 such as Rieke Mn.[8–10] As
an alternative to using activated Mn0, Cahiez and Chavant
demonstrated that standard Mn0 powder is sufficiently re-
active to mediate allylation of aldehydes and ketones with
allylic halides in the presence of a catalytic quantity of
ZnCl2 at 50 °C.[11,12] The catalyst is proposed to facilitate
formation of a nucleophilic allylmanganese complex.[6] For-
mation of heterobimetallic complexes, similar to those pro-
posed as intermediates in Mn- and Cu-catalyzed reactions
of Grignard reagents, is also a mechanistic possibility.[13]
Introduction
Mild, functional group tolerant methods for the reaction
of an allylic anion equivalent with an aldehyde are required,
particularly for use in the late stages of natural product syn-
theses.[1] Reactions that proceed through organomanga-
nese(II) complexes[2] are attractive because these com-
pounds typically display broad functional-group tolerance
and manganese-containing byproducts are generally consid-
ered to be non-toxic.[3] Barbier-type reactions[4] that gener-
ate allylmanganese complexes in situ from allylic halides are
particularly practical because Mn0 powder is inexpensive,[5]
and allylic halides are common synthetic intermediates. In
this Communication, we report that allyl bromide and ben-
zyl bromide react with aldehydes and ketones in a silver-
catalyzed, manganese-mediated reaction [Equation (1)].
The reaction exhibits good functional group tolerance.
Mechanistic experiments are consistent with formation of a
nucleophilic organometallic reagent in situ.
Results and Discussion
As part of our studies in the development of new meth-
ods for allylation and alkylation reactions, we sought to de-
velop a reaction that avoids the cost of indium and the
functional group incompatibilities associated with pre-
formed Grignard reagents, highly reactive Rieke Mn, and
chlorosilanes. We hypothesized that silver salts could cata-
lyze the Mn-mediated allylation reaction.[14–16] In the pres-
ence of catalytic quantities of AgBr and stoichiometric
quantities of standard Mn0 powder, allylation of p-anisal-
dehyde with allyl bromide proceeds smoothly at room tem-
perature (Table 1). Most silver salts are effective catalysts,
although ligation by an N-heterocyclic carbene is detrimen-
tal to catalyst activity (Entry 9).[17,18] We chose inexpensive
AgBr as the catalyst for all subsequent studies. Lowering
the number of equivalents of allyl bromide decreases the
yield (Entry 10). We postulate that the low yield results
from consumption of allyl bromide by adventitious Wurtz
coupling,[19] and found that slow addition of allyl bromide
improves the yield of homoallylic alcohol 2a (Entries 11–
13). Under the optimized reaction conditions, 96% yield of
homoallylic alcohol can be obtained with 1.1 equiv. of allyl
bromide and 2 equiv. of Mn0.
(1)
Preparation of organomanganese complexes can be ac-
complished using several methods, often by transmetalla-
tion of a Grignard reagent and MnX2.[6,7] Synthesis directly
from the allylic bromide is most commonly accomplished
[a] Department of Chemistry, University of California, Irvine,
Natural Sciences 1, 4114, Irvine, CA 92697, USA
Fax: +1-949-824-9920
E-mail: erjarvo@uci.edu
URL: http://chem.ps.uci.edu/~erjarvo
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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N. T. Barczak, E. R. Jarvo
SHORT COMMUNICATION
Table 1. Optimization of silver-catalyzed, manganese-mediated re-
Table 2. Aldehyde scope.[a]
action of allyl bromide with p-methoxybenzaldehyde.
[a] Isolated yield of homoallylic alcohol 2 after chromatography.
[b] Slow addition of allyl bromide, as a 1.2  solution in THF, over
20 h.
[a] See Supporting Information for full experimental details. [b] Al-
lyl bromide was added as a 1.2  solution in THF over 20 h using
a syringe pump. [c] Isolated yield of homoallylic alcohol after
chromatography, reported as an average of two runs.
The allylation reaction has good scope with respect to
the aldehyde, and aromatic aldehydes react to afford the
highest yield of products (Table 2). Nitriles and halides are
tolerated, although 20 mol-% AgBr and 1.5 equiv. of allyl
bromide are required for good yields (Entries 4 and 5).[20]
Regioselective 1,2-addition to cinnamaldehyde affords
homoallylic alcohol 2g (Entry 6). Aliphatic aldehydes react
smoothly, particularly when α-branching slows competitive
pinacol coupling.[12,21] For example, cyclohexane carboxal-
dehyde reacts to afford 78% yield of homoallylic alcohol 2h
under the standard reaction conditions (Entry 7).
Scheme 1. Allylation of ketones.
Both aromatic and aliphatic ketones undergo silver-cata-
lyzed, manganese-mediated allylation reactions to afford
tertiary alcohols (Scheme 1). Reactions of aromatic ketones
are higher-yielding than those of aliphatic ketones. For ex-
ample, acetophenone reacts smoothly under our reaction
conditions to afford 74% yield of the requisite tertiary
alcohol.
We hypothesized that alkyl halides that provide stable
radical intermediates would be activated under our reaction
conditions.[16a,16b,22] This hypothesis was validated: benzyl
bromide may be used as an alkylating agent with both alde-
hydes and ketones (Scheme 2). Benzaldehyde and aceto-
phenone react to afford alcohols 3 and 4 in 73 and 58%
yield, respectively. These results contrast those observed in
other metal-catalyzed, manganese-mediated reactions,
Scheme 2. Benzylation reactions.
which have not been reported with benzylic halides.[9d,11,12] radical to o-vinylbenzaldehyde would generate an oxygen-
We undertook experiments to distinguish between centered radical, which would be expected to undergo a fac-
mechanisms wherein the active nucleophile is an allylic radi- ile 5-exo-trig cyclization. Upon treatment with the standard
cal or an allylmetal species. Two substrates that probe for a reaction conditions, however, o-vinylbenzaldehyde affords
radical addition are shown in Scheme 3. Addition of allyl the simple allylated product 5. In a similar experiment, we
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Allylation and Benzylation Reactions of Aldehydes and Ketones
(4 mL) over 10 min. Once the bubbling had subsided, the clear bi-
phasic mixture was poured into a separatory funnel, using ad-
ditional Et2O (60 mL). The aqueous phase was separated and the
organic phase was washed with 1  HCl (1ϫ25 mL) and brine
(1ϫ25 mL). The organic phase was dried with MgSO4, filtered,
and concentrated in vacuo to provide a yellow oil. Purification by
silica gel flash column chromatography, eluting with 10% EtOAc/
hexane, afforded homoallylic alcohol 2a (348 mg, 97% yield) as a
yellow oil.
observed that allylation of 6 afforded 7 with no cycliza-
tion.[23] An alternative mechanism would be single electron
transfer to form a ketyl radical, which could recombine
with an allyl radical.[24] Upon formation of a ketyl radical,
8 should undergo a facile 5-exo-trig cyclization reaction.[25]
Allylation of 8, however, proceeds smoothly to afford an
83% yield of homoallylic alcohol 9. Therefore, at this pre-
liminary stage, we propose that an organometallic interme-
diate, such as allylmanganese bromide, attacks the electro-
phile.[26]
Supporting Information (see also the footnote on the first page of
this article): Experimental procedures and analytical data for reac-
tion products.
Acknowledgments
Support has been provided by American Chemical Society Petro-
leum Research Fund (46043-G1G). New Faculty Awards from the
Amgen and Eli Lilly Foundation are gratefully acknowledged.
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S. E. Denmark, J. P. Fu, Chem. Rev. 2003, 103, 2763–2793.
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[3] a) G. Friour, G. Cahiez, J. F. Normant, Synthesis 1984, 37–40;
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[5] Manganese powder (325 mesh, Ͼ99%) may be purchased from
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tively.
[6] G. Cahiez, F. Mahuteau-Betzer, in Handbook of Functionalized,
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Scheme 3. Mechanistic experiments.
Conclusions
We report a new silver-catalyzed, manganese-mediated
allylation reaction that provides good yields of homoallylic
alcohols derived from aromatic and aliphatic aldehydes and
ketones. Benzylation using benzyl bromide afforded good
yields of the corresponding benzylic alcohols. This Barbier-
type reaction is functional group tolerant and inexpensive,
presenting an alternative to the use of highly reactive prepa-
rations of Mn0, preformed Grignard reagents, or indium.
Investigation of the mechanism of the transformation and
further development of related allylation and alkylation re-
actions are ongoing in our laboratories.
[8] S. H. Kim, M. V. Hanson, R. D. Rieke, Tetrahedron Lett. 1996,
37, 2197–2200.
[9] Other reagents have also been used to activate Mn0 in situ; a)
K/C: A. Fürstner, H. Brunner, Tetrahedron Lett. 1996, 37,
7009–7012; b) LiAlH4: T. Hiyama, M. Obayashi, A. Naka-
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Takai, T. Ueda, T. Hayashi, T. Moriwake, Tetrahedron Lett.
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[10] Chlorosilanes are also key reagents in manganese-mediated,
chromium- and nickel-catalyzed Nozaki–Hiyama–Kishi
(NHK) allylation reactions, wherein chlorosilane is proposed
to facilitate turnover of the resultant chromium alkoxide; a)
For a discussion of the mechanism of manganese-mediated
NHK reaction, see: A. Fürstner, N. Shi, Chem. Rev. 1999, 99,
991–1046; b) A. Fürstner, N. Shi, J. Am. Chem. Soc. 1996, 118,
12349–12357; c) G. Xia, H. Yamamoto, J. Am. Chem. Soc.
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Chem. Soc. 2007, 129, 2752–2753.
Experimental Section
General Experimental Procedure for Allylation of p-Anisaldehyde: A
round-bottom flask was charged with ground Mn powder
(325 mesh, 99%, 220 mg, 4.00 mmol, 2.00 equiv., see Supporting
Information for full experimental details) and AgBr (38 mg,
0.20 mmol, 10 mol-%) in the glovebox. The flask was removed from
the glovebox, and THF (3.0 mL) and p-anisaldehyde (240 µL,
1.97 mmol, 1 equiv.) were added. The mixture was stirred at room
temperature, and a solution of allyl bromide (190 µL, 2.2 mmol,
1.1 equiv., dissolved in 2.0 mL of THF) was added over 20 h using
a syringe pump. Care was taken to ensure the exclusion of light
from the reaction flask and the solution of allyl bromide. After the
addition was complete, Et2O (15 mL) was added to the reaction
flask and the brown mixture was quenched by adding 1  HCl
[11] G. Cahiez, P. Y. Chavant, Tetrahedron Lett. 1989, 30, 7373–
7376.
[12] Copper salts catalyze the manganese-mediated reaction of allyl
chloride with aromatic aldehydes: C. J. Li, Y. Meng, X. H. Yi,
J. Ma, T. H. Chan, J. Org. Chem. 1998, 63, 7498–7504.
[13] a) J. G. Donkervoort, J. L. Vicario, J. T. B. H. Jastrzebski, R. A.
Gossage, G. Cahiez, G. van Koten, J. Organomet. Chem. 1998,
Eur. J. Org. Chem. 2008, 5507–5510
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N. T. Barczak, E. R. Jarvo
SHORT COMMUNICATION
558, 7498–7504; b) E. Gallo, E. Solari, C. Floriani, A. Chiesiv-
illa, C. Rizzoli, Organometallics 1995, 14, 2156–2158; c)
Higher-order organomanganates have been proposed as inter-
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39, 2499–2502; b) Mn2(CO)10-mediated Wurtz coupling: B. C.
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ling: A. F. Barrero, M. M. Herrador, J. F. Q. del Moral, P. Arte-
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Certain substrates do not react under our standard allylation
conditions. For example, 4-acetamidobenzaldehyde, 4-ni-
trobenzaldehyde, and 3-hydroxybenzaldehyde afford less than
10% conversion to the requisite homoallylic alcohols.
Chromium-catalyzed, manganese-mediated pinacol coupling:
N. Takenaka, G. Xia, H. Yamamoto, J. Am. Chem. Soc. 2004,
126, 13198–13199.
Rieke manganese has been used to prepare benzylic manganese
halides: S. H. Kim, R. D. Rieke, J. Org. Chem. 2000, 65, 2322–
2330.
gents with electrophiles; see ref.[3b]
.
[14] One possible mechanism for catalysis would be activation of
the halide toward single electron transfer from Mn0. For acti-
vation of allylic bromides by indium salts, see: a) G. R. Cook,
R. Hayashi, Org. Lett. 2006, 8, 1045–1048; b) R. Hayashi,
G. R. Cook, Org. Lett. 2007, 9, 1311–1314.
[15] An alternative possible mechanism for catalysis would be for-
mation of a nucleophilic allylsilver complex. Silver-catalyzed
Sakurai-Hosomi allylation: M. Wadamoto, H. Yamamoto, J.
Am. Chem. Soc. 2005, 127, 14556–14557.
[16] a) A moderate yield of benzylated alcohols can be obtained in
a silver-catalyzed, zinc-mediated Barbier reaction: L. W. Bieber,
E. C. Storch, I. Malvestiti, M. F. da Silva, Tetrahedron Lett.
1998, 39, 9393–9396; b) Barbier-type reactions mediated by
stoichiometric silver iodide and indium: Z.-L. Shen, Y.-L. Yeo,
T. P. Loh, J. Org. Chem. 2008, 73, 3922–3924.
[17] IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene; see:
A. J. Arduengo, H. V. R. Dias, J. C. Calabrese, F. Davidson,
Organometallics 1993, 12, 3405–3409.
[20]
[21]
[22]
[23]
5-exo-trig cyclization of this substrate has been observed in in-
dium/silver-mediated alkylation reactions; see ref.[15b]
.
[24] R. D. Rieke, S. H. Kim, J. Org. Chem. 1998, 63, 5235–5239.
[25] J. Einhorn, C. Einhort, J.-L. Luche, Tetrahedron Lett. 1988, 29,
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[26] E. Kim, D. M. Gordon, W. Schmid, G. M. Whitesides, J. Org.
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[18] Addition of phosphane ligands such as DIFLUORPHOS and
MeDuPhos also resulted in lower yields of homoallylic alcohol.
[19] a) Copper-catalyzed, manganese-mediated Wurtz coupling in
aqueous media: J. H. Ma, T. H. Chan, Tetrahedron Lett. 1998,
Received: September 15, 2008
Published Online: October 13, 2008
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