Preparation of alkylmagnesium reagents from alkenes through hydroboration and boron-magnesium exchange

Article abstract of DOI:10.1002/anie.201201704

Tolerant: Alkylmagnesium reagents can be synthesized from alkenes through a sequence of hydroboration and subsequent boron-magnesium exchange using a method that tolerates different functional groups (see scheme). The resulting alkylmagnesium reagents can be used in carbon-carbon bond forming reactions, such as alkylation reactions or transition-metal-catalyzed cross-coupling reactions. Copyright

Full text of DOI:10.1002/anie.201201704

Angewandte
Chemie
DOI: 10.1002/anie.201201704
Synthetic Methods
Preparation of Alkylmagnesium Reagents from Alkenes through
Hydroboration and Boron–Magnesium Exchange**
Markus A. Reichle and Bernhard Breit*
For more than 100 years organomagnesium compounds have
alization of alkenes through hydroboration. A subsequent
boron–magnesium exchange reaction could provide the
corresponding alkylmagnesium reagents. However, this step
is indeed problematic.[9]
been one of the most important synthetic tools for the
[1]
À
construction of C C bonds in both academia and industry.
However, their most important formation method, the direct
À
synthesis by insertion of magnesium metal into the C X bond
Thus, early attempts to realize a boron–magnesium
exchange reaction by addition of ordinary alkylmagnesium
reagents to trialkylboranes 2 were not successful owing to
incomplete transfer of the alkyl substituents from boron to
magnesium.[10] A significant advance was reported by Mur-
ahashi and Kondo, who observed complete boron–magne-
sium exchange of trialkylboranes upon reaction with a 1,5-
dimagnesium reagent (Scheme 1) with concomitant forma-
of alkyl halides, involves highly reactive radical intermediates
that may lead to undesired homocoupling products or other
side reactions.[2] Unfortunately, these side reactions become
more problematic with bulky alkyl groups, long alkyl chains,
or substrates containing multiple protected functionalities.[3]
Applications of alkylmagnesium reagents towards the later
stages of a total synthesis are rare for two reasons. Firstly, they
are incompatible with many functional groups which are
likely to be present nearing the end of a synthesis. Secondly,
alkyl halides are usually too reactive and often cannot be
carried through many synthetic steps. Hence, alternative
methods for the formation of alkylmagnesium reagents have
been examined, such as hydromagnesiation[4] of olefins,
a method that is synthetically useful only in special cases.[5]
In contrast to alkylmagnesium reagents, mild methods for the
formation of arylmagnesium reagents from aryl halides or
heteroaryl compounds have been developed recently.[6]
In search for approaches to organometallic reagents
through anti-Markovnikov functionalization of olefins, Kno-
chel and co-workers have taken advantage of the high anti-
Markovnikov selectivity of hydroboration.[7] Thus, dialkyl
zinc reagents can be obtained efficiently through a sequence
of hydroboration followed by a boron–zinc exchange reac-
tion.[8] While organozinc reagents have been proven to be
highly useful reagents for organic synthesis, their reduced
nucleophilicity compared to organomagnesium compounds
also sets limitations regarding their reactivity towards weaker
electrophiles.[1,2a] Hence, it would be highly desirable to have
a general method to generate alkylmagnesium reagents from
alkenes by taking advantage of the high levels of regio- and
stereocontrol in the course of the well-established function-
Scheme 1. Access to alkylmagnesium reagents from olefins through
hydroboration and boron–magnesium exchange.
tion of the spiro[5,5]boron-ate[11] 4a as the proposed byprod-
uct.[12] However, the method suffers from three major
limitations: First the method is limited to the generation of
primary alkylmagnesium reagents starting from mono-sub-
stituted alkenes, because the boron–magnesium exchange
reaction is inhibited owing to steric hindrance. Second, the
method is restricted to the use of trialkylboranes. However,
the use of the more stable alkyl boronic esters obtained
through rhodium-catalyzed hydroboration would be highly
desirable. Finally, this protocol requests a special diethyl
ether/toluene solvent mixture for the boron–magnesium
exchange reaction to proceed, which limits the synthetic
utility of the resulting organomagnesium reagents signifi-
cantly, most notably for applications in subsequent cross-
coupling reactions.[13]
We herein report the development of a general method
for the preparation of primary and secondary alkylmagne-
sium reagents from alkenes through hydroboration and
boron–magnesium exchange and their use in a wide range
of carbon–carbon bond forming reactions, including iron-,
palladium-, and copper-catalyzed cross-coupling reactions as
well as a stereospecific directed copper-mediated allylic
substitution.
[*] M. A. Reichle, Prof. Dr. B. Breit
Albert-Ludwigs-Universitꢀt Freiburg
Institut fꢁr Organische Chemie und Biochemie
Freiburg Institute for Advanced Studies (FRIAS)
Albertstrasse 21, 79104 Freiburg (Germany)
E-mail: bernhard.breit@chemie.uni-freiburg.de
Homepage: http://www.breit-group.uni-freiburg.de/
[**] This work was supported by the Fonds der Chemischen Industrie,
the DFG (GRK 1038), the Krupp Foundation (Alfried Krupp Award
for young university teachers to B.B.), and Novartis (graduate
fellowship to M.A.R.). We thank M. Fritz for technical support and
BASF SE for donations of chemicals (esp. borane reagents).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201201704.
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To accelerate the problematic boron–magnesium
exchange reaction, we wondered whether the use of an 1,4-
dimagnesium reagent may be beneficial owing to faster
cyclization towards the corresponding spiro[4,4]boron-ate 4b
with concomitant liberation of the desired alkylmagnesium
reagent (Scheme 1).
Indeed, after the boron–magensium exchange reaction of
trioctylborane 2a with dimagnesium reagents 3a and 3b by
low-temperature 11B NMR spectroscopy, we observed that
formation of the corresponding spiro[4.4]boron-ate 4b occurs
faster than that of 4a (for details, see the Supporting
Information).[14] As a model electrophile to trap the newly
formed alkylmagnesium reagent we selected ethyl 2-(bromo-
methyl)acrylate (6). In initial experiments we investigated the
boron–magnesium exchange reaction with trialkylboranes 2a
and 2b (Table 1, entries 1–5), which were obtained by hydro-
boration of the corresponding alkene with either borane
dimethyl sulfide or 9-BBN.
which are easily prepared employing rhodium- or iridium-
catalyzed hydroboration of the corresponding terminal
alkene with catecholborane or pinacolborane (Table 1,
entries 6–11).[15,16] While the catechol-derived organodioxa-
borolane 2c failed to provide the desired alkylmagnesium
reagent in solution, the reaction of n-octylboronates 2d and
2e proceeded smoothly to furnish the corresponding alkyl-
magnesium reagent 5a and its subsequent alkylation product
with allylbromide 6 in good to high yields. The best results
were obtained for the pinacolborolane 2d, which could be
transformed into the alkylmagnesium reagent 5a in both
ether/toluene as well as THF/toluene solvent mixtures, thus
enabling a greater range of subsequent addition and coupling
reactions (see below Table 2).[13] Gratifyingly, even potassium
organotrifluoroborate[17] 2 f, which has proven to possess
a superior stability under a variety of reaction conditions[18]
and potentially can be carried through several steps in
a synthesis, could be employed as a substrate for the boron–
magnesium exchange reaction (Table 1, entry 12). However,
the limited solubility of 2 f in aprotic solvents caused the
exchange reaction to be slower (6 h instead of 0.5 h for the
pinacol derivative 2d).
Table 1: Screening of organoboranes suitable for the B–Mg-exchange
reaction.
Next, we explored the reactivity of the newly formed
À
alkylmagnesium reagent in a range of C C bond forming
reactions including cross-coupling reactions.[19] It was of major
interest to learn whether the byproducts formed in the course
of the boron–magnesium exchange reaction would have an
influence on the reactivity and selectivity of the newly formed
alkylmagnesium reagent (Table 2). Thus, reaction with stan-
dard electrophiles such as allyl bromide 6, a Weinreb amide,
aromatic and aliphatic aldehydes, and phenyl isothiocyanate
gave high yields of the corresponding addition products; the
yields were comparable to those obtained with classically
prepared octylmagnesium halides (Table 2, entries 1–6).[20]
When very reactive electrophiles were used to trap the
alkylmagnesium reagent 5a, lower reaction temperatures
were required to avoid undesired side products derived from
nucleophilic additions of the spiroboron-ate 4b, since it is also
a viable nucleophile (Table 2, entries 1, 2, and 4).[21] More
interestingly, cross-coupling reactions using the alkylmagne-
sium reagent derived from the corresponding pinacolboro-
lane could be carried out with success. The palladium-
catalyzed Kumada cross-coupling reaction with b-bromosty-
rene (Table 2, entries 12 and 13) proceeded smoothly without
being inhibited by the side products of the boron–magnesium
exchange and occurred independently of the solvent mixture
applied.[12,19] Copper-catalyzed cross-coupling[22] reactions
with benzyl bromide (Table 2, entries 9–11) also proceeded
in high yield. In contrast to palladium- and copper-catalyzed
reactions, other cross-couplings were more strongly influ-
enced by the byproducts of the boron–magnesium exchange
process or dependent on the solvent mixture. Thus, the iron-
catalyzed cross-coupling with aryl chloride[23] worked well
only in THF and required a higher proportion of NMP
cosolvent in comparison to the published conditions[23b] in
order to achieve full conversion (Table 2, entries 7 and 8).
We were also delighted to see that we could perform the
copper-mediated directed allylic substitution that was pre-
viously developed in our laboratories[24] (Table 2, entry 14).
Entry[a]
2
BY2
3
Cosolvent[b] Exchange
time[c] [h]
Yield[d]
[%]
(equiv)
1
2
3
3a (2) Et2O
1
1
8
81
85
n.d.
2a[e] B(nOct)2 3b (2) Et2O
3c (2) THF
4
5
3b (1) Et2O
2b[e] 9-BBN
4
8
89
n.d.
3c (1) THF
6
7
3b (2) Et2O
2c[e] Bcat
1
1
<5
n.d.
3c (2) THF
8
9
10
3b (2) Et2O
3b (2) THF
3c (2) THF
0.5
1
0.5
72
68
93
2d Bpin
11
12
2e
3c (2) THF
3c (2) THF
1
6
79
76
2 f
BF3K
[a] Reactions were executed with 0.50 mmol organoborane. [b] Solvent,
in which the dimagnesium reagent is prepared. [c] Determined by
11B NMR analysis of the reaction mixture. [d] Yields of isolated alkylation
products. [e] Organoborane freshly prepared in situ. nHex=n-hexyl,
nOct=n-octyl, 9-BBN=9-borabicyclo[4.4.1]nonane, cat=catechol,
pin=pinacol, n.d.=not determined.
Unfortunately, even though the boron–magnesium
exchange reaction employing the 1,4-dimagnesium reagent
was faster, the use of a solvent mixture of toluene and diethyl
ether proved necessary to achieve completion of the exchange
reaction. THF, dioxane, or other polar etheral solvents that
are usually used in other organomagnesium-reagent forma-
tions were not tolerated. Thus, we explored the reactivity of
other types of organoboranes, mainly organoborolanes 2c–e,
2
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Table 2: Scope of various electrophiles.
Entry[a]
Electrophile
Product
Dimagnesium reagent
(cosolvent)
Catalyst/additive
Temp.
[8C]
Solvent
Yield[b]
[%]
1
2
3b (Et2O)
3c (THF)
–
–
À20
À20
THF
THF
83
95
3
3c (THF)
–
0
THF
94
4
5
6
3c (THF)
3c (THF)
3c (THF)
–
–
–
À78
0
THF
THF
THF
95
92
85
0
7
8
3b (Et2O)
3c (THF)
[Fe(acac)3] (5 mol%)
[Fe(acac)3] (5 mol%)
RT
RT
THF/NMP (1:1)
THF/NMP (1:1)
trace
78
9
10
11
3b (Et2O)
3c (THF)
3c (THF)
Li2CuCl4 (3 mol%)
Li2CuCl4 (3 mol%)
CuCN·2 LiCl (2 mol%)
À20
À20
À20
THF
THF
THF
72
87
91
12
13
3b (Et2O)
3c (THF)
[Pd(PPh3)4] (2 mol%)
[Pd(PPh3)4] (2 mol%)
RT
RT
THF
THF
84
91
89
(93% ee)
14[c]
3b (Et2O)
CuBr·SMe2 (0.5 equiv)
RT
Et2O
[a] Reactions were executed with electrophile (0.40 mmol), organoborane (0.50 mmol, 1.2 equiv), and dimagnesium reagent (1.0 mmol, 2.4 equiv).
[b] Yields of isolated products after purification. [c] Ph(CH2)2Bpin was used instead. NMP=N-methylpyrrolidone, acac=acetylacetonate,
o-DPPB=ortho-diphenylphosphanylbenzoyl.
The reaction occurred with similar rates, high regio- and
reliable stereospecificity as observed with classically formed
alkylmagnesium reagents.
Further investigations focused on the scope of applicable
alkylborolanes (Table 3). We were particularly interested in
the formation of alkylmagnesium reagents that are not easily
accessible in high yields by classical methods such as the
alkylmagnesium reagents in benzylic and homobenzylic
position (Table 3, entries 1, 2, and 9).
Thus, boronic esters derived from styrene derivatives and
simple 1,1-disubstituted olefins could be readily transformed
to the corresponding alkylmagnesium reagents in high yields
(Table 3, entries 1–3). The reaction rate of the boron–
magnesium exchange was found to depend on the sterical
hindrance induced by the substituents next to the carbon–
boron bond. While borolanes derived from monosubstituted
alkenes showed a completion of the boron–magnesium
exchange reaction after about one hour reaction time, the
corresponding borolanes derived from 1,1-disubstituted
alkenes required two to four hours for the exchange reaction
to be complete. An exception was the limonene derivative,
which reacted unexpectedly slow, but still gave high yields of
the organomagnesium compound (Table 3, entry 4). Interest-
ingly, this substrate possesses an additional alkene function in
a 1,5-distance. Thus, preparation of the same alkylmagnesium
reagent from the corresponding alkyl halide through direct
synthesis is expected to furnish a bicyclic product through
radical intermediates.[25] Under our conditions, the formation
of such a cyclization side product could be completely
suppressed.
Synthetically useful methallylalcohol- and homomethal-
lylalcohol-derived borolanes equipped with typical silicon-
based protecting groups are more sensitive substrates and
required slow addition of the dimagnesium reagent at 08C
followed by slow warming to ambient temperature (see the
Supporting Information) to avoid side reactions (Table 3,
entries 5–8). For those sensitive substrates, 2-methyl-THF[27]
instead of THF may be a superior solvent (Table 3, entry 8).
Secondary alkyl boronates derived through branched-
selective hydroboration of arylalkenes or hydroboration of
1,2-disubstituted as well as trisubstituted alkenes may give
access to secondary alkylmagnesium reagents provided the
boron–magnesium exchange reaction could be realized at
a sterically more hindered secondary alkyl carbon. To our
delight, starting from the branched hydroboration product of
styrene, the corresponding benzylic organomagnesium
reagent was formed rather fast (4 h, Table 3, entry 9) and
could be alkylated in good yield. Conversely, the cyclo-
hexylborolane needed 16 h reaction time to reach full
conversion into the corresponding alkylmagnesium reagent
(Table 3, entry 10). On the other hand, the boron–magnesium
exchange of the norbornylborolane (Table 3, entry 11) oc-
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Table 3: Scope of various alkyl pinacolborolanes.[29]
Scheme 2. Access to alkylmagnesium reagents in presence of an ester.
tol=toluene.
Entry[a] Organoborane
Product
Exchange Yield[c]
time[b] [h] [%]
In summary, we have developed a general protocol for the
formation of a variety of primary and secondary alkylmagne-
sium reagents from alkenes through a sequence of hydro-
boration and boron–magnesium exchange with alkyl boro-
nates allowing for clean reaction conditions, broad substrate
scope, and high functional-group tolerance. The resulting
alkylmagnesium reagents were useful reaction partners in
a wide range of carbon–carbon bond forming reactions such
as alkylation reactions, 1,2-additions as well as transition-
metal-catalyzed cross-coupling reactions. Furthermore, we
have demonstrated the efficiency of the boron–magnesium
exchange to generate alkylmagnesium reagents that have
previously only been synthesized in several steps by the
established classical formation (Table 3, entries 1, 2, and 9;
Scheme 2). Application of this method in total syntheses and
its benefits are under investigation.
1
2
R’=H
R’=Me
1
2
82
76
3
4
2
84
71
12
5
4
4
74
61
6[d]
7
4
4
56
83
8[d]
9
4
86
81
10
16
Experimental Section
Typical procedure for the formation of the alkylmagnesium reagent
followed by trapping with electrophile 6: A solution of tetramethy-
lene bis(magnesiumchloride) (1.6–1.9m in THF, 1.0 mmol, 2.0 equiv)
was added dropwise to a cooled (08C) solution of the dioxaborolane
(0.50 mmol) in dry toluene (1.5–2.0 mL) and the solution was stirred
for the time indicated (monitored by 11B NMR spectroscopy, see the
Supporting Information) at ambient temperature. The reaction
mixture was cooled to À20 or À408C, and a solution of ethyl 2-
(bromomethyl)acrylate (1.4 equiv) in THF was added, and the
solution was stirred for one to three hours. A saturated aqueous
solution of NH4Cl was added to the mixture, and the mixture was
extracted three times with tert-butyl methyl ether (TBME) or diethyl
ether. The combined organic phases were washed with brine, dried
over magnesium sulfate, and concentrated in vacuo. The residue was
purified by flash chromatography by eluting with a mixture of
hexanes/diethyl ether.
11
8
68
12
cis/trans <2:98
cis/trans >98:2
cis/trans >98:2
d.r. 96:4
–
d.r. 92:8
16
16
16
76
0
61
13
14[e]
[a] Reactions were executed with organoborolane (0.50 mmol) and
dimagnesium reagent 3c (1.0 mmol, 2.0 equiv). [b] Determined by
11B NMR analysis of the reaction mixture. [c] Yields of isolated products.
[d] 2-Me-THF was used instead of THF. [e] Exchange reaction was carried
out at 408C. TBS=tert-butyldimethylsilyl, TIPS=triisopropylsilyl.
Received: March 2, 2012
Published online: && &&, &&&&
cured faster despite it is sterically more hindered than the
simple cyclohexylborolane. The borolanes derived from
a trisubstituted olefin appeared to be the greatest challenge
for the boron–magnesium exchange reaction. Interestingly,
À
Keywords: boranes · C C coupling · Grignard reaction ·
organoborates · synthetic methods
.
with
trans-2-phenylcyclohexyldioxaborolane
(Table 3,
entry 12) the exchange reaction proceeded smoothly at
ambient temperature, whereas the corresponding cis-boro-
lane required warming to 408C (Table 3, entries 13 and 14).
When the resulting alkylmagnesium reagent was trapped with
ethyl 2-(bromomethyl)acrylate, in both cases the trans-
diastereomer was obtained.[26]
Finally, we explored the formation of an alkylmagnesium
reagent in the presence of a reactive ester functionality.
Indeed, an alkyl boronate that contained a tert-butyl ester was
at À408C successfully transformed into the ester-functional-
ized alkylmagnesium reagent, which could be trapped by
allylation (Scheme 2).
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Angew. Chem. Int. Ed. Engl. 1974, 13, 701 – 706; c) H. Kotsuki, I.
Kadota, M. Ochi, J. Org. Chem. 1990, 55, 4417 – 4422; d) T.
Netscher, Chimia 1996, 50, 563 – 567; e) G. Cahiez, C. Chaboche,
M. Jezequel, Tetrahedron 2000, 56, 2733 – 2737.
[23] a) A. Fꢃrstner, A. Leitner, M. Mꢄndez, H. Krause, J. Am. Chem.
Soc. 2002, 124, 13856 – 13863; b) A. Fꢃrstner, A. Leitner, Angew.
Chem. 2002, 114, 632 – 635; Angew. Chem. Int. Ed. 2002, 41, 609 –
612; c) A. Fꢃrstner, A. Leitner, G. Seidel, Org. Synth. 2005, 81,
33 – 41; d) Review: B. D. Sherry, A. Fꢃrstner, Acc. Chem. Res.
2008, 41, 1500 – 1511.
[24] a) P. Demel, B. Breit, Adv. Synth. Catal. 2001, 343, 429 – 432;
b) P. Demel, M. Keller, B. Breit, Chem. Eur. J. 2006, 12, 6669 –
6683; c) C. Herber, B. Breit, Chem. Eur. J. 2006, 12, 6684 – 6691.
[25] In case a radical mechanism is involved, 5-exo-trig cyclization
could be expected. See: a) R. C. Lamb, P. W. Ayers, M. K. Toney,
J. F. Garst, J. Am. Chem. Soc. 1966, 88, 4261 – 4262; b) J. F. Garst,
F. E. Barton, Tetrahedron Lett. 1969, 10, 587 – 590; c) E. C.
Ashby, J. R. Bowers, J. Am. Chem. Soc. 1981, 103, 2242 – 2250.
[26] The involvement of a configurationally stable secondary alkyl-
magnesium reagent can be ruled out. Hoffmann et al. have
shown that the reaction of an alkylmagnesium reagent to ethyl 2-
(bromomethyl)acrylate involves single-electron transfer proces-
ses.[20c,28]
[12] K. Kondo, S.-I. Murahashi, Tetrahedron Lett. 1979, 20, 1237 –
1240.
[13] Examples for reactions of Grignard reagents in THF: G. Cahiez,
H. Avedissian, Synthesis 1998, 1199 – 1205; examples in diethyl
ether: K. G. Dongol, H. Koh, M. Sau, C. L. L. Chai, Adv. Synth.
Catal. 2007, 349, 1015.
[14] 11B NMR analyses were established for the determination of the
success and time frame of the boron–magnesium exchange as
intermediate borates easily could be distinguished from the final
desired spiroboron-ates 4a–c (see the Supporting Information).
[15] D. Mꢂnnig, H. Nçth, Angew. Chem. 1985, 97, 854 – 855; Angew.
Chem. Int. Ed. Engl. 1985, 24, 878 – 879.
[27] For properties of 2-Me-THF, see: D. F. Aycock, Org. Process
Res. Dev. 2007, 11, 156 – 159.
[16] Selected examples of catalyzed hydroborations of simple
alkenes with pinacolborolane: a) S. Pereira, M. Srebnik, J. Am.
Chem. Soc. 1996, 118, 909 – 910; b) S. Pereira, M. Srebnik,
[28] R. W. Hoffmann, Chem. Soc. Rev. 2003, 32, 225 – 230.
[29] For details on preparation of pinacol boranes through hydro-
boration see the Supporting Information.
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Synthetic Methods
M. A. Reichle, B. Breit*
&&&& — &&&&
Preparation of Alkylmagnesium Reagents
from Alkenes through Hydroboration and
Boron–Magnesium Exchange
Tolerant: Alkylmagnesium reagents can
be synthesized from alkenes through
a sequence of hydroboration and subse-
quent boron–magnesium exchange using
a method that tolerates different func-
tional groups (see scheme). The resulting
alkylmagnesium reagents can be used in
carbon–carbon bond forming reactions,
such as alkylation reactions or transition-
metal-catalyzed cross-coupling reactions.
6
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!