Iron-catalyzed borylation of alkyl electrophiles

Article abstract of DOI:10.1021/ja505199u

The use of low-cost iron(III) acetoacetate (Fe(acac)₃) and tetramethylethylenediamine (TMEDA) enables the direct cross-coupling of alkyl halides with bis(pinacolato)diboron. This approach allows for the borylation of activated or unactivated primary, secondary, and tertiary bromides. Moreover, even the borylation of benzylic or allylic chlorides, tosylates, and mesylates are possible. The reactions proceed under mild conditions at room temperature and show broad functional-group compatibility and "robustness" as measured by a modified Glorius robustness screen.

Full text of DOI:10.1021/ja505199u

Communication
pubs.acs.org/JACS
Iron-Catalyzed Borylation of Alkyl Electrophiles
Thomas C. Atack,† Rachel M. Lecker,† and Silas P. Cook*
Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, Indiana 47405-7102, United States
S
* Supporting Information
1e).6 Currently, examples with Pd,7 Ni,8 Cu,9 and Zn10 have
ABSTRACT: The use of low-cost iron(III) acetoacetate
(Fe(acac)3) and tetramethylethylenediamine (TMEDA)
enables the direct cross-coupling of alkyl halides with
bis(pinacolato)diboron. This approach allows for the
borylation of activated or unactivated primary, secondary,
and tertiary bromides. Moreover, even the borylation of
benzylic or allylic chlorides, tosylates, and mesylates are
possible. The reactions proceed under mild conditions at
room temperature and show broad functional-group
compatibility and “robustness” as measured by a modified
Glorius robustness screen.
been reported. While these methods have vastly improved
access to alkylboronic esters, expensive catalysts7 and/or
ligands7,10,11 and a limited substrate scope7−11 provide ample
incentive to devise a more general strategy. Based on our recent
findings that iron catalysts often perform better than their noble
metal counterparts in coupling reactions,12 we sought to
explore the generality of an iron-catalyzed borylation reaction.
Here we report a mild, room temperature borylation of alkyl
halides using inexpensive and benign iron salts (Scheme 1e).
The reaction shows a broad substrate scope and functional-
group compatibility.
The project began with the observation that bis(pinacolato)-
diboron (B2pin2) can couple with benzyl chloride in the
presence of FeCl2 and n-BuMgBr. Success with benzyl chloride
offered the exciting possibility of creating a general method for
the borylation of alkyl halides. Using 4-(4-methoxyphenyl)-2-
bromobutane (1w) as a less reactive model substrate, a variety
of iron sources, solvents, and ligands were evaluated (see
Supporting Information (SI)). The presence of both iron and
Grignard is required for the reaction. The ethylmagnesium
bromide activates the B2pin2 and reduces the iron to its low-
valent active state. Using ethylmagnesium bromide allowed for
simple removal of the EtBpin side product under vacuum.
While Fe(acac)3 alone provided 23% yield of borylated product
2w, the addition of TMEDA (10 mol %) increased the yield to
63%. While most iron precatalysts worked in the reaction,
Fe(acac)3 offered the optimal combination of reactivity and
simple reaction setup. Solvents other than THF and ligands
other than TMEDA proved inferior. While the reactions could
be run with a slight excess of B2pin2, 15−20% higher yields
were obtained with 3.5 equiv, likely due to overalkylation of
B2pin2 by ethylmagnesium bromide.13 Interestingly, either
raising or lowering the temperature from ambient compro-
mised yields and increased formation of the simple halide
reduction product. Finally, the reaction appears to be catalyzed
by iron since the use of 99.99% FeCl2 resulted in a 74% yield
and 99.9% Fe(acac)3 resulted in a 91% yield (compared to 80%
under standard conditions), while copper, nickel, palladium,
chromium, and manganese salts all produced substantially
diminished yields under our conditions (see SI).14 Based on
these observations, the reaction is performed by combining
Fe(acac)3 (10 mol %) with B2pin2 (3.5 equiv) in THF followed
by the addition of TMEDA (10 mol %), ethylmagnesium
bromide (4.5 equiv), and the electrophile (Scheme 2). The
addition of the electrophile last was critical to avoid the
lkylboronic esters represent an important class of reagents
A
with broad utility in the field of organic synthesis.1 The
most common methods to access these functional groups
include transmetalation from highly reactive organolithiums or
Grignards (Scheme 1a)2 and the hydroboration of olefins
Scheme 1. General Approaches to Access Alkyl Boronic
a
Esters
a
R = alkyl; X = halide or p-toluenesulfonate.
(Scheme 1b).3 Additionally, methods describing metal-
catalyzed C−H activation (Scheme 1c)4 and β-borylation of
α,β-unsaturated carbonyls (Scheme 1d)5 have been reported.
To overcome drawbacks such as limited functional-group
compatibility (Scheme 1a), regioselectivity (Scheme 1b and
1c), and narrow scope (Scheme 1d), recent efforts have focused
on the direct Miyaura-type borylation of alkyl halides (Scheme
Received: May 23, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja505199u | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
unproductive side reactions between the Grignard and
electrophile (e.g., E2).
Scheme 2. Substrate Scope of the Borylation Reaction
With the availability of mild reaction conditions for the
borylation of secondary bromides, a variety of substrates were
evaluated (Scheme 2). Unlike the reported Pd,7 Cu,9 and Zn10
methods, the reaction provided access to primary, secondary,
tertiary, benzylic, and allylic boronic esters in modest-to-
excellent yields. As can be seen in Scheme 2a, unactivated
primary bromides work well in the reaction (1a−1c), while
unactivated primary alkyl chlorides and tosylates furnished only
trace yields (1d and 1e). Primary benzylic chlorides generally
provided high yields (1f−1n), but benzyl tosylate (1r) and
cinnamyl chloride (1t) only proceeded in 31% and 28% yield,
respectively. Although the yields for the chlorides and tosylates
are currently low, these examples represent the first borylative
couplings of alkyl chlorides and tosylates without in situ
conversion to the iodides using tetrabutylammonium iodide
(TBAI).9b Unfortunately, the reaction does not tolerate the use
of unactivated secondary chlorides (1v and 1cc, Scheme 2b).
Interestingly, the secondary benzylic chloride 1ii proceeded in
higher yield than the analogous bromide (1jj) due to rapid
dimerization of 1jj (Scheme 2b). The success of secondary
allylic bromide 1ll, however, demonstrates that not all activated
bromides homocouple under the reaction conditions. To date,
few examples exist for borylation of tertiary halides, with the
nickel-based method by Fu and co-workers8 offering the only
examples beyond 1-bromoadamantane.9b,c Our examination of
tertiary halides revealed that unactivated and activated
bromides (1mm, 1oo, 1pp, and 1rr) work in the reaction,
while tertiary chlorides proceed in low yield (1nn and 1qq,
Scheme 2c). The reaction also performs well on gram scale. For
example, 1.0 g of 1w provides an 87% yield of borylated
product 2w under the optimized reaction conditions (Scheme
3).
Next, we sought to evaluate the functional-group tolerance of
the reaction. To that end, a modified-Glorius robustness screen
proved highly informative without the need for lengthy
substrate preparation.15 The standard borylation reaction was
performed in the presence of a variety of additives containing
common functional groups or heterocycles (see SI). A variety
of versatile and synthetically useful functional groups such as
esters, ketones, aldehydes, amides, internal alkenes, and alkyl
amines were found to have little-to-no effect on the borylation
reaction. By contrast, terminal alkenes, terminal alkynes, and
carboxylic acids significantly inhibited the formation of product.
Interestingly, functional groups such as aldehydes, ketones,
terminal alkenes, and terminal alkynes are consumed in the
reaction while nitriles, amides, and esters are not. The reaction
proceeded well in the presence of quinoline, pyrrole,
methylimidazole, benzofuran, and indole, while 3-methylbenzo-
thiophene moderately inhibited the reactionconsistent with
the lower yield of the reaction for substrate 1q. Importantly,
none of the functional groups or structural motifs tested
completely shut down the borylation.
Based on the interesting reactivity profile observed in
Scheme 2, we conducted simple competition experiments
(Scheme 4). Not surprisingly, the competition between a
primary bromide and a primary chloride using 1-bromo-6-
chlorohexane (3) produced borylation predominantly at the
primary bromide to form monoborylated product 4 with some
additional coupling at the primary chloride to form 5 (Scheme
4a). Interestingly, the competition between a primary bromide
and secondary bromide in 1,4-dibromopentane (6) revealed
a
All yields after isolation from silica column chromatography (except
1
<5%, which was detected by GC or H NMR). NR = no reaction.
b
PMP = p-methoxyphenyl. Change to reaction conditions: Fe(acac)3
(5 mol %), TMEDA (5 mol %), 1 h. c Change to reaction conditions:
Fe(acac)3 (20 mol %), TMEDA (20 mol %).
almost no preference, indicating very similar reaction rates for
primary and secondary bromides (Scheme 4b).
B
dx.doi.org/10.1021/ja505199u | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Notes
Scheme 3. Gram-Scale Borylation Reaction
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge generous start-up funds from Indiana
University in partial support of this work. We also gratefully
acknowledge the American Chemical Society Petroleum
Research Fund (PRF52233-DNI1) and Eli Lilly & Co. for
the Lilly Grantee Award used to support this work.
Scheme 4. Competition Experiments
REFERENCES
■
(1) Hall, D. G. Boronic Acids; John Wiley & Sons; Weinheim,
Germany, 2012.
(2) Brown, H. C.; Cole, T. E. Organometallics 1983, 2, 1316.
(3) (a) Brown, H. C. Hydroboration; W. A. Benjamin Inc.: New York,
1962. (b) Fu, G. C. Transition Metals for Organic Synthesis: Building
Blocks and Fine Chemicals; Beller, M., Bolm, C., Eds.; Wiley-VCH
Verlag GmbH: Weinheim, Germany, 2008; p 193.
(4) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.;
Hartwig, J. F. Chem. Rev. 2010, 110, 890.
(5) For a recent review on conjugate additions with B-based
nucleophiles, see: Hartmann, E.; Vyas, D. J.; Oestreich, M. Chem.
Commun. 2011, 47, 7917.
(6) (a) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60,
7508. (b) Takagi, J.; Takahashi, K.; Ishiyama, T.; Miyaura, N. J. Am.
Chem. Soc. 2002, 124, 8001.
(7) (a) Bej, A.; Srimani, D.; Sarkar, A. Green Chem. 2012, 14, 661.
(b) Yi, J.; Liu, J.-H.; Liang, J.; Dai, J.-J.; Yang, C.-T.; Fu, Y.; Liu, L. Adv.
Synth. Catal. 2012, 354, 1685. (c) Joshi-Pangu, A.; Ma, X.; Diane, M.;
Iqbal, S.; Kribs, R. J.; Huang, R.; Wang, C.-Y.; Biscoe, M. R. J. Org.
Chem. 2012, 77, 6629.
(8) Dudnik, A. S.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 10693.
(9) (a) Kleeberg, C.; Dang, L.; Lin, Z.; Marder, T. B. Angew. Chem.,
Int. Ed. 2009, 48, 5350. (b) Yang, C.-T.; Zhang, Z.-Q.; Tajuddin, H.;
Wu, C.-C.; Liang, J.; Liu, J.-H.; Fu, Y.; Czyzewska, M.; Steel, P. G.;
Marder, T. B.; Liu, L. Angew. Chem., Int. Ed. 2011, 51, 528. (c) Ito, H.;
Kubota, K. Org. Lett. 2012, 14, 890.
(10) Bose, S. K.; Fucke, K.; Liu, L.; Steel, P. G.; Marder, T. B. Angew.
Chem., Int. Ed. 2014, 53, 1799−1803.
(11) Liu, B.; Gao, M.; Dang, L.; Zhao, H.; Marder, T. B.; Lin, Z.
Organometallics 2012, 31, 3410.
(12) (a) Jarugumilli, G. K.; Cook, S. P. Org. Lett. 2011, 13, 1904−
1907. (b) Agrawal, T.; Cook, S. P. Org. Lett. 2013, 15, 96.
(13) Clary, J. W.; Rettenmaier, T. J.; Snelling, R.; Bryks, W.; Banwell,
J.; Wipke, W. T.; Singaram, B. J. Org. Chem. 2011, 76, 9602.
(14) Buchwald, S. L.; Bolm, C. Angew. Chem., Int. Ed. 2009, 48, 5586.
(15) Collins, K. D.; Glorius, F. Nat. Chem. 2013, 5, 597.
At this point in the investigation, little can be surmised about
the mechanistic course of these reactions. Since EtBpin is
formed in the reaction, it stands to reason that the alkyl halide
acts as the electrophile while the B2pin2-ate complex functions
as the nucleophile for coupling. Whether the reaction proceeds
through an oxidative addition-first or transmetalation-first
mode of coupling remains unknown. The only byproducts of
the reaction are EtBpin and simple reduction of the starting
electrophile. Whether the reaction proceeds through a radical-
based mechanism remains an open question. For example,
secondary benzylic bromide 1jj produced only a 23% yield with
70% of the material forming the homodimer, a result consistent
with benzylic radical formation. Yet, the success of benzyl
tosylate 1r and benzyl mesylate 1s (Scheme 2a) provides
evidence against benzylic radical formation for those substrates.
Moreover, when substrate 1w was subjected to standard
reaction conditions in the presence of TEMPO (1 equiv) or
BHT (1 equiv), the reaction proceeded as usual in 82% and
83% yields, respectively (compared to an 80% yield under
standard conditions). Clearly detailed mechanistic studies are
needed to clarify the mechanism(s) at work in these reactions.
In summary, we have developed a robust iron-catalyzed
borylation of alkyl electrophiles. The reaction generally
proceeds in high yields with an exceptional substrate scope.
The reactivity and selectivity provide a reaction profile unique
among the reported borylation methods, thereby offering
greater generality. The extremely low cost and low toxicity of
the reagents should simplify large-scale implementation of these
reactions. Further efforts will be directed toward understanding
the reaction mechanism of this interesting transformation.
ASSOCIATED CONTENT
* Supporting Information
Experimental details and spectroscopic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
sicook@indiana.edu
■
Author Contributions
†T.C.A. and R.M.L. contributed equally to this work.
C
dx.doi.org/10.1021/ja505199u | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX