Rapid, Mild, and Selective Ketone and Aldehyde Hydroboration/Reduction Mediated by a Simple Lanthanide Catalyst

Article abstract of DOI:10.1021/acscatal.6b03332

Rapid, clean hydroboration of ketones and aldehydes with HBpin is achieved using the homoleptic rare-earth catalyst La[N(SiMe₃)₂]₃ (La^NTMS). The reaction employs low catalyst loadings (0.01-1 mol % La^NTMS), proceeds rapidly (>99% in 5 min) at 25 °C, and is moderately air-tolerant. Additionally, this hydroboration has good functional group compatibility, including halides, nitro groups, and nitriles, and is exclusively carbonyl-selective in the presence of alkenes and alkynes.

Full text of DOI:10.1021/acscatal.6b03332

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Letter
Rapid, mild, and selective ketone and aldehyde hydroboration/
reduction mediated by a simple lanthanide catalyst
Victoria Lynn Weidner, Chris Jeffrey Barger, Massimiliano Delferro, Tracy L. Lohr, and Tobin J. Marks
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b03332 • Publication Date (Web): 09 Jan 2017
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Rapid, mild, and selective ketone and aldehyde hydroboration/
reduction mediated by a simple lanthanide catalyst
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Victoria L. Weidner,‡ Christopher J. Barger,‡ Massimiliano Delferro,† Tracy L. Lohr,* and Tobin
J. Marks*
Department of Chemistry, Northwestern University, Evanston, Illinois 60208ꢀ3113, USA
ABSTRACT. Rapid, clean hydroboration of ketones and aldehydes with HBpin is achieved using the homoleptic rare
earth catalyst La[N(SiMe3)2]3 (LaNTMS). The reaction employs low catalyst loadings (0.01ꢀ1 mol% LaNTMS), proceeds
rapidly (>99% in 5 min) at 25°C, and is moderately airꢀtolerant. Additionally, this hydroboration has good functional
group compatibility, including halides, nitro groups, and nitriles, and is exclusively carbonylꢀselective in the presence of
alkenes and alkynes.
KEYWORDS: homogeneous catalysis, carbonyl hydroboration, ketone/aldehyde reduction, lanthanide, chemoselective
hydroboration
The reduction of aldehydes and ketones serves as an
and acetylenes,23ꢀ29 however their reactivity with carbonꢀ
heteroatom multiple bonds remains relatively unexplored.
After discovering that [Cp*2LaH]2 efficiently catalyzes the
hydroboration/dearomatization of pyridines,30 we sought to
investigate hydroborations of other substrates having carbonꢀ
heteroatom multiple bonds and to enhance the reaction utility
by employing a more synthetically accessible/less airꢀ and
waterꢀsensitive catalyst than [Cp*2LaH]2. Homoleptic
lanthanide amides of the type Ln[N(SiMe3)2]3 are
commercially available for most lanthanides and are less airꢀ
and moistureꢀsensitive than many other organolanthanides.
These complexes (Ln[N(SiMe3)2]3) effectively catalyze
olefin/allene/alkyne hydroelementation,24ꢀ25,27ꢀ29 as well as
aldehyde amidation31 and the Tishchenko reaction,32ꢀ33 but the
potentially useful hydroboration of carbonylꢀcontaining
substrates has not been investigated.
efficient synthetic route to functionalized alcohols, making
this transformation an invaluable tool in fine chemical
production and natural product synthesis. Active hydride
reagents are used ubiquitously for this transformation, but
frequently show poor functional group tolerance (i.e., LiAlH4
reduction of nitro groups, nitriles, amides, etc.) and/or modest
reaction rates (i.e., NaBH4 with hindered ketones).1
Employing a catalyzed system with a less active reductant,
such as pinacolborane (HBpin), can greatly enhance both the
selectivity and the rate of carbonyl reduction. Unlike catalytic
carbonyl hydrosilylation, which has
a wellꢀestablished
literature precedent,2ꢀ5 catalytic carbonyl hydroboration
remains relatively unexplored, and as such, is currently of
great interest.
The catalyst scope for carbonyl hydroboration is rapidly
expanding, as detailed in a recent review.6 Alkaline earth,7ꢀ9
transition metal,10ꢀ17 and main group catalysts18ꢀ22 all mediate
this transformation. While most are effective in aldehyde
reduction, they typically perform poorly with ketones,
requiring high catalyst loadings, long reaction times, or
elevated temperatures. Additionally, many recently reported
catalysts require multiꢀstep, airꢀfree syntheses and rigorously
At a loading of 0.01 mol% in benzene, LaNTMS catalyzes
benzophenone hydroboration with HBpin in up to 99%
conversion in less than 5 min at 25 °C by 1H NMR assay (see
Supporting Information for details). This corresponds to a
TOF >40,000 hꢀ1, which is among the most rapid
pinacolboraneꢀbased reductions reported to date.6,9 Analogous
lanthanide amides (Y, Ce, Sm) were also investigated and
yielded full conversion with only slightly diminished rates
relative to La.34
Table 1 summarizes the full scope of ketones investigated
in this report (see Supporting Information for full product
characterization). Electronꢀrich, aromatic ketones (benzoꢀ
phenone, 4ꢀmethylbenzophenone, and 4,4’ꢀdimethylbenzoꢀ
phenone, Table 1 entries 2ꢀ4) proceed rapidly at a LaNTMS
dried substrates and solvents.
Here we report that
available homoleptic
inexpensive,
commercially
La[N(SiMe3)2]3 (abbreviated henceforth as LaNTMS) catalyzes
the rapid, regioselective hydroboration of diverse aldehydes
and ketones with HBpin at room temperature.
Organolanthanide catalysts were previously shown to
effectively catalyze hydroelementations of olefins, allenes,
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loading of only 0.01 mol%, while aliphatic and less electronꢀ
availability of the catalyst make such high loadings practical
if required. Rotenone (11), a natural product used as a
pesticide and insecticide,35 is likewise only reduced at the
ketone, exhibiting >99% selectivity over alkene hydroboration
and cyclic ether ringꢀopening, the latter of which is common
for other lanthanide Lewis acids.36 Note also that LaNTMS is
not deactivated by the potentially chelating catechol dimethyl
ether.
rich ketones require LaNTMS loadings of 0.1 mol% for
comparable rates. Otherwise, little variation in rate among the
various ketones is noted. Note that halogenated substrates are
tolerated (Table 1 entry 7) and no sideꢀreactions with alkenes
or nitro groups are observed (Table 1, entries 6 and
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Table 1. Scope of ketone hydroboration with LaNTMS
Benzophenone hydroboration serves as the basis for
further investigation into the general applicability of this
catalytic system, including scalability, ambient atmosphere
tolerance, and solvent minimization for “greener” processes.
Preparative scale reactions (1 g, repeated 4 times) do not show
any obvious loss in reactivity from exposure to ambient
atmosphere and no side reactions are observed; after
hydrolysis of the product boryl ester, diphenylmethanol is
obtained in 86% isolated yield. Note that this reaction was
conducted entirely on the bench, foregoing the use of a
Schlenk line and using unpurified benzophenone, LaNTMS, and
benzene, taking no special precautions to exclude air or
moisture. Further exploration of the catalyst’s tolerance to
ambient atmosphere was hindered by the moisture sensitivity
of HBpin, which we found to be at least as susceptible to
hydrolysis as LaNTMS. Other solvents can also be used (e.g.,
heptane, ether, THF, CH2Cl2), and this reaction can be run
neat, with HBpin acting as the solvent (safety note: the
reaction is exothermic and, without solvent to dissipate
evolved heat, should be run in an ice bath). This is highly
desirable from a wasteꢀreduction perspective and further
demonstrates the robustness of the catalyst. After removing
volatiles in vacuo, benzophenoxy pinacolborane is obtained in
97% isolated yield.
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Substrate
Product
Cat
Time
Yield
(1)
(2)
(%)
(min)
(%)a
ꢀꢀꢀ
1 week
15
<1
1
2
3
0.01
0.01
>99
>99
15
0.01
0.1
15
15
15
>99
>99
>99
4
5
6
0.1
Aldehydes are also cleanly reduced by this system,
showing high selectivity towards C=O reduction over alkenes,
alkynes, and nitriles, as well as exhibiting halide tolerance
(Table 2 entries 6, 4, 8, and 5 resp.). However, reaction rates
0.1
15
15
>99
>99
7
Table 2. Scope of aldehyde hydroboration with LaNTMS
.
0.1
0.1
8
9
15
90
50
98
Substrate
Product
Yield
(%)a
0.1
1.0
15
15
>99
>99
10
11
Cat.
(%)
Time
(min)
(3)
(4)
ꢀꢀꢀ
0.1
1.0
60
11%
1
2
3
15
60
50
>99
aNMR yield. Ketone (0.25mmol) added to 0.5 mL HBpin
solution (0.30mmol) and C6Me6 internal standard in C6D6.
LaNTMS added from
stock solution of appropriate
concentration, and reaction monitored by HNMR. Isolated
alcohol yields of novel boronic esters are reported in the SI.
15
15
>99
>99
a
1
Bpin
O
0.1
4
H
H
10, respectively). Benzalacetone (6) undergoes hydroboration
selectively at the ketone while preserving the olefin
functionality, even at catalyst loadings as high as 5 mol%.
This is significant since the low cost and commercial
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obtained in 91% yield (by NMR), with only 6% of the diꢀ
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hydroborated product (11b) and <1% of the ketoneꢀonly
hydroboration product (11c). Subsequent addition of a second
equivalent of HBpin gives 11b in >99% yield by H NMR.
1.0
1.0
0.1
0.1
15
15
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15
>99
>99
>99
>99
5
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7
1
Similar intramolecular selectivity was reported using a metalꢀ
free diazaphospholene catalyst19 and an aluminum
monohydride catalyst.22 However in those cases ketones are
much less reactive than aldehydes in isolated reactions,
requiring longer reaction times, higher temperatures, or higher
catalyst loadings. In a competition study, where equimolar
acetophenone and benzaldehyde are allowed to compete for
1.0 equiv. HBpin (Scheme 1b), preference for aldehyde
hydroꢀboration is again observed, reaching 91% conversion of
benzaldehyde and only 9% conversion of acetophenone.
When a second equiv. of HBpin is introduced, both borylated
products are obtained in >99% yield. Such selectivity for
aldehyde vs ketone hydroboration with pinacolborane is also
noteworthy and has only been reported twice before using
Bpin
H
9
O
H
8
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NC
O Bpin
H H
0.1
0.1
15
15
>99
>99
Fe
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a.NMR yield. Aldehyde (0.25mmol) added to 0.5 mL
solution of HBpin (0.30 mmol) and C6Me6 (0.05mmol)
internal standard in C6D6. LaNTMS added from stock solution
of appropriate concentration, and the reaction monitored by
1H NMR. Isolated alcohol yields of novel boronic esters are
reported in the SI.
13
either [Ru(pꢀcymene)Cl2]2 or an aluminum monohydride
catalyst.22 Again, these systems exhibit lowered activity with
ketones vs aldehydes in independent systems, requiring longer
reaction times and/or higher temperatures for ketone
reduction. The present system, which displays selectivity that
is contrary to what would be expected based on kinetic data, is
highly unusual and, to our knowledge, has not been reported
previously for pinacolboraneꢀbased reductions.
are generally slower than for ketones, and higher catalyst
loadings are required for comparable reaction rates (Table 2).
This observation is contrary to what has been observed
previously, where aldehydes are more reactive than ketones.6
The empirical rate law for catalytic ketone hydroboration
(eq. 1) was determined via 1H NMR monitoring with
reference to C6Me6 as internal standard (see Supporting
Information for details). The most sluggish ketone examined
11c
11
11b
11a
Rate = k [LaNTMS]1 [HBpin]1 [Ketone]1
(1)
was dicyclohexylketone, which was used for kinetic analysis
to enable precise rate monitoring at low conversions (< 20%).
Under the present reaction conditions the rate is found to be
firstꢀorder in [Ketone], [HBpin], and [LaNTMS], suggesting all
are involved in the turnoverꢀlimiting step or in a rapid preꢀ
equilibrium before this step. Activation parameters for the
dicyclohexylketone hydroboration are ꢁH≠ = +17 ± 1 kcal/mol
and ꢁS≠ = ꢀ15 ± 2 e.u. The large ꢁH≠ may reflect unfavorable
steric repulsions in the transition state.
The rate law for catalytic aldehyde hydroboration (eq. 2)
was determined in a similar manner (see Supporting
Information) using cyclohexylcarboxaldehyde due to its
structural similarity to dicyclohexylketone. Interestingly, the
rate is zero-order in [HBpin] and [Aldehyde] under the same
Scheme 1. Competitive Aldehyde/Ketone Hydroboration
Selectivity Study. A. 4ꢀAcetylbenzaldehyde. B. Benzaldehyde
and acetophenone.
In conclusion, we report the rapid catalytic hydroboration
of ketones and aldehydes with HBpin using a simple
lanthanum amido catalyst. High selectivity for aldehyde
hydroboration over ketones and CꢀC unsaturation is observed,
along with good functional group tolerance for many other
groups. Further investigations of scope and mechanism are in
progress.
AUTHOR INFORMATION
Corresponding Author
Rate = k [LaNTMS]1[HBpin]0[Aldehyde]0
(2)
conditions, and the activation parameters are markedly
different as well (ꢁH≠ = +12 ± 2 kcal/mol and ꢁS≠ = ꢀ33 ± 7
e.u.), suggesting distinct mechanistic departure from the
ketone hydroboration process. Further mechanistic details are
currently under investigation.
These surprising ketone vs aldehyde rate and mechanistic
differences prompted competition experiments to directly
probe hydroboration selectivity. In a reaction of 4ꢀacetylꢀ
benzaldehyde (11, Scheme 1a) with 1.0 equiv. HBpin at 97%
conversion, the aldehydeꢀonly hydroboration product (11a) is
*tꢀmarks@northwestern.edu, tracy.lohr@northwestern.edu
Present Addresses
†Chemical Sciences & Engineering Division, Argonne National
Laboratory, Lemont, Illinois 60439ꢀ4803, United States
Author Contributions
‡These authors contributed equally.
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13. Kaithal, A.; Chatterjee, B.; Gunanathan, C. Org. Lett. 2015, 17,
4790ꢀ4793.
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Notes
14. Guo, J.; Chen, J.; Lu, Z. Chem. Comm. 2015, 51, 5725ꢀ5727.
The authors declare no competing financial interest.
15. Bagherzadeh, S.; Mankad, N. P. Chem. Comm. 2016, 52, 3844ꢀ
3846.
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ASSOCIATED CONTENT
Supporting Information.
The supporting information is available free of charge at acs.org.
Experimental details, kinetic analysis, 1H, 11B, and 13C NMR
characterization of products.
16. Zhang, G.; Zeng, H.; Wu, J.; Yin, Z.; Zheng, S.; Fettinger, J. C.
Angew. Chem., Int. Ed. 2016, 55, 14369ꢀ14372.
17. Drover, M. W.; Schafer, L. L.; Love, J. A. Angew. Chem., Int. Ed.
2016, 55, 3181ꢀ3186.
8
18. Hadlington, T. J.; Hermann, M.; Frenking, G.; Jones, C. J. Am.
Chem. Soc. 2014, 136, 3028ꢀ3031.
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ACKNOWLEDGMENT
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Financial support was provided by National Science Foundation ꢀ
element grant CHEꢀ1213235. This work made use of the
IMSERC at Northwestern University, which has received support
from the NSF (CHEꢀ1048773 and CHEꢀ9871268); Soft and
Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF
NNCIꢀ1542205); the State of Illinois and International Institute
for Nanotechnology. V.L.W. was supported by an NSF graduate
research fellowship. We acknowledge R.J. Thomson
(Northwestern) for helpful discussions.
19. Chong, C. C.; Hirao, H.; Kinjo, R. Angew. Chem., Int. Ed. 2015,
54, 190ꢀ194.
20. Query, I. P.; Squier, P. A.; Larson, E. M.; Isley, N. A.; Clark, T.
B. J. Org. Chem. 2011, 76, 6452ꢀ6456.
21. Mukherjee, D.; Osseili, H.; Spaniol, T. P.; Okuda, J. J. Am.
Chem. Soc. 2016, 138, 10790ꢀ3.
22. Jakhar, V. K.; Barman, M. K.; Nembenna, S. Org. Lett. 2016, 18,
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