Versatile, mild, and selective reduction of various carbonyl groups using an electron-deficient boron catalyst

Article abstract of DOI:10.1039/c6ob00127k

A mild and selective new method was discovered to reduce acetanilides and other carbonyl compounds. Unlike sodium borohydride, which is selective in reducing aldehydes and ketones, this new protocol is uniquely selective in reducing acetanilides and nitriles over other carbonyl containing functional groups. Additionally, β-ketoamides were shown to be reduced at the ketone preferentially over the amide.

Full text of DOI:10.1039/c6ob00127k

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DOI: 10.1039/C6OB00127K.
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DOI: 10.1039/C6OB00127K
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Versatile, mild, and selective reduction of various carbonyl
groups using an electron-deficient boron catalyst
Received 00th January 20xx,
Accepted 00th January 20xx
Katherine M. Lucasa, Adam F. Klemana, Luke R. Sadergaskia †, Caitlyn L. Jollya, Brady S.
Bollingera, Brittany L. Mackeseya, and Nicholas A. McGratha*
DOI: 10.1039/x0xx00000x
www.rsc.org/
of carrying out these critical transformations, little is known about
the chemoselectivity13 of the overall processes. Additionally, the
conditions have not been used to selectively reduce amides or
nitriles to date. Therefore, we sought to gain a more thorough
understanding of the selectivity of the reaction, along with its
applicability toward the reduction of other carbonyl-derived
functional groups such as amides and nitriles.
A mild and selective new method was discovered to reduce
acetanilides and other carbonyl compounds. Unlike sodium
borohydride, which is selective in reducing aldehydes and
ketones, this new protocol is uniquely selective in reducing
acetanilides and nitriles over other carbonyl containing functional
groups. Additionally, β-ketoamides were shown to be reduced at
the ketone preferentially over the amide.
Electron-deficient boron Lewis acids have recently been utilized
by the synthetic community for a variety of diverse applications1.
These include forming frustrated Lewis acid-base pairs for metal-
2
free hydrogenation reactions1b,
and co-catalyzing olefin
polymerization reactions3. Two of the more synthetically useful are
the deprotection of methyl aryl ethers4 (Scheme 1A) and the
reduction of carbonyl groups to the corresponding alkanes (Scheme
1B) or silyl ethers, depending on the number of equivalents
(Scheme 1C)5 and nature of silane employed (Scheme 1D)6. The silyl
ethers, accessed by only using 1 equivalent of triethylsilane5, 7, can
then be mildly deprotected to the corresponding alcohols using a
fluoride source such as tetrabutylammonium fluoride (TBAF)8. A
boron Lewis acid was also shown to selectively cleave a very
complex methyl aryl ether9 when other standard deprotection
conditions such as boron tribromide treatment caused complete
decomposition10. The most common electron-deficient borane
employed for these reactions is tris(pentafluorophenyl)borane7
Scheme 1. Known reactivity of B(C6F5)3 and Et3SiH with aryl
methyl ethers and aldehydes and ketones. Depending on the
amount and type of silane employed, the carbonyl reduction can
form either silyl ethers or alkanes.
The most commonly employed conditions to reduce an amide
to its corresponding amine utilize highly reactive and non-selective
lithium aluminum hydride (LiAlH4)14. While effective, the functional
group tolerance of LiAlH4 is meager at best, competitively reacting
with aldehydes and ketones, all carboxylic acid derivatives, nitriles,
imines, oximes, azides, epoxides, alkyl halides and nitro groups15.
Additionally, LiAlH4 reacts violently with water requiring the use of
anhydrous ether solvents and caution must be taken during the
workup of the reaction. Clearly a mild and selective alternative
approach would be of great interest to the synthetic community. To
initially screen the reactivity of carbonyl-containing compounds
versus ethers we purchased a set of selectivity probes shown in
Scheme 2. In all three cases treatment with 2 equivalents of silane
and 10 mol % borane catalyst was selective in reducing and
deoxygenating the carbonyl functionalities while leaving the aryl
ether intact. It should be noted that treatment with excess
triethylsilane eventually reacts with the methyl aryl ethers as well.
(B(C6F5)3) in conjunction with
a trialkylsilane, most often
triethylsilane. A remarkable quality of (B(C6F5)3 that sets it apart
from most boron-based Lewis acids of equal strength, such as
boron trifluoride, is that it has been shown to be much more
hydrolytically stable and even catalytically active in aqueous
systems11. Aldehydes, ketones, esters, lactones, acid chlorides,
alcohols, carboxylic acids, and ethers have all been reduced,
depending on conditions and silane equivalents to silyl ethers,
alcohols or alkanes5. More recently, non-symmetric cyclic ethers
were also shown to be reduced regioselectively using these
conditions12. Although this boron/silane system has proven capable
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Moving on to probe the relative reactivity ofVitehweArtcicaletaOlnyltiniec
DOI: 10.1039/C6OB00127K
B(C6F5)3/Et3SiH system to the reduction of acetanilide amides, a set
of functionalized acetanilides were purchased and other anilines
were acetylated to their corresponding acetanilide derivatives16.
The addition of 3 equivalents of triethylsilane and a catalytic
amount of B(C6F5)3 in non-anhydrous dichloromethane cleanly and
efficiently accomplished the reduction of the acetanilides without
any indication of significant by-product formation (Table 1). In
addition, we were able to show that even more sterically hindered
N-substituted acetanilides such as N-methylacetanilide are also
susceptible to reduction under these conditions, even though they
require the use of a less sterically hindered silane (diethyl silane)
and elevated temperatures (Table 1, Entry 5). To our knowledge,
this represents the first report of such a mild reduction of an
acetanilide to the corresponding N-ethylaniline. In addition, these
substrates clearly show that both electron-rich and electron-
deficient acetanilides are capable of being reduced using this
system, even though the electron-rich variant required a higher
catalyst loading to accomplish the task (Table 1, Entry 2). The
reactions proceed efficiently at room temperature without the
need of anhydrous solvents or an inert gas atmosphere.
Scheme 2. Selective aldehyde and ketone deoxygenation in
presence of methyl aryl ethers
Table 1. Mild reduction of acetanilides to secondary amines in
the presence of a variety of functional groups.
The next question to be answered was what the selectivity
would be when more than one carbonyl-containing functional
group was present. To probe this, two dual-functionalized aromatic
compounds were used, the first being an amide-ketone (Table 1,
Entry 6) and the second an amide-ester (Table 1, Entry 7). Not only
were the amides reduced again under these conditions, but they
were also selectively deoxygenated over the “more reactive”
ketone and ester in each case. This reaction is therefore quite
complimentary to reduction by sodium borohydride, which has long
been known to selectively reduce aldehydes and ketones while
being incapable of reducing amides. It seems the reaction indeed
likely undergoes “pre-coordination” of the silyl group with the more
nucleophilic amide carbonyl oxygen and is subsequently attacked
by an in-situ formed borohydride nucleophile as previously
reported6a. In addition to being complementary to sodium
borohydride, the mild nature of these conditions clearly make it an
obvious replacement for the harsh conditions of lithium aluminum
hydride otherwise needed to accomplish the comparable reduction
of an amide.
The successful reduction of the more sterically hindered N-
methylacetanilide with diethylsilane when the standard conditions
proved ineffective prompted an additional examination of the
generality of this reaction. Therefore several different silanes were
screened to test their relative reactivity. To accomplish this,
another tertiary silane (Ph3SiH) along with a secondary (Et2SiH2) and
a primary silane (PhSiH3) were used (Table 2). Each time an amide
was tested first by treatment with 3 molar equivalents of silane.
Under these conditions, the triphenyl silane struggled to generate
adequate product formation, the diethyl silane worked equally well
as the triethyl silane, and the monophenyl silane resulted in
decomposition. Even with ten equivalents of triphenyl silane the
reaction still struggled, suggesting a potential steric hindrance to
reactivity. Stepping down to two molar equivalents of monophenyl
silane eliminated the decomposition initially observed, cleanly
deoxygenating the amide. Therefore, it is concluded that the less
sterically hindered the silane is, the more reactive it is in this
process.
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Table 2: Probing the effect of varying the sterics of the silane
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reducing agent on the reaction progress.
DOI: 10.1039/C6OB00127K
Scheme 4. Inhibitory effect of alkyl amides on the reduction of
acetanilides
The successes of selective acetanilide reduction prompted us to
explore the potential reduction of another carbonyl derivative that
typically requires harsh conditions to reduce, the largely unreactive
nitrile group. Due to the known nucleophilicity of the nitrogen atom
of a nitrile17, we hypothesized our reduction system could also
successfully reduce a nitrile. The choice of nitriles also extended the
selectivity screening of this reaction by testing the relative reactivity
of a few different functional groups. Both of the first two substrates
cleanly reduced the nitrile functionality while leaving the ester and
methyl aryl ether intact (Scheme 5).
In an effort to further investigate the reduction of amide
groups, a set of alkyl-based amides were purchased or synthesized
through acetylation of the corresponding amine. All attempts to
apply these conditions to the various alkyl-amides proved
unsuccessful. Even when the equivalents of silane and borane were
increased and the reactions were heated in 1,2-dichloroethane with
more reactive silanes, the alkyl-amides were completely unreactive
(Scheme 3). Therefore, in a complex system containing multiple
amide functionalities, these conditions could be used to selectively
reduce the acetanilides present while leaving the alkyl amides
unreacted.
Scheme 5. Competition reactions between nitriles and esters,
methyl aryl ethers, and amides
Scheme 3. Alkyl-amides unreactive even under forcing
conditions
Another interesting aspect of the nitrile reduction is that both
of these products were isolated as the corresponding N,N-
Bis(triethylsilyl) amine. Comparing nitrile reduction to amide
reduction, the latter involves overall deoxygenation, likely resulting
in formation of a disilylether byproduct. The nitrile reduction,
however, involves successive silyl activation of the nitrile and
hydride additions, resulting in the incorporation of two silyl groups
and two hydride equivalents. No attempts were made to remove
the silyl group although treatment with TBAF would very likely
liberate the free amine in each case. The third substrate in Scheme
5 was used to probe the relative reactivity of an amide compared to
a nitrile. Both functionalities are typically challenging to reduce and
The inability to reduce alkyl amides led us to investigate
competition experiments that sought to better explain this lack of
reactivity. Along these lines an alkyl amide was mixed 1:1 with
various acetanilides and the mixture was subjected to the standard
reaction conditions (Scheme 4). Surprisingly, it appears the alkyl
amide actually has some form of inhibitory effect under these
reaction conditions, as all of the acetanilides screened were now
unreactive when in the presence of an equivalent of alkyl amide.
Not until 1.5 equivalents of borane and 10 equivalents of
triethylsilane were used did we observe conversion of the
acetanilide to the corresponding N-ethylaniline. This inhibitory
effect will be the focus of future investigations.
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require harsh conditions, so we sought to compare their reactivity
under these conditions. By employing our standard conditions, the
amide was cleanly deoxygenated while the nitrile remained intact.
Therefore, acetanilides appear to reduce quite chemoselectively13
under these conditions.
Notes and references
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Any new compounds that were not prevDioOuIs: l1y0.i1n03t9h/eC6lOitBe0ra0t1u27rKe
or whose 1H-NMR and 13C-NMR data is not readily available have
been fully characterized and the NMR spectra and HRMS data
are available in the supporting information.
In a further examination of the selectivity of the carbonyl
reductions, we sought to determine if the proximity of the carbonyl
groups would affect the reaction outcome. To accomplish this, two
β−ketoamides were used (Scheme 6). Interestingly, both examples
resulted in ketone reduction rather than amide as observed in Table
1. Also, regardless of the number of equivalents of silane used, the
reaction outcome was the same and we never observed any
deoxygenation of either of the carbonyl groups. A possible
explanation for this change in reactivity could originate from the
previously reported mechanistic study6a. If the initial rate-
determining step for the process involves the carbonyl oxygen
coordinating to the silyl group, and the amide previously proved the
better nucleophile for the task, then it might be assumed that the
same initial coordination occurs. Due to the proximity of the
neighboring ketone in these cases, the silyl could chelate or bridge
between the two carbonyl groups, thus activating both for
nucleophilic attack by the borohydride. At this point the more
electrophilic ketone is attacked and the resulting species remains
chelated until the reaction is complete and the product is isolated.
This also explains the lack of subsequent reactivity.
1. (a) Hoshimoto, Y.; Kinoshita, T.; Ohashi, M.; Ogoshi, S.,
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McGrath, N. A.; Bartlett, E. S.; Sittihan, S.; Njardarson, J. T.,.
Angew. Chem. Int. Ed. 2009, 48 (45), 8543-8546.
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J. J. Am. Chem. Soc. 1998, 120 (25), 6287-6305; (b) Chen, Y. X.;
Stern, C. L.; Yang, S. T.; Marks, T. J. J. Am. Chem. Soc. 1996, 118
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2000, 65 (10), 3090-3098; (b) Rendler, S.; Oestreich, M. Angew.
Chem. Int. Ed. 2008, 47 (32), 5997-6000.
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M.; Njardarson, J. T. Chem. Commun. 2011, 47 (1), 209-211.
10. Kosak, T. Eur. J. Org. Chem. 2015, 34, 7460-7467.
11. Ishihara, K.; Hanaki, N.; Funahashi, M.; Miyata, M.;
Yamamoto, H. B. Chem. Soc. Jpn. 1995, 68 (6), 1721-1730.
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2012, 48 (63), 7844-7846.
13. Trost, B. M.; Salzmann, T. N. J. Am. Chem. Soc. 1973, 95
(20), 6840-6842.
14. Finholt, A. E.; Bond, A. C.; Schlesinger, H. I. J. Am. Chem.
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Scheme 6. Reduction of β-Keto-Amides results in TES-ethers of
the ketone even when treated with excess silane reagent
15. Paquette, L. A., Ollevier, T., Desyroy, V. 2004. Lithium
Aluminum Hydride. e-EROS Encyclopedia of Reagents for
Organic Synthesis.
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Conclusions
The relative reactivities of a variety of functional groups with a
silane and an electron-deficient boron catalyst were examined.
Carbonyl reduction was found to be faster than methyl aryl
ether cleavage. The known reactivity was extended to
acetanilide amides and nitriles to produce aryl amines and
silyl-protected amines respectively. Locally distant ketones and
esters proved to be less reactive than their corresponding
acetanilide amides, while β-ketoamides were shown to react
at the ketone exclusively and stop prior to deoxygenation.
Acetanilide amides were found to be more reactive than
nitriles cleanly affording the corresponding ethyl aniline
derivative without any reduction of the nitrile functionality.
Finally, the reaction was shown to work with a variety of silane
reagents, although the sterically hindered triphenyl silane was
limited in utility. These results help shed light onto the relative
reactivity of various functional groups under these mild
reduction conditions.
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