Chemoselective reduction of aldehydes: Via a combination of NaBH4 and acetylacetone

Article abstract of DOI:10.1039/c9nj03210j

A bench-stable combination of NaBH₄-acetylacetone was developed for the efficient chemoselective reduction of aldehydes in the presence of ketones. This method offers a useful synthetic protocol for distinguishing carbonyl reaction sites, and its synthetic utility is reflected by its moisture tolerance and high efficiency in a variety of complex settings.

Full text of DOI:10.1039/c9nj03210j

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DOI: 10.1039/C9NJ03210J
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Chemoselective Reduction of Aldehyde via a Combination of
NaBH4 and Acetylacetone
Guoqing Sui, a Qingyun Lv, a Xiaoqing Song, a Huihui Guo, a Jiatong Dai, a Li Ren, a Chi-Sing Lee, d
Received 00th January 20xx,
Accepted 00th January 20xx
Wenming Zhou, *a and Hong-Dong Hao*a,b,c
DOI: 10.1039/x0xx00000x
so-formed diol. While this strategy can synthesis the desired product
‘steadily’, it will need four steps. The second strategy need selective
oxidation of the secondary alcohol, which is not
A
bench-stable combination of NaBH4-Acetylacetone was
developed for the efficient chemoselective reduction of aldehydes
in the presence of ketones. This method offers a useful synthetic
protocol for distinguishing carbonyl reaction sites, and its synthetic
utility is reflected by its moisture tolerance and high efficiency in a
variety of complex settings.
a trivial
transformation considering the chemoselective.4 Alternatively, a
straight forward way to directly chemoselective reduce5 the
aldehyde would make the synthesis more efficiency. Several
methods have been reported based on the tunable reactivity of
borohydrides. For example, Ward has excellently shown6 that
aldehydes can be selectively reduced using CH2Cl2 and EtOH as co-
solvents at 78oC, the excess NaBH4 was quenched with distilled
acetaldehyde. Toshima has also disclosed the combination of NaBH4
with hexafluoroisopropanol to obtain the NaBH(HFIP)3. While the
method has been successfully applied in total syntheses,7 this
reagent is reported to be moisture sensitive when handling in the
solid state. Several methods based on metal-catalyzed hydrogen
transfer have also reported,8 which show further potential
application. In this regard, an aldehyde reduction method possessing
both chemoselectivity and mild operability is still needed, and the
formed primary alcohol can be further modified in natural product
synthesis and biorthogonal chemistry. During a total synthesis
project, we settled this chemoselective reduction challenge, taking
Functional group transformation is important for the strategic
execution in organic synthesis, and chemoselective functional
transformation can facilitate to synthesis the desired product
with minimal of redox manupulation.1 Carbonyl group, as one
of the most ubiquitous and important functional groups in the
repertoire of organic chemistry, many of its various
transformations have become trivial reaction in organic
synthesis. Among the transformations, the reduction of
carbonyl groups to alcohols is one of the most basic chemical
transformations, and its significance is reflected in the many
reagents that have been developed for this purpose,2 such as
LiAlH4, NaBH4, and DIBAL-H. Limitations in chemoselectivity3
still exist, however, and in complex settings, such as the
selective reduction of aldehydes in the presence of ketones and
other functional groups can present a difficult challenge in
many scenarios.
Strategy 1: four steps with selective protection of primary alcohol
O
O
HO
R
OPG
O
OH
H
3) oxidation
1) reduction
In this regard, several strategies have been developed to address
this problem. For instance, global reduction of both aldehyde and
ketone motifs followed by selective protection and oxidation of the
H
R
H
4) deprotection
2) selective
protection
R
H
H
Strategy 2: selective oxidation of secondary alcohol
O
O
2) selective
oxidation
HO
R
OH
H
O
OH
H
1) reduction
R
H
a. Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of
Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi 712100,
China. Email: hongdonghao@nwafu.edu.cn
H
H
R
Strategy 3: chemoselective reduction of aldehyde
b. State Key Laboratory of Bioorganic & Natural Products Chemistry, Shanghai
Institute of Organic Chemistry (SIOC), Chinese Academy of Science, Shanghai
200032, China.
O
O
selective
reduction
Previous Work:
low temperature
or moisture senstive
O
OH
H
R
H
R
H
c. Key Laboratory of Chemical Genomics, School of Chemical Biology and
Biotechnology, Peking University, Shenzhen Graduate School, Shenzhen 518055,
China.
This Work (strategy 3):
d. Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong
Kong SAR, China.
NaBH4, acac
THF, 0 o
(89%)
C
OHC
O
O
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
OH
inspiration from an earlier total synthesis project.9
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Scheme 1 Strategies for chemoselective reduction of aldehyde
Table 1. Optimization of Reaction Conditionsa
more efficient solvent, dramatically reducing the reaction time to 40
DOI: 10.1039/C9NJ03210J
mins (entry 4). To pursue a more efficient protocol, the screening of
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other solvents that might facilitate this transformation was further
conducted. Among the tested solvents, acetonitrile (CH3CN) and THF
outweighed others in terms of yield and reaction time (entry 5 and
7). Lowering the reaction temperature to 0oC further increased the
yield to 95% (entry 9). It should be noted that wet THF or even a
THF/acetone mixture as the solvent allowed smooth reduction,
showcasing the mildness of the condition. NaBH(OAc)3 was also test
for the selective reduction, the product 2a only isolated in 43% yield
after 24 h (entry 11).
5
6
7
8
CHO
OH
NaBH4, acacH
solvent
O
O
9
1a
2a
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Reaction
time
Entry
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
CH2Cl2
EtOAc
12 h
67
37
70
77
93
78
85
81
95
Table 2. Superior Reduction Selectivity of Aldehyde to Ketone Motifa
16 h
Toluene
24 h
O
O
O
OH
H
NaBH4, acacH
THF, 0 o
C
1,4-dioxane
CH3CN
CHCl3
40 min
10 min
22 h
R
H
R
H
2
1
Time
(min)
Yield
(%)
Entry
1
2
CHO
THF
THFb
THF (0 oC)
5 min
5 min
12 min
2b R = Et
2c R = n-Bu
2d R = Ph
12
15
3
76
92
86
OH
1b R = Et
1c R = n-Bu
1d R = Ph
1
2
3
R
R
O
O
O
CHO
CHO
1e
1f
OH
OH
2e
2f
25
20
94
85
4
5
10
11
THF/acetone (10:1)
THFc
aReaction conditions: 1a (1.0 mmol), NaBH4 (1.25 mmol),
acetylacetone (1.0 mmol) in dry solvent at r.t bCommercial available
THF was used. cNaBH(OAc)3 (2 mmol) was used instead of NaBH4 and
acetylacetone.
12 min
24 h
80
43
O
O
O
CHO
OH
2g
2h
10
15
65
73
1g
1h
6
7
O
O
CHO
CHO
OH
Sodium borohydride (NaBH4) which was first synthesized by
Schlesinger and H. C. Brown,10 have become the most common used
reagent for carbonyl reduction, however the used condition (NaBH4
in MeOH or EtOH) can not differentiate between aldehyde and
ketone. So several modifications to decrease the reactivity of NaBH4
were reported. For example, sodium triacetoxyborohydride
(NaBH(OAc)3) ,11 with the B-H bond being stabilized by the steric and
electron-withdrawing effects of the acetoxy groups, acts as a mild
and widely used reducing reagent. This strategy has been applied to
prepare both NaBH(OAc)3 and NaBH(OCH(CF3)2)3, but their
reactivities are deactivated significantly, thus both reagents require
higher temperatures and/or long reaction times to reduce aldehydes.
Herein, we report an efficient chemoselective aldehyde reduction
approach enabled by a novel bench-stable combination with a
mixture of NaBH4 and a bidentate ligand acetylacetone.
O
O
1i R = Me
1j R = Et
1k R = n-Bu
1l R = Ph
2i R = Me
2j R = Et
2k R = n-Bu
2l R = Ph
15
20
30
20
87 (83)b
80
81
83
8
9
10
11
OH
O
O
R
R
O
O
2m R = Me
2n R = Et
2o R = n-Bu
2p R = Ph
20
15
70
80
67
75
74
95
CHO
1m R = Me
1n R = Et
1o R = n-Bu
1p R = Ph
12
13
14
15
R
R
OH
CHO
OH
16
S
2q
8
81 (32)c
1q
S
S
S
Ph
O
Ph
O
O
O
S
17
1r
2r
10
84 (32)c
N
S
N
CHO
CHO
OH
N
N
N
N
N
N
OH
2s
N
1s
1t
S
25
25
97 (19)c
83 (39)c
18
19
N
S
O
O
O
O
CHO
CHO
N
O
2t
N
O
OH
Initially, the preparation of the combination was simply accessed
by mixing NaBH4 (1.25 equiv) and acetylacetone (1.0 equiv) in THF at
0 C. After stirring for 2 hs, the reaction solvent was evaporated to
obtain a white powder which is stable in open air. 12 Then we start to
test the reactivity of this combination with 4-acetylbenzaldehyde (1a)
as the substrate. As shown in Table 1, solvent effect seemed to be
rather significant in this process. Dichloromethane and EtOAc only
gave moderate yields with long reaction time (entry 1 and 2).
Toluene provided a better yield while a further decreased reaction
efficiency (entry 3). 1,4-dioxane, by contrast, proved to be a much
O
O
O
20
21
13
91 (0)c
O
OH
2u
o
1u
N
O
N
O
1v
5
89
2v
OHC
O
O
OH
aReaction conditions: 1a to 1v (1.0 mmol), NaBH4 (1.25 mmol),
o
b
c
acetylacetone (1.0 mmol) in dry THF at 0 C. 1.0 g scale. Reaction
conditions: 1q to 1u (1.0 mmol), NaBH4 (1.0 mmol) in MeOH at 0 oC.
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With the optimized conditions established, efforts began to and 1ab) from fenofibrate (a drug used VfieowrArtipclreiOmnalinrye
evaluate the substrate scope. Several aromatic aldehydes (1b to 1g) hypercholesterolemia or mixed dyslipidemia) and pleuromutilin (a
15
DOI: 10.1039/C9NJ03210J
were prepared form 4-(hydroxymethyl)benzaldehyde through tricyclic diterpene fungal metabolite as starting material for further
Grignard addition and global oxidation while aliphatic aldehyde antibiotic development) also yielded the corresponding primary
substrates (1i to 1p) were synthesized rapidly in three steps from the alcohols in good yield. In this regard, this representative structural
corresponding 10-undecenoid acid and ethyl chrysanthemumate elaboration demonstrated that the developed sequence may provide
(cis/trans mixture) through Weinreb amide formation, Grignard facile access to a focused library of an array of structural analogues.
addition followed by ozonolysis (For details, see Supporting
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Information). Then these substrates were submitted to the above
reaction conditions. As compiled in Table 2, the superior selectivity
Conclusions
toward the aldehyde motif to the ketone group was shown in cases
of aromatic as well as aliphatic ones. In each case, the desired
selective aldehyde reduction products were isolated in satisfactory
In summary, a convenient, highly efficient, and chemoselective
reduction of aldehyde carbonyl moiety to primary alcohols
enabled by a bench-stable solid through combination of NaBH4
yields ranging from 67% to 97%. Notably, substrates with labile and acetylacetone is reported. The diversity of substrates, the
high degree of compatibility with common organic functional
groups, as well as the operability and stability of the reducing
reagent raised the prospect of its applications in the
pharmaceutical industry, general organic synthesis and natural
product modification. Application in natural product total
synthesis is actively pursued and will be reported in due course.
functional groups such as aldimine (1s), succinimide derivatives 1t
and 1u (for the preparation of these substrates, see Supporting
Information), also underwent the anticipated reduction (entry 18-20).
The disulfide aldehyde substrate 1q can be reduced efficiently in 81%
yield while NaBH4/MeOH will reduce the “fragile”disulfide bond.
Meanwhile, selective reduction in the presence of tetrazole 1r also
worked well (84% yield) while in NaBH4/MeOH condition, only 1-
phenyl-1,2,3,4-tetrazole resulting from C-S bond cleavage was
isolated.13 Furthermore, this approach was conducted on a 1.0 g
gram scale, furnishing the desired product 2i in 83% yield (87% yield
when in 1 mmol). During the study, we also found that under
reaction condition, the monosubstituted conjugated ketone 1g
underwent both selective reduction and 1,4-reduction.14 Substrates
(1h, 1v) from chiral terpene (limonene and camphor) also works well
under the reduction condition (entry 7 and 21).
Conflicts of interest
There are no conflicts to declare.
Acknowledgement
We are grateful for financial support from the
National Natural Science Foundation of China (21901211), the
start-up fund (Z111021705) of Northwest A&F University and
the Open Fund (K3290218001) of State Key Laboratory of
Bioorganic & Natural Products (SIOC), the Open Fund of Key
Laboratory of Chemical Genomics (PKU, Shenzhen) is also
acknowledged. H. D thank Dr. Julius R. Reyes (NYU, Dirk Trauner
group) and Dr. Lili Shi (PKU, Zhen Yang group) for helpful
discussions during the preparation of this manuscript.
Table 3 Selective reduction of complex molecules
Me
O
Me
O
H
Me
H
OH
Me Me
H
Me Me
OH
HO
H
H
Me
O
H
H
H
O
Me
O
H
O
from oleanolic acid
2x
from deoxycholic acid
2w
2y
(76%)
(83%)
(76%)
Notes and references
OH
OTs
O
O
O
Me
Me
OH
OH
1
(a) N. Z. Burns, P. S. Baran and R. W. Hoffmann, Angew. Chem.
Int. Ed., 2009, 48, 2854; (b) T. Newhouse, P. S. Baran and R.
W. Hoffmann, Chem. Soc. Rev., 2009, 39, 3010.
O
O
Me
Me
OH
O
O
Me
Me
Cl
O
OH
Me
from pleuromutilin
2aa (82%)
Me
O
2
3
For a review on metal hydride reductants, see: H. C. Brown
and S. Krishnamurthy, Tetrahedron, 1979, 35, 567.
from fenofibrate
2z
H
H
2ab (80%)
(77%)
aReaction conditions: 1w to 1ab (1.0 mmol), NaBH4 (1.25 mmol),
acetylacetone (1.0 mmol) in dry THF at 0 oC.
For selected references about chemoslective transformation,
see: (a) Y. Sasano, N. Kogure, S. Nagasawa, K. Kasabata and Y.
Iwabuchi, Org. Lett., 2018, 20, 6104; (b) R. M. B. Dyer, P. L.
Hahn and M. K. Hilinski, Org. Lett., 2018, 20, 2011; For
references on discussing chemoslective issue, see: (c) R. A.
Shenvi, D. P. O’Malley and P. S. Baran, Acc. Chem. Res., 2009,
42, 530; (d) B. M. Trost and T. N. Salzmann, J. Am. Chem. Soc.,
1973, 95, 6840; (e) B. M. Trost, Science, 1983, 219, 245.
(a) R. V. Stevens, K. T. Chapman and H. N. Weller, J. Org.
Chem., 1980, 45, 2030; (b) R. V. Stevens, K. T. Chapman, C. A.
Stubbs, W. W. Tam and K. F. Albizati, Tetrahedron Lett., 1982,
23, 4647; (c) B. M. Trost and Y. Masuyama, Tetrahedron Lett.,
The synthetic utility of this protocol further illustrated through
complex molecule applications. As shown in Table 3, several
substrates derived from natural products and clinical medicines were
submitted to the above optimized reaction conditions. For example,
1x and 1y served as excellent examples as the structure possess
sterically hindered aldehydes groups, and the formed alcohol was
isolated in good yield. In the case of 1w, aldehyde was selective
reduced in the presence of two ketone groups. Substrates (1z, 1aa
4
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1984, 25, 173; For applications, see: M. Miyashita, M. Sasaki,
I. Hattori, M. Sakai and K. Tanino, Science, 2004, 305, 495.
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12 For the detail procedure of preparing this combination, see
Supporting Information.
13 Compounds 1q to 1u also test under NaBH4 (1 equiv), MeOH
condition, for details, see Supporting Information.
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Lancefield, O. S. Ojo, F. Tran, N. J. Westwood, Angew. Chem.
Int. Ed., 2015, 54, 258; (b) Y. Li, D. Xue, W. Lu, C. Wang, Z. T.
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