An efficient FeCl3-mediated approach for reduction of ketones through N-heterocyclic carbene boranes

Article abstract of DOI:10.1016/j.tetlet.2017.01.011

An efficient FeCl₃-mediated approach for reduction of ketones by NHC-BH₃ has been developed. A series of ketones were smoothly converted to the corresponding alcohols in good to excellent yields through NHC-BH₃ reductive process.

Full text of DOI:10.1016/j.tetlet.2017.01.011

Accepted Manuscript
An efficient FeCl3-mediated approach for reduction of ketones through N-het-
erocyclic carbene boranes
Ming-Hui Wang, Ling-Yan Chen
PII:
S0040-4039(17)30011-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.011
TETL 48514
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 December 2016
30 December 2016
3 January 2017
Please cite this article as: Wang, M-H., Chen, L-Y., An efficient FeCl3-mediated approach for reduction of ketones
through N-heterocyclic carbene boranes, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.
2017.01.011
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
An efficient FeCl3-mediated approach for
reduction of ketones through N-heterocyclic
carbene boranes
Leave this area blank for abstract info.
Ming-hui Wang, Ling-yan Chen*

1
Tetrahedron Letters
An efficient FeCl3-mediated approach for reduction of ketones through N-heterocyclic
carbene boranes
Ming-Hui Wang, Ling-Yan Chen*
College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai, 201620, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient FeCl3-mediated approach for reduction of ketones by NHC-BH3 has been developed. A
series of ketones were smoothly converted to the corresponding alcohols in good to excellent yields
through NHC-BH3 reductive process.
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
ketones
N-heterocyclic carbene boranes
FeCl3
Reduction
Introduction
was afforded in moderate yield.8 It is worth mentioning that
acetic acid was an excellent additive in this reduction process.10
Since 1,3-bis (2,6-diisopropylphenyl)- imidazol-2-ylidene
borane (dipp-Imd-BH3) (Figure 1, 1) was firstly synthesized by
Robinson1 in 2007, N-heterocyclic carbene boranes (NHC-
boranes or NHC-BH3)2 have been developed rapidly in organic
chemistry. Most of the applications of NHC-BH3 were focused
on radical3, ionic4, reductive5, hydroborations6 and
organometallic reactions7. Solids of NHC-boranes present
practical advantages such as readily accessibility, stability
towards air or water and so on. Moreover, the hazardous
chemicals (metallic hydrides) could be effectively avoided in the
reduction process.
To our knowledge, there was no example for the reduction of
ketones by NHC-BH3 in the presence of other Lewis acid. We
herein described an efficient approach for the reduction of
ketones by NHC-BH3 in the presence of anhydrous FeCl3.
In 2012, Curran's results revealed that NHC-BH3 was a good
hydride donor in the reduction of aldimines5c. Interestingly,
aldehydes could be smoothly converted to the corresponding
alcohols in excellent yields through the reduction of NHC-BH3
on silica gel8. Very recently, our results demonstrated the tert-
butanesulfinyl ketimines could asymmetrically reduced by NHC-
BH3 based on a triazole core (Figure 1, 6) in the presence of
TsOH with high diastereoselectivity (de > 99%) in 95% yield.9
Compared to common reagents of NaBH4, NaBH3CN or BH3-
THF, NHC-BH3 exhibited excellent reductive abilities. While for
the reduction of ketones, Curran used the silica gel as additive in
the NHC-BH3 reduction process. Once the reaction was treated in
the absence of the essential additive, the reduction time
commonly needed several days and the desired secondary alcohol
Figure 1 Several synthesized NHC-Boranes
Results and discussion
Several different NHC-BH3 1-6 were easily prepared by
known process3a,3d: depronation of the corresponding NHC
precursors with NaHMDS and followed by addition of BH3 in
*
Corresponding author. Tel./fax: +0862167791220
E-mail address: lingyan.chen@hotmail.com (L.-Y. Chen)

2
Tetrahedron
THF at -78oC to give NHC-BH3 1-6 in high overall yields
was a significant decrease in yield after longer time (Table 2,
entry 8). This suggests that not all hydride atoms of NHC-BH3 4
could be utilized in the reduction. Finally, 0.8 eq. of NHC-BH3 4
with 0.6 eq. FeCl3 was supposed to be the best amount. The
chemical yield could keep quantative in 30 min.
(Figure 1). Firstly, acetophenone 8a was selected as the substrate
to explore the reductive abilities of different NHC-BH3 in the
presence of several additives (Table 1). When the hindered dipp-
Imd-BH3 1 and TsOH was used, the result was fruitless (Table 1,
entry 1). The least hindered diMe-Imd-BH3 2 was used, the
desired product 9a was smoothly obtained in 45% yield (Table 1,
entry 2). Several other NHC-BH3 3-6 was also investigated in the
presence of TsOH, and the results were still unsatisfactory (Table
1, entries 3-6). To improve the reactivity of this reduction, other
additives of brønsted acids were screened. The results indicated
that the stronger acids like TFA and TfOH could improve yields
of 9a (60% and 85%, Table 1, entries 10 and 11). Fortunately,
when the Lewis acids of FeCl3, BF3.Et2O or Yb(OTf)3 were used,
the excellent yield of 9a were obtained (Table 1, entries 14, 16-
17). Anhydrous FeCl3 could effectively prompt the quantitative
conversion of ketone 8a to alcohol 9a in 15 min (Table 1, entry
14). It is worth noting that all the reactions were open to air and
the solvent was directly used without any purification in advance.
Table 2 Investigation of the effects of different solvents on
the reduction of acetophenone 8a.a
entry
1
Solvent
DCM
Time
15 min
3 h
Yieldb (%)
99
33
25
35
88
40
95
80
99
2
MeOH
THF
3
3 h
4
MeCN
toluene
EtOAc
DCM
3 h
5
3 h
6
3 h
Table 1 Investigation of the effects of different NHC-BH3 1-6
and acids on the reduction of acetophenone 8a.a
7c
8d
9e
1 h
DCM
3 h
DCM
30 min
a
Unless otherwise noted, all reactions were carried out using 6a (0.25
mmol), NHC-BH3 (0.25 mmol), and FeCl3 (0.25 mmol) in solvent (1.0mL) at
rt for 15 min-3 h.
b Isolated yield.
Yieldb (%)
c FeCl3 (0.5 equiv.) was used.
Entry
NHC-BH3
Additive
TsOH
Time
3 h
3 h
3 h
3 h
3 h
3 h
3 h
3 h
d NHC-BH3 4 (0.5 equiv.) was used.
e NHC-BH3 (0.8 equiv.), FeCl3 (0.6 equiv.) were used.
1
2
3
4
5
6
7
8
-
1
2
3
4
5
6
4
4
TsOH
45
35
56
20
10
20
15
Using the optimized conditions, the scope of the reduction of
ketones has been further explored. A wide range of aryl alkyl-,
diaryl-, dialkyl- and cycloketones were tested. As shown in Table
3, almost all the reactions of different types of ketones proceeded
quite well and gave good to excellent yields. On the one hand,
when using the substrate with strong electron-withdrawing group
like 8c, the yield was slightly lower (85%, Table 3, entry 3).
When using the substrate with steric hindered group like 8p, the
chemical yield was relatively lower with high stereoselectivity
(68%, dr > 99/1, Table 3, entry 16). On the other hand, 1.0 equiv.
of anhydrous FeCl3 was needed to promote the reductions for the
types of diaryl- and cyclo- ketones (Table 3, entries 10-15).
Additionally, ,-unsaturated ketones and ester substituted
ketones were also examined. For ,-unsaturated ketone, the
yield was rather low possibly due to the partial reduction of
alkene (Table 3, entry 19), while ester substituted ketones could
be selectively reduced to corresponding alcohols (Table 3, entries
20). However, if there was a hydroxyl group or an amino group
in the phenyl ring, the yields sharply decreased (Table 3, entries 8
and 11).
TsOH
TsOH
TsOH
TsOH
CH3COOH
PhCOOH
9
HCOOH
TFA
3 h
3 h
45
60
4
4
10
11
12
13
14
15
16
17
TfOH
AlCl3
SnCl2
FeCl3
ZnCl2
3 h
3 h
85
30
17
99
28
90
80
4
4
4
4
4
4
4
3 h
15 min
3 h
.
BF3 Et2O
1 h
Yb(OTf)3
3 h
a
Unless otherwise noted, all reactions were carried out using 8a (0.25
mmol), NHC-BH3 (0.25 mmol), and acid (0.25 mmol) in CH2Cl2 (1.0 mL) for
15 min-3 h.
b Isolated yield.
Table 3 The scope of reduction of ketones by NHC-BH3 4 in
the presence of anhydrous FeCl3.a
With these preliminary results, we turned our attention to
investigate the effect of solvent on the reaction (Table 2). The
result showed that when DCM was used, desired 9a was obtained
in quantitative yield (Table 2, entry 1). Toluene also gave good
yield up to 88% (Table 2, entry 5). For other solvent systems
such as THF, methanol, acetonitrile and ethyl acetate, the yields
of 9a were lower (Table 2, entries 2-4 and 6). In addition, when
the amount of FeCl3 was decreased to 0.5 eq., the yield of 9a
would slightly decreased (Table 2, entry 7). The acid, FeCl3, was
believed to activate ketone during reduction5b-c, and therefore it
may not be necessary to use stoichiometric amount to achieve
optimal yield. However, if we used 0.5 eq. of NHC-BH3 4, there
Yieldb
(%)
Entry
1
Ketone
Product
9
8
99

3
2
3
93
85
18
98
19
20
53
92
4
5
98
96
a Unless otherwise noted, all reactions were carried out using 6 (0.25
mmol), NHC-BH3 (0.20 mmol), and FeCl3 (0.15-0.25 mmol) in DCM (1.0
mL) at rt for 30 min-1 h.
b Isolated yield.
In summary, we have demonstrated an efficient and
convenient approach for reduction of ketones by NHC-BH3 in the
presence of anhydrous FeCl3. This strategy tolerated a wide range
of ketones and good to excellent yields were achieved. As NHC-
BH3 often is so stable and easy to prepare, handle, react, and
separate from target products, which made NHC-BH3 a valuable
alternative reductive reagent. Further explorations of new chiral
NHC-BH3 complex and asymmetric transformations are in
progress.
6
7
8
90
98
65
Acknowledgments
The authors thank Professor Zhihua Sun for helpful
discussions and are grateful for financial support from the
Scientific Research Foundation for the Returned Overseas
Chinese Scholars, State Education Ministry and the students
Innovation Program in Shanghai University of Engineering
Science (15KY0404).
98
dr:19/1
9
10
11
90
72
References and notes
1.
Wang, Y.; Quillian, B.; Wei, P.; Wannere, C. S.; Xie,Y.; King, R. B.;
Schaefer, H. F.; Schleyer, P. V. R.; Robinson, G. H. J. Am. Chem. Soc.
2007, 129, 12412-12413.
12
13
98
2.
For reviews, see: (a) Curran, D. P.; Solovyev, A.; Makhlouf Brahmi, M.;
Fensterbank, L.; Malacria, M.; Lacôte, E. Angew. Chem., Int. Ed. 2011,
50, 10294–10317. (b) Lacote, E.; Curran, D. P.; Lalevee, J. Chimia,
2012, 66, 382-385.
3.
For selected examples, see: (a) Ueng, S.-H.; MakhloufBrahmi, M.;
Derat, É .; Fensterbank, L.; Lacôte, E.; Malacria, M.; Curran, D. P. J.
Am. Chem. Soc. 2008, 130, 10082–10083. (b) Ueng, S.-H.; Solovyev,
A.; Yuan, X.; Geib, S. J.; Fensterbank, L.; Lacôte, E.; Malacria, M.;
Newcomb, M.; Walton, J. C.; Curran, D. P. J. Am. Chem. Soc. 2009,
131, 11256–11262. (c) Walton, J. C.; Makhlouf Brahmi, M.;
Fensterbank, L.; Lacôte, E.; Malacria, M.; Chu, Q.; Ueng, S.-H.;
Solovyev, A.; Curran, D. P. J. Am. Chem. Soc. 2010, 132, 2350–2358.
(d) Ueng, S.-H.; Fensterbank, L.; Lacôte, E.; Malacria, M.; Curran, D. P.
Org. Lett. 2010, 12, 3002−3005. (e) Ueng, S.-H.; Fensterbank, L.;
Lacôte, E.; Malacria, M.; Curran, D. P. Org. Biomol. Chem. 2011, 9,
3415−3420. (f) Pan, X.; Lacôte, E.; Lalevée, J.; Curran, D. P. J. Am.
Chem. Soc. 2012, 134, 5669-5674. (g) Pan, X.; Vallet, A.-L.; Schweizer,
S.; Dahbi, K.; Delpech, B.; Blanchard, N.; Graff, B.; Geib, S. J.; Curran,
D. P.; Lalevée, J.; Lacôte, E. J. Am. Chem. Soc. 2013, 135, 10484–
10491. (h) Pan, X.; Lalevée, J.; Lacôte, E.; Curran, D. P.
Advanced Synthesis & Catalysis 2013, 355, 3522-3526. (i) Kawamoto,
T.; Geib, S. J.; Curran, D. P. J. Am. Chem. Soc. 2015, 137, 8617-8622.
(j) Tambutet, G.; Guindon, Y. J. Org. Chem. 2016, 81, 11427-11431.
(a) Lee, K. S.; Zhugralin, A. R.; Hoveyda, A. H. J. Am. Chem. Soc.
2009, 131, 7253–7255. (b) Chu, Q.; Makhlouf Brahmi, M.; Solovyev,
A.; Ueng, S.-H.; Curran, D.; Malacria, M.; Fensterbank, L.; Lacôte, E.
Chem.Eur. J. 2009, 15, 12937−12940. (c) Solovyev, A.; Chu, Q.; Geib,
S. J.; Fensterbank, L.; Malacria, M.; Lacôte, E.; Curran, D. P. J. Am.
82
16
14
15
95
95
68
dr>99/1
16
17
4.
96

4
Tetrahedron
Chem. Soc. 2010, 132, 15072−15080. (d) Pan, X.; Curran, D. P. Org.
Lett. 2014, 16, 2728−2731.
Chem. Soc. 2013, 135, 12076−12081. (d) Damodaran, K.; Li, X.; Pan,
X.; Curran, D. P. J. Org. Chem. 2015, 80, 4465-4469.
5. (a) Farrell, J. M.; Hatnean, J. A.; Stephan, D.W. J. Am. Chem. Soc. 2012,
134, 15728–15731. (b) Lindsay, D. M.; McArthur, D. Chem. Commun.
2010, 46, 2474–2476. (c) Horn, M.; Mayr, H.; Lacôte, E.; Merling, E.;
Deaner, J.; Wells, S.; McFadden, T.; Curran, D. P. Org. Lett. 2012, 14,
82−85. (d) Eisenberger, P.; Bestvater, B. P.; Keske, E. C.; Crudden, C.
M. Angew. Chem., Int. Ed. 2015, 54, 2467–2471.(e) Farrell, J. M.;
Posaratnanathan, R. T.; Stephan, D. W. Chemical Science 2015, 6,
2010-2015.
8. Taniguchi, T.; Curran, D. P. Org. Lett. 2012, 14, 4540−4543.
9. Liu, T.; Chen, L.-Y.; Sun, Z. H. J. Org. Chem. 2015, 80, 11441-11446.
10. Lamm, V.; Pan, X.; Tanigichi, T.; Curran, D. P. Beilstein J. Org. Chem.
2013, 9, 675-680.
Supplementary Material
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org
6. (a) Pan, X.; Boussonnière, A.; Curran, D. P. J. Am. Chem. Soc. 2013,
135, 14433−14437. (b) Boussonnière, A.; Pan, X.; Geib, S. J.; Curran, D.
P. Organometallics 2013, 32, 7445−7450.
7. (a) Monot, J.; MakhloufBrahmi, M.; Ueng, S.-H.; Robert, C.; Murr, M.
D.-E.; Curran, D. P.; Malacria, M.; Fensterbank, L.; Lacôte, E. Org. Lett.
2009, 11, 4914–4917. (b) Toure, M.; Chuzel, O.; Parrain, J.-L. J. Am.
Chem. Soc. 2012, 134, 17892−17895. (c) Li, X.; Curran, D. P. J. Am.
Click here to remove instruction text...

5
Highlights:
1. Inexpensive and easily handled Lewis acid
FeCl3 was used to promote the reaction.
2. The reduction by N-heterocyclic carbene
boranes was highly efficient (15 min-1 h, up to
99% yield).
3. N-heterocyclic carbene boranes were proved to
be a valuable alternative reductive reagent.