Visible Light Enabled Formal Cross Silyl Benzoin Reaction as an Access to α-Hydroxyketones

Article abstract of DOI:10.1002/adsc.202100186

In this work, a visible-light enabled coupling of acylsilanes with aldehydes to give a range of cross-benzoin type products α-hydroxyketones is described. The reaction could proceed at ambient temperature, with the irradiation of low energy visible light, and without addition of photosensitizer or any other additives. (Figure presented.).

Full text of DOI:10.1002/adsc.202100186

COMMUNICATIONS
DOI: 10.1002/adsc.202100186
Visible Light Enabled Formal Cross Silyl Benzoin Reaction as an
Access to α-Hydroxyketones
Liyao Ma,b, c Yinghua Yu,b Luoting Xin,b Lei Zhu,b Jiajin Xia,b Pengcheng Ou,b, c
and Xueliang Huanga, b,*
a
Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research, Ministry of Education of China, Key
Laboratory of the Assembly and Application of Organic Functional Molecules of Hunan Province, College of Chemistry and
Chemical Engineering, Hunan Normal University, Changsha, Hunan 410081, People's Republic of China
E-mail: huangxl@hunnu.edu.cn
b
Key Laboratory of Coal to Ethylene Glycol and Its Related Technology, Center for Excellence in Molecular Synthesis, Fujian
Institute of Research on the Structure of Matter, Fujian College, Chinese Academy of Sciences, Fuzhou, Fujian 350002, People's
Republic of China
E-mail: huangxl@fjirsm.ac.cn
College of Chemistry, Fuzhou University, Fuzhou 350116, People's Republic of China.
c
Manuscript received: March 15, 2021; Revised manuscript received: March 15, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100186
Recently, Kusama and coworkers have reported an
elegant method on ZnI2 assisted photoinduced coupling
Abstract: In this work, a visible-light enabled
coupling of acylsilanes with aldehydes to give a
of acylsilanes with aldehydes with an irradiation of
range of cross-benzoin type products α-hydroxyke-
500 W super-high-pressure Hg lamp.[9] In line with our
tones is described. The reaction could proceed at
continuing research interests in the reaction of alde-
ambient temperature, with the irradiation of low
hydes with reactive carbene intermediates,[10] we have
energy visible light, and without addition of photo-
unexpectedly uncovered an efficient protocol to
sensitizer or any other additives.
prepare α-hydroxyketones through formal cross silyl
benzoin reaction between acylsilanes with aldehydes
under extremely mild conditions. Compared with
Keywords: cross-benzoin reaction; visible-light; al-
Kusama’s work, the reaction described in this work
dehydes; acylsilanes; α-hydroxyketones; additive-free
could proceed well without addition of any Lewis acid
catalysts or photosensitizers. Irradiation by low energy
blue LEDs with a wavelength at 425 nm at room
α-Hydroxyketones are ubiquitous structural motifs temperature is already enough to enable the reaction to
existing in many natural products and biologically occur.[11] In view of the mild reaction conditions and
active compounds (Scheme 1).[1,2] They are also operational simplicity, we decide to report our prelimi-
valuable synthons for chemical synthesis. Classical
approach to access these molecules normally relies on
reaction of two aldehydes via benzoin condensation.[3,4]
However, when two aldehydes with similar properties
are employed, the reaction may lose the regiochemical
control, and lead to the formation of four isomeric
products.[5]
The cross silyl benzoin reaction of acylsilanes and
aldehydes has been reported as regiospecific alterna-
tive to traditional benzoin condensation, while this
reaction generally requires toxic cyanide salts or
moisture sensitive metallophosphites as umpolung
catalysts.[6] Acylsilanes are known to undergo [1,2]-
Scheme 1. Bioactive compounds containing α-hydroxyketone
scaffolds.
Brook rearrangement to generate siloxycarbene inter-
mediates through thermolysis or photoirradation.[7,8]
Adv. Synth. Catal. 2021, 363, 1–6
1
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
Table 2. Substrate scope.[a]
nary results on this metal- and additive-free protocol to
access α-hydroxyketones.
Initially, we selected the reaction of benzaldehyde
1a and (4-methoxybenzoyl)trimethyl-silane 2a as the
model reaction to explore the conditions (Table 1). To
our delight, the desired α-hydroxyketones 3i was
obtained in 50% yield using n-hexane as solvent under
irradiation with blue LEDs (30 W, 425 nm) (Table 1,
entry 1). Encouraged by this result, we subsequently
tested the effects of different solvents, including
cyclohexane, toluene, THF, dioxane, DCE, DCM,
CH3CN and PhCF3 (Table 1, entries 2–9). As depicted,
the yield of 3i could be enhanced to 82%, when the
reaction was carried out in DCM. In addition, we also
examined the influences of the wavelengths of the light
sources, and the results revealed that the blue LEDs
with wavelengths of 425 nm were still the best choice
(Table 1, entries 11–14). When the reaction was run in
more concentrated solution, the yield of 3i could be
enhanced to 85% (Table 1, entry 10).
With the optimal reaction conditions in hand, we
then explored the substrate scope. As depicted in
Table 2, the reaction of the acylsilane containing a
triethylsilyl (TES) group gave the desired product 3a
in 60% yield upon isolation. When the acylsilane
bearing the more sterically hindered triisopropyl
(TIPS) group was employed as carbene precursor, the
reaction became sluggish and the formation of desired
Table 1. Optimization of the reaction conditions.[a]
[a] Aldehyde (0.3 mmol), acylsilane (0.45 mmol) and DCM
(1 mL) was stirred at room temperature with LED (425 nm,
30 W) irradiation under argon.
[a] 1a (0.2 mmol), 2a (0.3 mmol) and solvent (1 mL) was stirred
at room temperature with LED (30 W) irradiation for 24 h
under argon.
[b] 1a (0.3 mmol), 2a (0.45 mmol) and solvent (1 mL).
Adv. Synth. Catal. 2021, 363, 1–6
2
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
product 3a was not observed. These results indicated could also be easily scaled-up to 1 mmol scale while
that this cross- coupling reaction was sensitive to the maintaining similar reaction efficiency (Scheme 2).
steric nature of the silyl groups. Aldehydes ranging
To understand the reaction mechanism, a compet-
from aromatic to aliphatic aldehydes could react well itive experiment was performed. As described in
with acylsilanes, giving a variety of substituted α- Scheme 3a, silane 2a reacted with equal equivalent of
hydroxyketones in moderate to high yields. With aldehydes bearing methyl or ester moiety at the para
respect to aromatic aldehydes, electron withdrawing position of the phenyl ring, giving α-hydroxyketones
groups on the phenyl ring seem to have positive effects 3k and 3w in 6% and 68% NMR yields, respectively.
on the reaction outcome. By contrast, the reactions of These results indicated that aldehyde with electron-
aldehydes bearing MeO-, Me-, i-Pr- or t-Bu- group at withdrawing group possessing higher reactivity. To
the para position of the phenyl ring gave the identify the significance of irradiation with visible
corresponding hydroxyketones in slightly lower yields. light, a light on-off experiment was carried out with 1a
Functional groups including bromo, chloro, nitrile, and 2a (Scheme 3b). The desired product yield
ester and sulfone moieties were tolerated as well. increased significantly only during the irradiated
Aldehydes containing heteroaromatic rings were com- period. By constrast, the reaction was almost shut
petent reactants and longer reaction time were required down during the dark period.
to reach full conversion.
Based on aforementioned results, a possible reac-
Next, we investigated reactions of benzoyltrimeth- tion mechanism is described in Scheme 4. First,
ylsilane with aldehydes bearing substituted groups on acylsilane A undergoes 1,2-Brook rearrangement upon
the phenyl ring at different positions, and the desired irradiation with visible-light to generate a transient
products 3a–3h were obtained in 81–92% yields.
Subsequently, the reactivities of aldehydes containing
different electron-donating groups including a meth-
oxyl group or alkyl substituents at the para position of
the phenyl ring were examined, and the corresponding
α-hydroxyketones 3j–3m were obtained in 31–75%
yields. For reactions of aldehydes bearing halogen
atoms on the phenyl ring, 3n–3r were obtained in 80–
Scheme 2. Scale-up experiment
87% yields. Aldehydes bearing different substituents
with different electronic properties, including
trifluoromethyl, trifluoromethoxy, phenyl, nitrile, ester
and sulfone, were viable substrates, and corresponding
α-hydroxyketones 3s to 3x were obtained in up to
96% isolated yields. Naphthaldehydes are also suitable
for this reaction, giving α-hydroxyketones 3y–3z in
57–68% yields. Aldehydes bearing heteroaromatic
rings were also tolerated under standard conditions, α-
hydroxyketones bearing thiophenyl and furanyl rings
could be synthesized (3aa and 3ab). Moreover,
cinnamaldehyde was also viable substrate for current
reaction, and α-hydroxyketone 3ac was obtained in
69% isolated yield. Interestingly, the geometry of the
double bond was isomerized from E to Z upon visible
light irradation. It is worth noting that aliphatic
aldehydes containing open chain or cyclic rings were
all compatible, giving corresponding the α-hydroxyke-
tones 3ad–3ak in moderate to high yields.
Subsequently, a variety of acylsilanes were pre-
pared, and their reactivity was tested under standard
conditions. As depicted, a range of acylsilanes could
react well, regardless of the electronic characters of
substituents on the aromatic ring (3ba–3bf). Pleas-
ingly, acylsilane derived from aliphatic aldehyde was a
competent carbene precursor as well, and α-hydrox-
yketone product 3bg was obtained in 65% yield, which
further highlight the benzoin reaction. The reaction
Scheme 3. Mechanistic studies.
Adv. Synth. Catal. 2021, 363, 1–6
3
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
H. Hilbi, Sensors (Basel) 2012, 12, 2899–2919; e) P.
Hoyos, J. V. Sinisterra, F. Molinari, A. R. Alcántara, P.
Domínguez de María, Acc. Chem. Res. 2010, 43, 288–
299; f) A. Tiaden, T. Spirig, H. Hilbi, Trends Microbiol.
2010, 18, 288–297.
[2] a) S. Jin, J. Gong, Y. Qin, Angew. Chem. Int. Ed. 2015,
54, 2228–2231; Angew. Chem. 2015, 127, 2256–2259;
b) S. Escandon-Rivera, M. Gonzalez-Andrade, R. Bye,
E. Linares, A. Navarrete, R. J. Mata, Nat. Prod. 2012,
75, 968–974; c) A. Takada, Y. Hashimoto, H. Takikawa,
K. Hikita, K. Suzuki, Angew. Chem. Int. Ed. 2011, 50,
2297–2301; Angew. Chem. 2011, 123, 2345–2349; d) T.
Tanaka, M. Kawase, S. Tani, Bioorg. Med. Chem. 2004,
12, 501–505; e) O. B. Wallace, D. W. Smith, M. S.
Deshpande, C. Polson, K. M. Felsenstein, Bioorg. Med.
Chem. Lett. 2003, 13, 1203–1206; f) R. Uchida, K.
Shiomi, T. Sunazuka, J. Inokoshi, A. Nishizawa, T.
Hirose, H. Tanaka, Y. Iwai, S. J. Omura, Antibiotica
1996, 49, 886–889.
[3] For selected reviews: a) M. M. Heravi, V. Zadsirjan, K.
Kafshdarzadeh, Z. Amiri, Asian J. Org. Chem. 2020, 9,
1999–2034; b) L. De Luca, A. Mezzetti, Synthesis 2019,
52, 353–364; c) P. P. Giovannini, O. Bortolini, A. Massi,
Eur. J. Org. Chem. 2016, 4441–4459; d) R. S. Menon,
A. T. Biju, V. Nair, Beilstein J. Org. Chem. 2016, 12,
444–461; e) B. M. Trost, M. J. Bartlett, Acc. Chem. Res.
2015, 48, 688–701.
[4] a) J. Yan, R. Sun, K. Shi, K. Li, L. Yang, G. Zhong, J.
Org. Chem. 2018, 83, 7547–7552; b) Y. Li, S. Yang, G.
Wen, Q. Lin, G. Zhang, L. Qiu, X. Zhang, G. Du, X.
Fang, J. Org. Chem. 2016, 81, 2763–2769; c) G. Wen, Y.
Su, G. Zhang, Q. Lin, Y. Zhu, Q. Zhang, X. Fang, Org.
Lett. 2016, 18, 3980–3983; d) N. Kuhl, F. Glorius,
Chem. Commun. 2011, 47, 573–575; e) L. Baragwanath,
C. A. Rose, K. Zeitler, S. J. Connon, J. Org. Chem. 2009,
74, 9214–9217; f) K. Iwamoto, H. Kimura, M. Oike, M.
Sato, Org. Biomol. Chem. 2008, 6, 912–915; g) Y. Li, Z.
Feng, S. L. You, Chem. Commun. 2008, 19, 2263–2265;
h) X. Linghu, J. R. Potnick, J. S. Johnson, J. Am. Chem.
Soc. 2004, 126, 3070–3071.
[5] a) E. G. Delany, S. J. Connon, Org. Biomol. Chem. 2018,
16, 780–786; b) N. Gaggero, S. Pandini, Org. Biomol.
Chem. 2017, 15, 6867–6887; c) S. M. Langdon, M. M.
Wilde, K. Thai, M. Gravel, J. Am. Chem. Soc. 2014, 136,
7539–7542; d) S. E. O’Toole, C. A. Rose, S. Gundala, K.
Zeitler, S. J. Connon, J. Org. Chem. 2011, 76, 347–357;
e) P. Dünkelmann, D. Kolter-Jung, A. Nitsche, A. S.
Demir, P. Siegert, B. Lingen, M. Baumann, M. Pohl, M.
Müller, J. Am. Chem. Soc. 2002, 124, 12084–12085.
[6] a) K. M. Steward, J. S. Johnson, Org. Lett. 2010, 12,
2864–2867; b) J. C. Tarr, J. S. Johnson, J. Org. Chem.
2010, 75, 3317–3325; c) J. C. Tarr, J. S. Johnson, Org.
Lett. 2009, 11, 3870–3873; d) X. Linghu, C. C. Bausch,
J. S. Johnson, J. Am. Chem. Soc. 2005, 127, 1833–1840;
e) X. Linghu, A. D. Satterfield, J. S. Johnson, J. Am.
Chem. Soc. 2006, 128, 9302–9303; f) M. R. Nahm, X.
Linghu, J. R. Potnick, C. M. Yates, P. S. White, J. S.
Johnson, Angew. Chem. Int. Ed. 2005, 44, 2377–2379;
Scheme 4. Proposed mechanism.
carbene species B. According to the competition
experiments shown in Scheme 3a, the resonance form
zwitterion C rather than the free carbene intermediate
B would prefer to react with aldehydes to generate
epoxide D, which is highly reactive to undergo ring-
opening to produce E. In situ removal of the trimethyl-
silyl group in E could eventually give the desired α-
hydroxyketone 3.
In summary, we have developed a visible-light-
enabled formal cross silyl benzoin reaction. The
reaction could proceed under extremely mild condition
while without the requirement of addition of any other
reagents. The ease operational procedure and broad
substrate scope may indicate a valuable synthetic
potential for preparation of different α-hydroxyketones
in a sustainable manner.
Experimental Section
General Procedure for Preparation of α-Hydroxy-
ketones 3
An oven-dried Schlenk tube under argon atmosphere was
charged with aldehyde 1 (0.30 mmol, 1.0 equiv), acylsilane 2
(0.45 mmol, 1.5 equiv) and DCM (1 mL). The mixture was
stirred at room temperature with the irradiation of LED
(425 nm, 30 W). The progress of the reaction was monitored by
TLC. Upon completion, p-toluenesulfonic acid (0.3 mmol,
1.0 equiv) was added to the reaction mixture, then the solvents
were evaporated under reduced pressure and the residue was
purified by flash chromatography on silica gel to afford the
desired products.
Acknowledgements
We thank the financial support by NSFC (Grant No. 21871259,
and 21901244), the Strategic Priority Research Program of the
Chinese Academy of Sciences (Grant No. XDB20000000).
References
[1] For selected reviews: a) Y. Que, H. He, Eur. J. Org.
Chem. 2020, 5917–5925; b) D. Albanese, N. Gaggero,
Catalysts 2018, 8, 181–200; c) H. C. Hailes, D. Rother,
M. Muller, R. Westphal, J. M. Ward, J. Pleiss, C. Vogel,
M. Pohl, FEBS J. 2013, 280, 6374–6394; d) A. Tiaden,
Adv. Synth. Catal. 2021, 363, 1–6
4
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
Angew. Chem. 2005, 117, 2429–2431; g) C. C. Bausch,
J. S. Johnson, J. Org. Chem. 2004, 69, 4283–4285; h) X.
Linghu, J. S. Johnson, Angew. Chem. Int. Ed. 2003, 42,
2534–2536; Angew. Chem. 2003, 115, 2638–2640;
i) A. G. Brook, R. Pearce, J. B. Pierce, Can. J. Chem.
1971, 49, 1622–1628.
[9] a) K. Ishida, H. Yamazaki, C. Hagiwara, M. Abe, H.
Kusama, Chem. Eur. J. 2020, 26, 1249–1253; b) K.
Ishida, F. Tobita, H. Kusama, Chem. Eur. J. 2018, 24,
543–546; c) K. Ito, H. Tamashima, N. Iwasawa, H.
Kusama, J. Am. Chem. Soc. 2011, 133, 3716–3719.
[10] a) L. Xin, W. Wan, Y. Yu, Q. Wan, L. Ma, X. Huang,
ACS Catal. 2021, 11, 1570–1577; b) Y. Yu, L. Ma, J.
Xia, L. Xin, L. Zhu, X. Huang, Angew. Chem. Int. Ed.
2020, 59, 18261–18266; Angew. Chem. 2020, 132,
18418–18423; c) L. Zhu, X. Ren, Y. Yu, P. Ou, Z. X.
Wang, X. Huang, Org. Lett. 2020, 22, 2087–2092; d) H.
Zhang, Y. Yu, X. Huang, Org. Biomol. Chem. 2020, 18,
5115–5119; e) Y. Yu, P. Chakraborty, J. Song, L. Zhu, C.
Li, X. Huang, Nat. Commun. 2020, 11, 461; f) C. Yan, Y.
Yu, B. Peng, X. Huang, Eur. J. Org. Chem. 2020, 723–
727; g) G. Chen, J. Song, Y. Yu, X. Luo, C. Li, X.
Huang, Chem. Sci. 2016, 7, 1786–1790; h) X. Yan, Y.
Xia, Chin. J. Org. Chem. 2020, 40, 3988–3989; i) Y. Yu,
Q. Lu, G. Chen, C. Li, X. Huang, Angew. Chem. Int. Ed.
2018, 57, 319– 323; Angew. Chem. 2018, 130, 325–329.
[7] For selected reviews: a) D. L. Priebbenow, Adv. Synth.
Catal. 2020, 362, 1927–1946; b) H. J. Zhang, D. L.
Priebbenow, C. Bolm, Chem. Soc. Rev. 2013, 42, 8540–
8571.
[8] a) D. L. Priebbenow, J. Org. Chem. 2019, 84, 11813–
11822; b) P. Becker, R. Pirwerdjan, C. Bolm, Angew.
Chem. Int. Ed. 2015, 54, 15493–15496; Angew. Chem.
2015, 127, 15713–15716; c) P. Becker, D. L. Priebbe-
now, H. J. Zhang, R. Pirwerdjan, C. Bolm, J. Org. Chem.
2014, 79, 814–817; d) P. Becker, D. L. Priebbenow, R.
Pirwerdjan, C. Bolm, Angew. Chem. Int. Ed. 2014, 53,
269–271; Angew. Chem. 2014, 126, 273–275; e) H. J.
Zhang, P. Becker, H. Huang, R. Pirwerdjan, F. F. Pan, C.
Bolm, Adv. Synth. Catal. 2012, 354, 2157–2161; f) Z.
Shen, V. M. Dong, Angew. Chem. Int. Ed. 2009, 48, 784– [11] J. H. Ye, L. Quach, T. Paulisch, F. Glorius, J. Am. Chem.
786; Angew. Chem. 2009, 121, 798–800.
Soc. 2019, 141, 16227–16231.
Adv. Synth. Catal. 2021, 363, 1–6
5
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

COMMUNICATIONS
Visible Light Enabled Formal Cross Silyl Benzoin Reaction
as an Access to α-Hydroxyketones
Adv. Synth. Catal. 2021, 363, 1–6
L. Ma, Y. Yu, L. Xin, Dr. L. Zhu, J. Xia, P. Ou, Prof. Dr. X.
Huang*