A chemoselective photolabile protecting group for aldehydes

Article abstract of DOI:10.1016/j.tetlet.2020.151709

A new and high-efficiency photolabile protecting group (PLPG) for aldehydes is described. The PLPG was introduced to aldehydes by using a Lewis acid. Results showed that the PLPG can be released rapidly and smoothly under ultraviolet (UV) irradiation with high efficiency and low cost. This PLPG can easily synthesized and also be selectively protect aldehydes in the presence of ketones.

Full text of DOI:10.1016/j.tetlet.2020.151709

Tetrahedron Letters 61 (2020) 151709
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A chemoselective photolabile protecting group for aldehydes
Jing Xu a, Shouguo Zhang a, Hongpeng Yang a, Xiaoxue Wen a, Tao Peng a, Kaijun Xu b,
,
⇑
a,
Gang Wang a, , Lin Wang
⇑
⇑
a Beijing Institute of Radiation Medicine, 27 Taiping Road, Haidian District, Beijing 100850, PR China
b School of Science, China Pharmaceutical University, Nan Jing 211198, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new and high-efficiency photolabile protecting group (PLPG) for aldehydes is described. The PLPG was
introduced to aldehydes by using a Lewis acid. Results showed that the PLPG can be released rapidly and
smoothly under ultraviolet (UV) irradiation with high efficiency and low cost. This PLPG can easily syn-
thesized and also be selectively protect aldehydes in the presence of ketones.
Received 30 October 2019
Revised 2 February 2020
Accepted 4 February 2020
Available online 5 February 2020
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
Photolabile protecting group
Photodeprotection
Aldehyde compound
O-nitrobenzyl group
Photolabile protecting groups (PLPGs) can be removed by irra-
diation [1] and can release substrates in a spatially and temporally
controlled manner. The releasing condition is mild, and no extra
chemical reagent is not required [2]. PLPGs can be used to protect
various chemical groups, such as alcohols [3], amines [4], and car-
boxylic acids [5]. Therefore, they are widely used in chemical syn-
thesis and life science, such as synthesis of polypeptide [6] or DNA
[7]. Many new PLPGs such as nitroaryl [8], coumarin-4-ylmethyl
[9], arylmethyl [10], miscellaneous [11], and arylsulfonyl groups
[12] have been developed and extensively used in many areas.
However, only a few practically useful photolabile protecting
groups for aldehydes, which are commonly used in modern organic
synthesis, have been reported [16]. These are diferent from the tra-
ditional protecting groups protected aldehydes through an acetal
moiety, and then are deprotected by reactions of acid catalysis
[13], Lewis acid coordination [14] or redox [15].The PLPG o-nitro-
phenylethylene glycol (Npeg, Fig. 1) was first reported by Gravel
[17] et al. in 1984. Npeg can protect aldehyde compounds and
ketone compounds, which will later be released under UV irradia-
tion via deprotection. However, Npeg still have deficiencies, such
as long reaction time for deprotection and inability to protect alde-
hyde selectively. 2-(2-nitrophenyl) propan1-ol (Npp, Fig. 1), a new
PLPG, was synthesized and used by Pfleiderer [9] et al. for protect-
ing hydroxyl groups in a series of nucleosides nucleosides; Npp
was also applied to the synthesis of cyclic peptide as PLPG for car-
boxylic groups in our previous studies [18], and the results of these
studies indicated that Npp does not affect the stability of polypep-
tide. In this study, on the basis of Npeg and Npp, we further devel-
oped a new, simple, and efficient PLPG particularly for protecting
aldehydes. 2-(2-nitrophenyl)-1,3-propanediol (Nppd), as a devel-
oped PLPG for protecting aldehydes, was prepared from 2-nitro-
toluene,
a cheap raw material, via only one step reaction
(Scheme 1). Nppd has various advantages, such as simple synthesis
with low cost, high efficiency and selectivity for protecting aldehy-
des without affecting ketones. In addtion, the protected products of
aldehydes (acetals) were stable in the absence of light and can
rapidly release original aldehydes under UV irradiation with high
efficiency.
Some aldehydes (1a-h) and ketones (1i-k) were used to test
Nppd’s protecting efficiency (Scheme 2, Table 1). The protection
of aldehydes by Nppd can be achieved by only a one-step reaction
in a relatively mild condition. Particularly, 1 equivalent aldehyde
and 2 equivalents of Nppd were dissolved in CH2Cl2. Then, 1 equiv-
alent of Lewis acid BF3ꢀOEt2 was added as promoter, and anhy-
drous magnesium sulfate was added as dehydrating agent. The
reaction was conducted at À15 for 90 min to generate the pro-
tected product (acetal). Results showed that the low temperature
can promote the reaction. For example, the protection yield of 1b
was 25% at room temperature, 37% at 0 , and 47% at À15 °C
(Table 2). However, the protection yield of 1b in the 24 h reaction
was nearly the same with that in the 90 min reaction (Table 3). It
can be concluded that the protection yield cannot be increased
only by extending the reaction time. Other promoters, such as
⇑
Corresponding authors.
E-mail addresses: xukaijun@126.com (K. Xu), wgang85@126.com (G. Wang),
wanglin@bmi.ac.cn (L. Wang).
https://doi.org/10.1016/j.tetlet.2020.151709
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.

2
J. Xu et al. / Tetrahedron Letters 61 (2020) 151709
Table 2
The protection yields of 1b under different reaction Time (90 min).
Reaction temperature( )
Yield(%)
À15
47
0
25
25
37
Fig. 1. Structure of Npeg (left) and Npp (right).
Table 3
The protection yields of 1b under different reaction Time (0 ).
Reaction time
Yield(%)
90 min
47
24 h
43
p-toluenesulfonic acid (TsOH), Pyridinium 4-toluenesulfonate
(PPTS), and FeCl3, were also used for protecting the aldehyde.
Among them, BF3ꢀOEt2 has showed a best result.
Scheme 1. Synthesis of Nppd.
The reactivity of phenyl carbonyl groups vary depending on the
substituents on the benzene ring. The electron-withdrawing sub-
stituents can enhance the reactivity while the electron-donating
substituents reduce it, both of which will affect Nppd’s protective
ability. This conclusion has been proven by the production of 2a-
c formed by 1a-c. Protective experiments on ketone groups were
also studied and the results showed that the protective yields on
cyclohexanone, phenylacetone, and diphenyl ketone were 0%, 4%,
and 0%, respectively. Even if the MgSO4 was replaced by a more
effective dehydrating agent, such as P2O5, the ketone group still
can’t be protected by Nppd. Therefore, only the aldehyde group
can be protected by Nppd even in the presence of the ketone group.
Photodeprotection then released the corresponding aldehyde.
Some aldehydes releasing reaction was performed under UV light
at 365 nm in acetonitrile, instead of methanol reported by Wang
[16] et al, because the protected product (acetal) has the good
solubility in acetonitrile. It is noticed that the photodeprotection
Scheme 2. Protection of Carbonyls with Nppd.
Table 1
Protection and photorelease of the Aldehydes.
Entry
1a
Carbonyl Compounds
Protection Yielda (%)
64
Deprotection Yieldb(%)
71c
Irradiation Time (min)
120
2b
3c
47
78
83c
96e
60
60
4d
39
87e
60
5e
6f
83
70
86e
75e
120
75
7g
8h
73
59
74d
65e
80
90
9i
0
4
–
–
–
–
10j
11k
0
–
–
a
b
c
Reaction conditions: 1 (1 mmol), Nppd (2 mmol), BF3.OEt2 (1 mmol), MgSO4 (8.0 mmol) in 6 mL CH2Cl2, À15 °C, 90 min, isolated yield.
Reaction conditions: Irradiated with a 250 W UV lamp (365 nm) equipped with a Pyrex filter sleeve, CH3CN (0.05 M), isolated yield.
Isolated as the oxime derivatives.
Isolated as the semicarbazone derivative.
Isolated as the aldehyde without derivatization.
d
e

J. Xu et al. / Tetrahedron Letters 61 (2020) 151709
3
Fig. 3. HPLC traces recorded during irradiation of 2f.
Scheme 3. Possible photodeprotection mechanism.
with protection yield of 59% and deprotection yield of 65%. Partic-
ularly, a certern amount of water (1 equivalent) has been added
into the reaction mixture for every 15 min, to inhibit the thermal
effects during the illumination, and to avoid side reaction of the
amino aldehyde caused by excessive water.
1c was protected by Nppd to obtain 2c, and the process of
deprotection was detected by UV spectrophotometer (Fig. 2). A
new absorption peak appeared at the wavelength of 265 nm in
the photolysis reaction and would increase gradually with the
reaction time prolonging. This peak was the characteristic peak
of 1c [22], indicating that the original compound 1c could be
released rapidly at a constant speed from its protected compound
2c under UV at 365 nm.
reaction will not proceed without the presence of a certain amount
of water. On this basis, a possible photodeprotection mechanism
(Scheme 3) according to that of Npp [9] was infered herein. The
photorelease of Nppd from the aldehyde’s protected product (ac-
etal) via a property-labile semiacetal formed from the acetal by a
b-elimination mechanism. The semiacetal was decomposed imme-
diately andyields were lower than the actual values due to their
volatility. These aldehydes need to be processed by derivation after
the deprotection to eliminate the volatility. For example, if 1a
released from 2a after the deprotection is unprocessed by deriva-
tion, the releasing yield will fall to 13%.
Results of Nppd’s application are illustrated in Table 1, which
show that the Nppd can protect aldehydes with relatively high pro-
tection and deprotection yields. The protection yields on the aro-
matic aldehydes (1a, 1b, 1c, 1d, 1e), the unsaturated aldehyde
(1f), the amino aldehyde protected by Fmoc (1h), and the aliphatic
aldehyde (1g) were 64%, 47%, 78%, 39%, 83%, 70%, 73%, and 59%,
respectively. In addition, their deprotection yields were 71%, 83%,
96%, 87%, 86%, 75%, 65%, and 74%. Amino aldehydes are widely
used to synthesize medicine and can be served as precursors of
synthetic antimicrobial drugs penicillin [19] or anticancer drug
[20], and they also play an important role in synthesizing pseu-
dopeptide. In the meanwhile, the amino groups or aldehyde groups
of amino aldehydes are usually protected when they are used
because of their chemical instability [21]. In this study, the amino
aldehyde protected by Fmoc (1h) can be protected by the Nppd,
Reversed-phase HPLC was used to investigate the photodepro-
tection progress of protected aldehydes. For example, 2f (0.02 M
in CH3CN) was investigated during irradiation at 365 nm (Fig. 3).
The analysis was performed on Agilent 1100 apparatus equipped
with a Agela Venusil ASB C18 column (5
l
m, 4.6 mm  250 mm)
over a 10–70% gradient of acetonitrile: water with 0.1% TFA using
a gradient elution in 30 min and flow rate of 1 mL/min. The wave-
length for the detector was set at 220 nm, and the injection volume
was 10
lL. Before irradiation, a peak with a retention time of
31.0 min, corresponding to 2f, was observed. During irradiation,
this peak gradually disappeared, and a new peak (retention time
21.2 min, corresponding to 1f) appeared instead, proving that 2f
released aldehyde under photoirradiation.
The performance of Nppd and Npeg in protecting efficiency,
protecting selectivity, and deprotecting efficiency was compared
(Table 4). The results shown in Table 2 indicated that Nppd’s pro-
tecting efficiency for the carbonyls was lower than that of Npeg.
Npeg formed five-membered cyclic acetals, which were easy to
obtain, but the aldehyde group cannot be selectively protected
by Npeg, and the releasing speed of aldehydes from the Nppd
acetal is faster than that from the Npeg acetal. The deprotecting
yield of Nppd (65%–96%) is nearly the same with Npeg (31%–
90%). However, the reaction time for Nppd was only approximately
Table 4
Comparative protecting efficiency of Nppd and Npeg.
Protecting
group
Protection yield for
Protection yield for
Nppd
Npeg
0
96
78
97
.
Fig. 2. UV spectra of 2c.

4
J. Xu et al. / Tetrahedron Letters 61 (2020) 151709
[2] (a) C.G. Bochet, J. Chem. Soc. Perkin Trans. (2002) 125;
(b) C. Ma, Y. Zhang, H. Zhang, J. Li, Y. Nishiyama, H. Tanimoto, T. Morimoto, K.
Kakiuchi, Synlett 28 (2017) 560.
[3] P. Klán, A.P. Pelliccioli, T. Pospíšil, J. Wirz, Photochem. Photobiol. Sci. 1 (2002)
920.
[4] L. Kammari, L. Plíštil, J. Wirz, P. Klán, Photochem. Photobiol. Sci. 6 (2007) 50.
[5] (a) A.G. Griesbeck, M.S. Gudipati, J. Hirt, J. Lex, M. Oelgemoller, H. Schmickler,
F. Schouren, J. Org. Chem. 65 (2000) 7151;
33% of that for Npeg. Meanwhile, the amount of solvent for Nppd
(15 mL CH3CN) was just only 10% of that for Npeg (200 mL
benzene). The speed of Nppd’s releasing protected aldehydes is fas-
ter than that of Npeg, and the amount of solvent required is also
less, and the solvent is more environmentally friendly.
(b) M. Abe, Y. Chitose, S. Jakkampudi, P.T.T. Thuy, Q. Lin, B.T. Van, A. Yamada, R.
Oyama, M. Sasaki, C. Katan, Synthesis 49 (2017) 3337;
(c) H. Saneyoshi, A. Ono, Chem. Pharm. Bull. 66 (2018) 147;
(d) V. Tiwari, A.K. Singh, P. Chaudhary, P.H. Seeberger, J. Kandasamy, Org.
Chem. Front. 6 (2019) 3859.
Conclusion
Nppd, a new PLPG for aldehydes was designed and prepared
from a cheap material, namely, 2-nitrotoluene, by a one-step reac-
tion. The aldehydes can be protected by Nppd in mild condition
and released rapidly and smoothly under the UV irradiation with
high yields. This new PLPG can be used to protect aliphatic, aro-
matic, unsaturated, and amino aldehydes protected by Fmoc, and
has a good application prospect in the field of organic synthesis.
[6] (a) M. Goard, G. Aakalu, O.D. Fedoryak, C. Quinonez, J. St. Julien, S.J. Poteet, E.
M. Schuman, T.M. Dore, Chem. Biol. 12 (2005) 685;
(b) Tamao, K.; Kumada, M. In The Chemistry of the Metal–Carbon Bond;
Hartley, F. R., Ed.; Wiley: New York, 1987; Chapter 9, p. 819.
[7] (a) D.D. Young, M.O. Lively, A. Deiters, J. Am. Chem. Soc. 132 (2010) 6183;
(b) A. Momotake, N. Lindegger, E. Niggli, R.J. Barsotti, G.C.R. Ellis-Davies, Nat.
Methods. 3 (2006) 35.
[8] (a) A. Patchornik, B. Amit, R. Woodward, B, J. Am. Chem. Soc. 92 (1970) 6333;
(b) N. Komori, S. Jakkampudi, R. Motoishi, M. Abe, K. Kamada, K. Furukawa, C.
Katan, W. Sawada, N. Takahashi, H. Kasai, B. Xue, T. Kobayashi, Chem.
Commun. 52 (2016) 331;
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
(c) N.D.A. Watuthanthrige, P.N. Kurek, D. Konkolewicz, Polymer. Chem. 9
(2018) 1557.
[9] (a) A. Hasan, K.P. Stengele, H. Giegrich, P. Cornwell, K.R. Isham, R.A. Sachleben,
W. Pfleiderer, R. Foote, S. Tetrahedron. 53 (1997) 4247;
(b) C.A. Hammer, K. Falahati, A. Jakob, R. Klimek, I. Burghardt, A. Heckel, J.J.
Wachtveitl, Phys. Chem. Lett 9 (2018) 1448.
Acknowledgments
[10] A.M. Piloto, D. Rovira, S.P.G. Costa, M.S.T. Gonçalves, Tetrahedron 62 (2006)
11955.
The authors are grateful to the National Natural Science Foun-
dation of China (Grant No. 81273431, 21102176 and 21272273)
for its financial support for this project.
[11] N. Kotzur, B. Briand, M. Beyermann, V. Hagen, J. Am. Chem. Soc. 131 (2009)
16927.
[12] G. Cosa, M. Lukeman, J.C. Scaiano, Chem. Res. 42 (2009) 599.
[13] T. Hiyama, H. Oishi, H. Saimoto, Tetrahedron Lett. 26 (1985) 2459.
[14] W. Johnson, C. Edington, J. Elliott, I. Silverman, J. Am. Chem. Soc. 106 (1984)
7588.
Appendix A. Supplementary data
[15] C.E. McDonald, L.E. Nice, A.W. Shaw, N.B. Nestor, Tetrahedron Lett. 34 (1993)
2741.
Supplementary material that may be helpful in the review pro-
cess should be prepared and provided as a separate electronic file.
That file can then be transformed into PDF format and submitted
along with the manuscript and graphic files to the appropriate edi-
torial office. Supplementary data to this article can be found online
at https://doi.org/10.1016/j.tetlet.2020.151709.
[16] (a) P. Wang, H. Hu, Y. Wang, Org. Lett. 9 (2007) 1533;
(b) R. Sugiura, R. Kozaki, S. Kitani, Y. Gosho, H. Tanimoto, Y. Nishiyama, T.
Morimoto, K. Kakiuchi, Tetrahedron 69 (2013) 3984;
(c) P. Wang, Y. Wang, H. Hu, C. Spencer, X. Liang, L. Pan, J. Org. Chem. 73
(2008) 6152.
[17] J. Hébert, D. Gravel, Can. J. Chem. 61 (1983) 400.
[18] G. Wang, T. Peng, S. Zhang, J. Wang, X. Wen, H. Yang, L. Hu, L. Wang, RSC. Adv. 5
(2015) 28344.
[19] J.C. Sheehan, K.R. Henbry-Logan, J. Am. Chem. Soc. 79 (1957) 1262.
[20] E.M. Acton, A.N. Fujiwara, D.W. Henry, J. Med. Chem. 17 (1974) 659.
[21] L. Mestrom, P. Bracco, U. Hanefeld, Eur. J. Org. Chem. 47 (2017) 7019.
[22] M. Zarei, M.A. Zolfigol, A.R. Moosavi-Zare, E. Noroozizadeh, J. Iran. Chem. Soc
14 (2017) 2187.
References
[1] P. Klán, T. Šolomek, C.G. Bochet, A. Blanc, R. Givens, M. Rubina, V. Popik, A.
Kostikov, J. Wirz, Chem. Rev. 113 (2013) 119.