Organotin-catalyzed synthesis of hydroxyalkylamides from lactones via a ring-opening process

Article abstract of DOI:10.1016/j.tetlet.2021.152821

A new strategy for the facile synthesis of hydroxyalkylamides through the ring-opening reaction of lactone with amine promoted by dibutyltin acetate was developed. A series of hydroxyalkylamide compounds were obtained and the method was successfully applied to the synthesis of pharmaceutically active molecules tyrosinase inhibitor V and HDAC inhibitor VI via a three-step synthetic pathway. The broad substrate scope, mild reaction conditions and practical application proved the effectiveness, compatibility and practicality of this method.

Full text of DOI:10.1016/j.tetlet.2021.152821

Tetrahedron Letters 66 (2021) 152821
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Organotin-catalyzed synthesis of hydroxyalkylamides from lactones via
a ring-opening process
⇑
Xiayu Liang, Peng Yu, Chen Fu, Yongcun Shen
School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, No. 122, Luoshi Road, Wuhan 430070, 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 strategy for the facile synthesis of hydroxyalkylamides through the ring-opening reaction of lac-
tone with amine promoted by dibutyltin acetate was developed. A series of hydroxyalkylamide com-
pounds were obtained and the method was successfully applied to the synthesis of pharmaceutically
active molecules tyrosinase inhibitor V and HDAC inhibitor VI via a three-step synthetic pathway. The
broad substrate scope, mild reaction conditions and practical application proved the effectiveness, com-
patibility and practicality of this method.
Received 21 November 2020
Revised 21 December 2020
Accepted 3 January 2021
Available online 16 January 2021
Keywords:
Ó 2021 Elsevier Ltd. All rights reserved.
Hydroxyalkylamide
Ring-opening
Lactone
Amine
Dibutyltin acetate
Introduction
reaction temperature limited the application scope of this method.
Guo et al. revealed the ammonolysis of lactones for the synthesis of
Amide structure exists widely and plays an important role in
many natural products, pharmaceuticals, ligands, and functional
materials [1–4]. The hydroxyl amides obtained from the ring open-
ing reaction of lactones and amines are utilized in novel surfac-
tants, carrier-prodrugs and drug intermediates [5–11]. However,
the reaction is usually restricted by the activity of lactones and
the nucleophilicity of amines, thus defining the optimal condition
for ring-opening is to be addressed and currently under intensive
exploration. Matsumoto and co-workers provided the primary
example of ammonolysis of lactones with amines at room temper-
ature and under a high pressure in 1989 [12]. Then, Lesimple et al.
reported that a series of hydroxyalkamides were obtained in good
yields by ring opening reaction in the presence of AlCl3 [13] Later
on, the ring opening reaction catalyzed by AlMe3, which is sensi-
tive and flammable, was reported [14,15]. In 2001, Huang et al.
successfully used DIBAL-H-H2NR and DIBAL-H-HNR1R2ÁHCl com-
N-aryl amide through organocatalysis of aniline and various lac-
tones in 2017, which proceeded under milder and more favorable
reaction conditions [17]. As mentioned above, some limitations
might jeopardize these synthesis schemes reported, for instance,
the harsh reaction conditions, and the relatively long reaction
times. Therefore, a practical and efficient synthesis strategy for
these valuable hydroxyalkamide compounds is on the call. Organ-
otin catalysts, a new kind of neutral multifunctional homogeneous
catalysts developed in recent years, are different from other metal
compounds in terms of structural stability due to its insensitivity
to air and water [18,19], which have been utilized in the ring-open-
ing polymerization of lactones and alcohols [20–23]. The coordina-
tion of tin and carbonyl oxygen increases the electrophilicity of
carbonyl carbon and facilitates the attack of nucleophile to form
polyester compound [24–26]. Multiple polyester products are
commonly obtained under the initiation of strong nucleophiles,
due to the fact that the traditional tin salts have poor control over
the polymerization process. Different from polyesters, we hypoth-
esized whether the lactone ammonolysis reaction can run
smoothly when using organotin as catalyst and amine as a nucle-
ophilic reagent, which is capable to obtain corresponding hydrox-
yalkanamide compounds (Scheme 1).
plexes as amidating reagents for the aminolysis of c- butyrolactone
[31]. In 2017, Barreto et al. prepared hydroxyl amides from a vari-
ety of amines and lactones by microwave irradiation under the
conditions without solvent and catalysis [16]. Compared with all
the works described so far, the microwave-mediated reaction is
milder and with the ability to shorten the reaction time more effi-
ciently. However, the restrict requirements for equipment and high
Thereafter, our group reported that the amines could react with
lactones efficiently and produce hydroxyalkylamides in good
yields under a mild condition without using inert gas and dry
solvent through the dibutyltin acetate catalysis. The method is
⇑
Corresponding author.
E-mail address: Sycmichael@163.com (Y. Shen).
https://doi.org/10.1016/j.tetlet.2021.152821
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

X. Liang, P. Yu, C. Fu et al.
Tetrahedron Letters 66 (2021) 152821
generally applicable to various types of amines and lactones with
different ring sizes, and moreover, the reaction conditions required
are milder, and the reaction time is shorter, when compared to
other existing methods (Table 1).
Results and discussion
Initially, we explored the direct ring-opening amidation of e-
caprolactone (2a) with benzylamine (1a) in the presence of
10 mol% of various organotin catalysts in THF. The reaction ran
smoothly at 65 °C with the dibutyltin acetate catalyst and gave
Benzyl-6-hydroxyhexanamide 3aa in 76% yield within 12 h. No
reaction happened in the absence of the catalyst (entry 8). The
results of catalyst screening showed that the disubstituted organ-
otin catalysts had a relatively intensive catalytic activity (entry 2,
5, 6), and the steric effect of the catalysts had a great impact on
the reaction progression. The reactions with bis(tributyltin) oxide,
dioctyltin oxide and dibutyltin dilaurate displayed (entry7, 4, 6),
the larger the steric effect of organotin catalysts, the lower the con-
version rate. Meanwhile, we also investigated the effects of the
reaction temperature (entries 23–24), and found that the yield
could reach 80% after 16 h of reaction under 40℃. Lower reaction
temperature effectively increased the yield, but accompanying
the reaction time prolonged. Through the extensive screening of
catalyst loading (entries 8–12), stoichiometric ratio (entries
11,13–17), and solvent (entries18-22), it was found that reaction
of e-caprolactone, benzylamine (2 equivalents), and 20 mol% dibu-
tyltin acetate in THF at 65 °C for 4 h afforded the optimal isolated
yield of 77% of 3aa (entry 11).
A series of N-benzyl hydroxyalkylamides were synthesized
under the optimal reaction conditions found above. As shown in
Scheme 2, we examined the substrate scope by varying the sub-
stituents of benzylamines. When a set of electron-withdrawing
Scheme 1. The strategies to the synthesis of hydroxyalkylamides.
Table 1
Optimization of the Reaction Conditions.a
Entry
Catalyst (mol%)
Solvent
Ratio (1a:2a)
Time (h)
Yield (3aa, %)b
1
2
3
4
5
6
7
8
Butyltin oxide (10)
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
1:1
1.2:1
1.5:1
1.8:1
2.5:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
12
12
12
12
12
12
12
12
10
6
4
4
4
4
4
4
4
4
51
57
18
41
76
63
50
0
57
74
77
76
67
69
72
75
77
54
67
42
72
37
80
21
Dibutyltin oxide (10)
Bis(tributyltin) oxide (10)
Dioctyltin Oxide (10)
Dibutyltin acetate (10)
Dibutyltin dilaurate (10)
Bis(lauroyloxy)dioctyltin (10)
Dibutyltin acetate (0)
Dibutyltin acetate (5)
Dibutyltin acetate (10)
Dibutyltin acetate (20)
Dibutyltin acetate (30)
Dibutyltin acetate (20)
Dibutyltin acetate (20)
Dibutyltin acetate (20)
Dibutyltin acetate (20)
Dibutyltin acetate (20)
Dibutyltin acetate (20)
Dibutyltin acetate (20)
Dibutyltin acetate (20)
Dibutyltin acetate (20)
Dibutyltin acetate (20)
Dibutyltin acetate (20)
Dibutyltin acetate (20)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23b
24c
THF
DCE
Toluene
MeCN
1,4-Dioxane
DMSO
THF
4
4
4
4
16
30
THF
a
Reaction conditions: Benzylamine (1a, 4.38 mmol),
65 °C for 12 h.
e-caprolactone (2a, 2.19 mmol), Organotin catalyst (20 mol%), THF (5 mL) were added in a flask (20 mL) and reacted at
b
Reacting at 40 °C for 16 h.
Reacting at rt for 30 h.
c
2

X. Liang, P. Yu, C. Fu et al.
Tetrahedron Letters 66 (2021) 152821
Scheme 2. Substrate Scope of benzylamine and the expansion of amines. aConditions: substituted benzylamine (1, 4.38 mmol),
e
-caprolactone (2a) (2.19 mmol), Dibutyltin
acetate (20 mol%), THF (5 mL), reaction for 4 h at 65 °C, isolated yields are based on the amount of (2a). bUsing 1,4-dioxane as solvent and reacting for 12 h at 100 °C.
(3ba-3da) groups located on the benzene rings, such as halogen
and trifluoromethyl, the reaction yields decreased significantly,
and either prolonging reaction time or increasing catalyst loading
had no effect on it. Nevertheless, the opposite result was observed
for substrates with electron-donating groups (3ea-3ga) because
the electron-donating effect on the benzene ring improves the
nucleophilic ability of amino group. Generally, moderate to excel-
lent yields were obtained, and the highest conversion was achieved
for the product 3ga with a 89% yield. We also selected some ben-
zylamines with steric hindrance as substrate, and the hydroxyalky-
lamide products bearing a tertiary alkyl group (3ha-3ja) were
isolated in moderate to low yields. Beside benzylamines, some
3

X. Liang, P. Yu, C. Fu et al.
Tetrahedron Letters 66 (2021) 152821
Scheme 3. Substrate Scope of lactones with different ring sizes and substituent groups. aConditions: (1a, 4.38 mmol), lactone (2) (2.19 mmol), Dibutyltin acetate (20 mol%),
THF (5 mL), reaction for 4 h at 65 °C, isolated yields are based on the amount of (2). bThe enantioselectivity up to 97%. cUsing 1,4-dioxane as solvent and increasing the catalyst
loading to 30 mol%, reaction for 12 h at 100 °C. dUsing 1,4-dioxane as solvent and reacting for 20 h at 100 °C.
different heteroatoms (1oa–1qa) with 2a. Aromatic amines and
fatty amines including aniline, phenethylamine and n-butylamine
were also tested, which reacted with e-caprolactone smoothly to
that both 5-membered lactones (3ac-3af) and 6-membered lactones
(3ab) reacted smoothly and there were few by-products formed. The
results also showed this approach could be compatible with giving
secondary alcohols (3ad, 3ak-3al). Unfortunately, treatment of pen-
tadecanolide (2j) withbenzylamine and dibutyltin acetate under the
standard conditions did not incur any reaction. In addition, reactions
with higher reaction temperatures and longer reaction time led to a
relatively complicated mixture, and no expected product (3aj) was
successfully isolated. We also selected the 6-membered lactones
with oxygen aza-atom as substrate (3ai) and found clearly the pres-
ence of heteroatoms doesn’t affect the reaction efficiency. The ring-
opening of benzolactone (3ag) showed the conjugation of benzene
ring with carbonyl group reduced the positivity of the carbonyl car-
bon, leading to a challenge for amino attacked furthermore. For lac-
tones with chiral structure (3af), racemization was not observed in
the ring-opening process, and the enantioselectivity (up to 96%)
remained excellent when reacting on standard conditions or
increasing the reaction temperature. The results of these investiga-
tions are summarized in Scheme 3.
give yield up to 80%. However, because of aniline compounds with
lower nucleophilicity (3ka), we need to heat the system to 100 °C
in 1, 4-dioxane and extend the reaction time to 12 h to complete
the reaction. In order to further expand the product diversity, we
conducted the reactions of heterocyclic amines bearing various
heteroaton (3oa–3qa). All the corresponding products were
accessed in moderate yields, showing good compatibility of the
reaction conditions to the different amines. We carried this reac-
tion further with secondary amines (such as N-methylaniline, N-
methylbenzylamine and diisopropylamine), and the favourable
results were not obtained. The experimental results showed that
the reaction state remained in the
e-caprolactone ring-opening
and the amine hadn’t attack furthermore. We also carried this reac-
tion further with the nucleophilic cyclic amines (morpholine and
pyrrolidine), but the result was also not ideal. The results of these
investigations are summarized in Scheme 2.
Next, we explored the range of lactones with different ring sizes
and substituents as substrates. The reaction results demonstrated
Based on the above results, we propose the following possible
mechanism for the tin-catalyzed ring-opening reaction. The tin
4

X. Liang, P. Yu, C. Fu et al.
Tetrahedron Letters 66 (2021) 152821
conditions, 1.68 g (7.6 mmol) of 3aa was successfully produced
from 1.14 g (10 mmol) of starting material 2a and 2.15 g (20 mmol)
of 1a, and the yield reached to 76%. To further examine the feasibil-
ity of this method on constructing small molecule pharmaceuti-
cals, the tyrosinase inhibitor V [27] and HDAC inhibitor VI
[28,29] were synthesized through a three-step pathway based on
this ring-opening reaction (Scheme 5). The first step in the synthe-
sis of tyrosinase inhibitor V began with the ring-opening reaction
of butylactone with p-toluidine and the compound 4-hydroxy-N-
(4-methylphenyl)-butanamide reacted with the Lucas reagent to
provide the chlorinated product 5 in 65% yield. Then, 5 was treated
with N-phenylpiperazine at 80 °C overnight and successfully
formed the tyrosinase inhibitor (V) [30]. Furthermore, the ring-
opening products of aniline and caprolactone could be converted
into HDAC inhibitors (VI) by similar method. Comparing with tra-
ditional methods of obtaining these two compounds, this method
provides an alternative synthetic route.
Scheme 4. Proposed mechanism.
Conclusion
In summary, we have developed an effective strategy for the
synthesis of hydroxyalkanamide compounds by ring-opening reac-
tion of lactones and amines mediated by dibutyltin acetate. There
is a high compatibility in the substrate scope that various substi-
tuted hydroxyalkanamide compounds are synthesized1 and easily
scaled up to the gram level. Moreover, hydroxyalkylamides with
a single enantiomer can be prepared by this method under mild
conditions. Furthermore, the utility of this new method has been
demonstrated by the three-step synthesis of the bioactive mole-
cules V and VI. This effective strategy provides a direct pathway
atom with the empty d orbitals in outer shell can accept lone pair
electrons from p orbitals of oxygen atom to form coordination
bond and increase the electrophilicity of carbonyl carbon during
chemical reactions. Subsequently, amine as nucleophilic reagent
to attack the carbonyl carbon of lactone, causes the ring-opening
to form the hydroxyalkylamide compound. Nevertheless, the exact
reaction mechanism is still unclear (Scheme 4).
To examine the practicality and robustness of this method, we
performed the gram scale synthesis of 3aa. Under the standard
Scheme 5. The synthetic routes to compound V and VI.
5

X. Liang, P. Yu, C. Fu et al.
Tetrahedron Letters 66 (2021) 152821
to obtain hydroxyalkanamide compounds, which is possible to
apply in medicinal chemistry.
References
[1] A.K. Ghose, V.N. Viswanadhan, J.J. Wendoloski, J. Comb. Chem. 1 (1999) 55–68.
[2] V.R. Pattabiraman, J.W. Bode, Nature 480 (2011) 471–479.
[3] H. Sigel, R.B.J.C.R. Martin, Chem. Rev. 82 (2004) 2089–2092.
[4] A.D. Robertson, K.P. Murphy, Chem. Rev. 97 (1997) 1251–1268.
[5] D.-W. Zhang, X. Zhao, J.-L. Hou, Z.-T. Li, Chem. Rev. 112 (2012) 5271–5316.
[6] M. Fieser, L.F. Fieser, E. Toromanoff, Y. Hirata, H. Heymann, M. Tefft, S.
Bhattacharya, J. Am. Chem. Soc. 78 (1956) 2825–2832.
Experimental section
General information
[7] A. Conejo-Garcia, C.J. Schofield, Bioorg. Med. Chem. Lett. 15 (2005) 4004–4009.
[8] D. Shan, M.G. Nicolaou, R.T. Borchardt, B. Wang, J. Pharm. Sci. 86 (1997) 765–
767.
[9] D. Ogasawara, T. Suzuki, K. Mino, R. Ueda, M.N.A. Khan, T. Matsubara, K. Koseki,
M. Hasegawa, R. Sasaki, H. Nakagawa, T. Mizukami, N. Miyata, Biorg. Med.
Chem. 19 (2011) 3702–3708.
[10] L.H. Hellberg, C. Beeson, R. Somanathan, Tetrahedron Lett. 27 (1986) 3955–
3956.
[11] G.V. Kapustin, G. Fejer, J.L. Gronlund, D.G. McCafferty, E. Seto, F.A. Etzkorn, Org.
Lett. 5 (2003) 3053–3056.
All reagents and solvents were purchased from commercial
sources and used without further purification. All reactions were
carried out under an air atmosphere. Unless otherwise specified,
NMR spectra are recorded in CDCl3 or CD3OD on a 500 or
400 MHz (for 1H), or 126 MHz (for 13C) spectrometer. All chemical
shifts are reported in ppm relative to TMS (1H NMR, 0 ppm) as an
internal standard. Melting points of the products were measured
and uncorrected. MS experiments were performed on a TOF-Q
ESI instrument.
[12] K. Matsumoto, S. Hashimoto, T. Okamoto, S. Otani, J. Hayami, Chem. Lett.
(1987) 803–804.
[13] P. Lesimple, D.C.H. Bigg, ChemInform (1991) 306–308.
[14] E.C. Sun, S.V.W. Weerasinghe, M.K.H. Pflum, Bioorg. Med. Chem. Lett. 21 (2011)
6139–6142.
General procedure for ring-opening processes
[15] A.V. Bieliauskas, S.V.W. Weerasinghe, M.K.H. Pflum, Bioorg. Med. Chem. Lett.
17 (2007) 2216–2219.
[16] A. Barreto, C. Salvador, T. Rosalba, C. Andrade, Curr. Microwave Chem. 4 (2017)
168–172.
[17] W. Guo, J.E. Gomez, L. Martinez-Rodriguez, N.A.G. Bandeira, C. Bo, A.W. Kleij,
Chemsuschem 10 (2017) 1969–1975.
[18] G. Lima, T. Toupance, E. Arkißs, N. Chaniotakis, P. Cusack, P. Lacroix, N. Farfán, B.
Jousseaume, H. Sharma, K. Pannell, I. Haiduc, E. Tiekink, Schpector, J. Mater.
Chem. Struct. Chem. Tin Compd. (2008) 285–411.
An oven-dried reaction flask (20 mL) was charged with amine
(1, 4.38 mmol), lactone (2, 2.19 mmol, 1.0 equiv), dibutyltin acetate
(20 mol%) and THF (5 mL). The resulting mixture was stirred at
65 °C for 4 h. The crude products were purified by flash column
chromatography on silica gel to give the desired product.
Declaration of Competing Interest
[19] A.G. Davies, J. Chem. Res. (2010) 181–190.
[20] M. Bednarek, T. Biedron, K. Kaluzynski, P. Kubisa, J. Pretula, S. Penczek,
Macromol. Symposia 157 (2000) 1–11.
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.
[21] A. Bouyahya, S. Balieu, R. Beniazza, M. Raihane, A. El Kadib, D. Le Cerf, P.
Thebault, G. Gouhier, M. Lahcini, New J. Chem. 43 (2019) 5872–5878.
[22] A.C. Albertsson, I.K. Varma, Biomacromolecules 4 (2003) 1466–1486.
[23] M.B. Bassi, A.B. Padias, H.K. Hall, Polym. Bull. 24 (1990) 227–232.
[24] C.M. Kuo, S.J. Clarson, J. Inorg. Organomet. P 22 (2012) 577–587.
[25] H. Kricheldorf, I. Kreiser-Saunders, A. Stricker, Macromolecules (2000) 33.
[26] N. Iwasa, K. Miura, S. Kan, Y. Furukawa, Polym. Bull. 61 (2008) 207–216.
[27] H. Raza, M.A. Abbasi, A.-U. Rehman, S.Z. Siddiqui, M. Hassan, S.A.A. Shah, M.
Shahid, H. Hong, S.-Y. Seo, J. Mol. Struct. 1210 (2020) 127969.
[28] D. Desai, U. Salli, K.E. Vrana, S. Amin, Bioorg. Med. Chem. Lett. 20 (2010) 2044–
2047.
Acknowledgement
The synthetic and analytical facilities were supported by
Wuhan University of technology.
[29] N. Karelia, D. Desai, J.A. Hengst, S. Amin, S.V. Rudrabhatla, Yun, J. Bioorg. Med.
Chem. Lett. 20 (2010) 6816–6819.
Appendix A. Supplementary data
[30] Y. El-Ahmad, P. Maillet, E. Laurent, A. Talab, G. Tran, R.J.C. Ollivier, Heterocycles
(1997) 723–734.
[31] P.Q. Huang, X. Zheng, X.M Deng, Tetrahedron Lett 42 (2001) 9039–9041.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.152821.
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