Regioselective benzoylation of diols and carbohydrates by catalytic amounts of organobase

Article abstract of DOI:10.3390/molecules21050641

A novel metal-free organobase-catalyzed regioselective benzoylation of diols and carbohydrates has been developed. Treatment of diol and carbohydrate substrates with 1.1 equiv. of 1-benzoylimidazole and 0.2 equiv. of 1,8-diazabicyclo[5.4.0]undec-7-ene (DB

Full text of DOI:10.3390/molecules21050641

molecules
Communication
Regioselective Benzoylation of Diols and
Carbohydrates by Catalytic Amounts of Organobase
Yuchao Lu 1, Chenxi Hou 1, Jingli Ren 1, Xiaoting Xin 1, Hengfu Xu 1, Yuxin Pei 1, Hai Dong 2,
*
and Zhichao Pei 1,
*
1
Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Science,
Northwest A & F University, Yangling 712100, China; luyuchao_2006@126.com (Y.L.);
houchenxi2015@126.com (C.H.); renjingli12345@163.com (J.R.); 18700814753@163.com (X.X.);
xhf130@126.com (H.X.); peiyx@nwafu.edu.cn (Y.P.)
School of Chemistry & Chemical Engineering, Huazhong University of Science & Technology,
Luoyu Road 1037, Wuhan 430074, China
2
*
Correspondence: hdong@mail.hust.edu.cn (H.D.); peizc@nwafu.edu.cn (Z.P.); Tel.: +86-278-779-3243 (H.D.);
+86-298-709-1196 (Z.P.)
Academic Editor: Derek J. McPhee
Received: 23 March 2016; Accepted: 10 May 2016; Published: 17 May 2016
Abstract: A novel metal-free organobase-catalyzed regioselective benzoylation of diols and
carbohydrates has been developed. Treatment of diol and carbohydrate substrates with 1.1 equiv. of
1-benzoylimidazole and 0.2 equiv. of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in MeCN under mild
conditions resulted in highly regioselective benzoylation for the primary hydroxyl group. Importantly,
compared to most commonly used protecting bulky groups for primary hydroxyl groups, the benzoyl
protective group offers a new protection strategy.
Keywords: benzoylation; regioselectivity; DBU; benzoylimidazole; catalysis
1. Introduction
Selective protection of diols and polyols remains as a frequently encountered problem in
organic chemistry during the synthesis of natural products and new drug candidates, especially,
in carbohydrate chemistry [
medicinal agents from readily available monosaccharide derivatives [
developing environment-friendly, convenient, efficient and highly regioselective carbohydrate
protection methods remains as one of the most prominent challenges [ ]. Over the last several
decades, many protection methods have been developed, including the use of reagents such as
organotin [10 12], organoboron [13 14], organosilicon [15 17], metal salts [18 23], organobase [24 26],
and enzymes [27 30]. Although these reagents each have advantages, they also possess troublesome
1–
4
]. Regioselectivity is the major obstacle to the synthesis of novel
5–8]. More specifically,
9
–
,
–
–
–
–
shortcomings including inherent toxicity, high cost and the necessity to pre-protect secondary
hydroxyl groups. One of the most frequently used protection methods is benzoylation. Many
regioselective benzoylation methods using the above discussed reagents [20–22,25–27], have been
reported accordingly. The Mitsunobu reaction is widely used in substitution of primary or secondary
alcohols with nucleophiles mediated by a redox combination of a trialkyl or triarylphosphine
and a dialkyl azodicarboxylate [31]. It may lead to regioselective benzoylation in some cases,
but has poor regioselectivity and is more suitable for protection of secondary hydroxyls [32].
The DCC-mediated reaction, popularly known as the Steglich Esterification, may also lead to moderate
regioselectivities in the benzoylation of hydroxyl groups with an excess amount of alcohol [33]. Albert
and co-wokers used DMAP and DCC as counterion to obtain direct regioselective acetylation of octyl
β-D-glucopyranoside, but with unsatisfactory results [34]. Recently, a green regioselective benzoylation
Molecules 2016, 21, 641; doi:10.3390/molecules21050641
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method using benzoate anion as a catalyst was developed by us [35]. However, the method is
not suitable for monobenzoylation of the unprotected methyl D-pyranosides. We also developed
a regioselective acetylation method conducted in water with tetramethyl-ammonium hydroxide
(TMAH) as a catalyst [36]. Despite its high selectivity, its main drawback is that it cannot be applied
on substrates with poor water solubility. Thus, we started to investigate organobase-(DBU)-catalyzed
selective benzoylation of diols and carbohydrates in organic solvents such as acetonitrile, where
1-benzoylimidazole was used as the acylation reagent, as in our previous study. As expected, this
method showed good regioselectivity for the primary hydroxyl group in most cases (Scheme 1).
Compared to other methods, not only does this robust method show better regioselectivities, but the
catalyst is metal-free, and the reagents used are of lower cost, and easily acquired. Particularly, in
contrast to the most often used protecting bulky groups for primary hydroxyl groups such as silyl [37
]
or trityl groups [38] which are removed under acid conditions, removal of the benzoyl group can take
place in the presence of base.
Scheme 1. DBU-catalyzed benzoylation of 1,2 and 1,3-diols.
The carbonylimidazole derivatives are a class of highly acylation reagents, particularly in
the preparation of esters and amides [39
–42]. In several cases, they have shown superior
selectivity for selective acylation reactions [43
–
45] and N-acetylation of oxindoles and indoles
(Scheme 2) [46]. Inspired by these works, we decided to explore the possibility of replacing the
acyl halide, which is toxic and unstable, with 1-benzoylimidazole as the benzoylation reagent with
1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU) as the catalyst. DBU is often used as a organobase catalyst
in many base-catalyzed reactions [47–50], having been recognized as an excellent nucleophilic catalyst,
leading to rapid and efficient acetylation of non-nucleophilic azacycles, such as indoles, pyrroles,
and oxazolidinones.
Scheme 2. N-acetylation of heterocycles with carbonyl-azoles.
2. Results and Discussion
After a series of optimization studies on selective benzoylation of methyl
, Table 1), we determined the best condition to be the use of 0.2 equiv. of DBU and 1.1 equiv. of
1-benzoylimidazole in acetonitrile with a small amount of DMF (MeCN/DMF: 20/1) at 50 ˝C for 8 h
(Entry 1). Under this condition, methyl glucoside with a benzoylated primary hydroxyl group was
α-D-glucopyranoside
(1
2

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isolated in 70% yield. The yield of
2
was only increased to 72% when 1.3 equiv. of 1-benzoylimidazole
was used (Entry 2). Without the addition of DMF the yield decreased to 53%, which is likely due
to the low solubility of polyols in pure acetonitrile (Entry 3). If the reaction was performed at room
temperature, the yield of
2
decreased to only 21% (Entry 4). Increasing the reaction temperature to
70 C or prolonging the reaction time to 12 h. failed to improve the yield of (Entries 5–6). No reaction
occurred in the absence of DBU or with Et3N instead of DBU (Entries 7–8). Low yields were obtained
˝
2
with DMAP, DIPEA or DBN instead of DBU (Entries 9, 10 and 11). The yield of
amount of DBU used up to 0.4 equiv (Entries 12, 13 and 14).
2 increased with the
Table 1. Optimization studies on selective benzoylation of methyl α-D-glucopyranoside (1) a.
Yield b (%)
Entry 1
Various Conditions
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Optimized conditions
Benzoylimidazole (1.3 eq.)
Without DMF
70 (80 c)
72 (87 c)
53
21
69
71
Reaction at r.t.
Reaction at 70 ˝C
Reaction for 12 h.
Without DBU
d
-
-
d
Et3N (0.2 eq.) instead of DBU
DMAP (0.2 eq.) instead of DBU
DIPEA (0.2 eq.) instead of DBU
DBN (0.2 eq.) instead of DBU
DBU (0.05 eq.)
18
13
45
52
61
71
DBU (0.1 eq.)
DBU (0.4 eq.)
a
Conditions: methyl
α-D-glucopyranoside (1, 100 mg), catalyst (0.2 eq.), 1-benzoylimidazole (1.1 eq.),
MeCN (3 mL, dry), DMF (0.15 mL, dry), 50 ˝C, 8 h;
Isolated yield;
Yields determined by
b
c
1H-NMR; d No reaction; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene, DMAP: 4-dimethylaminopyridine, DBN:
1,5-diazabicyclo[4.3.0]non-5-ene.
In light of these results, a wide range of substrates was further selectively benzoylated under the
optimized conditions (Table 2), including 1,2-diols
and 19 (Entries 7–9), methyl D-pyranoside 1,3-diols 23
polyols 31 33
3
,
,
5
25
,
7
,
9
,
11 and 13 (Entries 1–6), 1,3-diols 15
, 17
, 27 and 29 (Entries 11–14), and carbohydrate
,
,
35 and 37 (Entries 15–18). The addition of DMF is not necessary for diols due to
their good solubility in acetonitrile. All of the substrates contain one primary hydroxyl group with
one or several secondary hydroxyl groups. Good yields (60%–96%) where the primary hydroxyl
group was selective protected were obtained in most cases. For non-carbohydrate diols, the only
by-products were a small amount of overbenzoylated compounds (Entries 1–7). Particularly, excellent
selectivities (87%–96%) were shown due to striking steric effects for the benzoylation of 1,3-diols 17
and 19 (Entries 8 and 9), containing a tertiary hydroxyl group, and the five carbohydrate diols 21
25, 27 and 29 (Entries 10–14).
, 23,

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Table 2. 1-Benzoylimidazole used for selective benzoylation of diols and carbohydrates.
Entry
Reactant
Products
Isolated Yield a (%)
1
a/b(82/8)
OR1
O
OR2
6a, b
2
3
a/b(75/12)
a/b(76/11)
a: R1= H, R2= Bz
b: R1= Bz, R2= Bz
OR1
O
OR2 8a, b
a: R1= H, R2= Bz
b: R1= Bz, R2= Bz
4
5
6
a/b(81/10)
a/b(75/15)
a/b(76/9)
7
8
a/b(78/14)
90
9
96
10
11
12
92
90
88
13
14
91
87
15
a/b(81/9)
60 b (70 c)
62 b (70 c)
71 b (80 c)
16
17
18
a
Reaction conditions: 1-benzoylimidazole (1.1 equiv.), DBU (0.2 equiv.), MeCN (3 mL, dry); b MeCN (3 mL, dry),
DMF (0.15 mL, dry); c Yields determined by 1H-NMR.

Molecules 2016, 21, 641
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Evidently, the benzoylation occcurs via by transacylation of imidazolides under basic
condition [51 53]. Based on the traditional base-catalysis principle, this transacylation is usually
–
proposed to start from a deprotonation of hydroxyl groups in the presence of strong base such as
DBU. Recently, it was proposed that the hydrogen bond between the hydroxyl group and the base
play a key role in the transacylation reaction [54–56]. Thus, a mechanism based on hydrogen bond
principle for this selective benzoylation is proposed in Figure 1. H-bond complexes A1 and A2 can be
formed between the hydroxyl group of substrate and DBU, following the formation of the transition
state intermediates B1 and B2 with the approach of 1-benzoylimidazole. It is clear that the formation
of intermediate B1 is more favoured due to the less steric hindrance of A1. In the transition state
(TS) B, the deprotonation of the hydroxyl group by DBU and the attack of the hydroxyl group on
1-Benzoylimidazole occur at the same time. Consequently, the markedly less steric hindrance in A1 and
B1 than in A2 and B2 explained the good selectivity for benzoylation of the primary hydroxyl group.
Figure 1. Proposed mechanism for selective benzoylation of primary OH using 1-benzoylimidazole as
acylation reagent catalyzed by DBU.
3. Materials and Methods
3.1. General Information
All commercially available starting materials and solvents were of reagent grade and dried prior
to use. Chemical reactions were monitored with thin-layer chromatography using precoated silica
gel 60 (0.25 mm thickness) plates. Flash column chromatography was performed on silica gel 60
1
(0.040–0.063 mm). H- and 13C-NMR spectra were recorded with a Bruker AVANCE III instrument
operating at 500 and 125 MHz, and using the residual signals from DMSO-d6 (1H:
CD3OD (1H: δ = 3.34 ppm) and CDCl3 (1H: δ = 7.27 ppm) as internal standard.
δ = 2.50 ppm),
3.2. General Procedure for Selective Benzoylation of Diols (a)
To a solution of substrate (100 mg) in 2.5 mL MeCN (dry) was added DBU (0.2 equiv.), and
the mixture was allowed to stir at 50 ˝C for 10 min. 1-Benzoylimidazole (1.1 equiv.) in MeCN (dry,
0.5 mL) was added to the reaction mixture in two portions and it was allowed to stir at 50 ˝C for 8 h.
MeCN was removed under reduced pressure and the resulting mixture was purified by flash column
chromatography (ethyl acetate/petroleum ether = 1:6 to 2:1) to afford benzoylated products.
3.3. General Procedure for Selective Benzoylation of Polyols (b)
To a solution of substrate (100 mg) in 2.5 mL MeCN (dry) and 0.15 mL DMF (dry) was added DBU
˝
(0.2 equiv.), and the mixture was allowed to stir at 50 C for 10 min. 1-Benzoylimidazole (1.1 equiv.) in

Molecules 2016, 21, 641
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0.5 mL MeCN (dry) was added to the reaction mixture in two portions and it was allowed to stir at 50
˝
C for 8 h. MeCN was removed under reduced pressure and the resulting mixture was purified by flash
column chromatography (ethyl acetate/petroleum ether = 1:1 to 10:1) to afford benzoylated products.
3.4. Product Characterization
3-(Allyloxy)propane-1,2-diyl dibenzoate (8b). Colorless oil, yield: 76%, Rf = 0.2 (ethyl acetate/petroleum
ether = 1:3), 1H-NMR (CDCl3)
δ 8.09–7.99 (m, 4H, ArH), 7.59–7.52 (m, 2H, ArH), 7.47–7.39 (m, 4H, ArH),
5.94–5.83 (m, 1H, -CH=CH2), 5.65–5.56 (m, 1H, -CH-), 5.33–5.15 (m, 2H, -CH=CH2), 4.72–4.58 (m, 2H,
-CH2COOPh), 4.09–4.04 (m, 2H, -CH2CH=CH2), 3.84–3.76 (m, 2H, -CH2OCH2CH=CH2). 13C-NMR
(CDCl3) δ 166.7, 166.3, 150.1, 148.0, 133.2, 129.8, 128.5, 122.6, 121.1, 115.8, 115.5, 112.1, 71.6, 68.6, 65.7,
55.9. HRMS m/z calcd for C20H20O5 [M + Na]+: 363.1203. Found 363.1207.
2-Hydroxy-3-(2-methoxyphenoxy)propyl benzoate (12a). Colorless oil, yield: 75%, Rf = 0.2 (ethyl
acetate/petroleum ether = 1:2), 1H-NMR (CDCl3)
δ
8.12–7.22 (m, 2H, ArH), 7.64–7.58 (m, 1H, ArH),
7.51–7.45 (m, 2H, ArH), 7.07–6.99 (m, 2H, ArH), 6.98–6.91 (m, 2H, ArH), 4.61–4.51 (m, 2H, PhCO2CH2-),
4.46–4.38 (m, 1H, -HCOH-), 4.28–4.12 (m, 2H, -PhOCH2-), 3.90 (s, 3H, -OCH3). 13C-NMR (CDCl3)
δ
165.9, 150.3, 148.0, 133.3, 133.2, 129.9, 128.5, 122.6, 121.0, 115.8, 112.5, 70.7, 68.2, 63.4, 55.9. HRMS m/z
calcd for C17H18O5 [M + Na]+: 325.1046. Found 325.1051.
3-(2-Methoxyphenoxy)propane-1,2-diyl dibenzoate (12b). Colorless oil, yield: 15%, Rf = 0.2 (ethyl
acetate/petroleum ether = 1:3), 1H-NMR (CDCl3)
δ
8.11–8.05 (m, 4H, ArH), 7.63–7.57 (m, 2H,
ArH), 7.50–7.43 (m, 4H, ArH), 7.09–6.99 (m, 2H, ArH), 6.96–6.93 (m, 2H, ArH), 5.87–5.80 (m, 1H,
-CH2CHCH2-), 4.88 (dd, J = 12.0, 3.8 Hz, 1H, PhCO2CH2-), 4.80 (dd, J = 12.0, 6.0 Hz, 1H, PhCO2CH2-),
4.46 (d, J = 5.4 Hz, 2H, -PhOCH2-), 3.84 (s, 3H, -OCH3). 13C-NMR (CDCl3)
166.3, 165.9, 150.2, 148.0,
δ
δ
134.3, 133.3, 133.2, 133.1, 129.8, 129.7, 128.5, 128.4, 122.7, 121.1, 117.5, 112.1, 71.1, 68.3, 63.6, 55.9. HRMS
m/z calcd for C24H22O6 [M + Na]+: 429.1309. Found 429.1312.
4. Conclusions
In conclusion, a simple and efficient method for regioselective benzoylation of diols and
carbohydrates has been developed, where the primary hydroxyl groups can be selectively benzoylated
by using 1-benzoylimidazole as an acylation reagent catalyzed by DBU. In comparison to other
methods, not only does this robust method appear to have provided a new protection strategy for the
primary hydroxyl group, but also the used reagents are associated with lower cost, metal-free, and
displayed better regioselectivity.
Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/21/
5/641/s1.
Acknowledgments: We thank National Natural Science Foundation of China (Nos. 31270861 and 21272083), and
Agricultural Science and Technology Innovation Project of Shaanxi Province (2012 NKC01-12) for financial support.
Author Contributions: Yuchao Lu designed the experiments, analyzed the data, and drafted the manuscript.
Chenxi Hou, Jingli Ren, Xiaoting Xin and Hengfu Xu performed data acquisition and analysis. Yuxin Pei assisted
with the revision of the manuscript. Hai Dong and Zhichao Pei directed the entire research study and drafted the
manuscript. All authors read and approved the final manuscript for submission.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 21–30, 34, 36, 38 are available from the authors.
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