Efficient method for propargylation of aldehydes promoted by allenylboron compounds under microwave irradiation

Article abstract of DOI:10.3762/bjoc.16.19

The propargylation of aldehydes promoted by microwave irradiation using allenylboron compounds in a chemo- and regioselective way is described. The corresponding products were obtained in short reaction time, high yield and purity without the need of any solvent when allenylboronic acid pinacol ester was used, or using a minimal amount of acetone when potassium allenyltrifluoroborate was used.

Full text of DOI:10.3762/bjoc.16.19

Efficient method for propargylation of aldehydes promoted by
allenylboron compounds under microwave irradiation
Jucleiton J. R. Freitas*1, Queila P. S. B. Freitas2, Silvia R. C. P. Andrade2,
Juliano C. R. Freitas3, Roberta A. Oliveira2 and Paulo H. Menezes*2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2020, 16, 168–174.
1Universidade Federal Rural de Pernambuco - UACSA, PE, Brazil,
2Departamento de Química Fundamental, Universidade Federal de
Pernambuco, UFPE, Recife, Pernambuco 50740-560, Brazil and
3Universidade Federal de Campina Grande, Centro de Educação e
Saúde: Cuité, Paraíba, Brazil
doi:10.3762/bjoc.16.19
Received: 31 October 2019
Accepted: 30 January 2020
Published: 04 February 2020
Email:
Associate Editor: D. Y.-K. Chen
Jucleiton J. R. Freitas* - jucleitonrufino@gmail.com;
Paulo H. Menezes* - pmenezes@ufpe.br
© 2020 Freitas et al.; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
boron compounds; microwave; propargylation; regioselectivity;
synthesis
Abstract
The propargylation of aldehydes promoted by microwave irradiation using allenylboron compounds in a chemo- and regioselective
way is described. The corresponding products were obtained in short reaction time, high yield and purity without the need of any
solvent when allenylboronic acid pinacol ester was used, or using a minimal amount of acetone when potassium allenyltrifluoro-
borate was used.
Introduction
The propargylation of carbonyl compounds is widely used in is still a major concern. This is mainly due to the metallotropic
the synthesis of biologically active natural products [1]. Some rearrangement of propargyl and allenyl organometallics in solu-
examples can be found in the synthesis of histrionicotoxin [2], tion resulting in mixtures of the two reagents [15]. Thus, upon
rhizopodin [3], bafilomycin [4], bryostatin [5], vancosamine [6] reaction with an aldehyde, mixtures of propargylic and allenic
and macrolactin A [7].
alcohols can be obtained through a chelate transition state
(SE2').
Although there are several stereoselective methods described
for the reaction of propargyl or allenyl organometallics with Attempts to improve the regioselectivity of the propargylation
carbonyl compounds [8-14], the control of the regioselectivity reaction by using allenic organometallic species of Cd [16], Ga
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Beilstein J. Org. Chem. 2020, 16, 168–174.
[17], In [18], Ti [19], Al [20] and Bi [21] were described. How- Results and Discussion
ever, the majority of these methods involve reagents that are For preliminary optimization of the reaction conditions,
difficult to prepare and to handle due to the sensitivity to air and 2-naphthaldehyde (1 mmol) and allenylboronic acid pinacol
moisture.
ester (1, 1.5 mmol) in a capped vial were irradiated in a MW
synthesizer for 30 minutes under different temperatures. The
The use of less reactive species based on tin [22-24], silicon results are depicted in Table 1.
[25] or boron [26-28] to perform propargylation reactions typi-
cally requires catalysis by Lewis acids or bases and although In all cases, the desired propargylic product 2a was obtained
the utility of allenylstannanes is further indicated by the com- together with a small amount of the corresponding allenic prod-
mercial availability of some of them, the toxicity of these com- uct 3a. When the reaction was performed at 75 °C, good
pounds makes them inappropriate for the use in pharmaceutical conversions of 2-naphthaldehyde into the corresponding prod-
synthesis [29]. Moreover, the removal of tributyltin residues ucts were observed (Table 1, entry 1). The best result was ob-
from reaction mixtures is also a major issue.
served when the temperature was increased to 100 °C affording
the products in 97% yield in a 98:2 ratio (Table 1, entry 2).
The use of microwave irradiation for the formation of new C–C Higher temperatures gave lower yields or the decomposition of
bonds is nowadays widely used and offers several advantages the boron reagent 1 (Table 1, entries 3 and 4). It is worth to note
such as the increment in the product yield, reduction of reac- that when the reaction was carried out with conventional
tion time and the possibility to perform solvent-free reactions heating (100 °C), the desired product was not observed after
[30]. However, the relative “greenness” of microwave-assisted 1 h. A similar behavior was previously observed by Schaus
reactions is still a point of discussion. For example, the ques- [32].
tion about the energy efficiency of microwave vs convention-
ally heated reactions must, in general, be evaluated with great Next, the shortest time necessary for the formation of the prod-
care on a case-by-case basis. Even so, the search for safer alter- ucts at 100 °C under microwave irradiation was evaluated. The
natives to current synthetic methodologies avoiding the use of results are shown in Table 2. From Table 2, it can be seen that
moisture/air-sensitive organometallics and, more important, the the increment in the reaction time resulted in higher yields with-
development of solvent-free protocols are in accordance with out major changes in the ratio of 2a:3a.
the concept of environmental impact factor (E factor) [31].
The optimized reaction conditions, namely: 2-naphthaldehyde
Within this context, the development of solvent-free methods is (1.0 mmol), 1 (1.5 mmol) under microwave irradiation (300 W)
highly desirable since the difficult for solvent recycling in aca- were then applied for the propargylation reaction of aldehydes
demic laboratories and chemical manufacturing plants is containing a wide range of functional groups and the results are
universal. In addition, a reliable method for the propargylation shown in Scheme 1. In all cases the reaction proceeded
reaction which could involve the use of commercially available smoothly leading to the conversion of aldehydes into the
and stable allenyl or propargyl compounds without the need of corresponding homopropargylic alcohols 2 in moderate to
special conditions such as dry solvents or complex catalysts is a high yields and in a very regioselective way, while the propar-
subject of great interest.
gylated product was obtained as the major product in all cases.
Table 1: Propargylation of 2-naphthaldehyde with allenylboronic acid pinacol ester (1) at different temperatures.a
Entry
Temp. (°C)
2a/3ab
Yield (%)c
1
2
3
4
75
97:3
98:2
98:2
98:2
94
97
81
84
100
125
150
aReaction conditions: Reactions were performed with 2-naphthaldehyde (1 mmol), 1 (1.5 mmol) under MW irradiation (300 W) for 30 min at the tem-
perature indicated. bDetermined by GC analysis. cIsolated yield.
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Beilstein J. Org. Chem. 2020, 16, 168–174.
Table 2: Propargylation of 2-naphthaldehyde with allenylboronic acid pinacol ester (1) using different reaction times.a
Entry
Time (min)
2a/3ab
Yield (%)c
1
2
3
4
5
5
98:2
98:2
97:3
98:2
97:3
87
88
88
95
97
10
15
20
30
aReaction conditions: Reactions were performed with 2-naphthaldehyde (1 mmol), 1 (1.5 mmol) under MW irradiation (300 W) at 100 °C for the time
indicated. bDetermined by GC analysis. cIsolated yield.
Scheme 1: Scope of the propargylation reaction. Reactions were performed with the appropriate aldehyde (1 mmol), 1 (1.5 mmol) under microwave
irradiation (300 W) at 100 °C for 30 min. Isolated yields are given. The number in parentheses refers to the mixture of propagyl and allenyl regio-
isomers determined by GC analysis.
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Beilstein J. Org. Chem. 2020, 16, 168–174.
Table 3: Number of cycles to remove pinacol from the crude product.a
Entry
Cycle
Ratio 2h/pinacol (%)b
1
2
3
4
5
1
2
3
4
5
70:30
77:23
84:16
93:7
99:1
aReaction conditions: The reaction was performed using 3,4,5-trimethoxybenzaldehyde (1 mmol) and 1 (1.5 mmol) under microwave irradiation
(300 W) at 100 °C for 0.5 h. The crude product was dissolved in 50% aqueous methanol (10 mL) and the solvents were removed on a rotary evapo-
rator (45–50 °C/25–15 mbar). bDetermined by GC analysis.
Aromatic aldehydes such as benzaldehyde, 2-methylbenzalde- sponding products 2q and 2r were obtained in good yields. The
hyde and 3,5-dimethylbenzaldehyde gave the corresponding use of a heteroaromatic or an aliphatic aldehyde as substrates
products 2b–d in good yields in a regioselective way regardless under the optimized conditions gave the corresponding homo-
of the position of the substituent on the aromatic ring.
propargylic alcohols 2s,t in moderate yields.
When aldehydes containing electron-donating groups such as The development of a solvent-free protocol for propargylation
2-, 3- or 4-methoxybenzaldehyde or 3,4,5-trimethoxybenzalde- of aldehydes based on microwave irradiation should take into
hyde were used, the corresponding products 2e–h were ob- account not only the reaction itself but also an effective method
tained in good yields and regioselectivities. In the same way, for the extraction of the obtained products. Despite the excel-
aldehydes containing electron-withdrawing groups such as the lent results described on Scheme 1, a factor that must be taken
nitro group also reacted without influence of the substituent into consideration is the removal of the desired alcohols 2a–t
location to give the corresponding homopropargylic alcohols from pinacol – the byproduct obtained in the reaction. There are
2m and 2n in good yields. It is interesting to note that the nitro some examples in the literature based on the removal of pinacol
group remained intact under the reaction conditions. Usually, by distillation in vacuo (50 °C/0.05 mbar) [34]. However, this
this group is sensitive to reduction when alternative methods in- technique can only be applied for non-volatile samples. More
volving zinc or tin are used [33].
recently, Aggarwal and co-workers [35] described an efficient
method for removal of pinacol based on the formation of an
In addition, aldehydes containing halogens also gave the corre- azeotrope with water under moderate vacuum. Thus, a test ex-
sponding products 2j–l in moderate yields. These results indi- periment was performed using compound 2h. The crude prod-
cated that the substituent nature, whether electron-donating or uct obtained from the reaction was dissolved in 50% aqueous
electron-withdrawing, has no dramatic influence on the product methanol and the volatile materials were removed using a rotary
yields.
evaporator. The procedure was monitored by gas chromatogra-
phy and was repeated until the crude mixture contained less
When the α,β-unsaturated aldehyde, cinnamaldehyde was used, than 1 mol % of pinacol remaining. The results are described in
the corresponding 1,2-addition product 2i was obtained exclu- Table 3.
sively.
Although the desired products 2a–t having been obtained along
The chemoselectivity of the method was evaluated using alde- with a small proportion of the corresponding regioisomer in
hydes containing different functionalities. For example, the use some cases, in the development of new synthetic methods, it is
of vanillin, an aldehyde containing the acidic phenol group as desirable that it gives the corresponding product as a single
substituent, gave the corresponding product 2o in 93% yield in compound. Our group described the synthesis of homoprop-
an 82:18 ratio of regioisomers. In the same way, when alde- argylic alcohols using potassium allenyltrifluoroborate as the
hydes containing an ester or nitrile group were used, the corre- propargylating agent in a very regioselective way [36,37]. Thus,
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Beilstein J. Org. Chem. 2020, 16, 168–174.
allenylboronic acid pinacol ester (1) was converted into the cor- Two factors must be considered when allenylboron species are
responding trifluoroborate using the procedure described by used in the propargylation reaction. The first is that the atomic
Lloyd-Jones and co-worker [38]. The desired product 4 was ob- efficiency [40] using potassium allenyltrifluoroborate (4, 62%)
tained in good yield and characterized by 1H, 13C, 11B and or allenylboronic acid pinacol ester (1, 58%) is higher when
19F NMR [39] (Scheme 2).
compared to the commercially available allenyltributyltin
(22%) for similar reactions.
The second refers to the regioselectivity of the reaction. Despite
the reaction using 2-naphthaldehyde led only to the propargyl
isomer 2a, when the same reaction conditions were applied to
4-nitrobenzaldehyde, the desired product 2m was once again
obtained with a small amount of the corresponding regioisomer
3m in a 97:3 ratio (Scheme 3).
Scheme 2: Synthesis of potassium allenyltrifluoroborate (4).
Potassium allenyltrifluoroborate (4) is a crystalline solid and
despite several microwave promoted reactions can be con-
ducted without the use of solvents, the propargylation reaction
using 2-naphthaldehyde and 4 under the previously optimized
conditions gave the desired product in only low conversion
(Table 4, entry 1).
In order to find an appropriate and suitable solvent that could be
used in small amounts to promote the reaction different sol-
vents were screened and the best result was observed when a
small amount of acetone was used, where 2a was obtained in
92% yield as a single regioisomer (Table 4, entry 2). Low
conversions were observed when water or a 1:1 mixture of ace-
tone and water was used in the reaction (Table 4, entries 3 and
4). The use of alcohols also gave the desired product in lower
yields (Table 4, entries 5–7). Finally, when a less polar solvent
was used, the observed conversion was only 10% (Table 4,
entry 8).
Scheme 3: Propargylation of aldehydes using potassium allenyltri-
fluoroborate (4).
Table 4: Propargylation of 2-naphthaldehyde with potassium allenyltrifluoroborate (4) using different solvents.a
Entry
Solvent
Time (min)
2a/3ab
Yield (%)c
1
2
3
4
5
6
7
8
–
–
–
6
92
3
10
45
45
30
10
acetone
water
acetone/water
ethylene glycol
ethanol
30
30
30
20
20
20
20
100:0
100:0
100:0
100:0
100:0
100:0
100:0
methanol
dichloromethane
aReaction conditions: Reactions were performed with 2-naphthaldehyde (1 mmol), 4 (1.5 mmol) under MW irradiation (300 W) at 100 °C for the time
indicated using the appropriate solvent (500 μL). bDetermined by GC analysis. cIsolated yield.
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In summary, we have shown an efficient method for the propar-
gylation of aldehydes promoted by microwave irradiation using
allenylboron compounds in a chemo- and regioselective way.
The corresponding products were obtained after a short reac-
tion time in high yield and purity without the need of a solvent
when allenylboronic acid pinacol ester was used, or using a
minimal amount of acetone when potassium allenyltrifluoro-
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Jucleiton J. R. Freitas - https://orcid.org/0000-0001-6349-8764
Silvia R. C. P. Andrade - https://orcid.org/0000-0002-0929-715X
Juliano C. R. Freitas - https://orcid.org/0000-0003-4617-4084
Roberta A. Oliveira - https://orcid.org/0000-0001-7905-2433
Paulo H. Menezes - https://orcid.org/0000-0002-0327-6032
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