Regioselective propargylation of aldehydes using potassium allenyltrifluoroborate promoted by tonsil

Article abstract of DOI:10.1016/j.tetlet.2016.01.017

The propargylation of aldehydes using potassium allenyltrifluoroborate promoted by tonsil, an inexpensive and readily available clay, in a chemo- and regioselective way is described. The method is simple and avoids the use of air and moisture sensitive organometallics and products were obtained in good to moderate yields.

Full text of DOI:10.1016/j.tetlet.2016.01.017

Tetrahedron Letters 57 (2016) 760–765
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regioselective propargylation of aldehydes using potassium
allenyltrifluoroborate promoted by tonsil
Jucleiton J. R. Freitas a, Tulio R. Couto a, Italo H. Cavalcanti a, Juliano C. R. Freitas b, Queila P. S. Barbosa a,
Roberta A. Oliveira a,
⇑
a Departamento de Química Fundamental, Universidade Federal de Pernambuco, Recife, PE 50740-540, Brazil
b Centro de Educação e Saúde, Universidade Federal de Campina Grande, Cuité, PB 58175-000, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
The propargylation of aldehydes using potassium allenyltrifluoroborate promoted by tonsil, an inexpen-
sive and readily available clay, in a chemo- and regioselective way is described. The method is simple and
avoids the use of air and moisture sensitive organometallics and products were obtained in good to mod-
erate yields.
Received 17 November 2015
Revised 30 December 2015
Accepted 6 January 2016
Available online 7 January 2016
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Potassium organotrifluoroborates
Propargylation
Tonsil clay
The most used method for the formation of new C–C bonds is
based on the addition of organometallic reagents to carbonyl com-
pounds.1 In this context, the propargylation reaction plays an
important role due to the high density of functional groups in
the resulting products.2 However, there are two major issues asso-
ciated with the propargylation reaction, both intrinsically related:
the use of propargyl of allenyl organometallics and the regioselec-
tivity of the obtained products.
In this work, we report the use of tonsil, an inexpensive and
easily available commercial clay, to promote the addition of alle-
nyl-boron compounds to aldehydes.
In the course of developing milder reaction conditions, first
the type of boron compound and the appropriate reagent to
promote the propargylation reaction was examined. Thus,
allenylboronic acid pinacol ester, 1a or potassium allenyltrifluo-
roborate, 1b (1.5 mmol) and 3-nitro-benzaldehyde, 2a (1 mmol)
were treated at room temperature with different reagents using
CH2Cl2 as the reaction solvent. The results are presented in
Table 1.
When the reaction was performed using 1a, a commercially
available reagent, without the use of any promoter, the corre-
sponding product 3a was not observed after 48 h (Table 1, entry
1). The change of boron reagent to potassium allenyltrifluorobo-
rate, 1b, gave 3a in only 30% conversion after 12 h (Table 1, entry
2). A dramatic effect was observed when different clays were
used to promote the reaction where higher conversions were
observed in all cases (Table 1, entries 3–6). Shorter reaction times
were observed when tonsil clay was used as the reaction
promoter, however, the reaction using 1b proved to be more
regioselective (Table 1, entries 3 and 4). The use of montmoril-
lonite K-108 and KSF also gave 3a in a regioselective way, but
both reactions required longer reaction times for completion
(Table 1, entries 5 and 6). This result is probably due to the higher
superficial area of tonsil clay when compared to montmorillonites
tested.9
It is know that some propargyl and allenyl organometallics can
undergo metallotropic rearrangements during reactions with car-
bonyl compounds to give the corresponding products in low
regioselectivity.3 For propargyl magnesium bromide, for example,
4
the regioselectivity of the reaction can be improved by HgCl2 or
ZnCl2 poisoning, however, the high Lewis base character6 of
5
propargyl magnesium bromide makes the search for more stable
and selective reagents to achieve the propargylation reaction a
subject of the great interest.
The regioselectivity of reactions involving the less reactive tin,
silicon and boron allenyl- or propargyl organometallics, generally
proceed through a SE20 mechanism by the direct addition of the
organometallic to a carbonyl compound catalyzed by a Lewis acid
or base,6 so the use of an allenyl organometallic generally yields
the corresponding propargyl alcohol and vice versa.7
⇑
Corresponding author. Tel.: +55 81 2126 7473; fax: +55 81 2126 8442.
E-mail address: roberta.ayres@pq.cnpq.br (R.A. Oliveira).
http://dx.doi.org/10.1016/j.tetlet.2016.01.017
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

J. J. R. Freitas et al. / Tetrahedron Letters 57 (2016) 760–765
761
Table 1
Effect of promoter in the propargylation of 3-nitro-benzaldehyde 2a by allenyl-boron compoundsa
O2N
O
OH
OH
•
2a
O2N
O2N
•
[B]
+
promoter (100% m/m)
CH2Cl2, 25oC
1a, [B] = BPin
1b, [B] = BF3K
3a
3b
Entry
1
Promoter
Time (h)
3a:3bb
Conv.c (%)
1
2
3
4
5
6
1a
1b
1a
1b
1b
1b
—
—
Tonsil
Tonsil
Montmorillonite K-10
Montmorillonite KSF
48.0
12.0
12.0
4.0
6.0
6.5
—
—
100:0
70:30
100:0
100:0
100:0
30
87
99
99
99
a
b
c
Reaction conditions: Reactions were performed with 2a (1 mmol), 1a–b (1.5 mmol) in CH2Cl2 (5 mL) at 25 °C for the time indicated.
Determined by 1H NMR.
The conversion was determined by GC with respect to 1a.
Table 2
Table 3
Effect of the amount of tonsil on the propargylation of 3-nitro-benzaldehyde 2a by
Effect of different solvents on the propargylation of 3-nitro-benzaldehyde 2a by
potassium allenyltrifluoroborate 1ba
potassium allenyltrifluoroborate 1ba
O2N
O2N
O
O
OH
OH
2a
O2N
2a
O2N
•
BF3K
•
BF3K
tonsil (% m/m)
CH2Cl2, 25oC
tonsil (150% m/m)
solvent, 25oC, 4h
1b
1b
3a
3a
Conv.b (%)
Entry
Solvent
Conv.b (%)
Entry
Tonsil (% m/m)
Time (h)
1
2
3
4
5
CH2Cl2
CH2Cl2/H2O (1:1)
EtOH
H2O
Et2O
99
52
46
75
80
1
2
3
4
5
25
50
100
150
200
48
24
4
3.5
3.15
94
97
91
99
98
a
a
Reaction conditions: Reactions were performed with 2a (1 mmol), 1b
Reaction conditions: Reactions were performed with 2a (1 mmol), 1b
(1.5 mmol) in the appropriate solvent (5 mL) using tonsil (150% m/m) at 25 °C for
(1.5 mmol) in CH2Cl2 (5 mL) using different amounts of tonsil (% m/m) at 25 °C for
4 h.
the time indicated.
b
b
The conversion was determined by GC with respect to 2a.
The conversion was determined by GC with respect to 2a.
The optimized reaction conditions were then applied to a vari-
ety of aldehydes and the results are described in Table 4.10 The
reaction tolerates a wide range of functional groups, for example,
aldehydes containing functionalities such as halides, ester, and
nitrile were chemoselectively propargylated using the developed
reaction conditions.
The reaction seemed to be more sensitive to steric than elec-
tronic effects. For example, when 2-nitrobenzaldehyde (Table 4,
entry 3), 2-methyl-benzaldehyde (Table 4, entry 8) and 2-fluo-
robenzaldehyde (Table 4, entry 19) were used, the corresponding
products were obtained in good yields but the reactions required
longer periods of time for completion. Noteworthy, it is known that
the addition of organometallic reagents to compounds functional-
ized with the nitro group is sometimes difficult, while this group is
sensitive to reduction by metals.11 Under the developed reaction
conditions the reduction of the nitro group was not observed
(Table 4, entries 1–3).
The above results demonstrated the viability of potassium
allenyltrifluoroborate, 1b as air and moisture stable reagent for
the regioselective propargylation of aldehydes.
Next we investigated the effect of the amount of tonsil on the
reaction yield. The load of tonsil was varied from 25% to 200% m/
m (Table 2). Higher conversions of 2a into 3a were observed in
all cases. However, by increasing the amount of tonsil shorter reac-
tion times were required (Table 2, entries 2–5). No significant
changes were observed by using 150% or 200% m/m of tonsil
(Table 2, entries 4 and 5).
Finally, the solvent potentially suitable for the propargylation
reaction was investigated. Accordingly, good conversions of 2a into
3a were observed when dichloromethane was used as the reaction
solvent (Table 3, entry 1). When a 1:1 mixture of dichloromethane
and water was used as the reaction medium, lower conversions
into the desired product 3a were observed (Table 3, entry 2).
A similar result was observed when ethanol was used as the
reaction solvent, where only moderate conversions were observed
(Table 3, entry 3). Surprisingly, when water was used as the reac-
tion solvent, a moderate conversion was observed together with
some decomposition of potassium allenyltrifluoroborate, 1b
(Table 3, entry 4). Lastly, the use of diethyl ether also gave moder-
ate conversions (Table 3, entry 5).
The chemoselectivity of the reaction was evaluated using ethyl
4-formylbenzoate, 2d and 4-cyano-benzaldehyde, 2e. In both
cases, the only product observed was that derived from the addi-
tion into the aldehyde moiety (Table 4, entries 4 and 5).
Other aromatic aldehydes such as b-naphthaldehyde 2f (Table 4,
entry 6), benzaldehyde 2g (Table 4, entry 7) and electron-rich

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J. J. R. Freitas et al. / Tetrahedron Letters 57 (2016) 760–765
Table 4
Propargylation of compounds 2a–v by potassium allenyltrifluoroborate 1b promoted by tonsila
H(R)
R
2a-x
O
OH
•
BF3K
R
H(R)
3a-x
tonsil (150% m/m)
CH2Cl2, 25oC
1b
b
Entry
1
2
3
Time(h)
4.0
%
O2N
OH
OH
O
O
O2N
84
93
91
2a
2b
3a
O2N
2
3
3.5
7.0
O2N
3b
NO2 OH
NO2
O
3c
2c
OH
O
MeO2C
4
5
6
7
8
6.0
6.0
6.0
4.0
7.0
89
90
73
72
85
2d
MeO2C
3d
OH
O
NC
2e
NC
3e
OH
O
2f
3f
OH
O
O
2g
3g
Me OH
Me
3h
2h
Me
OH
OH
O
O
Me
9
7.0
3.0
70
83
Me
Me
2i
3i
10
2j
3j

J. J. R. Freitas et al. / Tetrahedron Letters 57 (2016) 760–765
763
Table 4 (continued)
b
Entry
2
3
Time(h)
6.0
%
MeO
OH
O
O
MeO
11
12
13
93
96
93
2k
2l
3k
OH
MeO
MeO
6.0
7.0
3l
OMe
OMe OH
O
3m
2m
MeO
OH
O
MeO
MeO
14
8.0
92
MeO
OMe
OMe
2n
3n
OMe OH
MeO
OMe
MeO
O
15
16
17
18
19
5.0
7.0
6.0
7.0
7.0
90
75
66
89
70
2o
3o
OH
O
O
Br
Cl
F
2p
Br
3p
OH
2q
Cl
3q
OH
O
2r
F
3r
F
F
OH
O
O
3s
2s
OH
OH
OH
20
5.0
70
78
OMe
2t
OMe
O
3t
OH
O
O
21
22
3.0
6.0
2u
3u
OH
n-Hexyl
O
60
n-Hexyl
2v
3v
(continued on next page)

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J. J. R. Freitas et al. / Tetrahedron Letters 57 (2016) 760–765
Table 4 (continued)
b
Entry
2
3
Time(h)
7.0
%
O
OH
c
23
—
3x
2x
a
Reaction conditions: Reactions were performed with 2a–v (1 mmol), 1b (1.5 mmol) in CH2Cl2 (5 mL) using tonsil (150% m/m) at 25 °C for the time indicated.
Isolated yield.
No product was observed after 7 h.
b
c
aldehydes (Table 4, entries 11–15) also gave the corresponding
homopropargylic alcohols in moderate to excellent yields. When
the ,b-unsaturated aldehyde 2j was used as substrate, only the
were obtained as major products together with a complex mixture
of other compounds regardless of the method used (Table 5, entries
1 and 2). Better conversions were observed when 2z was used as
the starting material, however, the tonsil-promoted propargylation
gave the desired product 3z in higher yield and purity (Table 5,
entries 3 and 4).
In summary, we have demonstrated that tonsil, an inexpensive
and readily available clay, can efficiently promote the propargyla-
tion of aldehydes in a chemo- and regioselective way using potas-
sium allenyltrifluoroborate.
a
1,2-addition product 3j was observed (Table 4, entry 10).
Other aldehydes containing electronegative atoms such as
4-bromo-benzaldehyde, 4-chloro-benzaldehyde, and 2- and
4-fluoro-benzaldehyde also gave similar yields (Table 4, entries
16–19). Aldehydes containing acidic functionalities such as
3-methoxysalicylaldehyde 2t gave the corresponding product 3t
in 70% yield after 5 h (Table 1, entry 20). Furfuraldehyde 2u reacted
under the optimized conditions, to give the corresponding homo-
propargylic alcohol 3u in 78% yield (Table 4, entry 21).
For aliphatic aldehydes, the tonsil-promoted propargylation
exhibited moderate efficiency, since 3v was obtained in 60% yield
after 6 h (Table 4, entry 22). Noteworthy that when the reaction
conditions were applied to acetophenone, 2x only unreacted start-
ing material was recovered indicating that the reaction is selective
or specific for aldehydes (Table 4, entry 23).
A major concern in the development of new methods for the
formation of C–C bonds is their application in the synthesis of com-
plex natural products and therefore its ability to tolerate the pres-
ence of protective groups. Recently, our group developed a regio-
and chemoselective method for propargylation of aldehydes using
Amberlyst A-31, an acidic resin, to promote the reaction.12 Thus, in
order to compare which of the methods would be the most effec-
tive in maintaining protecting groups vanillin was converted into
the corresponding THP and TBS derivatives 2y and 2z, respectively,
and these compounds were submitted to propargylation reactions.
The results are described in Table 5.
The method is simple and avoids the use of air and moisture
sensitive organometallics. The application of the method in the
propargylation of more complex molecules toward the synthesis
of natural products is undergoing in our laboratories.
Acknowledgments
We gratefully acknowledge CNPq (482299/2013-4) for financial
support. The authors are also grateful to CNPq and CAPES for their
fellowships.
Supplementary data
Supplementary data (experimental procedures and spectro-
scopic characterization data, as well as 1H, 13C, 19F and 11B NMR
spectra for all synthesized compounds) associated with this article
can be found, in the online version, at http://dx.doi.org/10.1016/j.
tetlet.2016.01.017. These data include MOL files and InChiKeys of
the most important compounds described in this article.
When 2y was used as the starting material the desired product
3y and the product correspondent to the removal of THP group 4
References and notes
1. Yus, M.; Gonzalez-Gomez, J. C.; Foubelo, F. Chem. Rev. 2011, 111, 7774.
2. Ding, C.-H.; Hou, X.-L. Chem. Rev. 2011, 111, 1914.
3. (a) Wisniewska, H. M.; Jarvo, E. R. J. Org. Chem. 2013, 78, 11629; (b) Bejjani, J.;
Botuha, C.; Chemla, F.; Ferreira, F.; Magnus, S.; Perez-Luna, A. Organometallics
2012, 31, 4876.
Table 5
Propargylation of protected aldehydes by potassium allenyltrifluoroborate 1b using
different conditions
OH
OH
4. (a) Stadler, P. A.; Nechvatal, A.; Frey, A. J.; Eschenmoser, A. Helv. Chim. Acta
1957, 40, 1373; (b) Sondheimer, F.; Wolovsky, R.; Ben-Efraim, D. A. J. Am. Chem.
Soc. 1961, 83, 1686; (c) Sondheimer, F.; Amiel, Y.; Gaoni, Y. J. Am. Chem. Soc.
1962, 84, 270; (d) Viola, A.; MacMillan, J. H. J. Am. Chem. Soc. 1968, 90, 6141.
5. Acharya, H. P.; Miyoshi, K.; Kobayashi, Y. Org. Lett. 2007, 9, 3535.
6. (a) Fandrick, D. R.; Reeves, J. T.; Bakonyi, J. M.; Nyalapatla, P. R.; Tan, Z.;
Niemeier, O.; Akalay, D.; Fandrick, K. R.; Wohlleben, W.; Ollenberger, S.; Song, J.
J.; Sun, X.; Qu, B.; Haddad, N.; Sanyal, S.; Shen, S.; Ma, S.; Byrne, D.; Chitroda, A.;
Fuchs, V.; Narayanan, B. A.; Grinberg, N.; Lee, H.; Yee, N.; Brenner, M.;
Senanayake, C. H. J. Org. Chem. 2013, 78, 3592; (b) Grayson, M. N.; Goodman, J.
M. J. Am. Chem. Soc. 2013, 135, 6142; (c) Jain, P.; Wang, H.; Houk, K. N.; Antilla, J.
C. Angew. Chem., Int. Ed. 2012, 51, 1391; (d) Hirayama, L. C.; Haddad, T. D.;
Oliver, A. G.; Singaram, B. J. Org. Chem. 2012, 77, 4342; (e) Ghosh, P.;
Chattopadhyay, A. Tetrahedron Lett. 2012, 53, 5202; (f) Reddy, L. R. Org. Lett.
2012, 14, 1142; (g) Usanov, D. L.; Yamamoto, H. Angew. Chem., Int. Ed. 2010, 49,
8169; (h) Chen, M.; Roush, W. R. J. Am. Chem. Soc. 2012, 134, 10947; (i) Lee, P.
H.; Kim, H.; Lee, K. Adv. Synth. Catal. 2005, 347, 1219.
1b
O
A or B
MeO
+
MeO
MeO
OP
OH
OP
2y
3y-z
, P = THP
4
2z
, P = TBS
Entry
Conditiona
Aldehyde
Ratio (3:4)b
Conv.c (%)
1
2
3
4
A
B
A
B
2y
2y
2z
2z
1:2
1:27
2.5:1
99:1
30d
15d
53d
75
a
Condition A: 2y or 2z (1 mmol), 1b (1.5 mmol), CH2Cl2 (5 mL), Amberlyst A-31
(200% m/m), 25 °C, 7 h; Condition B: 2y or 2z (1 mmol), 1b (1.5 mmol), CH2Cl2
(5 mL), tonsil (150% m/m), 25 °C, 7 h.
7. Yamamoto, H. Propargyl and Allenyl Organometallics In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: London, 1991; Vol. 2, p
81.
8. Nowrouzi, F.; Thadani, A. V.; Batey, R. A. Org. Lett. 2009, 11, 2631.
9. Hussin, F.; Aroua, M. K.; Daud, W. M. A. W. Chem. Eng. J. 2011, 170, 90.
b
The ratio was determined by GC.
The conversion was determined by GC with respect to 2y or 2z;
A complex mixture of products was obtained.
c
d

J. J. R. Freitas et al. / Tetrahedron Letters 57 (2016) 760–765
765
10. Typical experimental procedure: In a flask containing the appropriate aldehyde
2a–z (1.0 mmol) in CH2Cl2 (5.0 mL) at 25 °C was added tonsil (150% m/m)
followed by the potassium allenyltrifluoroborate, 1b (1.50 mmol, 218 mg). The
mixture was stirred for the time indicated in Table 4 and at then diluted with
CH2Cl2 (5.0 mL) and filtered. The filtrate was washed with water (2 ꢀ 15 mL),
the organic phase was separated and dried over anhydrous MgSO4. The
solution was again filtered and the solvent was removed in vacuo to yield 3a–z.
11. Chan, T. H.; Isaac, M. B. Pure Appl. Chem. 1996, 68, 919.
12. Couto, T. R.; Freitas, J. J. R.; Freitas, J. C. R.; Cavalcanti, I. H.; Menezes, P. H.;
Oliveira, R. A. Synthesis 2015, 47, 71.