Synthesis of functionalized organotrifluoroborates via the 1,3-dipolar cycloaddition of azides

Article abstract of DOI:10.1021/ol060826r

We have successfully prepared potassium azidoalkyltrifluoroborates from the corresponding halogen compounds in 94-98% yields through a nucleophilic substitution reaction with NaN₃. In the presence of various alkynes and Cu(I) as a catalyst, these azidotrifluoroborates easily formed 1,4-disubstituted organo-[1,2,3]-triazol-1-yl-trifluoroborates in 85-98% yields. This method was then developed into a facile one-pot synthesis for the preparation of various organo-[1,2,3]-triazol-1-yl-trifluoroborates using haloalkyltrifluoroborates as the starting materials.

Full text of DOI:10.1021/ol060826r

ORGANIC
LETTERS
2006
Vol. 8, No. 13
2767-2770
Synthesis of Functionalized
Organotrifluoroborates via the
1,3-Dipolar Cycloaddition of Azides
Gary A. Molander* and Jungyeob Ham
Roy and Diana Vagelos Laboratories, Department of Chemistry,
UniVersity of PennsylVania, Philadelphia, PennsylVania 19104-6323
gmolandr@sas.upenn.edu
Received April 5, 2006
ABSTRACT
We have successfully prepared potassium azidoalkyltrifluoroborates from the corresponding halogen compounds in 94
a nucleophilic substitution reaction with NaN3. In the presence of various alkynes and Cu(I) as a catalyst, these azidotrifluoroborates easily
formed 1,4-disubstituted organo-[1,2,3]-triazol-1-yl-trifluoroborates in 85 98% yields. This method was then developed into a facile one-pot
synthesis for the preparation of various organo-[1,2,3]-triazol-1-yl-trifluoroborates using haloalkyltrifluoroborates as the starting materials.
−98% yields through
−
Organotrifluoroborates1 have recently attracted considerable
interest as synthetic intermediates for Suzuki-Miyaura-type
cross-coupling reactions,1a,2 rhodium-catalyzed 1,4-addition
reactions,3 and allylations of aldehydes4 and N-toluenesulfo-
nylimines.5 Moreover, potassium organotrifluoroborate salts
are easily prepared by the addition of inexpensive KHF2 to
various organoboron intermediates.6 These substrates are air-
and moisture-stable crystalline solids that are readily iso-
lated.1,6 However, despite the advantages and potential
applications of potassium organotrifluoroborates, to date they
are still prepared from commercially available boronic acids
or via transmetalation,1 hydroboration,1,7 or C-H activation.8
Therefore, new methods to prepare highly functionalized
potassium organotrifluoroborates are of great synthetic
interest.
(1) For reviews of organotrifluoroborate salts, see: (a) Molander, G. A.;
Figueroa, R. Aldrichimica Acta 2005, 38, 49-56. (b) Darses, S.; Geneˆt,
J.-P. Eur. J. Org. Chem. 2003, 4313-4327.
As part of a study to prepare functionalized potassium
organotrifluoroborates through nucleophilic substitution reac-
tions of potassium halomethyltrifluoroborates (XCH2BF3K),9
we were pleased to discover that azide-containing potassium
organotrifluoroborates are readily obtained in good yield
from the treatment of bromo- or iodomethyltrifluoroborate
with NaN3. In the presence of various alkynes and a Cu(I)
catalyst, azide-containing potassium organotrifluoroborates
(2) (a) Molander, G. A.; Felix, L. A. J. Org. Chem. 2005, 70, 3950-
3956. (b) Molander, G. A.; Figueroa, R. Org. Lett. 2006, 8, 75-78. (c)
Cella, R.; Cunha, R. L. O. R.; Reis, A. E. S.; Pimenta, D. C.; Klitzke, C.
F.; Stefani, H. A. J. Org. Chem. 2006, 71, 244-250. (d) Molander, G. A.;
Sommers, E. M.; Baker, S. R. J. Org. Chem. 2006, 71, 1563-1568. (e)
Molander, G. A.; Yokoyama, Y. J. Org. Chem. 2006, 71, 2493-2498.
(3) (a) Batey, R. A.; Thadani, A. N. Org. Lett. 1999, 1, 1683-1686. (b)
Pucheault, M.; Darses, S.; Geneˆt, J.-P. Tetrahedron Lett. 2002, 43, 6155-
6157. (c) Pucheault, M.; Darses, S.; Geneˆt, J.-P. Eur. J. Org. Chem. 2002,
3552-3557. (d) Navarre, L.; Pucheault, M.; Darses, S.; Geneˆt, J.-P.
Tetrahedron Lett. 2005, 46, 4247-4250.
(6) (a) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf, M.
R. J. Org. Chem. 1995, 60, 3020-3027. (b) Vedejs, E.; Fields, S. C.;
Hayashi, R.; Hitchcock, S. R.; Powell, D. R.; Schrimpf, M. R. J. Am. Chem.
Soc. 1999, 121, 2460-2470.
(4) (a) Batey, R. A.; Thadani, A. N.; Smil, D. V. Tetrahedron Lett. 1999,
40, 4289-4292. (b) Batey, R. A.; Thadani, A. N.; Smil, D. V. Synthesis
2000, 990-998. (c) Thadani, A. N.; Batey, R. A. Org. Lett. 2002, 4, 3827-
3830. (d) Thadani, A. N.; Batey, R. A. Tetrahedron Lett. 2003, 44, 8051-
8055.
(5) (a) Li, S.-W.; Batey, R. A. Chem. Commun. 2004, 12, 1382-1383.
(b) Solin, N.; Wallner, O. A.; Szabo´, K. J. Org. Lett. 2005, 7, 685-688.
(7) Clay, J. M.; Vedejs, E. J. Am. Chem. Soc. 2005, 127, 5766-5767.
(8) Lawrence, J. D.; Takahashi, M.; Bae, C.; Hartwig, J. F. J. Am. Chem.
Soc. 2004, 126, 15334-15335.
(9) Molander, G. A.; Ham, J. Org. Lett. 2006, 8, 2031-2034.
10.1021/ol060826r CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/02/2006

could be used to generate the corresponding triazole products
through a 1,3-dipolar cycloaddition reaction (“click reac-
tion”).10
removed under high vacuum at 60-70 °C. The pure azides
were obtained in 94-98% yields by recrystallization.
Interestingly, 5-bromopentyltrifluoroborate, as well as 1-,
2-, and 3-(chloromethyl)phenyltrifluoroborates (Table 1,
entries 3-6), had shorter reaction times than bromo- or
iodomethyltrifluoroborate (Table 1, entries 1 and 2) under
the same conditions.
Using the potassium azidoalkyltrifluoroborates generated
according to the method illustrated in Table 1, we next
attempted the click reaction of phenylacetylene and potas-
sium azidomethyltrifluoroborate (Table 2).
Thus, the 1,3-dipolar cycloaddition reaction of azides
would produce a variety of [1,2,3]-triazole-containing potas-
sium organotrifluoroborates which could be employed in
organic synthesis, medicinal chemistry, and materials sci-
ence.11
Table 2. Optimization of Reaction Conditions for the
Synthesis of 12
Herein, we report a novel and convenient preparation of
potassium azidoalkyltrifluoroborates in good yields via the
direct nucleophilic substitution of the corresponding ha-
loalkyltrifluoroborates with NaN3, followed by a facile and
regioselective synthesis of potassium organo-[1,2,3]-triazol-
1-yl-trifluoroborates with various alkynes using Cu(I) as a
catalyst under mild reaction conditions.
catalyst
entry (10 mol %)
temp reaction conversion
solventa
(°C)
time (h)
(%)b
It was first necessary to determine the reactivity of
potassium haloalkyltrifluoroborates with NaN3, as well as
the stability of the resulting azide compounds under the
reaction and purification conditions prior to development of
a one-pot cycloaddition sequence (Table 1).
1
2
3
4
5
6d
7
8
9e
Cu powder DMSO-d6
80
80
80
80
rt
80
80
75
75
65
65
48
3
1.5
1
48
3
24
24
2
67
CuCN
CuBr
Cu(I)
Cu(I)
Cu(I)
Cu(I)
Cu(I)
Cu(I)
Cu(I)
Cu(I)
DMSO-d6
DMSO-d6
DMSO-d6
DMSO-d6
DMSO-d6
D2O
CD3CN
CD3CN
THF-d8
CD3OD
100 (84)c
100 (88)c
100 (90)c
82
100 (87)c
trace
trace
trace
no reaction
no reaction
Table 1. Preparation of Potassium Azidoalkyltrifluoroborates
from Potassium Haloalkyltrifluoroboratesa
10
11
2
2
a All reactions were performed in 500 µL of solvent. b Percentage
conversion was calculated by 1H NMR. c Isolated yields. d 5 mol % of Cu(I)
was used. e Pyridine-d5 (10 mol %) was added as a nitrogen-containing
ligand to solubilize Cu(I).
A number of different Cu catalysts were screened for their
effectiveness in promoting the cycloaddition reaction (Table
2, entries 1-4). Although all of the catalysts generated the
target compound 12 under the standard reaction conditions,
Cu(I) provided the fastest reaction time and the highest
isolated yield. By decreasing the catalyst loading from 10
mol % to 5 mol % (Table 2, entries 4 and 6), reaction times
were slightly increased. Changes in reaction temperature had
a much greater impact on reaction rates. When the reaction
(10) (a) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa,
A., Ed.; Wiley: New York, 1984; Chapter 1, pp 1-176. (b) Padwa, A. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 4, pp 1069-1109. (c) Gothelf, K. V.;
Jørgensen, K. A. Chem. ReV. 1998, 98, 863-910. (d) Kolb, H. C.; Finn,
M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004-2021. (e)
Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew.
Chem., Int. Ed. 2002, 41, 2596-2599. (f) Tornoe, C.; Christensen, C.;
Meldal, M. J. Org. Chem. 2002, 67, 3057-3064.
(11) Recent examples: (a) Li, H.; Cheng, F.; Duft, A. M.; Adronov, A.
J. Am. Chem. Soc. 2005, 127, 14518-14524. (b) Burley, G. A.; Gierlich,
J.; Mofid, M. R.; Nir, H.; Tal, S.; Eichen, Y.; Carell, T. J. Am. Chem. Soc.
2006, 128, 1398-1399. (c) Beryozkina, T.; Appukkuttan, P.; Mont, N.;
Van der Eycken, E. Org. Lett. 2006, 8, 487-490. (d) Srinivasan, R.;
Uttamchandani, M.; Yao, S. Q. Org. Lett. 2006, 8, 713-716.
a All reactions were performed on a 0.1 mmol scale in 500 µL of DMSO-
d6. b Yields are given for isolated products.
Potassium azidoalkyltrifluoroborates were readily prepared
from the corresponding halogen compounds and NaN3 at 80
°C. To determine the exact reaction time, all reactions were
performed in an NMR tube using DMSO-d6 (500 µL) as the
solvent. After the reaction was complete, the solvent was
2768
Org. Lett., Vol. 8, No. 13, 2006

temperature was decreased from 80 °C to room temperature,
the reaction time increased from 1 to 48 h (Table 2, entries
4 and 5). In addition, it was observed that D2O, CD3CN,
THF-d8, and CD3OD were inferior solvents, leading to very
low conversion by NMR. This is most likely due to poor
solubility of the reactants and catalysts (Table 2, entries
7-11). On the other hand, when pyridine-d5 (10 mol %)
was added as a ligand to solubilize the Cu(I) under the same
reaction conditions, no improvement of the reaction was
observed after 2 h (Table 2, entry 9).
and 10 mol % of Cu(I) at 80 °C in an NMR tube. After
removing the solvent under high vacuum at 60-70 °C, the
salt products were purified by recrystallization. The 1,4-
disubstituted organo-[1,2,3]-triazol-1-yl-trifluoroborates were
obtained in 85-98% yields. Interestingly, increasing the
carbon chain length or steric hindrance of the alkyne resulted
in prolonged reaction times (Table 3, entries 4-6, 8, and
9). When 1-ethynylnaphthalene (Table 3, entry 8) was used,
the reaction proceeded slowly despite the use of 30 mol %
of Cu(I).
Next, we turned our attention to the one-pot, multicom-
ponent preparation of potassium organo-[1,2,3]-triazol-1-yl-
trifluoroborates from the corresponding halogen salts (Table
4).
Using the optimized conditions of 12 as a model reaction,
we were able to perform the 1,3-dipolar cycloaddition
reaction of potassium azidomethyltrifluoroborate using vari-
ous alkynes. The results are summarized in Table 3.
Table 4. One-Pot Synthesis of Potassium
Organo-[1,2,3]-triazol-1-yl-trifluoroborates from Potassium
Haloalkyltrifluoroborates
Table 3. Preparation of Potassium
Organo-[1,2,3]-triazol-1-yl-trifluoroborates from Various
Alkynes and Potassium Azidomethyltrifluoroborate
a Yields are given for isolated products. b Reaction was performed with
30 mol % of Cu(I). c Product was obtained as a 9:1 mixture of regioisomers.
As previously shown, 5-bromopentyltrifluoroborate and
2-, 3-, and 4-(chloromethyl)phenyltrifluoroborates reacted
efficiently when treated with NaN3 in DMSO-d6 at 80 °C.
The resulting azido intermediates were smoothly transformed
to the triazole products even though the 1,3-dipolar cycload-
dition of these azide salts were slightly slower than that of
azidomethyltrifluoroborate. The overall conversion of ha-
loalkyltrifluoroborates to [1,2,3]-triazol-1-yl-trifluoroborates
a Yields are given for isolated products. b Reaction was performed with
30 mol % of Cu(I).
All reactions were carried out in DMSO-d6 with potassium
azidomethyltrifluoroborate (0.1 mmol), 1.2 equiv of alkyne,
Org. Lett., Vol. 8, No. 13, 2006
2769

was accomplished as a one-pot method by simply adding
the Cu(I) catalyst and the alkyne substrate to the DMSO-d6
solution once the SN2 displacement of haloalkyltrifluorobo-
Table 5. One-Pot Synthesis of Potassium
Organo-[1,2,3]-triazol-4-yl-trifluoroborates from Compound 26
1
rate with NaN3 had reached completion as indicated by H
NMR.
When ethyl propiolate was used, the reaction proceeded
slightly faster than with phenylacetylene, and its product (22)
was isolated in 93% yield (Table 4, entry 2). In the reaction
of 2-, 3-, and 4-(chloromethyl)phenyltrifluoroborates, the use
of 30 mol % of Cu(I) was required for obtaining good yields
(Table 4, entry 3). Moreover, compound 24 was obtained as
a 9:1 mixture of regioisomers (major isomer shown).
Finally, we investigated the one-pot reaction using potas-
sium prop-2-ynyloxymethyltrifluoroborate (26) that was
prepared from the nucleophilic substitution reaction with the
corresponding sodium alkoxide and bromomethyltrifluo-
roborate (Table 5).9
As expected, all of the alkyl azides were quickly prepared
from the corresponding bromides when treated with NaN3
in DMSO-d6 at 80 °C. Benzyl bromide and electron-poor
4-nitrobenzyl bromide reacted quickly with accompanying
high yields (Table 5, entries 1 and 3). However, ethyl
bromoacetate and electron-rich 4-methylbenzyl bromide
required longer reaction times or 30 mol % of Cu(I) for the
completion of these reactions (Table 5, entries 2 and 4).
Unfortunately, when subjected to standard reaction condi-
tions, the products (28 and 30) were obtained as a mixture
containing approximately 10% of the 1,5-disubstituted tria-
zole compound. Therefore, long reaction times in the 1,3-
dipolar cycloaddition step appear to result in lower regiose-
lectivity of the desired 1,4-disubstituted triazoles.
a Yields are given for isolated products. b Reaction was performed with
30 mol % of Cu(I). c Products were obtained as a 9:1 mixture of
regioisomers.
organotrifluoroborates would appear to be very useful
precursors for the Suzuki-Miyaura-type cross-coupling
reaction. Further applications using these compounds are
currently in progress and will be reported in due course.
In summary, we have successfully prepared potassium
azidoalkyltrifluoroborates from the corresponding halogen
compounds in 94-98% yields through a nucleophilic
substitution reaction with NaN3. In the presence of various
alkynes and Cu(I) as a catalyst, these azidotrifluoroborates
easily formed 1,4-disubstituted organo-[1,2,3]-triazol-1-yl-
trifluoroborates in good yields. Moreover, we developed a
facile synthetic method for the preparation of novel, func-
tionalized potassium organo-[1,2,3]-triazol-1-yl- and organo-
[1,2,3]-triazol-4-yl-trifluoroborates through a one-pot reaction
using 5-bromopentyltrifluoroborate (3), 2-, 3-, and 4-(chlo-
romethyl)phenyltrifluoroborates (4-6), and prop-2-yny-
loxymethyltrifluoroborate (26) as the starting materials. These
Acknowledgment. This work was supported by the Korea
Research Foundation Grant funded by the Korean Govern-
ment (MOEHRD) (KRF-2005-214-C00170). We thank the
National Institutes of Health (GM35249), Merck Research
Laboratories, and Amgen for their generous support.
Supporting Information Available: Experimental pro-
cedures, spectral characterization, and copies of 1H, 13C, 19F,
and 11B NMR spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL060826R
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Org. Lett., Vol. 8, No. 13, 2006