Ambient temperature nitrogen-directed difluoroalkynylborane carboni-lindsey cycloaddition reactions

Article abstract of DOI:10.1021/ol902573x

Chemical Equation Presented The in situ generation of alkynyldifluoroboranes in the presence of W-heterocycle substituted tetrazines provides a convenient and direct method for the synthesis of pyridazine difluoroboranes. The reactions proceed in 10 min under ambient conditions and provide the opportunity to assemble unsymmetrical products with complete regiocontrol

Full text of DOI:10.1021/ol902573x

ORGANIC
LETTERS
2010
Vol. 12, No. 1
160-163
Ambient Temperature Nitrogen-Directed
Difluoroalkynylborane Carboni-Lindsey
Cycloaddition Reactions
Je´roˆme F. Vivat, Harry Adams, and Joseph P. A. Harrity*
Department of Chemistry, UniVersity of Sheffield, Brook Hill, Sheffield S3 7HF, U.K.
j.harrity@sheffield.ac.uk
Received November 5, 2009
ABSTRACT
The in situ generation of alkynyldifluoroboranes in the presence of N-heterocycle substituted tetrazines provides a convenient and direct
method for the synthesis of pyridazine difluoroboranes. The reactions proceed in 10 min under ambient conditions and provide the opportunity
to assemble unsymmetrical products with complete regiocontrol.
The inverse electron demand Diels-Alder reactions of 3,6-
disubstituted 1,2,4,5-tetrazines (Carboni-Lindsey reaction)
provides an effective method for the synthesis of highly
substituted pyridazines.1 When alkynes are employed as
substrates, the reactions typically require extensive heating
and/or suffer from long reaction times unless highly reactive
ynamines or ynol ethers or strained alkynes are employed.2
In connection with our interest in the cycloaddition reactions
of alkynylboronates, we demonstrated that the Carboni-
Lindsey reaction can be employed to rapidly generate
pyridazine boronic esters.3 In line with the aforementioned
alkyne reactivity profile, these cycloadditions require elevated
temperatures but provide the corresponding products in high
yield (Scheme 1).
Scheme 1
(1) (a) Carboni, R. A.; Lindsey, R. V. J. Am. Chem. Soc. 1959, 81,
4342. (b) Boger, D. L.; Sakya, S. M. J. Org. Chem. 1988, 53, 1415. (c)
Hamasaki, A.; Ducray, R.; Boger, D. L. J. Org. Chem. 2006, 71, 185. (d)
Hamasaki, A.; Zimpleman, J. M.; Hwang, I.; Boger, D. L. J. Am. Chem.
Soc. 2005, 127, 10767. (e) Rusinov, G. L.; Ishmetova, R. I.; Latosh, N. I.;
Ganebnych, I. N.; Chupakhin, O. N.; Potemkin, V. A. Russ. Chem. Bull.
2000, 49, 355.
(2) (a) Boger, D. L. Tetrahedron 1983, 39, 2869. (b) Sauer, J.; Heldmann,
D. K.; Hetzenegger, J.; Krauthan, J.; Sichert, H.; Schuster, J. Eur. J. Org.
Chem. 1998, 2885.
We were intrigued by the potential of alkynyltrifluorobo-
rates to perform as dienophiles in the [4 + 2] cycloaddition
to generate pyridazine trifluoroborates. In addition to potential
synthetic utility, we were particularly interested in the relative
ease of cycloaddition of these alkynes by comparison with
(3) (a) Helm, M. D.; Moore, J. E.; Plant, A.; Harrity, J. P. A. Angew.
Chem., Int. Ed. 2005, 44, 3889. (b) Gomez-Bengoa, E.; Helm, M. D.; Plant,
A.; Harrity, J. P. A. J. Am. Chem. Soc. 2007, 129, 2691. (c) Helm, M. D.;
Plant, A.; Harrity, J. P. A. Org. Biomol. Chem. 2006, 4, 4278.
10.1021/ol902573x  2010 American Chemical Society
Published on Web 12/02/2009

the corresponding boronic esters.4 Aromatic trifluoroborates
have recently emerged as practical alternatives to boronic
acid derivatives for cross-coupling and functionalization
reactions.5 These compounds are typically air- and moisture-
stable crystalline solids and usually are generated from the
corresponding boronic acid derivatives after treatment by
KHF2. While many of the reactions of organoboronic acid
derivatives have been found to be compatible with the
corresponding trifluoroborates, cycloaddition processes are
significantly under-represented. Indeed, only recently has it
been shown that 1,3-dienyl 2-trifluoroborates undergo
Diels-Alder reactions with activated dienophiles, albeit at
elevated temperatures.6 Accordingly, we decided to inves-
tigate the potential of alkynyltrifluoroborates in [4 + 2]
cycloaddition reactions with tetrazines, and our preliminary
observations are reported herein.
alkynyltrifluoroborates are more reactive toward the Car-
boni-Lindsey reaction than the corresponding pinacol bo-
ronic esters as these dienophiles required significantly higher
reaction temperatures and longer reaction times (cf. Schemes
1 and 2). We then extended our studies to the corresponding
bis(3,5-dimethylpyrazol-1-yl) (DMPY) substituted tetrazine
4. To our surprise, alkynyltrifluoroborates were found to be
significantly less reactive in this case toward cycloaddition,
independent of the counterion.
In an effort to further explore this dichotomy, we attempted
to prepare 9 (Scheme 2) from the corresponding pinacol
boronate 5 to aid characterization in any subsequent cy-
cloaddition optimization studies.7
Accordingly, treatment of 5 with KHF2 followed by
addition of Et4NOH provided a new compound. To our
1
surprise, however, the H NMR spectrum indicated the
We began our studies by investigating the cycloaddition
of alkynyltrifluoroborates bearing potassium and tetraethy-
lammonium counterions with tetrazine 1; our results are
depicted in Scheme 2. Our initial observations were rather
absence of the expected tetraethylammonium counterion
while HRMS suggested the product to be the pyridazine
difluoroborane 10.
Scheme 2
Aromatic difluoroboranes with adjacent amines have been
reported and are known to exist as Lewis acid-base
complexes.8 We therefore suspected that the surprising
formation of the difluoroborane over the expected trifluo-
roborate was due to complexation from the adjacent pyrazole
moiety. This led us to speculate that the tetrazine cycload-
dition could well be promoted by these Lewis basic substit-
uents if the corresponding alkynyldifluoroboranes were
employed.9 The difluoroboranes can be generated in situ by
addition of mild Lewis acids such as TMSCl.10 Indeed,
exposing a solution of alkyne 11 and tetrazine 4 in CH2Cl2
to TMSCl resulted in rapid consumption of both starting
materials at room temperature within 10 min. Chromato-
graphic purification provided the corresponding pyridazine
12 in excellent yield. The product was characterized by X-ray
crystallography and allowed the proposed pyrazole-borane
complex to be confirmed (Scheme 3).11
surprising; heating a mixture of potassium salt 6 and 1 in
various solvents at reflux resulted in consumption of the
tetrazine, but the corresponding pyridazine could not be
identified from the resulting crude mixture. In marked
contrast, however, the corresponding tetraethylammonium
salt 7 underwent a remarkably smooth cycloaddition with 1
to provide the corresponding pyridazine 8 in quantititative
yield. This observation suggested that tetraethylammonium
(4) For recent overviews, see: (a) Hilt, G.; Bolze, P. Synthesis 2005,
2091. (b) Gandon, V.; Aubert, C.; Malacria, M. Chem. Commun. 2006,
2209.
Scheme 3
(5) (a) Darses, S.; Geneˆt, J.-P. Chem. ReV. 2008, 108, 288. (b) Molander,
G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275.
(6) (a) De, S.; Welker, M. E. Org. Lett. 2005, 7, 2481. (b) De, S.; Day,
C.; Welker, M. E. Tetrahedron 2007, 63, 10939.
(7) Perrin and co-workers have recently used the alkynylboronate
cycloaddition chemistry followed by KHF2 to generate pyridazine trifluo-
roborates: Li, Y.; Asadi, A.; Perrin, D. M. J. Fluorine Chem. 2009, 130,
377.
(8) (a) Vedejs, E.; Nguyen, T.; Powell, D. R.; Schrimpf, M. R. Chem.
Commun. 1996, 2721. For a recent overview of these compounds and related
boronic acid derivatives, see: (b) Georgiou, I.; Ilyashenko, G.; Whiting, A.
Acc. Chem. Res. 2009, 42, 756.
(9) For a review of directed reactions, see: Hoveyda, A. H.; Evans, D. A.;
Fu, G. C. Chem. ReV. 1993, 93, 1307.
We next wished to explore the scope of the nitrogen-
directed cycloaddition, and our results are highlighted in
Table 1. Pleasingly, the remarkable rate enhancements
(10) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf, M. R.
J. Org. Chem. 1995, 60, 3020.
Org. Lett., Vol. 12, No. 1, 2010
161

significantly less reactive dienes. Specifically, 1,2,4-triazines
typically require strongly electron-withdrawing substituents
to facilitate a reaction with simple alkynes and alkenes.13
Indeed, we have found these heterocycles to be unreactive
toward alkynylboronates. These substrates therefore provided
an ideal opportunity to exploit this technique in this challenging
cycloaddition process. In the event, 3-(2-pyridyl)-1,2,4-triazine
23 required moderate heating to promote a reaction with 11;
however, complete conversion was observed within 20 min to
provide bipyridine 24 in good yield. Again, a single product
regioisomer was obtained (Scheme 4).14
Table 1. Nitrogen-Directed Cycloaddition Reactionsa
Scheme 4
With a series of novel pyridazine difluoroboranes in hand,
our final goal was to confirm the potential of the cycloadducts
in further functionalization reactions. We first wanted to
demonstrate that these products could be converted to the
corresponding pinacol esters, as we have shown that these
compounds can undergo various C-C and C-O bond-
forming reactions.3a,c Pleasingly, heating a THF solution of
pinacol and 13 in the presence of base provided pinacol ester
25 in good yield. We next wanted to demonstrate that the
difluoroboranes could undergo cross-coupling reactions
directly. Indeed, after examining a series of trifluoroborate
Scheme 5
a Reaction conditions: a CH2Cl2 solution of tetrazine (1 equiv) and
tetraethylammonium alkynyltrifluoroborate (1.5 equiv) was treated with
TMSCl (1.5 equiv), and the reaction was stirred at room temperature until
the red color of the tetrazine had faded (∼10 min). b Isolated yields. 2-Py:
2-pyridyl.
observed in these processes are maintained over a series of
alkyne substrates, and the corresponding products were
obtained in high yield (entries 1 and 2). Moreover, we were
able to extend these studies to the bis-2-pyridyl substituted
tetrazine 15 (entries 3 and 4); notably, this substrate is not
reactive enough to undergo cycloaddition with alkynylbor-
onates. Further evidence for the role of a basic N-atom in
promoting the cycloaddition was obtained by performing the
reaction with unsymmetrical tetrazine 18; pleasingly, the
reaction was completely regioselective and the expected
products 19 and 20 were obtained in excellent yield (entries
5 and 6). Finally, free aminotetrazine 21 was also found to
undergo cycloaddition to provide 22 as a single regioisomer,
albeit in a more modest yield (entry 7).12
The remarkable rate enhancements afforded by this N-
directed Carboni-Lindsey reaction suggested that this
paradigm could be employed to promote cycloadditions of
162
Org. Lett., Vol. 12, No. 1, 2010

cross-coupling conditions,5,15 we found Ag2O to be particu-
larly effective15a and were able to successfully prepare
compounds 26 and 27 after some Pd-catalyst screening
(Scheme 5).16
In conclusion, we report a novel N-directed cycloaddition
reaction of difluoroalkynylboranes for the mild and regiose-
lective synthesis of heteroaromatic borane derivatives. Stud-
ies are underway to establish the scope and generality of
this strategy.
Acknowledgment. The authors are grateful to the EPSRC
for financial support (EP/D03213X/1).
Supporting Information Available: Full experimental
details and characterizaton data, copies of 1H and 13C NMR
spectra for all products, and a crystallographic information
file (CIF) for compounds 12 and 22. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL902573X
(11) CCDC-750154 contains the supplementary crystallographic data
for compound 12. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
(12) Despite the higher reactivity of diester tetrazine 1 in alkyne
cycloadditions (see ref 1e), this diene fails to react under the conditions
shown in Table 1. This observation suggests that the enhanced reaction
rates are not simply due to an inherently more reactive alkynyldifluoroborane
dienophile.
(14) The regiochemistry of compounds 19 and 24 were assigned by NOE
spectroscopy, and the regiochemistry of compound 22 was assigned by X-ray
crystallography (see Supporting Information). The regiochemistry of
compound 20 has been assigned by inference.
(15) (a) Adonin, N. Y.; Babushkin, D. E.; Parmon, V. N.; Bardin, V. V.;
Kostin, G. A.; Mashukov, V. I.; Frohn, H.-J. Tetrahedron 2008, 64, 5924.
(b) Molander, G. A.; Canturk, B.; Kennedy, L. E. J. Org. Chem. 2009, 74,
973. (c) Darses, S.; Michaud, G.; Geneˆt, J.-P. Eur. J. Org. Chem. 1999,
1875.
(13) Neunhoeffer, H. In ComprehensiVe Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford,
1996; Vol. 6, p 507.
(16) Reducing the catalyst loading in the coupling of 20 to 7.5% Pd2dba3,
18% t-Bu3P·HBF4 results in a 48% yield of 27.
Org. Lett., Vol. 12, No. 1, 2010
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