Synthesis of highly substituted pyridazines through alkynyl boronic ester cycloaddition reactions

Article abstract of DOI:10.1002/anie.200500288

(Chemical Equation Presented) A highly regioselective transformation of tetrazines through a cycloaddition reaction with alkynyl boronic esters provides highly substituted pyridazine boronic esters as intermediates for C-O and C-C bond-forming reactions (see scheme). Functionalization reactions of the C-B bond, such as oxidation and the Suzuki cross-coupling, show the versatility of these species.

Full text of DOI:10.1002/anie.200500288

Angewandte
Chemie
Synthetic Methods
Synthesis of Highly Substituted Pyridazines
through Alkynyl Boronic Ester Cycloaddition
Reactions**
Matthew D. Helm, Jane E. Moore, Andrew Plant, and
Joseph P. A. Harrity*
Aryl boronic acids and esters represent one of the most
heavily used classes of synthetic intermediates in recent
times.[1] The versatility of the C B bond allows the organo-
À
boron species to be transformed into numerous new synthetic
compounds through various functional group interconver-
À
sions and C C bond-forming reactions. In an effort to develop
new strategies toward the synthesis of highly substituted and
functionalized aromatic boronic esters, we have embarked on
a program that endeavors to access these compounds through
a series of benzannulation protocols. Specifically, we have
prepared benzenoid-derived boronic esters through a chro-
mium-mediated benzannulation reaction[2] and isoxazole
boronic esters through a [3+2] cycloaddition.[3] More recently,
we investigated the use of [4+2] cycloaddition reactions to
broaden the scope of our approach. Previous studies in this
area have demonstrated that alkynyl boronic esters, alkynyl
dihaloboranes, and alkynyl dialkyl boranes can all function as
dienophiles.[4] We report herein our efforts to exploit this
strategy for the synthesis of pyridazine boronic esters.
The inverse-electron-demand Diels–Alder reaction of 3,6-
disubstituted 1,2,4,5-tetrazines (developed by Carboni and
Lindsey) is an effective method for the synthesis of highly
substituted pyridazines and other aromatic systems.[5,6] We
envisaged that employing alkynyl boronic esters in this
reaction would allow the rapid assembly of highly substituted
pyridazine boronic esters with potential control of the
regiochemistry around the heteroaromatic ring (Scheme 1).
Indeed, Seitz and Haenel gave three examples of cyclo-
addition reactions of ethynyl boronic esters with symmetrical
tetrazines that provided the corresponding pyridazines in
good yield.[7] The authors did not explore the use of more
heavily substituted alkynyl boronic esters or investigate the
regiochemistry of this reaction. Nonetheless, it is notable that,
to the best of our knowledge, this report is the only
[*] M. D. Helm, J. E. Moore, Dr. J. P. A. Harrity
Department of Chemistry
University of Sheffield
Sheffield, S37HF (UK)
Fax: (+44)114-222-9346
E-mail: j.harrity@sheffield.ac.uk
Dr. A. Plant
Research Chemistry, Syngenta
Jealott’s Hill International Research Centre
Bracknell, Berkshire, RG426EY (UK)
[**] The authors are grateful to the EPSRC and Syngenta for a
studentship (M.D.H.) and to H. Adams for help obtaining the
X-ray diffraction data.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2005, 44, 3889 –3892
DOI: 10.1002/anie.200500288
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
cycloaddition reactions with alkynes 5 and 7 to provide the
simpler pyridazines 16 and 17 in good yield.
We next turned our attention to investigating the cyclo-
addition reactions of unsymmetrical tetrazines with a view to
developing a regioselective method for preparing the corre-
sponding pyridazine boronic esters. It has been reported that
the DMPY group can be readily displaced with a variety of O-
and N-containing nucleophiles,[9] and therefore
2 was
employed as a common intermediate for the preparation of
unsymmetrical tetrazines (Scheme 2). The treatment of 2 with
ammonia followed by Boc2O furnished a Boc-protected
tetrazine 18. Furthermore, oxazolidinone-substituted tetra-
zines 19 and 20 were readily prepared by addition of the
appropriate amino alcohol followed by acylation with tri-
phosgene.
Scheme 1. Synthesis of pyridazine boronic esters through cycloaddition
reactions of tetrazines.
documented method for the preparation of pyridazine
boronic esters.
We began our studies by investigating the cycloaddition
reactions of some substituted alkynyl boronic esters with the
readily prepared symmetrical tetrazines 1 and 2[8] (the results
are summarized in Table 1). The preliminary results were
encouraging, and we were pleased to find that the ester-
substituted tetrazine 1 participated smoothly in the cyclo-
addition process at 1408C to form the corresponding pyrid-
azine boronic esters 9–12 in moderate to high yield. An
interesting solvent effect was also observed, whereby the
reactions proceeded more quickly and cleanly when con-
ducted in nitrobenzene (Table 1, compare entries 1, 3, 5, and 7
with entries 2, 4, 6, and 8). Furthermore, the bis(3,5-dime-
thylpyrazol-1-yl) (DMPY) substituted tetrazine 2 furnished
the corresponding heteroaromatic boronic esters 13–15 in
high yield; moreover, these substrates were stable to chro-
matography on silica gel, whereas the purification of the ester-
substituted boronic esters was more successful when florisil
was used. Finally, the parent tetrazine 3 also participated in
Cycloaddition reactions with model alkynes were carried
out under the conditions optimized in the earlier studies
(Scheme 3). Accordingly, heating a solution of 18 and a
phenyl-substituted alkynyl boronic ester in nitrobenzene
resulted in smooth conversion into pyridazine 21, which was
isolated as the free amine[10] and, notably, as a single
regioisomer. NOE interaction studies were used to determine
the regiochemistry of this cycloaddition reaction, and it was
Scheme 2. a) 1. NH3 (excess), toluene, 98%; 2. Boc2O (2.2 equiv),
DMAP (10 mol%), THF (18: 70%); b) 1. H2N(CH2)2OH (1.2 equiv),
MeOH; 2. triphosgene (1.2 equiv), Et3N (2.1 equiv), CH2Cl2 (19: 73%
over 2 steps); or 1. (S)-H2NCH(Bn)CH2OH (1.2 equiv), MeOH; 2. tri-
phosgene (1.2 equiv), Et3N (2.0 equiv), CH2Cl2 (20: 63% over 2 steps).
Boc=tert-butoxycarbonyl, DMAP=4-dimethylaminopyridine, Bn=ben-
zyl.
Table 1: Cycloaddition reactions of alkynyl boronic esters with sym-
metrical tetrazines.
Entry R1
R2[a]
Solvent
t [h] Product Yield [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
CO2Me (1) Me (4)
CO2Me (1) Me (4)
CO2Me (1) nBu (5) xylene
CO2Me (1) nBu (5) nitrobenzene
CO2Me (1) Ph (6)
CO2Me (1) Ph (6)
CO2Me (1) TMS (7) xylene
CO2Me (1) TMS (7) nitrobenzene
DMPY (2) Me (4)
DMPY (2) Me (4)
DMPY (2) Ph (6)
DMPY (2) Ph (6)
xylene
nitrobenzene
16
3
16
6
16
4
16
4
16
7
16
6
16
8
6
9
9
39
44
62
75
68
75
62
89
82
81
80
84
70
69
60
64
10
10
11
11
12
12
13
13
14
14
15
15
16
17
xylene
nitrobenzene
xylene
nitrobenzene
xylene
nitrobenzene
DMPY (2) TMS (7) xylene
DMPY (2) TMS (7) nitrobenzene
H (3)
H (3)
Ph (6)
H (8)
nitrobenzene
nitrobenzene
6
[a] TMS=trimethylsilane.
Scheme 3. Preparation of unsymmetrical tetrazines.
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Angewandte
Chemie
shown that the boronic ester is adjacent to the pyrazolyl ring.
We extended this promising reaction to the oxazolidinone-
substituted tetrazine 19 to afford 22 and 23 and were pleased
that, once again, single regioisomers were isolated. Crystals of
22 suitable for X-ray crystallographic analysis were obtained,
and it was confirmed that the boronic ester moiety was again
incorporated adjacent to the pyrazole ring.[11] Finally, we
extended the cycloaddition chemistry to the chiral oxazolidi-
none-substituted tetrazine 20 and synthesized chiral pyrida-
zine boronic esters 24 and 25 with equally satisfying results.[12]
With a series of pyridazine boronic esters in hand, our
final goal was to investigate functionalization reactions of the
ized pyridazine boronic esters. We have also shown that these
À
À
intermediates can undergo C O and C C bond-forming
reactions; the latter transformation requires bulky and
electron-rich phosphine ligands to promote catalytic cross-
coupling over protodeboronation.
Experimental Section
Typical cycloaddition procedure, as exemplified by the formation of
16: 4,4,5,5-Tetramethyl-2-phenylethynyl[1,3,2]dioxaborolane (6;
306 mg, 1.34 mmol) and 1,2,4,5-tetrazine (3; 100 mg, 1.22 mmol)
were dissolved in nitrobenzene (2 mL) and heated at 1408C for 6 h.
The nitrobenzene was removed in vacuo, and the product recrystal-
lized from ethyl acetate to give 16 (206 mg, 60%) as a light-yellow
solid. M.p. 130.5–132.78C; 1H NMR (250 MHz, CDCl3): d = 1.25 (s,
12H), 7.40–7.50 (m, 5H), 9.22 (d, J = 1.0 Hz, 1H), 9.31 ppm (d, J =
1.0 Hz, 1H); 13C NMR (62.9 MHz, [D6]DMSO): d = 24.4, 84.8, 128.7,
129.0, 129.4, 136.0, 143.3, 150.8, 153.6 ppm; FTIR: 3063 (w), 2978 (m),
1573 (w), 1288 (w), 1148 (s), 1076 cmÀ1 (m). HRMS calcd for
C16H19N2O2B: m/z 282.1540, found: 282.1550.
À
C B bond. The primary objective was to establish the
viability of these substrates for Suzuki cross-coupling reac-
tions. It was anticipated that these reactions would require
significant optimization as electron-deficient boronic acid
derivatives are known to be prone to protodeboronation.[13]
Also, the significant steric crowding around the boronate
moiety in these compounds further suggested that they would
be very challenging substrates. Accordingly, we initiated our
studies by examining the cross-coupling of the parent pyrid-
azine boronic ester 17 (Scheme 4). After significant optimiza-
tion, we were pleased to find that 26 was successfully generated
in high yield by employing the protocol of Netherton and Fu[14]
for the Suzuki reaction. Pleasingly, these conditions could also
be applied to the cross-coupling reaction of the hindered
diester 9 to provide the coupled product 27 in 57% yield.
Finally, the cross-coupling reaction of 14 with iodobenzene
proved to be extremely difficult and resulted in the formation
of a substantial quantity of protodeboronated material with a
small amount of desired product. Nonetheless, the use of
microwave irradiation allowed the desired product 28 to be
isolated in 51% yield within a short reaction time.[15] Finally, we
explored a simple oxidation of 14 to the 1H-pyridazin-4-one 29
and were pleased to find that this transformation proceeded
smoothly and in high yield (Scheme 4).
Received: January 25, 2005
Published online: May 19, 2005
Keywords: boronic esters · cross-coupling · cycloaddition ·
.
heterocycles · regioselectivity
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Chem. 2002, 67, 8203.
In conclusion, we have reported that the cycloaddition of
tetrazines with alkynyl boronic esters provides a direct and
regioselective method for the synthesis of highly functional-
[5] a) R. A. Carboni, R. V. Lindsey, J. Am. Chem. Soc. 1959, 81,
4342; b) D. L. Boger, S. M. Sakya, J. Org. Chem. 1988, 53, 1415;
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[6] For cycloaddition reactions that involve heteroatom-substituted
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Eur. J. Org. Chem. 1998, 2885; b) T. J. Sparey, J. Harrison,
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[7] G. Seitz, F. Haenel, Arch. Pharm. 1994, 327, 673.
[8] a) D. L. Boger, R. S. Coleman, J. S. Panek, J. Sauer, F. X. Huber,
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khin, Russ. J. Org. Chem. 1999, 35, 1363; b) Z. Novꢁk, B. Bostai,
C. Mꢁrton, K. Lꢂrincz, A. Kotschy, Heterocycles 2003, 60, 2653.
Scheme 4. a) 26: [Pd2(dba)3] (5 mol%), [(tBu)3PH]BF4 (12 mol%), PhI,
K3PO4, MeCN, 858C, 90 min (72%); 27: [Pd2(dba)3] (5 mol%),
[(tBu)3PH]BF4 (12 mol%), PhI, K3PO4, MeCN, 508C, 90 min (57%);
28: [Pd2(dba)3] (5 mol%), [(tBu)3PH]BF4 (12 mol%), PhI, K3PO4,
MeCN, 1708C, microwave irradiation, 15 min (51%); b) iPrOH, H2O2,
Na2CO3, 858C (29: 96%).
Angew. Chem. Int. Ed. 2005, 44, 3889 –3892
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Communications
[10] For a related deprotection of a Boc-protected amine during
tetrazine cycloaddition reactions, see: D. L. Boger, R. P. Schaum,
R. M. Garbaccio, J. Org. Chem. 1998, 63, 6329.
[11] CCDC-260811 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
the Cambridge Crystallographic Data Centre via www.ccdc.ca-
m.ac.uk/data_request/cif.
[12] The regiochemistry of compounds 21, 23, and 24 was determined
by NOE interaction studies and NOESY spectroscopic analysis
(see the Supporting Information); the regiochemistry of 25 was
determined by inference.
[13] a) S. Gronowitz, V. Bobosik, K. Lawitz, Chem. Scr. 1984, 23, 120;
b) C. Coudret, V. Mazenc, Tetrahedron Lett. 1997, 38, 5293.
[14] M. R. Netherton, G. C. Fu, Org. Lett. 2001, 3, 4295.
[15] It is likely that the DMPY groups are responsible for retarding
the rate of metal-catalyzed arylation; indeed, the DMPY-
substituted tetrazine 2 can act as a good ligand for transition-
metal salts, see: J. Faragꢀ, Z. Novꢁk, G. Schlosser, A. Csꢁmpai,
A. Kotschy, Tetrahedron 2004, 60, 1991.
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