Regioselective de novo synthesis of cyanohydroxypyridines with a concerted cycloaddition mechanism

Article abstract of DOI:10.1021/ja804078v

An efficient cycloaddition reaction of 1-alkoxy-1-azadienes with α,α-dicyanoalkenes is described, which gives facile access to highly substituted 3-hydroxypyridines in very good yields and with complete regiocontrol and chemoselectivity. The reaction path was investigated in detail by quantum mechanics calculations, reporting that a concerted cycloaddition mechanism and thermodynamic control synergistically contribute to the observed selectivity. Copyright

Full text of DOI:10.1021/ja804078v

Published on Web 09/11/2008
Regioselective De Novo Synthesis of Cyanohydroxypyridines with a
Concerted Cycloaddition Mechanism
Jin-Yong Lu,†,‡ John A. Keith,§ Wei-Zheng Shen,† Markus Schu¨rmann,† Hans Preut,† Timo Jacob,*,§
and Hans-Dieter Arndt*,†,‡
Fakulta¨t Chemie, Technische UniVersita¨t Dortmund, Otto-Hahn-Strasse 6, D-44221 Dortmund, Germany,
Max-Planck-Institut fu¨r Molekulare Physiologie, Otto-Hahn-Strasse 11, D-44227 Dortmund, Germany, and Institut
fu¨r Elektrochemie, UniVersita¨t Ulm, Albert-Einstein-Allee 47, D-89081 Ulm, Germany
Received June 6, 2008; E-mail: timo.jacob@uni-ulm.de; hans-dieter.arndt@mpi-dortmund.mpg.de
Scheme 1. HDA Addition Screening with Alkyne Surrogates 2-6
The broad activity profile of pyridines and their derivatives fuels
constant progress in the development of pyridine syntheses.1,2 For
focused compound collections in drug discovery, target oriented
synthesis, and the development of new materials, novel and selective
de novo syntheses3 are in demand which facilitate versatile access to
pyridine scaffolds. Hetero-Diels-Alder (HDA) reactions of azadienes
open useful routes to six-membered ring aza-heterocycles in this
regard.4,5 It was recently shown that 3-hydroxypyridines can be
conveniently synthesized from alkynes and suitably functionalized
1-aza-dienes.6,7 Aryl or electron withdrawing groups (EWG) were
found preferable substituents, but variable regioselectivity was ob-
served.7
To expand the scope of 1-azadiene cycloadditions, we explored
alkenes that regenerate double-bonds by 1,2-elimination as alkyne
surrogates (Scheme 1).8 Initially the easily available7 azadiene 1a was
investigated in thermal cycloadditions with alkenes 2-5 and 6a.9
Interestingly, the alkenes 2-5 remained unproductive, but a clean
transformation to the pyridine 10a (R ) Ph) occurred for bis-cyano
alkene 6a without apparent formation of the intermediary bis-nitrile 7
or dihydropyridines (e.g., 8).10 This suggested rapid elimination of
HCN and TMSOH by putative 1,4- and 1,2-elimination processes10b
followed by loss of the phenolic TMS during workup (9 f 10).7 Our
initial analysis indicated the presence of a single regioisomer only.
The importance of the activating substituent on the nitrogen atom
for cycloaddition efficiency was then studied using different Z-
configured11 azadienes 1 (Table 1). Screening reactions with 1a-h
were conducted at 150 °C without solvent.7 It was found, that
O-alkylated oximes were superior to O-silyl groups, with OMe giving
best results (1d). The hydrazone derivative4 1b did not lead to
appreciable formation of pyridine products. The importance of steric
factors was evident as an increase in substituent size (1d vs 1f, 1d vs
1e) always attenuated reactivity. EWGs on the oxygen atom compro-
mised the productivity of the dienes (1g, 1h), probably as a result of
thermal instability.
Table 1. Variations of 1-aza-Diene 1
1-aza-diene
X
R
yielda of 10
1a
1b
1c
1d
1e
1f
OTMS
NMePh
OTES
OMe
OMe
OMOM
OAc
TMS
TES
TES
TMS
TES
TMS
TES
TMS
40%
<5%
20%
60%
30%
20%
4%
1g
1h
OMs
2%
a Reactions run at 150 °C for 12 h; (1c) 120 °C, 60 h; (1f) 150 °C,
7 h.
Diverse R,R-dicyanoalkenes 6a-h were then accessed by
base-mediated condensation of malono dinitrile with the respective
aldehydes.9 In the cycloadditions a broad spectrum of aromatic
substituents were nicely tolerated (Table 2, entry 10a-d), but also
heterocyclic and alkyl groups reacted productively (10e-h). Interest-
ingly, the alkynyl-phenyl-substituted dicyanoalkene 10i gave only the
alkene cycloaddition product, leaving the alkyne function untouched.10b
The 6-cyano isomer was obtained exclusively (>98:2) in all cases, as
shown by 2D-NMR and X-ray crystallography (Supporting Informa-
tion). Evidence for the 5-cyano regioisomer was not found, neither in
the crude mixtures (GC-MS, HPLC-MS) nor after purification.
A chemical microwave reactor allowed improving the transforma-
tion efficiency.6b,7,12 Conversions were cleanest in DMF solvent and
completed in 30-60 min at 130 °C core temperature, but considerable
decomposition of diene 1d was observed above 130 °C. In this way,
high yields could be achieved (Table 2). Electron-poor aromatics (6b,
6c, 6i, 90-97%) transformed very well, and electron-rich aromatics
(6a, 6d, 6e, 81-96%) performed almost equally well. The heterocycle-
and the alkyl-substituted samples had a wider range in performance
(6e-g, 66-87%), whereas an alkyl substituent showed reduced
reactivity (6h, 60%).
† Technische Universita¨t Dortmund.
‡ Max-Planck-Institut fu¨r Molekulare Physiologie.
§ Universita¨t Ulm.
Notably, alkenyl-alkyne 6i delivered the 3-hydroxypyridine 10i in
excellent yield with very high chemoselectivity for the dicyanoalkene
9
10.1021/ja804078v CCC: $40.75
2008 American Chemical Society
J. AM. CHEM. SOC. 2008, 130, 13219–13221 13219

C O M M U N I C A T I O N S
Figure 1. Reaction pathways as identified by DFT calculations, (A) for alkyne 11, (B) for dicyanoalkene 6a.
Table 2. Hydroxypyridines from Dicyanoalkenes 6a-i
Table 3. Overall Energetics (4E, kcal/mol) for Reactions A and B
path A1(f13) path A2(f15)
compound
vacuum
solvated
vacuum
solvated
1a + 11
12/14
16
MECP-1
17 (singlet)
17 (triplet)
MECP-2
13/15
0
32.5
not identified
not calculated
29.7
29.7
not calculated
-36.3
0
35.2
0
26.9
23.0
23.5
15.8
17.2
38.0
-34.5
0
30.4
25.3
26.6
18.1
19.5
39.3
-31.5
32.8
32.8
-33.3
path B1(f21)
path B2(f7a)
vacuum solvated
compound
vacuum
solvated
1d + 6a
0
0
0
0
stepwise TS
concerted TS (20/22)
21/7a
41.8
32.1
-2.7
44.5
33.9
1.0
relaxed to 22
23.9
21.7
-1.2
-3.3
computational work in the field concentrated on E-1-aza-1,3-butadiene
and ethylene as a dienophile in the gas-phase,13 and on “inverse-
electron-demand”-type cycloadditions of electron-poor 1-azadienes to
vinyl ethers14 or enamines.15 We evaluated the “normal-electron-
demand” type reactions of 1a with phenylacetylene 117 (Figure 1,
reaction A) and of 1d with 6a (reaction B) with density functional
theory (DFT).16
Concerted/asynchronous, singlet and triplet stepwise radicaloid,17
and stepwise polar mechanisms were considered for the cycloadditions
(Figure 1, Table 3). An advanced method was used to determine
minimum energy crossing points (MECPs) between singlet and triplet
states. This method uses a hybrid gradient of singlet and triplet states
to pinpoint the transition state (TS) intersection of the respective
surfaces.18 This algorithm was run in tandem with DFT and provided
more dynamical correlation than CAS wave function methods.
Furthermore, it reported the identities of multideterminental species
that would otherwise not be obtained by standard DFT techniques.18
For reaction A, a concerted pathway through TS 12 leads to 13.
Step-wise processes leading to 13 were not identified. For reactions
a Isolated yields of 10. All reactions were run either with 3 equiv of
1d at 150 °C without solvent for the time indicated (method A) or in a
microwave reactor at 130 °C for 60 min (method B) in DMF as solvent
(0.7-0.9 M alkene). b Reaction run for 30 min.
function, even when an excess of 1-azadiene 1d was employed (3
equiv). Nearly stoichiometric amounts of azadiene (1-1.5 equiv) still
gave reasonable yields (-20%), underscoring the practical utility of
this novel 3-hydroxypyridine synthesis.
The remarkable selectivity of the cycloadditions with the bis-nitriles
6 compared to alkynes7 prompted us to investigate the mechanism of
this transformation from first principle quantum mechanics. Earlier
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C O M M U N I C A T I O N S
with the beneficial effect of aryl substitutents.7 Stronger preference
for the concerted mechanisms can be expected for more electron-
withdrawing substituents on the alkyne.
In summary we have shown that highly functionalized 3-hydroxy-
pyridines can be directly obtained from R,R-dicyanoalkenes 6 with
excellent yield, chemoselectivity, and complete regiocontrol. DFT
calculations clearly report concerted Diels-Alder-type mechanisms
being operative for alkynes and dicyanoalkenes 6 in this novel
1-azadiene cycloaddition. These findings are expected to facilitate the
exploration of 3-hydroxypyridines in materials, synthesis, and medicinal
chemistry.
Acknowledgment. Funding by the Deutsche Forschungsgemein-
schaft (Emmy-Noether young investigator grants JA1072/4-1 to T.J.,
and AR493/1-1 and -2 to H.D.A.) and the Fonds der Chemischen
Industrie (to T.J. and H.D.A.) is most gratefully acknowledged. We
thank Dr. J. N. Harvey (U Bristol, U.K.) for discussions and for
assistance with computer code.
Supporting Information Available: Experimental procedures,
characterization data, X-ray structure determination of a derivative of
compound 10b, computational methodology, and computed energies
and coordinates for all reactant and TS structures. This material is
available free of charge via the Internet at http://pubs.acs.org.
Figure 2. Structures of reactants and transition states 14 and 22 with
annotated distances and NBO charges (red, -0.50 f blue, +0.50).
leading to 15, the stepwise process for C-C bond formation (16) was
lower than the concerted barrier (14). The MECP linking the closed-
shell singlet surface to the open-shell singlet surface (MECP-1) was
essentially isoenergetic to TS 16. Diradical intermediates 17 were found
metastable, but the MECP linking the open-shell surface of 17 to the
closed shell-surface of 15 (MECP-2) was prohibitively high in energy
(Table 3).
We investigated pathways leading to five- and four-membered rings
(18, 19); however, preliminary results on nonfully optimized structures
suggest that these processes are prohibitive. Thus, 12 (+35.2 kcal/
mol) and 14 (+30.4 kcal/mol) are deemed the most likely processes
to reach products 13 and 15, respectively. Considering the inherent
uncertainty of barrier heights and the omission of thermal corrections
(≈5 kcal/mol), our results agree well with the observed moderate
selectivity for A.7
References
(1) Recent examples: (a) Dediu, O. G.; Yehia, N. A. M.; Oeser, T.; Polborn,
K.; Mu¨ller, T. J. J. Eur. J. Org. Chem. 2005, 1834. (b) Craig, D.; Henry,
G. D. Tetrahedron Lett. 2005, 46, 2559. (c) McCormick, M. M.; Duong,
H. A.; Zuo, G.; Louie, J. J. Am. Chem. Soc. 2005, 127, 5030. (d) Senaiar,
R. S.; Young, D. D.; Deiters, A. Chem. Commun. 2006, 1313. (e)
Movassaghi, M.; Hill, M. D.; Ahmad, O. K. J. Am. Chem. Soc. 2007, 129,
10096. (f) Dash, J.; Lechel, T.; Reissig, H.-U. Org. Lett. 2007, 9, 5541.
(2) (a) Jones, G. In Comprehensive Heterocyclic Chemistry II; Mc Killop, A.
Ed.; Pergamon: Oxford, U.K., 1996, Vol. 5, pp 167. (b)Spitzner, D. In
Science of Synthesis; Thieme: Stuttgart, Germany, 2004; p 11.
(3) Henry, G. D. Tetrahedron 2004, 60, 6043.
(4) (a) Serckx-Poncin, B.; Hesbain-Frisque, A. M.; Ghosez, L. Tetrahedron
Lett. 1982, 23, 3261. (b) Pautet, F.; Nebois, P.; Bouaziz, Z.; Filion, H.
Heterocycles 2001, 54, 1095.
(5) Reviews: (a) Tietze, L. F.; Kettschau, G. Top. Curr. Chem. 1997, 189, 1.
(b) Behforouz, M.; Ahmadian, M. Tetrahedron 2000, 56, 5259. (c)
Jayakumar, S.; Ishar, M. P. S.; Mahajan, M. P. Tetrahedron 2002, 58, 379.
(6) (a) Igarashi, J.-e.; Kawakami, Y.; Kinoshita, T.; Furukawa, S. Chem. Pharm.
Bull. 1990, 38, 1832. (b) Fletcher, M. D.; Hurst, T. E.; Miles, T. J.; Moody,
C. J. Tetrahedron 2006, 62, 5454.
For reaction B (1d + 6a), concerted 20 (+33.9 kcal/mol) and
concerted-asynchronous 22 (+21.7 kcal/mol) were the lowest energy
pathways. TS calculations leading to the corresponding diradicals either
relaxed into Diels-Alder type TS 22 or were ≈10 kcal/mol higher
(23) than concerted process barriers. In contrast to the study on reaction
A, the activation barriers 20 and 22 were distinctly different (∆∆E‡
≈ 10 kcal/mol), fully consistent with the experiment. On the other
hand the net energy gain along the reaction coordinate was found to
be small (0 to -3 kcal/mol). Microscopic reversibility thus suggests
that the initial cycloadducts 21 and 7a should be in equilibrium with
the starting materials. In a scenario where CN-elimination precedes
aromatization, 7a is hence expected to easily convert to 8a and drive
the equilibrium assisted by the adjacent R-N lone pair (Figure 1B).
This agrees well with the observed regiospecificity.
Computational evidence for stepwise polar mechanisms was never
secured for reactions A and B, in line with the neutral reaction
conditions and negligible solvent effects.7 In fact we note that solvation
does not appear to play much of a role since vacuum energies lead to
the same conclusions (Table 3). When comparing the preferred TSs,
both 14 and 22 are clearly asynchronous with substantially longer C-N
than C-C distances (Figure 2). Mulliken charges and natural bond
order (NBO) analysis of 22 both show matching azadiene and
dienophile polarity. Although the forward barriers out of 20 were found
prohibitive, a partial opening of the diradical pathway would agree
(7) Lu, J.-Y.; Arndt, H.-D. J. Org. Chem. 2007, 72, 4205.
(8) de Lucchi, O.; Modena, G. Tetrahedron 1984, 40, 2585.
(9) Zhang, B.; Zhu, X.-Q.; Lu, J.-Y.; He, J.; Wang, P. G.; Cheng, J.-P. J. Org.
Chem. 2003, 68, 3295.
(10) (a) Sain, B.; Sandhu, J. S. J. Org. Chem. 1990, 55, 2545. (b) Hopf, H.;
Kreutzer, M. Angew. Chem., Int. Ed. Engl. 1990, 29, 393. (c) Tietze, L. F.;
Henrich, M.; Niklaus, A.; Buback, M. Chem.sEur. J. 1999, 5, 297.
(11) Lu, J.-Y.; Shen, W.-Z.; Preut, H.; Arndt, H.-D. Acta Cryst., E 2008, 64,
o602.
(12) Review: Kappe, O. Angew. Chem., Int. Ed. 2004, 43, 6250.
(13) (a) Traˆn Huu Daˆu, M. E.; Flament, J.-P.; Lefour, J.-M.; Riche, C.; Grierson,
D. S. Tetrahedron Lett. 1992, 33, 2343. (b) Bachrach, S. M.; Liu, M. J.
Org. Chem. 1992, 57, 6736. (c) Tietze, L. F.; Fennen, J.; Geiꢀler, H.; Schulz,
G.; Anders, E. Liebigs Ann. 1995, 1681. (d) Park, Y. S.; Lee, B.-S.; Lee,
I. New. J. Chem. 1999, 23, 707.
(14) Boger, D. L.; Corbett, W. L.; Curran, T. T.; Kaspar, A. M. J. Am. Chem.
Soc. 1991, 113, 1713.
(15) Domingo, L. R. Tetrahedron 2002, 58, 3765.
(16) Calculations utilized unrestricted and restricted DFT (B3LYP hybrid
functional. Jaguar, version 7.0; Schro¨dinger LLC: New York, 2007). Initial
geometry and vibrational frequencies were computed with mixed 6-31G**/
midi! basis sets to confirm intermediates. Geometries were then optimized
with the full 6-31G** basis set. Single point energies on these geometries
were calculated with the 6-311G**+ basis set. DMF solvent was treated
implicitly by Jaguar’s Poisson-Boltzmann continuum solver (ꢀ ) 36.7 and
r ) 2.49 Å) with the 6-311G** basis set. Colored graphics were created
with VMD, see: Humphrey, W.; Dalke, A.; Schulten, K. J. Mol. Graphics
1996, 14, 33.
(17) For a discussion and historical perspective on cycloaddition mechanisms
see: Houk, K. N.; Gonza´les, J.; Li, Y. Acc. Chem. Res. 1995, 28, 81.
(18) Harvey, J. N.; Aschi, M.; Schwarz, H.; Koch, W. Theor. Chem. Acc. 1998,
99, 95.
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