Non-precious metals catalyze formal [4 + 2] cycloaddition reactions of 1,2-diazines and siloxyalkynes under ambient conditions

Article abstract of DOI:10.1021/ol501254h

Copper(I) and nickel(0) complexes catalyze the formal [4 + 2] cycloaddition reactions of 1,2-diazines and siloxyalkynes, a reaction hitherto best catalyzed by silver salts. These catalysts based on earth abundant metals are not only competent, but the copper catalyst, in particular, promotes cycloadditions of pyrido[2,3-d]pyridazine and pyrido[3,4-d]pyridazine, enabling a new synthesis of quinoline and isoquinoline derivatives, as well as the formal [2 + 2] cycloaddition reaction of cyclohexenone with a siloxyalkyne.

Full text of DOI:10.1021/ol501254h

Letter
pubs.acs.org/OrgLett
Non-Precious Metals Catalyze Formal [4 + 2] Cycloaddition Reactions
of 1,2-Diazines and Siloxyalkynes under Ambient Conditions
Chintan S. Sumaria, Yunus E. Turkmen, and Viresh H. Rawal*
̈
Department of Chemistry, The University of Chicago, 5735 South Ellis Avenue, Chicago, Illinois 60637, United States
S
* Supporting Information
ABSTRACT: Copper(I) and nickel(0) complexes catalyze
the formal [4 + 2] cycloaddition reactions of 1,2-diazines and
siloxyalkynes, a reaction hitherto best catalyzed by silver salts.
These catalysts based on earth abundant metals are not only
competent, but the copper catalyst, in particular, promotes
cycloadditions of pyrido[2,3-d]pyridazine and pyrido[3,4-
d]pyridazine, enabling a new synthesis of quinoline and
isoquinoline derivatives, as well as the formal [2 + 2] cycloaddition reaction of cyclohexenone with a siloxyalkyne.
he axially chiral 1,1′-binaphthalene-2,2′-diol (binol) has
for the IEDDA reaction between phthalazine and electron-rich
alkynes.12 The reaction with siloxyalkynes,13 while promoted by
dual hydrogen bond donors, was catalyzed even by simple
pyridinium salts and afforded, rather than the anticipated 2-
naphthol derivative, an intriguing tetra-azapentacyclic com-
pound, arising from a formal [2 + 2 + 2] cycloaddition between
two phthalazines and a siloxyalkyne (Scheme 2, eq 1).14
Inspired by the ample precedent with normal electron demand
Diels−Alder reactions,15 we evaluated various metals for
promoting the desired IEDDA reaction and discovered that
Ag(I) salts, especially when paired with bidentate N-donor
ligands such as 2,2′-bipyridine and 1,10-phenanthroline,
catalyzed the desired process to afford 3-substituted 2-naphthol
1
Timpacted asymmetric catalysis profoundly. Used widely
as a chiral ligand and as a precursor to chiral ligands and
catalysts, binol is best prepared by the oxidative dimerization of
2-naphthol.1,2 Binol derivatives, particularly those with
substituents at the 3,3′-positions, allow fine-tuning of steric
and electronic properties as well as sculpting of the scaffold’s
chiral environment, thereby greatly enhancing the utility of this
scaffold.3−5 Such 3,3′-disubstituted binols are nearly always
made through a multistep sequence starting from a preformed
binol, since the direct oxidative dimerization of 3-substituted
naphthols is impractical given the limited availability of such
naphthol precursors.6 Recently, we reported a general route to
3-substituted naphthol silyl ethers via a silver salt-catalyzed
formal inverse electron-demand Diels−Alder (IEDDA) reac-
tion between phthalazines and siloxyalkynes.7 Since phthala-
zines are prepared by a one-pot procedure from aromatic
aldehydes,8 this cycloaddition methodology provides direct
access to a variety of 2-hydroxynaphthalene derivatives,9
potential precursors to modified binol ligands (Scheme 1).
Nearly all reported IEDDA reactions of heterocyclic
azadienes are thermal processes, typically requiring harsh
conditions.10 Our interest in hydrogen-bonding catalysis11
prompted us to explore pyridinium salts designed to form two
hydrogen bonds to the phthalazine nitrogen atoms as catalysts
Scheme 2. Cycloaddition Reactions of 1,2-Diazines and
Siloxyalkynes
Scheme 1. Route to 3-Substituted 2-Naphthols
Received: May 1, 2014
© XXXX American Chemical Society
A
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Letter
a
Table 1. Reaction Development and Optimization
b
entry
catalyst (mol %)
ligand (mol %)
time (h)
yield (%)
1
2
3
4
5
Ni(PPh3)4 (10)
24
24
24
24
24
24
24
24
4
21
43
Ni(cod)2 (10)
c
Ni(CO)2(PPh3)2 (10)
Ni(CO)2(PPh3)2 (10)
Ni(CO)2(PPh3)2 (10)
CuOTf (5)
81 (80)
PPh3 (10)
67
35
34
38
49
79
67
P(OMe)3 (10)
bpy (5)
d
6
d
7
d
Cu(MeCN)4OTf (5)
Cu(MeCN)4PF6 (5)
Cu(MeCN)4PF6 (10)
Cu(MeCN)4BF4 (10)
Cu(MeCN)4PF6 (10)
Cu(MeCN)4PF6 (10)
Cu(MeCN)4PF6 (10)
Cu(MeCN)4PF6 (10)
Cu(MeCN)4PF6 (10)
bpy (5)
8
bpy (5)
9
bpy (10)
10
11
12
13
14
15
bpy (10)
4
c
bpy (7.5)
4
83 (80)
1,10-phenanthroline (10)
pyr (20)
24
16
24
24
32
72
60
28
4,4′-di-tert-butyl-2,2′-dipyridine (10)
2,2′:6′,2″-terpyridine (10)
a
b
1
All reactions were carried out using 0.5 mmol of 1 and 1.0 mmol of 2 in 1 mL of CH2Cl2. Yields were determined by H NMR using 1,3,5-
trimethoxybenzene as an internal standard. Isolated yield. Reaction was carried out using 1.5 equiv of 2 per equivalent of 1 in CH2Cl2 (0.5 mmol of
1 in 1.0 mL of CH2Cl2).
c
d
Figure 1. Investigation of Cu(I)/Ni(0) catalyzed formal [4 + 2] cycloaddition reaction of 1,2-diazines and siloxyalkynes. (a) Unless otherwise stated,
reactions were carried out with 10 mol % of copper(I) or nickel(0) catalyst with with 2.0 equiv of siloxyalkyne. Yields are for the chromatographically
purified products. The major regioisomeric product is shown. (b) Carried out using 1 mol % of Cu(MeCN)4PF6 or 5 mol % of Ni(CO)2(PPh3)2 (1.5
equiv of siloxyalkyne). (c) Note that Ni(0) catalyst affords the other regioisomer (not shown) as the major product. (d) Reaction was carried out in
refluxing DCE.
silyl ethers in good yields (Scheme 2, eq 2).7,16 To make this
strategy more versatile and practical, we have examined
complexes of earth abundant metals as catalysts for the
IEDDA reaction and report here that Cu(I) and Ni(0)
complexes can supplant Ag(I) salts for these cycloadditions
(Scheme 2, eq 3).17 Significantly, the copper salt catalyzes not
only the cycloaddition of a broader range of substrates but also
the [2 + 2] cycloaddition reaction between a siloxyalkyne and
B
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Organic Letters
Letter
cyclohexenone, a transformation previously catalyzed by silver
salts.13c
We had recognized early on that extending the IEDDA
reactions to pyridopyridazines would open up a new route to
quinolines and isoquinolines but had found the silver catalyst to
be ineffective with most such substrates.21 We are delighted to
note that this limitation can be overcome with the Cu catalyst.
The reaction of pyrido[2,3-d]pyridazine and 1-siloxyhexyne
(2), under standard Cu-catalysis conditions, gave small
amounts of the quinoline product. When the same reaction
was carried out in refluxing DCE, siloxyquinoline 16 was
isolated in 41% yield, as a mixture of regioisomers.22 The
related trifluoromethyl-substituted pyrido[2,3-d]pyridazine re-
acted smoothly at room temperature, thus affording the
corresponding product mixture 17 in 64% yield.23 As observed
with phthalazine (1), the reaction with the phenyl-substituted
siloxyalkyne was more facile, giving the regioisomers of
siloxyquinoline 18 in 74% yield. Similar success was enjoyed
in the reaction between pyrido[3,4-d]pyridazine and phenyl-
siloxyalkyne, which gave the regioisomeric isoquinoline
products 19 in 67% yield.
The fruitful switch from a silver catalyst to a nickel or copper
catalyst spurred a brief look at other reactions that might be
amenable to such a change. Among the reactions of
siloxyalkynes, we examined its formal [2 + 2]-cycloaddition
with cyclohexenone, a transformation reported by Kozmin et al.
to be catalyzed by AgNTf2.13c Treatment of a solution of the
two reactants with 5 mol % of Cu(MeCN)4PF6 promoted its
clean conversion to the [2 + 2]-cycloadduct (20), isolated in
74% yield (Scheme 3).24
The contrasting reactivity displayed by pyridinium salts and
silver salts combined with a desire to identify non-precious
metals for catalysis motivated us to examine a broader range of
metal complexes for the IEDDA reaction of phthalazine (1)
and 1-siloxyhexyne (2) (Table 1). Commonly employed Lewis
acids, such as ZnBr2, TiCl4, Yb(OTf)3, Sc(OTf)3, Bi(OTf)3,
Co(BF4)2, La(OTf)3, In(OTf)3, and BF3·OEt2, all failed to
catalyze the reaction.18 Interestingly, while NiCl2 was also
ineffective, the corresponding Ni(0) complexes, Ni(PPh3)4 and
Ni(cod)2, afforded the desired cycloadduct 3 in 21% and 43%
yields, respectively (entries 1 and 2). This result suggests that
the metal is not activating the diazine simply through Lewis
acid/base interaction, since Ni(0) complexes are expected to be
weakly Lewis acidic, certainly compared to NiCl2. We were
pleased to find that Ni(CO)2(PPh3)2, at 10 mol % catalyst
loading, nicely catalyzed the cycloaddition at room temper-
ature, affording the product in 80% yield (entry 3). Further
addition of PPh3 or P(OMe)3 to the Ni(0) complex gave the
product in diminished yields (entries 4 and 5). Isoelectronic
with Ag(I) and Ni(0), Cu(I) salts were expected to also
catalyze the cycloaddition reactions. Indeed, CuCl when used
in conjunction with 2,2′-bipyridine did catalyze the reaction,
albeit poorly (5% yield). The efficacy of Cu(I) salts improved
with decreasing nucleophilicity of the counterion, as evidenced
by increasing yields on going from CuI to CuCl to Cu(OTf).
Even better results were obtained with highly dissociated
−
−
counterions, such as PF6 and BF4 (entries 7−10). The best
result was obtained using 10 mol % of tetrakis(acetonitrile)-
copper(I) hexafluorophosphate with 2,2′-bipyridine as the
ligand, which provided naphthalene 3 in 80% isolated yield
after 4 h reaction time (entry 11). Several other ligands were
examined, but they did not better the yields (entries 12−15).
Reactions proceeded in lower yields in acetonitrile and 1,4-
dioxane, and no product was formed in chloroform or in protic
solvents, such as methanol and water. The interchangeable use
of silver, copper, or nickel complexes for the catalysis of these
formal cycloadditions is noteworthy.17,19
Having defined effective conditions for Cu(I)- and Ni(0)-
catalyzed cycloaddition of the parent system, we next evaluated
the substrate scope for the new catalyst systems (Figure 1). The
two catalysts were expected to behave differently, since
Ni(CO)2(PPh3)2 is hindered, having a sterically crowded
neutral Ni(0) center, whereas Cu(I), as a soft Lewis acid, was
expected to coordinate more strongly.20 Indeed, as noted
above, while both provided silyl ether 3 in the same yield, the
reaction was noticeably faster with the Cu(I) catalyst.
Additionally, the two complexes displayed differing regiose-
lectivities with unsymmetrical phthalazines. Whereas Cu(I)
gave 1:1 mixture of the two regioisomeric products of 6-
methoxyphthalazine, the Ni(0) catalyst gave 4 in a 1.5:1
preference over its regioisomer (not shown). A similar
preference was observed with 5-chlorophthalazine and 5-
fluorophthalazine, which produced naphthalenes 5 and 6,
respectively, as the major products. In these instances, the
slower reaction was also the more regioselective one. Other
alkyl- and arylsiloxyalkynes were examined, and all gave the
naphthalene products (7−9) in good yields. Benzo-fused
derivatives of phthalazine enabled the synthesis of anthracene
and phenanthrene derivatives. Thus, benzo[g]phthalazine gave
anthracene products 10 and 11, whereas benzo[f]phthalazine
gave phenanthrenes 12 and 13.
Scheme 3. Cu(I) Catalysis of a formal [2 + 2] Cycloaddition
Reaction of Siloxyalkynes
In conclusion, we have demonstrated that Cu(I) and Ni(0)
complexes catalyze the formal [4 + 2] cycloaddition reactions
of 1,2-diazines and siloxyalkynes to give siloxy derivatives of
naphthalene, anthracene, and phenenathrene. The copper
catalyst was also effective in promoting the corresponding
cycloaddition to generate quinoline and isoquinoline deriva-
tives, as well as for the [2 + 2]-cycloaddition of siloxyalkyne and
cyclohexenone. In more general terms, this study demonstrates
the feasibility of switching from a precious metal to more
economical, isoelectronic metals for catalyzing reactions.
ASSOCIATED CONTENT
* Supporting Information
■
S
1
Experimental procedures, characterization, and copies of H
and 13C NMR spectra for all new compounds being reported in
the text. This material is available free of charge via the Internet
at http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: vrawal@uchicago.edu.
Notes
The authors declare no competing financial interest.
C
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Letter
699. (e) Schweighauser, L.; Bodoky, I.; Kessler, S. N.; Haussinger, D.;
̈
ACKNOWLEDGMENTS
■
Wegner, H. A. Synthesis 2012, 44, 2195. (f) Bader, S. L.; Kessler, S. N.;
Zampese, J. A.; Wegner, H. A. Monatsh. Chem. 2013, 144, 531.
(13) For other related reactions of siloxyalkynes, see: (a) Lal, G. S.;
Kowalski, C. J. J. Am. Chem. Soc. 1988, 110, 3693. (b) Brisbois, R. G.;
Kowalczyk, J. L.; Miller, R. F.; Danheiser, R. L. J. Am. Chem. Soc. 1990,
112, 3093. (c) Sweis, R. F.; Schramm, M. P.; Kozmin, S. A. J. Am.
Chem. Soc. 2004, 126, 7442. (d) Zhang, L.; Kozmin, S. A. J. Am. Chem.
Soc. 2004, 126, 10204. (e) Zhang, L.; Kozmin, S. A. J. Am. Chem. Soc.
2004, 126, 11806. (f) Austin, W. F.; Zhang, Y.; Danheiser, R. L. Org.
Lett. 2005, 7, 3905. (g) Qi, X.; Ready, J. M. Angew. Chem., Int. Ed.
2008, 47, 7068. (h) Zhao, W.; Wang, Z.; Sun, J. Angew. Chem., Int. Ed.
2012, 51, 6209. (i) Cabrera-Pardo, J. R.; Chai, D. I.; Liu, S.; Mrksich,
M.; Kozmin, S. A. Nat. Chem. 2013, 5, 423. (j) Zhao, W.; Li, Z.; Sun, J.
J. Am. Chem. Soc. 2013, 135, 4680. (k) Cabrera-Pardo, J. R.; Chai, D.
I.; Kozmin, S. A. Adv. Synth. Catal. 2013, 355, 2495.
We thank the National Institutes of Health for supporting this
work (P50GM086145 and GM 069990).
REFERENCES
■
(1) (a) Brunel, J. M. Chem. Rev. 2005, 105, 857. (b) Wang, H.
Chirality 2010, 22, 827.
(2) For selected examples of oxidative dimerization of naphthols, see:
(a) Guo, Q.-X.; Wu, Z.-J; Luo, Z.-B.; Liu, Q.-Z.; Ye, J.-L.; Luo, S.-W;
Cun, L.-F.; Gong, L.-Z. J. Am. Chem. Soc. 2007, 129, 13927. (b) Egami,
H.; Matsumoto, K.; Oguma, T.; Kunisu, T.; Katsuki, T. J. Am. Chem.
Soc. 2010, 132, 13633.
(3) Reviews: (a) Chen, Y.; Yekta, S.; Yudin, A. K. Chem. Rev. 2003,
103, 3155. (b) Berthod, M.; Mignani, G.; Woodward, G.; Lemaire, M.
Chem. Rev. 2005, 105, 1801. (c) Shibasaki, M.; Matsunaga, S. Chem.
Soc. Rev. 2006, 35, 269. (d) Pereira, M. M.; Calvete, M. J. F.; Carrilho,
R. M. B.; Abreu, A. R. Chem. Soc. Rev. 2013, 42, 6990.
(14) Montavon, T. J.; Turkmen, Y. E.; Shamsi, N. A.; Miller, C.;
̈
Sumaria, C. S.; Rawal, V. H.; Kozmin, S. A. Angew. Chem., Int. Ed.
2013, 52, 13576.
(4) For selected examples of binol derivatives in catalysis, see:
(a) Bao, J.; Wulff, W. D.; Dominy, J. B.; Fumo, M. J.; Grant, E. B.;
Rob, A. C.; Whitcomb, M. C.; Yeung, S.-M.; Ostrander, R. L.;
(15) Evans, D. A.; Johnson, J. S.; Jacobsen, E. N.; Pfaltz, A.;
Yamamoto, H. Comprehensive Asymmetric Catalysis; Springer: New
York, 1999; Vol. 3, p 1177 and references cited therein.
(16) For a study of ternary Ag(I) complexes of 1,2-diazines and
chelating heteroarenes, which found two silver atoms bound to a
Rheingold, A. L. J. Am. Chem. Soc. 1996, 118, 3392. (b) Knopfel, T. F.;
̈
Aschwanden, P.; Ichikawa, T.; Watanabe, T.; Carreira, E. M. Angew.
Chem., Int. Ed. 2004, 43, 5971. (c) Unni, A. K.; Takenaka, N.;
Yamamoto, H.; Rawal, V. H. J. Am. Chem. Soc. 2005, 127, 1336. (d) Li,
G.-Q.; Gao, H.; Keene, C.; Devonas, M.; Ess, D. H.; Kurti, L. J. Am.
Chem. Soc. 2013, 135, 7414.
(5) A particularly important class of binol derivatives are chiral
phosphoric acids: (a) Connon, S. J. Angew. Chem., Int. Ed. 2006, 45,
3909. (b) Terada, M. Synthesis 2010, 1929. For pioneering
applications, see: (c) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K.
Angew. Chem., Int. Ed. 2004, 43, 1566. (d) Uraguchi, D.; Terada, M. J.
Am. Chem. Soc. 2004, 126, 5356.
(6) (a) Simonsen, K. B.; Gothelf, K. V.; Jørgensen, K. A. J. Org. Chem.
1998, 63, 7536. (b) Maruoka, K.; Itoh, T.; Araki, Y.; Shirasaka, T.;
Yamamoto, H. Bull. Chem. Soc. Jpn. 1998, 61, 2975. (c) Huang, W.-S.;
Pu, L. Tetrahedron Lett. 2000, 41, 145. (d) Romanov-Michailidis, F.;
bridging pyridazine unit, see: Turkmen, Y. E.; Sen, S.; Rawal, V. H.
̈
CrystEngComm 2013, 15, 4221.
̈
(17) Bullock, R. M., Ed. Catalysis without Precious Metals; Wiley-
VCH: Weinheim, 2010.
(18) See the Supporting Information for a full list of catalysts
evaluated.
(19) For an example of silver and copper complexes giving two
different products from the same precursor, see: Fang, Y.; Wang, C.;
Su, S.; Yu, H.; Huang, Y. Org. Biomol. Chem. 2014, 12, 1061.
(20) Ho, T.-L. Chem. Rev. 1975, 75, 1.
(21) Other potential azadiene precursors to heterocycles were
evaluated. See the Supporting Information for details.
(22) The Ag(I) and Ni(0) catalysts did not promote this reaction.
(23) Interestingly, the reaction of the trifluoromethyl-substituted
pyrido[2,3-d]pyridazine, wherein the adjacent nitrogen atom is
expected to be less basic, can also be catalyzed by 5 mol% AgNTf2
to give the cycloadduct in 71% yield. See the Supporting Information
for a detailed procedure.
Guen
́
ee
́
, L.; Alexakis, A. Angew. Chem., Int. Ed. 2013, 52, 9266.
̈
(7) Turkmen, Y. E.; Montavon, T. J.; Kozmin, S. A.; Rawal, V. H. J.
Am. Chem. Soc. 2012, 134, 9062.
(8) Kessler, S. N.; Wegner, H. A. Org. Lett. 2012, 14, 3268.
(9) For reviews on the synthesis of substituted naphthalenes, see:
(a) Katritzky, A. R.; Li, J.; Xie, L. Tetrahedron 1999, 55, 8263.
(b) Rousseau, A. L.; de Koning, C. B.; van Otterlo, W. A. L.
Tetrahedron 2003, 59, 7. For recent examples for the synthesis of 2-
naphthols, see: (c) Juteau, H.; Gareau, Y.; Lachance, H. Tetrahedron
Lett. 2005, 46, 4547. (d) Zhang, X.; Sarkar, S.; Larock, R. C. J. Org.
Chem. 2006, 71, 236. (e) Dai, Y.; Feng, X.; Liu, H.; Jiang, H.; Bao, M.
J. Org. Chem. 2011, 76, 10068. (f) Xia, Y.; Qu, P.; Liu, Z.; Ge, R.; Xiao,
Q.; Zhang, Y.; Wang, J. Angew. Chem., Int. Ed. 2013, 52, 2543. (g) He,
Y.; Zhang, X.; Shen, N.; Fan, X. J. Org. Chem. 2013, 78, 10178.
(h) Chang, M.-Y.; Chan, C.-K.; Lin, S.-Y. Tetrahedron 2013, 69, 1532.
(10) For reviews on Diels−Alder reactions of azadienes, see:
(a) Boger, D. L. Tetrahedron 1983, 39, 2869. (b) Boger, D. L.
Chem. Rev. 1986, 86, 781. (c) Foster, R. A. A.; Willis, M. C. Chem. Soc.
Rev. 2013, 42, 63. For selected examples of Diels−Alder reactions of
1,2-diazines, see: (d) Higashino, T.; Miyashita, A.; Iwamoto, K.; Taido,
N.; Oishi, E. Chem. Pharm. Bull. 1990, 38, 3268. (e) Coleman, R. S.;
Boger, D. L. J. Am. Chem. Soc. 1987, 109, 2717. (f) Rastogi, S. K.;
Medellin, D. C.; Kornienko, A. Org. Biomol. Chem. 2014, 12, 410.
(11) (a) Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. Nature
2003, 424, 146. (b) Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am.
(24) This reaction was not catalyzed by Ni(CO)2(PPh3)2.
Chem. Soc. 2008, 130, 14416. (c) Turkmen, Y. E.; Rawal, V. H. J. Org.
̈
Chem. 2013, 78, 8340.
(12) For bidentate Lewis acid activation of 1,2-diazines, see:
(a) Kessler, S. N.; Wegner, H. A. Org. Lett. 2010, 12, 4062. (b) Kessler,
S. N.; Neuburger, M.; Wegner, H. A. Eur. J. Org. Chem. 2011, 3238.
(c) Kessler, S. N.; Neuburger, M.; Wegner, H. A. J. Am. Chem. Soc.
2012, 134, 17885. (d) Kessler, S. N.; Wegner, H. A. Synlett 2012, 5,
D
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