Silver-catalyzed exo-dig-azacyclization/[3+2] cycloaddition cascades on 1-tosylhydrazon-4-oxy-5-yne Substrates: Applicability to Diverse Alkenes

Article abstract of DOI:10.1002/adsc.201100263

We report the silver-catalyzed tandem 6-exo-dig-azacyclization/[3+2] cycloaddition cascade on 1-tosylhydrazon-4-oxy-5-ynes to form complicated azacyclic products regioselectively and efficiently. The new azacyclic syntheses have a wide range of reaction s

Full text of DOI:10.1002/adsc.201100263

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DOI: 10.1002/adsc.201100263
Silver-Catalyzed exo-dig-Azacyclization/[3+2]Cycloaddition
G
Cascades on 1-Tosylhydrazon-4-oxy-5-yne Substrates:
Applicability to Diverse Alkenes
Deepak B. Huple,a Chun-Hao Chen,a Arindam Das,a and Rai-Shung Liua,*
a
Department of Chemistry, National Tsing-Hua University, Hsinchu, Taiwan, Republic of China
Fax : (+886)-3-571-1082; e-mail: rsliu@mx.nthu.edu.tw
Received: April 7, 2011; Published online: August 10, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100263.
Abstract: We report the silver-catalyzed tandem 6-
exo-dig-azacyclization/[3+2]cycloaddition cascade
ACHTUNGTRENyNUNG ne substrates C; the tethered oxy group activates
G
this exo-dig cyclization to form s-trans-2-oxadienium
ion D that further reacts with electron-rich alkenes to
give formal [4+2]cycloadducts [Eq. (2)].
on 1-tosylhydrazon-4-oxy-5-ynes to form complicat-
ed azacyclic products regioselectively and efficient-
ly. The new azacyclic syntheses have a wide range
of reaction scope, with respect to both substrates
and alkenes.
AHCTUNGTREG[NNUN 3+2]Dipolar cycloadditions are useful methods to
obtain five-membered azacyclic compounds.[6,7] In the
presence of Lewis acids, nitrones and azomethines are
capable of undergoing [3+2]cycloadditions with elec-
tron-deficient alkenes.[6,7] Continuing our interest in
the exo-dig cyclization, as depicted in Scheme 1, we
Keywords: azacyclic synthesis; 6-exo-dig-azacycliza-
tion; cascade reactions;
catalysis
ACHTUNGTNER[NUNG 3+2]cycloaddition; silver
report herein a new 6-exo-dig-azacyclization/ACTHNUTRGNEUG[N 3+2]cy-
cloaddition cascade on 1-tosylhydrazon-4-oxy-5-ynes
1 involving the intermediacy of azomethine imines E.
Particularly notable is the applicability of this reaction
to various alkenes bearing both electron-donating and
Tandem cyclization/cycloaddition cascades are power- electron-withdrawing groups. The scope of substrates
ful tools to access complicated molecular frame- includes not only benzenoid, but also non-benzenoid
works.[1,2] Oxoalkyne substrates A serve as a platform species in some instances. Related to this work are
for gold and platinum catalysts to implement these the silver-catalyzed tandem reactions on N’-(2-alkyn-
cascades to give diverse carbo- or oxacycles.[3,4] Re-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
clization to form 2-oxodienium ions B[3] or a-carbonyl such a cascade sequence is restricted to benzenoid
ylides B’,[4] which undergo subsequent [3+2] or [4+ substrates that work only with special electron-defi-
2]cycloadditions with alkenes or alkynes to complete cient alkenes including acrolein (X=H) and ethyl ac-
the cascade sequence [Eq. (1)]. We reported the first rylate (X=OEt).[9]
exo-dig-cyclization/cycloaddition cascade[5] on oxoalk-
As presented in Table 1, we examined the cycliza-
tion of 1-tosylhydrazon-4-acetoxy-5-yne 1a with
ethoxyethene 2a (4 equiv.) using
PACTHNGUTERN(NUG t-Bu)2(o-bi-
AHCTUNGTRENGpNUN henyl)AuCl/AgNTf2 (5 mol%) that was previously
used for the 6-exo-dig cyclization of oxoalkynes C
[Eq. (2)].[5] With this catalyst mixture, we obtained
azacyclic product 3a in 66% yield (entry 1). Our con-
trol experiment reveals that AgNTf2 (5 mol%) alone
implemented this cascade reaction to produce the
same product in 58% yield (entry 2). AgOTf
(5 mol%) greatly enhanced the yield up to 83%
(entry 3). We were pleased to find this tandem reac-
tion to be compatible with various enol ethers includ-
ing 2-methoxyprop-1-ene (2b), 1-ethoxyprop-1-ene
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Scheme 1. Distinct cyclization modes for substrates 1 and 2.
Table 1. Ag-catalyzed cascade reactions using various enol ethers.
[a]
[b]
[c]
L=(o-biphenyl)PACHTNUTRGNEUNG(t-Bu)2, [substrate]=0.1M, dichloromethane, 258C.
Enol ether (4 equiv.).
Product yields are reported after purification from a silica column.
(2c) and (2-ethoxyvinyl)benzene (2d), delivering the cent alkyne to enhance the 6-exo-dig cyclization
desired compounds 3b–3d in 79–83% yields (en- mode.[5]
tries 4–6). We also prepared substrates 1b and 1c to
study the oxy effect; the methoxymethyl ether species yne derivatives 4a–4e and 5a–5d to examine the gen-
1c is better than its methoxy analogue 1b for the cy- erality of this exo-azacyclization/[3+2]cycloaddition
We prepared various 1-tosylhydrazon-4-acetoxy-5-
AHCTUNGTRENNUNG
cloadditions with enol ethers 2a and 2b. Acetoxy cascade. In a standard operation, these substrates
(OAc) and methoxymethyl (MOM) ethers presuma- were treated with ethoxyethene (4 equiv.) and AgOTf
bly exert an electron-withdrawing effect on the adja- (5 mol%) in CH2Cl2 (258C, 0.5–0.83 h); their corre-
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Silver-Catalyzed exo-dig-Azacyclization/ACTHNUTRGNE[NUG 3+2]Cycloaddition Cascades on 1-Tosylhydrazon-4-oxy-5-yne
Table 2. Ag-catalyzed cascade reactions using various sub-
strates.
Table 3. Scope for the reactions with electron-deficient
alkenes.
[a]
[Substrate]=0.11M.
Product yields are reported after purification from a
[b]
silica column.
sponding products 6a–6e and 7a–7d are listed in
Table 2. Entries 1–5 show the applicability of this cat-
alysis to benzenoid substrates 4a–4d bearing a fluoro
and chloro at the phenyl C-4 and C-5 positions (en-
tries 1–4); their corresponding products 6a–6d were
obtained in (79–83%) yields. The same catalysis also
worked well for electron-rich benzenoid product 6e
that was obtained in 78% yield. The scope of this re-
action is further expanded with its compatibility with
non-benzenoid products 7a–7d containing cyclohexen-
yl and cycloheptenyl linkages; the corresponding
yields were 54–72% (entries 6–9).
As shown in Table 3, this cascade reaction is partic-
ularly notable for its compatibility with various elec-
tron-deficient alkenes, including ethyl acrylate (en-
tries 1 and 2), methyl vinyl ketone (entry 3), methyl
vinyl sulfone (entry 4), diethyl fumarate (entry 5) and
cyclohexenone (entry 6). In a typical reaction, 1-tosyl-
[a]
[Substrate]=0.11M in dichloroethane/N,N-dimethyl-
AHCTUNGTRENNGaUN cetamide (2:1, 3 mL)/20 mol% 2,6-lutidine.
Product yields are reported after silica chromatography.
8d=3f.
[b]
[c]
hydrazon-4-acetoxy-5-yne 1a and its methoxymethyl adduct, but a 73% yield of compound 8d resulting
ether analogue 1c was treated with alkene (4 equiv.), from the elimination of the sulfone group.[10] This
AgOTf (5 mol%) and 2,6-lutidine (20 mol%) in a silver-catalyzed synthesis is extensible to benzenoid
mixed solvent of dichloroethane and N,N-dimethyl- products, bearing fluoro, chloro and methoxy at the
ACHTUNGTRENNUNGacetamide (2:1) at 708C; the resulting products 8a–8f C-4 or C-5 postions (entries 7–11); the resulting yields
were obtained as a single regioisomer with reasonable were 48–60% for the acetoxy derivatives 8g–8k and
yields (55–81%, entries 1–6). In the case of methyl 60-.66% for the methoxymethyl analogues 8g’–8i’ and
vinyl sulfone (entry 4), we obtained no desired cyclo- 8k’.
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transformation of 1-tosylhydrazon-4-acetoxy-5-yne 1a
into isoquinolinium-2-ylACTHNUTRGENUGN(tosyl)amide 9, appears to be
slow; the yields of compound 9 were 56% and 78% at
0.5 h and 1.0 h, respectively. Furthermore, the trans-
formation of isoquinolinium species 9 into azacyclic
compound 3a is also very slow under the catalytic
conditions; compound 3a was produced in only 12%
yield at 0.5 h, and 34% yield at 5 h. Accordingly, we
conclude that species 9 is not the reaction intermedi-
ate because of its slow formation, as well as the poor
activity with enol ether 2a. The low activity in the cy-
cloaddition of species 9 with enol ether is not surpris-
ing because such a process is expected to cause its
dearomatization.
Scheme 3 provides a plausible mechanism involving
the key zwitterionic intermediate H that is capable of
undergoing [3+2]cycloaddition with both electron-
rich and electron-deficient alkenes. The non-aromatic
nature of species H is expected to show high activity
for dipolar additions, including tranformations H!I
and H!K, which would proceed with energy barriers
smaller than those for isoquinolinium species 9. We
envisage that the resulting cycloadducts I and K are
subjected to aromatization reactions because of the
presence of AgOTf, and 2,6-lutidine.
Scheme 2. Control experiments to verify the intermediacy of
species 9.
In summary, we report the Ag-catalyzed tandem 6-
Scheme 2 presents data to clearify the reaction in- exo-dig-azacyclization/ACTHNUTRGNE[NUG 3+2]cycloaddition cascades on
termediate. As described previously (Table 1, 1-tosylhydrazon-4-oxy-5-ynes to form complicated
entry 3), azacyclic compound 3a was produced com- azacyclic products efficiently. In contrast with report-
pletely from starting 1a and ethoxyethene 2a within ed 6-endo-dig-azacyclizations,[8,9] the new azacyclic
0.5 h. In the absence of enol ether, the Ag-catalyzed syntheses have a wide reaction scope, with respect to
Scheme 3. A proposed mechanism.
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Silver-Catalyzed exo-dig-Azacyclization/ACTHNUTRGNE[NUG 3+2]Cycloaddition Cascades on 1-Tosylhydrazon-4-oxy-5-yne
References
both substrates and alkenes, including non-benzenoid
substrates, electron-rich and electron-deficient al-
kenes. Control experiments exclude the intermediacy
of isoquinolinium species 9 because of its poor activi-
ty in the cycloaddition with enol ether. We hypothe-
size that the [3+2]dipolar cycloadditions likely occur
on non-aromatic zwitterionic intermediates I.
[1] Reviews on gold-catalyzed annulation or cycloaddition
reactions, see: a) N. T. Patil, Y. Yamamoto, Chem. Rev.
2008, 108, 3395; b) N. T. Patil, Y. Yamamoto, ARKI-
VOC 2007, 5, 6; c) S. Md. Abu Sohel, R.-S. Liu, Chem.
Soc. Rev. 2009, 38, 2269; d) A. Fꢁrstner, P. W. Davies,
Angew. Chem. 2007, 119, 3478; Angew. Chem. Int. Ed.
2007, 46, 3410; e) N. D. Shapiro, F. D. Toste, Synlett
2010, 675.
[2] Selected examples for Au- and Pt-catalyzed cyclization/
cycloaddition cascades, see: a) C.-C. Lin, T.-M. Teng,
C. C. Tsai, H.-Y. Liao, R.-S. Liu, J. Am. Chem. Soc.
2008, 130, 16417; b) T. M. Teng, M. S. Lin, D. Vasu, S.
Bhunia, T.-A. Liu, R.-S. Liu, Chem. Eur. J. 2010, 16,
4744; c) H.-S. Yeom, J.-E. Lee, S. Shin, Angew. Chem.
2008, 120, 7148; Angew. Chem. Int. Ed. 2008, 47, 7040;
d) G. Zhang, X. Huang, G. Li, L. Zhang, J. Am. Chem.
Soc. 2008, 130, 1814; e) F. Liu, Y. Yu, J. Zhang, Angew.
Chem. 2009, 121, 5613; Angew. Chem. Int. Ed. 2009, 48,
5505; f) N. D. Shapiro, Y. Shi, F. D. Toste, J. Am. Chem.
Soc. 2009, 131, 11654; g) N. D. Shapiro, F. D. Toste, J.
Am. Chem. Soc. 2008, 130, 9244.
[3] For the [4+3]cycloaddition of s-cis-oxonium ions B,
see selected examples: a) N. Asao, T. Kasahara, Y. Ya-
mamoto, Angew. Chem. 2003, 115, 3628; Angew. Chem.
Int. Ed. 2003, 42, 3504; b) N. Asao, H. Aikawa, Y. Ya-
mamoto, J. Am. Chem. Soc. 2004, 126, 7458; c) Y.-C.
Hsu, C.-M. Ting, R.-S. Liu, J. Am. Chem. Soc. 2009,
131, 2090; d) X.-Z. Shu, S.-C. Zhao, K.-G. Ji, Z.-J.
Zheng, X.-Y. Liu, Y.-M. Liang, Eur. J. Org. Chem.
2009, 117.
Experimental Section
General Procedure for Synthesis of 5-Methyl-
pyrazoloACHTUNGTRENNUNG[5,1-a]isoquinolin-6-yl Acetate (3a)
To a stirred dichloromethane (2 mL) solution of AgOTf
(4.0 mg, 0.014 mmol) was added a dichloromethane (1 mL)
solution of 1-{2-[(2-tosylhydrazono)methyl]phenyl}prop-2-
ynyl acetate 1a (100 mg, 0.27 mmol) and ethyl vinyl ether
(58 mg, 0.81 mmol); the resulting mixture was kept stirring
for another 30 min before it was filtered over a short silica
bed. The solvent was removed under reduced pressure and
the crude product was eluted through a silica gel column to
provide 5-methylpyrazoloACTHUNRGTNE[NUG 5,1-a] isoquinolin-6-yl acetate 3a
as a yellow solid; yield: 54 mg (0.224 mmol, 83%). IR
(neat): n=3050 (m), 2915 (w), 1716 (s), 1256 cmꢀ1 (s);
1H NMR (400 MHz, CDCl3): d=8.10–8.07 (m, 1H), 7.99 (d,
J=2.2 Hz, 1H), 7.59–7.52 (m, 3H), 7.03 (d, J=2.2 Hz, 1H),
2.66 (s, 3H), 2.48 (s, 3H); 13C NMR (100 MHz, CDCl3): d=
169.0, 140.9, 137.3, 132.7, 128.9, 128.0, 127.3, 124.6, 123.7,
122.7, 120.8, 98.2, 20.5, 11.9; HR-MS (EI): m/z=240.090,
calcd. for C14H12N2O2: 240.0899.
[4] For the [3+2]cycloaddition of s-cis-oxonium ions B,
see selected examples: a) H. Kusama, K. Ishida, H.
Funami, N. Iwasawa, Angew. Chem. 2008, 120, 4981;
Angew. Chem. Int. Ed. 2008, 47, 4903; b) G. Li, X.
Huang, L. Zhang, J. Am. Chem. Soc. 2008, 130, 6944;
c) C. H. Oh, J. H. Lee, S. J. Lee, J. I. Kim, C. S. Hong,
Angew. Chem. 2008, 120, 7615; Angew. Chem. Int. Ed.
2008, 47, 7505; d) C. H. Oh, S. M. Lee, C. S. Hong, Org.
Lett. 2010, 12, 1308.
General Procedure for Synthesis of Ethyl 6-Acetoxy-
5-methylpyrazoloACHTUNGTRENNUNG[5,1-a]isoquinoline-1-carboxylate
(8a)
To a stirred dichloroethane/N,N-dimethylacetamide (2:1,
2 mL) and 2,6-lutidine(20 mol%) solution of AgOTf
AHCTUNGTRENNUNG
(4.0 mg, 0.014 mmol) was added a dichloroethane solution
of 1-{2-[(2-tosylhydrazono)methyl]-phenyl}prop-2-ynyl ace-
tate 1a (100 mg, 0.27 mmol) and ethyl acrylate (81 mg,
0.81 mmol); the resulting mixture was kept stirring for an-
other 24 h at 708C before it was filtered over a short silica
bed. The solvent was removed under reduced pressure and
the crude product was eluted through a silica gel column to
[5] T.-M. Teng, A. Das, D. B. Huple, R.-S. Liu, J. Am.
Chem. Soc. 2010, 132, 12565.
[6] a) Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry toward Heterocycles and Natural Products,
(Eds.: A. Padwa, W. H. Pearson), John Wiley and Sons.
Hoboken, NJ, 2003; b) S. Kanemasa, Synlett 2002, 1371;
c) C. Najera, J. M. Sansano, Curr. Org. Chem. 2003, 7,
1105.
[7] For metal-catalyzed [3+2]dipolar cycloadditions, see
selected reviews: a) L. M. Stanley, M. P. Sibi, Chem.
Rev. 2008, 108, 2887; b) K. V. Gothelf, K. A. Jogensen,
Chem. Rev. 1998, 98, 863; c) N. T. Patil, Y. Yamamoto,
Chem. Rev. 2008, 108, 3395.
[8] S. Ye, X. Yang, J. Wu, Chem. Commun. 2010, 46, 5238.
[9] Wu and co-workers also reported Ag-catalyzed 6-endo-
dig cyclizations of N’-(2-alkynylbenylidene) hydrazides
2 with alkynes,[9a] ketones[9b] and enones; these reac-
tions are distinct from our work; see a) Z. Chen, X.
Yang, J. Wu, Chem. Commun. 2009, 3469; b) X. Yu, S.
Ye, J. Wu, Adv. Synth. Catal. 2010, 352, 2050; c) Z.
Chen, J. Wu, Org. Lett. 2010, 12, 4856.
provide ethyl 6-acetoxy-5-methylpyrazolo
ACHTUNGTREN[NUGN 5,1-a]isoquino-
line-1-carboxylate 8a as yellow oil; yield: 43 mg
a
(0.138 mmol, 51%). IR (neat): n=3057 (m), 2910 (w), 1726
(s), 1722 (s), 1244 (s), 1126 cmꢀ1 (s); 1H NMR (600 MHz,
CDCl3): d=9.89–9.88 (m, 1H), 8.49 (s, 1H), 7.67–7.65 (m,
3H), 4.41 (q, J=7.1 Hz, 2H), 2.68 (s, 3H), 2.51 (s, 3H), 1.43
(t, J=7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3): d=168.6,
163.8, 145.2, 137.7, 134.3, 129.5, 129.1, 128.1, 127.7, 126.1,
122.8, 120.3, 108.4, 60.5, 20.5, 14.4, 12.4; HR-MS (EI): m/z=
312.1113, calcd. for C17H16N2O4: 312.1110.
Acknowledgements
The authors wish to thank the National Science Council,
Taiwan for supporting this work.
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[10] In the cycloaddition of substrate 1c with methyl vinyl
sulfone, we obtained compound 8d (3f) bearing no sul-
fone. We propose that the corresponding intermediate
L’ underwent a loss of HSO2Me rather than the expect-
ed oxidation step:
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