Zn(II)- or Ag(I)-catalyzed 1,4-metathesis reactions between 3-en-1-ynamides and nitrosoarenes

Article abstract of DOI:10.1021/ja412634w

Catalyst-dependent metathesis reactions between 3-en-1-ynamides and nitrosoarenes are described. Particularly notable are the unprecedented 1,4-metathesis reactions catalyzed by Ag(I) or Zn(II) to give 2-propynimidamides and benzaldehyde derivatives. With 3-en-1-ynamides bearing a cycloalkenyl group, 1,4-oxoimination products were produced efficiently. We have developed metathesis/alkynation cascades for unsubstituted 2-propynimidamides and benzaldehyde species generated in situ, to manifest 1,4-hydroxyimination reactions of 3-en-1-ynes. Both 1,4-oxoiminations and 1,4-hydroxyiminations increase the molecular complexity of products.

Full text of DOI:10.1021/ja412634w

Communication
pubs.acs.org/JACS
Zn(II)- or Ag(I)-Catalyzed 1,4-Metathesis Reactions between 3‑En-1-
ynamides and Nitrosoarenes
Sagar Ashok Gawade, Deepak B. Huple, and Rai-Shung Liu*
Department of Chemistry, National Tsing-Hua University, Hsinchu, Taiwan, ROC
S
* Supporting Information
[4+2]-cycloadditions between nitrosoarenes and 3-en-1-ynes.
Initial use of Au(I) catalysts affords 1,2-metathesis products,4 as
ABSTRACT: Catalyst-dependent metathesis reactions
between 3-en-1-ynamides and nitrosoarenes are described.
Particularly notable are the unprecedented 1,4-metathesis
reactions catalyzed by Ag(I) or Zn(II) to give 2-
propynimidamides and benzaldehyde derivatives. With 3-
en-1-ynamides bearing a cycloalkenyl group, 1,4-oxoimi-
nation products were produced efficiently. We have
developed metathesis/alkynation cascades for unsubsti-
tuted 2-propynimidamides and benzaldehyde species
generated in situ, to manifest 1,4-hydroxyimination
reactions of 3-en-1-ynes. Both 1,4-oxoiminations and 1,4-
hydroxyiminations increase the molecular complexity of
products.
depicted in eq 1, but a switch to Zn(II) and Ag(I) catalysts
surprisingly implements 1,4-enyne/nitroso metathesis reactions
to afford aldehydes and 2-propynimidamides efficiently (eq 4).
Herein, a bond order of 2 is increased or decreased between the
two neighboring (or interacting) atoms of reactants, thus
conforming a metathesis model. Similar 1,4-metathesis
reactions were noted between singlet oxygen and a few 3-en-
1-ynes, but prolonged photolysis was required to achieve good
yields of products (16−64 h).8 For the resulting unsubstituted
2-propynimidamides (R′ = H) and aldehydes, we also
accomplish their subsequent alkynations in a one-pot operation
to afford alkynol derivatives efficiently, highlighting new
hydroxyiminations of 3-en-1-ynes.
We first tested the reactions of 3-en-1-ynamide 1a with
nitrosobenzene (2a) using IPrAuNTf2 (5 mol%, IPr = 1,3-
bis(diisopropylphenyl)imidazol-2-ylidene) and LAuNTf2 (5
mol%, L = P(tBu)2(o-biphenyl)) in dichloroethane (DCE, 28
°C), from which we isolated a 1,2-metathesis product (5a) in
good yields (81−90%) together with a 2-propynimidamide
(3a) and benzaldehyde (4a) in 3−5% yields (Table 1).
Astonishingly, silver salts (5 mol%) like AgNTf2, AgOAc, and
AgOTs gave 1,4-metathesis products 3a and 4a in high yields
(88−95%, entries 3−5) in DCE (28 °C), with AgOAc being
the most effective. Cheap zinc catalysts Zn(OTf)2 and ZnCl2
were also active catalysts for such a 1,4-enyne/nitroso
metathesis in DCE at 60 °C (2−3 h) to give 3a and 4a in
90−98% yields. For AgOAc, the reactions were compatible with
various solvents, including dichloromethane (DCM), MeCN,
and THF, giving 3a and 4a in 85−92% yields. No reactions
occurred in the absence of a metal catalyst, even though the
starting mixture was heated in DCE (60 °C) for 10 h; UV
irradiation of the same reagents alone in DCE (0 °C, 10 h) gave
complicated mixtures of products.
etal-catalyzed metathesis reactions represent the prac-
M
tical value of catalytic reactions in the fields of materials
science and pharmaceuticals.1 Metathesis reactions between
alkynes and double-bond species XY (CC, CO, and
CN) are powerful tools to access various diene,1 enone,2 and
enimine3 compounds via a 1,2-metathesis route (eq 1). We
We examined the reactions of various 3-en-1-ynamides 1 and
nitrosoarenes 2 to assess the scope of applicable substrates. The
1,4-metathesis reactions were performed with Zn(OTf)2 (5 mol
%) in DCE (60 °C, 2 h). For 3-en-1-ynamides 1b−1d bearing
different sulfonamides (NR(EWG) = NMeTs, NPhTs, and
N(nBu)Ts), their resulting products 3b−3d and benzaldehyde
4a were obtained with yields exceeding 91% (Table 2, entries
1−3). We tested the reactions on other 3-en-1-ynamides 1e−
1h bearing a varied R1 substituent (R1 = 4-bromo- and 4-
methoxyphenyl, 2-furanyl, and cyclohexenyl), affording the
disclosed that nitrosoarenes could act as nucleophiles to react
with Au(I)-π-alkynes to furnish the first nitroso/alkyne
metathesis reactions (eq 1).4 Although 1,3-dienes and 3-en-1-
ynes are readily available for unsaturated four-carbon motifs,
their metal-catalyzed reactions with alkenes, carbonyl, imines,
or alkynes occur exclusively with [4+2]-cycloadditions (eqs 2
and 3).5,6 Lewis acid-catalyzed [4+2]-cycloadditions of 1,3-
dienes with nitrosoarenes7 are accessible to N- and O-
containing functionalized molecules after cleavage of a N−O
bond (eq 2). Our initial task is to achieve new metal-catalyzed
Received: December 18, 2013
Published: February 12, 2014
© 2014 American Chemical Society
2978
dx.doi.org/10.1021/ja412634w | J. Am. Chem. Soc. 2014, 136, 2978−2981

Journal of the American Chemical Society
Communication
Table 1. 1,2- versus 1,4-Metathesis Reactions
Table 3. Zn-Catalyzed 1,4-Oxoimination of 3-En-1-ynamides
b
c
conditions
products (%)
a
entry
catalyst
solvent T (°C) t (h) 3a
4a
5a
1
IPrAuCI/AgNTf2
LAuCI/AgNTf2
AgNTf2
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCM
MeCN
THF
DCE
28
28
28
28
28
60
60
28
28
28
60
15
0.5
20
5
5
3
5
3
81
90
−
−
−
−
−
−
−
−
−
2
3
88
95
92
98
90
92
88
85
10
88
95
92
98
90
92
88
85
−
4
AgOAc
5
AgOTs
8
6
Zn(OTf)2
ZnCI2
2
7
3
8
AgOAc
2
9
AgOAc
3.5
3.5
10
10
11
AgOAc
−
a
IPr = l,3-bis(diisopropylphenyl)imidazol-2-ylidene), L = P(tBu)2(o-
b
c
biphenyl). [1a] = 0.14 M. Product yields are reported after
purification from a silica column.
desired 2-propynimidamide 3a and aldehydes 4e−4h in 83−
97% yields (entries 5−7). These Zn(II)-catalyzed reactions
were extensible to enyne substrates 1i−1k bearing an alkyl or
phenyl substituent (R2 = methyl, isopropyl, and phenyl), giving
2-propynimidamides 3i−3k and benzaldehyde 4a in 87−94%
yields (entries 8−10). This synthetic method was applicable to
additional nitrosoarenes 2b,2c (X = NO2, isopropyl), giving
desired 3l,3m and benzaldehyde 4a in 91−95% yields (entries
10−12).
To demonstrate the feasibility of a new 1,4-oxoimination of
3-en-1-ynes with nitrosobenzene 2a, we prepared cyclic alkenes
bearing an ethynylamide group, 6a−6h; the resulting products
7a−7h would hence contain both oxo and imine functionalities
(Table 3). Such 1,4-oxoiminations were implemented by
Zn(OTf)2 (5 mol%) and 2a (2.0 equiv) in hot DCE (60 °C,
0.5 h). Entries 1−3 show the efficient productions of desired
a
b
[6] = 0.14 M. Product yields are reported after purification from a
silica column.
benzaldehyde derivatives 7a−7c with yields >91% from cyclic
alkene derivatives 6a−6c of various sizes (n = 1−3). These 1,4-
oxoimination reactions were also applicable to oxacyclic alkene
derivatives 6d,6e (R = H, Me), giving desired products 7d,7e in
82−95% yields (entries 4 and 5). For disubstituted indenes
6f,6g bearing a 2-ethynylamide, 7f,7g were produced with 95−
96% yields (entries 6 and 7). For the 3-indenyl ethynylamide
analogue 6h, the same reaction afforded an aliphatic aldehyde
(7h) in 95% yield (entry 8).
Table 2. Scope for 1,4-Nitroso/Enyne Metathesis
enyne
products (yield, %)
entry
1
R1
R2
NR (EWG)
nitroso 2 (X)
3
4
1
1b
1c
1d
1a
1f
Ph
Ph
Ph
H
N(Me)Ts
N(Ph)Ts
2a (H)
2a (H)
2a (H)
2a (H)
2a (H)
2a (H)
2a (H)
2a (H)
2a (H)
2a (H)
2b (NO2)
2c (iPr)
3b (92)
3c (91)
3d (98)
3a (94)
3a (97)
3a (83)
3a (93)
3i (94)
3j (90)
3k (87)
3l (91)
3m (95)
4a (92)
4a (91)
4a (98)
4e (94)
4f (97)
4g (83)
4h (93)
4a (94)
4a (90)
4a (87)
4a (91)
4a (95)
2
H
3
H
N(nBu)Ts
N(Me)Ms
N(Me)Mb
N(Me)Ms
N(Me)Mb
N(Me)Ms
N(Me)Ms
N(Me)Ms
N(Me)Ms
N(Me)Ms
4
4-BrC6H4
4-MeOC6H4
2-furanyl
cyclohexenyl
PH
H
5
H
6
1g
1h
1i
H
7
H
8
Me
iPr
Ph
H
9
1j
Ph
10
11
12
1k
1a
1a
Ph
Ph
Ph
H
a
b
[1] = 0.14 M. Product yields are reported after purification from a silica column.
2979
dx.doi.org/10.1021/ja412634w | J. Am. Chem. Soc. 2014, 136, 2978−2981

Journal of the American Chemical Society
Communication
Simultaneous production of unsubstituted 2-propynimida-
mides and aldehydes allows their further elaborations with
catalytic formation of a carbon−carbon bond. Scheme 1 depicts
reactions were applicable to 3-en-1-ynamides bearing different
styryl groups (R1 = XC6H4, X = Cl, Br, and MeO, entries 3−5),
giving desired alkynols 10c−10e in 75−82% yields. These zinc-
catalyzed reactions were amenable to the synthesis of
heteroaryl-substituted alkynols 10f,10g (R1 = 2-furanyl and 2-
thienyl) with satisfactory yields (76−81%, entries 6 and 7). For
3-en-1-ynamides bearing varied alkenyl substituents, the related
4-en-1-yn-3-ols 10h−10j were produced efficiently (72−73%,
entries 8−10).
Scheme 1. Two One-Pot Cascade Reactions
Shown in Scheme 2 is a plausible mechanism to rationalize
catalyst-dependent chemoselectivity of 1,2- versus 1,4-meta-
Scheme 2. A Plausible Mechanism for 1,2- and 1,4-
Metathesis Reactions
two one-pot cascade reactions between 3-en-1-ynamide 1l and
nitrosobenzene 2a (2 equiv) under optimized conditions.
Treatment of these reactants with AgOAc (5 mol%) in DCM
(50 °C, 0.5 h) delivered 2-iodobenzaldehyde (4l) and a 2-
propynimidamide 3b efficiently; to this solution were added
PdCl2(PPh3)2, CuI (10 mol%), and Et3N (15 equiv) to effect
an in situ Sonogashira reaction,9 giving a desired coupling
product 8 in 78% yield. Alternatively, we employed Zn(OTf)2
(5 mol%) to catalyze the initial metathesis reaction in a sealed
flask (DCM, 50 °C, 2.5 h), followed by a reported
alkynylation10 in situ of aldehyde 4l with ZnBr2 (20 mol%),
TMSOTf (1.1 equiv), and iPr2NEt (1.5 equiv) in the same
solution. A final workup with Bu4NF in THF afforded alkynol
derivative 9 in 81% yield.
thesis reactions; we envisage that both reactions proceed via an
initial attack of nitrosobenzene at metal π-alkyne species A. In
recent work, we demonstrated that LAu+ (L = P(tBu)2(o-
biphenyl)) is more electron-rich than Ag+ to direct a 1,2-shift of
the neighboring group through a hyperconjugation effect.11 For
LAu (L = P(tBu)2(o-biphenyl)), the alkenylgold CC bond of
intermediate B is thus highly electron-rich and nucleophilic to
attack the oxygen of the nitrosonium moiety to generate species
C, of which the weak N−O bond is readily cleaved by LAu to
give 1,2-metathesis product 5a. In contrast, dienylsilver species
D behaves like normal dienes to undergo a well-known [4+2]-
cycloaddition,7 giving a cycloadduct intermediate, E. We
envisage that its weak N−O bond is the major reason for
molecular fragmentation to generate the terminal 3-iminoal-
kyne 3a and benzaldehyde, rather than giving a [4+2]-nitroso
cycloadduct through a protodemetalation.
The formation of an alkynol product like 9 from 3-en-1-
ynamide 1l is synthetically interesting because this trans-
formation represents a novel 1,4-hydroxyimination of a 3-en-1-
yne. Table 4 shows the generalization of such reactions with
Table 4. One-Pot Metathesis/Alkynylation Cascades
We have developed new synthetic use of an alkynol
derivative, 10. As depicted in Scheme 3, treatment of an
alkynol 10b with aqueous HX (1.2 equiv, X = Cl, Br, and I) in
DCE (28 °C, 10−15 min) delivered highly substituted
aminofurans 11a−11c in excellent yields (97−98%). We have
1
determined their structures with H NOE spectra. Likewise,
treatment of this alkynol with indoles (1.2 equiv) and BF3·Et2O
(1.1 equiv) afforded aminofurans 11d,11e of the same type; the
Scheme 3. Synthetic Applications of 3-Imidoylalkynol 10b
a
b
[1] = 0.14 M TMSOTf (1.0 equiv), iPr2NEt (1.5 equiv). External 4-
MeOC6H4CHO (1.0 equiv) was added in entry 5, and 2-furyl- and 2-
thienyl aldehydes (0.5 equiv) were added in entries 6 and 7 before
c
their alkynylations. Products are reported efter separation from a silica
column.
additional examples. In entries 5−7, external aldehydes R1CHO
(R1 = 4-MeOC6H4, 2-furyl, and 2-thienyl, 0.5 or 1.0 equiv)
were added before the alkynation because of their lower
reactivity. These one-pot reactions were accessible to alkynols
10a,10b bearing various sulfonamides (NR2EWG = NMeMs,
NMeTs); the yields were 67−85% (entries 1 and 2). The
2980
dx.doi.org/10.1021/ja412634w | J. Am. Chem. Soc. 2014, 136, 2978−2981

Journal of the American Chemical Society
Communication
(4) Mukherjee, A.; Dateer, R. B.; Chaudhuri, R.; Bhunia, S.; Karad, S.
N.; Liu, R.-S. J. Am. Chem. Soc. 2011, 133, 15372.
corresponding yields were 78−82%. The molecular structure of
11e was confirmed by X-ray diffraction.12 The mechanism of
these new cyclizations is provided in the Supporting
Information. Alkynol 10b was transformed into an E-configured
enone 12 according to a reported DABCO-catalyzed rearrange-
ment;13 its structure is distinct from that of the enone 5a given
from a 1,2-nitroso/alkyne metathesis reaction (Table 1).
In summary, we report catalyst-dependent chemoselectivities
in the metathesis reactions of 3-en-1-ynamides14 with nitro-
soarenes. LAuNTf2 (L = P(tBu)2(o-biphenyl) catalyzed 1,2-
metathesis reactions, whereas AgNTf2 or Zn(OTf)2 imple-
mented unprecedented 1,4-metathesis reactions. Before this
work, metal-catalyzed metathesis reactions were strictly limited
to a 1,2-metathesis mode, whereas 1,3-dienes and 3-en-1-ynes
exclusively undergo metal-catalyzed [4+2]-cycloadditions with
double bond species. We prepared cycloalkene derivatives of 3-
en-1-ynamides in a series to achieve new 1,4-oxoimination
reactions of 3-en-1-ynes. We have developed one-pot cascade
reactions to activate an alkynation between unsubstituted 2-
propynimidamides and benzaldehyde derivatives generated in
situ. The feasibility of such metathesis/alkynation cascades is
manifested with sufficient examples, further highlighting novel
1,4-hydroxyiminations of 3-en-1-ynes. These alkynol products
are readily transformed into substituted aminofurans or
functionalized enones. The focus of this work is not only on
the discovery of 1,4-metathesis reactions, but also includes the
development of their new synthetic utility.
(5) For Diels−Alder and hetero-Diels−Alder reactions of 1,3-dienes,
see selected reviews: (a) Fringuelli, F.; Taticchi, A. The Diels-Alder
Reactions; Wiley-VCH: New York, 2001. (b) Nicolaou, K. C.; Snyder,
S. A.; Montagnon, T.; Vassilikogiannakis, G. Angew. Chem., Int. Ed.
2002, 41, 1668. (c) Boger, D. L.; Weinreb, S. M. Hetero-Diels-Alder
Methodology. In Organic Synthesis; Academic Press: San Diego, 1987.
(d) Tietze, L.-F.; Kettschau, G. Top. Curr. Chem. 1997, 189, 1.
(6) For [4+2]-cycloaddition of 3-en-1-ynes with alkynes6a−e and
alkenes,6f see: (a) Saito, S.; Salter, M. M.; Gevorgyan, V.; Tsuboya, N.;
Tando, K.; Yamamoto, Y. J. Am. Chem. Soc. 1996, 118, 3970.
(b) Gevorgyan, V.; Takeda, A.; Homma, M.; Sadayori, N.;
Radhakrishnan, U.; Yamamoto, Y. J. Am. Chem. Soc. 1999, 121,
6391. (c) Dunetz, J. R.; Danheiser, R. L. J. Am. Chem. Soc. 2005, 127,
5776. (d) Rubina, M.; Conley, M.; Gevorgyan, V. J. Am. Chem. Soc.
2006, 128, 5818. (e) Gorin, D. J.; Watson, I. D. G.; Toste, F. D. J. Am.
Chem. Soc. 2008, 130, 3736. (f) Nieto-Oberhuber, C.; Lop
Echavarren, A. M. J. Am. Chem. Soc. 2005, 127, 6178. (g) Lop
Carrillo, V.; Echavarren, A. M. J. Am. Chem. Soc. 2010, 132, 9292.
́
ez, S.;
́
ez-
(7) (a) Bodnar, B. S.; Miller, M. J. Angew. Chem., Int. Ed. 2011, 50,
5630. (b) Yamamoto, Y.; Momiyama, N.; Yamamoto, H. J. Am. Chem.
Soc. 2004, 126, 5962. (c) Yamamoto, Y.; Yamamoto, H. Angew. Chem.,
Int. Ed. 2005, 44, 7082. (d) Yamamoto, Y.; Yamamoto, Y. J. Am. Chem.
Soc. 2004, 126, 4128.
(8) Under this photolytic condition, a six-membered cyclic allene
intermediate was postulated in the photo-activated [4+2]-cyclo-
addition of enynes with singlet oxygen: Lee-Ruff, E.; Maleki, M.;
Duperrouzel, P.; Lien, M. H.; Hopkinson, A. C. Chem. Commun. 1983,
346.
(9) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467.
ASSOCIATED CONTENT
■
(10) Downey, C. W.; Mahoney, B. D.; Lipari, V. R. J. Org. Chem.
2009, 74, 2904.
S
* Supporting Information
X-ray crystallographic data of 11e; experimental procedures and
characterization data of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(11) This hyperconjugation arises from the stabilization of a σ M−C
bond on its neighboring carbocation. This effect is very significant for
electron-rich M = P(tBu)2(o-biphenyl)Au but becomes less
pronounced for electron-deficient M = Ag. See: Ghorpade, S.; Su,
M.-D.; Liu, R.-S. Liu Angew. Chem., Int. Ed. 2013, 52, 4229.
(12) Crystallographic data of 11e are deposited in the Cambridge
Crystallographic Data Center (CCDC-977801), and also available in
the Supporting Information.
(13) Sonye, J. P.; Koide, K. J. Org. Chem. 2006, 71, 6254.
(14) For chemistry of ynamides, see: (a) DeKorver, K. A.; Li, H.;
Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev.
2010, 110, 5064. (b) Evano, G.; Coste, A.; Jouvin, K. Angew. Chem.,
Int. Ed. 2010, 49, 2840. (c) Wang, X.-N.; Yeom, H.-S.; Fang, L.-C.; He,
S.; Ma, Z.-X.; Kedrowski, B. L.; Hsung, R. P. Acc. Chem. Res. 2014, 47,
560.
AUTHOR INFORMATION
■
Corresponding Author
rsliu@mx.nthu.edu.tw
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the National Science Council and the
Ministry of Education, Taiwan, for supporting this work.
REFERENCES
■
(1) (a) Vougioukalakis, G. C.; Grubbs, R. H. Chem. Rev. 2010, 110,
1746. (b) Hansen, E. C.; Lee, D. Acc. Chem. Res. 2006, 39, 509.
(c) Diver, S. T.; Giessert, A. J. Chem. Rev. 2004, 104, 1317.
(d) Furstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012. (e) Mori, M. In
̈
Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH; Weinheim,
2003. (f) Jimenez-Nunez, E.; Echavarren, A. M. Chem. Rev. 2008, 108,
́
̌
̃
3326. (g) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180.
(2) For alkyne/carbonyl metathesis reactions, see: (a) Kurtz, K. C.
M.; Hsung, R. P.; Zhang, Y. Org. Lett. 2006, 8, 231. (b) Jin, T.;
Yamamoto, Y. Org. Lett. 2008, 10, 3137. (c) Rhee, J. U.; Krische, M. J.
Org. Lett. 2005, 7, 2493. (d) Saito, A.; Umakoshi, M.; Yagyu, N.;
Hanzawa, Y. Org. Lett. 2008, 10, 1783.
(3) For alkyne/imine metathesis reactions, see selected examples:
(a) Ishitani, H.; Nagayama, S.; Kobayashi, S. J. Org. Chem. 1996, 61,
1902. (b) Abramovitch, R. A.; Mavunkel, B.; Stowers, J. R.; Wegrzyn,
M.; Riche, C. Chem. Commun. 1985, 845. (c) Ruck, R. T.; Zuckerman,
R. L.; Kyska, S. W.; Bergman, R. G. Angew. Chem., Int. Ed. 2004, 43,
5372. (d) Saito, A.; Kasai, J.; Konishi, T.; Hanzawa, Y. J. Org. Chem.
2010, 75, 6980.
2981
dx.doi.org/10.1021/ja412634w | J. Am. Chem. Soc. 2014, 136, 2978−2981