Gold-catalyzed formal [3 + 3] and [4 + 2] cycloaddition reactions of nitrosobenzenes with alkenylgold carbenoids

Article abstract of DOI:10.1021/ja209980d

We report two new formal cycloaddition reactions between nitrosobenzenes and alkenylgold carbenoids. We obtained quinoline oxides 3 in satisfactory yields from the gold-catalyzed [3 + 3]-cycloadditions between nitrosobenzenes and alkenyldiazo esters 1. For propargyl esters 5, its resulting gold carbenes react with nitrosobenzene to give alkenylimine 8, followed by a [4 + 2]-cycloaddition with nitrosobenzene.

Full text of DOI:10.1021/ja209980d

Communication
pubs.acs.org/JACS
Gold-Catalyzed Formal [3 + 3] and [4 + 2] Cycloaddition Reactions of
Nitrosobenzenes with Alkenylgold Carbenoids
Vinayak Vishnu Pagar,† Appaso Mahadev Jadhav,† and Rai-Shung Liu*
Department of Chemistry, National Tsing-Hua University, Hsinchu, Taiwan 30013, ROC
S
* Supporting Information
Scheme 2. Two New Formal Cycloaddition Reactions
ABSTRACT: We report two new formal cycloaddition
reactions between nitrosobenzenes and alkenylgold
carbenoids. We obtained quinoline oxides 3 in satisfactory
yields from the gold-catalyzed [3 + 3]-cycloadditions
between nitrosobenzenes and alkenyldiazo esters 1. For
propargyl esters 5, its resulting gold carbenes react with
nitrosobenzene to give alkenylimine 8, followed by a [4 +
2]-cycloaddition with nitrosobenzene.
the reactions of metal carbenoids with nitrosobenzenes were
reported to give nitrone species,12 such a reaction route does
not influence our new cycloadditions in most instances.
itrogen-containing frameworks are important skeletons in
Shown in Table 1 is the generation of metal carbenoids from
Nnumerous naturally occurring compounds, especially in
alkenyldiazoacetates 1a over various metal catalysts.2 We first
the alkaloid family.1 Cycloaddition reactions of alkenylcarbe-
noids with nitrogen-based dipolarophiles are powerful tools to
access nitrogen-containing heterocycles of medium sizes.2
Table 1. Catalyst Screening for Formal [3 + 3]-Cycloadditions
between Nitrosobenzenes and Alkenyldiazocarbonyls
Scheme 1 summarizes various cycloadditions of alkenylmetal
Scheme 1. Metal-Catalyzed Cycloadditions for the Synthesis
of Nitrogen-Containing Heterocycles
a
b
entry
catalyst (mol %)
time (h)
compounds (yields)
1
2
Rh2(OAc)4 (2.5)
CuCl (5)
1.5
0.35
0.8
3a (62%)
messy mixture
3a (52%)
3
IPrCuCl/AgNTf2 (5)
IPrCuCl/AgSbF6 (5)
IPrAuCl/AgNTf2 (5)
PPh3AuCl/AgNTf2 (5)
LAuCl/AgNTf2 (5)
LAuCl/AgSbF6 (5)
AgNTf2 (5)
4
0.5
3a (22%)
5
0.5
3a (61%), 3a′ (8%)
3a (65%), 3a′ (10%)
3a (72%), 3a′ (11%)
3a (47%), 3a′ (9%)
messy mixture
6
2.1
7
2.0
8
2.0
9
0.15
0.5
10
HOTf (5)
messy mixture
a
carbenoids (I) with imines, pyrroles, pyridines, alkenyl imines,
azomethine imines, and nitrones, yielding diverse cycloadducts
with high regioselectivities.3−8 Cycloaddition reactions on
nitrosobenzenes are synthetically useful because the product
skeletons incorporate both oxygen and nitrogen function-
alities.9−11 Reported examples are much fewer than for alkenes,
organic carbonyls, and imines; notable instances include [4 + 2]
cycloadditions with dienes9 and [3 + 2]-cycloadditions with
alkynes.10 In this work, we report two distinct [3 + 3] and
[4 + 2] formal cycloadditions between nitrosobenzenes with
alkenylgold carbenoids I, as depicted in Scheme 2. Although
L = P(t-Bu)2(o-biphenyl), IPr=1,3-bis(diisopropylphenyl)imidazol-2-
b
ylidene), [substrate] = 0.05 M. Product yields are reported after
purification from silica column.
examined the reaction in the presence of Rh2(OAc)4 (2.5 mol %)
and nitrosobenzene 2a (1.1 equiv) in dichloroethane (DCE) at
25 °C for 1.5 h, during which starting 1a was completely consumed
Received: October 24, 2011
Published: November 30, 2011
© 2011 American Chemical Society
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to give compound 3a in 62% yield. Among various copper catalysts
at 5 mol % loading (entries 2−4), IPrCuCl/AgNTf2 showed the
best performance to give desired 3a in 52% yield. As shown in
entries 5−7, gold catalysts (5 mol %) were efficient for this
intermolecular cycloaddition with a 61% yield of desired 3a for
IPrAuCl/AgNTf2, 65% yield for PPh3AuCl/AgNTf2, and 72% yield
for ClAuP(t-Bu)2(o-biphenyl)/AgNTf2; we also obtained quinoline
species 3a′ in small proportion (8−11%). An alteration of silver salt
as in ClAuP(t-Bu)2(o-biphenyl)/AgSbF6 gave 3a in diminished
yield (47%) together with byproduct 3a′ in 9%. In control
experiments, AgNTf2 and HOTf gave products in a complicated
mixture (entries 9 and 10). For compound 3a, we confirmed its
molecular structure through X-ray diffraction of its related
compound 3b (Table 2, entry 1).13 The better performance of
the phenyl substrate (entry 7) gave nitrone 4h in 48% yield.
Alkenyldiazo species comprising various C(2)-substituents
(R2 = 2-pyridinyl, Me, n-Bu, 2-furanyl, 2-thienyl, entries 8−
12) gave consistently quinoline oxides 3i−3m in satisfactory
yields (58−77%). We tested also the cycloaddition on both
electron-deficient and -rich nitrosobenzenes (FG = OMe, Cl,
Br, acetyl), which all proceeded well to give desired products
3n−3q with yields exceeding 67% (entries 13−16).
We propose a plausible mechanism in Scheme 3. The success
of this formal cycloaddition relies on an attack of nitrosobenzene
Scheme 3. Proposed Mechanisms for the Formal [3 + 3]
Cycloaddition
Table 2. Reaction Scopes with the [3 + 3] Formal
Cycloaddition of Nitrosobenzenes with
Alkenyldiazocarboxylates
at the C(3)-carbon of carbenoids A (path a) bearing a small R
substituent. The resulting species B attains an oxime/nitroso
tautomeric equilibrium17 to generate gold-containing alkenyl
iminium C that undergoes a 6-π electrocyclization to form a
cyclized species D. A further loss of the proton of species D gives
N-hydroxy dihydroquinoline E, further delivering observed
product 3 after an oxidative aromatization or dehydrogenation.
In the case of diazo substrate 1h, its bulky phenyl substituent
(R = Ph) exerts steric hindrance to impede the attack at the
C(3)-carbon; the attack at the carbene carbon (path b) is
expected to give nitrone product 4h.12 Applicable diazo
substrates and nitrosobenzenes over a wide range highlight the
utility of this [3 + 3] formal cycloaddition reaction.
We sought a distinct cycloaddition via an attack of
nitrosobenzene at the carbene carbon of carbenoids (II′),
generated in situ from the rearrangement of propargyl benzoate
5a (Table 3).6b,7,15 This task is challenging because nitrone
formation is known to be a competitive process.12 As shown in
Table 3, the reaction of starting substrate 5a with nitroso-
benzene (2.2 equiv) and PPh3AuCl/AgNTf2, in DCE (25 °C,
3 h) gave 3,6-dihydro-2H-[1,2]-oxazine 6a and 2-en-1-al 7a in
30% and 18% yields, respectively. To our pleasure, the use of
ClAu(t-Bu)2P(o-biphenyl/AgNTf2 and IPrAuCl/AgNTf2 in-
creased further the yields of oxazine 6a to 68% and 74% yields
together with 2-en-1-al 7a in 12−18% yields (entries 2 and 3).
Other silver salts, such as ClAu(t-Bu)2P(o-biphenyl)/AgSbF6,
led to a diminished yield (60%) of oxazine 6a together with
2-en-1-al 7a in small proportion (15%, entry 4). AuCl3 gave a
complicated product mixture (entry 5). IPrCuCl/AgNTf2 and
Rh2(OAc)4 were inactive to recover unreacted 5a in 65−71%
yields (entries 6 and 7). We have performed the X-ray
diffraction study of compound 6a to determine its molecular
structure.13 Notably, side product 2-en-1-al (7) was completely
absent for many other substrates upon the generalization of the
reaction scope (see Table 4). This information indicates that
compounds 6a and 7a are not produced concurrently from the
disproportionation of one nitrosobenzene molecule.
a
L = P(t-Bu)2(o-biphenyl), [substrate] = 0.05 M. All product yields
are reported after purification from silica column.
gold catalysts than copper and rhodium is attributed to a significant
contribution of resonance structure I′ (M = Au) that is visualized as
a gold-stabilized allylic cation to facilitate an attack of nitro-
sobenzene.14,15
Table 2 shows the generalization of this [3 + 3] formal
cycloaddition using various alkenyldiazo esters and nitro-
sobenzenes. In a typical operation, starting diazo compound
1 was treated with nitrosobenzene 2 (1.1 equiv) and ClAuP-
(t-Bu)2(o-biphenyl)/AgNTf2 (5 mol %) in DCE (25 °C) for
1.5−2.0 h to attain a complete conversion. We obtained
quinoline oxides 3 almost exclusively, except entry 7 that gave
nitrone 4h in 48% yield. Entries 1 and 2 show the compatibility
of this cycloaddition with unsubstituted alkenyldiazo species
1 (R1 = R2 = H) bearing various esters (R3 = Et, t-Bu), giving
desired compounds 3b and 3c in 70−72% yields. We examined
also the reactions of substrates containing varied C(3)-
substituents (R1 = Me, Et, Cl, OMe; entries 3−6), producing
desired quinoline oxides 3d and 3g in 51−74% yields, whereas
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Communication
4-methylphenyl); their resulting products 6k−6m (entries 10−
12) were produced in 68−72% yields. In contrast, electron-rich
nitrosobenzene (Ar = 4-methoxyphenyl) gave product in a
complicated mixture under the same condition.
Table 3. Gold-Catalyzed Metathesis/Cycloaddition Cascades
of Propargyl Esters
Structural analysis of oxazine 6a leads us to postulate that it
might be produced from an unprecedented gold-catalyzed
cycloaddition of nitrosobenzene 2a with alkenyl imine 8a
(Scheme 4). To verify this hypothesis, we prepared authentic
a
b
entry
catalyst (mol %)
time (h)
compounds (yields)
1
2
3
4
5
6
7
PPh3AuCl/AgNTf2 (5)
LAuCl/AgNTf2 (5)
IPrAuCl/AgNTf2 (5)
IPrAuCl/AgSbF6 (5)
AuCl3 (5)
3
6
6a (30%), 7a (18%)
6a (68%), 7a (16%)
6a (74%), 7a (12%)
6a (60%), 7a (15%)
complicated mixture
5a (65%)
Scheme 4. Control Experiment to Clarify the [4 + 2]
Cycloaddition
6
8
1.5
10
12
IPrCuCl/AgNTf2 (5)
Rh2(OAc)4 (2.5)
5a (71%)
a
L = P(t-Bu)2(o-biphenyl), IPr = 1,3-bis(diisopropylphenyl)imidazol-
b
2- ylidene), DCE = dichloroethane, [substrate] = 0.05 M. Product
yields are reported after purification from silica column.
sample 8a that reacted with nitrosobenzene 2a (1.1 equiv) in
DCE (25 °C, 2 h) to give desired oxazine 6a in 92% yield in the
presence of IPrAuCl/AgNTf2 (5 mol %). In the absence of the
gold catalyst, this mixture failed to give tractable amount of
desired product 6a at 25 °C in DCE (12 h) but gave 6a in 63%
yield at elevated temperatures (DCE, 80 °C, 12 h). We observed
no reaction among nitrone 4a, nitrosobenzene 2a (1.1 equiv),
and the same gold catalyst. Alkenyl imine 8a, rather than nitrone
4a, is truly the reaction intermediate.
Table 4. Reaction Scopes for the Reactions of
Nitrosobenzenes with Propargyl Esters
Scheme 5. A Proposed Mechanism for the Metathesis/
Cycloaddition Cascades
a
IPr =1,3-bis(diisopropylphenyl)imidazol-2-ylidene), [substrate] =
Shown in Scheme 5 is a plausible mechanism to rationalize
the formation of oxazine 6a. We envisage that nitrosobenzene
initially attacks at the C(1)-carbene carbon to generate
nitrosonium species G that subsequently forms gold-containing
oxazetidine H via a unprecedented metathesis pathway.16 For
species H, a subsequent loss of [AuO]+ fragment gave
alkenyl imine 8a that underwent a hypothetic tautomerization
to establish an equilibrium17 with 1-aminodiene I. The
analogues of aminoalkyne I bearing a sec-amino group were
documented.7 We envisage that gold-coordinate nitrosobenzene
is highly electrophilic and becomes attacked by 1-aminodiene I to
give observed oxazine 6a ultimately.
To balance the oxygen mass, we propose the generation of
[AuO]+ in the catalytic circle, which presumably undergoes a
disproportionation to regenerate cationic gold catalyst and
oxygen. To test its occurrence, we added isopropanol (0.95 equiv)
to a reaction system containing propargyl ester 5a, nitrosobenzene
2a (2.2 equiv), and IPrAuCl/AgNTf2 (5 mol %) in CD2Cl2. At
the end of reaction (25 °C, 4 h), this CD2Cl2 solution shows a
0.05 M. All Product yields are reported after purification from silica
column.
We prepared also various propargyl esters 5a−5i to test their
reactions with various nitrosobenzene; the results are shown in
Table 4. In a typical operation, a propargyl ester was treated
with nitrosobenzene (2.2 equiv) and IPrAuCl/AgNTf2 (5 mol
%) in DCE (25 °C) for 4−6 h before the workup. Notably, side
products 7b and 7c were obtained in small proportions only
from substrates 5b and 5c (entries 1 and 2). Entries 1−6 show
the applicability of this reaction to several substrates bearing
variable ester groups (R2 = 4-methoxyphenyl, 4-chlorophenyl,
methyl, t-butyl, 2-furanyl, 2-thienyl); their corresponding
products 6b−6g were obtained in 68−74% yields. This catalytic
reaction works well for substrates bearing different R1
substituents (R1 = phenyl, 4-chlorophenyl, 4-methoxyphenyl),
giving desired products 6h−6j in 67−73% yields (entries 7−9).
We examined the reactions between propargyl ester 5a and
various nitrosobenzenes (Ar = 4-chlorophenyl, 4-bromophenyl,
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azacyclic compounds from nitroalkyne substrates through a hypothetic
[2 + 2 + 1] cycloaddition among nitrosobenzene, its tethered carbenes
and external alkenes; see Jadhav, A. M.; Bhunia, S.; Liao, H. Y.; Liu,
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complete disappearance of isopropanol and ester 5a, whereas
acetone and oxazine 6a were observed in the NMR spectra. We
hypothesize that [AuO]+ oxidizes isopropanol to form acetone.
Before this work, the participation of nitrosobenzenes in
metal-catalyzed cycloaddition reactions had few precedents.9,10
We report two new formal cycloadditions between nitro-
sobenzenes and alkenylgold carbenoids. We obtained [3 + 3]
cycloaddition products using alkenyldiazo esters 1, nitro-
sobenzenes, and suitable gold catalyst under ambient
conditions. For propargyl esters 5, its resulting gold carbenes
initially react with nitrosobenzenes to give alkenyl imine 8a,
followed by a [4 + 2] cycloaddition with nitrosobenzene. The
utility of these two reactions is manifested by a wide scope of
substrates and nitrosobenzenes.
ASSOCIATED CONTENT
* Supporting Information
■
S
(13) X-ray crystallographic data of compounds 3b and 6a are
provided in Supporting Information.
(14) (a) Hashmi, A. S. Angew. Chem., Int. Ed. 2008, 47, 6754.
(b) Bhunia, S.; Liu, R.-S. J. Am. Chem. Soc. 2008, 130, 16488.
(c) Benitez, D.; Shapiro, N. D.; Tkatchouk, E.; Wang, Y.; Goddard,
W. A. III; Toste, F. D. Nat. Chem. 2009, 1, 483. (d) Seidel, G.; Mynott,
Experimental procedures, characterization data of new
compounds, X-ray crystallographic data of compounds 3b
and 6a. This material is available free of charge via the Internet
at http://pubs.acs.org.
R.; Furstner, A. Angew. Chem., Int. Ed. 2009, 48, 2510. (e) Jimen
́
ez-
̈
AUTHOR INFORMATION
Corresponding Author
rsliu@mx.nthu.edu.tw
■
Nunez, E.; Clavarie, C. K.; Bour, C.; Cardenas, D. J.; Echavarren, A. M.
́
̃
Angew. Chem., Int. Ed. 2008, 47, 5030.
(15) For the use of alkenylgold carbenoids to construct medium-
sized carbocyclic rings, see: (a) Gorin, D. J.; Watson, I. D. G.; Toste,
F. D. J. Am. Chem. Soc. 2008, 130, 3736. (b) Garayalde, D.; Kruger., K.;
Nevado, C. Angew. Chem., Int. Ed. 2011, 50, 911.
Author Contributions
†These authors contributed equally.
(16) This metathesis pathway is distinct from the nitroso/alkyne
metathesis reported by us recently, see: Mukherjee, A.; Dateer, R. B.;
Chaudhuri, R.; Bhunia, S.; Karad, S. N.; Liu, R. S. J. Am. Chem. Soc.
2011, 133, 15372.
ACKNOWLEDGMENTS
The authors thank the National Science Council and the
Ministry of Education, Taiwan, for supporting this work.
■
(17) Raczyn
́ ́
ska, E. J.; Kosinska, W.; Osmialowski, B.; Gawinecki, R.
Chem. Rev. 2005, 105, 3561.
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