Au(I)-catalyzed cycloaddition pathways of non-terminal propargyl substrates

Article abstract of DOI:10.1080/00397911.2020.1731550

Novel chiral menthol-based pyridyl nitrone ligands were synthesized and Au(I) coordination of the ligands gave chiral Au(I)–nitrone complexes. ¹H NMR studies of the gold(I) coordination experiments with nitrone ligands afforded a convenient method for monitoring complex formation. The catalytic effect of Au(I)–nitrone complexes, shown to tune catalytic systems to produce uncommon products, was evaluated in [2 + 2 + 2] cyclotrimerization and [2 + 4] cyclodimerization reactions of non-terminal propargyl acetals. Alternative gold(I)-catalyzed [2 + 2], [2 + 4] and [3 + 4] cycloaddition reaction pathways of non-terminal propargyl acetals with imine substrates gave a diverse range of N-heterocyclic products. The present screening study demonstrates the potential and the versatility of non-terminal propargyl acetals in gold(I)-catalyzed cycloaddition reactions.

Full text of DOI:10.1080/00397911.2020.1731550

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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Au(I)-catalyzed cycloaddition pathways of non-
terminal propargyl substrates
Huey-San Melanie Siah, Helgi Freyr Jónsson & Anne Fiksdahl
To cite this article: Huey-San Melanie Siah, Helgi Freyr Jónsson & Anne Fiksdahl (2020): Au(I)-
catalyzed cycloaddition pathways of non-terminal propargyl substrates, Synthetic Communications,
DOI: 10.1080/00397911.2020.1731550
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https://doi.org/10.1080/00397911.2020.1731550
Au(I)-catalyzed cycloaddition pathways of non-terminal
propargyl substrates
ꢀ
Huey-San Melanie Siah, Helgi Freyr Jonsson, and Anne Fiksdahl
Department of Chemistry, Norwegian University of Science and Technology, Hoegskoleveien,
Trondheim, Norway
ABSTRACT
ARTICLE HISTORY
Received 30 January 2020
Novel chiral menthol-based pyridyl nitrone ligands were synthesized
and Au(I) coordination of the ligands gave chiral Au(I)–nitrone com-
plexes. H NMR studies of the gold(I) coordination experiments with
1
KEYWORDS
nitrone ligands afforded a convenient method for monitoring com-
plex formation. The catalytic effect of Au(I)–nitrone complexes,
shown to tune catalytic systems to produce uncommon products,
was evaluated in [2 þ 2 þ 2] cyclotrimerization and [2 þ 4] cyclodime-
rization reactions of non-terminal propargyl acetals. Alternative
gold(I)-catalyzed [2 þ 2], [2 þ 4] and [3 þ 4] cycloaddition reaction
pathways of non-terminal propargyl acetals with imine substrates
gave a diverse range of N-heterocyclic products. The present screen-
ing study demonstrates the potential and the versatility of non-ter-
minal propargyl acetals in gold(I)-catalyzed cycloaddition reactions.
Azetidine; benzazepine;
cyclo-trimerization/-dimer-
ization; gold(I)-nitrone
complexes; non-terminal
propargyl acetals; piperidine
GRAPHICAL ABSTRACT
Introduction
The intensive development of gold chemistry the last decade has mainly focused on the
discovery and understanding of new gold(I)-catalyzed reactions as well as the construc-
tion of new gold(I)-ligated complexes. We have contributed to the development of gold
catalysis in organic synthesis in recent years by the development of a number of cyclo-
addition reactions based on the highly reactive terminal propargyl acetal substrates and
a series of reactants, including nitrones.[1–10]
We have previously studied the interesting dual aspect of nitrones in gold-catalyzed
reactions, both as substrate in gold(I)-catalyzed [3 þ 3] cycloaddition with propargyl
acetals,[5] but also as catalytic additives in gold(I)-catalyzed reactions, tuning the
CONTACT Anne Fiksdahl
anne.fiksdahl@ntnu.no
Department of Chemistry, Norwegian University of Science and
Technology, Hoegskoleveien, Trondheim, 7491, Norway.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License
(http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium,
provided the original work is properly cited, and is not altered, transformed, or built upon in any way.

2
H.-S. M. SIAH ET AL.
catalytic system to produce uncommon products. We have shown that gold(I)-nitrone
complexes, either generated in situ or isolated prior to reaction, may catalyze unusual
transformations, such as regio- and chemo-selective [2 þ 2 þ 2] cyclotrimerization of
non-terminal 1,3-diaryl propargyl acetals 1 (Scheme 1).[8,10] The cyclohexylidene tri-
meric products 2a–c (up to 74% yield) were obtained as a mixture of three stereoisom-
ers. Hydrolysis allowed isolation of 46% of the main trans,trans,cis-diastereomer.
The cyclotrimerization approach demonstrates the ability of nitrones to tune the cata-
lytic activity of Au(I) complexes and that unusual transformations may take place in the
presence of Au(I)–nitrone complexes, which represent an interesting group of Au(I)
_catalysts with specific properties. Chiral nitrones have been used as Lewis bases to
induce enantioselectivity in organic reactions[11,12] and would have the potential to act
as chiral ligands and thereby afford enantioselective gold-catalyzed reactions.
Our previous results show that non-terminal propargyl substrates have ability to
undergo uncommon cycloaddition reactions. Therefore, we have further studied the
potential cycloaddition pathways which may take place with non-terminal propargyl
acetals in the presence of either new prepared chiral Au(I)–nitrone complexes or con-
ventional Au(I) catalysts.
Results and discussion
Synthesis of chiral nitrone ligands and Au(I)–nitrone complexes
The chiral nitrone ligands 6a and 6b were synthesized via 2-pyridyl-menthol intermedi-
ate 5a, which was formed (33%, Scheme 2) by enantioselective addition of lithiated
Scheme 1. Gold(I)-nitrone-catalyzed [2 þ 2þ2] cyclotrimerization of diarylpropargyl acetal 1.
Scheme 2. Synthesis of chiral nitrone ligands 6a and 6b.

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Scheme 3. In situ generation of Au(I)–nitrone complexes (I–6a,b,c) by ligand exchange of
JohnPhosAu(I)(ACN)SbF6 complex I with nitrones 6a–c.
Scheme 4. Coordination of nitrone 6a with JohnPhosAu(ACN)SbF6 I, shown as an equilibrium
between [complex I þ 6a] and [complex I–6a þ “free” ACN].
pyridine to (-)-menthone 4.[9] The methyl-ether 5b was obtained in quantitative yields
by methylation of alcohol 5a. Oxidation of pyridyl-menthol derivatives 5a and 5b gave
the chiral nitrone ligands 6a and 6b in high yields (81–82%).
Prior to use in reactions, Au(I)–nitrone complexes I–6a, I–6b and I–6c were gener-
ated in situ by acetonitrile ligand exchange of the JohnPhos Au(I)–ACN complex I with
the chiral pyridyl-nitrone ligands 6a and 6b as well as the non-substituted pyridine
N-oxide 6c (Scheme 3; 1:2 ratio of complex I:nitrone 6).
1H NMR coordination studies
1H NMR analysis of gold(I) coordination experiments with nitrone ligands (Fig. 1), afforded
a convenient method for monitoring Au(I) coordination (Scheme 4). The coordination abil-
ities of pyridine-nitrones 6a and 6b to JohnPhosAu(I)SbF6 complex I to give chiral nitrone
1
complexes I–6a and I–6b were clearly ascertained by comparing the changes in H NMR
shifts going from pure nitrone (6a or 6b) and gold(I) complex I, respectively (Fig. 1a,b,d), to
1:1 mixtures of the relevant nitrone (6a or 6b) and Au(I) complex I (Fig. 1c,e).
Formation of gold complex I–6b by coordination of nitrone ligand 6b with Au(I) com-
1
plex I is clearly visible by H NMR (Fig. 1d,e). All pyridine protons of nitrone 6b are
deshielded, but the most significant increases in chemical shifts (Dd1Hcoord ¼ d1Hcomplex
–
d1Hligand) were observed for the pyr-Ha proton signal (Dd1Hcoord 0.11 ppm). The opposite
effect was seen for menthyl protons ROCCHb and ROCCHc2, which were strongly shielded

4
H.-S. M. SIAH ET AL.
t-Bu (d, 3JH-P = 16.3 Hz)
2x d
a) JPAu(ACN)SbF
I
6,
ACN
b) Nitrone 6a
menth-Hc
pyr-Ha
pyr-Ha
c) 1:1 I:6a
menth-Hb
menth-Hc
d) Nitrone 6b
e) 1:1 I:6b
Figure 1. 1H NMR study of nitrones 6a and 6b coordination with JohnPhosAu(ACN)SbF6 I (1:1 in CDCl3).
(Dd1Hcoord ꢀ0.29 ppm and ꢀ0.17 ppm, respectively). The up-field shift of the ligated ACN
signal of Au(I)-complex I (from 2.39 ppm to 2.20 ppm; Dd1Hcoord ꢀ0.19 ppm, Fig. 1a,e) is
a characteristic proof of ACN de-coordination and ligand exchange to give non-ligated
“free” acetonitrile.[13] Also the aromatic protons of the phosphane ligand experienced
minor deshielding effects.
Similar changes were observed for the I:6a mixture, indicating coordination of
nitrone 6a, as well. However, a weaker observed effect on the Au(I)–ACN signal
(Fig. 1a,c), may indicate less efficient displacement of the ACN ligand and, hence, that
nitrone 6a is less strongly coordinated to the Au(I) than nitrone 6b. A minor change of
the t-Bu doublet (3JH–P ¼ 16.3 Hz), which appears as two doublets in the I:6a mixture,
indicates that diastereotopic t-Bu groups are formed by coordination of the chiral ligand
(Fig. 1b, expanded). Thus, the chiral nitrone 6a may have a greater steric effect on the
phosphane ligand than nitrone 6b when coordinated to the Au(I) center.
Generally, the nitrone (6a and 6b) signals in the 1:1 mixtures are broader, indicating
a dynamic ligand exchange (Scheme 4). Several observations confirm that nitrone 6b is
more strongly bonded to the Au center than nitrone 6a, as the menthol proton signals
are more strongly shielded and the ligated ACN peak is more affected for mixture I:6b
compared to mixture I:6a. Intramolecular H-bonding in the non-methylated nitrone 6a
unit (Scheme 4), shown in the crystal structure for I–6a (X-ray, Fig. 2), provides one
explanation for the weaker coordination of ligand 6a, compared to ligand 6b, as
H-bonding is not possible in the methylated nitrone 6b
The Au(I) complexation of chiral nitrones 6a and 6b appears to be weaker compared
1
to previously reported gold-nitrone complexes[10] which gave sharp H NMR peaks for
1:1 mixtures of complex I and nitrones. The bulkiness of the chiral nitrones 6a and 6b
may affect the ability to undergo coordination to gold(I). To get better understanding
of the dynamics of the Au(I)–nitrone coordination and the equilibrium between coordi-
1
nated and uncoordinated states (Scheme 4), further H NMR studies of complex I and
nitrone 6a were carried out with increasing amounts of nitrone (ratio I:6a 1:1, 1:2, 1:5
and 1:10, Fig. 2 and Table 1).

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Complex
O-Au
Au-P
N-O
O-Au-P
angle
176.9
177.4
I-6a
2.064 2.225 1.349
2.074 2.230 1.349
I-6c10
I-6d10
2.096 2.243 1.340
174.9
Figure 2. 1H NMR coordination study of nitrone 6a with Au(I) complex I with different I:6a ratios.
t-Bu
(d)
ACN
Au(I) complex I
6a
pyr-Ha
1:6a:
1:1
1:2
1:5
2x d
1:10
Figure 3. Crystal structure (X-ray) of Au(I)–nitrone complex I–6a. Selected bond lengths (Å) and
angles (ꢁ) in gold(I)-nitrone complexes I–6a, I–6c and I–6d are given.
1
a
Table 1. Changes in H NMR peak shifts, Dd1Hcoord (ppm), of mixtures with decreasing I:6a ratio.
I:6a ratio:
Dd1Hcoord
a
Entry
Signal observed
6a: Ha
I; ACN
I: t-Bu (d)
I–6a (2ꢂ d)
d (ppm)
1:1
1:2
1:5
1:10
1
2
3
4
8.17
2.39
1.40
1.40
0.07
0.08
0
0.05
0.13
0
0.04
0.19
0.01
0.25 (d 2.14)
ꢀ0.01
ꢀ0.01
0.003b
0.005b
0.007b
0.009b
aDd1Hcoord ¼ d1Hcomplex – d1Hligand
.
bDd1Hdiastereomer ¼ d1Hisomer 1 – d1Hisomer 2
.

6
H.-S. M. SIAH ET AL.
A minor deshielding effect on the pyr-Ha proton was initially observed by a 1:1 ratio
(Table 1, entry 1). By increasing to excess amount of ligand 6a, the presence of only
one pyr-Ha doublet indicates a dynamic process, and not two distinct nitrone states.
1H NMR of the mixtures showed that the ACN methyl signal was strongly affected by
increased amount of nitrone 6a, almost reaching the expected value of 2.10 ppm[14] for
“free” acetonitrile at 1:10 (I:6a) ratio (Table 1, entry 2). In contrast to ligand 6b
(Fig. 1a,e), ligand exchange of nitrone 6a with the ACN is less favored, as excess of
nitrone appears necessary to promote full coordination to the gold center. By excess
amount of ligand 6a, the phosphane tert-butyl doublet splits into two doublets with
increased difference in chemical shift (Dddiastereomer up to 0.009 ppm), demonstrating a
significant diastereotopic effect by Au(I)–nitrone 2a coordination (Table 1, entry 4), as
also seen to a lesser extent above (Fig. 1c).
1
Similar H NMR coordination studies of nitrones 6a and 6b with the Au(I)-phos-
phane complex Ph3PAuSbF6 showed possible Au(I) coordination, in addition to decom-
position of the phosphane or nitrone ligand. Coordination of Me3PAuSbF6 failed. The
previously isolated Ph3PAu(I)–nitrone complex II–6d[10] (Fig. 2) was obtained in much
lower yields (38%) than the corresponding JohnPhos-Au(I)–nitrone complex I–6d
(74%), indicating lower coordination ability of the less electron-rich PPh3 ligand to give
stable gold(I)-nitrone complexes.
Crystal structures (X-ray)
Crystalline complex I–6a was successfully obtained and the crystal structure was confirmed
by X-ray analysis (Fig. 3), which showed the expected nearly linear nitrone-O-Au(I)-P
coordination mode (176.9ꢁ). The deviation from linearity is less than for previously char-
acterised[10] complex I–6d, and slightly more than observed for pyridine-N-oxide complex
I–6c, likely due to steric effects. The shorter O-Au bond length (2.064 Å) of chiral complex
I–6a than for I–6c and benzaldimine nitrone I–6d, indicates that nitrone ligand 6a is
more strongly bonded to the Au(I) center. This may be due to an electron donating effect
of the menthol unit. The short N–O bond length of complex I–6a (1.349 Å) was similar to
complex I–6c, indicating a N–O double bond character. The Au–P bond length (2.225 Å)
in complex I–6a was comparable to that for complex I–6c, but shorter than for complex
I–6d, likely due to the size of nitrone.
An uncoordinated nitrone 6a unit, also visible in the crystal structure (Fig. 3, right),
enables Au(I)–nitrone coordination by hindering intramolecular hydrogen-bonding of
ligand 6a, as the O-atom of the “free” nitrone unit forms an intermolecular H-bond to
the OH group of the ligated nitrone 6a. The intramolecular H-bond within the uncoor-
dinated nitrone also supports the theory that nitrone 6a has a poorer coordination
ability to the Au center than MeO–nitrone 6b because of competing internal H-bonds.
Cycloaddition reactions of non-terminal propargyl acetals
The catalytic properties of the gold-nitrone complexes I–6a, I–6b and I–6c were eval-
uated in gold-catalyzed [2 þ 2 þ 2] cyclotrimerization[8] and [2 þ 4] cyclodimerisation of
novel propargyl acetal 10 (Tables 2–4).

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Table 2. Gold(I)-catalyzed [2 þ 2 þ 2] cyclotrimerisation of propargyl acetal 1 to trimer 2.
Entry
Au(I) complexa
Time
Yield[8]
2ab:2b:2c
[8]
1
2
3
4
5
I
2–24 h
18 h
18 h
18 h
2 h
–
–
I–6a
40%
73%
66%
74%
55:25:20
45:35:20
45:25:30
n.r.d
I–6b
I–6c[10]
I–6cc[8]
aComplex product mixture.
b2a ¼ trans,trans,cis; main product.
c(JohnPhosAuCl)AgNTf2)–6c[8]
.
dn.r.: ratio not reported.
Table 3. Gold(I)-catalyzed dimerization of propargl acetal 10.
Au(I) complex
Time
Yield
I
2 h
24 h
11, 25%a
I–6c
12, 30%a
aUnstable.
Catalytic effect of gold-nitrone complexes
[2 þ 2 þ 2] Cyclotrimerisation. The catalytic ability of complexes I–6a, I–6b and I–6c
were tested in the gold(I)-nitronecatalysed [2 þ 2 þ 2] cyclotrimerization reaction of
1,3-diarylpropargyl acetals (1), which we have reported[10] to give cyclohexylidene prod-
ucts 2. The presence of catalytic amounts of different nitrones was previously shown to
be essential for successful selective cyclotrimerization, as Au(I) complex I gave no prod-
uct 2 and complex product mixtures from diarylpropargyl acetal 1 in the absence of
nitrone (Table 2, entry 1). A relevant hypothesis is that Au catalyst I is too active to
afford selective trimerization, and that the reduced Au-catalyst activity by nitrone-Au
coordination allows controlled chemoselective trimerization to take place.
The trimer 2 was obtained in moderate to good yields (40–73%) as mixtures of three
diastereomers (2a-c, Table 2, entries 2–4). Complex I–6b gave highest yield (73%, entry
3), similar to the best yields reported[8] for this reaction (74%, entry 5, nitrone 6c, coun-
terion NTf2). Complex I–6a gave lower yield (40%, entry 2), possibly because nitrone
6a is more poorly coordinated to gold(I) than nitrone 6b, as discussed above. The

8
H.-S. M. SIAH ET AL.
Table 4. Cycloaddition reactions of (a) diene 14 with phenylbenzaldimine[18] and (b) aryl-alkyl-prop-
argyl acetals 10 and 100 with imines 15a–d.
Yield
Entry
Acetal
Imine
16
17b
18
19
1
2
3
4
5
10
10
10
10
100
15a
15b
15c
15d
15a
16a, 33%
16b, 30%
–
21%
–
–
–
18%
–
–
–
29%
Full conv. of 10, no prod. isolated
16a0 <15%
–
–
success of the cyclotrimerisation reaction demands careful tuning of catalytic activity of
the gold complex, and a stronger deactivation of the gold center than that provided by
nitrone 6a appears to be necessary.
Some differences in the diastereoisomeric product distribution (2a–c) were observed.
Complex I–6a gave highest stereoselectivity toward the main trans,trans,cis-diastereomer
(55%, entry 2), while nitrone complex I–6b was slightly more selective toward isomer 2b
than nitrone complex I–6c (35% vs 25%). The different isomer ratios could be attributed to
a combination of factors, such as the bulk of the nitrones, as well as the strength of nitrone
coordination to the gold center. Chiral HPLC separation of the three pairs of enantiomers in
the product mixture for determination of possible % ee, was unsuccessful in our hands.
[2 þ 4] Cyclodimerisation. As previous studies on non-terminal propargyl substrates
only included phenyl-substituted propargyl acetals, such as diarylpropargyl substrate
1[10] above, the reactivity of methyl-aryl-propargyl acetal 10 was explored. Catalytic
amounts of both complexes I and I–6c gave full conversion of acetal 10, however, to

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Scheme 5. Proposed pathways for (a) gold-catalyzed generation of allene 13 and diene 14 intermedi-
ates from propargyl acetal 10; (b) dimerization of diene 14 with allene 13 to give open dimer 11 and
(c) dimerization of two units of diene 14 to give cyclic dimer 12.
different products; proposed to be the open and the cyclic dimeric products 11 (25%)
and 12 (30%), respectively (Table 3). Both products were rather unstable.
The different dimerization reaction pathway of methyl-aryl-propargyl acetal 10 from
the trimerization taking place with diaryl-propargyl substrate 1, may be explained by
the proposed pathways for the formation of the octatriene 11 and cis,trans-cyclohexene
12 dimer products (Scheme 5). The trimerization of diaryl substrate 1 is proposed to
proceed through [2 þ 2 þ 2] cycloaddition of allenic intermediates after gold-catalyzed
1,3-alkoxy rearrangement.[10] In accordance with literature,[8] the propargyl acetal 10
undergoes a gold-catalyzed 1,3-methoxy shift to give allenic intermediate 13. However,
unlike the mechanism for diaryl-propargyl acetals, the methyl-substituted allene 13
may undergo proton shift and isomerization to give diene 14 (Scheme 5a). Such
gold catalyzed transformations are reported[15,16] to be faster for electron-rich than
electron-deficient allenes.[17] Diene 14, formed by isomerization of allene 13 may
subsequently undergo two alternative dimerization pathways; either with allene 13 or
with a second unit of diene 14 to give the open and the cyclic dimers 11 and 12,
respectively (Scheme 5b,c). NMR analysis of cyclohexene dimer 12 showed NOE
correlations, such as between benzylic H3 and allylic H4 protons, which were used to
establish the relative cis-trans stereochemistry of the diphenyl-vinyl-trisubstituted cyclo-
hexene 12.
In contrast to Au(I) complex I, producing the open dimer 11, the results indicate
that nitrone complex I–6c may have higher catalytic capacity for allene-to-diene

10
H.-S. M. SIAH ET AL.
isomerization (Scheme 5a), which enables dimerization of two units of diene 14 to give
cyclic dimer 12 by a Diels-Alder-like [2 þ 4] cycloaddition.
Cycloaddition studies of in situ generated intermediates from non-terminal
propargyl acetals
Since alkyl-arylpropargyl acetal 10 seemed to generate allene 13 or diene 14 intermedi-
ates in the presence of Au(I) complexes, a series of possible Diels-Alder reactions were
tested with substrate 10 and dienophiles. The reactions with alkene, alkyne, nitrile and
carbonyl compounds failed to incorporate the dienophiles, and only dimers such as 11
and 12 (21–53%) were formed. However, as diene 14 is known to undergo hetero-
Diels-Alder reactions with imines (48% yield of piperidine product 17a, Table 4),[18] the
ability of gold(I) to catalyze possible cycloaddition reactions of imines with in situ gen-
erated allene 13 or diene 14 from alkyl-arylpropargyl acetal 10, was more promising. In
fact, propargyl acetal 10 and aldimines 15a–d did undergo several cycloaddition reac-
tions in the presence of Au(I) complex I with in situ generated intermediates 13 or 14
(Table 4). The polarized nitro-phenyl imines (15a and 15 b) mainly afforded the novel
E,trans-benzylidene-diarylazetidine 16 (30–33%, entries 1 and 2), explained by the pro-
posed [2 þ 2] cycloaddition of imine and allene 13 (Scheme 6a). The more sterically
hindered n-butyl-propargyl acetal 100 gave similar product 16a0 in lower yield (<15%,
entry 5). An analogous [2 þ 2] cycloaddition is reported by the Fiksdahl group for
dimerization of a diaryl propargyl ester to give a di-benzylidene-cyclobutyl product.[8]
Azetidines, such as products 16, are relatively stable; useful as biological scaffolds, react-
ive intermediates and chiral ligands.[19,20] They can be synthesized by several routes,
commonly by intramolecular ring-closing, ring expansion or ring contraction, and a few
Scheme 6. Proposed mechanisms for formation of products 16–19.

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11
intermolecular methods are known.[19–21] Further chemical transformations of the azeti-
dine moiety are useful in organic synthesis.[20] A few copper-catalyzed [2 þ 2] cycloaddi-
tions between allenes and imines are reported to give azetidines.[20,22] The presently
reported gold(I)-catalyzed [2 þ 2] cycloaddition of propargyl acetal 10 and imines 15a,b
via in situ generated allene 13 represents a novel synthetic pathway to azetidines.
The reaction of polarized imine 15a with diene 14 also generated the [2 þ 4] cyclo-
addition by-product 17b (21%, Table 4, entry 1 and Scheme 6b), while the more polar-
ized and electron-rich 15 b followed an unusual competing [3 þ 4] cycloaddition,
involving the e-rich MeO-phenyl unit to give the benzazepine-type by-product 18 via
an uncommon gold-carbenoid II (18%, Table 4, entry 2 and Scheme 6c). This product
is similar to the [2 þ 5] cycloaddition product 21 formed with imine and terminal aryl-
propargyl acetals, reported in earlier studies,[3] but the mechanism is different. The
trans stereochemistry of heterocyclic products 16–18 was established from NMR NOE
correlations between the respective substituents on the ring. The Z-configuration of 16
was based on NOE correlations between the relevant benzylidene protons and the R1-
aryl and Me/MeO groups.
Reaction with the less polarized and more electron-rich methoxy-phenyl imine 15c
followed a different reaction pathway than the cycloaddition seen for the polarized
imine 15a (Scheme 6b). The main product was a fully conjugated E,E,E-pentadien-1-
imine 19 (29%, Table 4, entry 3), which may be formed by diene 14 attack on imine
15c, followed by hydride shift and methanol elimination (Scheme 6d). The E,E,E-config-
1
uration of product 19 was assigned based on H NMR coupling constants and NOE
correlations. Reaction with very electron-rich aldimine 15d gave no products, indicating
that the polarization of the imine bond is important to enable nucleophilic attack on
the imine.
Conclusions
Two novel chiral menthol-based pyridyl nitrones 6a and 6b were synthesized.
Au(I)–nitrone complexes (I–6a and I–6b) were prepared by coordination of ligands 6a
1
and 6b to JohnPhosAu(ACN)SbF6 complex I. H NMR coordination studies indicated
that the new nitrones coordinated poorer to Au(I) than previously studied nitrones,
probably due to the bulk of the chiral menthol-based substituent, as well as the compet-
ing intramolecular hydrogen-bonds in non-methylated ligand 6a.
The catalytic effect of Au(I)–nitrones 6a and 6b was evaluated in [2 þ 2 þ 2] cyclotri-
merization and [2 þ 4] cyclodimerization reactions. Complex I–6b gave highest yield
(73%, entry 3), similar to the best yields reported previously (74%, nitrone 6c with
counterion NTf2).[8] The obtained diastereoisomeric ratio of the Au(I)–nitrone catalyzed
cyclotrimerization products 2 from diaryl-propargyl substrate 1, was different than in
previous studies,[8] indicating that the nitrones have a special effect in this particular
reaction. Chiral HPLC analysis of trimeric products 2a–c failed to give enantiosepara-
tion. Methyl-aryl-propargyl acetal 10 followed a different dimerization reaction pathway,
based on in situ generated allene 13 and diene 14 intermediates, compared to the trime-
rization of diaryl-propargyl substrate 1. The Au(I) nitrone complex I–6c afforded the

12
H.-S. M. SIAH ET AL.
cyclic dimer 12 by a Diels-Alder-like [2 þ 4] cycloaddition from methyl-aryl-propargyl
10, in contrast to Au(I) complex I, producing the open dimer 11.
Alternative pathways of non-terminal methyl-aryl propargyl acetal 10 were explored
by testing the ability to undergo possible gold(I)-catalyzed cycloaddition reactions with
different imines. Specific [2 þ 2], [2 þ 4] and [3 þ 4] cycloaddition reactions of imines
15a–d with in situ generated allene 13 and diene 14 intermediates from acetal 10 gave a
diverse range of N-heterocyclic products 16–19 (18–30%). Mechanistic discussions of
the selective reaction pathways are presented.
The present screening study demonstrates the potential and the versatility of non-ter-
minal propargyl acetals in gold(I) catalyzed cycloaddition reactions. Further optimiza-
tion of reaction conditions, substrate variation and gold catalyst tuning may give
improved yields and more efficient synthetic methods for preparation of selective cyclo-
addition products.
Experimental
(1S,2S,5R)-2-Isopropyl-5-methyl-1-(pyridin-2-yl)cyclohexanol (5a)
Butyllithium (2.0 M in cyclohexane, 2.9 mL, 5.8 mmol) under inert atmosphere was
cooled to 0 ꢁC and 2-(dimethylamino)ethanol (0.29 mL, 2.9 mmol) in dry heptane
(2 mL) was added slowly. The mixture was stirred at the same temperature for 15 min.
The mixture was then cooled to ꢀ78 ꢁC and pyridine (0.12 mL, 1.5 mmol) in dry hept-
ane (2 mL) was added. The mixture became bright orange over 30 mins, then
(2S,5R)ꢀ2-isopropyl-5-methylcyclohexanone (0.50 mL, 2.9 mmol) in dry THF (5 mL)
was added slowly. The mixture was stirred at this temperature for 1 h. The reaction was
quenched with sat. aq. NH4Cl (25 mL) and extracted with DCM (3 ꢂ 25 mL), dried with
brine and Na2SO4, filtered and evaporated in vacuo. Flash chromatography (1:1
1
DCM:pentane) gave the desired product as a colorless oil (114.6 mg, 33%). H and 13C
NMR data were in accordance with published literature.[9]
2-((1S,2S,5R)-2-Isopropyl-1-methoxy-5-methylcyclohexyl)pyridine (5 b)
Compound 5a (114.6 mg, 0.491 mmol) in dry THF (3 mL) was added dropwise to a sus-
pension of NaH (93.8 mg, 3.91 mmol) in dry THF (12 mL). The mixture was stirred at
r.t. for 30 mins then MeI (0.30 ml, 4.8 mmol) was added and the solution was stirred at
r.t. for 3 h. The reaction was quenched carefully dropwise with sat. aq. NH4Cl (20 mL)
and extracted with EtOAc (3 ꢂ 20 mL). The combined organic phases were dried with
sat. aq. NaCl (20 mL), dried over Na2SO4, filtered and evaporated in vacuo. Flash chro-
matography (1:30 EtOAc:pentane) gave 5b as a colorless oil (119.6 mg, 99%). [a]20 D ¼
1
ꢀ51.1ꢁ (c 1.01, CH2Cl2); H NMR (400 MHz, CDCl3): d 8.61 (ddd, 1H, J ¼ 4.8/1.7/
0.9 Hz, NCHAr), 7.65 (td, 1H, J ¼ 7.8/1.8 Hz, CHAr), 7.45 (dt, 1H, J ¼ 7.9/1.0 Hz, CHAr),
7.12 (ddd, 1H, J ¼ 7.4/4.8/1.2 Hz, CHAr), 3.22 (s, 3 H, OCH3), 2.03–1.94 (m, 2 H,
CH3OCCH2), 1.85–1.82 (m, 1H, CH3OCCH2CHCH2), 1.73–1.63 (m, 2 H, CH3CH and
CH3OCCHCH2), 1.56–1.49 (m, 2 H, (CH3)2CHCH and CH3OCCHCH2), 1.29 (sepd,
1H, J ¼ 6.9/1.5 Hz, (CH3)2CH), 1.11 (qd, 1H, J ¼ 12.6/3.4 Hz, CH3OCCH2CHCH2), 0.96
(d, 3 H, J ¼ 6.5 Hz, CH3), 0.87 (d, 3 H, J ¼ 6.7 Hz, (CH3)2), 0.58 (d, 3 H, J ¼ 6.9 Hz,

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13
(CH3)2); 13C NMR (100 MHz, CDCl3): d ppm 164.0, 149.4, 135.3, 121.5, 121.2, 84.8,
51.7, 50.3, 39.9, 35.2, 28.0, 26.5, 23.6, 22.4, 21.2, 18.2; HRMS (ASAP) calcd for
C16H26NO [M þ H]þ 248.2014, found 248.2012.
2-((1S,2S,5R)-1-Hydroxy-2-isopropyl-5-methylcyclohexyl)pyridine 1-oxide (6a)
Compound 5a (95.0 mg, 0.41 mmol) was dissolved in dry DCM (2 mL) under inert
atmosphere at 0 ꢁC. 3-chlorobenzoperoxoic acid (210.3 mg, 0.938 mmol) was added. The
reaction mixture was stirred at 0 ꢁC for 5 min then the ice bath was removed and the
reaction was allowed to come to r.t. overnight (17.5 h). The reaction mixture was
diluted with DCM (10 mL) and washed with aq. KOH (6 N, 3 ꢂ 5 mL) and the organic
layer was dried over Na2SO4, filtered and the solvent evaporated in vacuo. Flash chro-
matography (1:1 EtOAc:pentane) gave 6a as a colorless oil (82.0 mg, 81%). [a]20 D ¼
1
ꢀ79.4ꢁ (c 1.01, CH2Cl2); H NMR (400 MHz, CDCl3): d ppm 8.58 (br s, 1H, OH), 8.20
(dd, 1H, J ¼ 6.5/0.8 Hz, CHAr), 7.38 (td, 1H, J ¼ 7.8/1.3 Hz, CHAr), 7.28 (dd, 1H, J ¼ 8.2/
1.8 Hz, CHAr), 7.21 (td, 1H, J ¼ 6.9/2.0 Hz, 1H, CHAr), 2.43–2.39 (m, 1H, CH2COH),
2.09–1.96 (m, 1H, CHCOH), 1.87–1.77 (m, 3 H, CH2CHCOH and CH2CH2CHCOH
and CH(CH3)2), 1.66–1.59 (m, 2 H, CHCH(CH3)2 and CH2CH2CHCOH), 0.98 (d, 3 H,
J ¼ 6.7 Hz, CH(CH3)2), 0.93 (d, 3 H, J ¼ 7.0 Hz, CH(CH3)2), 0.87 (d, 3 H, J ¼ 6.7 Hz,
CHCH3); 13C NMR (100 MHz, CDCl3): d ppm 155.1 (CAr), 141.3 (CHAr), 127.8
(CHAr), 123.7 (CHAr), 123.6 (CHAr), 79.6 (COH), 47.8 (CHCH(CH3)2), 46.6
(CH2COH), 35.0 (CH2CHCOH), 27.8 (CH(CH3)2), 27.2 (CHCH3), 23.8 (CH(CH3)2),
22.0 (CHCH3), 21.1 (CH2CH2CHCOH), 18.7 (CH(CH3)2); HRMS (ASAP) calcd for
C15H24NO2 [M þ H]þ 250.1807, found 250.1809.
General procedure for gold(I)-catalyzed reaction of propargyl acetal 10 and
imines 15a-d
JohnPhosAu(ACN)SbF6 (4.5 mmol) was dissolved in DCM (0.5 mL) and a mixture of
acetal 10 (46 mmol) and the appropriate imine (0.138 mmol) in DCM (1 mL) was added.
The reaction mixture was stirred at r.t. for 4 h, then the reaction was quenched with
NEt3 and solvent removed in vacuo. Product isolation and purification was done by sil-
ica chromatography (EtOAc:pentane).
Supporting information: Additional Supporting information with Full experimental
1
detail, H and 13 C NMR spectra, may be found online in the Supplementary material.
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