From ynamides to highly substituted benzo[b]furans: Gold(I)-catalyzed 5-endo-dig-cyclization/rearrangement of alkylic oxonium intermediates

Article abstract of DOI:10.1002/chem.201301595

A series of arylynamides with alkyloxy groups at the ortho position of the aryl group was prepared through a short alkylation/cross-coupling/amidation sequence. The gold-catalyzed conversion of these substrates combined both C-O and C-C formation steps, thus providing benzofurans with amine functionalities at the 2-position and alkyl groups at the 3-position. Cross-over experiments showed that the alkyl-migration step was an intermolecular process. X-ray crystal-structure analysis of two of the products supported our structural assignment. In some cases, the corresponding benzofurans without the alkyl group at the 3-position were obtained as side-products, which were formed through a competing protodeauration process. Golden touch: Arylynamides with o-alkyloxy groups were prepared through an alkylation/cross-coupling/amidation sequence. Their Au-catalyzed conversion provided benzofurans with amine groups at the 2-position and alkyl groups at the 3-position. Copyright

Full text of DOI:10.1002/chem.201301595

FULL PAPER
Gold Catalysis
M. C. Blanco Jaimes, V. Weingand,
F. Rominger,
Golden touch: Arylynamides with o-
alkyloxy groups were prepared
through an alkylation/cross-coupling/
amidation sequence. Their Au-cata-
lyzed conversion provided benzofurans
with amine groups at the 2-position
and alkyl groups at the 3-position.
A. S. K. Hashmi* ............. &&&& — &&&&
From Ynamides to Highly Substituted
Benzo[b]furans: Gold(I)-Catalyzed 5-
endo-dig-Cyclization/Rearrangement
of Alkylic Oxonium Intermediates
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DOI: 10.1002/chem.201301595
From Ynamides to Highly Substituted Benzo[b]furans: Gold(I)-Catalyzed
5-endo-dig-Cyclization/Rearrangement of Alkylic Oxonium Intermediates
Maria Camila Blanco Jaimes,[a] Vanessa Weingand,[a] Frank Rominger,[a] and
A. Stephen K. Hashmi*[a, b]
Abstract:
A
series of arylynamides
2-position and alkyl groups at the 3-po-
sition. Cross-over experiments showed
that the alkyl-migration step was an in-
termolecular process. X-ray crystal-
structure analysis of two of the prod-
ucts supported our structural assign-
ment. In some cases, the corresponding
benzofurans without the alkyl group at
the 3-position were obtained as side-
products, which were formed through a
competing protodeauration process.
with alkyloxy groups at the ortho posi-
tion of the aryl group was prepared
through a short alkylation/cross-cou-
pling/amidation sequence. The gold-
catalyzed conversion of these sub-
strates combined both C O and C C
formation steps, thus providing benzo-
furans with amine functionalities at the
Keywords: cyclization · gold · het-
erocycles · rearrangement · yna-
mides
ꢀ
ꢀ
Introduction
Over the last few decades, gold
has emerged as a powerful tool
in organic synthesis and, as
such, it has become one of the
major topics in catalysis re-
search. Owing to its high selec-
tivity, high atom economy, and
mild conditions, gold(I) cataly-
sis is now well-known and
widely used.[1] Ynamides have
gained special attention over
the last few years because they
are versatile building blocks
that offer a convenient route
for the introduction of nitrogen
Figure 1. a) Benzofuran-containing natural products; b) examples of benzofuran-containing molecules with
pharmaceutical activity.
functionalities into organic
molecules.[2] In the literature,
there are only a few reports of
gold-catalyzed reactions of ynamides,[3–5] most of which used
yncarbamates[3] or ene-ynamides[4] as the starting materials.
Our group[4d] reported the synthesis of dihydroindoles and
tetrahydroquinones from the intramolecular reaction of an
ynamide moiety with furan, whilst Skrydstrup and co-work-
ers[5] reported the intermolecular hydroamination of yna-
mides with anilines to give imidoyls.
[a] M. C. Blanco Jaimes, V. Weingand, Dr. F. Rominger,+
Prof. Dr. A. S. K. Hashmi
Organisch-Chemisches Institut
Benzo[b]furans are an important class of heterocyclic
compounds that have attracted much interest over the years
because of their occurrence in many natural products (Fig-
ure 1a)[6] and their wide range of pharmaceutical activities
(Figure 1b).[7] In the literature, many different synthetic
routes to benzo[b]furan systems have been described. The
major synthetic strategies are based on the use of transition-
metal catalysts,[8] such palladium,[9] platinum,[10] copper,[11]
rhodium,[12] and gold.[13]
Ruprecht-Karls-Universitꢁt Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax : (+49)711-685-4205
E-mail: hashmi@hashmi.de
[b] Prof. Dr. A. S. K. Hashmi
Chemistry Department, Faculty of Science
King Abdulaziz University
Jeddah 21589 (Saudi Arabia)
[+] Crystallographic investigation.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301595.
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From Ynamides to Highly Substituted Benzo[b]furans
FULL PAPER
mediate, which can easily react
with
N-bromosuccinimide.[15]
The previously mentioned al-
kynyl bromides (3) were used
in
a copper-catalyzed cross-
coupling reaction with sulfona-
mides 4, thereby resulting in
the formation of ynamides 5 in
moderate-to-high yields (69–
81%). All of the coupling re-
actions were performed with
10 mol% CuSO4·5H2O and
20 mol% 1,10-phenanthroline
in toluene at 708C.[16] This
route provides a general entry
to a wide variety of ynamides,
which are shown in Table 1.
Scheme 1. a) Previously reported methods: PtCl2-catalyzed carboalkoxylation reaction by Fꢂrstner’s group and
rhodium-catalyzed demethylation/cyclization by Oppenheimer’s group. b) Our approach: gold(I)-catalyzed
tandem 5-endo-dig-cyclization/rearrangement of an alkyl-oxonium intermediate.
In the context of the reaction that we have investigated
herein, Fꢂrstner and Davies[10] reported the PtCl2-catalyzed
carboalkoxylation reaction of phenolic allyl ethers (Sche-
me 1a), whilst Oppenheimer and co-workers[12] described
the only previous method in which ynamides were used as
precursors of benzo[b]furans, which proceeded through a
rhodium-catalyzed demethylation/cyclization process with
ortho-anisole-substituted ynamides (Scheme 1a).[12]
We showed that the presence of various moieties on the
oxygen atom, such as allyl, cinammyl, and benzyl groups,
were well-tolerated. We also established that the copper-cat-
alyzed cross-coupling reaction performed efficiently, by
Taking into account these facts, we decided to investigate
an intramolecular gold(I)-catalyzed alkyl-shift reaction. The
aim was to promote a 5-endo-dig cyclization reaction, fol-
lowed by an O!C alkyl shift of the alkylic oxonium species
(A), thus obtaining highly functionalized 2-amidobenzo[b]-
furans (Scheme 1b), in a similar fashion to that reported by
Fꢂrstner and Davies for platinum catalysts and other sub-
strates.[10] Apart from the fact that there is not much infor-
mation pertaining to the gold-catalyzed reactions of yna-
mides, their use as starting materials offers a different per-
spective on this reaction type, thereby also allowing the in-
troduction of a nitrogen functionality into the final product.
Scheme 2. Straightforward four-step synthetic route to ynamides 5.
NBS=N-bromosuccinimide.
using a variety of sulfonamides that contained different
alkyl chains and sulfonyl groups (Table 1).
Results and Discussion
With the starting ynamides (5) in hand, we decided to in-
vestigate the corresponding gold-catalyzed reaction. Count-
ing on the strong possibility of obtaining compound 7 as a
side-product, through a cyclization reaction followed by pro-
todeauration, we started by performing a screening with de-
rivative 5a. The aim was to find the best, most-efficient, and
most-selective conditions for synthesizing highly substituted
benzofurans (6) through a cyclization/O!C alkyl-rearrange-
ment pathway. In a first stage, various different catalysts
were screened, whilst always using AgNTf2 as a counterion
and CH2Cl2 as the solvent (Table 2). The catalysts were
carefully chosen to include various types of ligands, namely,
phosphane ligands, Buchwald-type ligands, carbene ligands,
and phosphite ligands. The initially tested phosphane and
phosphite ligands (Table 2, entries 1 and 2) only showed low
conversions, low yields, and moderate selectivities for highly
substituted benzofuran 6a. Although Buchwald-type ligands
showed higher conversions, that is, up to 62% for the most
The starting point of our investigation was the synthesis of
ynamides 5. These compounds were easily accessible
through a four-step synthetic route starting from 2-iodophe-
nol (Scheme 2). Compounds 1 and 2 were synthesized in
high yields by using known procedures.[14] They were ob-
tained after an O-alkylation reaction by using carefully
chosen bromides or chlorides, followed by a Sonogashira
coupling reaction. In this case, the reaction was allowed to
take place at room temperature to avoid the formation of
side products, which could be formed at higher temperatures
as a result of a Pd-catalyzed cyclization step.
Then, silylated alkynes 2 were submitted to a deprotec-
tion/halogenation reaction sequence that was catalyzed by
silver nitrate, thus affording the corresponding bromoal-
kynes (3) in high yields (79–91%). This process presumably
takes place through the formation of an alkynyl-silver inter-
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A. S. K. Hashmi et al.
Table 1. Copper-catalyzed formation of ynamides 5.
Entry
Starting bromo
derivative
Ynamide
Yield of
5 [%]
Entry
11
Starting bromo
derivative
Ynamide
Yield of
5 [%]
1
3a
3a
3b
3c
5a
5b
5c
5d
81
72
79
78
3 f
3g
3h
3h
5k
5l
70
74
78
72
2
3
4
12
13
14
5m
5n
5
6
7
3d
3e
3e
5e
5 f
5g
76
72
73
15
16
17
3h
3i
5o
5p
5q
77
70
75
3i
8
3e
5h
71
18
19
3e
3e
5r
5s
70
76
9
3e
3e
5i
5j
77
69
10
sterically hindered ligand (Table 2, entry 3), the desired se-
lectivity was still poor. Pleasingly, we detected complete
conversion of the starting material after only 3 h when the
carbene complex IPrAuCl was used (Table 2, entry 5). In
this case, a high yield were observed, as well as high selec-
tivity for the formation of compound 6a (78%). Disappoint-
ingly, the use of similar carbene ligands did not offer such
results. After 20 h, only moderate conversions and selectivi-
ties were detected (Table 2, entry 6 and 7). The low reactivi-
ties of carbene complexes 9 and 10 can possibly be ex-
plained by the flexibility of the twelve- and fifteen-mem-
bered rings, which do not allow them to be as sterically hin-
dered as the IPrAuCl complex. Finally, AuCl showed moder-
ate conversion after 20 h, but, in contrast to the other
experiments, the selectivity slightly favored the formation of
compound 7a (Table 2, entry 8). Control experiments with
TsOH (Table 2, entry 9) and AgNTf2 (Table 2, entry 10) did
not exhibit any significant conversion after 48 h.
Having identified a gold complex that converted the sub-
strate in high yield and with high selectivity for the forma-
tion of the desired, highly substituted benzofuran (6a), vari-
ous counterions and solvents were also screened. As shown
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From Ynamides to Highly Substituted Benzo[b]furans
FULL PAPER
Table 2. Catalyst screening.[a]
the combination IPrAuCl/AgNTf2. When the reaction was
performed in acetone (Table 3, entry 5) and benzene
(Table 3, entry 7), although complete conversion was ob-
served after 3 h, compound 7a was formed in almost the
same proportion as compound 6a. The use of CHCl3
(Table 3, entry 4) or MeCN (Table 3, entry 6) did not afford
any better result; only moderate conversions were detected.
Finally, as expected, no formation of the product was ob-
served in DMSO (Table 3, entry 8).
Entry
[Au]
t [h]
Conversion
[%][b]
Yield A/B
[%][b]
1
2
3
Ph3PAuCl
PhosphiteAuCl
SPHOSAuCl
20
10
10
28
35
62
13:10
13:10
25:20
Figure 2 shows a NMR-monitoring experiment with deri-
vate 5a under the optimized conditions. By following the
shift of the signal of the allylic proton, we clearly demon-
strated that the O!C migration took place. The methylene
protons (H1 and H2) that corresponded to the O-allylic
fragment, which were initially located at d=4.5 ppm, were
shifted to higher field (H1’ and H2’, d=3.4 ppm) after mi-
grating onto the carbon atom in the benzofuran ring, owing
to the loss of the deshielding effect of the oxygen atom.
From the NMR experiments, it can be also inferred that the
starting material is converted into the benzofuran within a
relatively short length of time, with high selectivities and
minimal decomposition or side reactions.
With the optimized conditions and ynamides 5 in hand
(Table 1), we could now investigate the scope of the gold-
catalyzed reaction. Table 4 summarized the results that were
obtained with various ynamides. In most cases, the corre-
sponding benzofurans were obtained in moderate-to-high
yields. To understand the mechanism of the O!C alkyl-
shift step, different fragments in the alkyl-oxonium inter-
mediate were investigated. We decided to start with allylic
fragments that could either undergo an intramolecular shift
through a [3,3]-sigmatropic rearrangement[17] or an intermo-
lecular process with the formation of an allyl cation and a
vinylgold(I) intermediate.[18] Derivatives 5a (Table 4,
entry 1), 5b (Table 4, entry 2), and 5e (Table 4, entry 5)
were obtained in high yields. In those cases, no information
about the nature of the O!C shift could be acquired, owing
to the symmetry of the allylic moieties. However, derivate
5c offered some insight into the nature of the O!C alkyl
shift. In this case, the formation of two isomeric benzofurans
in nonequivalent proportions was observed (Table 4,
entry 3). This result excludes the possibility of a [3,3]-sigma-
tropic rearrangement, which would lead to the formation of
only one isomer, and can only be explained by considering
the formation of two different stabilized carbocations from
the allyl-oxonium intermediate. As expected, the product
that corresponded to the attack of the more-stable carboca-
tion was obtained in a higher proportion (50% compared to
26% of the other isomer).
4
20
35
16:14
5
6
IPrAuCl
3
100
26
78:8
20
14:10
7
20
48
35:8
8
9
10
AuCl
20
48
48
55
6
12
15:16
0:0
0:2
TsOH
[c]
–
[a] The reactions were carried out in a NMR tube in the corresponding
deuterated solvent. [b] Determined by 1H NMR spectroscopy by using
hexamethylbenzene (HMB) as an internal standard. [c] Only AgNTf2 was
used. Phosphite= Tris(2,4-di-tert-butylphenyl)phosphite, SPHOS=2-dicy-
clohexylphosphino-2’,6’-dimethoxybiphenyl, IPr=1,3-bis(diisopropylphe-
nyl)imidazol-2-ylidene, Ts=tosyl.
in Table 3, complete conversion within 3 h was detected
with all three silver salts that were used (Table 3, entries 1–
3); nevertheless, AgSbF6 (Table 3, entry 2) and AgOTf
(Table 3, entry 3) exhibited lower selectivities, thereby cata-
lyzing the formation of compound 7a in larger proportions
than the previously screened AgNTf2 (Table 3, entry 1). Be-
cause the best results were obtained with AgNTf2 as a coun-
terion, the solvent screening was always performed by using
Table 3. Silver salt and solvent screening.
Entry
AgX
Solvent
t [h]
Conversion
[%][a]
Yield A/B
[%][a]
1
2
3
4
5
6
7
8
AgNTf2
AgSbF6
AgOTf
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
acetone
CH3CN
benzene
DMSO
3
3
3
20
3
20
3
100
100
100
56
100
72
78:8
69:12
60:36
33:14
54:40
30:30
46:36
0:0
Next, we decided to investigate the possibility of achiev-
ing the selective formation of only one isomer by introduc-
ing functionalities that could stabilize one of the carboca-
tions, thereby directing the reaction along a thermodynami-
cally controlled pathway. Nevertheless, the insertion of car-
bocation-stabilizing groups onto the allyl fragment leads to
steric hindrance at that position, thus favoring the attack on
the less-hindered carbocation and causing a change in reac-
100
39
20
[a] The reactions were carried out in a NMR tube in the corresponding
deuterated solvent; yield was determined by 1H NMR spectroscopy by
using hexamethylbenzene (HMB) as an internal standard.
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A. S. K. Hashmi et al.
Figure 2. NMR-monitoring experiment.
tivity towards a kinetically controlled pathway. This reactivi-
ty path was shown by derivative 5d (Table 4, entry 4), for
which isomer 6d’ was formed in a larger proportion (54%
compared to 19% of isomer 6d) as a result of the attack on
the less-hindered carbocation. In the case of derivative 5k
(Table 4, entry 11), the two isomers were formed in similar
proportions, owing to the high stability of the benzylic car-
bocation; nevertheless, the attack on the less-hindered car-
bocation was favored.
With these results in hand, we focused our investigation
on carefully chosen ynamides that allowed the formation of
only one regioisomer. Derivatives 5 f–5j, which contained
O-cyclohexenyl substituents (Table 4, entries 6–10), afforded
their corresponding products in moderate-to-high yields
(62–74%). When a five- (Table 4, entry 7) or six-membered
ring (Table 4, entry 8) was located on the nitrogen atom, the
yields were slightly lower and the reactions were slower,
thus needing 12 h to afford complete conversion. This be-
havior is probably due to the size of the carbon ring, which,
in combination with the cyclohexenyl ring, hinders the cycli-
zation reaction, thereby increasing the activation energy.
Benzylic and heteroarylic substituents were also used to es-
tablish the scope of the reaction. Although these derivatives
(Table 4, entries 12–15) performed quite well in the reaction,
with complete conversion within only 4 h, the products were
obtained with the lowest observed yields (45–67%). In
those cases, large proportions of the protodeaurated prod-
ucts (7) were detected, thus indicating that the stabilization
of the benzyl-type carbocations by the aromatic ring proba-
bly slowed down the reaction rate, thereby favoring the pro-
todeauration side-reaction. Thereafter, the O-methoxymeth-
yl (O-MOM) fragment was explored as a migrating group.
To our delight, the reaction resulted in high yields (73%),
with complete conversion within 3 h (Table 4, entries 16 and
17). Finally, we decided to investigate the influence of differ-
ent electron-withdrawing groups (EWGs) on our ynamide
precursors. To our satisfaction, we established that various
EWGs could be used without affecting the course or the
yield of the reaction. Compounds 6r (Table 4, entry 18) and
6s (Table 4, entry 19) were obtained in high yields (up to
76%), thus confirming the wide applicability of this method.
In some cases, suitable crystals for X-ray analysis were ob-
tained. Figure 3 shows the solid-state molecular structures of
benzo[b]furans 6a and 6g.[19] The results of X-ray structural
analyses unequivocally confirmed the migration of the alkyl
fragment, as well as the construction of the 2-amidoben-
zo[b]furan structure.
Figure 3. Solid-state molecular structures of benzo[b]furans 6a (left) and
6g (right).
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From Ynamides to Highly Substituted Benzo[b]furans
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Table 4. Reaction scope.
Entry[a]
Starting
material
t
Product
Yield
[%]
Entry[a]
Starting
material
t
Product
Yield
[%]
[h]
[h]
1
3
4
74
64
11
12
32 (6k’)
2
3
38 (6k’)
50 (6c) 12
26 (6c’) 13
4
4
54
2
51
67
45
19 (6d) 14
3
4
4
3
54 (6d’) 15
5
6
4
2
72
61
16
17
3
3
73
73
7b
12
66
18
19
3
3
76
73
8[b]
12
4
64
74
9
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A. S. K. Hashmi et al.
Table 4. (Continued)
Entry[a]
Starting
material
t
Product
Yield
[%]
Entry[a]
Starting
material
t
Product
Yield
[%]
[h]
[h]
10
12
68
[a] Unless otherwise stated, the reactions were carried out at 408C by using 3 mol% IPrAuCl/AgNTf2 in CH2Cl2. [b] PhosphiteAuCl was used instead of
IPrAuCl.
Thus, we have demonstrated that the synthesis of highly
substituted benzo[b]furans by gold-catalyzed 5-endo-dig cyc-
lization/rearrangement of oxonium intermediates proceeded
successfully when allyl-type, cinammyl-type, benzyl-type,
and oxygen-stabilized carbocations were formed. Next, we
decided to investigate whether the O!C alkyl shift could
take place with non-stabilized carbocations. For this pur-
pose, we used compound 8, which possessed a methyl group
as a leaving group. Disappointingly, no conversion into the
expected products was observed. After 24 h at 408C, only
the starting material and decomposition products were re-
covered (Scheme 3). This result clearly shows the need for a
well-stabilized carbenium ion as a leaving group that is
stable enough to be formed through a low-activation-energy
pathway and to perform the O!C shift under mild condi-
tions.
compound 6e was observed, whilst the other cross-coupled
product was not, indicates that the reaction of the vinylgol-
d(I) intermediate with the allyl cation from compound 5a
must be rapid.[21] This result can also be explained by consid-
ering that the cyclohexenyl carbocation is more stable, thus
allowing the reactions with the two different vinylgold(I) in-
termediates to take place.
In Scheme 5, a possible catalytic cycle is proposed, based
on the previously obtained results. The first stage involves
Scheme 3. Gold-catalyzed reaction of ynamide 8.
To unequivocally establish whether the gold-catalyzed re-
action of ynamides 5 takes place through a [3,3]-sigmatropic
rearrangement[20] or through an intermolecular process with
the formation of a stabilized carbocation and a vinylgold(I)
intermediate, we performed a cross-over experiment with
derivatives 5a and 5s. The results, which were monitored by
1H NMR spectroscopy and mass spectrometry, are shown in
Scheme 4. In addition to the two expected products (6a and
6s), cross-coupled compound 6e was also formed. This out-
come indeed indicates the formation of a stabilized carboca-
tion that attack the vinylgold(I) intermediate. The fact that
Scheme 5. Proposed reaction mechanism.
the activation of the ynamide (5) by the gold species, which
enables the nucleophilic attack of the oxygen atom, thus
forming alkyl-oxonium intermediate C. This species gener-
ates vinylgold(I) intermediate D and a stabilized alkyl car-
bocation (E). Then, the latter species shifts to the most-nu-
cleophilic position on the benzofuran ring, thus giving rise
to the highly substituted benzo[b]furan (6) and regenerating
the gold species, thereby completing the catalytic cycle.
Conclusion
This reported method is based
ꢀ
on
a
copper-catalyzed C N
coupling reaction for the syn-
thesis of new ynamides, which
Scheme 4. Cross-coupling reaction between ynamides 5a and 5s.
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then undergo a gold(I)-catalyzed 5-endo-dig cyclization re-
action, followed by a rearrangement of the alkylic oxonium
intermediate. This procedure represents one of only a few
examples of gold-catalyzed reactions of ynamides. We have
shown that allyl-type, cinammyl-type, benzyl-type, and
oxygen-stabilized carbocations can successfully undergo
O!C migration. This method is limited to the use of frag-
ments that can easily generate stable carbocations. New
highly substituted benzo[b]furans have been synthesized in
high yields and with high atom economy.
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Acknowledgements
M.C.B.J. is grateful to the DAAD for a fellowship. The gold salts were
generously donated by Umicore AG & Co. KG.
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Received: April 25, 2013
Revised: May 26, 2013
Published online: && &&, 0000
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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