[2+2+2]-Cyclotrimerization of 1-Cyclopropyl-1,6-diynes with Alkynes: Formation of Cyclopropylarenes.

Article abstract of DOI:10.1002/adsc.201500851

Cyclotrimerization of 1-cyclopropyl-1,6-diynes with various terminal alkynes was tested under catalytic conditions using rhodium and ruthenium catalysts. We observed that the regioselectivity of the reaction, that is, formation of 1,2- or 1,3-regioisomers, was opposite for the two metals. For the ruthenium complex [Cp Ru(cod)Cl]-catalyzed reactions the yields were in many cases high with a strong preference for the formation of 1,3-substituted regioisomers. In the case of catalysis by the rhodium complex [RhCl(PPh₃)₃], 1,2-substituted products were generally preferred, albeit the selectivity was often modest. However, by changing the ligand environment around the central rhodium atom the regioselectivity as well as yields of the products were significantly improved. For example, by using a combination of the rhodium complex [Rh(cod)₂BF₄] and 1,4-bis(diphenylphosphino)butane the regioselectivity was changed from 1:1 to 1:12 in favor of the 1,2-regioisomer. This catalytic system was also applied for synthesis of a substituted 4-cyclopropyl-3-hydroisobenzofuran-1-one that could serve as a potential intermediate for preparation of antihypertensive agents.

Full text of DOI:10.1002/adsc.201500851

FULL PAPERS
DOI: 10.1002/adsc.201500851
[
2+2+2]-Cyclotrimerization of 1-Cyclopropyl-1,6-diynes with Al-
kynes: Formation of Cyclopropylarenes.
a
b
b
a,
Eli sˇ ka Matou sˇ ovµ, Robert Gyepes, Ivana Císa rˇ ovµ, and Martin Kotora *
a
Department of Organic Chemistry, Faculty of Science, Charles University in Prague, Hlavova 8, 128 43 Praha 2, Czech
Republic
Fax: +420 221 951 326; Phone: +420 221 95 1334; e-mail: martin.kotora@natur.cuni.cz
Department of Inorganic Chemistry, Faculty of Science, Charles University in Prague, Hlavova 8, 128 43 Praha 2, Czech
b
Republic
Received: September 17, 2015; Revised: November 3, 2015; Published online: January 11, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500851.
Abstract: Cyclotrimerization of 1-cyclopropyl-1,6- atom the regioselectivity as well as yields of the
diynes with various terminal alkynes was tested products were significantly improved. For example,
under catalytic conditions using rhodium and ruthe- by using a combination of the rhodium complex
nium catalysts. We observed that the regioselectivity [Rh(cod) BF ] and 1,4-bis(diphenylphosphino)butane
2
4
of the reaction, that is, formation of 1,2- or 1,3-re- the regioselectivity was changed from 1:1 to 1:12 in
gioisomers, was opposite for the two metals. For the favor of the 1,2-regioisomer. This catalytic system
ruthenium complex [Cp*Ru(cod)Cl]-catalyzed reac- was also applied for synthesis of a substituted 4-cy-
tions the yields were in many cases high with clopropyl-3-hydroisobenzofuran-1-one that could
a strong preference for the formation of 1,3-substi- serve as a potential intermediate for preparation of
tuted regioisomers. In the case of catalysis by the antihypertensive agents.
rhodium complex [RhCl(PPh ) ], 1,2-substituted
3
3
products were generally preferred, albeit the selec-
tivity was often modest. However, by changing the Keywords: arenes; cyclotrimerization; homogeneous
ligand environment around the central rhodium catalysis; rhodium; ruthenium
[
6]
[7]
[8]
Introduction
HIV, antihepatitis, antiautoimmune, antihyper-
[9] [10]
tensive (Figure 1) or pesticidal effects. The cyclo-
Cyclotrimerization of alkynes, thanks to their structur- propylarenes have also served as starting materials
al variability, constitutes one of the most efficient and for synthesis of chiral intermediates via enzymatic ox-
[11]
straightforward synthetic techniques for the construc- idation. They are commonly prepared by cycloaddi-
[12]
tion of variously substituted benzenes and other aro- tion of alkynes with dienes or cross-coupling reac-
[13]
[14]
matic compounds. The cyclotrimerization can be pro- tions using Suzuki or other protocols.
moted by either catalytic or stoichiometric amounts Interestingly, there has been just a handful of scat-
of transition metal compounds, each of these method- tered reports regarding the formation of cyclopropy-
ologies having its pros and cons, but they complement larenes via cyclotrimerization reaction. Among them
each other. This reaction has also been used in syn- belong Cp*Ru(cod)Cl and {[Ir(H)(rac-BINAP)] (m-
2
theses of valuable synthetic building blocks and has I) } I catalyzed cyclotrimerization of diynes with cy-
3
3
served as the key step in syntheses of numerous natu- clopropylethyne leading to cyclopropylated isoindoli-
[
1]
[15]
[16]
ral products.
nones and isoindolines (1 example in each case),
One such class of interesting building blocks are cy- Ni(cod) /PPh catalyzed homocyclotrimerization to
2
3
[17]
clopropylbenzenes (cyclopropylarenes) that have a mixture of regioisomeric triscyclopropylbenzenes
found applications in diverse fields of chemistry, and intramolecular cyclotrimerization of cyclopropy-
thanks to the special electronic and steric properties lated triynes catalyzed by Ru-carbene complexes to
[
2,3]
[18]
exerted by the cyclopropyl group.
The cyclopropyl- the corresponding tricycles (3 examples).
Reports
arene moiety can be found in a number of compounds regarding cyclotrimerization of the structurally relat-
[19]
possessing various biological activities, such as ed iso-propylated alkynes have been scarce as well.
enzyme inhibitory, lipooxygenase inhibitory, anti-
[
4]
[5]
2
54
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2016, 358, 254 – 267

FULL PAPERS
[2+2+2]-Cyclotrimerization of 1-Cyclopropyl-1,6-diynes
the desired ester 1c was obtained (65%). All the al-
kynes tested in cyclotrimerization reaction are listed
in Figure 2.
Initially, we screened the cyclotrimerization of 1a
with terminal alkynes 2a, 2b, 2 f, 2h, 2i and 2m in
the presence of a catalytic amount of RhCl(PPh3)3
(
Wilkinsonꢁs catalyst) in toluene (Table 1). In almost
all cases arenes 3 (4-cyclopropyl-1,3-dihydro-6-(substi-
tuted)-isobenzofurans, the 1,3-regioisomer) and 4 (4-
cyclopropyl-1,3-dihydro-5-(substituted)-isobenzofur-
ans, the 1,2-regioisomer) were formed, even though in
rather low isolated yields (4-26% range) (Entries 1-
Figure 1. Compounds A and B tested in in vivo studies as
renal outer medullary potassium channel (ROMK) inhibi-
[9]
tors (potential antihypertensive agents).
1
0). In addition, the formation of regioisomeric ho-
Because of our interest to explore the possibility of mocyclotrimerization products 5a and 5b, which were
synthesizing cyclopropylated aromatic compounds by in many cases the major products, along with (Z)-(5-
using the cyclotrimerization strategy, we undertook an (3-cyclopropylprop-2-ynyloxy)pent-3-en-1-ynyl)ben-
effort to explore this approach and assess its scope zene 6 - the result of an alkyne addition to diyne 1a -
and limitations with respect to transition metal based was observed. A slight preference for the formation
catalytic systems and the substrate structure. From 1,2-regioisomer 4 was observed in toluene (3/4 ratio
the synthetic point of view, compounds A and B was in the range of 1/1-1.8). Interestingly, there were
(
Figure 1) attracted our attention, because they could, two exceptions from this rule: a) in the reaction with
in principle, be accessed by cyclotrimerization of ferrocenylethyne 2 f the formation of 1,3-regioisomer
a suitably substituted cyclopropylated diyne with 3 f was preferred (Entry 6); b) the reaction with the
propargylic or homopropargylic alcohol or derivatives TBS-protected propargyl alcohol 2m furnished 1.9/
thereof.
1 mixture of 3m and 4m (Entry 10). In addition, two
cyclotrimerizations were performed in ethanol; but in
both cases the yields were low and each led to prefer-
ential formation of a different regioisomer (Entries 4
and 8). Since it has been shown that the cationic Rh-
Results and Discussion
[1g,23]
The starting 1-cyclopropyl-1,6-diynes 1a-1c (Figure 2) complex prepared from Rh(cod) BF and BINAP
2
4
were prepared by using standard organic transforma- efficiently catalyzes cyclotrimerization of alkynes, it
tions from the commercially available cyclopropyle- was applied in cyclotrimerization of 2h. However, its
thyne. It was treated with n-butyllithium followed by use did not result in a better yield of the correspond-
addition of paraformaldehyde to give 3-cyclopropyl- ing arenes 3h and 4h (18%) or regioselectivity (3h/
[
20]
prop-2-yn-1-ol
in 83-90% yield. The alcohol was 4h=1/1) (Entry 11). The cyclotrimerization of 2b was
then reacted either with NaH and propargyl bromide also tested in the presence of the cobalt (CpCo(CO)2)
to obtain diyne 1a (in 79-89% yield) or with DCC and nickel (NiBr (PPh ) /Zn) catalytic systems. None-
2
3 2
[
21]
and propiolic acid to yield diyne 1b (70%). For the theless, the yields of the products 3b and 4b did not
synthesis of compound 1c cyclopropylethyne was improve much, being 20 and 30%, respectively (En-
again deprotonated using n-butyllithium, this time tries 12 and 13). Interestingly, regioselectivity differed
treated with carbon dioxide in the form of dry ice, to significantly, the Co-catalyzed reaction provided 3b/
[
22]
give 3-cyclopropylpropiolic acid
After the reaction with DCC and propargyl alcohol nificantly favored formation of 1,3-regioisomer 3b
3b/4b=3.5/1). Our attempts to carry out cyclotrime-
rization with 3-hexyne 2p (using RhCl(PPh ) ) did
in 92% yield. 4b in 1/1 ratio, whereas the Ni-catalyzed reaction sig-
(
3
3
not provide any products and only homocyclotrimeri-
zation to 5 (81%, 1/1) was observed.
Then we tested Cp*Ru(cod)Cl as a catalyst to bring
about cyclotrimerization (Table 2). Gratifyingly, its
use led to higher conversions of the starting material
furnishing the desired products 3 and 4 in better iso-
lated yields (17-72%). The general preference for 1,3-
substituted regioisomer was prevailing in all cases and
was in the range of 6-15/1 (3/4). The reaction with
phenylacetylene 2a provided 3a in a rather low yield
Figure 2. Diynes and alkynes used in the cyclotrimerization of 20% in both dichloromethane or 1,2-dichloro-
study.
ethane (Entries 1 and 2). On the other hand, reaction
Adv. Synth. Catal. 2016, 358, 254 – 267
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255

Eli sˇ ka Matou sˇ ovµ et al.
FULL PAPERS
Table 1. Cyclotrimerization of 1a with various alkynes 2 in the presence of Rh, Co, and Ni catalysts.
[
a]
Catalysts A=RhCl(PPh3)3 (5 mol%), B=Rh(cod) BF /BINAP (8 mol%), C=CpCo(CO) (10 mol%), D=
2
4
2
NiBr (PPh ) /Zn (20 mol%).
Reactions were carried out at 228C unless otherwise noted. DCE=CH ClCH Cl.
Isolated yields.
2
3 2
[
[
[
[
[
[
[
[
[
[
[
[
[
b]
c]
d]
e]
f]
2
2
5
6
6
5
6
2
4
a/5b ratio in brackets.
was isolated in 5% yield.
was isolated in 15% yield.
was formed but yield not determined.
was isolated in 25% yield.
1% of 1a was recovered.
0% of 1a was recovered.
g]
h]
i]
j]
k]
l]
At 508C.
0% of 1a was recovered.
Microwave irradiation, 1208C.
3% of 1a was recovered.
1
m]
n]
6
with an electron rich 4-methoxyphenylacetylene 2b or internal alkynes 3-hexyne 2p and 1,4-butyndiol did
gave the corresponding 3b in a nice yield of 72% not proceed, and only products of homocyclotrimeri-
(
Entry 3). The cyclotrimerization with bulky ferroce- zation 5 were observed in yields of 25% (6/1), 12%
nylethyne 2 f gave rise to 3 f and 4 f in a good yield of (8/1), 3%, 33% (10/1), and 78% (6/1), respectively.
51% (Entry 4). The reaction with cyclopropylethyne Attempts to add the diynes dropwise to the solution
2
h and 1-hexyne 2i furnished the corresponding prod- of the catalyst and excess monoalkynes did not have
ucts in 35 and 17% yield, respectively (Entries 5 and substantial effect on the product distribution.
). Furthermore, the reaction with 2 f catalyzed by Our attention then turned to ester 1b, because its
6
st
a Ru-carbene complex (Grubbs 1 generation cata- cyclotrimerization could provide products possessing
lyst) was attempted, giving 3 f and 4 f in 31% yield structural features found in compounds A and B
[
24]
(
Entry 7). Interestingly, the reactions with electron- (Figure 1). A considerable improvement in yields of
poor alkynes such as (4-trifluoromethylphenyl)ethyne cyclotrimerizations of 1b, in comparison with corre-
c and (4-methoxycarbonylphenyl)ethyne 2d, sterical- sponding reactions of 1a, with alkynes 2a-2n was
ly hindered alkynes such as trimethylsilylethyne 2g, seen when Ru-catalysts were applied (Table 3). In
2
2
56
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FULL PAPERS
[2+2+2]-Cyclotrimerization of 1-Cyclopropyl-1,6-diynes
[
a]
Table 2. Cyclotrimerization of 1a with various alkynes 2 in the presence of Ru catalysts.
[
[
[
[
[
[
[
[
a]
b]
c]
d]
e]
f]
Cp*Ru(cod)Cl (10 mol%) was used unless otherwise mentioned.
2
28C, DCE=CH ClCH Cl, DCM=CH Cl .
2 2 2 2
Isolated yields.
5
3
1
3
a/5b ratio in brackets.
6% of 1a was recovered.
4% of 1a was recovered.
g]
h]
7% of 1a was recovered.
st
Grubbs 1 generation catalyst was used.
general, the corresponding 4-cyclopropyl-6-(substitut- catalyst loading of 10 mol% (this amount was used
ed)isobenzofuran-1(3H)-ones 7 and 4-cyclopropyl-5- because of a relatively small reaction scale using
(
substituted)isobenzofuran-1(3H)-ones 8 were formed 0.25 mmol of 1b), additional experiments aiming to
and isolated in high yields with a significant prefer- reduce the loading and to evaluate solvent effects
ence for the 1,3-substituted products (7/8 ratio was in were carried out. Cyclotrimerization of 1b with cyclo-
the range of 2.5-8/1). Homocyclotrimerization of 1b propylethyne 2h was chosen as a model reaction. The
was not observed. Only the reactions with trimethylsi- results summarized in Table 4 clearly show that the
lylethyne 2g and methyl propynoate 2j gave mediocre reaction proceeded with excellent yields in DCE even
isolated yields of the corresponding products: 49 and in the presence of 2 mol% of the catalyst at 228C
2
2
8% (Entries 7 and 11). In addition, the reaction with (Entry 4). As far as the solvents are concerned, the
f catalyzed by Grubbs 1 generation catalyst was cyclotrimerization was also carried out in THF and
st
conducted and furnished 7 f and 8 f in 46% yield but cyclopentyl methyl ether (CPME), both used as the
no regioselectivity (Entry 16). The reaction of 1b with solvent of choice in previous reports (Entries 6-
[15,23c]
3-hexyne 2p provided the corresponding product in 8).
In both instances the yields were very high. It
a very low yield of 9%. The attempts to utilize Rh- is worth mentioning that in CPME the 7h/8h ratio
catalysis (RhCl(PPh ) ) for cyclotrimerization of 1b was slightly increased to 8/1 in comparison with other
3
3
with cyclopropylethyne 2h, 1-hexyne 2i, and 3-hexyne cases (Entry 8). The reaction proceeded well even in
2
p furnished products in very low if any yields: 4 (1/ chloroform (Entry 9). These results indicate that not
1), 7 (1/1) and 0%, respectively, along with the forma- only chlorinated solvents, but also ether-based sol-
tion of homocyclotrimerization products of 1b (9) vents could be optimal media to carry out Ru-cata-
and unreacted starting material.
lyzed cyclotrimerization.
Although the regioisomeric products 3/4 and 7/8
As for the regioselectivity of the Ru-catalyzed cy-
were generally inseparable by means of chromato- clotrimerization, the preferential formation of 1,3-re-
graphic methods, the recrystallization of the products gioisomer in the Ru-catalyzed reactions is in line with
7
f and 8 f obtained from the reaction of 1b with fer- the previously reported data and could be reasonably
rocenylethyne 2 f gave a mixture of differently shaped explained by steric factors during the insertion of an
[25]
yellow and red crystals that were separated manually. alkyne to the formed ruthenium intermediate. The
The subsequent X-ray structure analysis enabled us to better regioselectivity in case of products 3/4 in com-
unequivocally determine the structure of 7 f (yellow parison to products 7/8 can be attributed to the elec-
crystals) and 8 f (red crystals) (Figure 3). We were tron deficient nature of the terminal triple bond in
also able to obtain crystals of 7d suitable for X-ray the substrate 1b which observation is in a good
[25c]
analysis (see the SI).
accord with the results of Yamamoto.
Diyne 1b is
Since the above mentioned reactions catalyzed by also less prone to homocyclotrimerization than 1a for
the Ru-complex were carried out with a rather high the same reason.
Adv. Synth. Catal. 2016, 358, 254 – 267
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257

Eli sˇ ka Matou sˇ ovµ et al.
FULL PAPERS
Table 3. Cyclotrimerization of 1b with various alkynes 2 in
the presence of Ru-catalysts.
Figure 3. PLATON plot of 7 f (left, yellow crystals) and 8 f
(right, red crystals) showing the atom labeling and displace-
ment ellipsoids drawn on 50% probability level.
Table 4. Effect of Cp*Ru(cod)Cl loading and solvent on cy-
clotrimerization of 1b with 2h.
[
a]
Entry Catalyst
mol%)
Solvent
T
Yields
7h/
8h
[
b]
(
(8C) (%)
1
2
3
4
5
6
7
8
9
10
5
5
2
2
10
5
5
DCE
DCE
DCE
DCE
DCE
THF
THF
CPME
CDCl3
22
22
50
22
50
22
22
22
22
86
91
97
96
95
92
97
98
92
6.5/1
6/1
6/1
6.5/1
6/1
6.5/1
6/1
8/1
6.5/1
5
[
a]
DCE=CH ClCH Cl, CPME=cyclopentyl methyl ether.
1H NMR yields, internal standard: 1,4-dimethoxyben-
zene.
2
2
[
[
[
[
a]
b]
c]
d]
[b]
2
equiv of alkynes were used.
Isolated yields.
CH Cl was used as a solvent.
The reaction was run in CH Cl in the presence of
Grubbs 1 generation catalyst (10 mol%).
2
2
2
2
st
with a terminal alkyne have been published, several
reports regarding ligand effect on the course of cyclo-
On the other hand, the regioselectivity of the Rh- trimerization have been described. These involve: a)
catalyzed cyclotrimerization seems to be a more com- an effect of a ligand on regioselectvity of homocyclo-
[
28a,b]
[28c]
plex issue. Examples of the preferential formation of trimerization catalyzed by Co-,
Rh-
and Ir-
[
24c,26]
[27]
[28d]
1
,2-
It appears that in each case the corresponding regio- trimerization of diynes with akynes,
selectivity could be the result of a combination of selectivity of Rh-catalyzed reaction of diyne with a dis-
or 1,3- regioisomers have been reported. complexes,
b) on the course of Ir-catalyzed cyclo-
[28e,f,g]
c) on regio-
[28h]
electronic and steric factors, as well as structural fea- ubstituted alkyne,
d) on the rate of a Ni-phosphine
tures of the linker connecting both triple bonds. complex catalyzed homocyclotrimerization of 1,4-bu-
[
28i,j]
These effects by no doubts affect the course of com- tyndiol,
and e) a Rh-catalyzed cyclotrimerization
[28k]
petitive insertion of the alkyne into both RhÀC bonds of a symmetrical diyne with a disubstituted alkyne.
in the intermediate rhodacycle along with the orienta- A distantly related study deals with the effect of vari-
tion of the substituent on the alkyne with respect to ously substituted Cp’-Rh complexes on co-cyclotrime-
[29]
the rhodium atom.
rization of terminal alkynes with nitriles.
Since it
Although neither theoretical studies addressing has been shown that the ligand environment around
these issues nor any detailed studies regarding the central metal atom in a catalyst can crucially
[30]
a ligand effect on the regioselectivity of cyclotrimeri- affect reaction yields, rates, regioselectivities, etc.,
zation between an unsymmetrically substituted diyne we decided to explore whether the change of a ligand
2
58
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FULL PAPERS
[2+2+2]-Cyclotrimerization of 1-Cyclopropyl-1,6-diynes
could affect not only the yields of the Rh-catalyzed fact that both ligands have bite angles of similar
cyclotrimerization but also the regioselectivity. values (93 and 948, respectively) it is obvious that
Once again we decided to use cyclotrimerization of such a difference cannot be explained simply by the
1
b with cyclopropylethyne 2h as a model reaction. bite angle effect and obviously other factors must be
The complexes were prepared in situ by mixing of involved concomitantly. Besides, the bite angle in
Rh(cod) BF with appropriate phosphine and expos- a particular complex might take different values de-
2
4
ing the mixture to hydrogen prior to the addition of pending on an anion, on additional ligands, and also
[
31]
[32]
alkynes. The results summarized in Table 5 suggest on ligandꢁs coordination modes. Nonetheless, these
that the regioselectivity might be dependent on the results clearly indicate that the course of the reaction,
bite angle of a bidentate ligand. In general, the use of that is, regioselectivity and conversion, could be con-
ligands with small (65-938) or large bite angles (99- trolled by judicious selection of ligands. Last but not
1
088) provide the product in rather low yields and least, it should be mentioned that the activation of
mostly low regioselectivity (Entries 1-9 and 13-17, re- the catalytic systems by hydrogen had a positive
spectively). Interestingly in the case of Xanthphos effect on the reaction rates and yields (compare En-
a reversal of the regioselectivity in favor of 1,3-isomer tries 6 with 8, 7 with 9, and 10 with 11 and 12).
was observed (Entries 16 and 17). Gratifyingly, the
The above depicted results sparked our interest in
use of a ligand with a medium size bite angle (948), exploring a possibility to utilize Rh-complex catalyzed
such as dppb, led to a highly selective formation of cyclotrimerization for synthesis of 8m (1,2-regioiso-
1
,2-regioisomer 8h (7h/8h=1/12) and also the overall mer), a potential advanced intermediate for synthesis
yield of products was considerably increased up to of A and B (Figure 1). Running the reaction in the
2% (Entries 10-12). When dppf (998) and dppp (918) presence of Wilkinsonꢁs catalyst provided 1/1 mixture
6
were used (Entries 5 and 13), still good regioselectivi- of 7m and 8m in low yield of 14% (Scheme 1). How-
ties (7h/8h=1/3.5 and 1/3) and reasonable yields (55
and 41%) were obtained. Taking into the account
considerably different results obtained for the cata-
lysts possessing BINAP and dppb ligands, despite the
Table 5. Cyclotrimerization of 1b with various Rh catalysts
(5 mol%). Influence of a ligand on 7/8 ratio.
Scheme 1. Regioselective formation of 8m.
t (h) b [a]
Yields (%)
[b]
7h/8h
Entry Ligand
[
c]
ever, using the catalytic system based on a combina-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
Segphos
3
3
24
3
24
3
24
3
24
3
3
24
3
658
868
868
918
918
938
938
938
938
948
948
948
998
22
16
41
18
41
13
15
23
25
58
17
62
55
1/3
[
[
c]
c]
tion of Rh(cod) BF and dppb not only resulted in in-
dppe
dppe
dppp
dppp
1/1.3
1/1.4
1/3
2
4
creased yield of the desired product (58%) but also
in a significantly raised regioselectivity favouring 8m
(7m/8m=1/4.5). An attempt to carry out the same re-
action in CPME (cyclopentyl methyl ether) provided
[
c]
c]
[
1/3
[
d]
BINAP
BINAP
BINAP
BINAP
nd
1/1.8
1/1.3
1/1.3
1/12
1/11
1/11
1/3.5
1/1.4
1/1.5
1.5/1
1.5/1
1
only traces of the desired product (judged by H
[
[
c]
c]
MNR analysis of the reaction mixture). The low reac-
tivity could probably be attributed to a low solubility
of the catalytic system in CPME. The reaction was
also performed with unprotected propargyl alcohol
[
c]
0
1
2
3
4
5
6
7
dppb
dppb
dppb
[
c]
2
o and it proceeded to give the desired products 7o/
dppf
[
[
c]
c]
DPEPhos
DPEPhos
Xantphos
Xantphos
3
24
3
1048 16
1048 34
1088
8o in 72% isolated yield after 3 h reaction time; how-
ever in a low 1/1.5 regioisomer ratio.
[
c]
c]
5
This catalytic system was also tested for cyclotrime-
rization of 1b with the TBS-protected homopropargyl
alcohol 2n (Scheme 2), for compound 8n could be
a precursor of compound B (Figure 1). The reaction
proceeded as expected to give a mixture of 7n and
8n, albeit in a lower but synthetically still interesting
[
24
1088 13
[
[
[
[
a]
Bite angle. For values see ref. [30].
H NMR yields, internal standard: 1,4-dimethoxybenzene.
Catalyst was activated by H2.
b]
c]
d]
Regioisomer ratio was not determined.
Adv. Synth. Catal. 2016, 358, 254 – 267
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
259

Eli sˇ ka Matou sˇ ovµ et al.
FULL PAPERS
to 60% (24 h), but the obtained regioisomer ratios
were reduced ~1/1.3. In addition, the reaction cata-
lyzed by Rh(cod) BF and Segphos was carried out.
2
4
Although it provided 7n and 8n in 48% yield after
3
h, 7n/8n regioisomer ratio remained as low as 1/1.3.
The above mentioned experiments imply that the
ability to control regioselectivity of the cyclotrimeri-
zation of unsymmetrically substituted substrates, for
example, by changing the ligand, might offer an alter-
native pathway to important synthetic building blocks.
Finally, we decided to check cyclotrimerization of
diyne 1c possessing inverted positions of the cyclo-
propyl and ester groups with selected terminal al-
kynes 2 in the presence of Cp*Ru(cod)Cl and
Scheme 2. Regioselective formation of 8n.
1
1
/2.5 ratio and in a rather low yield of 19% ( H NMR Rh(cod) BF /dppb (Table 6). The catalysis by the Ru-
2 4
yield). Prolonging the reaction time to 24 h did not complex proceeded well, and, as expected, 1,3-iso-
have a substantial effect on the yield. mers 10 were obtained as major products. Regioiso-
Attempts to improve the selectivity as well as the mer ratios were in general high and the corresponding
yield by changing the ligand environment to dppp and 7-cyclopropyl-5-(substituted)isobenzofuran-1(3H)-
dppf were undertaken. The use of the former led to ones 10 and 7-cyclopropyl-6-(substituted)isobenzofur-
the improvement in yield to 64% (3 h) and the latter an-1(3H)-ones 11 were isolated in very good yields
Table 6. Cyclotrimerization of 1c with various alkynes 2 in the presence of Ru and Rh catalysts.
[
[
[
a]
b]
c]
2
equiv of alkynes were used.
Isolated yields unless otherwise mentioned.
In case of the Ru-catalyzed reactions 12a/12b ratio was 20:1, whereas for the Rh-catalyzed reaction 12a/12b=
1
:3–4.
Activated by hydrogen.
H NMR yields, internal standard: 1,4-dimethoxybenzene.
[
[
[
[
[
d]
e]
f]
1
Yield after 20 h at 508C in brackets.
Yield after 24 h in brackets.
At 508C.
g]
h]
2
60
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Adv. Synth. Catal. 2016, 358, 254 – 267

FULL PAPERS
[2+2+2]-Cyclotrimerization of 1-Cyclopropyl-1,6-diynes
Since the mechanism of the Rh-phosphine complex
catalyzed [2+2+2]-cycloaddition reaction of diynes
with monoynes was studied by density functional
theory (DFT) to support the structural proposal made
[33]
for the monoyne insertion intermediate,
we have
also attempted to determine the reaction pathway of
RhCl(PPh ) catalyzed cyclotrimerization by means of
3
3
DFT computations in order to shed light on the
course of the reaction. However, despite numerous at-
tempts we were unable to locate a properly defined
transition-state structure of the reaction intermediate.
Although geometry optimizations starting with the
alkyne moiety oriented differently in the initial geo-
metries could always reach chemically plausible geo-
Figure 4. PLATON plot of 10h showing the atom labeling
and displacement ellipsoids drawn on 50% probability level.
(
Entries 1-6). The 10/11 ratios were in all instances metries, none of these final geometries had a single
higher than those obtained in the reactions with 1b imaginary vibration in their IR spectra, thus neither
under the same reaction conditions (see Table 3). This of these geometries could be classified as the transi-
observation further supports the above mentioned tion-state structure of the reaction. We thus conclude,
[
25c]
theory
that the more electron deficient the RhÀC that our theoretical model for describing the reaction
bond means slower addition of the terminal alkyne mechanism of the insertion step was incomplete and
into it. The subsequent X-ray structure analysis of the true reaction pathway proceeds apparently in
5
,7-dicyclopropylisobenzofuran-1(3H)-one 10h ena- a more complicated way than by a mere cleavage of
bled us to unequivocally confirm its structure one of the RhÀC bonds in the rhodacyclopentadiene
Figure 4). cycle followed by alkyne insertion. In addition, more
The cyclotrimerization reactions of 1c catalyzed by complex structures of our substrates (an unsymmetri-
(
the Rh-catalyst proceeded also as expected, giving cally substituted diyne, additional functionalities in
rise preferentially to 1,2-isomers 11 (Entries 7-12). the linker connecting the triple bond, and hence dif-
The obtained regioisomer ratios were rather low, as ferent electron densities on the triple bonds) could
well as the yields. Some important observations were contribute to overall failure of the theoretical calcula-
made from these results, though. Firstly, again, as in tions. Probably, more sophisticated theoretical models
the case of the reaction of 1a with Wilkinsonꢁs cata- will have to be employed in order to get reliable in-
lyst, the reaction was slowest with electron-deficient formation; however, such an endeavor is beyond the
(
4-methoxycarbonylphenyl)ethyne 2d. Also, diyne 1c scope of this study.
was more prone to homocyclotrimerization than 1b
due to the more electron-rich terminal alkyne. And,
lastly, in the cyclotrimerization with ferrocenylethyne Conclusions
2
f the 1,3-regioisomer 11 f was formed as the major
product. The same reversal of regioselectivity was A synthetic pathway to 1,2- and 1,3-substituted cyclo-
again observed for diyne 1a and Wilkinsonꢁs catalyst propylated benzene derivatives based on cyclotrimeri-
(
see Table 1, Entry 6).
zation catalyzed by Ru- and Rh-complexes was ex-
The reaction with cyclopropylethyne 2h provided plored. The cyclotrimerization catalyzed by Cp*Ru-
the corresponding mixture of 10h and 11h in reasona- (cod)Cl usually proceeded with good yields of the cor-
ble yields of 31 and 39% after 3 and 24 h, respectively responding products. The preferential formation of
(
Entry 11). In this instance the best selectivity was ob- 1,3-regioisomers with good regioselectivity ratios
tained, in favor of 1,2-regioisomer 11h (10h/11h=1/ ranging from 2.5 to 28/1, depending on the structural
). An attempt to carry out the reaction of 1c with cy- features of both substrates, was observed in all cases.
clopropylethyne 2h in CPME was undertaken as well, The reaction pattern is in agreement with the previ-
5
[25]
but the reaction did not proceed and the starting ously outlined hypothesis. On the other hand, the
diyne remained unreacted (as judged by H NMR of use of Rh-catalysts proceeded with the preferential
1
the reaction mixture). As in the previous case formation of 1,2-regioisomers. Unlike the Ru-cata-
(
Scheme 1, conditions C), a low solubility of the cata- lyzed reactions the yields were generally lower as well
lytic system could be accounted for that. Finally, the as the observed regioisomeric ratios. In general, the
reaction with 1-hexyne 2i was tried. It did not pro- catalytic activity of the Wilkinsonꢁs catalyst
ceed at 228C and had to be executed at 508C to (RhCl(PPh ) ) was low for all the starting diynes used
3
3
obtain the desired products 10i and 11i in 35% yield in this study and highly depended on the structure of
in 1/1.5 ratio after 24 h (Entry 12).
both substrates. To establish whether the ratio as well
as the yields could be improved by varying the ligand
Adv. Synth. Catal. 2016, 358, 254 – 267
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asc.wiley-vch.de
261

Eli sˇ ka Matou sˇ ovµ et al.
FULL PAPERS
environment around the central rhodium atom, the
Rh-catalyzed reaction of 1b with cyclopropylethyne
4-Cyclopropyl-6-(4-methoxyphenyl)isobenzofuran-1(3H)-
one (7b) and 4-cyclopropyl-5-(4-methoxyphenyl)isobenzo-
furan-1(3H)-one (8b). A yellowish crystalline solid, m.p.=
2
h was studied in the presence of various ligands.
1
21–1228C (recrystallized from DCM/hexanes). 7b:
This study clearly showed that both the ratio and the
yields can be positively affected by judicious choice of
the ligand (dppb): the 7h/8h ratio was increased from
1
H NMR (600 MHz, CDCl ) d 7.87 (d, J=1.3 Hz, 1H), 7.52–
3
7.49 (m, 2H), 7.38 (d, J=1.1 Hz, 1H), 7.01–6.98 (m, 2H),
5
1
.41 (s, 2H), 3.86 (s, 3H), 1.85 (tt, J=8.4, 5.2 Hz, 1H), 1.10–
.06 (m, 2H), 0.85–0.82 (m, 2H); C NMR (150 MHz,
1/1 to 1/12 and the isolated yield to 62%. Thus, the
13
catalytic system composed of Rh(cod) BF /dppb was
2
4
CDCl ) d 171.5, 159.7, 144.1, 142.7, 138.5, 130.4, 128.5, 128.3,
3
1
then applied for the selective preparation of 8m -
1
26.0, 120.7, 114.4, 69.1, 55.4, 12.0, 7.8. 8b: H NMR
a potential intermediate for the synthesis of A. Un- (600 MHz, CDCl ) d 7.78 (d, J=7.8 Hz, 1H), 7.43 (d, J=
3
fortunately, the use of this catalyst with other sub- 7.8 Hz, 1H), 7.37–7.34 (m, 2H), 7.00–6.96 (m, 2H), 5.41 (s,
strates was not as successful as expected indicating 2H), 3.88 (s, 3H), 1.93 (tt, J=8.7, 6.0 Hz, 1H), 0.80–0.76 (m,
1
3
that this catalytic system is not generally applicable 2H), 0.28–0.24 (m, 2H); C NMR (150 MHz, CDCl
) d
3
1
1
3
1
71.4, 159.2, 148.5, 148.3, 134.2, 132.6, 132.2, 131.6, 124.0,
23.4, 113.5, 69.3, 55.3, 11.7, 7.6. 7b+8b: IR (KBr) nmax
078, 3001, 2953, 2932, 2836, 1757, 1607, 1521, 1488, 1251,
183, 1069, 1039, 1018, 949, 830, 776 cm ; MS (EI) m/z 280
M , 100%), 281 (20), 251 (42), 223 (9), 178 (11), 165 (19),
52 (10), 115 (9), 44 (23); HRMS (ESI) m/z (M+H·) calcd
for C H O 281.1172, found 281.1173. R (8:2 hexanes/
EtOAc)=0.35.
-Cyclopropyl-6-[4-(trifluoromethyl)phenyl]isobenzofur-
and probably for each pair of reactants, that is,
a diyne and an alkyne, a screening of different reac-
tion conditions would have to be performed. None-
theless, the obtained results indicate that regioselec-
tivity as well as the reaction yield in [2+2+2]-cyclotri-
merization can be controlled by changing of the
ligand environment around a central metal atom of
the catalytically active species.
À1
+
·
(
1
+
1
8
17
3
f
4
an-1(3H)-one (7c) and 4-cyclopropyl-5-[4-(trifluoromethyl)-
phenyl]isobenzofuran-1(3H)-one (8c). A brownish crystal-
Experimental Section
line solid, m.p.=180–1818C (recrystallized from DCM/hex-
1
anes). 7c: H NMR (600 MHz, CDCl ) d 7.91 (d, J=1.1 Hz,
3
1
H), 7.71 (d, J=8.2 Hz, 2H), 7.67 (d, J=8.2 Hz, 2H), 7.42
For further experimental details, compound characteriza-
tion, X-ray data, and copies of H and C NMR data see
the supporting information section.
[
34]
1
13
(d, J=1.2 Hz, 1H), 5.43 (s, 2H), 1.89 (tt, J=8.4, 5.2 Hz,
1
3
1
H), 1.14–1.10 (m, 2H), 0.87–0.83 (m, 2H); C NMR
(
(
150 MHz, CDCl ) d 171.1, 145.6, 143.3, 141.6, 139.2, 130.1
q, J=32.6 Hz), 128.9, 127.6, 126.3, 125.9 (q, J=3.5 Hz),
3
Cyclotrimerization of 1b catalyzed by Cp*Ru(cod)Cl.
1
1
21.4, 69.1, 12.0, 7.9 (CF group is overlapped). 8c: H NMR
3
(
600 MHz, CDCl ) d 7.82 (d, J=7.9 Hz, 1H), 7.71 (d, J=
.1 Hz, 2H), 7.55 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz,
3
A solution of diyne 1b (37 mg, 0.25 mmol) in dry DCE
8
1
2
1
3
(
4 mL) maintained under an atmosphere of argon was treat-
ed with an alkyne 2 (0.5 mmol) and Cp*Ru(cod)Cl (9.7 mg,
.025 mmol). The reaction mixture was stirred at 228C for
H), 5.43 (s, 2H), 1.94 (tt, J=8.4, 5.8 Hz, 1H), 0.80–0.76 (m,
1
3
H), 0.27–0.23 (m, 2H); C NMR (150 MHz, CDCl ) d
0
3
71.0, 148.2, 147.2, 144.0, 131.4, 134.6, 129.5, 129.8 (q, J=
2.6 Hz), 123.7, 125.1 (q, J=3.5 Hz), 123.2, 69.3, 11.6, 7.5
the time specified in Table 3. Then it was concentrated
under reduced pressure and column chromatography of the
(CF group overlapped). 7c+8c: IR (KBr) n
3084, 3013,
residue on silica gel (hexanes/Et O) provided the corre-
3
max
2
2
1
1
2
926, 2851, 1775, 1757, 1613, 1485, 1329, 1177, 1117, 1072,
sponding 4-cyclopropyl-3-hydroisobenzofuran-1-ones 7 and
À1
+
036, 1018, 845, 776 cm ; MS (CI) m/z 319 [(M+H·) ,
8.
+
·
00%], 320 (18), 318 (M , 77), 299 (34), 289 (33), 275 (8),
4-Cyclopropyl-6-phenylisobenzofuran-1(3H)-one (7a) and
+
46 (5), 191 (4), 165 (2), 115 (1); HRMS (CI) m/z (M+H·)
4
-cyclopropyl-5-phenylisobenzofuran-1(3H)-one (8a).
A
calcd for C H O F 319.0946, found 319.0948. R (8:2 hex-
anes/EtOAc)=0.36.
colorless crystalline solid,1 m.p.=115.48C (recrystallized
18 14
2
3
f
from DCM/hexanes). 7a: H NMR (600 MHz, CDCl ) d
3
Methyl 4-(7-cyclopropyl-3-oxo-1,3-dihydroisobenzofuran-
-yl)benzoate (7d) and methyl 4-(4-cyclopropyl-1-oxo-1,3-di-
7
7
1
.91–7.90 (m, 1H), 7.58–7.55 (m, 2H), 7.48–7.43 (m, 3H),
5
.42–7.41 (m, 1H), 5.41 (s, 2H), 1.87 (tt, J=8.5, 5.2 Hz, 1H),
13
hydroisobenzofuran-5-yl)benzoate (8d). A yellow crystalline
solid, m.p.=147.38C (recrystallized from DCM/hexanes).
7d: H NMR (600 MHz, CDCl
(d, J=1.4 Hz, 1H), 7.64–7.62 (m, 2H), 7.44 (d, J=1.3 Hz,
.11–1.07 (m, 2H), 0.86–0.83 (m, 2H); C NMR (150 MHz,
CDCl ) d 171.4, 144.7, 143.1, 139.8, 138.7, 129.0, 128.9, 128.0,
3
1
1
1
27.2, 126.0, 121.2, 69.0, 12.0, 7.8. 8a: H NMR (600 MHz,
) d 8.13–8.11 (m, 2H), 7.93
3
CDCl ) d 7.79 (d, J=7.8 Hz, 1H), 7.46–7.44 (m, 1H, over-
3
lapped), 7.42–7.37 (m, 5H), 5.42 (s, 2H), 1.94 (tt, J=8.5,
1H), 5.43 (s, 2H), 3.95 (s, 3H), 1.88 (tt, J=8.4, 5.2 Hz, 1H),
1
3
5
.7 Hz, 1H), 0.77–0.73 (m, 2H), 0.27–0.24 (m, 2H);
1.12–1.09 (m, 2H), 0.87–0.84 (m, 2H); C NMR (150 MHz,
CDCl ) d 171.2, 166.7, 145.5, 144.1, 142.0, 139.0, 130.3, 129.7,
128.9, 127.2, 126.3, 121.5, 69.1, 52.2, 12.0, 7.9. 8d: H NMR
(600 MHz, CDCl ) d 8.13–8.10 (m, 2H), 7.82 (d, J=7.9 Hz,
1H), 7.51–7.48 (m, 2H), 7.44 (d, J=8.0 Hz, 1H), 5.43 (s,
2H), 3.96 (s, 3H), 1.94 (tt, J=8.6, 5.8 Hz, 1H), 0.77–0.74 (m,
2H), 0.25–0.22 (m, 2H); C NMR (150 MHz, CDCl ) d
171.1, 166.8, 148.3, 147.7, 145.0, 134.5, 131.4, 129.4, 129.2,
125.1, 123.6, 69.3, 52.2, 11.6, 7.5 (one signal is overlapped).
1
3
C NMR (150 MHz, CDCl ) d 171.3, 148.8, 148.1, 140.3,
3
3
1
1
7
1
31.6, 134.4, 129.1, 128.1, 127.6, 124.4, 123.4, 69.3, 11.7, 7.4.
a+8a: IR (KBr) nmax 3078, 3052, 3004, 1760, 1595, 1479,
3
À1
452, 1344, 1230, 1066, 1054, 1027, 1009, 946, 764 cm ; MS
+
+·
(
(
CI) m/z 251 [(M+H·) , 100%], 252 (18), 250 (M , 69), 221
26), 207 (8), 178 (11), 165 (6), 152 (4), 115 (3); HRMS (CI)
1
3
3
+
m/z (M+H·) calcd for C H O 251.1072, found 251.1074.
17
15
2
R (8:2 hexanes/EtOAc)=0.45.
f
2
62
asc.wiley-vch.de
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2016, 358, 254 – 267

FULL PAPERS
[2+2+2]-Cyclotrimerization of 1-Cyclopropyl-1,6-diynes
7
1
7
2
d+8d: IR (KBr) nmax 3066, 3013, 2956, 1757, 1718, 1601,
1446, 1350, 1293, 1251, 1108, 1072, 1018, 952, 890, 839,
À1
+·
434, 1353, 1278, 1227, 1180, 1105, 1066, 1015, 952, 863,
758 cm ; MS (EI) m/z 246 (M , 20), 247 (3), 231 (100), 157
(8), 128 (13), 115 (8), 73 (14), 49(19); HRMS (ESI) m/z
À1
+·
67 cm ; MS (EI) m/z 308 (M , 100), 309 (21), 279 (90),
+
65 (20), 205 (12), 191 (24), 178 (12), 165 (23), 152 (9), 115
(M+Na) calcd for C H O SiNa 269.0968, found 269.0970.
1
4
18
2
+
(7), 59 (11), 44 (14); HRMS (ESI) m/z (M+Na) calcd for
R (8:2 hexanes/EtOAc)=0.54.
f
C H O Na 331.0941, found 331.0942. R (8:2 hexanes/
EtOAc)=0.26.
4,6-Dicyclopropylisobenzofuran-1(3H)-one (7h) and 4,5-
1
9
16
4
f
dicyclopropylisobenzofuran-1(3H)-one (8h). A yellowish
1
4-(7-Cyclopropyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-
oil. 7h: H NMR (600 MHz, CDCl ) d 7.32 (d, J=1.5 Hz,
3
benzonitrile (7e) and 4-(4-cyclopropyl-1-oxo-1,3-dihydroiso-
benzofuran-5-yl)benzonitrile (8e). A brownish crystalline
1H), 6.98 (d, J=1.4 Hz, 1H), 5.31 (s, 2H), 1.93 (tt, J=8.4,
5
0
.0 Hz, 1H), 1.77 (tt, J=8.4, 5.2 Hz, 1H), 1.03–0.99 (m, 4H),
1
3
solid, m.p.=213.88C (recrystallized from DCM/hexanes,
.77–0.74 (m, 2H), 0.72–0.69 (m, 2H), C NMR (150 MHz,
1
then from MeOH). 7e: H NMR (600 MHz, CDCl ) d 7.91
3
CDCl ) d 171.6, 146.2, 143.1, 137.8, 128.4, 124.7, 118.7, 69.0,
3
1
(d, J=1.5 Hz, 1H), 7.77–7.75 (m, 2H), 7.68–7.66 (m, 2H),
1
(
2
5.3, 11.8, 9.6, 7.6. 8h: H NMR (600 MHz, CDCl ) d 7.65
3
7
1
.40 (d, J=1.5 Hz, 1H), 5.44 (s, 2H), 1.89 (tt, J=8.4, 5.2 Hz,
H), 1.14–1.10 (m, 2H), 0.87–0.84 (m, 2H); C NMR
d, J=8.0 Hz, 1H), 6.94 (d, J=8.0 Hz, 1H), 5.35 (s, 2H),
.46 (tt, J=8.5, 5.3 Hz, 1H), 1.98–1.95 (m, 1H), 1.13–1.10
(m, 2H), 1.07–1.04 (m, 2H), 0.79–0.76 (m, 2H), 0.69–0.66
13
(
150 MHz, CDCl ) d 170.9, 146.0, 144.2, 141.1, 139.4, 132.8,
3
1
28.8, 127.9, 126.5, 121.5, 118.6, 111.8, 69.1, 12.0, 8.0. 8e:
13
(
m, 2H), C NMR (150 MHz, CDCl ) d 171.4, 151.2, 146.8,
3
1
H NMR (300 MHz, CDCl ) d 7.81 (d, J=7.8 Hz, 1H), 7.77–
3
135.3, 125.5, 123.7, 122.7, 69.2, 13.4, 10.8, 9.7, 6.3. 7h+8h:
7.73 (m, 2H), 7.57–7.53 (m, 2H), 7.41 (d, J=7.8 Hz, 2H),
IR (KBr) nmax 3081, 3010, 2947, 2869, 1763, 1500, 1464, 1356,
5
0
.42 (s, 2H), 2.00–1.89 (m, 1H), 0.82–0.74 (m, 2H), 0.26–
.19 (m, 2H). C NMR signals intensity was too low to be
À1
1
284, 1096, 1012, 958, 937, 773 cm ; MS (CI) m/z 215 [(M+
13
+
+·
H·) , 100%], 216 (15), 214 (M , 36), 185 (23), 171 (5), 155
assigned. 7e+8e: IR (KBr) nmax 3090, 3007, 2953, 2929,
+
(
4), 129 (6), 115 (7); HRMS (CI) m/z (M+H·) calcd for
2
217, 1766, 1607, 1488, 1443, 1362, 1180, 1066, 1009, 949,
C H O 215.1072, found 215.1070. Rf (8:2 hexanes/
À1
+·
14 15
2
842, 770 cm ; MS (EI) m/z 275 (M , 74), 276 (16), 246
EtOAc)=0.41.
-Butyl-4-cyclopropylisobenzofuran-1(3H)-one (7i) and 5-
(
(
100), 232 (25), 217 (12), 203 (35), 190 (29), 177 (13), 165
6
6), 151 (7), 140 (12), 115 (15), 63 (7), 44 (21); HRMS (ESI)
butyl-4-cyclopropylisobenzofuran-1(3H)-one (8i). A brown-
+
m/z (M+Na) calcd for C H O NNa 298.0839, found
1
18
13
2
ish oil. 7i: H NMR (600 MHz, CDCl ) d 7.50 (d, J=0.8 Hz,
3
2
98.0840. R (8:2 hexanes/EtOAc)=0.36.
f
1
2
(
3
1
2
H), 7.00 (d, J=0.8 Hz, 1H), 5.32 (s, 2H), 2.66–2.63 (m,
H), 1.77 (tt, J=8.4, 5.2 Hz, 1H), 1.60–1.54 (m, 2H), 1.32
4
-Cyclopropyl-6-ferrocenylisobenzofuran-1(3H)-one (7 f)
and 4-cyclopropyl-5-ferrocenylisobenzofuran-1(3H)-one
8 f). 7 f: A yellow crystalline solid, m.p.=151.18C (recrys-
sext, J=7.4 Hz, 2H), 1.03–1.00 (m, 2H), 0.90 (t, J=7.4 Hz,
(
1
3
H), 0.76–0.73 (m, 2H); C NMR (150 MHz, CDCl ) d
1
3
tallized from DCM/hexanes). H NMR (600 MHz, CDCl ) d
3
71.6, 144.7, 143.4, 137.9, 130.2, 125.4, 122.1, 69.0, 35.3, 33.5,
7
2
1
.80 (d, J=1.2 Hz, 1H), 7.29 (d, J=1.1 Hz, 1H), 5.34 (s,
H), 4.67–4.65 (m, 2H), 4.36–4.34 (m, 2H), 4.03 (s, 5H),
.82 (tt, J=8.4, 5.2 Hz, 1H), 1.09–1.05 (m, 2H), 0.82–0.79
1
2.1, 13.8, 11.8, 7.6. 8i: H NMR (600 MHz, CDCl ) d 7.67
3
(
d, J=7.8 Hz, 1H), 7.32 (d, J=7.8 Hz, 1H), 5.34 (s, 2H),
2.93–2.90 (m, 2H), 1.87–1.81 (m, 1H), 1.63–1.60 (m, 2H),
13
(m, 2H); C NMR (150 MHz, CDCl ) d 171.7, 143.4, 141.8,
3
1
7
.41 (sext, J=7.4 Hz, 2H), 1.04–1.01 (m, 2H), 0.95 (t, J=
138.0, 127.7, 125.8, 119.8, 84.2, 70.1, 69.8, 69.2, 67.0, 11.9, 7.8.
1
3
.4 Hz, 3H), 0.62–0.59 (m, 2H); C NMR (150 MHz,
) d 171.4, 150.6, 147.1, 134.4, 130.5, 123.5, 123.2, 69.3,
2.9, 32.8, 22.8, 13.9, 10.8, 6.1. 7i+8i: IR (KBr) nmax 3004,
956, 2926, 2872, 2857, 1772, 1497, 1461, 1320, 1281, 1147,
8
f: A red crystalline solid, m.p.=179.48C (recrystallized
1
CDCl
3
from DCM/hexanes). H NMR (600 MHz, CDCl ) d 7.92 (d,
3
3
2
J=8.0 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 5.35 (s, 2H), 4.63–
4
1
.62 (m, 2H), 4.38–4.37 (m, 2H), 4.10 (s, 5H), 1.89–1.83 (m,
H), 0.87–0.83 (m, 2H), 0.26–0.22 (m, 2H); C NMR
À1
+
13
1063, 1015, 955, 770 cm ; MS (CI) m/z 231 [(M+H·) ,
+
·
1
1
00%], 232 (17), 230 (M , 45), 202 (18), 188 (11), 159 (5),
(
150 MHz, CDCl ) d 171.5, 148.5, 146.9, 134.2, 132.4, 122.9,
3
+
29 (6), 115 (5); HRMS (CI) m/z (M+H·) calcd for
122.6, 85.2, 71.03, 70.1, 69.3, 68.8, 11.9, 8.1. 7 f+8 f: IR
C H O 231.1385, found 231.1386. Rf (8:2 hexanes/
(
1
KBr) nmax 3093, 3004, 2923, 1757, 1515, 1449, 1347, 1308,
15 19
2
À1
EtOAc)=0.51.
224, 1066, 1012, 952, 842, 779, 486 cm ; MS (EI) m/z 358
+·
Methyl 7-cyclopropyl-3-oxo-1,3-dihydroisobenzofuran-5-
carboxylate (7j) and methyl 4-cyclopropyl-1-oxo-1,3-dihy-
(
(
3
M , 100), 359 (25), 191 (9), 178 (6), 165 (10), 121 (18), 56
4); HRMS (ESI) m/z (M+Na) calcd for C H O FeNa
+
21
18
2
droisobenzofuran-5-carboxylate (8j). A colorless amorphous
81.0548, found 381.0547. R (8:2 hexanes/EtOAc)=0.38.
f
1
solid. 7j: H NMR (600 MHz, CDCl ) d 8.36 (d, J=1.1 Hz,
4-Cyclopropyl-6-(trimethylsilyl)isobenzofuran-1(3H)-one
3
1
H), 7.87–7.86 (m, 1H), 5.43 (s, 2H), 3.95 (s, 3H), 1.82 (tt,
J=8.4, 5.1 Hz, 1H), 1.13–1.09 (m, 2H), 0.88–0,84 (m, 2H);
(
1
7 g) and 4-cyclopropyl-5-(trimethylsilyl)isobenzofuran-
(3H)-one (8 g). A colorless amorphous solid. 7g: H NMR
1
1
3
C NMR (150 MHz, CDCl ) d 170.4, 165.9, 149.9, 139.1,
(
600 MHz, CDCl ) d 7.88–7.87 (m, 1H), 7.35–7.34 (m, 1H),
3
3
1
5
0
.36 (s, 2H), 1.82 (tt, J=8.5, 5.2 Hz, 1H), 1.06–1.02 (m, 2H),
.80–0.77 (m, 2H), 0.28 (s, 9H); C NMR (150 MHz,
132.1, 130.4, 125.9, 124.3, 69.1, 52.5, 11.8, 8.3. 8j: H NMR
13
(600 MHz, CDCl ) d 7.80 (d, J=7.9 Hz, 1H), 7.76 (d, J=
3
CDCl ) d 171.8, 146.6, 142.6, 137.2, 134.5, 127.8, 124.7, 69.1,
7.9 Hz, 1H), 5.41 (s, 2H), 3.97 (s, 3H), 2.16 (tt, J=8.6,
5.8 Hz, 1H), 1.03–1.00 (m, 2H), 0.55–0.52 (m, 2H).
C NMR intensity of signals was too low to be assigned.
3
1
1
1.9, 7.4, À1.2. 8g: H NMR (600 MHz, CDCl ) d 7.72 (d,
3
1
3
J=7.6 Hz, 1H), 7.68 (d, J=7.6 Hz, 1H), 5.37 (s, 2H), 2.08
(
tt, J=8.6, 5.8 Hz, 1H), 1.04–1.01 (m, 2H), 0.76–0.73 (m,
7j+8j: IR (KBr) nmax 3084, 3007, 2950, 2851, 1763, 1727,
13
2
1
7
H), 0.41 (s, 9H); C NMR (150 MHz, CDCl ) d 171.4,
1625, 1592, 1437, 1302, 1251, 1224, 1192, 1066, 1015, 949,
3
À1
+·
48.9, 145.1, 142.8, 135.7, 126.4, 122.4, 69.8, 15.1, 7.5, 0.6.
g+8g: IR (KBr) nmax 3072, 3025, 3004, 2947, 2893, 1763,
761 cm ; MS (EI) m/z 232 (M , 27), 233 (4), 201 (100), 189
(20), 173 (14), 145 (11), 128 (25), 115 (62), 83 (27), 77 (39),
Adv. Synth. Catal. 2016, 358, 254 – 267
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263

Eli sˇ ka Matou sˇ ovµ et al.
FULL PAPERS
+
+
4
2
4 (14); HRMS (CI) m/z (M+H·) calcd for C H O
4
(EI) m/z 303 [(M-Me·) , 2%], 261 (100), 231 (73), 187 (18),
1
3
13
33.0814, found 233.0815. R (8:2 hexanes/EtOAc)=0.23.
N-[(7-Cyclopropyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-
methyl]acetamide (7k) and N-[(4-cyclopropyl-1-oxo-1,3-di-
hydroisobenzofuran-5-yl)methyl]acetamide (8k). A colorless
159 (13), 143 (12), 128 (17), 115 (18), 91 (8), 75 (57), 57 (19),
f
+
41 (14); HRMS (ESI) m/z (M+Na)
SiNa 341.1543, found 341.1544. R
EtOAc)=0.49.
calcd for
C
H O
26
(8:2 hexanes/
18
3
f
crystalline solid, m.p.=120.38C (recrystallized from DCM/
6-{2-[(tert-Butyldimethylsilyl)oxy]ethyl}-4-cyclopropyliso-
benzofuran-1(3H)-one (7n) and 5-{2-[(tert-butyldimethylsi-
1
hexanes). 7k: H NMR (600 MHz, CDCl ) d 7.53 (s, 1H),
3
7
2
2
1
4
.12 (s, 1H), 6.58 (bs, 1H), 5.29 (s, 2H), 4.43 (d, J=6.0 Hz,
lyl)oxy]ethyl}-4-cyclopropylisobenzofuran-1(3H)-one (8n).
1
H), 2.02 (s, 3H), 1.75 (tt, J=8.4, 5.2 Hz, 1H), 1.04–1.00 (m,
A yellowish oil. 7n: H NMR (600 MHz, CDCl
) d 7.55 (s,
3
13
H), 0.76–0.73 (m, 2H); C NMR (150 MHz, CDCl ) d
1H), 7.08 (s, 1H), 5.35 (s, 2H), 3.80 (t, J=6.6 Hz, 2H), 2.86
(t, J=6.6 Hz, 2H), 1.78 (tt, J=8.4, 5.2 Hz, 1H), 1.04–1.00
(m, 2H), 0.85 (s, 9H), 0.78–0.75 (m, 2H), À0.04 (s, 6H);
3
71.4, 170.3, 144.9, 140.7, 138.7, 129.4, 125.5, 121.2, 69.1,
1
2.9, 23.1, 11.8, 7.9. 8k: H NMR (600 MHz, CDCl ) d 7.61
3
1
3
(
6
d, J=7.8 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 5.31 (s, 2H),
.40 (bs, 1H), 4.71 (d, J=5.8 Hz, 2H), 2.06 (s, 3H), 1.88 (d,
J=6.0 Hz, 1H), 1.86 (tt, J=8.4, 6.0 Hz, 1H), 1.07–1.04 (m,
C NMR (150 MHz, CDCl ) d 171.6, 143.9, 141.4, 137.8,
3
1
8
7
2
1
6
1
31.2, 125.4, 123.0, 69.0, 64.0, 39.2, 25.8, 18.2, 11.8, 7.6, À5.5.
1
n: H NMR (600 MHz, CDCl ) d 7.70 (d, J=7.8 Hz, 1H),
3
13
.38 (d, J=7.8 Hz, 1H), 5.36 (s, 2H), 3.87 (t, J=6.8 Hz,
H), 3.19 (t, J=6.8 Hz, 2H), 1.88 (tt, J=8.4, 5.9 Hz, 1H),
.07–1.04 (m, 2H), 0.84 (s, 9H), 0.66–0.63 (m, 2H), À0.03 (s,
2
1
4
2
1
2
H), 0.64–0.61 (m, 2H); C NMR (150 MHz, CDCl ) d
3
71.2, 170.3, 146.9, 145.5, 134.6, 128.8, 124.5, 123.8, 69.4,
1.0, 29.6, 10.5, 6.1. 7k+8k: IR (KBr) nmax 3300, 3084, 3001,
938, 1754, 1640, 1562, 1497, 1452, 1317, 1287, 1153, 1072,
1
3
H); C NMR (150 MHz, CDCl ) d 171.5, 147.0, 147.0,
3
À1
+·
35.3, 131.4, 123.8, 123.5, 69.4, 63.4, 36.4, 25.8, 18.3, 10.9, 6.3,
030, 1012, 776 cm ; MS (EI) m/z 245 (M , 89), 246 (16),
À5.5. 7n+8n: IR (KBr) n
2953, 2929, 2881, 2854, 1769,
1473, 1461, 1359, 1254, 1144, 1099, 1066, 1018, 836, 776 cm ;
03 (63), 188 (82), 158 (22), 144 (24), 128 (26), 115 (35), 91
max
À1
+
(23), 84 (16), 49 (31), 43 (100); HRMS (ESI) m/z (M+Na)
+
MS (EI) m/z 317 [(M-Me·) , 2%], 275 (100), 245 (69), 201
calcd for C H O NNa 268.0944, found 268.0945. R (3:7
14
15
3
f
(
(
7), 171 (11), 128 (8), 115 (5), 75 (23), 57 (7), 41 (5); HRMS
hexanes/EtOAc)=0.20.
-Cyclopropyl-6-ethoxyisobenzofuran-1(3H)-one (7l) and
-cyclopropyl-5-ethoxyisobenzofuran-1(3H)-one (8l). A col-
+
ESI) m/z (M+Na) calcd for C H O SiNa 355.1700,
4
19 28
3
found 355.1701. R (8:2 hexanes/EtOAc)=0.55.
4
f
4-Cyclopropyl-6-(hydroxymethyl)isobenzofuran-1(3H)-
orless crystalline solid, m.p.=85.08C (recrystallized from
1
one (7o) and 4-Cyclopropyl-5-(hydroxymethyl)isobenzofur-
DCM/hexanes). 7l: H NMR (600 MHz, CDCl ) d 7.11 (d,
3
an-1(3H)-one (8o). A white crystalline solid, m.p.=75.68C
J=2.1 Hz, 1H), 6.74 (d, J=2.0 Hz, 1H), 5.30 (s, 2H), 4.03
1
(recrystallized
from
DCM/hexanes).
7o:
H NMR
(q, J=7.0 Hz, 2H), 1.74 (tt, J=8.4, 5.1 Hz, 1H), 1.41 (t, J=
(
600 MHz, CDCl ) d 7.62 (s, 1H), 7.21 (s, 1H), 5.32 (s, 2H),
3
7
.0 Hz, 3H), 1.03–0.99 (m, 2H), 0.76–0.73 (m, 2H);
13
4.72 (s, 2H), 2.68 (bs, 1H), 1.77 (tt, J=8.4, 5.1 Hz, 1H),
C NMR (150 MHz, CDCl ) d 171.6, 160.4, 139.7, 138.4,
3
13
1
1.05–1.01 (m, 2H), 0.79–0.76 (m, 2H); C NMR (150 MHz,
126.4, 118.8, 105.0, 69.0, 63.9, 14.6, 11.8, 8.0. 8l: H NMR
CDCl ) d 171.6, 145.1, 143.1, 138.5, 128.3, 125.3, 120.6, 69.2,
3
(
600 MHz, CDCl ) d 7.71 (d, J=8.4 Hz, 1H), 6.96 (d, J=
3
1
6
4.3, 11.8, 7.9. 8o: H NMR (600 MHz, CDCl ) d 7.70 (d, J=
3
8.4 Hz, 1H), 5.29 (s, 2H), 4.13 (q, J=7.0 Hz, 2H), 1.73 (tt,
7.9 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H), 5.33 (s, 2H), 4.99 (s,
J=5.6 Hz, 1H), 1.47 (t, J=7.0 Hz, 3H), 0.95–0.91 (m, 2H),
1
3
2H), 2.68 (bs, 1H), 1.84 (tt, J=8.5, 5.8 Hz, 1H), 1.06–1.01
0
1
5
1
1
2
1
.80–0.77 (m, 2H); C NMR (150 MHz, CDCl ) d 171.3,
3
13
(
m, 2H), 0.63–0.59 (m, 2H); C NMR (150 MHz, CDCl ) d
3
62.7, 147.7, 125.0, 124.7, 117.4, 112.6, 68.7, 64.5, 14.7, 8.1,
.6. 7l+8l: IR (KBr) nmax 3081, 3016, 2983, 2932, 1763,
745, 1625, 1500, 1458, 1377, 1335, 1290, 1239, 1165, 1084,
069, 1042, 949, 863, 773 cm ; MS (EI) m/z 218 (M , 90),
19 (14), 189 (100), 175 (20), 161 (97), 147 (30), 133 (28),
1
5
71.4, 148.1, 146.5, 133.6, 128.0, 124.4, 123.8, 69.4, 62.2, 10.2,
.8. 7o+8o: IR (KBr) nmax 3461, 3007, 2914, 1745, 1452,
À1
À1
+·
1428, 1374, 1353, 1263, 1144, 1063, 1012, 949, 848, 776 cm ;
+·
MS (EI) m/z 204 (M , 53%), 205 (7), 175 (100), 161 (13),
47 (10), 129 (20), 115 (27), 91 (22), 77 (11); HRMS (EI) m/
1
15 (30), 105 (33), 77 (31), 49 (47); HRMS (ESI) m/z (M+
+·
+
z M calcd for C12
H O 204.0786, found: 204.0787. R (7:3
12 3 f
Na) calcd for C H O Na 241.0835, found 241.0835. R (8:2
13
14
3
f
hexanes/EtOAc)=0.11.
hexanes/EtOAc)=0.43.
-[(tert-Butyldimethylsilyl)oxymethyl]-4-cyclopropyliso-
6
benzofuran-1(3H)-one (7m) and 5-[(tert-butyldimethylsily-
l)oxymethyl]-4-cyclopropylisobenzofuran-1(3H)-one (8m).
Cyclotrimerization of 1c catalyzed by Cp*Ru(cod)Cl.
A colorless crystalline solid, m.p.=135.18C (recrystallized
A solution of diyne 1c (37 mg, 0.25 mmol) in dry DCE
(4 mL) maintained under an atmosphere of argon was treat-
ed with an alkyne 2 (0.5 mmol) and Cp*Ru(cod)Cl (4.8 mg,
0.0125 mmol). The reaction mixture was stirred at 228C for
the time specified in Table 6. Then it was concentrated
under reduced pressure and column chromatography of the
residue on silica gel (hexanes/EtOAc) provided the corre-
sponding 7-cyclopropyl-3-hydroisobenzofuran-1-ones 10 and
11.
1
from DCM/hexanes). 7m: H NMR (600 MHz, CDCl ) d
3
7.65 (s, 1H), 7.19 (s, 1H), 5.36 (s, 2H), 4.77 (s, 2H), 1.79 (tt,
J=8.4, 5.2 Hz, 1H), 1.06–1.03 (m, 2H), 0.94 (s, 9H), 0.79–
1
3
0
1
1
.76 (m, 2H), 0.10 (s, 6H); C NMR (150 MHz, CDCl ) d
3
71.5, 144.7, 143.6, 138.2, 127.4, 125.4, 120.1, 69.0, 64.4, 25.9,
1
8.4, 11.8, 7.9, À5.3. 8m: H NMR (600 MHz, CDCl ) d 7.79
3
(
d, J=7.9 Hz, 1H), 7.73 (d, J=7.9 Hz, 1H), 5.37 (s, 2H),
4
0
.99 (s, 2H), 1.92 (tt, J=8.3, 5.9 Hz, 1H), 1.03–0.99 (m, 2H),
.97 (s, 9H), 0.62–0.59 (m, 2H), 0.14 (s, 6H); C NMR
13
7-Cyclopropyl-5-phenylisobenzofuran-1(3H)-one
(10a)
(
150 MHz, CDCl ) d 171.4, 148.6, 146.2, 132.7, 127.4, 124.4,
and 7-cyclopropyl-6-phenylisobenzofuran-1(3H)-one (11a).
3
1
23.9, 69.3, 62.4, 25.9, 18.4, 10.1, 5.8, À5.4. 7m+8m: IR
A brownish crystalline solid, m.p.=137.58C (recrystallized
1
(KBr) n
2950, 2926, 2884, 2857, 1772, 1461, 1356, 1263,
from DCM/hexanes). 10a: H NMR (600 MHz, CDCl ) d
max
3
À1
1138, 1102, 1087, 1063, 1018, 955, 860, 836, 779 cm ; MS
7.57–7.54 (m, 2H), 7.49–7.45 (m, 2H), 7.43–7.40 (m, 1H),
2
64
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Adv. Synth. Catal. 2016, 358, 254 – 267

FULL PAPERS
[2+2+2]-Cyclotrimerization of 1-Cyclopropyl-1,6-diynes
7.37–7.36 (m, 1H), 7.04–7.03 (m, 1H), 5.28 (s, 2H), 3.22 (tt,
137.0, 125.6, 119.0, 86.1, 70.8, 69.6, 68.2, 68.1, 11.4, 10.1.
J=8.5, 5.1 Hz, 1H), 1.22–1.18 (m, 2H), 0.90–0.87 (m, 2H);
10 f+11 f: IR (KBr) nmax 3096, 3075, 2929, 1742, 1613, 1449,
1350, 1207, 1045, 1006, 806 cm ; MS (EI) m/z 358 (M ,
13
À1
+·
C NMR (150 MHz, CDCl ) d 171.3, 147.7, 147.4, 147.0,
3
1
40.0, 129.0, 128.4, 127.4, 121.9, 121.8, 117.0, 68.6, 11.0, 10.0.
100%), 359 (26), 191 (8), 178 (10), 165 (16), 152 (10), 121
1
+·
11a: H NMR (600 MHz, CDCl ) d 7.51–7.29 (m, 7H), 5.27
(55), 56 (13); HRMS (EI) m/z M calcd for C21
H
18
O
2
Fe
3
(s, 2H), 2.21 (tt, J=8.7, 5.8 Hz, 1H), 0.87–0.84 (m, 2H),
358.0656, found: 358.0655. R (8:2 hexanes/EtOAc)=0.32.
f
13
0
1
1
3
8
2
6
.23–0.19 (m, 2H); C NMR (150 MHz, CDCl ) d 170.1,
5,7-Dicyclopropylisobenzofuran-1(3H)-one (10h) and 6,7-
dicyclopropylisobenzofuran-1(3H)-one (11h). A white crys-
3
46.5, 144.2, 141.7, 140.6, 136.1, 129.4, 129.0, 128.0, 127.2,
25.8, 119.6, 68.2, 11.0, 9.6. 10a+11a: IR (KBr) nmax 3081,
058, 3007, 2926, 1742, 1607, 1470, 1353, 1201, 1063, 1006,
90, 764, 698 cm ; MS (EI) m/z 250 (M , 100%), 235 (15),
05 (65), 191 (24), 178 (22), 165 (19), 152 (8), 115 (6), 89 (4),
talline solid, m.p.=112.68C (recrystallized from DCM/hex-
1
anes). 10h: H NMR (600 MHz, CDCl
) d 6.80 (s, 1H), 6.56
3
À1
+·
(s, 1H), 5.16 (s, 2H), 3.11 (tt, J=8.4, 5.2 Hz, 1H), 1.92 (tt,
J=8.4, 5.0 Hz, 1H), 1.15–1.10 (m, 2H), 1.07–1.03 (m, 2H),
+·
13
3 (4); HRMS (EI) m/z M calcd for C H O 250.0994,
0.81–0.77 (m, 2H), 0.75–0.72 (m, 2H); C NMR (150 MHz,
17
14
2
CDCl ) d 171.4, 151.7, 147.6, 146.3, 120.5, 120.4, 114.5, 68.4,
found: 250.0996. R (8:2 hexanes/EtOAc)=0.39.
3
f
1
1
6.1, 10.7, 10.4, 9.7. 11h: H NMR (600 MHz, CDCl ) d 7.19
7-Cyclopropyl-5-(4-methoxyphenyl)isobenzofuran-1(3H)-
3
(d, J=7.9 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 5.16 (s, 2H),
one (10b) and 7-cyclopropyl-6-(4-methoxy-phenyl)isobenzo-
furan-1(3H)-one (11b). A yellowish crystalline solid, m.p.=
2
1
0
.44 (tt, J=8.5, 5.4 Hz, 1H), 2.05 (tt, J=8.6, 5.7 Hz, 1H),
1
.22–1.17 (m, 2H), 1.09–1.05 (m, 2H), 0.76–0.71 (m, 2H),
119.38C (recrystallized from DCM/hexanes). 10b: H NMR
1
3
.70–0.67 (m, 2H). C NMR intensity of signals was too low
(600 MHz, CDCl ) d 7.51–7.48 (m, 2H), 7.33–7.32 (m, 1H),
3
to be assigned. 10h+11h: IR (KBr) nmax 3087, 3007, 2929,
866, 1739, 1613, 1440, 1350, 1201, 1069, 1006, 985, 872,
7
3
0
1
6
.01–6.97 (m, 2H), 6.99–6.98 (m, 1H), 5.26 (s, 2H), 3.85 (s,
2
H), 3.19 (tt, J=8.4, 5.1 Hz, 1H), 1.20–1.16 (m, 2H), 0.89–
À1
+·
13
695 cm ; MS (EI) m/z 214 (M , 93%), 215 (16), 199 (22),
85 (13), 169 (66), 155 (64), 141 (51), 128 (89), 115 (87), 84
.85 (m, 2H); C NMR (150 MHz, CDCl ) d 171.4, 160.0,
47.8, 147.0, 146.9, 132.3, 128.5, 121.3, 121.2, 116.4, 114.4,
8.6, 55.4, 10.9, 10.0. 11b: H NMR intensity of signals was
3
1
+·
1
(45), 63 (22), 49 (100), 35 (47); HRMS (EI) m/z M calcd
for C H O 214.0994, found: 214.0993. R (8:2 hexanes/
13
too low to be assigned. C NMR intensity of signals was too
low to be assigned. 10b+11b: IR (KBr) nmax 3040, 3010,
14 14
2
f
EtOAc)=0.34.
-Butyl-7-cyclopropylisobenzofuran-1(3H)-one (10i) and
6-butyl-7-cyclopropylisobenzofuran-1(3H)-one (11i).
5
2962, 2839, 1745, 1604, 1524, 1446, 1251, 1183, 1054, 1036,
À1
+·
A
1006, 824 cm ; MS (EI) m/z 280 (M , 100%), 281 (25), 265
white crystalline solid, m.p.=41.28C (recrystallized from
(13), 235 (42), 205 (10), 178 (11), 165 (12), 152 (7), 115 (5),
1
+·
DCM/hexanes). 10i: H NMR (600 MHz, CDCl ) d 6.99 (s,
3
89 (3); HRMS (EI) m/z M calcd for C H O 280.1099,
18 16 3
1
2
2
H), 6.64 (s, 1H), 5.19 (s, 2H), 3.13 (tt, J=8.5, 5.1 Hz, 1H),
.65–2.61 (m, 2H), 1.61–1.54 (m, 2H), 1.34 (sext, 7.4 Hz,
H), 1.15–1.11 (m, 2H), 0.92 (t, J=7.3 Hz, 3H), 0.81–0.78
found: 280.1101. R (8:2 hexanes/EtOAc)=0.29.
f
Methyl 4-(7-cyclopropyl-1-oxo-1,3-dihydroisobenzo-furan-
-yl)benzoate (10d) and methyl 4-(4-cyclopropyl-3-oxo-1,3-
5
1
3
(m, 2H); C NMR (150 MHz, CDCl ) d 171.5, 150.1, 147.5,
3
dihydroisobenzofuran-5-yl)benzoate (11d). A yellow crystal-
line solid, m.p.=194.88C (recrystallized from DCM/hex-
anes). 10d: H NMR (600 MHz, CDCl ) d 8.13–8.10 (m,
1
46.4, 122.9, 120.7, 118.1, 68.4, 36.1, 33.4, 22.3, 13.8, 10.8, 9.7.
1
1
11i: H NMR (600 MHz, CDCl
3
) d 7.43 (d, J=7.8 Hz, 1H),
.22 (d, J=7.8 Hz, 1H), 5.16 (s, 2H), 2.94–2.90 (m, 2H),
.93 (tt, J=8.6, 5.8 Hz, 1H), 1.62–1.57 (m, 2H), 1.42–1.36
3
7
1
2
1
1
H), 7.63–7.60 (m, 2H), 7.41–7.39 (m, 1H), 7.05–7.03 (m,
H), 5.29 (s, 2H), 3.94 (s, 3H), 3.21 (tt, J=8.5, 5.2 Hz, 1H),
13
(m, 2H), 1.20–1.16 (m, 2H), 0.95 (t, J=7.3 Hz, 3H), 0.66–
.23–1.19 (m, 2H), 0.90–0.87 (m, 2H); C NMR (150 MHz,
13
0
.63 (m, 2H). C NMR intensity of signals was too low to
CDCl ) d 171.1, 166.6, 147.8, 147.4, 146.2, 144.4, 130.2, 130.0,
3
1
be assigned. 10i+11i: IR (KBr) nmax 3078, 2956, 2926, 2863,
127.4, 122.6, 122.0, 117.2, 68.6, 52.2, 11.1, 10.0. 11d: H NMR
À1
13
1751, 1607, 1455, 1329, 1207, 1045, 1012, 991, 943, 692 cm ;
intensity of signals was too low to be assigned. C NMR in-
tensity of signals was too low to be assigned. 10d+11d: IR
+·
MS (EI) m/z 230 (M , 100%), 231 (18), 215 (16), 185 (43),
73 (50), 143 (24), 129 (37), 115 (27), 91 (8), 77 (5); HRMS
1
(KBr) nmax 3093, 2947, 2872, 1751, 1718, 1604, 1446, 1290,
+·
À1
(EI) m/z M calcd for C15
R (8:2 hexanes/EtOAc)=0.49.
f
H O 230.1307, found: 230.1310.
18 2
1
3
269, 1222, 1120, 1060, 1009, 857, 776 cm ; MS (EI) m/z
08 (M , 100%), 308 (21), 293 (13), 277 (11), 263 (33), 205
+·
+·
(23), 189 (13), 165 (8), 115 (4); HRMS (EI) m/z M calcd
for C H O 308.1049, found: 308.1051. R (8:2 hexanes/
19
16
4
f
EtOAc)=0.20.
-Cyclopropyl-5-ferrocenylisobenzofuran-1(3H)-one (10 f)
and 7-cyclopropyl-6-ferrocenylisobenzofuran-1(3H)-one
11 f). An orange crystalline solid, m.p.=211.18C (recrystal-
Acknowledgements
7
This work was supported by the Czech Science Foundation
grant No. 13–15915S). The authors also thank Lach-Ner
(
(
1
lized from DCM/hexanes). 10 f: H NMR (600 MHz, CDCl )
3
s.r.o. for generous gift of chemicals as a part of the award
given to MK.
d 7.25 (s, 1H), 6.92 (s, 1H), 5.23 (s, 2H), 4.67–4.64 (m, 2H),
4
1
.41–4.38 (m, 2H), 4.04 (s, 5H), 3.16 (tt, J=8.4, 5.1 Hz, 1H),
.21–1.16 (m, 2H), 0.87–0.83 (m, 2H); C NMR (150 MHz,
13
CDCl ) d 171.4, 147.5, 146.9, 146.3, 120.5, 120.3, 115.4, 83.3,
3
1
6
9.9, 69.8, 68.4, 67.1, 10.8, 9.8. 11 f: H NMR (600 MHz, References
CDCl ) d 8.05 (d, J=7.8 Hz, 1H), 7.28 (d, J=7.8 Hz, 1H),
3
5
.20 (s, 2H), 4.56 (s, 2H), 4.34 (s, 2H), 4.10 (s, 5H), 2.04 (tt,
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13
C NMR (150 MHz, CDCl ) d 170.1, 145.5, 141.6, 141.3,
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Adv. Synth. Catal. 2016, 358, 254 – 267
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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