Cyclotrimerization of unsymmetrically bromo-substituted diynes: Toward the synthesis of potential selective inhibitors of tyrosine kinase 2

Article abstract of DOI:10.1016/j.tet.2012.07.087

A study on transition metal catalyzed alkyne cyclotrimerization of unsymmetrically bromo-substituted diynes with ethynyltrimethylsilane was carried out to prepare bicyclic bromobenzene key intermediates for the total synthesis of five potential tyrosine k

Full text of DOI:10.1016/j.tet.2012.07.087

Tetrahedron 68 (2012) 8463e8471
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Cyclotrimerization of unsymmetrically bromo-substituted diynes: toward the
synthesis of potential selective inhibitors of tyrosine kinase 2
,
Silje Melnes a, Annette Bayer b, Odd Reidar Gautun a
*
a Department of Chemistry, Norwegian University of Science and Technology (NTNU), NO-7491 Trondheim, Norway
b Department of Chemistry, University of Tromsø (UiT), N-9037 Tromsø, Norway
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 April 2012
Received in revised form 25 June 2012
Accepted 23 July 2012
Available online 31 July 2012
A study on transition metal catalyzed alkyne cyclotrimerization of unsymmetrically bromo-substituted
diynes with ethynyltrimethylsilane was carried out to prepare bicyclic bromobenzene key in-
termediates for the total synthesis of five potential tyrosine kinase 2 inhibitors. Two different pre-cat-
alysts (Cp*RuCl(cod) and [Rh(cod)2]BF4/BINAP) and different reaction conditions have been examined.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Alkyne cyclotrimerization
Total synthesis
Bromo-substituted alkynes
Bromobenzene derivatives
Selective inhibitors of tyrosine kinase 2
1. Introduction
methods.7 Transition metal catalyzed alkyne cyclotrimerization is
a more straightforward strategy to highly substituted aromatic
Multiple myeloma (MM) is the second most common hemato-
logic cancer, accounting for about 1% of all cancer deaths world-
wide.1 The median survival time after diagnosis is 3e4 years, and
there are currently no cures. Tyrosine kinase 2 (Tyk2) has been
identified as a potential target for MM cancer therapy.2
compounds from rather simple alkyne precursors.8e13 The sub-
stitution pattern in the resulting benzene product is determined by
the substituents of the parent alkynes, but regioselectivity has to be
controlled. Both the steric- and electronic properties of the catalyst
and substrates might influence the selectivity.9,14 Today, several
Based on computational work, Tøndel and co-workers sug-
gested the 1,2,3,5-substituted benzene derivatives 1e5 as potential
selective Tyk2-inhibitors (Fig. 1).3,4 However, 1e5 are not readily
available and must be synthesized before their biological activity
can be evaluated. Structural similarities allow for common syn-
thetic strategies. Retrosynthetic analyses pointed at compounds
6aed as key intermediates in the synthesis of 1e5 (Scheme 1).
The TMS-substituent of 6 can be converted to both OH- and
NH2-groups, making 6 masked phenol- and/or aniline compounds.
Several methods for such transformations exist, typically utilizing
electrophilic ipso-desilylation processes.5,6 The bromo-substituent
of 6 is a potential site for oxidative addition to palladium cata-
lysts, and facilitating the linkage of the vinylic side chains of 1e5. In
general, bromobenzene derivatives can be prepared from already
existing aromatic compounds by electrophilic aromatic sub-
stitution, directed ortho-metalation, or other conventional
* Corresponding author. Tel.: þ47 73594101; fax: þ47 73594256; e-mail address:
odd.gautun@chem.ntnu.no (O.R. Gautun).
Fig. 1. Potential selective inhibitors of tyrosine kinase 2; 1e5.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.07.087

8464
S. Melnes et al. / Tetrahedron 68 (2012) 8463e8471
Scheme 1. Possible precursors to 1e5.
catalysts and good methods exist for high yielding selective alkyne
cyclotrimerization reactions.8e13 Therefore, the compounds
6
might be available from the unsymmetrically bromo-substituted
diynes (8) and ethynyltrimethylsilane (9) (Scheme 2) if the for-
mation of regioisomers 7 can be suppressed.
Scheme 3. Synthesis of 6a-OMe from 10. (a) (i) BuLi, Me2NCH2CH2NMe2 (ii) CBr4 (b)
(EtO)2POCH2CO2Et, NaH (c) H2, 5% RheAl2O3 (d) NaOH (e) (i) SOCl2 (ii) AlCl3 (f) (i)
MeMgBr (ii) HCl (g) (i) O3 (ii) NaBH4 (h) p-TsOH.
requirements have to be fulfilled. First, the diyne precursors 8
(Scheme 4) should be easily accessible from commercially available
starting materials. Second, the regioselectivity of the cyclo-
trimerization reactions of 8 and 9 must be controllable.
Scheme 2. The [2þ2þ2]-cyclotrimerization strategy for the preparation of 6. ‘M’:
transition metal catalyst.
In general, bromoalkynes are easily accessible from the corre-
sponding terminal alkynes via mild and convenient methods, such
as the silver catalyzed bromination with NBS developed by Hof-
meister et al.15 However, these compounds are most extensively
used in reactions involving insertion of a metal to the C(sp)eBr
bond. To the best of our knowledge, only two examples of cyclo-
trimerization reactions of bromo-substituted alkynes have been
reported; an intramolecular co-catalyzed cyclization of a symmet-
rically dibromo-substituted triyne16 and a Ru-catalyzed cyclo-
trimerization of a symmetrically substituted dibromodiyne with
acetylene.17 Concerning iodoalkynes, Yamamoto and co-workers
have described Ru-catalyzed cyclotrimerization reactions of iodo-
diynes with mono-alkynes18 and used this methodology in the
synthesis of spirocyclic C-arylribosides with potential biological
activity.19
Scheme 4. Diynes 8, precursors of 6.
The ether linked 1,7-diynes 8a and 8b (Scheme 4) were pre-
pared by the three step Nicholas reaction from the propargylic al-
cohols 18a or 18b and 4-bromo-3-butyn-1-ol (19b) (Scheme 5, Eq.
1) in 60% and 50% yield, respectively.21 The brominated alkyne 19b,
was readily accessible by bromination of the terminal alkyne 19a
according to the method of Hofmeister et al. (Scheme 5, Eq. 2).15
2. Results and discussion
To compare the efficiency of a cyclotrimerization strategy to 6
(Scheme 2) with a classical approach, the methoxy-substituted
variant of 6a (6a-OMe) was prepared by eight classical steps from
p-anisaldehyde (10) in 22% total yield (Scheme 3). Bromination
with CBr4 after the ortho-lithiation20 of 10 gave 11 in 67% yield. A
HWE-olefination of 11 provided pure E-12 in 82% yield. Hydroge-
nation of 12 followed by hydrolysis of the ester 13, yielded the acid
14 in 98%. The highest yield of 15 (50%) was obtained from an
intramolecular FriedeleCraft acylation of 14 mediated by AlCl3.
Addition of MeMgBr to 15 followed by HCl-mediated elimination
gave 16 in quantitative yield. Finally, ozonolysis of 16 with re-
ductive work-up (NaBH4) gave diol 17 in 94%, which easily cyclized
to 6a-OMe in the presence of acid (p-TsOH, 87%).
Scheme 5. Preparation of 8a and b by the Nicholas reaction (Eq. 1); preparation of 19b
from bromination of 19a (Eq. 2).
For the preparation of ester-linked 1,6-diynes 8c and 8d (Table 1),
the Mitsunobu reaction22 of propargylic alcohols 18 with propargylic
acids 20 was the initially planned strategy. Unfortunately, while 8d
was prepared from 4-bromobut-3-yn-2-ol (18c) and propiolic acid
(20a) in 65% yield (Table 1, entry 2), only 22% yield of 8c was
Despite several high yielding steps in the synthesis of 6a-OMe
(Scheme 3), a more direct and less time-consuming route to 6 was
desirable. Thus, the transition metal catalyzed alkyne cyclo-
trimerization strategy (Scheme 2) has been investigated. For this
method to be superior to a classical total synthesis approach, some

S. Melnes et al. / Tetrahedron 68 (2012) 8463e8471
8465
Table 1
formation of the electronically favored rhodium metallacycle in-
termediate.31 Method B was developed by Yamamoto and co-
workers, and employs Cp*RuCl(cod) as a pre-catalyst.32,33 Cyclo-
additions of unsymmetrical 1,6-diynes with terminal mono-
alkynes in the presence of Cp*Ru(cod)Cl have displayed excellent
selectivity for the sterically favored meta-products. The regiose-
lectivity has its origin in steric interactions between the bulky Cp*
ligand and the terminal alkyne substituents under formation of
ruthenium metallacycle intermediates.32,33 Opposite ortho-selec-
tivity has been observed under reactions of terminal mono-alkynes
with unsymmetrically substituted diynes bearing a conjugated
carbonyl group in the tether. The inversed regioselectivity was
explained by direct electronic effects from the electron-
withdrawing group para to the electron-donating substituent on
the mono-alkyne.34 The results obtained from reactions of 8 with 9
by both methods, are given in Table 2.
Preparation of diynes 8ceg by the Mitsunobu reaction22
Entry
18 (R1)
20 (R2)
Product (% yield)a
1
2
3
4
5
18a (H)
18c (Br)
18d (TMS)
18d (TMS)
18a (H)
20b (Br)
20a (H)
20b (Br)
20a (H)
20c (Me)
8c (22%)
8d (65%)
8e (25%)
8f (73%)
8g (77%)
a
Isolated yield after column chromatography.
Both 8a and b reacted smoothly under the Rh-catalytic condi-
tions applied in method A (Table 2, entries 1 and 3). High total
yields of cyclotrimerization products were obtained (81 and 95%,
respectively). In case of 8a, the ortho-isomer 7a was formed se-
lectively over the wanted meta-product 6a (meta/ortho 15:85, entry
1). However, low selectivity (43:57) was observed under the re-
action of 8b, where the ortho-isomer 7b was formed in a slightly
excess (entry 3). Method A required 10 equiv of compound 9 to
provide the desired reaction. When the amount of 9 was reduced to
2 equiv, only self-trimerization products of 8a and b were observed.
It should also be noted that successful cyclotrimerization by
method A was only achieved when dilution (c¼0.1 M) and dropwise
addition of 8 were employed. If the addition went too fast, and/or
the solutions were more concentrated, considerable amounts of
self-trimerization products of 8 were observed. Under the Ru-
catalytic conditions in method B, the selectivity changed in favor
of the wanted 6a and 6b (Table 2, entries 2, 4, and 5). The meta/
ortho ratio of 9:1 was obtained in reactions of both 8a and b, in-
dicating a lesser importance of the methyl-substituent on 8a re-
garding selectivity in method B compared to method A. However,
higher yields were obtained of the methyl-substituted products 6a
and 7a (28%, entry 2) compared to the unsubstituted products 6b
and 7b (7%, entry 4), probably due to an increased ThorpeeIngold
effect35 of 8a. The yield of 6b/7b was improved when a higher load
of Ru-catalyst (10 mol %) and 9 (10 equiv) were applied on 8b (23%,
entry 5), but the selectivity remained 9:1.
obtained by the same procedure applied on 18a and
3-bromopropiolic acid (20b) (Table 1, entry 1). Attempts on esteri-
fication of 20b with 18a by other methods did not improve the
isolated yield of the diyne. Only 20% yield of 8c was isolated after
a DCC/DMAP-mediated esterification,23 and a standard acid cata-
lyzed (p-TsOH) Fischer-esterification24 with 18a in excess showed
only traces of product. In addition, the preparation of 20b also turned
out to be troublesome. Several methods were tried without success;
bromination of 20a by AgNO3/NBS15 and LHMDS/Br2,25 and basic
hydrolysis of the corresponding ethyl ester (ethyl 3-
bromopropiolate). The best result was obtained by bromination of
20a with NaOBr,26 which afforded 20b in 37% yield. To examine the
problem concerning the preparation of 8c, a Mitsunobu test reaction
of 20b with the TMS-protected propargylic alcohol 18d was pre-
formed (Table 1, entry 3). The isolated 25% yield of the resulting
diyne 8e was not convincing, and decomposition or side reactions of
20b were suspected. With this result in hand, an alternative route to
8c employing the unsymmetrically TMS-protected diyne 8f was in-
vestigated (Scheme 6). This diyne, 8f, was prepared in 73% yield by
the Mitsunobu reaction of 20a and 18d (Table 1, entry 4). Bromina-
tion of the terminal alkyne 8f by LHMDS and Br2 gave 8e in 77% yield.
Silver catalyzed TMS-deprotection of 8e in the presence of water27
gave 8c in 89% yield. To compare with the 22% yield of 8c obtained
from the Mitsunobu reaction (Table 1, entry 1), this three step pro-
cedure gave a 50% total yield of 8c.
Only moderate yields of cyclotrimerization products were
obtained when applying method A on 8c and 8d (Table 2, entries 6
and 8), and formation of side products were observed by TLC and 1H
NMR-analyses of the crude. A 17:83 mixture of 6c and 7c was
obtained from 8c in 56% isolated yield (entry 6). Selectivity in slight
favor of 6d over 7d was observed from the reaction of 8d, where
a 60:40 mixture of products were isolated in 40% yield (entry 8).
More contrasting results on both reactivity and selectivity were
observed for the cyclotrimerization of 8c compared to 8d by
method B (Table 2, entries 7, 9, and 10). While 8c reacted com-
pletely after 30 min (entry 7), 8d needed an elevated temperature
(80 ꢀC) and higher load of both Ru-catalyst and 9 (10 mol %,
10 equiv) to react completely (compare entries 9 and 10). Excellent
selectivity (97:3) from the reaction of 8c was observed, and the
wanted meta-product 6c was isolated as a sole product in 64%. The
reactions of 8d gave a moderate selectivity in favor of 6d over 7d
(77:23), and a total yield of 42%.
To illustrate the significance of the diyne bromo-substituent on
the reaction outcome, the bromo-substituent of 8c was replaced
with a methyl group (8g). The diyne 8g was prepared by the Mit-
sunobu reaction in 77% (Table 1, entry 5). Cyclotrimerization of 8g
with 9 by method B gave excellent meta-selectivity (97:3), and the
product 6g was isolated as a sole product in 97% yield (Table 2,
entry 11).
Scheme 6. Preparation of 8c from 8f.
Ethynyltrimethylsilane (9) has been used extensively by Voll-
hardt and co-workers in co-mediated [2þ2þ2] cycloadditions.28
Both the sterically demanding TMS substituent and the polariza-
tion of the CeSi bond,6 might influence regioselectivity in the for-
mation of cycloaddition products. With diynes 8aed in hand,
cyclotrimerization of 8 with 9 was carried out using two different
methods (A and B, Table 2). Method A refers to the cationic Rh(I)/
BINAP-complex catalyzed alkyne cyclotrimerization procedure
discovered by Tanaka and co-workers in 2003.29,30 Under mild
conditions, moderate to high yields of bicyclic products from cy-
cloadditions of 1,6-diynes and, the in general less reactive, 1,7-
diynes, have been obtained with both electron-deficient and
electron-rich mono-alkynes.30 Cationic Rh(I)/BINAP catalyzed cy-
cloadditions of 9 with diethyl acetylenedicarboxylate has given
only moderate yields, but excellent regioselectivity.29,31 In general,
regioselectivity is under electronic control and depends on the

8466
S. Melnes et al. / Tetrahedron 68 (2012) 8463e8471
Table 2
Cyclotrimerization of unsymmetrically bromo-substituted diynes 8 with ethynyltrimethylsilane (9)
Entry
8
Methoda
% Conv.
Products (6:7)b
% Yieldc
8b
1
2
8a
8a
A
B
100
100
15:85
90:10
81
28
3
4
8b
8b
A
B
100
58
43:57
90:10
95
7
5
8b
Bd
100
90:10
23
6
7
8c
8c
A
100
100
17:83
97:3
56
64
Be
8
9
8d
8d
A
B
100
70
60:40
77:23
40
traces
10
8d
Bd,f
100
77:23
42
11
8g
B
100
97:3
97
a
Method A: 5% [Rh(cod)2]BF4/BINAP, 10 equiv 9 in DCE.29,30 Method B: 5% Cp*Ru(cod)Cl, 5 equiv 9 in DCM or DCE.32,33
b
c
d
e
f
Determined by 1H NMR analysis of the crude.
Total isolated yield of 6 and 7 after column chromatography.
10% catalyst, 10 equiv 9.
Reaction finished after 30 min.
80 ꢀC.
3. Conclusion
yields of cyclotrimerization products (6þ7), but the regioselectivity
was in general favoring the ortho-isomers 7. Using Yamamoto’s
method with Cp*RuCl(cod) as a pre-catalyst (method B), the
regioselectivity shifted toward the meta-isomers 6, but the isolated
yields were in general lower. The best result regarding both yield
and selectivity was obtained from the Ru-catalyzed cyclo-
trimerization of diyne 8c, which gave 6c as a sole product in 64%
Cyclotrimerization of unsymmetrically bromo-substituted
diynes 8aed with ethynyltrimethylsilane (9) has been examined
as a key step for the preparation of intermediates 6aed in the total
synthesis of 1e5 (Fig.1). The cationic Rh/BINAP catalyzed procedure
developed by Tanaka (method A) gave moderate to excellent total

S. Melnes et al. / Tetrahedron 68 (2012) 8463e8471
8467
isolated yield. A Ru-catalyzed test reaction with the methyl-
substituted analogue 8g gave 6g in 97% yield, indicating that the
bromo-substituted diynes might be labile under the reaction con-
ditions. To compare cyclotrimerization to a classical approach, 6a
was prepared from 8a and 9 by method B in 25% yield. An eight step
synthesis of the methoxy-substituted analogue 6a-OMe from
p-anisaldehyde (10) was achieved in 22% total yield. This classical
strategy included several high yielding steps, but it was time con-
suming compared to the more direct alkyne cyclotrimerization
strategy. In addition, the cyclotrimerization strategy is a more
general and faster approach to both the phenol- and aniline pre-
cursors 6aed.
reduced to ca. 50 mL under vacuum. The mixture was extracted
with DCM (3ꢂ50 mL). The combined organic layers were washed
with NaHCO3 (satd aq, 100 mL) and brine (100 mL), dried (MgSO4),
and concentrated under reduced pressure. The resulting yellow oil
was purified by column chromatography (n-hexane/EtOAc, 9:1).
The title compound was isolated as a colorless oil (7.50 g,
26.3 mmol, 82%), which transformed to a white solid when stored
in freezer. Mp 39e40 ꢀC; Rf (20% EtOAc/n-hexane) 0.37. IR (KBr):
3047 (w), 2975 (w), 2927 (w), 1697 (s), 1599 (s), 1488 (s), 1298 (s),
1276 (s), 1264 (s), 1231 (s), 1042 (s), 1025 (s), 975 (m), 858 (m), 809
(m) cmꢁ1 1H NMR (300 MHz, CDCl3):
; d 8.00 (1H, d, J 15.9 Hz,
ArCHCHCO2Et), 7.56 (1H, d, J 8.8 Hz, AreH6), 7.14 (1H, d, J 2.6 Hz,
AreH3), 6.87 (1H, dd, J 8.8, 2.6 Hz, AreH5), 6.29 (1H, d, J 15.9 Hz,
CHCO2Et), 4.27 (2H, q, J 7.1 Hz, CH2), 3.83 (3H, s, OCH3), 1.34 (3H, t, J
4. Experimental section
4.1. General information
7.1 Hz, CH3); 13C NMR (100 MHz, CDCl3):
d 166.7, 161.2, 142.4, 128.4,
126.8, 126.3, 118.6, 118.1, 114.3, 60.5, 55.6, 14.3; HRMS (EI): m/z calcd
for C12H1379BrO3 [M]þ: 284.0043; found: 284.0044.
Chemicals were purchased from SigmaeAldrich and used
without further purification. All reactions sensitive to air or mois-
ture were performed under argon or nitrogen atmosphere with
dried solvents and reagents. DCM, THF, and Et2O were dried using
MBRAUN solvent purification system (MB SPS-800). DCE and tol-
uene were dried by distillation after treatment with CaH2, and
4.2.3. Ethyl 3-(2-bromo-4-methoxyphenyl)-propanoate (13). A so-
lution of 12 (4.14 g,14.5 mmol) in MeOH (110 mL) was added 5% Rh-
alumina (414 mg, 10 wt %). The mixture was stirred under an at-
mosphere of H2 (balloon) for 3 h. The catalyst was removed by
filtration through a plug of silica packed with MeOH, and the sol-
vent was removed under vacuum to give 13, as a mixture of clear oil
and white solid (4.10 g, 14.3 mmol, 99%). Rf (20% EtOAc/n-hexane)
0.37. IR (neat): 2979 (w), 2836 (w), 1730 (s), 1605 (m), 1492 (s), 1237
ꢀ
stored over activated 4 A molecular sieves. DCM and DCE were
degassed with helium for 10e20 min prior to use in cyclo-
trimerization by method B (Ru-catalysis). Melting points were de-
termined on a Buchi 535 apparatus and are uncorrected. TLC was
performed on Merck silica gel 60 F254 plates, using UV light at
312 nm and a 5% solution of molybdophosphoric acid in 96% EtOH
for detection. Column chromatography was performed with Silica
(s), 1179 (s), 1028 (s), 856 (m) cmꢁ1
;
1H NMR (300 MHz, MeOD):
d
7.17 (1H, d, J 8.6 Hz, AreH6), 7.09 (1H, d, J 2.6 Hz, AreH3), 6.82 (1H,
dd, J 8.6, 2.6 Hz, AreH5), 4.09 (2H, q, J 7.2 Hz, CH2CH3), 3.74 (3H, s,
OCH3), 2.95 (2H, t, J 7.7 Hz, ArCH2CH2CO2Et), 2.56 (2H, t, J 7.7 Hz,
CH2CO2Et), 1.20 (3H, t, J 7.2 Hz, CH3); 13C NMR (100 MHz, MeOD):
ꢀ
gel (pore size 60 A, 230e400 mesh particle size) purchased from
Fluka. 1H and 13C NMR spectra were recorded from Bruker Advance
DPX instruments (300/75 MHz and 400/100 MHz). Chemical shifts
d 173.3, 160.3, 132.8, 132.0, 125.1, 119.1, 114.6, 61.6, 56.0, 35.4, 31.5,
14.5; HRMS (EI): m/z calcd for C12H1579BrO3 [M]þ: 286.0199;
(d
) are reported in parts per million. Where CDCl3 has been used,
found: 286.0203.
shift values for proton are reported with reference to TMS (0.00) via
the lock signal of the solvent. Reference values for other NMR-
solvents are taken from Silverstein.36 Signal patterns are in-
dicated as s (singlet), d (doublet), t (triplet), q (quartet) or m
(multiplet). 1H and 13C NMR signals were assigned by 2D correla-
tion techniques (COSY, HSQC, HMBC). IR spectra were recorded
from a Thermo Nicolet FT-IR NEXUS instrument, and only the
strongest/structurally most important peaks are listed (cmꢁ1). Ac-
curate mass determination, EI and ESI, was performed on MAT95XL
ThermoFinnigan and Agilent G1969 TOF MS instrument, re-
spectively. For ESI analyses, samples were injected into the in-
strument using an Agilent 1100 series HPLC. A direct injection
analysis without any chromatography was performed for the EI
analyses.
4.2.4. 3-(2-Bromo-4-methoxyphenyl)propanoic acid (14). A solution
of 13 (2.80 g, 9.75 mmol) in MeOH (60 mL) was added NaOH (1 M in
H2O, 20 mL). The mixture was stirred at rt for 24 h. HCl (1 M in H2O,
ca. 30 mL) was added until pH w2. The white precipitate was
extracted into Et2O (3ꢂ100 mL). The organic layers were washed
with brine (200 mL) and dried (MgSO4). The solvent was removed
under reduced pressure, and 14 was isolated as a white solid
(2.50 g, 9.65 mmol, 99%). Mp: 89e91 ꢀC; Rf (20% EtOAc/n-hexane)
0.18. IR (KBr): 3063 (s, br), 2937 (w), 1714 (s), 1604 (s), 1489 (s), 1434
(s), 1317 (s), 1279 (s), 1233 (s), 1214 (s), 1037 (s), 810 (s) cmꢁ1
;
1H
NMR (400 MHz, CDCl3): 11.34 (1H, br s, COOH), 7.16 (1H, d, J
d
8.5 Hz, AreH6), 7.10 (1H, d, J 2.6 Hz, AreH3), 6.80 (1H, dd, J 8.5,
2.6 Hz, AreH5), 3.78 (3H, s, OCH3), 3.01 (2H, t, J 7.8 Hz, ArCH2
-
CH2CO2H), 2.77 (2H, t, J 7.8 Hz, CH2CH2CO2H); 13C NMR (100 MHz,
4.2. Synthesis of 6a-OMe
CDCl3): d 178.9, 158.8,131.3,130.8,124.4, 118.1,113.7, 55.5, 34.1, 30.2;
HRMS (EI): m/z calcd for C10H1179BrO3 [M]þ: 257.9886; found:
4.2.1. 2-Bromo-4-methoxybenzaldehyde (11). 2-Bromo-4-methoxy-
benzaldehyde (11) was prepared in 67% from 10, as described by
Durst,37 by the method of Comins and Brown.20 Mp 77e79 ꢀC; lit.37
d 10.21 (1H, d, J 0.8 Hz,
CHO), 7.88 (1H, d, J 8.7 Hz, AreH5), 7.13 (1H, d, J 2.5 Hz, AreH3), 6.93
(1H, ddd, J 8.7, 2.5, 0.8 Hz, AreH6), 3.88 (3H, s, CH3).
257.9889.
4.2.5. 4-Bromo-6-methoxy-2,3-dihydro-1H-inden-1-one (15). A so-
lution of 14 (0.740 g, 2.86 mmol) and SOCl2 (20 mL) was refluxed
under a flow of N2 for 3 h. The solution was cooled to rt and SOCl2
was removed under reduced pressure. The resulting yellow oil was
dissolved in CH2Cl2 (60 mL), cooled to 0 ꢀC, and added AlCl3
(0.500 g, 3.75 mmol) against a positive N2-flow. The mixture was
warmed to rt and stirred for 20 h. The red suspension was cooled to
0 ꢀC. HCl (1 M in H2O, 15 mL) was added, followed by H2O (40 mL).
The phases were separated, and the water phase was extracted
with DCM (2ꢂ50 mL). The organic extracts were treated with brine
(100 mL), dried (MgSO4), filtered, and concentrated. The title
compound 15 was isolated after column chromatography (10%
EtOAc/n-hexane) as a white solid (0.345 g, 1.43 mmol, 50%). Mp
mp 70e71 ꢀC. 1H NMR (300 MHz, CDCl3):
4.2.2. (E)-Ethyl 3-(2-bromo-4-methoxyphenyl)-acrylate (12). To
a suspension of NaH (1.24 g, 51.7 mmol) in THF (300 mL) at 0 ꢀC was
added triethyl phosphonoacetate (7.20 mL, 36.6 mmol) dropwise
over 5 min. The mixture was stirred at 0 ꢀC for 1 h. A solution of 11
(6.90 g, 32.1 mmol) in THF (210 mL) was added dropwise over 1 h.
The resulting solution was stirred at 0 ꢀC for 30 min, warmed to rt,
and stirred for additional 3 h. The reaction was quenched by ad-
dition of NH4Cl (satd aq, 40 mL), and the solvent volume was

8468
S. Melnes et al. / Tetrahedron 68 (2012) 8463e8471
102e103 ꢀC; Rf (20% EtOAc/n-hexane) 0.31. IR (KBr): 3049 (w), 2961
2.87e2.77 (1H, m, OCH2CH2Ar), 2.72e2.64 (1H, m, OCH2CH2Ar),
1.51 (3H, d, J 6.4 Hz, CH3); 13C NMR (100 MHz, CDCl3):
158.0, 142.6,
(w), 2927 (w), 2827 (w), 1705 (s), 1608 (m), 1479 (s), 1299 (s), 1257
d
(s), 1031 (s) cmꢁ1; 1H NMR (400 MHz, CDCl3):
d
7.38 (1H, d, J 2.3 Hz,
125.4, 125.2, 115.7, 110.1, 72.3, 63.6, 55.5, 29.1, 21.7; HRMS (EI): m/z
AreH), 7.16 (1H, d, J 2.3 Hz, AreH), 3.83 (3H, s, OCH3), 3.03e2.98
calcd for C11H1379BrO2 [M]þ: 256.0093; found: 256.0093.
(2H, m, ArCH2CH2CO), 2.77e2.72 (2H, m, ArCH2CH2CO); 13C NMR
(100 MHz, CDCl3):
d
206.0, 160.2, 147.2, 139.5, 125.9, 122.1, 104.9,
4.3. Silver catalyzed bromination of terminal alkynes; prep-
aration of 18c and 19b
55.9, 36.8, 26.0; HRMS (EI): m/z calcd for C10H979BrO2 [M]þ:
239.9785; found 239.9780.
The brominated alkynes 18c and 19b was prepared in according
4.2.6. 7-Bromo-5-methoxy-3-methyl-1H-indene
(16). MeMgBr
with a procedure developed by Hofmeister et al.15
(3.0 M in Et2O, 2.35 mL, 7.05 mmol) was added dropwise to a sus-
pension of 15 (1.00 g, 4.15 mmol) in Et2O (30 mL) at rt. The mixture
transformed temporary into a yellow solution, before formation of
a new suspension was observed. After stirring at rt for 30 min, the
suspension was cooled to 0 ꢀC, and added HCl (concn, 22 mL). The
mixture was warmed to rt and stirred for 30 min, before H2O
(50 mL) and Et2O (50 mL) was added. The phases were separated,
and the water phase was extracted with Et2O (2ꢂ50 mL). The col-
lected organic extracts were treated with brine (150 mL), dried
(MgSO4), filtered, and concentrated, to give 16 (0.991 g, 4.14 mmol,
100%) as a white solid. Mp 54e55 ꢀC; Rf (20% EtOAc/n-hexane) 0.51.
IR (neat): 3066 (w), 3004 (w), 2938 (w), 2830 (w), 1558 (m), 1473
(m), 1253 (m), 1213 (m), 1060 (s), 831 (s) cmꢁ1; 1H NMR (400 MHz,
4.3.1. 4-Bromobut-3-yn-2-ol (18c).38 To a mixture of NBS (12.5 g,
70.2 mmol) and AgNO3 (1.09 g, 6.42 mmol) in acetone (100 mL) was
added 18a (5.0 mL, 64 mmol). The suspension was stirred for 1 h at
rt before it was concentrated under vacuum. The resulting gray
mass was partitioned between ice water (100 mL) and Et2O
(100 mL). The phases were separated and the water phase was
extracted with Et2O (2ꢂ100 mL). The collected organic extracts
were treated with brine (300 mL), dried (MgSO4), filtrated, and
concentrated under reduced pressure. The title compound (7.59 g,
50.9 mmol, 80%) was isolated as a yellow oil after column chro-
matography (10e20% EtOAc/n-hexane). 1H NMR (400 MHz, CDCl3):
d
4.54 (1H, q, J 6.6 Hz, CH), 2.11 (1H, br s, OH), 1.46 (3H, d, J 6.6 Hz,
CDCl3):
d
6.90 (1H, d, J 2.2 Hz, AreH), 6.82 (1H, d, J 2.2 Hz, AreH),
CH3).
6.28e6.24 (1H, m, alkeneeH), 3.83 (3H, s, OCH3), 3.23 (2H, app. p, J
2.1 Hz, CH2), 2.11 (3H, app. q, J 2.1 Hz, CH3); 13C NMR (100 MHz,
4.3.2. 4-Bromobut-3-yn-1-ol (19b).39 The title compound was
obtained from 19a (5.0 mL, 66 mmol) following the procedure
described for 18c. Purification by column chromatography (10e20%
EtOAc/n-hexane) afforded 19b (9.09 g, 61.0 mmol, 92%) as a yellow
CDCl3):
d 159.8, 148.3, 139.9, 136.5, 130.7, 118.3, 113.0, 104.7, 55.8,
38.5, 13.2; HRMS (EI): m/z calcd for C11H1179BrO [M]þ: 237.9988;
found: 237.9984.
oil. 1H NMR (400 MHz, CDCl3):
d 3.74 (2H, app q, J 6.0 Hz,
4.2.7. 1-(3-Bromo-2-(2-hydroxyethyl)-5-methoxyphenyl)ethanol
(17). A solution of 16 (3.03 g, 12.7 mmol) in DCM (50 mL) was
cooled to ꢁ78 ꢀC. A flow of O3 was added, until a persisting blue
color was observed. O2 was bubbled through the solution until the
color disappeared (ca. 5 min). NaBH4 (4.81 g, 127 mmol) and MeOH
(50 mL) was added, and the mixture was slowly warmed to rt and
stirred for 18 h. The solvents were removed under reduced pres-
sure, and the resulting white mass was stirred with CHCl3 (100 mL)
and NH4Cl (satd aq, 100 mL) for 30 min. The phases were separated,
the water phase extracted with CHCl3 (2ꢂ100 mL), and the col-
lected organic extracts were dried (MgSO4), filtered and, concen-
trated, to yield 17 as a white solid (3.27 g, 11.9 mmol, 94%). Mp
115e117 ꢀC; Rf (10% MeOH/DCM) 0.32. IR (neat): 3271 (br m), 2954
(w), 2869 (w),1601 (m),1468 (m),1252 (s),1037 (s),1027 (s), 854 (s)
CH2CH2OH), 2.50 (2H, t, J 6.2 Hz, CH2CH2OH), 1.82 (1H, br t, J 6.1 Hz,
OH).
4.3.3. 3-Bromopropiolic acid (20b).26 The title compound was
prepared from 20a (6.15 mL, 99.9 mmol) and isolated as a white
solid (5.45 g, 36.6 mmol, 37%), as reported by Morisawa and co-
workers26 Mp 84e85 ꢀC; lit.26 mp 84e85 ꢀC. IR (neat): 2540 (m, br),
2186 (m), 1682 (s), 1605 (s), 1264 (s), 903 (s), 742 (s), 714 (s), 679 (s),
579 (m) cmꢁ1; 1H NMR (400 MHz, DMSO-d6): 13.97 (br s, OH); 13
d C
NMR (100 MHz, DMSO-d6): d 153.1, 73.6, 54.1; HRMS (EI) m/z calcd
for C3H79BrO2 [Mþ]: 147.9154; found: 147.9157.
4.4. Preparation of diynes 8
cmꢁ1; 1H NMR (400 MHz, CDCl3):
d
7.08 (1H, d, J 2.7 Hz, AreH), 7.04
4.4.1. Preparation of 8a and b by the Nicholas reaction. Diynes 8a
and b were obtained from a Nicholas reaction procedure described
by Martin, Martin and Ortega et al.40
(1H, d, J 2.7 Hz, AreH), 5.14 (1H, q, J 6.4 Hz, CH), 3.94e3.82 (2H, m,
CH2CH2OH), 3.79 (3H, s, OCH3), 3.50 (1H, br s, OH), 3.16e3.03 (2H,
m, CH2CH2OH), 2.30 (1H, br s, OH) 1.49 (3H, d, J 6.4 Hz, CH3); 13C
NMR (100 MHz, CDCl3):
d
158.7, 146.9, 127.1, 126.0, 117.6, 111.1, 66.3,
4.4.1.1. 1-Bromo-4-(but-3-yn-2-yloxy)but-1-yne(8a). To a solu-
tion of Co2(CO)8 (6.71 g, 19.6 mmol) in DCM (70 mL) was added 18a
(1.38 mL, 17.6 mmol) at rt. The mixture was stirred for 2 h under
a flow of N2. The deep red solution was concentrated under reduced
pressure. To the resulting oil was added a solution of 19b (13.1 g,
87.9 mmol) in DCM (35 mL), and the solution was cooled to 0 ꢀC
under Ar-atm. BF3ꢂOEt2 (5.61 mL, 44.7 mmol) was added slowly,
and the reaction mixture was stirred at 0 ꢀC for 1 h. A solution of
NaHCO3 (satd aq, 30 mL) was added, the mixture was warmed to rt
and stirred for 15 min. The phases were separated, and the water
phase was extracted with DCM (3ꢂ30 mL). The collected organic
extracts were dried (MgSO4), filtered, and concentrated to a deep
red oil. The oil was dissolved in acetone (100 mL) and cooled to 0 ꢀC.
Ceric ammonium nitrate (CAN, 39.1 g, 71.3 mmol) was added in
portions over 15 min. The mixture was warmed to rt and stirred
until no gas evolution was observed (ca. 15 min). The resulting pink
solution was concentrated to a solid pink residue, which was par-
titioned between Et2O (70 mL) and H2O (70 mL). The phases were
61.7, 55.5, 33.4, 23.1; HRMS (ESI): m/z calcd for C11H1579BrNaO3
[MþNa]þ: 297.0097; found: 297.0088.
4.2.8. 5-Bromo-7-methoxy-1-methylisochroman (6a-OMe). A mix-
ture of 17 (3.20 g, 11.6 mmol) and p-TsOH (0.227 g, 1.19 mmol) was
added toluene (100 mL) and DCM (50 mL), and warmed to reflux for
24 h. The resulting dark red solution was cooled to rt and con-
centrated under vacuum. The crude oil was dissolved in DCM
(50 mL), washed with H2O (50 mL) and brine (50 mL), dried
(MgSO4), filtered, and concentrated. Purification by column chro-
matography (2% EtOAc/n-hexane) gave 6a-OMe as a yellow oil
(2.59 g, 10.1 mmol, 87%). Rf (50% EtOAc/n-hexane) 0.59. IR (neat):
2933 (w), 2834 (w), 1604 (m), 1558 (m), 1474 (s). 1270 (s), 1118 (s),
1093 (s), 1042 (s), 854 (s), 793 (s) cmꢁ1; 1H NMR (400 MHz, CDCl3):
d
7.02 (1H, d, J 2.5 Hz, AreH), 6.60 (1H, d, J 2.5 Hz, AreH), 4.77 (1H,
q, J 6.4 Hz, CH), 4.17 (1H, ddd, J 11.5, 5.8, 3.3 Hz, OCH2CH2Ar), 3.78
(3H, s, OCH3), 3.74 (1H, ddd, J 11.5, 9.8, 4.2 Hz, OCH2CH2Ar)

S. Melnes et al. / Tetrahedron 68 (2012) 8463e8471
8469
separated, and the water phase was extracted with Et2O (2ꢂ70 mL).
The collected organic phases were treated with brine (150 mL),
dried (MgSO4), filtered, and concentrated. The title compound 8a
was isolated as a pale yellow oil (2.12 g, 10.5 mmol, 60%), after
column chromatography (2% EtOAc/n-hexane). Rf (20% EtOAc/n-
hexane) 0.60. IR (neat): 3295 (m), 2988 (w), 2870 (w), 1327 (m),
NMR (100 MHz, CDCl3):
d
151.4, 102.1, 91.1, 72.6, 63.1, 53.6, 21.4,
ꢁ0.2; HRMS (EI): m/z calcd for C10H1379BrO2Si [M]þ: 271.9863;
found: 271.9865.
4.4.2.4. 4-(Trimethylsilyl)but-3-yn-2-yl propiolate (8f). Diyne 8f
(4.60 g, 23.7 mmol, 73%) was prepared from 20a (2.00 mL,
32.5 mmol) and 18d (8.20 mL, 48.8 mmol) in accordance with the
general Mitsunobu procedure, and isolated as a colorless liquid
after column chromatography (5% EtOAc/n-hexane). Rf (10% EtOAc/
n-hexane) 0.39. IR (neat): 3267 (w, br), 2961 (w), 2117 (m), 1716 (s),
1104 (s), 636 (s) cmꢁ1; 1H NMR (400 MHz, CDCl3):
d 4.20 (1H, dq, J
6.6, 2.1 Hz, CH), 3.82 (1H, dt, J 9.1, 7.0 Hz, OCH2CH2C), 3.53 (1H, td, J
9.1, 7.0 Hz, OCH2CH2C), 2.51 (2H, t, J 7.0 Hz, OCH2CH2C), 2.43 (1H, d, J
2.1 Hz, CCH), 1.45 (3H, d, J 6.6 Hz, CH3); 13C NMR (100 MHz, CDCl3):
d
83.5, 77.1, 73.3, 66.5, 65.4, 39.3, 22.1, 21.1; HRMS (EI): m/z calcd for
1218 (s), 839 (s), 755 (s) cmꢁ1
(1H, q, J 6.7 Hz, CH), 2.92 (1H, s, alkyneeH), 1.54 (3H, d, J 6.7 Hz,
CH3), 0.18 (9H, s, TMS); 13C NMR (100 MHz, CDCl3):
151.6, 102.1,
; d 5.51
1H NMR (400 MHz, CDCl3):
C7H779BrO [MꢁCH2]þ: 185.9675; found: 185.9677. The excess of
19b was recycled from column chromatography (Rf (20% EtOAc/n-
hexane) 0.15).
d
91.1, 75.4, 74.6, 63.0, 21.4, ꢁ0.17; HRMS (ESI): m/z calcd for
C10H18NO2Si [MþNH4]þ: 212.1101; found: 212.1103.
4.4.1.2. 1-Bromo-4-(prop-2-ynyloxy)but-1-yne (8b). Diyne 8b
was obtained from 18b (0.29 mL, 5.0 mmol) and 19b (3.69 g,
24.8 mmol), following the procedure described for 8a. Purification
by column chromatography (2% EtOAc/n-hexane) gave 8b (0.469 g,
2.51 mmol, 50%) as a pale yellow oil. Rf (10% EtOAc in n-hexane)
4.4.2.5. But-3-yn-2-yl but-2-ynoate (8g). Diyne 8g (0.621 g,
4.56 mmol, 77%) was prepared from 20c (0.496 g, 5.90 mmol) and
18a (0.69 mL, 8.8 mmol) in accordance with the general Mitsunobu
procedure, and isolated as a pale yellow oil after column chroma-
tography (5% EtOAc/n-hexane). Rf (10% EtOAc/n-hexane) 0.26. IR
(neat): 3293 (m), 2994 (w), 2310 (w), 2240 (m), 1709 (s), 1242 (s),
0.40. IR (neat): 3293 (m), 2870 (w),1356 (m), 1097 (s), 634 (s) cmꢁ1
;
1H NMR (400 MHz, CDCl3):
t, J 6.9 Hz, OCH2CH2C), 2.52 (2H, t, J 6.9 Hz, OCH2CH2C), 2.45 (1H, t, J
d 4.19 (2H, d, J 2.4 Hz, OCH2C), 3.65 (2H,
1059 (s) cmꢁ1 1H NMR (400 MHz, CDCl3):
; d 5.47 (1H, dq, J 6.7,
2.4 Hz, CH); 13C NMR (100 MHz, CDCl3):
d
79.5, 76.9, 74.8, 67.7, 58.3,
2.2 Hz, CH), 2.49 (1H, d, J 2.2 Hz, alkyneeH), 2.00 (3H, s, alky-
39.5, 21.0; HRMS (ESI): m/z calcd for C7H1179BrNO [MþNH4]þ:
neeCH3), 1.55 (3H, d, J 6.7 Hz, CH3); 13C NMR (100 MHz, CDCl3):
204.0019; found: 204.0020.
d 152.4, 86.5, 81.2, 73.6, 72.0, 61.4, 21.0, 3.8; HRMS (ESI): m/z calcd
for C8H12NO2 [MþNH4]þ: 154.0863; found: 154.0862.
4.4.2. General procedure for the Mitsunobu reaction. A solution of
20 (1 equiv) and DEAD (40 wt % in toluene, 1 equiv) in Et2O was
added dropwise over 20 min to a cooled (0 ꢀC) solution of PPh3
(1 equiv) and 18 (1.5 equiv) in Et2O (concn 20¼0.3 M). The resulting
suspension was stirred and warmed to rt. After 20 h, the mixture
was filtered through a silica-pad, pre-packed with Et2O. The pad
was washed with Et2O. The filtrate was concentrated, and the crude
product was purified by column chromatography.
4.4.3. But-3-yn-yl 3-bromopropiolate (8c) from 8f. A solution of 8f
(0.983 g, 5.06 mmol) in THF (15 mL) was cooled to ꢁ78 ꢀC and
added LHMDS-solution (1.0 M in THF, 6.1 mL, 6.1 mmol) dropwise
over 15 min. The mixture was stirred at ꢁ78 ꢀC for 1 h. Br2 (0.31 mL,
6.1 mmol) was added dropwise over 5 min. The deep red solution
was warmed to 0 ꢀC, and stirred for 1 h. A solution of NH4Cl (satd
aq, 15 mL) was added to quench the reaction. The mixture was
warmed to rt and the phases were separated. The water phase was
extracted with Et2O (2ꢂ15 mL). The collected organic extracts were
treated with Na2S2O3 (satd aq, 2ꢂ30 mL), dried (MgSO4), filtered,
and concentrated to a deep red oil. The crude was purified by col-
umn chromatography (2% EtOAc/n-hexane) to give 8e as a pale
yellow oil (1.063 g, 3.891 mmol, 77%). Spectroscopic data for 8e are
given in chapter 4.4.2.3.
To a solution of 8e (0.955 g, 3.49 mmol) in acetone (25 mL) was
added AgNO3 (59.4 mg, 0.349 mmol) and water (6.30 mL,
0.349 mol). The mixture was stirred at rt in darkness. After 20 h, the
yellow suspension was poured into brine (40 mL). The phases were
separated and the water phase was extracted with Et2O (3ꢂ40 mL).
The collected organic extracts were washed with brine (150 mL),
dried (MgSO4), filtered, and concentrated. The crude was purified
by column chromatography (2% EtOAc/n-hexane) to afford 8c
(0.623 g, 3.10 mmol, 89%) as a yellow liquid. Spectroscopic data for
8c are given in chapter 4.4.2.1.
4.4.2.1. But-3-yn-yl 3-bromopropiolate (8c). Diyne 8c (0.496 g,
2.47 mmol, 22%) was prepared from 20b (1.67 g, 11.2 mmol) and 18a
(1.32 mL, 16.8 mmol) in accordance with the general Mitsunobu
procedure, and isolated as a yellow liquid after column chromatog-
raphy (10% EtOAc/n-hexane). Rf (10% EtOAc/n-hexane) 0.36. IR (neat):
3297 (m), 2993 (w), 2215 (m), 2191 (m), 1709 (s), 1222 (s), 1022 (s)
cmꢁ1; 1H NMR (400 MHz, CDCl3):
d
5.48 (1H, dq, J 6.7, 2.1 Hz, CH), 2.52
(1H, d, J 2.1 Hz, alkyneeH), 1.56 (3H, d, J 6.7 Hz, CH3); 13C NMR
(100 MHz, CDCl3): d 151.4, 80.9, 74.2, 72.5, 62.4, 53.9, 21.1; HRMS (EI):
m/z calcd for C7H579BrO2 [M]þ: 199.9467; found: 199.9464.
4.4.2.2. 4-Bromobut-3-yn-2-yl propiolate (8d). Diyne 8d (0.554 g,
2.76 mmol, 65%) was prepared from 20a (0.260 mL, 4.22 mmol) and
18c (0.95 g, 6.4 mmol) in accordance with the general Mitsunobu
procedure, and isolated as a yellow liquid after column chromatog-
raphy (5% EtOAc/n-hexane). Rf (20% EtOAc/n-hexane) 0.42. IR (neat):
3289 (m), 2998 (w), 2214 (w), 2116 (m), 1712 (s), 1213 (s), 1032 (s),
753 (s) cmꢁ1; 1H NMR (400 MHz, CDCl3):
d
5.50 (1H, q, J 6.6 Hz, CH),
4.5. Preparation of 6 by cyclotrimerization of 8 and 9
2.94 (1H, s, alkyneeH),1.56 (3H, d, J 6.6 Hz, CH3); 13C NMR (100 MHz,
CDCl3):
d
151.4, 77.1, 75.5, 74.2, 63.0, 47.1, 20.9; HRMS (EI): m/z calcd
General procedures for each method are given under. Yields and
selectivity data are given in Table 2. Characterization data and
work-up details for the products are given under the general
procedures.
for C7H579BrO2 [M]þ: 199.9467; found: 199.9465.
4.4.2.3. 4-(Trimethylsilyl)but-3-yn-2-yl 3-bromopropiolate
(8e). Diyne 8e (0.240 g, 0.880 mmol, 25%) was prepared from
20b (0.530 g, 3.56 mmol) and 18d (0.90 mL, 5.4 mmol) in accor-
dance with the general Mitsunobu procedure, and isolated as a pale
yellow oil after column chromatography (2% EtOAc/n-hexane). Rf
(10% EtOAc/n-hexane) 0.46. IR (neat): 2961 (w), 2210 (w), 2193 (w),
4.5.1. Method A: Rh-catalyzed cyclotrimerization. The Rh-catalyzed
alkyne cyclotrimerization reactions were performed as described
by Tanaka and co-workers29,30
[Rh(cod)2]BF4 (15 mg, 0.037 mmol) and BINAP (23 mg, 0.037)
were added DCM (5 mL) at rt, and the solution was stirred for 5 min.
The flask was evacuated, and 1 atm of H2 was introduced (balloon).
1716 (s), 1222 (s), 838 (s) cmꢁ1
; d 5.50
1H NMR (400 MHz, CDCl3):
(1H, q, J 6.7 Hz, CH), 1.53 (3H, d, J 6.7 Hz, CH3), 0.17 (9H, s, TMS); 13
C

8470
S. Melnes et al. / Tetrahedron 68 (2012) 8463e8471
After stirring at rt for 1 h, the mixture was concentrated to dryness,
re-dissolved in DCE (4 mL), and 9 (1.06 mL, 7.50 mmol) was added.
A solution of 8 (0.75 mmol) in DCE (3.5 mL) was added dropwise
over 10 min via cannula, and the mixture was stirred at rt for 20 h.
The resulting crude solution was concentrated under vacuum, an-
alyzed by 1H NMR, and purified by column chromatography.
n-hexane) (Table 2, entries 6 and 7). Mp 95e97 ꢀC; Rf (10% EtOAc/n-
hexane) 0.20. IR (neat): 2953 (w), 1755 (s), 1319 (s), 1043 (s), 875 (s),
835 (s), 755 (s) cmꢁ1
;
1H NMR (400 MHz, CDCl3):
d
7.75 (1H, s,
AreH), 7.45 (1H, s, AreH), 4.48 (1H, q, J 6.7 Hz, CH), 1.64 (3H, d, J
6.7 Hz, CH3), 0.33 (9H, s, TMS); 13C NMR (100 MHz, CDCl3):
168.0,
d
153.0, 151.4, 138.3, 125.1, 124.5, 120.7, 76.2, 20.6, ꢁ1.2; HRMS (ESI):
m/z calcd for C12H1979BrNO2Si [MþNH4]þ: 316.0363; found:
316.0360.
4.5.2. Method B: Ru-catalyzed cyclotrimerization. The Ru-catalyzed
alkyne cyclotrimerization reactions were performed as described
by Yamamoto and co-workers32,33
4.5.8. 7-Bromo-3-methyl-6-(trimethylsilyl)iso-benzofuran-1(3H)-
one(7c). The title compound was prepared from 8c and 9, and
isolated as a yellow oil in mixture with the regioisomer 6c after
column chromatography (10% EtOAc/n-hexane) (Table 2, entry 6). Rf
A degassed solution of
8 (0.75 mmol) and 9 (0.53 mL,
3.75 mmol) in DCE (3.75 mL) was added dropwise at rt over 10 min
to Cp*Ru(cod)Cl (14.2 mg, 0.0375 mmol) via cannula. The deep red
solution was stirred at rt for 20 h. The resulting crude mixture was
concentrated under reduced pressure, analyzed by 1H NMR, and
purified by column chromatography.
(10% EtOAc/n-hexane) 0.17. 1H NMR (400 MHz, CDCl3):
d 7.70 (1H, d,
J 7.5 Hz, AreH), 7.35 (1H, d, J 7.5 Hz, AreH), 4.45 (1H, q, J 6.6 Hz, CH),
1.62 (3H, d, J 6.6 Hz, CH3), 0.45 (9H, s, TMS); 13C NMR (100 MHz,
CDCl3):
d 168.2, 154.5, 144.5, 141.2, 128.8, 124.2, 120.0, 75.4,
4.5.3. (5-Bromo-1-methylisochroman-7-yl)trimethylsilane (6a). The
title compound was prepared from 8a and 9, and isolated as a yel-
low oil after column chromatography (2% EtOAc/n-hexane) (Table
2, entries 1 and 2). Rf (10% EtOAc/n-hexane) 0.44. IR (neat): 2954
20.5, ꢁ0.2.
4.5.9. 4-Bromo-3-methyl-6-(trimethylsilyl)iso-benzofuran-1(3H)-
one (6d) and 4-bromo-3-methyl-5-(trimethylsilyl)iso-benzofuran-
1(3H)-one (7d). Cyclotrimerization experiments of 8d and 9 (Table
2, entries 8, 9, and 10) afforded inseparable mixtures of 6d and 7d.
The mixtures were isolated as yellow oils after column chroma-
tography (5% EtOAc/n-hexane).
(w), 1370 (m), 1249 (s), 1116 (s), 835 (s), 753 (s) cmꢁ1
;
1H NMR
(400 MHz, CDCl3):
d 7.54 (1H, s, AreH), 7.14 (1H, s, AreH), 4.82 (1H,
q, J 6.4 Hz, CH), 4.17 (1H, ddd, J 11.5, 5.8, 3.5 Hz, OCH2CH2Ar), 3.77
(1H, ddd, J 11.5, 9.6, 4.2 Hz, OCH2CH2Ar), 2.94e2.84 (1H, m, OCH2
-
CH2Ar), 2.79e2.71 (1H, m, OCH2CH2Ar), 1.54 (3H, d, J 6.4 Hz, CH3),
Analytical data for a 1:0.6 mixture of 6d and 7d: Rf (10% EtOAc/n-
hexane): 0.28. IR (neat): 2954 (w),1769 (s), 1317 (m), 1250 (m),1095
(s), 1046 (s), 834 (s), 755 (s) cmꢁ1; HRMS (EI): m/z calcd for
C12H1579BrO2Si [M]þ: 298.0019; found: 298.0013.
0.26 (9H, s, TMS); 13C NMR (100 MHz, CDCl3):
d 141.7, 140.4, 134.7,
133.9,128.4, 125.7, 72.2, 63.2, 30.0, 21.8, ꢁ1.2; HRMS (ESI): m/z calcd
for C13H2379BrNOSi [MþNH4]þ: 316.0727; found: 316.0724.
NMR data for 6d: 1H NMR (400 MHz, CDCl3):
d 7.98 (1H, s,
4.5.4. (5-Bromo-1-methylisochroman-6-yl)trimethylsilane (7a). The
title compound was prepared from 8a and 9, and isolated in
a mixture with the regioisomer 6a as a yellow oil, after column
chromatography (2% EtOAc/n-hexane) (Table 2, entries 1 and 2). 1H
AreH), 7.87 (1H, s, AreH), 5.52 (1H, q, J 6.6 Hz, CH), 1.75 (3H, d, J
6.6 Hz, CH3), 0.32 (9H, s, TMS); 13C NMR (100 MHz, CDCl3):
d 169.6,
150.4, 146.0, 142.1, 129.7, 127.8, 116.8, 78.5, 18.7, ꢁ1.1.
NMR data for 7d: 1H NMR (400 MHz, CDCl3):
d 7.81 (1H, d, J
NMR (400 MHz, CDCl3):
d
7.26 (1H, d, J 7.8 Hz, AreH), 7.03 (1H, d, J
7.5 Hz, AreH), 7.61 (1H, d, J 7.5 Hz, AreH), 5.53 (1H, q, J 6.5 Hz, CH),
7.8 Hz, AreH), 4.81 (1H, q, J 6.5 Hz, CH), 4.19 (1H, ddd, J 11.5, 5.8,
3.3 Hz, OCH2CH2Ar), 3.77 (1H, ddd, J 11.5, 9.8, 4.2 Hz, OCH2CH2Ar),
2.94e2.84 (1H, m, OCH2CH2Ar), 2.81e2.74 (1H, m, OCH2CH2Ar),
1.52 (3H, d, J 6.5 Hz, CH3), 0.39 (9H, s, TMS); 13C NMR (100 MHz,
1.77 (3H, d, J 6.5 Hz, CH3), 0.46 (9H, s, TMS); 13C NMR (100 MHz,
CDCl3):
d 169.4, 150.3, 149.6, 137.0, 128.8, 124.1, 123.7, 79.1,
18.9, ꢁ0.4.
CDCl3):
21.7, ꢁ0.4.
d
143.2, 139.7, 133.8, 133.5, 133.4, 123.1, 72.2, 63.6, 30.6,
4.5.10. 3,7-Dimethyl-5-(trimethylsilyl)isobenzo-furan-1(3H)-one
(6g). 3,7-Dimethyl-5-(trimethylsilyl)iso-benzofuran-1(3H)-one (6g)
was prepared by the Ru-catalytic general procedure from 8g and 9,
and isolated as a white solid after column chromatography (5%
EtOAc/n-hexane) (Table 2, entry 11). Mp 77e78 ꢀC; Rf (10% EtOAc/n-
hexane) 0.34. IR (neat): 2953 (m),1745 (s),1329 (s),1242 (s),1046 (s),
4.5.5. (5-Bromoisochroman-7-yl)trimethylsilane (6b). The title
compound was prepared from 8b and 9, and isolated as a yellow oil
after column chromatography (2% EtOAc/n-hexane) (Table 2, en-
tries 3, 4 and 5). Rf (10% EtOAc/n-hexane) 0.39. IR (neat): 2954 (w),
877 (s), 825 (s), 752 (s) cmꢁ1 1H NMR (400 MHz, CDCl3):
; d 7.38
2851 (w), 1248 (m), 1235 (m), 1089 (m), 863 (s), 833 (s) cmꢁ1
;
1H
(1H,s, AreH), 7.34 (1H, s, AreH), 5.48 (1H, q, J 6.7 Hz, CH), 2.69 (3H, s,
NMR (400 MHz, CDCl3):
d 7.53 (1H, s, AreH), 7.05 (1H, s, AreH), 4.74
AreCH3), 1.62 (3H, d, J 6.7 Hz, CH3), 0.31 (9H, s, TMS); 13C NMR
(2H, s, ArCH2O), 3.99 (2H, t, J 5.8 Hz, OCH2CH2Ar), 2.81 (2H, t, J
(100 MHz, CDCl3): d 170.8,150.8,148.5,138.2,135.4,123.7,123.4, 76.8,
5.8 Hz, OCH2CH2Ar), 0.25 (9H, s, TMS); 13C NMR (100 MHz, CDCl3):
20.6, 17.3, ꢁ1.3; HRMS (EI): m/z calcd for C13H18O2Si [M]þ: 234.1071;
d
140.5, 137.0, 134.8, 133.6, 128.2, 125.7, 67.9, 65.5, 29.3, ꢁ1.2; HRMS
found: 234.1074.
(EI): m/z calcd for C12H1779BrOSi [M]þ: 284.0227; found: 284.0224.
4.5.6. (5-Bromoisochroman-6-yl)trimethylsilane (7b). The title
compound was prepared from 8b and 9, and isolated as a yellow oil
in mixture with the regioisomer 6b, by column chromatography
(2% EtOAc/n-hexane) (Table 2, entries 3, 4, and 5). 1H NMR
Acknowledgements
We gratefully acknowledge the NT-faculty at NTNU for financial
support and Dr. Susana Villa Gonzales for helping with the MS-
analyses.
(400 MHz, CDCl3): d 7.25 (1H, d, J 7.5 Hz, AreH), 6.93 (1H, d, J 7.5 Hz,
AreH), 4.72 (2H, s, ArCH2O), 3.99 (2H, t, J 5.9 Hz, OCH2CH2Ar), 2.81
(2H, t, J 5.9 Hz, OCH2CH2Ar), 0.39 (9H, s, TMS); 13C NMR (100 MHz,
CDCl3):
d
139.8, 138.5, 133.8, 133.4, 133.2, 122.8, 67.8, 65.7,
Supplementary data
29.9, ꢁ0.3.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.07.087.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
4.5.7. 7-Bromo-3-methyl-5-(trimethylsilyl)iso-benzofuran-1(3H)-
one (6c). The title compound was prepared from 8c and 9, and
isolated as a white solid after column chromatography (10% EtOAc/

S. Melnes et al. / Tetrahedron 68 (2012) 8463e8471
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