Aryl N-methyliminodiacetic acid (MIDA) boronates from cyclotrimerization of ethynyl MIDA boronate with diynes

Article abstract of DOI:10.1016/j.tet.2013.07.027

Cyclotrimerizations of ethynyl N-methyliminodiacetic acid (MIDA) boronate (1) with 1,6-diynes 2 have been studied, using three different catalysts (based on ruthenium, rhodium, and iridium) and variable reaction conditions. Successful cyclotrimerization reactions were obtained with both Cp*RuCl(cod) and Rh(cod)₂BF₄/BINAP as pre-catalysts in THF or acetone. Ruthenium-catalyzed cyclotrimerization of an unsymmetrically bromo-substituted diyne (2f) with 1 was successfully scaled up (2 g) and included in a total synthesis strategy toward potential selective inhibitors of tyrosine kinase 2.

Full text of DOI:10.1016/j.tet.2013.07.027

Tetrahedron 69 (2013) 7910e7915
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Tetrahedron
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Aryl N-methyliminodiacetic acid (MIDA) boronates from
cyclotrimerization of ethynyl MIDA boronate with diynes
,
Silje Melnes a, Annette Bayer b, Odd R. 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:
Cyclotrimerizations of ethynyl N-methyliminodiacetic acid (MIDA) boronate (1) with 1,6-diynes 2 have
been studied, using three different catalysts (based on ruthenium, rhodium, and iridium) and variable
reaction conditions. Successful cyclotrimerization reactions were obtained with both Cp*RuCl(cod) and
Rh(cod)2BF4/BINAP as pre-catalysts in THF or acetone. Ruthenium-catalyzed cyclotrimerization of an
unsymmetrically bromo-substituted diyne (2f) with 1 was successfully scaled up (2 g) and included in
a total synthesis strategy toward potential selective inhibitors of tyrosine kinase 2.
Received 29 April 2013
Received in revised form 19 June 2013
Accepted 9 July 2013
Available online 16 July 2013
Keywords:
Alkyne cyclotrimerization
Aryl MIDA boronates
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
Alkynes are important components in several synthetic trans-
formations. For instance, transition metal catalyzed cyclo-
The high stability of N-methyliminodiacetic acid (MIDA) che-
lated boronic acids was first mentioned in the late 1980s.1,2 Two
decades later, the great value of the MIDA boronates was demon-
strated. In 2007, Burke and Gillis reported MIDA as a highly ver-
satile boronic acid protective group, and showed how the reactivity
could be controlled between two different reaction sites in iterative
SuzukieMiyaura cross coupling reactions of MIDA-protected hal-
oboronic acids.3 Since then, MIDA boronates have gained increased
popularity and shown to be remarkably useful in small molecule
synthesis of important building blocks,4e15 and in the synthesis of
natural products3,16e20 and peptides.21 In general, MIDA boronates
are stable to air, tolerant to a wide range of common reaction
conditions, and compatible to silica chromatography.4,17 Yet, they
can easily be deprotected to the corresponding boronic acids by
mild basic hydrolysis. Several MIDA boronates are now commer-
cially available. Among them is the alkyne building block ethynyl
MIDA boronate (1, Fig. 1), first described by Struble and co-workers
in 2010.22
trimerization of alkynes is a direct route to highly substituted
aromatic compounds.23e25 In our synthetic studies toward potential
selective inhibitors of tyrosine kinase 2, we have prepared highly
substituted aromatic key-compounds by ruthenium- and rhodium-
catalyzed cyclotrimerization of unsymmetrically substituted diynes
with ethynyltrimethylsilane.26 Our main goal is to selectively prepare
meta-substituted bicyclic products in high yield from simple alkyne
precursors (Scheme 1). In this context, we found MIDA-protected
arylboronic acids attractive [Y¼B(MIDA), Scheme 1], as boronic
acids can be precursors for hydroxyl-27,28 and amino groups.29 Nor-
mally, aryl MIDA boronates are prepared by condensation of MIDA
and the arylboronic acid.1,3,17 If the boronic acids are not easily ac-
cessible however, transition metal catalyzed cyclotrimerization of 1
should be a highly direct and powerful approach to more complex
aryl MIDA boronates, as those depicted in Scheme 1. Interestingly,
while our work was ongoing, Iannazzo and co-workers30 reported
failed attempts on cyclotrimerization of 1 under different reaction
conditions. The reason of their failure was not clarified.
We will here report the first successful formation of highly
substituted aryl MIDA boronates by transition metal catalyzed
cyclotrimerization reactions of 1 with diynes 2.
2. Results and discussion
Fig. 1. Ethynyl MIDA boronate (1).
A short screen for suitable reaction conditions was performed
with the unsymmetrically methyl-substituted diyne 2a (Table 1).
Three different transition metal complexes were tested as pre-
* Corresponding author. Tel.: þ47 73594101; fax: þ47 73550877; e-mail address:
odd.r.gautun@ntnu.no (O.R. Gautun).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.07.027

S. Melnes et al. / Tetrahedron 69 (2013) 7910e7915
7911
in Table 2. Diyne 2b has been utilized as a model substrate in many
studies of transition metal catalyzed alkyne cyclotrimerizations.37
Being an electron poor 1,6-diyne with two CO2Me-substituents
contributing positively to the kinetic ThorpeeIngold effect,38 2b is
especially suitable for such reactions. In this study, 2b reacted with
1 both under ruthenium- and rhodium-catalyzed conditions to give
the product 3b in high isolated yields (87 and 70%, respectively,
Table 2, entries 1 and 2). For the rhodium-catalyzed reaction, one
extra purification step was necessary to obtain pure 3b, which
might explain the lower isolated yield. Again, the iridium-catalyzed
cyclotrimerization did not proceed sufficiently, even though
cyclotrimerizations of 2b with this catalyst and selected monoynes
have been described.35 Only traces of 3b were observed (Table 2,
entry 3). The iridium-based catalyst was therefore concluded not
suitable for reactions with 1. As expected, the activated38 tosyl
amide tethered diyne 2c reacted smoothly under the ruthenium-
catalyzed conditions to afford aryl MIDA boronate 3c in 80% yield
(Table 2, entry 4).
Scheme 1. Synthetic goal: the preparation of meta-substituted bicyclic aromatic
compounds from simple alkyne precursors.
catalysts; Cp*RuCl(cod),31,32 Rh(cod)2BF4/BINAP,33,34 and Ir(cod)Cl/
DPPE35 [Cp*¼pentamethylcyclopentadienyl, cod¼1,5-cyclooctadi-
ene, BINAP¼2,20bis(diphenylphosphino)-1,10-binaphthyl, and DPPE-
¼ethylenebis(diphenylphosphine)]. Room temperature and 5 mol %
of catalyst were generally used. Initially, a ruthenium-catalyzed re-
action of 1 and 2a was performed in dichloroethane (DCE), a solvent
earlier employed for this catalyst (Table 1, entry 1).26 None of the
desired products, 3a and 4a, were detected by 1H NMR analysis of the
crude reaction mixture. A mixture of autotrimerizationproducts of 2a
was however seen. As the solubility of 1 in DCE was observed to be
poor, THF and acetone were tested as alternative solvents. In both
cases, the reaction worked smoothly, giving the meta-product 3a
selectively over 4a (Table 1, entries 2 and 5). The observed regiose-
lectivity in favor of the meta-product was in accordance with reports
from Yamamoto and co-workers,36 and with our own experience.26
The isolated total yield of 3a and 4a was slightly higher when ace-
tone was employed, compared to THF. The rhodium-based catalyst
also worked well both in THF and acetone (Table 1, entries 3 and 7).
However, the regioselectivity was only moderate in both cases, and in
favor of the ortho-product 4a. Unfortunately, the air-stable and easy-
to-handle iridium-based catalyst did not afford any reaction products
of 1 and 2a (Table 1, entries 4, 9, and 10), even though successful
cyclotrimerization of selected alkynes has been reported to work well
with this catalyst in both THF and acetone.35 Under no circumstances
were autotrimerization or other by-reactions of 1 observed. In gen-
eral, the total yield of 3a/4a increased when a large excess of 1 was
employed inthe reactions (compare Table 1, entries 5 and 6, and 7 and
8). However, removal of excess 1 from the product mixtures turned
out to be challenging, and hence, the amounts of 1 had to be kept as
low as possible. For the ruthenium-based catalyst, 1.5 equiv of 1 gave
satisfying results. Slightly more, 2 equiv of 1, were needed for the
rhodium-based catalyst to work effectively.
Table 2
Cyclotrimerization of 1 and 2
Entry
Diyne
1 (equiv)
Catalysta
Product (3/4)b
% Yieldc (3þ4)
1
2
3
4
5
6
7
8
2b
2b
2b
2c
2d
2d
2e
2e
2f
1.5
2
1.5
1.5
1.5
2
1.5
1.01
1.5
1.5
5
Ru
Rh
Ir
3b
3b
3b
3c
3d
3d
3e
3e
87
70
Based on our experience with 2a (Table 1), cyclotrimerization of
different diynes 2beh with 1 was examined. The results are given
Tracesb
80
Ru
Ru
Rh
Ru
Rh
Ru
Ru
Ru
Ru
53
64
Tracesb
46d,e
53f
Table 1
Cyclotrimerization of 1 and 2a
9
3fþ4f (87:13)
3gþ4gþ5 (1:0:1)
3gþ4gþ5 (4:0:1)
d
10
11
12
2g
2g
2h
ndg
ndg
nrh
1.5
a
Ru¼Cp*RuCl(cod); Rh¼[Rh(cod)2]BF4/BINAP; Ir¼[Ir(cod)Cl]2/DPPE.
b
c
d
e
f
Determined by 1H NMR of the crude.
Entry
1 (equiv)
Catalysta
Solvent
Time (h)
% Yieldb (3a/4a)c
Isolated yield after work-up.
Slow addition of 2.
1
2
3
4
5
6
7
8
9
1.5
1.5
2
1.5
1.5
1.1
2
1.1
1.5
3
Ru
Ru
Rh
Ir
DCE
THF
20
1
2
20
1
20
20
20
20
20
No reactiond
65 (88:12)
67 (37:63)
No reaction
84 (87:13)
59d (87:13)
66 (39:61)
Tracesd
Estimated yield from 1H NMR. Traces of 1 were still present after purification.
Pure 3f was isolated in 19% after washing the mixture with acetone.
nd¼not determined. Pure 3g was not isolated. Various amounts of 5 (Fig. 2) were
THF
g
THFe
obtained.
Ru
Ru
Rh
Rh
Ir
Acetone
Acetone
Acetone
Acetone
Acetonee
Acetonee
h
nr¼no reaction. A complex mixture of autotrimerization products of 2h was
observed after 1H NMR analysis of the crude.
No reaction
No reaction
10
Irf
Cyclotrimerization of the less activated oxygen-tethered diyne
2d with 1 resulted in the product 3d in slight lower yields. Here,
a higher yield was obtained from the rhodium-catalyzed procedure
(64%, entry 6), compared to the ruthenium-catalyzed method (53%,
entry 5). Slow addition of the diyne to a solution of 1 and the
rhodium-catalyst using a syringe pump, did not improve the yield
of 3d. Ruthenium-catalyzed cyclotrimerization of the terminally
a
Ru¼5 mol % Cp*RuCl(cod); Rh¼5 mol % [Rh(cod)2]BF4/BINAP; Ir¼2 mol % [Ir(cod)
Cl]2/DPPE.
b
c
d
e
f
Isolated yield after work-up.
Determined by 1H NMR analysis of crude.
A mixture of autotrimerization products of 2a was observed.
Reflux.
5 mol %.

7912
S. Melnes et al. / Tetrahedron 69 (2013) 7910e7915
methyl-substituted diyne 2e with 1 afforded only traces of the
product 3e (Table 2, entry 7). Fortunately, rhodium-catalysis was
more successful. The rhodium-catalyst afforded 3e in 46% yield
(estimated from 1H NMR, Table 2, entry 8) when 2e was added by
slow addition.
isolated in 19% yield after washing the product mixture with ace-
tone. The reaction was easily scaled up (2.7 g, 13 mmol 2f, Scheme
3), and fortunately, 1H NMR analysis of the crude showed no change
in regioselectivity. The crude mixture of 3f and 4f was directly
transformed to the wanted phenols by treatment with NaOH/H2O2
(aq). The pure regioisomer 7 was isolated in 40% yield after simply
washing the product mixture with acetone.
We then turned our attention to the more challenging diynes
2feh (Table 2, entries 9e12). Not unexpectedly, the yields dropped.
The reduced yields can partly be explained by the less suitable
electronic and/or steric properties of the diynes. In some cases,
autotrimerization of the diyne gained increased importance. The
formation of 3g by ruthenium-catalyzed cyclotrimerization of 2g
with 1 competed with formation of the by-product 5 (Fig. 2) from
autotrimerization of 2g (Table 2, entries 10 and 11). The formation
of 5 could, however, be suppressed by increasing the load of 1 in the
reaction. Applying 5 equiv of 1 instead of 1.5, the ratio 3g/5 changed
from 1:1 to 4:1. The unwanted regioisomer 4g was not observed
from the reactions of 2g. For diyne 2h, only autotrimerization
products were observed after ruthenium catalysis (Table 2, entry
12). Increasing the equivalents of 1 from 1.5 to 5 did not help. The
rhodium catalyst was neither efficient, and applying slow addition
of 2h did not help. These results probably originate from unfavor-
able steric- and electronic properties of the diyne.
Scheme 3. Preparation of 7 from 2f and 1.
3. Conclusion
In summary, we have described the first successful transition
metal catalyzed cyclotrimerization reactions of 1 with different
diynes 2. Three different pre-catalysts have been tested, Cp*
RuCl(cod), [Rh(cod)2]BF4/BINAP, and [Ir(cod)Cl]2/DPPE, of which
the former two worked well in acetone and THF at rt. The cyclo-
trimerization reactions of 1 with 2 provided rapid construction of
highly substituted aryl MIDA boronates not easily accessible from
other conventional methods. Several synthetic transformations of
aryl MIDA boronates are available, and hence, cyclotrimerization of
1 is a promising new approach to molecules of high complexity.
Fig. 2. Side-product 5 from autotrimerizaton of 2g.
In addition to the diyne properties, another important factor for
the reduced yields obtained, was the challenging separation of 1, 3,
and 4. The purification of MIDA boronates has in details been de-
scribed by Burke and Gillis.4,39 In many cases, MIDA boronates can
be easy to purify. However, 1, 3, and 4 showed strikingly similar
behavior regarding both Rfdvalues on silica with several mobile
phases, such as Et2O/CH3CN, Et2O/acetone, and hexane/EtOAc/
MeOH, and solubility/crystallization properties. The only remark-
able difference found between the alkyne and the aryl MIDA bor-
onate products, was the behavior on C18-modified SiO2 TLC-plates.
However, purification was sensitive to amounts of 1 present, and
several repeating purification steps were necessary in some cases.
For 3g (Table 2, entries 10 and 11), we were not able to remove the
remaining 1, even after extensive work-up. Removal of excess 1
from the product mixture by chemical modification, hydrogenation
(RheAl2O3/H2), terminal bromination (NBS/AgNO3),40 or com-
plexation to cobalt [Co2(CO)8]41 was unsuccessful. Fortunately,
transforming the crude mixture containing 3g to the corresponding
boronic acid 6 by basic hydrolysis (Scheme 2), proved feasible, as 1
decomposes under the reaction conditions. The boronic acid 6 was
hence isolated in 40% yield.
4. Experimental section
4.1. General information
Chemicals were purchased from SigmaeAldrich and used
without further purification. The non-commercial diynes 2a, 2f,
and 2h were prepared as described earlier.26 The diynes 2b,42 2c,43
and 2e44 were prepared according to the literature. All reactions
sensitive to air or moisture were performed under argon atmo-
sphere with dried solvents and reagents. DCM, THF, and Et2O were
dried using MBRAUN solvent purification system (MB SPS-800).
ꢀ
Acetone was dried over activated 4 A molecular sieves. For the
Ru-catalyzed procedure, acetone was degassed with helium for
10e20 min prior to use. Melting points were determined 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 or a KMnO4 solution (1.5 g KMnO4, 10 g K2CO3, 2.5 mL 5 M
NaOH, 200 mL H2O) for detection. Column chromatography was
ꢀ
performed with Silica gel (pore size 60 A, 230e400 mesh particle
size) from Fluka. Crude products from cyclotrimerization reactions
were concentrated on FlorisilÒ and dry-loaded on top of the pre-
packed silica gel columns. Reverse phase preparative TLC was per-
formed using Analtech TLC uniplates C18-silica gel matrix,
20 cmꢀ20 cm, purchased from SigmaeAldrich. 1H and 13C NMR
spectra were recorded from Bruker Advance DPX instruments (300/
Scheme 2. Preparation of the boronic acid 6 after basic hydrolysis of the cyclo-
trimerization product mixture of 3g and 5.
75 MHz and 400/100 MHz). Chemical shifts (d) are reported in parts
Finally, we wanted to include cyclotrimerization of 1 with the
unsymmetrically bromo-substituted diyne 2f in our synthetic work
toward potential selective inhibitors of tyrosine kinase 2. The
ruthenium-catalyzed reaction of 1 and 2f gave 53% total yield of the
products 3f and 4f in an 87:13 ratio (Table 2, entry 9). Pure 3f was
per million. Where CDCl3 has been used, 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
Silverstein45 (1H NMR: CD3CN: 1.93, acetone-d6: 2.04, DMSO-d6:
2.49; C NMR: CD3CN: 1.30; acetone-d6: 29.8, DMSO-d6: 39.7, CD3Cl:

S. Melnes et al. / Tetrahedron 69 (2013) 7910e7915
7913
77.0). Signal patterns are indicated as s (singlet), d (doublet), t
(triplet), q (quartet) or m (multiplet). 1H and 13C NMR signals were
assigned by 2D correlation techniques (COSY, HSQC, HMBC). Carbons
bearing boron substituents were often not observed due to quad-
rupolar relaxation. IR spectra were recorded from a Thermo Nicolet
FT-IR NEXUS instrument, and only the strongest/structurally most
important peaks are listed (cmꢁ1). Accurate mass determination, EI
and ESI, was performed on MAT95XL ThermoFinnigan and Agilent
G1969 TOF MS instrument, respectively. For ESI analyses, samples
were injected into the instrument using an Agilent 1100 series HPLC.
A direct injection analysis without any chromatography was per-
formed for the EI analyses.
added DCM (7.5 mL), and the resulting yellow solution was stirred
at rt for 5 min under argon atmosphere. The flask was evacuated,
and 1 atm of H2 was introduced (balloon). After stirring for 1 h at rt,
the red solution was concentrated to dryness under vacuum, and an
atmosphere of argon was introduced. A solution of 1 (0.271 g,
1.50 mmol) in acetone (4.5 mL) was added. To the stirred solution,
a solution of 2 (1.00 mmol) in acetone (4 mL) was slowly added at rt
over 10 h via a syringe pump. The resulting mixture was stirred at rt
over night, then concentrated under vacuum and analyzed by 1H
NMR (acetone-d6).
4.3.4. Representative procedure for iridium-catalyzed cyclotrimeri-
zation. Iridium-catalyzed cyclotrimerization reactions were per-
formed as described by Kezuka and co-workers.35
A mixture of [Ir(cod)Cl]2 (14 mg, 0.02 mmol, 2 mol %), DPPE
(17 mg, 0.04 mmol, 4 mol %), and 2 (1.00 mmol, 1 equiv) was dis-
solved in acetone or THF (5 mL), and added 1 (0.271 g, 1.50 mmol,
1.5 equiv) against a positive argon-flow. The resulting suspension
was warmed to reflux and stirred for 20 h. After cooling to rt, the
crude solution was concentrated under vacuum, and analyzed by
1H NMR (acetone-d6).
4.2. Preparation of but-3-yn-2-yl 3-(trimethylsilyl)propiolate
(2g)
A
solution of 3-(trimethylsilyl)propynoic acid (1.06 g,
7.28 mmol, 1 equiv) and DEAD (40wt % in toluene, 3.32 mL,
7.28 mmol, 1 equiv) in THF (10 mL) was added dropwise over
20 min to a cooled (0 ꢂC) solution of PPh3 (1.91 g, 7.28 mmol,
1 equiv) and 3-butyn-2-ol (0.86 mL, 11 mmol, 1.5 equiv) in THF
(12 mL). The resulting suspension was stirred and slowly warmed
to rt. After 16 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 (1.5% EtOAc in n-hexane) to give the title com-
pound (0.944 g, 4.86 mmol, 67%) as a colorless oil. Rf (10% EtOAc/n-
hexane) 0.46. IR (neat): 3297 (w), 2963 (w), 2190 (w), 2125 (w),
4.3.5. General procedure for work-up after cyclotrimerization. The
products 3 and 4 were purified in accordance with a procedure
described by Gillis and Burke17 with modifications.
The crude product was dissolved in MeCN and added FlorisilÒ.
The mixture was concentrated to dryness, and loaded on top of
a silica column pre-packed with Et2O. The column was flushed with
copious amounts of Et2O, before the product was eluated with
a gradient of MeCN in Et2O (5e30%). KMnO4 was used for visuali-
zation on TLC. If 1 still remained in the product after the column,
this product mixture was further purified by a second column,
crystallization, washing, and/or C18-modified preparative TLC with
5% MeCN in H2O as mobile phase.
1712 (s), 1214 (s), 842 (s) cmꢁ1 1H NMR (400 MHz, CDCl3):
; d 5.48
(1H, dq, J 6.7, 2.2 Hz, CH), 2.50 (1H, d, J 2.2 Hz, alkyneeH), 1.56 (3H,
d, J 6.7 Hz, CH3), 0.25 (9H, s, TMS); 13C NMR (100 MHz, CDCl3):
d
151.8, 95.1, 94.0, 81.0, 73.8, 61.7, 21.0, ꢁ0.9; HRMS (EI): m/z calcd
for C9H11O2Si [MꢁCH3]þ: 179.0523; found: 179.0524.
4.3. Representative procedures for transition metal catalyzed
cyclotrimerization of 1 and 2
4.4. Experimental details for aryl MIDA boronates 3 and 4
4.3.1. Representative procedure for ruthenium-catalyzed cyclo-
trimerization. Ruthenium-catalyzed cyclotrimerization reactions
were performed as described by Yamamoto and co-workers.31,32
A solution of 2 (1.00 mmol, 1 equiv) in acetone (3 mL) was added
dropwise over 10 min to a mixture of 1 (0.271 g, 1.50 mmol,
1.5 equiv) and Cp*RuCl(cod) (19 mg, 0.050 mmol, 5 mol %) in ace-
tone or THF (2 mL). The resulting dark red mixture was stirred at rt
until TLC (10% EtOAc/n-hexane) showed complete conversion of 2.
The crude mixture was concentrated under reduced pressure, and
analyzed by 1H NMR (acetone-d6).
4.4.1. 3,7-Dimethyl-1-oxo-1,3-dihydroisomenzofuran-5-yl MIDA boro-
nate (3a) and 1,4-dimethyl-3-oxo-1,3-dihydroisomenzofuran-5-yl
MIDA boronate (4a). Conditions and results from the preparation
of 3a and 4a are summarized in Table 1.
The representative procedure for ruthenium-catalysis, using 1
(0.201 g, 1.16 mmol) and 2a (0.105 g, 0.771 mmol) in acetone (4 mL)
for 1 h, gave an 87:13 mixture of the products 3a and 4a (0.205 g,
0.645 mmol, 84%, Table 1, entry 5) as a white solid after column
chromatography (general procedure). Pure 3a (white solid) was
obtained after crystallization of the product mixture from acetone
(1 mL).
4.3.2. Representative procedure for rhodium-catalyzed cyclotrimeri
zation. Rhodium-catalyzed cyclotrimerization reactions were per-
formed as described by Tanaka and co-workers.34
The representative procedure for rhodium-catalysis, using 1
(0.362 g, 2.00 mmol) and 2a (0.136 g, 1.00 mmol) in acetone (10 mL)
for 20 h, gave a 39:61 mixture of 3a and 4a (0.209 g, 0.659 mmol,
66%, Table 1, entry 7) as a colorless oil after column chromatogra-
phy (general procedure). The regioisomers were inseparable.
Rf (3aþ4a, 40% MeCN/Et2O) 0.57.
A mixture of [Rh(cod)2]BF4 (20 mg, 0.050 mmol, 5 mol %) and
BINAP (31 mg, 0.050 mmol, 5 mol %) was added DCM (7.5 mL), and
the resulting yellow solution was stirred at rt for 5 min. The flask
was evacuated, and 1 atm of H2 was introduced (balloon). After
stirring at rt for 1 h, the red solution was concentrated to dryness,
and an atmosphere of argon was introduced. A solution of 1
(0.362 g, 2.00 mmol, 2 equiv) and 2 (1.00 mmol, 1 equiv) in acetone
or THF (10 mL) was added dropwise over 20 min. The mixture was
stirred at rt until TLC (10% EtOAc/n-hexane) showed complete
conversion of 2. The crude mixture was concentrated under vac-
uum and analyzed by 1H NMR (acetone-d6).
Data for 3a: mp >250 ꢂC. IR (neat): 2955 (w), 1739 (s), 1698 (m),
1279 (s), 1251 (m), 1022 (s, br), 956 (s), 859 (s) cmꢁ1 1H NMR
;
(400 MHz, CD3CN): d 7.47 (1H, s, ArH), 7.42 (1H, s, ArH), 5.50 (1H, q, J
6.7 Hz, CH), 4.10 (2H, d, J 17.1 Hz, MIDAeCH2), 3.93 (2H, app. dd, J
17.1, 7.2 Hz, MIDAeCH2), 2.62 (3H, s, ArCH3), 2.50 (3H, s, NCH3), 1.55
(3H, d, J 6.7 Hz, CH3); 13C NMR (100 MHz, CD3CN):
d 171.5 (CO),
169.41 (MIDAeCO), 169.35 (MIDAeCO),167.6 (ArCeB(MIDA)), 152.7,
139.0, 135.5 (ArCH), 124.8, 124.3 (ArCH), 77.9 (CH), 63.0 (MID-
AeCH2), 48.7 (NCH3), 20.7 (CH3), 17.3 (ArCH3); HRMS (EI): m/z calcd
for C15H1610BNO6 [M]þ: 316.1102; found: 316.1100.
4.3.3. Representative procedure for rhodium-catalyzed cyclotrimeri
zation using slow addition. A mixture of [Rh(cod)2]BF4 (20 mg,
0.050 mmol, 5 mol %) and BINAP (31 mg, 0.050 mmol, 5 mol %) was
Data for 4a: 1H NMR (400 MHz, CD3CN):
d
7.75 (1H, d, J 7.8 Hz,
ArH), 7.35 (1H, d, J 7.8 Hz, ArH), 5.48 (1H, q, J 6.7 Hz, CH), 4.11 (2H, d,

7914
S. Melnes et al. / Tetrahedron 69 (2013) 7910e7915
J 17.2 Hz, MIDAeCH2), 3.94 (2H, d, J 17.2 Hz, MIDAeCH2), 2.74 (3H, s,
ArCH3), 2.55 (3H, s, NCH3), 1.54 (3H, d, J 6.7 Hz, CH3); 13C NMR
62.8 (MIDAeCH2), 48.5 (NCH3); HRMS (EI): m/z calcd for
C13H1411BNO5 [M]þ: 275.0960; found: 275.0962.
(100 MHz, CD3CN):
d 171.7 (CO), 169.4 (MIDAeCO), 169.3 (MID-
AeCO), 154.5, 145.5, 140.8 (ArCH), 124.4, 119.7 (ArCH), 76.8 (CH),
63.8 (MIDAeCH2), 48.6 (NCH3), 20.6 (CH3), 16.3 (ArCH3).
4.4.5. 2,2-Bis(ethoxycarbonyl)-4,7-dimethyl-2,3-dihydro-1H-inden-
5-yl MIDA boronate (3e). Conditions and results from the prepa-
ration of 3e are given in Table 2, entries 7 and 8.
4.4.2. 2,2-Bis(methoxycarbonyl)-2,3-dihydro-1H-inden-5-yl
boronate (3b). Conditions and results from the preparation of 3b
are given in Table 2, entries 1e3.
The representative procedure for ruthenium-catalysis, us-
ing 1 (0.136 g, 0.752 mmol) and 2b (0.104 g, 0.500 mmol) in
acetone (2.5 mL) for 30 min, afforded 3b (0.169 g, 0.434 mmol,
87%) as a white solid after column chromatography (general
procedure).
MIDA
The representative procedure for rhodium-catalysis with slow
addition, using 1 (0.182 g, 1.01 mmol) and 2e (0.264 g, 0.999 mmol)
in acetone (8 mL), afforded 3e (0.206 g, 0.463 mmol, 46%, estimated
yield from 1H NMR analysis) in mixture with 1 as a colorless oil
after column chromatography (general procedure).
Data for 3e (analytical sample): Rf (20% MeCN/Et2O) 0.22. IR
(neat): 2982 (m), 1768 (s, br), 1730 (s), 1286 (s), 1241 (s), 1023 (s),
1001 (s) cmꢁ1; 1H NMR (400 MHz, acetone-d6):
d 7.10 (1H, s, ArH),
The representative procedure for rhodium-catalysis, using 1
(0.362 g, 2.00 mmol) and 2b (0.208 g, 1.00 mmol) in acetone
(10 mL) for 1 h, afforded 3b (0.272 g, 0.700 mmol, 70%) as a white
solid after column chromatography (general procedure) and crys-
tallization from acetone (1 mL).
4.30 (2H, d, J 17.0 Hz, MIDAeCH2), 4.18 (4H, q, J 7.1 Hz, COCH2CH3),
4.11 (2H, d, J 17.0 Hz, MIDAeCH2), 3.51 (4H, app d, J 7.9 Hz, 2ꢀ CH2),
2.75 (3H, s, NCH3), 2.29 (3H, s, ArCH3), 2.18 (3H, s, ArCH3), 1.23 (6H,
t, J 7.1 Hz, COCH2CH3); 13C NMR (100 MHz, acetone-d6):
d 172.3
(CO2Et), 169.3 (MIDAeCO), 140.6, 140.4, 136.1, 135.0, 130.6, 63.3
(OCH2CH3), 62.1 (MIDAeCH2), 59.8 (C(CH2CH3)2), 48.0 (NCH3), 40.8
(CH2), 40.2 (CH2),18.8 (ArCH3),18.5 (ArCH3),14.3 (OCH2CH3); HRMS
(EI): m/z calcd for C22H2811BNO8 [M]þ: 445.1902; found: 445.1909.
Rf (20% MeCN/Et2O) 0.37. Mp 206e207 ꢂC. IR (neat): 2959 (w),
1772 (m), 1728 (s), 1250 (s), 1031 (s), 1008 (s) cmꢁ1 1H NMR
;
(400 MHz, CD3CN):
d 7.33 (1H, s, ArH), 7.29 (1H, d, J 7.6 Hz, ArH),
7.21 (1H, d, J 7.6 Hz, ArH), 4.04 (2H, d, J 17.0 Hz, MIDAeCH2), 3.86
(2H, d, J 17.0 Hz, MIDAeCH2), 3.69 (6H, s, CO2CH3), 3.54 (4H, s, CH2),
4.4.6. 7-Bromo-3-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl
MIDA boronate (3f). Conditions and results from the preparation of
3f are given in Table 2, entry 9.
2.47 (s, 3H, NCH3); 13C NMR (100 MHz, CD3CN):
d 173.0 (CO), 169.5
(MIDAeCO), 142.4, 140.8, 132.2 (AreCH), 129.3 (ArCH), 124.8
(ArCH), 62.8 (MIDAeCH2), 60.9 (CH2), 53.5 (CH2), 48.5 (NCH3), 41.1
(OCH3), 41.0 (OCH3); HRMS (EI): m/z calcd for C18H2010BNO8 [M]þ:
388.1313; found: 388.1314.
The representative procedure for ruthenium-catalysis, using 1
(0.267 g, 1.48 mmol) and 2f (0.198 g, 0.985 mmol) in acetone (5 mL)
for 1 h, gave an 87:13 mixture of the regioisomers 3f and 4f
(0.201 g, 0.526 mmol, 53%) as a white solid after column chroma-
tography (general procedure). Pure 3f (70 mg, 0.18 mmol, 19%) was
afforded after washing the product mixture with acetone (5ꢀ1 mL).
Mp >250 ꢂC. Rf (20% MeCN/Et2O) 0.22. IR (neat): 2998 (w), 1751
(s, br), 1199 (s), 1044 (s), 1008 (s), 862 (s) cmꢁ1; 1H NMR (400 MHz,
4.4.3. 2-Tosylisoindolin-5-yl MIDA boronate (3c). Conditions and
result from the preparation of 3c are given in Table 2, entry 4.
The representative procedure for ruthenium-catalysis, using 1
(0.273 g, 1.51 mmol) and 2c (0.246 g, 0.994 mmol) in acetone (5 mL)
for 30 min, afforded 3c (0.339 g, 0.792 mmol, 80%) as white crystals
after column chromatography (general procedure).
DMSO-d6): d 7.77 (1H, s, ArH), 7.71 (1H, s, ArH), 5.63 (1H, q, J 6.6 Hz,
CH), 4.39 (2H, app. dd, J 17.2, 2.6 Hz, MIDAeCH2), 4.18 (2H, app. dd, J
17.2, 12.0 Hz, MIDAeCH2), 2.58 (3H, s, NCH3), 1.56 (3H, d, J 6.6 Hz,
Rf (20% MeCN/Et2O) 0.20. Mp 147e150 ꢂC. IR (neat): 3013 (w),
2959 (w), 1768 (s), 1752 (s), 1159 (s), 1043 (s), 815 (s), 666 (s), 565
CH3); 13C NMR (100 MHz, DMSO-d6):
d 169.33 (MIDAeCO), 169.28
(s) cmꢁ1
;
1H NMR (400 MHz, acetone-d6):
d
7.78 (2H, d, J 8.0 Hz,
(MIDAeCO), 167.4 (CO), 166.4 (ArCeB(MIDA)), 153.8, 137.2 (ArCH),
126.0 (ArCH), 123.7, 118.9, 76.3 (CH), 62.54 (MIDAeCH2), 62.50
(MIDAeCH2), 48.2 (NCH3), 20.1 (CH3); HRMS (EI): m/z calcd for
C14H1310B79BrNO6 [M]þ: 381.0014; found: 381.0014.
TseH), 7.42e7.38 (4H, m, ArH, TseH), 7.24 (1H, d, J 7.9 Hz, AreH),
4.59 (4H, s br, 2ꢀ CH2), 4.32 (2H, d, J 17.0 Hz, MIDAeCH2), 4.10 (2H,
d, J 17.0 Hz, MIDAeCH2), 2.67 (3H, s, NCH3), 2.37 (3H, s, TseCH3); 13
C
NMR (100 MHz, CD3CN):
d 169.2 (MIDAeCO), 144.5, 138.1, 136.8,
134.8, 132.7 (AreCH), 130.6 (AreCH), 128.5 (TseCH), 127.6 (AreCH),
122.9 (TseCH), 62.7 (MIDAeCH2), 54.4 (CH2), 54.3 (CH2), 48.2
(NCH3), 21.3 (TseCH3); HRMS (EI): m/z calcd for C20H2111BN2O6S
[M]þ: 428.1208; found: 428.1208.
4.4.7. 3-Methyl-1-oxo-7-(trimethylsilyl)-1,3-dihydroisobenzofuran-5-
yl MIDA boronate (3g) and 1-(3-methyl-1-oxo-7-(trimethylsilyl)-1,3-
dihydroisobenzofuran-5-yl)ethyl 3-(trimethylsilyl)propiolate (5). Cyclo
trimerization reactions of 1 and 2g afforded mixtures of 3g and 5
(Fig. 2). Conditions and results are given in Table 2, entries 10 and 11.
The representative procedure for ruthenium-catalysis, using 1
(0.172 g, 0.951 mmol) and 2g (0.123 g, 0.633 mmol) in acetone
(6 mL) for 24 h, afforded a 1:1 mixture of 3g and 5 (observed by 1H
NMR of the crude), in addition to excess 1.
The MIDA boronate 3g was isolated in mixture with 1 (1:0.65,
52 mg) as a white solid after column chromatography (standard
procedure), followed by preparative C18-TLC (3% NaCl in H2O) and
a second column (standard procedure). Rf (20% MeCN/Et2O) 0.37. 1H
4.4.4. 1,3-Dihydroisobenzofuran-5-yl MIDA boronate (3d). Conditions
and results from the preparation of 3d are given in Table 2, entries 5
and 6.
The representative procedure for ruthenium-catalysis, using 1
(0.271 g, 1.50 mmol) and 2d (0.103 mL, 1.00 mmol) in acetone
(5 mL) for 30 min, afforded 3d (0.147 g, 0.534 mmol, 53%) as white
crystals after column chromatography (general procedure).
The representative procedure for rhodium-catalysis, using 1
(0.362 g, 2.00 mmol) and 2d (0.10 mL, 1.0 mmol) in acetone (10 mL)
for 1 h, afforded 3d (0.178 g, 0.64 mmol, 64%) as white crystals after
column chromatography (general procedure, two columns).
Rf (20% MeCN/Et2O) 0.19. Mp 191e192 ꢂC. IR (neat): 2856 (w),
NMR(400 MHz, acetone-d6):d7.89(1H, s, ArH),7.82(1H, s, ArH), 5.62
(1H, q, J 6.6 Hz, CH), 4.41 (2H, d, J 17.0 Hz, MIDAeCH2), 4.19 (2H, app.
dd, J 17.0, 6.2 Hz, MIDAeCH2), 2.78 (3H, s, NCH3),1.60 (3H, d, J 6.6 Hz,
CH3), 0.36 (9H, s, TMS); 13C NMR (100 MHz, acetone-d6):
d 171.7 (CO),
1746 (s, br), 1275 (s), 1241 (s), 1031 (s), 993 (s), 813 (s) cmꢁ1
;
1H
169.11 (MIDAeCO), 169.06 (MIDAeCO), 152.0, 139.83 (ArC-TMS),
139.80 (ArCH), 131.5, 127.9 (ArCH), 78.2 (CH), 62.90 (MIDAeCH2),
62.88 (MIDAeCH2), 48.4 (NCH3), 20.7 (CH3), ꢁ0.9 (TMS).
NMR (400 MHz, CD3CN): 7.41e7.36 (2H, m, ArH), 7.28 (1H, d, J
d
8.1 Hz, ArH), 5.02 (4H, s br, 2ꢀ CH2), 4.06 (2H, d, J 17.1 Hz, MID-
AeCH2), 3.88 (2H, d, J 17.1 Hz, MIDAeCH2), 2.48 (3H, s, NCH3); 13C
The autotrimerization product 5 (colorless oil, 60 mg, 0.15 mmol,
47%) was isolated as a mixture of diastereomers (observed in the 13C
NMR spectrum) after column chromatography (10% EtOAc in n-
NMR (100 MHz, CD3CN):
d 169.6 (MIDAeCO), 167.8 (ArCeB(MIDA)),
141.7, 140.2, 132.4, 126.0, 121.6, 73.82 (OCH2Ar), 73.79 (OCH2Ar),

S. Melnes et al. / Tetrahedron 69 (2013) 7910e7915
7915
hexane) of the concentrated Et2O-fractions from the first purifica-
tion step of 3g (see above). The diastereomers are symbolized a and
b under assignation of 13C NMR shift values. Rf (10% EtoAc/n-hexane)
0.34. IR (neat): 2958 (w), 1759 (m), 1709 (m), 1218 (s), 1050 (s), 839
d br, J 1.9 Hz, ArH), 6.95e6.92 (1H, m, ArH), 5.48 (1H, q, J 6.6 Hz, CH),
1.48 (3H, d, J 6.6 Hz, CH3); 13C NMR (100 MHz, DMSO-d6):
167.2
(COOH), 163.8 (ArCOH), 156.6, 121.0 (ArCH), 120.3, 114.0, 108.1
(ArCH), 75.4 (CH), 20.3 (CH3); HRMS (ESI): m/z calcd for
C9H679BrO3 [(MꢁH)ꢁH2O]ꢁ: 240.9506; found 240.9504.
d
(s) cmꢁ1; 1H NMR (400 MHz, CDCl3):
d 7.59 (1H, app. br d, J 5.6 Hz,
H6), 7.41e7.39 (1H, m, H4), 6.03 (1H, q, J 6.6 Hz, H20), 5.52 (1H, q, J
6.6 Hz, H3), 1.66e1.61 (6H, m, H10 and H10), 0.41 (9H, s, H11), 0.26
Acknowledgements
(9H, s, H70); 13C NMR (100 MHz, CDCl3):
d
170.6 (C1), 152.2 (C40b),
152.1 (C40a), 151.9 (C9a), 151.8 (C9b), 145.6 (C5a), 145.5 (C5b), 142.45
(C7a), 142.43 (C7b), 133.11 (C6b), 133.07 (C6a), 130.0 (C8b), 129.9
(C8a), 119.7 (C4b), 119.4 (C4a), 94.9 (C60a), 94.4 (C60b), 77.2 (br, C50),
77.17 (C3a), 77.15 (C3b), 73.84 (C20a), 73.77 (C20b), 22.4 (C10a), 22.1
(C10b), 20.4 (C10), ꢁ0.9 (C70), ꢁ1.2 (C11); HRMS (EI): m/z calcd for
C19H25O4Si2 [MꢁCH3]þ: 373.1286; found: 373.1293.
We gratefully acknowledge the NT-faculty at NTNU for financial
support and Dr. Susana Villa Gonzales for helping with the MS-
analyses.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.07.027.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
4.4.8. 4-Borono-2-(1-hydroxyethyl)-6-(trimethylsilyl)benzoic
(6). Conditions and results from the preparation of 6 from 1 and 2g
are illustrated in Scheme 2.
acid
The representative procedure for ruthenium-catalysis, using 1
(1.38 g, 7.63 mmol) and 2g (0.298 g, 1.53 mmol) in acetone (15 mL)
gave a 4:1 mixture of 3g and 5 (observed by 1H NMR of the crude),
in addition to excess 1, after 24 h at rt. The crude was suspended in
THF (20 mL) and cooled to 0 ꢂC. NaOH (1 M in H2O, 25 mL) was
added. The resulting solution was warmed to rt and stirred. After
7 h, the mixture was cooled to 0 ꢂC. HCl (1 M in H2O, 16 mL) was
added (pH 3), and the mixture was warmed to rt and diluted with
Et2O (30 mL). The phases were separated. The water phase was
extracted with THF/Et2O (1:1, 3ꢀ40 mL). The collected organic
phases were dried (MgSO4), filtered, and concentrated under re-
duced pressure. The resulting crude was recrystallized from THF/
MeOH (9:1, 4 mL), to afford a light brown mass. Washing the mass
with EtOAc (3ꢀ0.5 mL) afforded 6 (0.173 g, 0.613 mmol, 40%) as
a white powder.
References and notes
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(m), 3334 (m, br), 2969 (w), 1735 (s), 842 (s), 705 (s) cmꢁ1; 1H NMR
(400 MHz, DMSO-d6):
d 8.39 (1.7H, s br), 8.25 (0.14H, s, ArH), 8.09
(0.14H, s, ArH), 8.06 (1H, s, ArH), 7.98 (1H, s, ArH), 5.72 (0.14H, q, J
6.7 Hz, CH), 5.67 (1H, q, J 6.7 Hz, CH), 1.59 (0.42H, d, J 6.7 Hz, CH3),
1.54 (3H, d, J 6.7 Hz, CH3), 0.38 (1.35H, s, TMS), 0.34 (9H, s, TMS); 13
C
NMR (100 MHz, DMSO-d6):
d 171.1 (COOH), 166.5 (app. d, J 1.5 Hz,
ArCB(OH)2), 150.8, 140.5 (ArCH), 138.1, 130.6, 128.6 (ArCH), 77.5
(CH), 20.4 (CH3), ꢁ0.72 (TMS); HRMS (ESI): m/z calcd for
C14H2010BO6Si [(MþCH3COO)ꢁH2O]ꢁ: 323.1131; found 323.1135.
4.4.9. 2-Bromo-4-hydroxy-6-(1-hydroxyethyl)benzoic acid (7). Con-
ditions and results from the preparation of 7 from 1 and 2f are given
in Scheme 3. The oxidative work-up was performed in accordance
with a procedure described by Yamamoto and Hattori.28
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The representative procedure for ruthenium-catalysis, using 1
(3.60 g, 19.9 mmol) and 2f (2.67 g, 13.3 mmol) in acetone (65 mL)
was followed. After 24 h at rt, the resulting suspension was con-
centrated to dryness. 1H NMR analysis (acetone-d6) conformed the
formation of 3f (87%) and 4f (13%). The crude was suspended in THF
(60 mL), and cooled to 0 ꢂC. A mixture of NaOH (1 M in H2O) and
H2O2 (35 wt % in H2O) (2:1,120 mL) was slowly added. The resulting
solution was warmed to rt and stirred. After 2 h, the mixture was
cooled to 0 ꢂC. HCl (1 M in H2O, 40 mL) was added (pH w3), the
mixture was warmed to rt and diluted with Et2O/THF (3:2, 250 mL).
The phases were separated. The water phase was extracted with
THF/Et2O (1:1, 3ꢀ200 mL). The collected organic phases were dried
(MgSO4), filtered, and concentrated under reduced pressure. The
resulting light brown mass was washed with acetone (5 mL) and
EtOAc (2 mL) to afford 7 (1.37 g, 5.25 mmol, 40%) as a white powder.
Rf (50% acetone/n-hexane) 0.38. Mp 248e249 ꢂC. IR (neat): 3175
(m, br), 1730 (s), 1610 (m), 1578 (m), 1056 (s), 865 (s) 741 (s), 708
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(s) cmꢁ1; 1H NMR (300 MHz, DMSO-d6):
d 11.08 (1H, s br), 7.11 (1H,