Highly efficient and chemoselective α-iodination of acrylate esters through Morita-Baylis-Hillman-type chemistry

Article abstract of DOI:10.1039/c2ob27341a

The chemoselective α-iodination of various simple and multi-functionalised acrylic esters is efficiently accomplished by a Morita-Baylis-Hillman protocol involving the use of N-iodophthalimide, 3-quinuclidinol and KF-Celite in acetonitrile. No degradation of the obtained compounds was observed under the optimized conditions thus, furnishing α-iodoacrylates suitable for organometallic reactions (i.e. Nozaki-Kishi-Hiyama type coupling).

Full text of DOI:10.1039/c2ob27341a

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Highly efficient and chemoselective α-iodination of
acrylate esters through Morita–Baylis–Hillman-type
chemistry†
Cite this: DOI: 10.1039/c2ob27341a
Received 2nd December 2012,
Accepted 2nd January 2013
Vittorio Pace,*a,b Gytė Vilkauskaitė,a,c Algirdas Šačkusc and Wolfgang Holzera
DOI: 10.1039/c2ob27341a
www.rsc.org/obc
The chemoselective α-iodination of various simple and multi-func- analogous (a)cyclic α-iodo-α,β-unsaturated ketones, however it
tionalised acrylic esters is efficiently accomplished by a Morita– provides less efficient results in the case of α-iodoacrylates,
Baylis–Hillman protocol involving the use of N-iodophthalimide, thus hitherto decreasing its synthetic versatility. The latter
3-quinuclidinol and KF-Celite in acetonitrile. No degradation of methodology was firstly explored for the α-iodination of α,β-
the obtained compounds was observed under the optimized con- unsaturated ketones by Johnson31 and Mc Nelis32 independently
ditions thus, furnishing α-iodoacrylates suitable for organometal- in the early 1990s. It involves a classical MBH-mechanism
lic reactions (i.e. Nozaki–Kishi–Hiyama type coupling).
(Scheme 1) of (a) 1,4-nucleophilic addition of the aminic cata-
lyst to the acrylate to afford an ammonium enolate II, followed
by (b) its electrophilic capture of the iodinating agent to give
III, which (c) upon base-mediated elimination of the catalyst
releases the desired iodoolefin IV. According to this mechanis-
tic pathway, it is clear that the overall efficiency of the process
depends on the use of the optimal conditions for each of the
single steps involved. Considering this, two possible draw-
backs connected to this procedure should be taken into
account. Firstly, as pointed out by Mc Nelis,32 difficulties in
iodinating acyclic systems may arise: compared to their cyclic
counterparts, which have the tendency to maintain
α-Haloacrylates are extremely versatile building blocks with
broad applications in different areas of organic chemistry, for
instance in the synthesis of polymers,1 natural products2 and
biologically active compounds.3,4 In particular, α-iodoacrylates
are of high interest due to their outstanding usefulness as pri-
vileged scaffolds for transition metal-catalysed cross
coupling,5–7 iodine–metal exchange reactions,8 radical reac-
tions and displacement processes carried out with nucleo-
philes.9 Whereas different sufficient approaches are nowadays
available for the preparation of α-chloro, α-bromo and α-fluoro
acrylate esters,10–15 the synthesis of the analogous α-iodo con-
geners has been only partially addressed.16–18 In principle, the
latter can be achieved via addition of HI to an alkyne, however
this approach has found to be encountered with many difficul-
ties.19,20 As a consequence, two other main strategies have
been thought up: (a) Wittig-type reactions between
a
phosphorous21–25 or an arsonium26,27 ylide and an (activated)
aldehyde, and (b) Morita–Baylis–Hillman (MBH)28 type pro-
cesses.29,30 Evidently, the first protocol could not be applied to
aliphatic aldehydes and is highly limited by the difficulties in
obtaining the very unstable iodoylide. On the other hand, the
MBH approach is indeed applicable for the synthesis of
aDepartment of Drug and Natural Product Synthesis, University of Vienna,
Althanstrasse 14, 1090 Vienna, Austria. E-mail: vpace@farm.ucm.es;
Fax: +43-1-4277-9556; Tel: +43-1-4277-55623
bDepartment of Organic and Pharmaceutical Chemistry, Complutense University of
Madrid, Pza. Ramon y Cajal s/n, 28040 Madrid, Spain
cInstitute of Synthetic Chemistry, Kaunas University of Technology, Radvilėnų pl. 19,
50254 Kaunas, Lithuania
Scheme 1 α-Iodination of acrylic esters through an MBH pathway and degra-
dation of the formed α-iodoacrylate via a base-mediated dehydroiodination–
hydrolysis sequence.
†Electronic supplementary information (ESI)
available. See DOI:
10.1039/c2ob27341a
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conjugation, the former ones can twist out of conjugation and the elimination of HI – did not increase the efficiency (entries
thus hindering the process. Secondly, an α-iodo-α,β-unsatu- 5–7). Effectively, a solution to the problem was provided by
rated ester formed in this way can very easily lose HI in the using the supported base KF-Celite,35–39 which increased the
presence of a base, thus affording the corresponding propio- yield of 2 up to a moderate 49% (entry 9) and significantly, as
1
late ester V (sensitive to further basic hydrolysis to the acid VI) shown by the crude H-NMR, no dehalogenation was observed
as suggested by Chenault.33,34 In view of this, the optimal at all. Subsequently, we looked to the iodine source/loading as
selection of catalysts, bases and reaction conditions seems to a possible key for further improvement of the process, because
be vital in such kind of reaction.
of the well-known fact that the electrophile (iodine source)
As pointed out, despite the simple architecture of α-iodoacry- addition to the ammonium enolate is the rate determining
lates, there is still a lack of efficient methods to prepare such type step of the whole process.28 As a consequence of the well-
of compounds. Thus, we herein report an improved MBH proto- known low electrophilicity of molecular iodine,40 more active
col for the chemoselective α-iodination of acrylate esters by using iodonium species were screened. Interestingly, both N-iodosacc-
3-quinuclidinol as the catalyst, N-iodophthalimide as the iodinat- harine and N-iodosuccinimide afforded 2 in satisfactory 74%
ing agent, and KF-Celite as a mild base in acetonitrile.
and 79% yields, respectively (entries 10 and 11). However, as
We started our synthetic studies by using the challenging reported by Carreira the removal of NIS/succinimide residues
allyl acrylate 1, which additionally contains an allylic moiety is somewhat complicated41 and as a possible alternative N-
exposed to iodination (Table 1). The use of I2/quinuclidine/ iodophthalimide (PhthI) can be used.42 Pleasingly, with this
K2CO3 afforded the desired α-iodoacrylate 2 in a modest 32% reagent we were able to increase the yield of 2 up to 83% (entry
yield (entry 1). The increase in the catalyst loading or the 12). By increasing the amount of PhthI no evident improve-
iodine amount did not improve the yield. Interestingly, per- ment occurred. Based on the correlations between basicity
forming the reaction at 80 °C reduced it to 11%, and the detec- and catalytic activity of quinuclidine-type bases shown by
tion of propiolic acid by analysis of the crude via 1H-NMR Aggarwal,43 we were able to replace the highly expensive quinucli-
confirms that the dehydroiodination–ester hydrolysis sequence dine with the cheaper 3-quinuclidinol without any noticeable
is the main degradation pathway for α-iodoacrylates. Therefore, decrease in the efficiency (entry 14). In contrast, by employing
suppression of the latter is crucial for the further development a different catalyst often used in MBH reactions such as
of the synthetic strategy. Foremost, by simply replacing the (n-Bu)3P, a dramatic decrease in the yield was evidenced (entry
CH3CN–H2O mixture with CH3CN, compound 2 was isolated 15). It should be stressed that carrying out reactions in the
in a 45% yield along with 23% of the propiolic ester (entry 8). dark contributes to improve the efficiency of the process. It is
These preliminary results suggested that K2CO3 is not ade- worth noting that under the developed reaction conditions no
quate in promoting the elimination of the amine catalyst, iodination occurs in the allylic moiety of 1, thus demonstrating
since it further acts as a base in the undesired dehydroiodina- that the process proceeds with a remarkable chemoselectivity.
tion. Attempts to replace it with milder bases such as NaHCO3,
Using the established optimised conditions, the scope of
triethylamine, 2,6-lutidine – although effective in suppressing the reaction was evaluated. As shown in Table 2, the protocol
Table 1 Optimization of the model reactiona
Entry
Catalyst (equiv.)
Iodine source (equiv.)
Base (equiv.)
Solvent
Yield of 2 (%)
1
2
Quinuclidine (0.2)
Quinuclidine (0.4)
Quinuclidine (0.4)
Quinuclidine (0.2)
Quinuclidine (0.2)
Quinuclidine (0.2)
Quinuclidine (0.2)
Quinuclidine (0.2)
Quinuclidine (0.2)
Quinuclidine (0.2)
Quinuclidine (0.2)
Quinuclidine (0.2)
Quinuclidine (0.2)
Quinuclidinol (0.2)
(n-Bu)3P (0.2)
I2 (1.5)
I2 (1.5)
I2 (3.0)
I2 (1.5)
I2 (1.5)
I2 (1.5)
I2 (1.5)
I2 (1.5)
K2CO3 (1.2)
K2CO3 (1.2)
K2CO3 (1.2)
K2CO3 (1.2)
MeCN : H2O
MeCN : H2O
MeCN : H2O
MeCN : H2O
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
32
36
38
11
21
25
12
45
49
74
79
83
85
82
16
59
3
4b
5
NaHCO3 (1.2)
NEt3 (1.2)
2,6-Lutidine (1.2)
K2CO3 (1.2)
KF-Celite (1.1)
KF-Celite (1.1)
KF-Celite (1.1)
KF-Celite (1.1)
KF-Celite (1.1)
KF-Celite (1.1)
KF-Celite (1.1)
KF-Celite (1.1)
6
7
8
9
10
11
12
13
14
15
16c
I2 (1.5)
I-sacc. (1.5)
NIS (1.5)
PhthI (1.5)
PhthI (3.0)
PhthI (1.5)
PhthI (1.5)
PhthI (1.5)
MeCN
MeCN
MeCN
MeCN
Quinuclidinol (0.2)
MeCN
a Unless otherwise specified reactions were carried out during 24 h at rt in the dark. b 80 °C. c Reaction not run in the dark.
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Table 2 Scope of the reaction using different acrylate estersa
Entry
1
Substrate
Product
Yield (%)
76
2
3
4
5
6
69
93
66
82
75
Scheme 2 Examples of chemoselective α-iodinations in the case of bis-acrylic
esters (paths 1 and 2) and in the case of the presence of a crotonate (path 3).
improve the iodination of few known acrylates such as the
methyl derivative29 (entry 8) and the tert-butyl derivative (entry
9), the latter could be previously obtained in only 20% yield by
application of a DABCO mediated process.30 It is worth noting
that a bis-ester type acrylate undergoes iodination exclusively
at the vicinal position to the ester leaving unaffected the rela-
tively activated allylic type ester (entry 11).
To gain further insight into the chemoselectivity of the
process, we focused our attention towards systems bearing two
differently substituted acrylate moieties. Significantly, complex
acrylate 14 could be chemoselectively iodinated only at the
unsubstituted α-position; thus, leaving untouched both the
metacrylic system and the secondary alcohol (Scheme 2, path
1). To our surprise, this approach allows us to differentiate
between an acrylic system and a cinnamoyl one being present
in the same molecule 15. In fact, iodination occurs exclusively
at the acrylic moiety without any modification in the cinna-
moyl residue (Scheme 2, path 2). This result further demon-
strates the chemoselectivity of the process because of the
possible activation effect exerted by the phenyl substituent on
the attack of the catalyst.28 Furthermore, the selective iodina-
tion of an acrylic ester was also observed in an intermolecular
process when a 1 : 1 mixture of ester 5 and (E)-methyl crotonate
16 was reacted. Under the standard reaction conditions, only
compound 5 underwent iodination, while the crotonate 16 was
completely recovered (Scheme 2, path 3). Interestingly, croto-
nate ester 16 did not react at all also in the absence of acrylate
5: in this sense, we argued that the sterical hindrance in both
β-substituted systems 15 (cinnamoyl) and 16 (crotonyl)
accounts for the observed chemoselectivity.
7
8
73
79
9
88
10
11
83
87
The synthetic usefulness of α-iodoacrylate 11a was demon-
strated by the chemoselective Nozaki–Kishi–Hiyama (NKH)44,45
reaction with the electron-rich aldehyde 1746 (Scheme 3). Inter-
estingly, such an aldehyde failed to react under standard
Morita–Baylis–Hillman conditions with a simple tert-butyl
acrylate, while the attempted NKH coupling with the corres-
ponding α-bromo acrylate47 provided the desired allylic
alcohol in only 37% yield.
In conclusion, we have developed a general, efficient and
chemoselective procedure for preparing synthetically versatile
α-iodoacrylates under mild conditions. The reaction works well
not only with simple acrylate esters, but also with multi-
a Reaction conditions: acrylate (1.0 equiv.), N-iodophthalimide (1.5
equiv.), 3-quinuclidinol (0.2 equiv.), KF-Celite (1.1 equiv.), 24 h, rt, dark.
affords the chemoselective and efficient iodination of variously
functionalised acrylates. Interestingly, no concomitant iodina-
tion occurred in sensitive substrates, for instance, bearing acti-
vated aromatic systems such as benzylic (entry 1) or phenolic
ones (entries 2 and 3). Remarkably, the protocol tolerates sen-
sitive functionalities towards oxidative processes such as an
alcohol (entry 4), ethers (entries 5 and 6) or an epoxide (entry
7). Pleasingly, the procedure herein described allows us to
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