Synthesis of Polysubstituted Iodoarenes Enabled by Iterative Iodine-Directed para and ortho C?H Functionalization

Article abstract of DOI:10.1002/anie.201809657

Among halogenated aromatics, iodoarenes are unique in their ability to produce the bench-stable halogen(III) form. Earlier, such iodine(III) centers were shown to enable C?H functionalization ortho to iodine via halogen-centered rearrangement. The broader implications of this phenomenon are explored by testing the extent of an unusual iodane-directed para C?H benzylation, as well as by developing an efficient C?H coupling with sulfonyl-substituted allylic silanes. Through the combination of the one-shot nature of the coupling event and the iodine retention, multisubstituted arenes can be prepared by sequentially engaging up to three aromatic C?H sites. This type of iodine-based iterative synthesis will serve as a tool for the formation of value-added aromatic cores.

Full text of DOI:10.1002/anie.201809657

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Accepted Article
Title: Polysubstitued iodoarene synthesis enabled by iterative iodine-
directed para and ortho C-H functionalization
Authors: Yichen Wu, Sébastien Bouvet, Susana Izquierdo, and
Alexandr Shafir
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Polysubstitued iodoarene synthesis enabled by iterative iodine-
directed para and ortho C-H functionalization
Yichen Wu,[a] Sébastien Bouvet,[a] Susana Izquierdo,[a] and Alexandr Shafir*[a, b]
Dedication ((optional))
Abstract: Among halogenated aromatics, iodoarenes are unique in
their ability to produce the bench-stable halogen(III) form. Earlier,
such iodine(III) centers were shown to enable C-H functionalization
ortho to iodine via halogen-centered rearrangement. We now explore
the broader implications of this phenomenon, by testing the extent of
an unusual iodane-directed para C-H benzylation, as well as by
developing an efficient C-H coupling with sulfonyl-substituted allylic
silanes. Combining the one-shot nature of the coupling event with
iodine retention, we now introduce an iterative synthesis of multi-
substituted arenes by sequentially engaging up to three aromatic C-H
sites. We envision that such iodine-based iterative synthesis will serve
as tool for the formation of added value aromatic cores.
functionalization in a sulfoxide-based system (Scheme 1, E).[7c]
However, such an iterative manifold has not been used to engage
more than two C-H sites, and never for an λ3-iodane system. It
can easily be imagined, however, that an iterative iodane-directed
C-H functionalization would constitute an attractive approach
towards multi-substituted arenes, particularly since iodine itself
could ultimately be transformed into a plethora of substituents. In
this report, we discuss an alternative iodane-directed para-
selective C-H benzylation, and introduce a strategy for ortho-
selective sulfonylallylation tolerant of the iodoarene electronics.
Combined with the recently-introduced mild ArI oxidation[9], these
tools have now been employed to iteratively construct multi-
substituted iodoarenes cores (Scheme 1, F)
Haloarenes are an essential class of synthetic targets. In addition,
to their use as building blocks, the bromo and iodo derivatives
represent a structural element of growing interest in drug design
due to the potential for halogen bonding as a recognition
element.[1] New halogenation approaches have thus been
introduced, including the ortho-directed C-H halogenation.[2-3] For
iodoarene synthesis, an interesting complementary approach
exploits the iodine(III) state[4] to promote an oxidative C-H
substitution at the iodoarene core, as seen in a reaction between
phenyliodine diacetate and propargyl(trimethyl)silane to form the
ortho-propargyl iodobenzene. While first reported by Ochiai et al.
in 1991, the synthetic potential of this manifold was only recently
showcased in our laboratory.[5] The exclusive ortho selectivity has
been rationalized via a [3,3]–sigmatropic rearrangement of an
allenyl iodonium intermediate I (Scheme 1A). The concept was
recently expanded to additional manifolds,[6] including C-H
[6b,c]
allylation,[6a] C-H coupling with enols (via enolate II)
and
naphthols (Scheme 1B-D).[6d] Related sulfoxide-directed coupling
reactions have also been developed, particularly through
contributions from the groups of Procter, Maulide and
Yorimitsu.[7,8] The general preference of such reactions for
electron-rich iodoarenes cores may lead in some cases to
stringent scope limitation, as seen in the iodane-directed allylation
(example B, Scheme 1).[6a] An interesting feature of these
reactions is the intrinsic “safety-catch” feature, which prevents a
second C-H functionalization event[7c,8b] but opens the door to
iterative processes. The latter was recently shown for a double
Scheme 1. Selected precedents in iodane- and sulfoxide-directed C-H
functionalization.
Provided that the iodane-directed coupling commonly relies on a
Si-to-I transfer in the presence of acidic additives, we tested the
viability of a C-H benzylation via a possible ligand exchange-
rearrangement sequence similar to the one depicted in Scheme
1-A and B. In line with this assumption, the model coupling
between PhI(OAc)2 and BnSiMe3 in the presence of 1.0
equivalent of BF3·Et2O produced species 1 with the molecular
mass consistent with the bezylated iodobenzene. However,
unexpectedly the NMR analysis showed 1 to be the para-benzyl
[a]
[b]
Dr. Y. Wu, Dr. S. Bouvet, Dr. S. Izquierdo, Dr. A. Shafir
Institute of Chemical Research of Catalonia (ICIQ), Barcelona
Institute of Science and Technology, Avda. Països Catalans 16,
43007 Tarragona (Spain); e-mail: ashafir@iciq.es
Dr. A. Shafir
Dept. of Biological Chemistry, IQAC-CSIC, c/Jordi Girona 18–26,
08034 Barcelona (Spain); alexandr.shafir@iqac.csic.es
o
regioisomer, formed in a 34% yield after 1 h at -78 C, with an
80% yield reached after an additional 5h (Table 1, entries 1 and
2). The reaction was accelerated by using an excess of BF3·Et2O
Supporting information for this article is given via a link at the end of
the document.
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(entries 3-4). Activation was also possible with additives such as
Tf2O, TMSOTf or HOTf (Table 1, entries 5-7).[10] We note that
during the writing of this report, the para-benzylation phenomenon
was independently communicated by the Hyatt laboratory.[11]
approach of the benzylic carbon to the PhI para position. It should
also be noted that in addition to the proposed desilylation of V to
VI in Path B, species such as V are also known to readily convert
(via H+ loss) to a diaryliodonium cation, such as VII.[13] Yet, the
intermediacy of VII on route to 1 appears unlikely, given that the
diaryliodonium species VII, when synthesized independently via
the Ar-Sn route (Scheme 3, middle), remained intact when
submitted to the reaction conditions; a similar conclusion
regarding the role diaryliodonium formation was also made by
Hyatt et al.[11a] Concerning the path A, our DFT analysis failed to
arrive to an energetic minimum for the putative intermediate IV. In
contrast, the cationic π-adduct VI in path B did correspond to a
local minimum, poised to undergo the C-C bond formation via a
low-lying TS (ΔG‡ =1.6 kcal/mol, bottom).[14] Hence, in addition to
the interrupted transmetallation path (Hyatt et al)[11a], our path B
also appears to constitute a plausible mechanistic hypothesis.
Table 1. Condition screen for the reaction between PhI(OAc)2 and BnSiMe3.[a]
Entry
Additive (equiv)
%GC Yield of 1 [b]
1
2
3
4
5
6
7
none
nd
34 (80)[c]
84
BF3·OEt2 (1.0)
BF3·OEt2 (1.2)
BF3·OEt2 (1.2)
Tf2O (1.2)
59[d]
84
TMSOTf (1.2)
HOTf (1.2)
74
<1 (66) [d]
[a] Using 0.2 mmol PhI(OAc)2 and 0.3 mmol BnSiMe3 in 1.4 mL of solvent. [b] %
GC yield using CyCN as int. st. [c] 6 h. [d] Room temp.
The observation of small amounts of BnOAc and BnNHC(O)Me
(the latter from CH3CN) is consistent with iodine(III)-induced
umpolung reactivity of a benzyl cation. In addition, no deuterium
KIE could be observed for the para C-H position on PhI(OAc)2 nor
for the benzylic CH2/CD2 position. (Scheme 2A, B). Nevertheless,
a simple Friedel-Crafts benzylation could be ruled out, given that
a competition between PhI(OAc)2 and m-iodoanisole produced 1
as the only product (Scheme 2-B).
Scheme 3. Top: Two of possible reaction paths for the iodane-directed para C-
H
benzylation. Middle: Synthesis and x-ray crystal structure of the
diaryliodonium species VII. Bottom: DFT profile for the C-C bond-forming step
in path B. Yellow squares denote relative free energy in kcal/mol.
The para-C-H benzylation could be applied to a series of
iodoarene cores, as seen in Table 2. Good to excellent yields
were obtained for substrates bearing the meta-Me, -OMe or the -
NHCbz substituents (Table 2, 2-4). While the reaction was also
efficient for substrates bearing an ortho Me group, their use was
accompanied by moderate amounts of the meta-benzyl
derivatives 5’ and 6’, in line with non-negligible electrophilic
contribution from the aromatic core.[8b] While no product could be
detected for the ortho-bromo iodobenzene core, the meta-bromo
derivative afforded a 68% yield of 8 when activated using TMSOTf.
Alternatively, the presence of a deactivating ortho-bromide could
be compensated by an electron-donating o,p-directing meta-Me
substituent, leading to 9 in an 83% yield. Benzylation was also
efficient for the 1-iodonaphthalene core (prod. 10). The presence
of a para-Me substituent diverted the coupling to the meta position
(Table 2, 11 and 12), likely via a [1,2]-shift of the initially formed
para-benzylated intermediate similar to 1-H+.[15]
Scheme 2. Control experiments in the para-benzylation of PhI(OAc)2.
The observed para selectivity has been rationalized by Hyatt et al
via an interesting “interrupted transmetallation” path, whereby the
BnSi··OAc(I) interaction triggers a concerted desilylation/C-C
bond formation process.[11a] We have also considered possibility
of the benzylsilane precursor interacting directly with the acid-
activated iodine center, as has been proposed for other electron-
rich arenes.[10] The desilylation of such PhI··(BnSiMe3) adduct
could then lead to a putative [PhI-Bn]+ intermediate (Scheme 3).12]
Hence, in path A, a Si-to-I benzyl transfer produces the σ-bound
species III, which might then undergo two consecutive [3,3]-
sigmatropic rearrangements (via IV) to give the protonated 1H+.
In path B, the initial π-arene adduct V would be desilylated to the
π-complex VI (isomeric with III), positioned to facilitate the
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Table 2. The scope of the ArI(OAc)2 derivatives in the C-H benzylation.[a
the di-ortho substituted λ3-aryliodanes, the incoming group is
redirected to the meta C-H position (prod. 33), in line with a [3,3]-
rearrangement followed by an ortho-to-meta [1,2] -shift.[15, 7f] As
seen in Table 4-B, the open-chain sulfonylated allylsilane 34 was
also reactive, providing the corresponding ortho coupling product
35 in 92% yield. Importantly, controls using the parent
allyl(trimethyl)silane afforded <15% of ortho-allyliodobenzene.
Intriguingly, DFT calculations revealed comparable activation
barriers for the [3,3] rearrangement step of the H- and RSO2-
substituted allylsilanes (Table 4-C). This may suggest that the
superlative performance of allylsulfones 26 and 34 stems from the
higher resistance of the intermediate allyliodonium species
toward external nucleophilic attack.[5c] Incidentally, a related
sulfonyl-containing cationic species [PhI-CH2SO2Ar]+ have been
described as bench-stable.[16] We note that vinylsulfones feature
prominently as drug design element[17] and (for the
benzothiophene scaffold) in organic electronics.[18]
Table 4. The ortho C-H allylation with the sulfonated nucleophiles 26 and 34.
Only in the case of the 2-iodothiophene core did the coupling
occur ortho to iodine (13, Table 2). We note that the C-H
benzylation could be conducted on scales of up to 30 mmol (see
1, Table 2). The coupling of PhI(OAc)2 with additional ArCH2SiMe3
reagents was also briefly explored (Table 3). A number of
functional groups was tolerated, albeit requiring, at times, the use
of alternative activators, such as TfOH, Tf2O or TMSOTf.
Table 3. The scope of the benzylic fragments capable of undergoing a C-H
[a]
coupling with PhI(OAc)2
The C-H benzylation and the C-H sulfonylallylation reactions
described thus far expand the possibilities of iodane-directed
coupling beyond those illustrated in Scheme 1. In addition, the
benzylation manifold is fully complementary to the other
benzylation approaches developed in recent years in response to
the growing interest in diarylmethanes cores.[19] We were now
encouraged to tackle the iterative formation of multi-substituted
arenes. During our efforts to oxidize 1, the oxidizing ability of
Interestingly, treating PhI(OAc)2 with the benzothiophene dioxide-
based silane 26 resulted in a quantitative formation of the ortho-
substituted iodoarene 27 (Table 4-A). Considering that 26 is a
cyclic allylsilane, we assume that this reaction proceeds via the
more classical [3,3] sigmatropic rearrangement mechanism, thus
representing the first efficient ortho-allylation of a non-activated
iodoarene. In fact, the versatility of silane 26 is illustrated by the
synthesis of the structurally diverse series 28-32 (Table 4-A). For
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Selectfluor® proved to be a game-changer,[9a] which avoids
oxidation at the benzylic position and allows for a clean formation
of λ3-1-(OAc)2. This, in turn, enabled us to successfully engage
the iodobenzene core in up to three sequential oxidation/C-H
alkylation rounds (Scheme 4). Thus, the PhI para position was
transformed in the first round using PhCH2SiMe3 to give 1.
Reoxidation of 1 then enabled the first ortho alkylation using either
26 or 34, and the resulting 36 and 37 were once again reactivated,
currently underway to engage the remaining meta positions (e.g.
as seen for 35) on route to a modular synthesis of multi-
substituted aromatic cores. We also envisage that as a wider
range of iodine-retentive transformations become available,[20]
these could also be integrated into such iterative sequences.
Acknowledgements
using
this
time
the
“acid-free”
Selectfluor/TMSOAc
combination.[9b] The remaining ortho’ C-H position in 36 was then
engaged using our recently adapted C-H propargylation
protocol[5d] to give the tri-alkylated species 38 (see the X-Ray
structure in Scheme 4). Alternatively, treating λ3-37-(OAc)2 with
silane 26 afforded the differentially trialkylated iodoarene 39 in a
76% yield. While the downstream λ3-iodane intermediates such
as 36-(OAc)2 could be isolated in pure form (see ESI), these
proved unstable upon storage. Nevertheless, the crude 36-(OAc)2
and 37-(OAc)2 could be conveniently telescoped to the C-H
coupling step after a simple aqueous workup. Finally, the iodine
atom can be substituted, e.g. via a Sonogashira alkynylation (prod.
40).
This work was funded by Fundació ICIQ, MINECO (CTQ2013-
46705-R, CTQ2017-86936-P and SEV-2013-0319). We thank the
CELLEX Foundation for a contract to S. I., and COFUND
(291787-ICIQ-IPMP) for a fellowship to S. B.
Keywords: hypervalent iodine • C-H functionalization • C-C
coupling • oxidative coupling• iterative methods
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10 mol% PdCl2(PPh3)2, 20 mol% CuI in Et3N/THF at 60 oC.
In summary, two iodane-directed C-H alkylation reactions
have been developed. While the use of benzyl(trimethyl)silane
allows for benzylation para to the iodine, switching to the sulfonyl-
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coupling cycles can be conducted iteratively to build-up multi-
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Entry for the Table of Contents
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Y. Wu, S. Bouvet, S. Izquierdo, A Shafir*
Page No. – Page No.
Polysubstitued iodoarene synthesis
enabled by iterative iodine-directed
para and ortho C-H functionalization
The aromatic iodine substituent is shown to enable two new types of aromatic C-H
alkylation reactions from the readily accessible aryliodine λ3-diacetate form. Hence, a
benzyl group is coupled selectively at the para C-H position, while the sulfonylallylation
takes place ortho to iodine. Taken together with the previously developed iodane-
directed processes, this manifold enables the synthesis of multi-substituted arenes via
iterarative rounds of oxidation/C-H alkylation.
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