Hypervalent iodine-guided electrophilic substitution: Para-selective substitution across aryl iodonium compounds with benzyl groups

Article abstract of DOI:10.3762/BJOC.14.91

The reactivity of benzyl hypervalent iodine intermediates was explored in congruence with the reductive iodonio-Claisen rearrangement (RICR) to show that there may be an underlying mechanism which expands the reasoning behind the previously known C–C bond

Full text of DOI:10.3762/BJOC.14.91

Hypervalent iodine-guided electrophilic substitution:
para-selective substitution across aryl iodonium
compounds with benzyl groups
Cyrus Mowdawalla, Faiz Ahmed, Tian Li, Kiet Pham, Loma Dave, Grace Kim
and I. F. Dempsey Hyatt*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 1039–1045.
Department of Chemistry and Biochemistry, Adelphi University,
1 South Ave., Garden City, NY, 11530, USA
doi:10.3762/bjoc.14.91
Received: 14 February 2018
Accepted: 25 April 2018
Published: 14 May 2018
Email:
I. F. Dempsey Hyatt* - ihyatt@adelphi.edu
* Corresponding author
This article is part of the Thematic Series "Hypervalent iodine chemistry in
organic synthesis".
Keywords:
electrophilic aromatic substitution; hypernucleofugality; hypervalent
iodine; iodonio-Claisen; transmetallation
Guest Editor: T. Wirth
© 2018 Mowdawalla et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The reactivity of benzyl hypervalent iodine intermediates was explored in congruence with the reductive iodonio-Claisen rearrange-
ment (RICR) to show that there may be an underlying mechanism which expands the reasoning behind the previously known C–C
bond-forming reaction. By rationalizing the hypervalent iodine’s metal-like properties it was concluded that a transmetallation
mechanism could be occurring with metalloid groups such as silicon and boron. Hypervalent iodine reagents such as Zefirov’s
reagent, cyclic iodonium reagents, iodosobenzene/BF3, and PhI(OAc)2/BF3 or triflate-based activators were tested. A desirable
facet of the reported reaction is that iodine(I) is incorporated into the product thus providing greater atom economy and a valuable
functional group handle for further transformations. The altering of the RICR’s ortho-selectivity to form para-selective products
with benzyl hypervalent iodine intermediates suggests a mechanism that involves hypervalent iodine-guided electrophilic substitu-
tion (HIGES).
Introduction
Hypervalent iodine compounds have been known for over a have also found their own niche in useful C–C bond-formation
hundred years, but it was not until their renaissance in the and C–H activation reactions [3-5]. One such C–C bond forma-
1990’s that many of these useful reagents became a staple in tion (Scheme 1) was discovered by Oh and co-workers in 1988,
synthetic chemistry laboratories [1,2]. Although hypervalent and although it was based on previous work by the Ochiai
iodine reagents are commonly used in oxidation reactions, they group, the paper was the first to suggest a six-membered transi-
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Beilstein J. Org. Chem. 2018, 14, 1039–1045.
Scheme 1: Examples of the reductive iodonio-Claisen rearrangement compared to new reactivity seen with benzyl metalloids.
tion state indicative of a Claisen reaction [6,7]. In 1991, Ochiai mediate. To the best of our knowledge, no allyl, propargyl, or
and co-workers coined the phrase reductive iodonio-Claisen re- alkyl hypervalent iodine species have been isolated at room
arrangement (RICR) to describe the product selectivity they en- temperature (besides fluorinated alkyl chains [17]), thus trap-
countered [8].
ping an intermediate to validate the mechanism seemed
unlikely. The process in which these hypervalent iodine inter-
More recently, exceptional progress has been made in investi- mediates form from metalloid substituted substrates has not
gating the RICR’s substrate scope (electron-donating versus been fully explored. It has been suggested that there may be a
electron-withdrawing substituents on PhI(OAc)2 (1a)), mecha- more all-inclusive iodine-guided mechanism that could account
nism (deuterium labelling studies), product yields and selectivi- for a wider range of hypervalent iodine reactivity [12]. To this
ties based on appropriate solvents, temperatures, and Lewis end, it is theorized that hypervalent iodine’s metal-like proper-
acids [9-11]. A recent digest of RICR theorized an underlying ties allow it to undergo transmetallation with an appropriate
mechanistic concept dubbed iodine-guided electrophilic aromat- metalloid substrate. This concept is counter to previous mecha-
ic substitution (IGEAS) [12]; the basis for which the work nisms in which the electrophilic hypervalent iodine reagent is
herein is titled. Other related work focused on the activation of attacked by unsaturated C–C bonds [18-22]. To show evidence
hypervalent iodine [13], and a computational study that sug- for this transmetallation event, benzyl metalloid groups were
gested a concerted iodination/deprotonation (CID) that is analo- used under the same reaction conditions as the RICR. The re-
gous to concerted metallation/deprotonation (CMD) for cationic sulting diphenylmethane structure obtained after the C–C bond
hypervalent iodine [14]. These studies and others on the electro- formation could have relevant medicinal applications since it is
philic nature and metal-like properties of iodine(III) were par- the core of many marketed pharmaceutical drugs with antihista-
ticularly significant in the development of the reaction reported minic and anxiolytic properties [23-26].
in this communication [15,16].
Results and Discussion
A commonality in the RICR is that the proposed mechanisms In the reaction with PhI(OAc)2 (1a), 0.5 equiv triflic anhydride,
involve an unstable allyl or propargyl hypervalent iodine inter- and BnM (where M is TMS or BF3K), a 72% yield of a coupled
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Beilstein J. Org. Chem. 2018, 14, 1039–1045.
product was isolated, but the connection was unexpectedly at Another result is that by changing the metalloid substrate to
the para- not the ortho-position as the RICR might have pre- BnBF3K (Table 1, entries 8–12), the reaction proceeds to give a
dicted (Table 1). Further experiments of this hypervalent product with generally lower yield. This fact is potentially ex-
iodine-guided electrophilic substitution (HIGES) reaction were plained by the partial solubility of trifluoroborates in the sol-
performed by varying the hypervalent iodine starting material, vents used. The displacement of silyl and boron groups with
the activator, the solvent, and the temperature at which the acti- hypervalent iodine seems to suggest that a transmetallation
vated hypervalent iodine reagent formed (Table 1). Varying the event from Si/B to I is occurring rather than an addition reac-
temperature at 25 °C, 0 °C, and −50 °C did not cause a substan- tion to the unsaturation of the benzyl group followed by elimi-
tial difference in yield, but at −50 °C the solubility of the acti- nation of the metalloid group. The latter of which would be
vated hypervalent iodine species seemed poor upon visual consistent with the mechanism currently theorized for making
inspection. It should be noted that the only other major prod- alkenyl and alkynyl hypervalent iodine species [18-22].
ucts in the resultant reaction mixture were the decomposition of
PhI(OAc)2 (1a) or PhIO to PhI, and unreacted BnTMS or While investigating the substrate scope it was found that the
BnBF3K. The results in Table 1 show that silyl groups seem to substitution pattern is dependent upon the substituents on the
be superior to boron groups for the reaction to afford a good I(III) reactant (Table 2). The trend of para-substitution to spe-
yield. The solvent choices were made based on low nucleo- cific substituents appears to provide some evidence for a simi-
philicity and polarity being high enough to dissolve the hyper- lar intermediate that relates to each reaction (for instance,
valent iodine starting material. Surprisingly, the protic solvent Table 1, entry 1 compared to entry 8 or 9). Also, the optimiza-
methanol worked to synthesize the product albeit in low yield. tion study showed comparable yields for activating reagents yet
Table 1: Optimization of HIGES reaction.a
Entry
Metalloid (M)
I(III) Reactant
Activator
Solvent
Yield (%)
1
2
3
4
5
TMS
TMS
TMS
TMS
TMS
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhIO
Tf2O (0.5 equiv)
Tf2O (1.0 equiv)
CDCl3
CDCl3
CDCl3
CDCl3
MeOH
72
73
64
80
13
BF3·Et2O (1.0 equiv)
BF3·Et2O (1.0 equiv)
BF3·Et2O (1.0 equiv)
PhIO
6
7
TMS
TMS
Tf2O (1.0 equiv)
Tf2O (1.0 equiv)
DCM
0
0
3
CH3CN
3
8
BF3K
BF3K
BF3K
BF3K
BF3K
TMS
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhIO
Tf2O (1.0 equiv)
Tf2O (0.5 equiv)
BF3·Et2O (1.0 equiv)
BF3·Et2O (1.0 equiv)
Tf2O (0.5 equiv)
none
CH3CN
CH3CN
CDCl3
CDCl3
CH3CN
CDCl3
17
24
24
43
18
0
9
10
11
12
13
PhIO
PhI(OAc)2
aAll reactions used 0.055 M to 0.115 M I(III) reactant with the specified solvent and activator at 0 °C for 30 min followed by the addition of 1.0 equiv of
BnTMS or BnBF3K and allowing the mixture to warm to room temperature. Isolated yields are reported.
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Beilstein J. Org. Chem. 2018, 14, 1039–1045.
Table 2: Substrate scope of substituted hypervalent iodine species.
Entry
I(III) Reactant
Product
Yielda (%)
2, 15b,c
1
1b
1c
2b
2c
2
3
6, 23b,c
23
1d
1e
2d
2e
4
25
5
6
52
45
1f
2f
1g
2g
7
8
28
1h
2h
2i
4, 50b
1i
1j
9
76
0
2j
10
NA
1k
1l
11
NA
0
aAll reactions used 0.055 M to 0.115 M I(III) reactant with 0.5 equiv of Tf2O in CH2Cl2 or CDCl3 at 0 °C for 30 minutes followed by 1.0 equiv of BnTMS
unless otherwise specified. Isolated yields are reported. bReaction used 1.0 equiv BF3·Et2O as an activator instead of Tf2O. cNMR yield in CDCl3.
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Beilstein J. Org. Chem. 2018, 14, 1039–1045.
the use of BF3·Et2O seemed to be superior to Tf2O in the case In the article and further in a footnote of Khatri and Zhu’s
of some I(III) reactants.
publication [11] compelling evidence was shown by deuterium
labelling studies supporting a concerted intramolecular mecha-
In all the reactions tested, there were no products formed with nism (RICR) occurring rather than a stepwise intermolecular
the ortho-substitution pattern in contrast to the RICR, however, one. To corroborate their findings with our own, we investigat-
it is clear that electron-donating groups influence the ring sub- ed the HIGES reaction through crossover experiments which
stitution. When weaker electron-donating and electron-with- appear to conclude a concerted mechanism is occurring
drawing groups are used (Table 2, entries 1, 2, 4, 5 and 6), the (Scheme 2). Two crossover reactions were performed for both
C–C bond formation occurs para to the iodine, but when strong iodobenzene (4) and 2-iodoanisole (5) to prevent substrate bias.
electron-donating groups are used (Table 2, entries 7 and 8) One stepwise mechanism that the results in Scheme 2 eliminate
then the para-selectivity is dictated by that group. The effect of is the possibility that the I(III) is decomposing to I(I) and then
electron donation is also demonstrated in the thiophene (1j) subsequently reacts in an electrophilic substitution on the trans-
group tested (Table 2, entry 9). In the case of electron-with- metallated benzyl hypervalent iodine intermediate. If such a
drawing groups, deactivation occurs and the only reaction is the stepwise mechanism were to occur then one would expect to see
decomposition of the I(III) to I(I) (Table 2, entries 10 and 11). an additional coupling product.
The fact that no product was formed when using electron-with-
drawing groups could also explain how the carbonyl of the Based on the evidence provided by these crossover reactions it
cyclic iodonium (3) caused that specific reagent to fail (Table 1, rules out such a stepwise reaction thus we propose a concerted
entries 6 and 7). Several para-substituted I(III) reactants were mechanism. The mechanism speculated in Scheme 3 shows a
attempted but all led to complex mixtures with the exception of concerted demetallation of the metalloid as the C–C bond is
the diaryliodonium triflate 2d (Table 2, entry 3). These key fea- forming. Before the transmetallation of the metalloid group, an
tures in the substitution pattern of the substrate scope led to ex- interruptive process could be occurring that provides an orbital
periments where tests were performed to better understand, if overlap at the benzylic methylene and the para-position of the
the HIGES reaction is a concerted mechanism, like RICR, or a aryl iodine. In the case of entry 7 from Table 2, the methoxy
stepwise process.
group of 1h directs the para-positioning in a similar manner,
Scheme 2: Crossover reaction experiments.
Scheme 3: Suggested mechanism based on product formation and crossover experiments.
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Beilstein J. Org. Chem. 2018, 14, 1039–1045.
yet entry 8 from Table 2 would likely result from a different
intermediate (Scheme 4).
Supporting Information
Supporting Information File 1
Synthetic procedures, characterization data and copies of
spectra.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-91-S1.pdf]
Acknowledgements
This research was supported by Faculty Development Grants
and a Frederick Bettelheim Research Award from Adelphi
University to I. F. Dempsey Hyatt. We are grateful to Dr. Brian
Stockman for his NMR expertise and Dr. Daniel A. Todd for
acquisition of the high resolution mass spectrometry data at the
Triad Mass Spectrometry Laboratory at the University of North
Carolina at Greensboro.
Scheme 4: Proposed mechanism for the generation of 2i from
Table 2, entry 8.
In Scheme 4, a mechanism where a C–C bond forms by an
intramolecular attack on a benzylic methylene with the hyper-
nucleofuge attached (6). The mechanism in Scheme 4 shows the
transmetallation occuring instead of being interrupted as in
Scheme 3. The combination of both mechanisms (Scheme 3 and
Scheme 4) explains how substitution ortho to the iodine (para
to the methoxy group) could be generated from a benzyl–I(III)
intermediate (7), while the products found from the interruptive
transmetallation process obey the mechanism shown in
Scheme 3. Another point to note is that since a product can
form ortho to the iodine, sterics are unlikely the sole cause of
the para-selectivity of the other reactions shown. Further inves-
tigation of in situ generated benzyl–I(III) and alkyl–I(III) inter-
mediates is still being conducted in the research group.
ORCID® iDs
Cyrus Mowdawalla - https://orcid.org/0000-0002-3908-1771
Faiz Ahmed - https://orcid.org/0000-0002-3280-843X
Grace Kim - https://orcid.org/0000-0002-6044-483X
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