para-Selective Benzylation of Aryl Iodides by the in situ Preparation of ArIF2: a Hypervalent Iodine-Guided Electrophilic Substitution

Article abstract of DOI:10.1002/ejoc.202000393

Hypervalent iodine-guided electrophilic substitution (HIGES) was described previously for the para-selective benzylation of aryl-λ³-iodane diacetates. One drawback of the method was the synthesis and isolation of hypervalent iodine starting mat

Full text of DOI:10.1002/ejoc.202000393

A Journal of
Accepted Article
Title: para-Selective benzylation of aryl iodides via the in situ
preparation of ArIF2: A hypervalent iodine-guided electrophilic
substitution
Authors: Jennifer Noorollah, Haram Im, Fatima Siddiqi, Nirvanie Singh,
Nicholas R Spatola, Azka Chaudhry, Taro J Jones, and Ivan
Dempsey Hyatt
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000393
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10.1002/ejoc.202000393
European Journal of Organic Chemistry
COMMUNICATION
para-Selective benzylation of aryl iodides via the in situ
preparation of ArIF2: a hypervalent iodine-guided electrophilic
substitution
Jennifer Noorollah, Haram Im, Fatima Siddiqi, Nirvanie Singh, Nicholas R. Spatola, Azka Chaudhry,
Taro J. Jones, and I. F. Dempsey Hyatt*
Abstract: Hypervalent iodine-guided electrophilic substitution
(HIGES) was previously described for the para-selective benzylation
of aryl-3-iodane diacetates. One drawback of the method was the
synthesis and isolation of hypervalent iodine starting materials. An
improvement is reported herein in which the benzylation product can
be afforded from an aryl iodide via an in situ oxidation. Hypervalent
iodine’s metal-like properties have been demonstrated in the
transmetallation of metalloid groups such as silicon and boron and
are compatible with multiple Lewis acid activators. A desirable facet
of both the previous method and the newly reported procedure is
that the iodine atom is incorporated into the product thus providing
greater atom economy and a valuable functional group handle for
further transformations. The following communication contributes to
other articles in the field that imply there is a general HIGES
mechanism yet to be fully understood.
The recent and rapid development of hypervalent iodine-
guided electrophilic substitutions (Scheme 1) began from a
series of papers by Khatri and Zhu in which they rediscovered
and evaluated of the reductive iodonio-Claisen rearrangement
(RICR).[1–3] RICR-type reactions have undergone review by
Shafir and also in a section of a review on C-C bond forming
reactions by Hyatt et al. in 2019.[4–6]
While allylic and benzylic groups often have similarities,
substituting the allyl metalloid with a benzyl metalloid in the
RICR would seem to theoretical fail due to their different π-
systems and the theorized Claisen-type rearrangement.[7–12]
However, when the allyl metalloid was replaced by a benzyl
metalloid under the RICR reaction conditions, different
Scheme 1. Examples of the Reductive Iodonio-Claisen Rearrangement
regioselectivity was discovered; a para-selective substitution of
the aryl iodine as opposed the RICR’s ortho selectivity.[13,14]
The C-C bond forming methodology described herein hints
at, and provides increasing evidence for, a new class of
reactions involving HIGES. Elegant synthetic pathways
incorporating HIGES have resulted in tetraasubstituted
benzenes via four C-C bond forming reactions from
iodobenzene,[13] the total synthesis of clopidogrel,[3] the total
synthesis of broussin,[2] the synthesis of various heterocycles,[1]
and the selective bromination of arenes.[15]
compared to previous work and the newly devised in-situ HIGES methodology.
DFT-calculations investigating the mechanistic aspects of
RICR propargylation found an acid-activated hypervalent iodine
intermediates was required.[16,17] Calculations have also shown
that transition state energies are easier to achieve with
PhI(OAc)2•BF3 as opposed to PhI(OAc)2 alone,
a result
congruent with experimental yields.[18] While the acid-activated
hypervalent iodine intermediates are key to the reactivity of the
RICR and the para-selective benzylation, the fundamental
differences of how each π-system behaves varies the
regioselectivity of products. Mechanisms for para-selective
benzylation, both involving HIGES, have thus far withstood
scrutiny by calculation and control experiments (Scheme 2).[14,19]
One such critical control experiment revealed that the
mechanism cannot be intermolecular electrophilic substitution
similar to Friedel-Crafts reactivity; it must occur through a yet
unknown intramolecular reaction or iodine coordination.
[*]
Dr. I. F. D. Hyatt
Department of Chemistry and Biochemistry
Adelphi University
1 South Ave., Garden City, NY 11530
E-mail: ihyatt@adelphi.edu
Homepage:
https://home.adelphi.edu/~ih21353/HyattResearchGroup/
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.202000393
European Journal of Organic Chemistry
COMMUNICATION
The use of Selectfluor as a mild oxidant for the formation
of ArIF2 has been demonstrated in several articles,[21–23] yet in
our lab the isolation of the ArIF2 compounds encountered
difficulty and impurities caused decomposition. The inability to
isolate pure ArIF2 compounds led us to develop an in situ
process that could bypass isolation steps. Over 46 optimization
conditions were explored and the most relevant ones are shown
in Table 1. Several Lewis-acids and solvent systems were found
to be tolerated. Another interesting fact is that the reactions can
be performed at room temperature with moderate success.
Table 1. Reaction optimization.[a]
Entry
1
Lewis Acid
Solvent
ACN
ACN
ACN
ACN
ACN
ACN
ACN
ACN
ACN
ACN
ACN
ACN
ACN
THF
Temp.
-40 ˚C
-40 ˚C
-40 ˚C
0 ˚C
Selectfluor
2.6 equiv.
2.6 equiv.
1.3 equiv.
1.1 equiv.
2.6 equiv.
2.6 equiv.
2.6 equiv.
2.6 equiv.
2.6 equiv.
2.6 equiv.
2.6 equiv.
1.3 equiv.
2.6 equiv.
2.6 equiv.
2.6 equiv.
2.6 equiv.
2.6 equiv.
Yield
84%
48%
20%
15%
24%
7%
TMSOTf (2 equiv.)
TMSOTf (1 equiv.)
TMSOTf (1 equiv.)
TMSOTf (2 equiv.)
TMSOTf (1 equiv.)
Tf2O (2 equiv.)
2
3
4
5
0 ˚C
6
0 ˚C
7
Tf2O (2 equiv.)
-40 ˚C
-40 ˚C
0 ˚C
13%
24%
18%
10%
10%
46%
52%
0%
Scheme 2. Current mechanistic proposals of the HIGES para-selective
benzylation
8
Tf2O (0.5 equiv.)
Tf2O (1 equiv.)
9
Three proposed mechanistic routes are shown in Scheme
2, with one being unlikely due to the high energy barrier
associated with intermediates C2 and C3.[20] The
transmetallation of—or at least the interaction between—
hypervalent iodine intermediates and metalloid groups is key to
theorizing a mechanism for the benzylation shown in Scheme 2.
From A1, if the benzylsilane interacts to coordinate to the HVI
and form complex A2, the mechanistic path relies on the weak
nucleophilicity of the [AcOBF3]- anion to remove the metalloid
group. Another issue is that, upon deprotonation, intermediate
A4 could result in a diaryl-3-iodane which was shown not to
produce benzylation products.[20] The mechanism resulting from
the formation of intermediate B1 relies on a large ring that
occurs during a speculated transmetallation process. Note that
the work herein does not use acetate anions and that the
fluoride of ArIF2 would be involved with the transmetallation step.
Our group mentioned these differences in ring size between
using an acetate and a fluoride in our previous report and it was
determined that the fluoride could potentially still form the ring
due to the negligible energy difference between a 8- and 10-
membered ring.[14] The key conceptual leap that intermediate B1
relies on is the positioning of the benzyl carbon as it rests over
the para position of the aryl iodonium and causes an interruption
in the transmetallation process that subsequently leads to
product, B2.
10
11
12
13
14
15
16
17
BF3·Et2O (2 equiv.)
BF3·Et2O (2 equiv.)
BF3·Et2O (1 equiv.)
TMSOTf (2 equiv.)
TMSOTf (2 equiv.)
TMSOTf (2 equiv.)
TMSOTf (2 equiv.)
TMSOTf (2 equiv.)
0 ˚C
-40 ˚C
-40 ˚C
RT
0 ˚C
MeNO2
TFE
-40 ˚C
-40 ˚C
RT
53%
50%
34%
TFE
[a] Iodobenzene (1.0 equiv) and Selectfluor™ (2.6 equiv) were dissolved in
dry solvent and stirred for 24 h under nitrogen at room temperature.
Varying amounts of Lewis-acid were then added to the reaction mixture
followed by benzyltrimethylsilane (1.0 equiv).
The substrate scope for the in situ benzylation of aryl iodides
is shown in Table 2. Evidence seemed to imply that yields were
dependent upon whether the groups on either substrate were
electron-donating or electron-withdrawing. It was difficult to find
a general method that worked with a range of substrates. The
type of Lewis acid, the equivalents of Lewis acid, the
temperature at which the Lewis acid was added, the time
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10.1002/ejoc.202000393
European Journal of Organic Chemistry
COMMUNICATION
TMSOTf (1.0 equiv). [c] NMR yield.
allowed for the initial ArIF2 formation, and solvent were different
for each substrate attempted. We conclude that the dominating
aspects of electron demand in the reaction largely govern the
optimal reaction conditions for each substrate. With this in mind,
we decided to run the substrate scope at room temperature to
demonstrate the robustness of the method, with TMSOTF as the
Lewis activator to better match our previous method in
The yields shown in Table 2 are higher than, or the similar
to, the overall yields associated with our previous method. Since
there is no need to oxidize the aryl iodide and isolate the aryl-3-
iodane diacetate, there is also a considerable amount of waste
and time removed from the method. For example, the yield of
synthesizing m-tolyl-3-iodane diacetate was 80%, and our
previous reported method afforded a yield of 45% for the same
product (3d). The overall yield of the previous method was 36%
while the new method afforded a similar 31% yield (Table 2,
Entry 3). Other reactions such as o-tolyl-3-iodane diacetate to
the benzylated product, 3c, show a substantial increase in yield
with the new method; a 42% overall yield for the previous
method as opposed to the 82% yield (Table 2, Entry 2) of the in
situ method described herein.
comparison, and acetonitrile for the solubility of the SelectfluorTM
.
Table 2. Substrate scope.[a]
Entry
1
ArI
Ar’
Product
Yield
14%
The difficulty in finding a suitable general procedure is also
demonstrated by Entry 2 in that the reaction only required one
equivalent of TMSOTf to produce a high yielding benzylation
product. Within the substrate scope, varying amounts of
TMSOTf were used and the highest yields are reported. The
explanation to the varying optimal reaction conditions stems
from the electron demands of the reaction. Entry 10 of Table 2
shows a reaction in which the methodology is extended to
encompass mixed substituents on the aryl iodide as well as the
benzyl-TMS derivatives.
1-chloro-3-
iodobenzene
(1c)
Ph (2a)
2
2-iodotoluene
(1e)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
82%[b]
31%
3
3-iodotoluene
(1f)
Previous methods that isolated the aryl-3-iodane diacetate
precursor were capable of benzylating 2-iodothiophene, 2-
iodobiphenyl, and 2-iodonapthalene while the in situ method
described herein produced only trace amounts of benzylation.
The poor benzylation of these substrates with the in situ method
could be related to side reactions with Selectfluor or the
Selectfluor byproduct, or from the reaction mechanism involving
fluoride rather than acetate.
4
2-iodoanisole
(1h)
14%
22%[c]
5
3-iodoanisole
8%[c]
19%
23%
22%
33%
26%
(1i)
Electron-withdrawing groups on the aryl iodide that failed to
achieve benzylation include 2-iodobenzoic acid, 2-iodohippuric
acid, 2-iodonitrobenzene, 3-iodonitrobenzene, 3-iodobenzonitrile,
6
Iodobenzene
(1a)
3-CF3
(2b)
2-iodobenzotrifluoride,
3-iodobenzotrifluoride,
1-bromo-3-
iodobenzene, and ethyl 3-iodobenzoate. The failure to benzylate
the aryl iodide containing electron-withdrawing groups resulted
in the benzyl-TMS converting to benzyl alcohol (5); a fact that
provides evidence towards a complete transmetallation (4,
Scheme 3) instead of our hypothesized interrupted
transmetallation (B1, Scheme 2).
7
Iodobenzene
(1a)
3-Cl (2c)
8
Iodobenzene
(1a)
3-CN
(2d)
9
Iodobenzene
(1a)
3-COOEt
(2e)
10
1-chloro-3-
iodobenzene
(1c)
3-CF3
(2b)
Scheme 3. Possible mechanism to explain benzyl alcohol formation
[a] Aryl iodide (1.0 equiv) and Selectfluor™ (2.6 equiv) were dissolved in dry
acetonitrile and stirred for 24 h under nitrogen at room temperature.
TMSOTf (2.0 equiv) was then added to the reaction mixture followed by a
benzyltrimethylsilane derivative (1.0 equiv) at room temperature. [b]
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10.1002/ejoc.202000393
European Journal of Organic Chemistry
COMMUNICATION
Electron-donating groups on the benzyl-TMS derivatives
failed to create benzylated aryl iodide products. The specific
benzyl-TMS substituents that failed included: 4-methyl, 2,4-
dimethyl, and 3-methoxy. The major product when the
benzylation failed was the conversion of the benzyl-TMS
derivatives to their corresponding benzyl alcohol (i.e. 4-
methylbenzyl-TMS to p-tolylmethanol, and 3-methoxybenzyl-
TMS to 3-methoxyphenylmethanol).
NEB calculations that helped substantiate the HIGES
mechanism for us.
Keywords: hypervalent iodine • C-C bond formation • HIGES •
benzylation • Selectfluor
[1]
H. R. Khatri, H. Nguyen, J. K. Dunaway, J. Zhu, Front. Chem. Sci.
Eng. 2015, 9, 359–368.
From the substrate scope, the optimal combination appears
to be when electron-donating groups are on the aryl iodide and
when electron-withdrawing groups are on the benzyl-TMS
derivative. A hypothesized benzyl-aryl-iodonium (4) is a possible
explanation for the formation of benzyl alcohols. The yields
reported are higher than the previously reported yields over two-
steps. Cross reactions (Entry 10 of Table 2) demonstrate the
potential of the methodology to be incorporated into total
synthesis targets.
[2]
[3]
H. R. Khatri, J. Zhu, Chem. - A Eur. J. 2012, 18, 12232–12236.
H. Nguyen, H. R. Khatri, J. Zhu, Tetrahedron Lett. 2013, 54, 5464–
5466.
[4]
[5]
A. Shafir, Tetrahedron Lett. 2016, 57, 2673–2682.
S. Izquierdo, S. Bouvet, Y. Wu, S. Molina, A. Shafir, Chem. - A Eur.
J. 2018, 24, 15517–15521.
[6]
[7]
I. D. Hyatt, L. Dave, N. David, K. Kaur, M. Medard, C. Mowdawallla,
Org. Biomol. Chem. 2019, 17, 7822–7848.
M. Ochiai, E. Fujita, M. Arimoto, H. Yamaguchi, Chem. Pharm. Bull.
1985, 33, 41–47.
[8]
[9]
M. Ochiai, T. Ito, J. Org. Chem 1996, 60, 2274–2275.
M. Ochiai, T. Ito, Y. Masaki, N. Fujita, A. Kato, J. Chem. Soc. Chem.
Commun. 1992, 64, 15.
Experimental Section
General procedure for the synthesis of benzylsilanes: Procedure is in
accordance with that reported by Shafir et al.[20] Iodine(I) reagent (1.0
equiv) and Ni(acac)2 (0.05 equiv) was dissolved in dry THF (25 mL) and
stirred for a period of 5 min under nitrogen at room temperature. The
reaction is cooled to 0 °C and a solution of Me3SiCH2MgCl in THF (1.0
equiv) was added to reaction mixture and was allowed to stir for 2 h. The
reaction is then quenched with saturated NH4Cl, filtered through Celite,
and extracted with Et2O. The combined organic layers were dried over
anhydrous Na2SO4 and then concentrated in vacuo. The crude reaction
mixtures were purified via silica gel flash column chromatography to give
the desired benzyltrimethylsilane products.
[10]
[11]
M. Ochiai, T. Ito, Y. Takaoka, Y. Masaki, J . Am. Chem. SOC 1991,
113, 1319–1323.
D. A. Gately, T. A. Luther, J. R. Norton, M. M. Miller, O. P. Anderson,
J. Org. Chem. 1992, 57, 6496–6502.
[12]
[13]
K. Lee, D. Y. Kim, D. Y. Oh, Tetrahedron Lett. 1988, 29, 667–668.
Y. Wu, S. Bouvet, S. Izquierdo, A. Shafir, Angew. Chemie Int. Ed.
2019, 58, 2617–2621.
[14]
[15]
[16]
C. Mowdawalla, F. Ahmed, T. Li, K. Pham, L. Dave, G. Kim, I. F. D.
Hyatt, Beilstein J. Org. Chem. 2018, 14, 1039–1045.
A. Granados, A. Shafir, A. Arrieta, F. P. Cossío, A. Vallribera, J. Org.
Chem. 2020, 85, 2142–2150.
General procedure for para benzylation: Iodine(I) reagent (1.0 equiv) and
Selectfluor™ (2.6 equiv) was dissolved in dry acetonitrile (5 mL) and
stirred for a period of 24 h under nitrogen at room temperature. At this
point, trimethylsilyl trifluoromethanesulfonate (2.0 equiv) and
benzyltrimethylsilane derivative (1.0 equiv) was added subsequently and
was allowed to stir for 1 h. To the crude reaction, water was added and
extracted with hexane. The combined organic layers were dried over
anhydrous Na2SO4 and then concentrated in vacuo. The crude reaction
mixtures were purified by PREP-TLC to give the desired Csp2–Csp3
products.
J. Tian, F. Luo, C. Zhang, X. Huang, Y. Zhang, L. Zhang, L. Kong, X.
Hu, Z.-X. Wang, B. Peng, Angew. Chemie Int. Ed. 2018, 57, 9078–
9082.
[17]
[18]
X. Huang, Y. Zhang, C. Zhang, L. Zhang, Y. Xu, L. Kong, Z.-X.
Wang, B. Peng, Angew. Chemie Int. Ed. 2019, DOI
10.1002/anie.201900745.
S. Izquierdo, S. Essafi, I. del Rosal, P. Vidossich, R. Pleixats, A.
Vallribera, G. Ujaque, A. Lledós, A. Shafir, J. Am. Chem. Soc. 2016,
138, 12747–12750.
Acknowledgements
[19]
[20]
Y. Wu, S. Bouvet, S. Izquierdo, A. Shafir, Angew. Chemie Int. Ed.
2019, 58, 2617–2621.
The research conducted was supported by Adelphi University
Faculty Development Grants, Frederick Bettelheim Research
Award, and the ACS PRF# 59555-UNI1. 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. We are also grateful to Dr.
Andrew L. Sargent at East Carolina University for completing
W. W. Chen, A. B. Cuenca, A. Shafir, Angew. Chemie Int. Ed. 2019,
DOI 10.1002/anie.201908418.
[21]
[22]
C. Ye, B. Twamley, J. M. Shreeve, Org. Lett. 2005, 7, 3961–3964.
J. C. Sarie, C. Thiehoff, R. J. Mudd, C. G. Daniliuc, G. Kehr, R.
Gilmour, J. Org. Chem. 2017, 82, 11792–11798.
J. Tao, G. K. Murphy, Synthesis (Stuttg). 2019, 51, 3055–3059.
[23]
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10.1002/ejoc.202000393
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Jennifer Noorollah, Haram Im, Fatima
Siddiqi, Nirvanie Singh, Nicholas R.
Spatola, Azka Chaudhry, Taro J. Jones,
and I. F. Dempsey Hyatt*
Page No. – Page No.
para-Selective benzylation of aryl
iodides via the in situ preparation of
hypervalent iodine: a hypervalent
iodine-guided electrophilic
substitution
Delving into the HIGES: Hypervalent iodine-guided electrophilic substitution
(HIGES) was previously described for the para-selective benzylation of aryl-3-
iodane diacetates. To make our methodology more accessible to the synthetic
community, a procedure was developed in which the benzylation product can be
afforded from an aryl iodide via an in situ oxidation with an overall higher yield for
most substrates.
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