1,2-Difunctionalization of Aryl Triflates: A Direct and Modular Access to Diversely Functionalized Anilines

Article abstract of DOI:10.1021/acs.orglett.0c00320

ortho-Amino difunctionalization of aryl triflates has been achieved via a three-component reaction. The cascade reaction proceeds through a zincate base-mediated deprotonative formation of a reactive aryne intermediate, in situ nucleophilic addition, and coupling with electrophilic partners. This strategy leverages the advantageous reactivity of organozincate intermediates, enabling the installation of various functionalities such as amine, azide, oxygen, sulfur, halide, alkynyl, aryl, vinyl, and alkyl groups in a modular manner for the synthesis of diverse aniline skeletons.

Full text of DOI:10.1021/acs.orglett.0c00320

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Letter
1,2-Difunctionalization of Aryl Triflates: A Direct and Modular Access
to Diversely Functionalized Anilines
Seoyoung Cho and Qiu Wang*
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ABSTRACT: ortho-Amino difunctionalization of aryl triflates has
been achieved via a three-component reaction. The cascade
reaction proceeds through a zincate base-mediated deprotonative
formation of a reactive aryne intermediate, in situ nucleophilic
addition, and coupling with electrophilic partners. This strategy
leverages the advantageous reactivity of organozincate intermedi-
ates, enabling the installation of various functionalities such as
amine, azide, oxygen, sulfur, halide, alkynyl, aryl, vinyl, and alkyl groups in a modular manner for the synthesis of diverse aniline
skeletons.
Scheme 1. Arene Difunctionalization from Readily Available
Monofunctionalized Arene Precursors Such as Aryl Halides
and Triflates
olysubstituted arenes are valuable skeletons ubiquitously
found in medicine,1 natural products, and functional
P
materials.2 For the preparation of polyfunctionalized arenes, an
attractive strategy is to introduce multiple functional groups
simultaneously from readily available aryl precursors. For
example, Catellani-type reactions have emerged as an effective
approach for vicinal difunctionalization of aryl iodides and
bromides, utilizing palladium/norbornene (Pd/NBE) cooper-
ative catalysis to introduce a nucleophile and an electrophile in
a single step (Scheme 1a).3 As an alternative strategy, aryne
chemistry is known to concurrently functionalize two adjacent
carbon atoms with a myriad of reaction partners,4 yet most
aryne precursors are difunctionalized aryl derivatives,5 such as
the most commonly used o-silyl aryl triflates.6 Very few from
readily available monofunctionalized precursors (e.g., aryl
halides or triflates) have been reported for three-component
reactions to enable versatile combination of a nucleophile and
an electrophile7 (Scheme 1b).
Aryne generation from aryl halides and triflates typically
relies on strong base-mediated deprotonative elimination8 and
often occurs via lithiate intermediates (Scheme 1b). Thus, the
high reactivity of aryl lithiates8a,b,9 and their incompatibility
constrained the reactions most to alkyl or aryl nucleophiles and
the SN2-type electrophilic trappings, limiting the capability and
potentials of aryne chemistry in the synthesis of polysub-
stituted arenes. We envisioned that such restraints could be
overcome by using a strong, non-nucleophilic zincate base for
deprotonative aryne formation and in situ nucleophilic addition
for the formation of an organozincate intermediate (Scheme
1c). Leveraging an organozincate intermediate in this
difunctionalization approach would offer a powerful platform
that allows for the introduction of diverse functionalities by
cross-coupling reactions with different electrophiles. The mild
reactivity of organozinc bases also offers good tolerance of
sensitive functional groups, overcoming the limitations of
strong lithium bases. In this work, we explored this strategy to
develop 1,2-amino difunctionalization reactions of aryl triflates,
using anilines and amines as nucleophiles with versatile capture
with carbon-, nitrogen-, oxygen-, sulfur-, and halide-based
Received: January 22, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00320
© XXXX American Chemical Society
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electrophiles. These reactions afford a direct and modular
access to diversely functionalized aminoarene skeletons that
are quite valuable in medicine and agrochemicals.
Scheme 2. Scope of Nitrogen Nucleophiles in
Aminoiodination of Phenyl Triflate 1a
d
Our studies began with developing an aminoiodination
reaction of phenyl triflate 1a using N-methylaniline as a
nucleophile and I2 as the electrophile (Table 1). We chose
Table 1. Evaluation of Bases and Nucleophile Forms for 1,2-
a
Aminoiodination of Phenyl Triflate 1a
b
yield (%)
entry
base
M-NMePh
LiNMePh
Zn(NMePh)2
Li[Zn(NMePh)TMP2]
LiNMePh
LiNMePh
LiNMePh
LiNMePh
1a
2a
c
1
Li[Zn(nBu)TMP2]
Li[Zn(nBu)TMP2]
Li[Zn(nBu)TMP2]
Li[Zn(Et)2TMP]
Li[ZnTMP3]
−
86
−
22
−
71
−
50
−
47
−
2
3
4
5
6
7
ZnTMP2
90
18
LiTMP
−
a
Reactions run with 1a (0.2 mmol, 1.0 equiv). TMP, 2,2,6,6-
b
tetramethyl-1-piperidyl. Yields determined by 1H NMR of the crude
reaction mixture with dibromomethane as an internal standard.
c
Chosen as standard conditions.
a
b
Reaction on a 1.0 mmol scale. Li[Zn(NRR′)TMP2] (3.0 equiv)
Li[Zn(nBu)TMP2] as the base to promote benzyne formation
via the deprotonative β-elimination of phenyl triflate, based on
previous studies of alkylzincate bases.7d,8f We first examined
different forms of N-methylaniline for the nucleophilic addition
step. Encouragingly, the reaction of LiNMePh afforded the
desired product 2a in 71% yield (Table 1, entry 1). Treatment
of Zn(NMePh)2 as the nucleophile failed to give 2a while the
zincate form Li[Zn(NMePh)TMP2] formed 2a in 50% yield
(entries 2 and 3, respectively). With LiNMePh as the
nucleophile, we next tested different bases for the formation
of 2a (entries 4−7). Other zincate bases (entries 4 and 5) were
less effective in this reaction, in comparison to Li[Zn(nBu)-
TMP2] (entry 1). Neutral zinc base Zn(TMP)2 resulted in the
recovery of 1a (entry 6), confirming that a strong zincate base
is required for benzyne formation. On the other hand, LiTMP
as a base led to direct addition to phenyl triflate with N-
triflated aniline observed as a major byproduct and no
formation of 2a (entry 7).10
We first examined the scope of anilines using the
aminoiodination reaction of phenyl triflate 1a (Scheme 2).
The reaction of N-ethylaniline afforded 2b in 58% yield,
comparable to that of N-methylaniline 2a. However, the
reaction of N-isopropylaniline gave 2c in only 27% yield,
suggesting that the increased bulkiness of the isopropyl group
impedes the nucleophilic addition of aniline to benzyne. Next,
a series of N-methylanilines were examined, all of which
delivered desired iodoaniline derivatives successfully (2d−2j),
including those bearing an electron-donating group (2d) or an
electron-withdrawing group (2e), as well as those containing
sensitive functional groups such as nitrile (2f), ester (2g), and
halides (2f−2j). The fact that Li/Zn−halogen exchange was
not observed in these reactions demonstrates the good
functional group compatibility of this transformation. The
reaction of 4-(methylamino)pyridine also afforded the desired
instead of Li[Zn(nBu)TMP2] (1.0 equiv) and LiNRR′ (1.0 equiv).
c
Li[Zn(NiPr2)2TMP] was used instead of Li[Zn(NiPr2)TMP2].
d
Reactions on a 0.2 mmol scale unless noted otherwise. Isolation
yields.
heteroarene-containing product 2k. Even fewer nucleophilic
diarylamines provided the desired products 2l−2n, which
offers an effective approach to rapidly constructing triarylamine
derivatives containing different aryl groups, including the
carbazole moiety. We next looked into the feasibility of using
aliphatic amines as nucleophiles in this cascade aryne
difunctionalization strategy (Scheme 2). However, aliphatic
amines, more nucleophilic than anilines, tend to increase the
level of addition of an undesired nucleophilic to triflate under
standard conditions using Li[Zn(nBu)TMP2]. To address this
challenge, we examined the zincate form of aliphatic amines
Li[Zn(NRR′)TMP2] as the base for aryne formation and as
the nucleophile for the addition step, which was found to be
effective in both roles. With these modified conditions, we
tested various acyclic and cyclic amines in the aminoiodination
reaction of phenyl triflate 1a, which successfully afforded a
diverse range of aniline products (2o−2w). In the reaction of
the sterically hindered diisopropyl amine, the zincate form
Li[Zn(NiPr2)2TMP] was used to suppress the undesired TMP
addition. Note that N,N-diallyl-2-iodoaniline (2r) can be
readily converted to the primary aniline by the removal of the
allyl protecting group. Furthermore, the transformation proved
to be reliable and scalable as seen in the formation of 2j
efficiently on both a 0.2 mmol scale and a 1.0 mmol scale.
A notable attribute of this arene difunctionalization strategy
is to tactically leverage organozinc intermediates and their
versatile coupling reactions for the installation of diverse
functional groups in a modular manner.11 Using the reactions
B
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of phenyl triflate 1a and N-methylaniline, we examined the
capability of arylzinc intermediate I in the subsequent reactions
using different electrophiles (Scheme 3). The introduction of
Scheme 4. 1,2-Amino Difunctionalization of Various Aryl
Triflates
c
Scheme 3. Modular Synthesis of Diverse ortho-
Functionalized Anilines by Versatile Difunctionalization of
a
PhOTf with a Broad Scope of Electrophilic Partners
a
Reaction conditions in the Supporting Information.
diverse heteroatom-containing groups was realized, for
example, by direct halogenation (2a and 3b), cobalt-mediated
carbon−sulfur bond formation (3c),12 and copper-catalyzed
hydroxylation (3d).13 Amination reactions with various
nitrogen electrophiles were also achieved for the installation
of a primary amine (3e),13 N-Boc piperazine (3f),14 and azide
(3g)14 in the presence of a copper catalyst. Furthermore, a
diverse range of carbon−carbon bonds were generated,
including copper-catalyzed alkylation (3h) and allylation
(3i), nickel-catalyzed coupling with aldehyde (3j),15 palla-
dium-catalyzed arylation (3k), and vinylation (3l),16 as well as
copper-catalyzed alkynylation (3m). Considering that neutral
organozinc reagents are most used as nucleophilic partners in
the coupling reactions, the adaptability of zincate intermediate
I in the analogous coupling reactions was noteworthy, in which
only slight or no modifications on reaction conditions were
required.10 The generality of this method demonstrated on a
broad range of carbon, nitrogen, oxygen, sulfur, and halide
electrophiles suggests its great potentials to access diversely
functionalized aminoarenes that are valued widely in organic
synthesis, drug discovery, and functional materials.
a
Significant amount of TMP addition byproduct observed.
Desilylation performed with crude 4 using TFA (excess) at 50 °C.
b
c
All reactions on a 0.2 mmol scale. E+ = I2 (3.5 equiv) or MeOH. See
the details in the Supporting Information. Isolation yields and major
isomer shown. r.s., regioselectivity determined by 1H NMR analysis of
the crude mixture.
yields of 63% and 64%, respectively. The reactions of 2-
methylphenyl triflate 1b delivered desired products 4b and 5b
regioselectively (4.8:1), with N-methylaniline added at the
more accessible 3 position as the major isomer. In the reactions
of 3-methoxyphenyl triflate 1c, only a single isomer was formed
(4c and 5c) yet in lower yields, because of the higher reactivity
of methoxybenzyne that gave rise to the formation of
We next evaluated a three-component difunctionalization
strategy for its scope of aryl triflates, using either I2 or MeOH
as the electrophile in the formation of iodoamination product
4 and hydroamination product 5 (Scheme 4). The reactions of
simple phenyl triflate 1a afforded 2a and 5a in comparable
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competitive TMP addition byproducts. Reactions of 1-
naphthyl triflate 1d also formed desired products 4d and 5d
in a regioselective manner. In comparison to simple aryl
triflates, we tested 2-TMS-aryl triflates 1e−1h, which were
used commonly as aryne precursors. The applicability of
difunctionalization reactions on such 2-TMS-aryl triflates was
nicely demonstrated by successful formations of 4e−4h and
5e−5h. Interestingly, exclusive regioselectivity was observed in
the formation of 4e−4h and 5e−5h, directed by the steric
influence effect of the TMS group rather than by electronic
effects.17 Note that the reaction of 2-TMS-aryl triflate 1g gave
4g/5g in higher yields, in comparison to the poor formation of
4c/5c in the reaction of 3-methoxyphenyl triflate 1c. This
improved efficiency is because the presence of the TMS
substituent impedes the unwanted TMP nucleophilic addition
to its highly reactive aryne intermediate. Thus, in the reactions
of 2-TMS-aryl triflates, TMS can serve as an advantageous,
removable group to direct regioselectivity as demonstrated in
the formation of 4f′, 4g′, and 4h′ by facile desilylation. It can
also potentially be used for subsequent coupling reactions to
introduce other functional groups.
promoted formation of aryne intermediates, in situ nitrogen
nucleophilic addition, and coupling reactions of organozinc
intermediates with a wide variety of electrophilic functional
groups. Such a strategy presents great potentials for developing
extensive difunctionalization reactions of aryl triflates with
other nucleophiles for the synthesis of polysubstituted arenes.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00320.
Experimental procedures, condition optimization data,
compound characterization, and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Qiu Wang − Department of Chemistry, Duke University,
Durham, North Carolina 27708, United States; orcid.org/
0000-0002-6803-9556; Email: qiu.wang@duke.edu
This method is further highlighted in the synthesis of diverse
carbazole-containing skeletons using 2-bromo-N-methylaniline
as both the nucleophilic and electrophilic coupling partner in
the aminoarylation reactions of aryl triflates (Scheme 5).
Author
Seoyoung Cho − Department of Chemistry, Duke University,
Durham, North Carolina 27708, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00320
Scheme 5. One-Step Synthesis of Carbazoles from Various
Aryl Triflates
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge financial support by Duke
University, the National Science Foundation (CHE-
1455220), and the Burroughs Wellcome fellowship (S.C.).
The authors thank Dr. Peter Silinski of the Department of
Chemistry at Duke University for the assistance with high-
resolution mass spectrometry data.
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