A Selective C?H Deprotonation Strategy to Access Functionalized Arynes by Using Hypervalent Iodine

Article abstract of DOI:10.1002/anie.201603222

Described here is an efficient method to access highly functionalized arynes from unsymmetrical aryl(mesityl)iodonium tosylate salts. The iodonium salts are prepared in a single pot from either commercially available aryl iodides or arylboronic acids. The

Full text of DOI:10.1002/anie.201603222

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201603222
German Edition: DOI: 10.1002/ange.201603222
Arynes
À
A Selective C H Deprotonation Strategy to Access Functionalized
Arynes by Using Hypervalent Iodine
Sunil K. Sundalam, Aleksandra Nilova, Thomas L. Seidl, and David R. Stuart*
Abstract: Described here is an efficient method to access
rary methods to access arynes have primarily focused on
highly functionalized arynes from unsymmetrical aryl-
ortho-difunctionalized arenes (Scheme 1b). The pioneering
[3]
(
mesityl)iodonium tosylate salts. The iodonium salts are
work of Kobayashi and co-workers remains the archetypal
approach though modifications have been made to both the
prepared in a single pot from either commercially available
aryl iodides or arylboronic acids. The aryne intermediates are
[4]
[5]
triflate leaving group and the silyl activating group
(Scheme 1b). Collectively, these methods provide a mild
approach to benzyne. However, access to elaborate and
highly functionalized arynes remains a limitation of contem-
porary methodology because of the length of the synthesis (3–
generated
by
ortho-CÀH
deprotonation
of
aryl-
(
mesityl)iodonium salt with a commercially available amide
base and trapped in a cycloaddition reaction with furan in
moderate to good yields. Coupling partners for the aryne
intermediates beyond furan are also described, including
benzyl azide and alicyclic amine nucleophiles. The regio-
and chemoselectivity of this reaction is discussed and evidence
for the spectator aryl ligand of the iodonium salt as a critical
control element in selectivity is presented.
[6]
5 steps) needed to install the requisite ortho-situated groups.
Conversely, the seminal discovery and ensuing mechanis-
tic investigation of aryne reactivity was found to occur by
ortho-CÀH deprotonation of an aryl halide at low temper-
[7]
ature (À338C) followed by halide elimination. Despite the
inherent efficiency of this strategy over contemporary meth-
ods, application to highly functionalized substrates has also
been limited in practice because of challenges in both
regioselective deprotonation at CÀH bonds and chemoselec-
A
rynes are a unique class of reactive intermediate in organic
synthesis. Their high reactivity enables rapid elaboration of
aryl moieties through the formation of multiple carbon–
carbon or carbon–heteroatom bonds and therefore provides
tive elimination of a single leaving group when multiple
[
1]
[8]
access to diverse product structures (Scheme 1a). Conse-
quently, arynes have been used strategically in the early stages
of synthetic sequences toward natural products. Contempo-
potential groups are present. A recent example of this
strategy at ambient temperature further exemplifies the
challenge of substrates having multiple leaving groups
[
2]
wherein polysubstitution and competing S Ar reactivity
N
[
9]
were observed.
Herein, we describe the discovery and development of an
approach that offers recourse to difunctionalized aryne
precursors and provides high and predictable selectivity in
the formation of aryne intermediates by CÀH deprotonation.
In this work, unsymmetrical aryl(mesityl)iodonium salts
engage an amide base at mild temperature and the transient
aryne intermediate is trapped in cycloaddition and nucleo-
philic addition reactions (Scheme 2a). The hypervalent
iodine moiety serves as an element of regiocontrol over
CÀH deprotonation and as a broadly chemoselective leaving
group in this process. Unsymmetrical iodonium salts are novel
relative to contemporary aryne precursors because of their
[10]
facile one-pot syntheses from either aryl iodide or arylbor-
[11]
onic acid
building blocks (Scheme 2b). Ultimately they
provide access to elaborate arynes in an efficient manner.
Scheme 1. Representative benzyne reactivity and contemporary ben-
zyne precursors. Tf=trifluoromethynesulfonyl, TMS=trimethylsilyl.
[
*] S. K. Sundalam, A. Nilova, T. L. Seidl, Prof. Dr. D. R. Stuart
Department of Chemistry, Portland State University
Portland, OR 97201 (USA)
E-mail: dstuart@pdx.edu
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201603222.
Scheme 2. CÀH deprotonation strategy to access arynes. Mes=mesi-
tyl.
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[
15]
On the basis of our recent success in the arylation
of alkoxide nucleophiles with unsymmetrical aryl-
1408C) and in low yield (ca. 10%). Therefore, given the
[
10,11]
facile synthesis of elaborate aryl(mesityl)iodonium salts
and the promising reactivity observed here, we viewed this
development as an opportunity to address the limitations of
[
12]
(
mesityl)iodonium salt electrophiles we turned our atten-
tion to N nucleophiles. Morpholine is a privileged motif in
biologically active compounds and was selected as a repre-
sentative alicyclic amine nucleophile. The compound 1,
bearing an electron-deficient aryl ring, was used as the
iodonium electrophile to survey reaction conditions. We
found that the combination of morpholine and sodium tert-
butoxide produced the desired and expected ipso-substitution
product 3 along with a second and unexpected product 5 in
equimolar quantity (Table 1, entry 1). Moreover, the com-
bined yield of ipso- and cine-substitution products was
[
3–5]
accessibility of difunctionalized aryne precursors.
The electron-rich substrate 2 was selected to further study
the influence of reaction conditions on this transformation
and the putative aryne was trapped with furan as further
evidence of this intermediate. The identity of the base was
first explored at 258C and NaHMDS provided the highest
yield of 7 (Table 1, entry 4–6). Moreover, we found that the
identity of the counter ion of 2 or the base had little influence
[10c]
on the yield (entry 6–8). The accessibility
of the tosylate
derivative and the yield of 7 obtained with LiHMDS
as base prompted us to continue the study with this
combination. A solvent screen revealed that the use
of toluene improved the yield of 7 from 39 to 48%
[
a]
Table 1: Reaction discovery and optimization.
(entries 8 and 9) and an additional small increase in
yield was observed when the reaction was conducted
at 138C (entry 10). The reaction stoichiometry of
furan and LiHMDS had a significant influence on the
yield of 7 (entries 10–13). Specifically, excess furan
+
Entry Ar2I
Arynophile
equiv)
Base
(equiv)
Solvent
T
Yield [%]
[
b]
(
[8C] (ratio)
(4 equiv) and stoichiometric LiHMDS provided 7 in
[
[
[
c]
c]
c]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1-OTf morpholine (2) NaOtBu (1.1) TBME
1-OTf morpholine (2) NaOtBu (1.1) TBME
2-OTf morpholine (2) NaOtBu (1.1) TBME
50
25
50
25
25
25
25
25
3+5: 89 (1:1)
3+5: 82 (1:1)
4+6: 24 (1:1)
7: 22
7: 20
7: 39
7: 36
7: 39
7: 48
7: 52
6
7
2% yield (entry 13). The yield of 7 was increased to
8% (70% upon isolation) when the stoichiometry
of furan was increased to 5.5 equivalents and the
reaction was carried out for 3 hours (entry 14).
The scope with respect to the aryl-
(mesityl)iodonium tosylate substrates which are
compatible in this CÀH deprotonative aryne-forming
2-OTf furan (4)
2-OTf furan (4)
2-OTf furan (4)
2-OTs furan (4)
2-OTs furan (4)
2-OTs furan (4)
2-OTs furan (4)
2-OTs furan (4)
2-OTs furan (1)
2-OTs furan (4)
2-OTs furan (5.5)
NaOtBu (2)
NaNH2
NaHMDS (2) TBME
NaHMDS (2) TBME
LiHMDS (2)
LiHMDS (2)
LiHMDS (2)
LiHMDS (3)
LiHMDS (3)
LiHMDS (1)
LiHMDS (1)
TBME
TBME
TBME
toluene 25
toluene 13
toluene 13
toluene 13
toluene 13
toluene 13
reaction are presented in Table 2. The oxabicyclic
products are obtained in moderate to excellent yield
0
1
2
3
4
7: 47
7: 14
(69% average) and illustrate several important
aspects of the preparation of aryne precursors and
selectivity of the formation of arynes. First, each
substrate presented in Table 2 was prepared in a one-
pot reaction from commercially available aryl iodide
7: 62
7: 78, 70
[
d]
[e]
[
a] Reaction conditions: 1 or 2 (0.2 mmol, 1 equiv), morpholine or furan (see table),
base (see table), solvent (3 ml total), temperature (see table), 90 minutes. [b] Yield
1
and ratio determined from H NMR spectrum of the crude reaction mixture versus (entries 1–3 and 7–14) or arylboronic acid (entries 4–
,3,5-trimethoxybenzene as an internal standard. [c] Solvent volume 0.66 mL total. 6 and 15–22). The synthesis of these aryne precursors
1
[
d] Reaction time of 3 hours. [e] Yield of isolated product is based on 0.5 mmol scale
of 2. HMDS=hexamethyldisilazide, TBME=tert-butyl methyl ether.
is practical as they are prepared in good yield (71%
average yield), on synthetically useful scale (> 1 g),
and are isolated by filtration after trituration with
ether. Second, the hypervalent iodine moiety imparts
high selectivity for the formation of the aryne intermediate. In
all cases, the CÀH deprotonation event is regioselective for
excellent (89%). The yield of 3 and 5 was only slightly
reduced at 258C (entry 2). However, when the iodonium salt
contained an electron-rich aryl group (2) the combined yield
of 4 and 6 was significantly lower (entry 3). The product
distribution observed for the reaction of morpholine with
either 1 or 2 is in stark contrast to our previous alkoxide
the ortho-position to the iodonium (2- or 6-position; Table 2).
Moreover, in the presence of halide and pseudohalide leaving
groups, the reaction is highly chemoselective for departure of
the iodonium leaving group (entries 1–6 and 12, 13, 21, and
22). Substituents at the ortho-, meta-, and para-positions on
the aryl moiety which becomes the aryne are tolerated.
[
12]
[16]
arylation chemistry, and to the best of our knowledge other
[
13]
recent O-arylation methods. The approximate 1:1 ratio of
ipso- and cine-substitution isomers formed in this reaction is,
however, consistent with classic reactivity of a 4-substituted
Importantly, when meta-substitution is present CÀH depro-
tonation is selective for the 2-position (entries 4–6, 9, 11–13,
18–21). As a limitation of the method we have noted that
several substrates resulted in low yield (ca. 30%). Specifically,
these substrates were one with an ester in the para-position
and a substrate with multiple electron-withdrawing groups.
We are continuing to investigate the source of poor reactivity
with these aryne precursors.
[
7]
aryne intermediate.
While the hypernucleofugality of
[
14]
iodine(III)
has been exploited to access high-energy
[4]
arynes (Scheme 1), there are virtually no reports of high-
yielding formation of arynes from diaryliodonium salts which
are initiated by ortho-CÀH deprotonation. Specifically, such
reactivity has only been observed at high temperature (80–
2
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[
a]
Table 2: Scope of substrates compatible in the formation of arynes.
Table 3: Auxiliary and temperature controlled selectivity of CÀH depro-
tonation.
[
b]
Entry
Aux
T [8C]
13/7
1
2
3
2’,4’,6’-trimethylphenyl (Mes)
2’,4’,6’-triisopropylphenyl
2’,4’,6’-triisopropylphenyl
13
13
À10
4.2:1
5.3:1
6.7:1
[a] Reaction conditions: 12 (0.2 mmol, 1 equiv), furan (80 mL, 1.1 mmol,
5
.5 equiv), LiHMDS (1m in toluene; 0.2 mL, 0.2 mmol, 1 equiv), toluene
1
(2.8 mL), temperature (see table), 3 h. [b] Ratio determined by H NMR
analysis of the crude reaction mixture.
the proton at the 2-position relative to that at the 6-
[
17]
position.
We were therefore surprised to find that an
electron-donating and sterically bulky methyl substituent in
the 3-position still led to a preference, albeit lower, for
deprotonation at the 2-position, thus producing 13 and 7 in
a 4.2:1 ratio (Table 3, entry 1). A survey of other auxiliaries
revealed that increasing the steric effect of the auxiliary from
2’,6’-dimethyl substitution to 2’,6’-di-isopropyl substitution
increased the selectivity for deprotonation at the less steri-
cally accessible 2-position (entry 2). When the reaction was
conducted at À108C the selectivity for 13 further improved to
6
.7:1 (entry 3). Taken together, these results are consistent
with the auxiliary steric effect and the temperature exerting
a modest influence on the population of reactive conformers
which lead to arynes. We are further exploring the identity of
the conformers and the nature of the selectivity determining
step in this process.
The oxabicyclic products from the reaction of arynes with
furan are useful synthetic intermediates toward natural
[
18]
[19]
products
and active pharmaceutical ingredients.
How-
ever, given that arynes participate in diverse reaction classes,
preliminary examples of reactions which incorporate nitrogen
coupling partners under slightly modified reaction conditions
are presented in Table 4. Specifically, cycloaddition of 8 with
Table 4: Representative examples of cycloaddition and nucleophilic
[
a]
addition reactions.
[a] Reaction conditions: aryl(mesityl)iodonium tosylate (0.5 mmol,
1
0
equiv), furan (200 mL, 2.75 mmol, 5.5 equiv), LiHMDS (1m in toluene;
.5 mL, 0.5 mmol, 1 equiv), toluene (7.0 mL), 138C, 3 hours. [b] Yield
1
determined by H NMR analysis of 0.2 mmol of the iodonium salt with
1
,3,5-trimethoxybenzene as an internal standard; average of 2 runs.
[
1
a] Reaction conditions: aryl(mesityl)iodonium tosylate (0.5 mmol,
equiv), benzyl azide, morpholine, piperidine (1 mmol, 2 equiv),
NaOtBu (0.55 mmol, 1.1 equiv), TBME (1.65 mL), 508C, 1.5 hours.
b] Combined yield of regioisomers. [c] Ratio of regioisomers; major
regioisomer shown.
The CÀH deprotonation selectivity we observed (> 20:1)
when an inductively electron-withdrawing group is present in
the 3-position is consistent with proximity-induced acidity of
[
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benzyl azide produced a mixture (3.8:1) of benzotriazole
products in 63% combined yield. Trapping of the electro-
philic aryne intermediate with morpholine or piperidine as
nucleophilic amines was also demonstrated. The aryl amines
Keywords: arynes · cycloaddition · hypervalent compounds ·
regioselectivity · synthetic methods
1
0 and 11 are the major regioisomeric products of this
reaction and were isolated in 58 and 62% yield, respectively.
The formation of regioisomers is consistent with an aryne
intermediate and the regioselectivity observed for the cyclo-
addition and nucleophilic addition in these cases is consistent
with previous experimental and theoretical analysis of
reactions of 3-substituted aryne intermediates bearing an
inductively electron-withdrawing group. We are continuing
to explore the compatibility of generating aryne intermedi-
ates in this way with other reaction classes.
[
1] For recent reviews, see: a) H. H. Wenk, M. Winkler, W. Sander,
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In conclusion, we have described a novel and efficient
method to access aryne intermediates and it avoids the need
for difunctionalized aryne precursors. The hypervalent iodine
moiety serves as a general and chemoselective leaving group
in the presence of other potential leaving groups such as
fluoride, chloride, bromide, iodide, and triflate and the aryne
intermediates are trapped with furan, benzyl azide, or
alicyclic amines. Insight into the CÀH deprotonation event
1
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2
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1
deprotonation strategy toward arynes from aryl-
[
(
mesityl)iodonium salts expands the breadth of reaction
1
manifolds accessible with this emergent class of transition-
metal-free arylation reagent. Mechanistic studies and
expanded scope of this reaction are underway in our
laboratories.
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Experimental Section
The iodonium salt (0.5 mmol, 1 equiv) is weighed out in air and placed
in an oven-dried vial containing a magnetic stir bar and is sealed with
a Teflon-lined septum cap. The vial is purged with nitrogen gas for
approximately 10 minutes. Toluene (7 mL) and furan (200 mL,
[
14] T. Okuyama, T. Takino, T. Sueda, M. Ochiai, J. Am. Chem. Soc.
1
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30; b) J. I. G. Cadogan, A. G. Rowley, J. T. Sharp, B. Sledzinski,
2
.75 mmol, 5.5 equiv) are added sequentially by syringe through the
septum. The vial is placed in an ice-cooled water bath maintained at
38C. LiHMDS (0.5 mL (1m in toluene), 0.5 mmol, 1 equiv) is added
[
2
1
N. H. Wilson, J. Chem. Soc. Perkin Trans. 1 1975, 1072 – 1074;
c) J. W. Graskemper, B. Wang, L. Qin, K. D. Neumann, S. G.
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by syringe through the septum and the reaction is stirred for 3 hours.
The vial is removed from the ice-bath and the reaction is quenched
with an aqueous solution of ammonium chloride (5 mL). The biphasic
mixture is placed in a separatory funnel and washed with DCM (3 ꢀ
[
[
16] See the Supporting Information for a representative example.
17] K. Shen, Y. Fu, J.-N. Li, L. Liu, Q.-X. Guo, Tetrahedron 2007, 63,
1568 – 1576.
5
mL). The combined organic phases are dried with MgSO , the
4
drying agent removed by suction filtration, and the solvent removed
on the rotary evaporator. The crude residue is purified by flash
column chromatography on silica gel with an ether/hexane mixture as
the eluent.
[
[
18] M. Lautens, T. A. Stammers, Synthesis 2002, 1993 – 2012.
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Acknowledgements
We acknowledge Portland State University and the donors of
the American Chemical Society Petroleum Research Fund
3511 – 3514, and references therein.
(
PRF DNI1 #54405) for support of this research.
Received: April 5, 2016
Published online: && &&, &&&&
4
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Communications
Arynes
S. K. Sundalam, A. Nilova, T. L. Seidl,
D. R. Stuart*
&&&& — &&&&
A Selective CÀH Deprotonation Strategy
to Access Functionalized Arynes by Using
Hypervalent Iodine
Strategy planning: Unsymmetrical aryl-
with high regio- and chemoselectivity. The
(
mesityl)iodonium salts as novel aryne
transient arynes react in cycloaddition
reactions with furan and azide and in
nucleophilic addition reactions with ali-
cyclic amines.
precursors are efficiently prepared in one-
pot reactions from aryl iodides and
arylboronic acids and facilitate the gen-
eration of elaborate aryne intermediates
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