Expanding the Strained Alkyne Toolbox: Generation and Utility of Oxygen-Containing Strained Alkynes

Article abstract of DOI:10.1021/jacs.6b01986

We report synthetic methodology that permits access to two oxacyclic strained intermediates, the 4,5-benzofuranyne and the 3,4-oxacyclohexyne. In situ trapping of these intermediates affords an array of heterocyclic scaffolds by the formation of one or more new C-C or C-heteroatom bonds. Experimentally determined regioselectivities were consistent with predictions made using the distortion/interaction model and were also found to be greater compared to selectivities seen in the case of trapping experiments of the corresponding N-containing intermediates. These studies demonstrate the synthetic versatility of oxacyclic arynes and alkynes for the synthesis of functionalized heterocycles, while further expanding the scope of the distortion/interaction model. Moreover, these efforts underscore the value of harnessing strained heterocyclic intermediates as a unique approach to building polycyclic heteroatom-containing frameworks.

Full text of DOI:10.1021/jacs.6b01986

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Article
Expanding the Strained Alkyne Toolbox: Generation
and Utility of Oxygen-Containing Strained Alkynes
Tejas K Shah, Jose M Medina, and Neil K. Garg
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b01986 • Publication Date (Web): 17 Mar 2016
Downloaded from http://pubs.acs.org on March 18, 2016
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Journal of the American Chemical Society
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Expanding the Strained Alkyne Toolbox: Generation
and Utility of Oxygen-Containing Strained Alkynes
Tejas K. Shah,† Jose M. Medina,† and Neil K. Garg*
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Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095
* neilgarg@chem.ucla.edu
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
TITLE RUNNING HEAD. Oxygen-Containing Strained Alkynes
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ABSTRACT. We report synthetic methodology that permits access to two oxacyclic strained
intermediates, the 4,5-benzofuranyne and the 3,4-oxacyclohexyne. In situ trapping of these
intermediates affords an array of heterocyclic scaffolds by the formation of one or more new C–C or C–
heteroatom bonds. Experimentally determined regioselectivities were consistent with predictions made
using the distortion / interaction model and were also found to be greater compared to selectivities seen
in the case of trapping experiments of the corresponding N-containing intermediates. These studies
demonstrate the synthetic versatility of oxacyclic arynes and alkynes for the synthesis of functionalized
heterocycles, while further expanding the scope of the distortion / interaction model. Moreover, these
efforts underscore the value of harnessing strained heterocyclic intermediates as a unique approach to
building polycyclic heteroatom-containing frameworks.
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Introduction
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New approaches for the synthesis of decorated heterocycles remain highly sought after because
of the prevalence of heterocycles in drugs, agrochemicals, materials, and natural products.1 One unique
strategy for heterocycle construction involves the trapping of transient heterocyclic arynes or alkynes.2
For example, pyridynes,2m,3 indolynes,4,5,6 and piperidynes7 (e.g., 1–3, Figure 1) can now be used as
building blocks for the synthesis of functionalized heterocycles in a predictable manner using the
distortion / interaction model.8
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Whereas advances in heterocyclic aryne and alkyne chemistry have focused on nitrogen-
containing reactive intermediates, the corresponding chemistry of oxacycles has remained
underdeveloped. The first aryne ever proposed was the 2,3-benzofuranyne;9 however, this structural
assignment was later called into question.2b Subsequent contributions in the area of oxacyclic arynes are
limited to scattered examples involving dehydrohalogenation of benzofuran derivatives10 and access to
the 6,7-benzofuranyne using butyllithium reagents.11 With regard to oxacyclohexynes, even less is
known, with only two studies involving metalated oxacyclohexynes in the literature.12 Silyl triflate
precursors to oxacyclic arynes or alkynes have not been synthesized previously; likewise, no general
methodologies for oxacyclic aryne or alkyne trapping have been reported to date.
We reasoned that mild methodologies involving the trapping of oxacyclic arynes and alkynes
through a multitude of cycloadditions would provide a new avenue for building O-containing
compounds. Oxygenated heterocycles, such as benzofuran and pyran derivatives, are often seen in
natural products and drugs.13 Notable examples include Saprisartan (treatment of hypertension),14
hopeafuran (antimicrobial agent),15 artemisinin (antimalarial drug),16 rhoeadine (sedative &
antitussive),17 and frenolicin B (kinase inhibitor).18 Moreover, some oxygen-containing heterocycles are
known bioisosteres for their nitrogen and sulfur-containting counterparts in medicinal chemistry.19
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In the present study, we describe synthetic methodology to access two oxacyclic strained
intermediates: the 4,5-benzofuranyne (4) and the 3,4-oxacyclohexyne (5) (Figure 1). In addition to
establishing synthetic routes to silyl triflate precursors to 4 and 5 and using these species to build an
assortment of functionalized heterocycles, we show that reliable regioselectivity predictions can be
made prior to experiment using the distortion / interaction model. Selectivities are compared to those
seen in the case of trapping experiments of the corresponding N-containing intermediates. Overall, our
studies demonstrate that oxacyclic arynes and alkynes can be harnessed to efficiently construct
decorated oxygen-containing heterocycles. The methodology is expected to prove useful in the synthesis
of new pharmaceuticals and natural products.
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N-Containing Strained Alkynes (Previous Studies)
4
4
4
3
5
3
N
R
N
R
N
3,4-pyridyne
(1)
4,5-indolyne
(2)
3,4-piperidyne
(3)
O-Containing Strained Alkynes (Present Study)
4
4
5
3
Building blocks for
heterocycle synthesis
O
O
Probes for
regioselectivity
4,5-benzofuranyne
(4)
3,4-oxacyclohexyne
(5)
Benzofuran- and Pyran-Containing Natural Products and Pharmaceuticals
HO
O
H2N
Br
OH
N
OH
N
O
O
Et
TfNH
Saprisartan
OH
treatment for hypertension
& heart failure
O
HO
Hopeafuran/Shoreaphenol
antimicrobial
O
Me
H
N
Me
H
O
O
H
HO
Me
H
MeO
O
O
O
H
O
O
n-Pr
O
O
O
O
H
O
O
Me
O
H
Artemisinin
antimalarial
Rhoeadine
sedative &
antitussive
Frenolicin B
AKT1 kinase
inhibitor
Figure 1. Well studied N-containing cyclic alkynes 1–3, O–containing strained alkynes 4 and 5 (present
study), and representative drugs and natural products.
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Results and Discussion
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Prediction of Regioselectivities Based on the Distortion / Interaction Model
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8
An attractive aspect of using strained alkynes as synthetic building blocks is the ability to make
reliable regioselectivity predictions prior to experiments using the distortion / interaction model.8 Briefly
stated, substituted arynes or cyclic alkynes are unsymmetrically distorted in their ground state.
Nucleophilic addition occurs at the terminus of the aryne (or alkyne) that is more distorted toward
linearity (i.e., the site that possesses a larger internal angle). The geometry of the unsymmetrical aryne
or alkyne can readily be determined by performing simple geometry optimization calculations using
DFT methods. In addition to revealing the preferred site of attack by nucleophiles, these calculations
can also be used to roughly assess the degree of regioselectivities. The greater the difference in internal
angles between the two aryne (or alkyne) termini (Δθ), the more pronounced regioselectivities are
expected.
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With the aim of predicting the site of nucleophilic attack on 4,5-benzofuranyne (4) and 3,4-
oxacyclohexyne (5), while drawing comparisons to the corresponding N-containing heterocyclic alkynes
6 and 7, we performed geometry optimizations using DFT calculations (B3LYP/6-31G(d)) (Figure 2).20
First, we compared the calculated structures of 4,5-benzofuranyne (4) and 4,5-indolyne (6); each is
distorted such that nucleophilic addition is expected to occur at C5, which is the more linear terminus.
4,5-Benzofuranyne (4) was found to be unsymmetrically distorted with the C5–C4 Δθ being 7°. In
comparsion, 4,5-indolyne (6) is less distorted, with the C5–C4 Δθ being 4°.5e,5f As the Δθ is greater in
the case of 4,5-benzofuranyne (4), we predicted this species will react with greater regioselectivity
compared to 4,5-indolyne (6). To see if this trend extended to non-aromatic strained alkynes, we
compared 3,4-oxacyclohexyne (5) and 3,4-piperidyne 7. For both cyclic alkynes, nucleophilic attack is
preferred to occur at C4, the site further distorted toward linearity. C4–C3 Δθ is 15° in the case of 3,4-
oxacyclohexyne (5), but slightly less (i.e., 12°) for 3,4-piperidyne 7.7c As such, we surmised that 3,4-
oxacyclohexyne (5) would react with greater regioselectivities compared to 3,4-piperidyne 7.
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Δθ = 7°
Δθ = 15°
1
2
4
123°
130°
5
136°
121°
3
4
O
O
4,5-benzofuranyne
(4)
3,4-oxacyclohexyne
(5)
5
6
7
8
9
Δθ = 12°
Δθ = 4°
4
136°
124°
5
125°
129°
N
H
N
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Cbz
4,5-indolyne
(6)
3,4-piperidyne
(7)
preferred site of attack by nucleophiles
Figure 2. Geometry optimized structures of 4–7 obtained at the B3LYP/6-31G(d) level and predicted
site of nucleophilic attack. Δθ represents the net distortion of the alkyne.
Synthesis of Silyl Triflate Precursors
Our study relied on developing efficient syntheses of suitable precursors to 4,5-benzofuranyne
(4) and 3,4-oxacyclohexyne (5). Given the well-known versatility of silyl triflate precursors to arynes,21
we targeted silyl triflates 10 and 14 (Scheme 1). The benzofuranyne precursor was derived from 5-
hydroxybenzofuran (8), which is commercially available or readily accessible from hydroquinone.22
Bromination of 8 proceeded smoothly to deliver the known bromoalcohol 9.23 Subsequent O-silylation,
followed by retro-Brook rearrangement and triflation, furnished silyl triflate 10 in 81% yield. 3,4-
Oxacyclohexyne precursor 14 could be synthesized in four steps beginning from commercially available
4-oxotetrahydropyran 11. α-Bromination of 11 was performed using a known two-step sequence to
provide bromoketone 12.24 Treatment of 12 with DABCO and TESCl afforded silyl enol ether 13 in
91% yield. Finally, lithiation, retro-Brook rearrangement, and triflation delivered silyl triflate 14.
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Journal of the American Chemical Society
Br
SiMe3
1. HMDS, THF, Δ
2. n-BuLi, –78 °C
HO
HO
TfO
Br2
1
2
3
4
5
6
O
O
then, Tf2O
–78 → 23 °C
MeOH
–78 °C
O
O
8
9
10
(81% yield)
O
(77% yield)
1. LDA, THF, –78 °C;
then, TMSCl
Br
DABCO, TESCl
DMF, 23 °C
2. NBS, THF, 0 °C
(84% yield)
7
8
O
O
(91% yield)
11
12
9
OSiEt3
OTf
10
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Br
Et3Si
n-BuLi, THF, –78 °C
then, Tf2O
O
O
13
14
(35–45% yield)
Scheme 1. Syntheses of Silyl Triflates 10 and 14.
Generation & Trapping of 4,5-Benzofuranyne
With the silyl triflate precursors in hand, we first investigated the generation and trapping of the 4,5-
benzofuranyne (4) with symmetrical cycloaddition partners (Table 1). Thus, silyl triflate 10 was
exposed to 2-pyrone and CsF in CH3CN at 50 °C; to our delight the desired benzannulated product was
obtained via a Diels–Alder / retro-Diels–Alder sequence (entry 1). We also performed trapping
experiments with furan and N-Boc pyrrole (entries 2 and 3). In each case, the corresponding [2.2.1]-
bridged bicyclic adduct was formed in synthetically useful yields. These results not only validated that
the 4,5-benzofuranyne (4) can be generated, but also demonstrated how this intermediate can be used to
build two new C–C bonds on the benzofuran motif in an efficient manner. In the latter case, the two
linkages formed are sp2–sp3 C–C bonds, which would be difficult to introduce by known means.
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Table 1. Diels–Alder Cycloadditions of 4,5-Benzofuranyne (4)
1
2
3
4
5
A
SiMe3
CsF
Trapping agent
(3 equiv)
4
A
TfO
5
O
MeCN, 23 °C
O
O
10
4
15
6
7
Entry
Trapping agent
Product
Yield a
8
9
O
O
1
68%b
96%
10
11
12
13
14
15
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20
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O
O
N
2
3
O
O
O
Boc
75%
N
Boc
a
Reported yields are the average of two experiments and are based on the amount of isolated
products. b Reaction performed at 50 °C.
With the aim of probing regioselectivity trends and accessing functionalized benzofurans, we
shifted our attention to trapping benzofuranyne 4 with nucleophiles and unsymmetrical cycloaddition
partners (Table 2). We found that p-cresol, morpholine, and N-Me-aniline could be employed as
trapping agents,25 to furnish benzofuranyne adducts in good yields (entries 1–3). In all cases, the major
product was indicative of nucleophilic attack occurring at C5, consistent with the prediction made by the
distortion / interaction model. To access more unique scaffolds and further examine regioselectivities,
we surveyed trapping agents that would allow for the appendage of seven-, six-, or five-membered
heterocycles on the benzofuran motif. In situ trapping of 4 with 1,3-dimethyl-2-imidazolidinone26
furnished the corresponding product of formal C–N bond insertion in 90% yield (entry 4). Only one
constitutional isomer was observed in this case, although the subsequent trappings led to mixtures with a
preference for initial bond formation also occurring at C5. The use of an amido acrylate trapping agent27
allowed for the appendage of substituted pyridine rings to the benzofuran unit (entry 5). With regard to
the formation of 5-membered rings, several trapping agents were deemed successful and could be used
to forge C–C, C–O, and C–N bonds (entries 6–11).28,29,30,31,32,33 In all cases, synthetically useful yields of
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substituted heterocycles were prepared with the expected regioselectivities. Thus, with access to a single
1
2
3
new aryne precursor (i.e., 10), one can build arrays of decorated benzofurans using this methodology.
4
5
6
7
8
Table 2. Reactions of Silyl Triflate 10 with Nucleophiles and Cycloaddition Partners
9
SiMe3
4
B
10
11
12
13
14
15
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20
21
22
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32
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60
Trapping agent
(3 equiv)
Nuc
CsF (3 equiv)
MeCN, 23 °C
TfO
5
A
or
O
O
O
O
10
4
16
17
Product(s)
Trapping
agent
Yield a
(ratio)
Trapping
agent
Yield a
(ratio)
Entry
Product(s)
Entry
O
Me
O
Me
Me
O
O
Me
OMe
O
O
66%
(12:1)
Me
+
6
Me
OMe
O
73%
(8.5:1)
+
1
O
MeO
IPh
OH
O
O
O
O
t-Bu
t-Bu
Ph
t-Bu
N
N
O
O
N
N
82%
(5.4:1)
O
+
7
8
Ph
Ph
O
O
O
78%
(4.2:1)
N
+
2
3
O
O
NH
O
O
Ph
O
N
N
N
N
64%
(4.5:1)
N
+
Ph
O
N
Ph
O
Me
N
83%
(10:1)
O
+
O
NH
Me
N
Me
Bn
N
N
N
N
O
N
O
N
N
71%
(6.2:1)
Bn
N
+
9
N
Me
Bn
Ph
N
O
N
O
Me
O
N
90%b
4
5
N
Ph
Ph
Me
O
Me
Me
N
N
N
N
N
85%
(1.3:1)
O
N
+
10
O
O
CO2Me
O
O
MeO2C
N
H
N
N
MeO2C
Me
51%
(2.9:1)
CO2Et
N
NH
+
N
N
Me
O
65%
(2.5:1)
EtO2C
HN
N
+
11
O
O
EtO2C
O
O
a
Reported yields are the average of two experiments and are based on the amount of isolated
products. b Reaction performed neat with 1,3-dimethyl-2-imidazolidinone (10 equiv) at 50 °C with yield
determined by 1H NMR analysis using 1,3,5-trimethoxybenzene as an external standard.
Generation & Trapping of 3,4-Oxacyclohexyne
Efforts were also put forth to generate and trap 3,4-oxacyclohexyne (5). To confirm the in situ
formation of the strained alkyne, we first examined trappings with dienes to give Diels–Alder adducts
(Table 3). Thus, silyl triflate 14 was treated with CsF in the presence of 3 equivalents of tetracyclone in
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THF at 60 °C. This furnished the desired benzannulated product in quantitative yield (entry 1). Trapping
with 2-pyrone, delivered the expected benzannulated product (entry 2). To arrive at more complex,
heterocyclic adducts, Diels–Alder trappings were performed with 2,5-dimethylfuran and N-Boc-pyrrole.
In each case, the desired [2.2.1]-bicycles, which would arguably be difficult to make by other means,
were formed (entries 3 and 4).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
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38
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Table 3. Diels–Alder Cycloadditions of 3,4-Oxacyclohexyne (5)
CsF
Trapping agent
(3 equiv)
OTf
A
4
Et3Si
3
A
THF, 60 °C
O
O
O
14
5
18
Entry
Trapping agent
Product
Yield a
Ph
Ph
Ph
Ph
Ph
Ph
1
100%
Ph
O
Ph
O
O
2
3
49%
50%
O
O
Me
Me
O
Me
O
Me
O
Boc
N
4
48%
N
Boc
O
a
Reported yields are the average of two experiments and are based on the amount of isolated
products.
Analogous to our studies involving the 4,5-benzofuranyne (4), we tested the generation and
trapping of 3,4-oxacyclohexyne (5) with nucleophiles and unsymmetrical cycloaddition partners (Table
4). Trapping with imidazole was examined primarily as a means to probe regioselectivity (entry 1). In
this case, the 4-substituted adduct was obtained in >20:1 regiochemical preference. Addition at C4 was
also seen in a variety of other trapping experiments, consistent with the predictions made by the
distortion / interaction model. For example, interception of 4 with methyl salicylate34 gave two products,
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both indicative of the same regioselectivity trend (entry 2). We also performed the trapping with an
amido acrylate species,27 which led to the appendage of pyridine motifs, albeit with modest selectivity
(entry 3). Several efforts to annulate the oxacyclohexyne with 5-membered heterocycles were also put
forth. Trapping with an iodoniun ylide28 led to the introduction of a furan (entry 4), whereas nitrone
trapping29 gave the expected isoxazoline product (entry 5). Similarly, an azide cycloaddition31 proceeded
smoothly to give triazole-containing products (entry 6). In two additional examples, pyrazole derivatives
could be obtained by trapping the oxacyclohexyne intermediate with either a sydnone32 or diazoester33
(entries 7 and 8). With this methodology, a variety of annulated oxacycles can be readily accessed from
silyl triflate 14, with good to excellent control of regioselectivity. It should be noted that the products
obtained from these trapping studies possess significant sp3 character. The generation of such sp3-rich
heterocyclic frameworks is an important direction in modern drug discovery.35
1
2
3
4
5
6
7
8
9
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12
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14
15
16
17
18
19
20
21
22
23
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27
28
29
30
31
32
33
34
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Table 4. Reactions of Silyl Triflate 14 with Nucleophiles and Cycloaddition Partners
1
2
3
4
5
OTf
CsF
Trapping agent
(3 equiv)
B
Nuc
4
Et3Si
A
3
or
THF, 60 °C
O
O
O
O
6
14
5
19
20
7
8
9
Trapping
agent
Yield a
(ratio)
Entry
Product(s)
N
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NH
N
59%
(>20:1)
1
O
O
O
O
O
79%
(>20:1)
2
and
OH
OMe
MeO2C
O
O
CO2Me
MeO2C
N
Me
O
H
N
71%
(2.6:1)
Me
N
+
3
OMe
Me
O
O
O
Me
O
O
O
70%b
4
5
MeO2C
Me
MeO
(>20:1)
IPh
O
t-Bu
t-Bu
N
O
N
73%
(>20:1)
O
Ph
Ph
O
Bn
N
N
Bn
N
N
N
N
Bn
69%
(7.2:1)
N
+
6
N
N
N
O
O
Ph
Ph
N
N
N
Ph
N
88%
(1.5:1)
+
+
7
8
N
O
O
O
O
CO2Et
N
NH
O
CO2Et
N
EtO2C
64%
(6.1:1)
HN
N
N
O
a Reported yields are average of two experiments and are based on the amount of isolated products. b
Reaction performed with MeCN as the solvent.
Comparison of Regioselectivities for N- and O-Containing Strained Alkynes
As noted earlier, we predicted that the 4,5-benzofuranyne (4) and the 3,4-oxacyclohexyne (5)
would react with significant regioselectivities to give nucleophilic addition preferentially at C5 and C4,
respectively. These predictions were verified, as described above. Additionally, we predicted that 4 and
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5 would undergo trapping with more significant regioselectivities in comparison to their N-containing
analogs, 23 and 7.
1
2
3
4
5
6
7
8
Table 5 shows a comparison of regioselectivities for trapping experiments of 4,5-benzofuranyne
(4) and N-Me-4,5-indolyne (22). When p-cresol was used as the nucleophile (entry 1), the indolyne
reacted to furnish the C5- and C4-substituted adducts in a 3.0 : 1 ratio. In the case of benzofuranyne 4, a
higher degree of selectivity was observed (8.5 : 1). Similarly, in the trapping of the arynes with
benzylazide (entry 2), selectivity was greater in the case of the benzofuranyne (2.4 : 1 vs 6.2 : 1),
consistent with predictions.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 5. Comparison of 4,5-Indolyne and 4,5-Benzofuranyne Regioselectivities.
SiMe3
B
Nuc
4
Fluoride source
Trapping agent
5
TfO
A
or
MeCN
X
X
X
X
21; X = NMe
10; X = O
22; X = NMe
4; X = O
X = NMe or O
Ratio
(Yield)
X = NMe X = O
Ratio
(Yield)
Trapping
agent
Entry
Products
Me
O
Me
Me
3.0 : 1a
(80%)
O
8.5 : 1b
(73%)
+
1
4
5
OH
X
X
Bn
N
N
N
N
N
2.4 : 1c
(86%)
N
6.2 : 1b
(71%)
4
Bn
N
N
+
2
5
Bn
N
X
X
a
b
Reaction performed with p-cresol (1.5 equiv) and CsF (3 equiv) at 50 °C. Reactions performed
c
with trapping agent (3 equiv) and CsF (3 equiv) at 23 °C. Reaction performed with benzyl azide (5
equiv) and TBAF (2 equiv) at 23 °C.
Similar comparisons were made between the 3,4-oxacyclohexyne (5) and the corresponding N-
Cbz-protected piperidyne 7 using cycloaddition reactions (Table 6). In the case of nitrone trapping
(entry 1), the piperidyne undergoes cycloaddition to give a 12.7 : 1 ratio of products. However, use of
the oxacyclic variant gave >20:1 selectivity. Likewise, slightly higher selectivities were seen in the
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trapping of oxacyclohexyne 5 with benzyl azide, compared to the trapping of piperidyne 7 (entry 2). The
more pronounced selectivities seen in the case of the 4,5-benzofuranyne (4) and the 3,4-oxacyclohexyne
(5), compared to their nitrogen-containing counterparts, can be attributed to the greater electronegativity
of oxygen. The oxygen atom has a stronger inductive effect that leads to increased distortion,36 which in
turn parlays into the more significant selectivities observed.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 6. Comparison of Oxacyclohexyne and Piperidyne Regioselectivities
CsF
Trapping agent
(3 equiv)
OTf
B
R3Si
A
solvent, 60 °C
X
X
X
23; X = NCbz, R = Me
14; X = O; R = Et
7; X = NCbz
5; X = O
X = NCbz or O
Ratio
(Yield)a
Ratio
(Yield)b
X = O
Trapping
agent
Entry
Products
X = NCbz
t-Bu
t-Bu
Ph
t-Bu
N
N
O
N
12.7:1
(84%)
>20:1
(73%)
O
O
+
1
2
Ph
4
3
Ph
X
X
Bn
N
N
Bn
N
N
N
N
Bn
5.3:1
(81%)
7.2:1
(69%)
N
+
4
3
N
N
X
X
a Reaction performed with MeCN as the solvent. b Reactions performed with THF as the solvent.
Conclusion
In summary, we have developed methodology that allows for the generation and trapping of two
oxacyclic strained intermediates, the 4,5-benzofuranyne and the 3,4-oxacyclohexyne. Interception of
these species by nucleophiles and cycloaddition partners provides a new means to prepare arrays of
heterocyclic scaffolds by the formation of one or more new C–C or C–heteroatom bonds. The distortion
/ interaction model was used to make regioselectivity predictions about the preferred sites of reactivity,
which were validated by experiments. Moreover, greater selectivities were seen in the trapping of the
oxacyclic strained intermediates compared to the corresponding N-containing compounds, also
consistent with computational predictions. Our studies demonstrate, for the first time, that oxacyclic
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arynes and alkynes can be generated from silyl triflate precursors and strategically harnessed to build
decorated oxygen-containing heterocycles. Given the abundance of aryne trapping reactions available in
the literature, this methodology is expected to find utility in the synthesis of medicinal substances and
natural products.
1
2
3
4
5
6
7
8
9
10
11
12
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14
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Acknowledgements
The authors are grateful to the NIH-NIGMS (R01 GM090007 for N.K.G.), Bristol–Myers
Squibb, the A. P. Sloan Foundation, the Dreyfus Foundation, the Foote Family (T.K.S.), the UCLA
Gold Shield Alumnae, and the UCLA Cota Robles Fellowship Program (J.M.M.) for financial support.
We thank Professor K. N. Houk (UCLA) for helpful discussions. These studies were supported by
shared instrumentation grants from the NSF (CHE-1048804) and the NIH NCRR (S10RR025631).
Author Contributions
†T.K.S. and J.M.M. contributed equally.
Supporting information available
Detailed experimental procedures, Cartesian coordinates and energies, as well as
characterization data for all new compounds is available. This material is available free of charge via the
Internet at http://pubs.acs.org.
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19 (a) Tomaszewski, Z.; Johnson, M. P.; Huang, X.; Nichols, D. E. J. Med. Chem. 1992, 35, 2061–2064.
(b) Marugán, J. J.; Manthey, C.; Anaclerio, B.; Lafrance, L.; Lu, T.; Markotan, T.; Leonard, K. A.;
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We have previously demonstrated that DFT calculations (B3LYP/6-31G(d)) are well suited for the
aryne distortion model, although ab initio methods (MP2/6-311+G**) can also be used; see reference
8a.
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Arynes and cyclic alkynes can be generated from silyl triflates using mild fluoride-based conditions.
In turn, an array of trapping experiments can be carried out in synthetically useful yields (see
references 2c–2n). For the initial use of silyl triflates as aryne precursors, see: Himeshima, Y.;
Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 12, 1211–1214.
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(a) Frlan, R.; Gobec, S.; Kikelj, D. Tetrahedron 2007, 63, 10698–10708. (b) Hisashi, S.; Takao, I.;
Hideki, Y. US Patent 6410561 B1, 2002.
23 Fliri, A. J.; O'Donnell, C. J.; Claffey, M.; Gallaschun; R. J. US Patent 0058361 A1, 2006
24 Smith III, A. B.; Empfield, J. R.; Vaccaro, H. A. Tetrahedron Lett. 1989, 30, 7325–7328.
25 Liu, Z.; Larock, R. C. J. Org. Chem. 2006, 71, 3198–3209.
26 Yoshida, H.; Shirakawa, E.; Honda, Y.; Hiyama, T. Angew. Chem. Int. Ed. 2002, 41, 3247–3249.
27 Gilmore, C. D.; Allan, K. M.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 1558–1559.
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For the trapping of arynes with iodonium ylides, see: Huang, X.-C.; Liu, Y.-L.; Liang, Y.; Pi, S.-F.;
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Wang, F.; Li, J.-H. Org. Lett. 2008, 10, 1525–1528.
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29 For the trapping of arynes with nitrones, see: Lu, C.; Dubrovskiy, A. V.; Larock, R. C. J. Org. Chem.
2012, 77, 2279–2284.
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For the trapping of arynes with azomethine imines, see: Shi, F.; Mancuso, R.; Larock, R. C.
Tetrahedron Lett. 2009, 50, 4067–4070.
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For the trapping of arynes with azides, see: Shi, F.; Waldo, J. P.; Chen, Y.; Larock, R. C. Org. Lett.
2008, 10, 2409–2412.
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For the trapping of arynes with sydnones, see: Wu, C.; Fang, Y.; Larock, R. C.; Shi, F. Org. Lett.
2010, 12, 2234–2237.
33 For the trapping of arynes with diazoesters, see: Jin, T.; Yamamoto, Y. Angew. Chem. Int. Ed. 2007,
46, 3323–3325.
34 Zhao, J.; Larock, R. C. Org. Lett. 2005, 7, 4273–4275.
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The ability to access heterocyclic scaffolds with significant aliphatic character is an important
direction in modern drug discovery; see: (a) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem.
2009, 52, 6752–6756. (b) Ritchie, T. J.; Macdonald, S. J. F. Drug Discovery Today 2009, 14, 1011–
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36 Bent, H. Chem. Rev. 1961, 61, 275-311.
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SYNOPSIS TOC.
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Me
N
Me
N
SiMe3
N
O
123°
130°
Me
O
TfO
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N
CsF, 50 °C
Me
O
O
4,5-Benzofuranyne
90% yield,
single regioisomer
O
O
Me
O
OTf
MeO
Me
136°
121°
Et3Si
IPh
CsF
MeCN, 60 °C
MeO2C
O
O
3,4-Oxacyclohexyne
70% yield, >20:1
ratio of regioisomers
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