A [3+2] Cyclization of Siloxyalkynes and Isocyanides for the Synthesis of Oxazoles

Article abstract of DOI:10.1055/s-0037-1610402

A mild and efficient [3+2] cyclization of siloxyalkynes for the synthesis of aromatic heterocycles is developed. It is a new addition to the cyclization reactions of these versatile species. In the presence of TBAF as promoter, siloxyalkynes react with el

Full text of DOI:10.1055/s-0037-1610402

SYNLETT
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Georg Thieme Verlag Stuttgart · New York
2018, 29, A–D
letter
A
en
A. Wu, J. Sun
Letter
Synlett
A [3+2] Cyclization of Siloxyalkynes and Isocyanides for the Syn-
thesis of Oxazoles
An Wu
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R3Si
[3+2]
cyclization
C
N
O
Jianwei Sun*
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Department of Chemistry, The Hong Kong University of Science and Technology,
Clear Water Bay, Kowloon, Hong Kong SAR, P. R. of China
sunjw@ust.hk
R'
EWG
EWG
68–86% yield
R'
HKUST-Shenzhen Research Institute, No. 9 Yuexing 1st Rd, South Area, Hi-tech
Park, Nanshan, Shenzhen 518057, P. R. of China
♦ mild conditions
♦ high efficiency
♦ metal-free
Published as part of the 30 Years SYNLETT – Pearl Anniversary Issue
Received: 29.09.2018
Accepted after revision: 31.10.2018
Published online: 27.11.2018
the first [3+2] cyclization of siloxyalkynes for the efficient
synthesis of five-membered aromatic heterocycles (1,3-ox-
azoles), in which siloxyalkynes serve as C–O cyclization
partners.
DOI: 10.1055/s-0037-1610402; Art ID: st-2018-w0621-l
License terms:
-
R3Si
δ
O
Abstract A mild and efficient [3+2] cyclization of siloxyalkynes for the
synthesis of aromatic heterocycles is developed. It is a new addition to
the cyclization reactions of these versatile species. In the presence of
TBAF as promoter, siloxyalkynes react with electron-withdrawing isocy-
anides to form a range of oxazole products. In this reaction, siloxy-
alkynes contribute the C–O unit for the cyclization, which is different
from previous typical examples where it is a two-carbon contributor.
Mechanistic studies provided insights into the mechanism, which in-
volves a ketene intermediate. Based on the mechanistic insight, an al-
ternative catalytic system was also demonstrated to be effective for the
same transformation.
[n+2]
cyclization
Nu
E
R3SiO
R'
Nu
E
+
δ
-
δ
R'
♦ well-studied: [2+2], [4+2], [6+2]
♦ rarely known: [3+2]
Scheme 1 Siloxyalkynes in cyclization reactions
Oxazoles are an important family of aromatic nitrogen-
containing heterocycles, widely present in a range of natu-
ral products and bioactive compounds.4 In these com-
pounds, the oxazole unit is known to contribute to antifun-
gal, cytotoxic, and anthelmintic activities, among others.
Some natural alkaloids even contain multiple oxazole units,
thereby indicating the importance of such motifs. For ex-
ample, marine natural products bengazole A and its homo-
logues, as well as the freshwater natural alkaloid muscoride
A, have two oxazole rings in their structures (Figure 1).5,6
Key words oxazoles, siloxyalkynes, isocyanides, cyclization
Siloxyalkynes, also known as silyl ynol ethers, are a use-
ful type of electron-rich alkynes and a versatile platform for
the discovery of new organic reactions.1 The presence of the
siloxy group attached directly to the alkyne triple bond not
only increases its electron density, but also polarizes the
triple bond. Consequently, siloxyalkynes can participate in
a variety of cyclization reactions with suitable dipolar com-
pounds (Scheme 1). Among these, the most studied cycliza-
tions are [2+2], [4+2], and [6+2] cyclizations to form four-,
six-, and eight-membered cyclic compounds.1,2 In contrast,
there are few reports on the formation of five-membered
rings by [3+2] cyclization of siloxyalkynes.3 Moreover, si-
loxyalkynes typically serve as two-carbon units in these cy-
clization reactions, and have rarely been demonstrated to
serve as providers of C–O units for cyclization. In continua-
tion of our studies on electron-rich alkynes,2h–k we report
O
Me
OH OH OH
N
H
N
N
Me
O
O
O
N
OH
Me Me
Me
N
Me
Me
nC13H27
O
N
O
O
O
O
Me
Me
bengazole A
muscoride A
Figure 1 Representative oxazole-containing natural alkaloids
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

B
A. Wu, J. Sun
Letter
Synlett
Isocyanides are known synthetic building blocks, widely
used for the synthesis of heterocycles.7 Specifically, when
substituted with an electron-withdrawing group, such
compounds can serve as a three-atom unit for cyclization.
Therefore, we envisioned that the reaction between a si-
loxyalkyne and such an isocyanide might proceed in a [3+2]
cyclization fashion. Indeed, after considerable efforts to
identify suitable conditions, we discovered that the reac-
tion can provide a direct and efficient approach toward the
synthesis of oxazoles under metal-free and mild conditions.
Notably, in this reaction, siloxyalkynes contribute a C–O
unit, rather than a C–C unit, for the cyclization (Scheme 2).
Table 1 Optimization of the Reaction Conditionsa
OTIPS
Ts
TBAF (1.0 equiv)
C
N
+
Ts
N
nBu
CH2Cl2 (0.1 M)
r.t.
O
nBu
2a
1a
3a
Entry
Variation from the standard conditions
Yield (%)b
1
2
none
Lewis or Brønsted acid, instead of TBAF
TBAF (10 mol%)
99 (83)c
0d
3
72
76
85
99
96
0
4
TBAF (20 mol%)
[3+2] cyclization with isocyanides
5
TBAF (50 mol%)
R3Si
6
nondry vial and nonanhyd CH2Cl2
C
N
O
[3+2]
cyclization
O
N
7
open air, nondry vial, and nonanhyd CH2Cl2
CsF or NH4F instead of TBAF, r.t.
8
EWG
R'
EWG
R'
9
CsF instead of TBAF, 60 °C
45
0
10
11
12
NH4F instead of TBAF, 60 °C
♦ mild conditions
♦ high efficiency
♦ metal-free
CsF instead of TBAF, H2O (2.0 equiv), r.t.
CsF instead of TBAF, H2O (2.0 equiv), 60 °C
0
Scheme 2 Synthesis of oxazoles from siloxyalkynes
74
a Reaction conditions: 1a (1.0 equiv), 2a (1.2 equiv). 1.0 M TBAF in THF (1.0
equiv), anhyd CH2Cl2 (0.1 M), under N2, r.t.
We began our study with the commercially available
isocyanide 4-toluenesulfonylmethyl isocyanide (TosMIC;
1a) and the siloxyalkyne 2a as model substrates (Table 1).
After screening of various activators, including Lewis acids
and bases, we found that tetrabutylammonium fluoride
(TBAF) was the optimum promoter for the desired cycliza-
tion (Table 1). The reaction in CH2Cl2 proceeded in the pres-
ence of one equivalent of TBAF to form oxazole 3a in essen-
tially quantitative NMR yield (Table 1, entry 1), and this
product was isolated in 83% yield. In contrast, Lewis acids
and Brønsted acids, including In(OTf)3, AgNTf2, AgOTf,
Sc(OTf)3, AgSbF6, HNTf2, BF3·OEt2, or TMSOTf, failed to pro-
mote the same transformation (entry 2). Aiming to further
improve the reaction by making it catalytic, we decreased
the amount of TBAF and, in fact, the reaction did show cata-
lytic potential. For example, in the presence of 10 mol% of
TBAF, the product was formed in 72% yield. However, fur-
ther improvement by increasing the TBAF loading to sub-
stoichiometric levels was not significant. As the commercial
TBAF solution (in THF) is typically not anhydrous, we real-
ized that this reaction might not need strict conditions.
Thus, the reaction was run without an anhydrous vial or
CH2Cl2. Notably, almost quantitative formation of 3a was
still achieved (entry 6). Furthermore, the reaction efficien-
cy was not affected when run in open air (entry 7).
b Determined by NMR spectroscopy with CH2Br2 as the internal standard.
c Isolated yield.
d The Lewis or Brønsted acid [In(OTf)3, AgNTf2, AgOTf, Sc(OTf)3, AgSbF6,
HNTf2, BF3·OEt2, or TMSOTf] was used on a 10 mol% scale.
ever, heating the reaction mixture to 60 °C led to the oxaz-
ole product in 45% yield with CsF, but there was still no re-
action with NH4F (entries 9 and 10). From a comparison
with the reaction in the water-containing TBAF solution, we
realized that a small amount of water might be needed.
With this in mind, we added two equivalents of water to
the above reaction system. Interestingly, the yield was fur-
ther improved to 74% with CsF, but not with NH4F (entries
11 and 12). Overall, one equivalent of TBAF was still consid-
ered to be optimal for this reaction.
With the standard conditions in hand, we next exam-
ined the scope of the reaction. As shown in Scheme 3, a
range of siloxyalkynes bearing various substituents reacted
with TosMIC (1a) to afford the desired oxazoles 3a–j with
high efficiency.8,9 Note that, for the siloxyalkyne bearing a
TMS group (R = TMS), the corresponding product was desil-
ylated under the standard conditions to give 5-methyl-4-to-
syloxazole (3h) as the observed product. In contrast, when
a siloxyalkyne containing a TIPS ether motif (2j) was used,
the TIPS group remained intact. Moreover, when the elec-
tron-withdrawing group in the isocyanide was changed
from a tosyl group to an ester group, the reaction was
equally efficient, providing the oxazole 3k in good yield. Fi-
nally, the structure of product 3i was confirmed by X-ray
crystallography (Figure 2).10
We hypothesized that TBAF might activate the siloxy-
alkyne by forming a strong Si–F bond. We therefore next
screened other fluoride sources. When cesium fluoride or
ammonium fluoride was used instead of TBAF, no product
was detected at room temperature (Table 1, entry 8). How-
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

C
A. Wu, J. Sun
Letter
Synlett
OTIPS
F
H
EWG
R
Si
TBAF (1.0 equiv)
N
O
C
O
R
O
R
CN
Ts
+
EWG
N
Ts
NC
C
CH2Cl2, r.t.
4 h
O
R
H
R
1
2
3
2
A
B
C
Ts
N
Ts
Ts
N
Ts
N
N
nBu
nOct
tBu
O
O
O
O
C
H2O
3a, 83%
3b, 85%
3c, 70%
3d, 86%
N
O
R
N
O
R
N
O
N
Ts
O
Ts
Ts
Ts
Ts
Ts
Ts
N
Ts
N
O
N
N
R
R
Ph
Ph
F
E
D
3
O
O
O
Ph
Me
Scheme 4 Proposed mechanism
3e, 76%
3f, 81%
3g, 80%
3h, 69%a
all obtained with good efficiency, thereby providing an im-
provement on the original protocol employing a stoichio-
metric amount of fluoride. Moreover, we also found that
isocyanides with a sterically hindered α-position did not
react efficiently [Scheme 5(b)]. In the absence of an α-hy-
drogen, the reaction did not occur, which is consistent with
the proposed mechanism. Furthermore, in the absence of
an electron-withdrawing group (e.g., Ts), isocyanide 1f did
not show any reactivity in this reaction, indicating that the
α-acidity is also critically important. Finally, we also carried
out the reaction in the presence of D2O with CsF as the fluo-
ride source [Scheme 5(c)]. In the oxazole product, two posi-
tions showed incorporation of deuterium. The presence of
deuterium in the oxazole ring is obviously consistent with
the mechanism. In addition, the benzylic position was also
found to have 27% incorporation of deuterium. This posi-
tion is the original acidic position in the isocyanide, which
might have pre-exchanged with D2O before the reaction. It
is also possible that the final aromatization step might be
assisted by a water molecule.
In summary, we have developed the first [3+2] cycliza-
tion of siloxyalkynes for the synthesis of aromatic heterocy-
cles. In contrast to the previous cyclization reactions of si-
loxyalkynes where they serve as two-carbon partners, in
this reaction the siloxyalkyne contributes a C–O unit to the
cyclization. In the presence of TBAF as the activator, the re-
action between siloxyalkynes and electron-deficient isocy-
anides proceed efficiently to form a range of substituted ox-
azoles under mild metal-free conditions. Mechanistic stud-
ies indicated that siloxyalkynes serve as the ketene
precursor. Inspired by careful analysis, complementary con-
ditions (such as the use of hydroxide as a catalyst) were also
identified for this transformation.
Ts
Ts
COOEt
nBu
N
N
N
OBn
O
O
O
OTIPS
3i, 85%
3j, 68%
3k, 69%
Scheme 3 Substrate scope. Reaction conditions: 1 (0.4 mmol or 0.5
mmol, 1.0 equiv), 2 (1.2 equiv) and TBAF (1.0 equiv, 1.0 M THF solu-
tion) in DCM (0.1 M) at r.t. for 4 h. Isolated yields are reported.a R = TMS
in substrate.
Ts
N
OBn
O
3i
Figure 2 XRD results for compound 3i
The proposed mechanism is shown in Scheme 4. We be-
lieve that the fluoride anion in TBAF activates the siloxy-
alkyne by forming an ynolate ion A, which then deproton-
ates the isocyanide to form the conjugate base B and a ke-
tene intermediate C. Subsequent nucleophilic addition to
ketene C by anion B leads to intermediate D, which cyclizes
to give E. A small amount of water present in the reaction
mixture then protonates E to form F. Further aromatization
of the ring delivers the observed oxazole product.
During the condition optimization, we noted that TBAF
can also be used in a catalytic amount, albeit with a slightly
decreased yield. To rationalize this catalytic feature, we rea-
soned that the hydroxide ion (OH–) generated from E to F
might also serve as an active promoter to turn over the re-
action. To confirm this possibility, we next evaluated the
catalytic ability of the hydroxide ion. In the presence of a
catalytic amount of Bu4NOH, the reaction of 1a and 2a pro-
ceeded with high efficiency under essentially the same con-
ditions, giving product 3a in 85% isolated yield [Scheme
5(a)]. To further probe the generality of this catalytic proto-
col, we selected and tested other examples under the new
conditions. We found that the corresponding oxazoles were
Funding Information
Financial support was provided by the National Science Foundation of
China (21572192, 21490570) and the Hong Kong RGC
(GRF16304714).
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Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

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A. Wu, J. Sun
Letter
Synlett
a) Catalytic ability of hydroxide ion
(3) We are aware of only two examples, see: (a) Qi, X.; Ready, J. M.
Angew. Chem. 2008, 120, 7176. (b) Buchner, K. M.; Woerpel, K.
A. Organometallics 2010, 29, 1661.
nBu4NOH (10 mol%)
1a
2
3
+
(4) Yeh, V. S. C. Tetrahedron 2004, 60, 11995.
CH2Cl2, r.t., 0.5 h
(5) (a) Adamczeski, M.; Quiñoá, E.; Crews, P. J. Am. Chem. Soc. 1989,
111, 647. (b) Searle, P. A.; Richter, R. K.; Molinski, T. F. J. Org.
Chem. 1996, 61, 4073.
(6) Nagatsu, A.; Kajitani, H.; Sakakibara, J. Tetrahedron Lett. 1995,
36, 4097.
(7) For reviews on isocyanides, see: (a) Boyarskiy, V. P.; Bokach, N.
A.; Luzyanin, K. V.; Kukushkin, V. Yu. Chem. Rev. 2015, 115,
2698. (b) Van Leusen, D.; Van Leusen, A. M. Org. React. (N. Y.)
2001, 57, 417.
entry
isolated yield
3
1
2
3
4
3a
3b
3g
3i
85%
88%
88%
82%
(8) For other examples of oxazole synthesis, including the use of
isocyanides, see: (a) Robinson, R. J. Chem. Soc., Trans. 1909, 95,
2167. (b) Gabriel, S. Ber. Dtsch. Chem. Ges. 1910, 43, 134.
(c) Wiley, R. H. Chem. Rev. 1945, 37, 401. (d) Nunami, K.-I.;
Suzuki, M.; Yoneda, N. J. Org. Chem. 1979, 44, 1887. (e) van de
Coevering, R.; Kuil, M.; Gebbink, R. J. M. K.; van Koten, G. Chem.
Commun. 2002, 1636. (f) Sladojevich, F.; Trabocchi, A.; Guarna,
A.; Dixon, D. J. J. Am. Chem. Soc. 2011, 133, 1710. (g) Franchino,
A.; Jakubec, P.; Dixon, D. J. Org. Biomol. Chem. 2016, 14, 93.
(h) Zhang, M.-Z.; Jia, C.-Y.; Gu, Y.-C.; Mulholland, N.; Turner, S.;
Beattie, D.; Zhang, W.-H.; Yang, G.-F.; Clough, J. Eur. J. Med.
Chem. 2017, 126, 669. (i) Suzuki, M.; Iwasaki, T.; Miyoshi, M.;
Okumura, K.; Matsumoto, K. J. Org. Chem. 1973, 38, 3571.
(j) Huang, W.-S.; Zhang, Y.-X.; Yuan, C.-Y. Synth. Commun. 1996,
26, 1149. (k) Baumann, M.; Baxendale, I. R.; Ley, S. V.; Smith, C.
D.; Tranmer, G. K. Org. Lett. 2006, 8, 5231. (l) El Kaim, L.;
Grimaud, L.; Schiltz, A. Tetrahedron Lett. 2009, 50, 5235. (m) Dos
Santos, A.; El Kaim, L.; Grimaud, L.; Ronsseray, C. Chem.
Commun. 2009, 3907. (n) Ma, Y.; Yan, Z.; Bian, C.; Li, K.; Zhang,
X.; Wang, M.; Gao, X.; Zhang, H.; Lei, A. Chem. Commun. 2015,
51, 10524. (o) Liao, J.-Y.; Ni, Q.; Zhao, Y. Org. Lett. 2017, 19, 4074.
(p) Pan, J.; Li, X.; Lin, F.; Liu, J.; Jiao, N. Chem 2018, 4, 1427.
(9) 5-Pentyl-4-tosyl-1,3-oxazole (3a); Typical Procedure
CH2Cl2 (4 mL) was added to a 10 mL vial charged with isocya-
nide 1a (0.4 mmol, 1.0 equiv) at r.t. under N2. Siloxyalkyne 2a
(0.48 mmol, 1.2 equiv) and a 1.0 M solution of TBAF in THF (0.4
mmol, 1.0 equiv) were added sequentially, and the mixture was
stirred at r.t. for 4 h. Next, H2O (5 mL) was added, and the layers
were separated. The aqueous layer was extracted with CH2Cl2 (3
× 5 mL). The combined organic layers were dried (Na2SO4), fil-
tered, and concentrated. The residue was purified by chroma-
tography [silica gel, hexanes–EtOAc (10:1)] to give a pale-yellow
semisolid; yield: 97.9 mg (83%). IR (neat): 3134, 3057, 2932,
b) Other isocyanides with hindered α−position or no α−hydrogen
Me
C
C
C
C
N
N
Ts
N
Ts
N
Me Me
Me
Me
1c
1d
1e
1f
no reaction
messy
no reaction
no reaction
c) Outcome with D2O
61% D
N
Ts
CsF (1.0 equiv)
D2O (2.0 equiv)
H/D
1a
+
2a
nBu
H/D
O
CH2Cl2, 60 °C
11 h
H/D
total 27% D
4
Scheme 5 Mechanistic studies
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610402.
S
u
p
p
orti
n
gInformati
o
n
S
u
p
p
orit
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gInform
a
References and Notes
(1) For reviews on siloxyalkynes, see: (a) Qian, H.; Zhao, W.; Sun, J.
Chem. Rec. 2014, 14, 1070. (b) Shindo, M. Synthesis 2003, 2275.
(c) Shindo, M. Tetrahedron 2007, 63, 10.
(2) For selected examples of cyclization reactions of siloxyalkynes,
see: (a) Sweis, R. F.; Schramm, M. P.; Kozmin, S. A. J. Am. Chem.
Soc. 2004, 126, 7442. (b) Danheiser, R. L.; Gee, S. K. J. Org. Chem.
1984, 49, 1672. (c) Danheiser, R. L.; Gee, S. K.; Perez, J. J. J. Am.
Chem. Soc. 1986, 108, 806. (d) Movassaghi, M.; Hill, M. D.;
Ahmad, O. K. J. Am. Chem. Soc. 2007, 129, 10096. (e) Türkmen, Y.
E.; Montavon, T. J.; Kozmin, S. A.; Rawal, V. H. J. Am. Chem. Soc.
2012, 134, 9062. (f) Montavon, T. J.; Türkmen, Y. E.; Shamsi, N.
A.; Miller, C.; Sumaria, C. S.; Rawal, V. H.; Kozmin, S. A. Angew.
Chem. Int. Ed. 2013, 52, 13576. (g) Cabrera-Pardo, J. R.; Chai, D.
I.; Liu, S.; Mrksich, M.; Kozmin, S. A. Nat. Chem. 2013, 5, 423.
(h) Zhao, W.; Wang, Z.; Sun, J. Angew. Chem. Int. Ed. 2012, 51,
6209. (i) Zhao, W.; Li, Z.; Sun, J. J. Am. Chem. Soc. 2013, 135,
4680. (j) Zhao, W.; Sun, J. Synlett 2014, 25, 303. (k) Zhao, W.;
Qian, H.; Li, Z.; Sun, J. Angew. Chem. Int. Ed. 2015, 54, 10005.
2865, 1589, 1516, 1455, 1325, 1145, 1084 cm–1 1H NMR (400
.
MHz, CDCl3): δ = 7.89 (d, J = 8.3 Hz, 2 H), 7.71 (s, 1 H), 7.32 (d, J =
8.0 Hz, 2 H), 3.08 (t, J = 7.6 Hz, 2 H), 2.40 (s, 3 H), 1.75–1.62 (m, 2
H), 1.38–1.26 (m, 4 H), 0.92–0.83 (m, 3 H). 13C NMR (101 MHz,
CDCl3): δ = 157.2, 149.4, 144.7, 137.3, 135.1, 129.7, 127.9, 31.0,
27.5, 25.2, 22.1, 21.5, 13.8. HRMS (CI): m/z [M + H]+ calcd for
C
15H20NO3S: 294.1164; found: 294.1158.
(10) CCDC 1869561 contains the supplementary crystallographic
data for compound 3i. The data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/getstructures.
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D