Electrophile-promoted cyclization of propargylic amides

Article abstract of DOI:10.1055/s-0034-1379320

Electrophilic cyclization of N-(3-arylprop-2-ynyl)amides to functionalized 4H-1,3-oxazines is described. It was found that the presence of an electron-rich aryl group next to the triple bond is crucial for a smooth and highly regioselective 6-endo-dig ring closure process.

Full text of DOI:10.1055/s-0034-1379320

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 479–483
letter
479
R. Bukšnaitienė, I. Čikotienė
Letter
Synlett
Electrophile-Promoted Cyclization of Propargylic Amides
Electrophile-Promoted Cyclization of Propargylic Amides
Rita Bukšnaitienė
E
E
catalyst-free
Inga Čikotienė*
N
EDG
O
Ph
Department of Organic Chemistry, Faculty of Chemistry, Vilnius University,
NH
Ph
Naugarduko 24, 03225 Vilnius, Lithuania
inga.cikotiene@chf.vu.lt
+
3
7
0
5
(2
)
3
3
0
9
8
7
O
EDG
Received: 07.08.2014
Accepted after revision: 21.09.2014
Published online: 17.10.2014
DOI: 10.1055/s-0034-1379320; Art ID: st-2014-d0660-l
Abstract Electrophilic cyclization of N-(3-arylprop-2-ynyl)amides to
functionalized 4H-1,3-oxazines is described. It was found that the pres-
ence of an electron-rich aryl group next to the triple bond is crucial for a
smooth and highly regioselective 6-endo-dig ring closure process.
Key words propargylic amides, electrophile, cyclization, oxazines,
oxazolines
Rita Bukšnaitienė was born in Panevėžys, Lithuania in 1982. She grad-
uated from Vilnius University, obtaining her Master of Science degree in
2007 and her Ph.D. in 2012. Currently she is working in Prof. Dr. Inga
Čikotienė’s group as a research associate. Her research interests include
heterocyclic chemistry, synthesis of pyrimidine, quinoline, indole and
thiophene derivatives, as well as reactivity of functionally substituted
alkynes..
Functionalized propargylic substrates are a class of
alkynes with useful chemical behavior. Generally, π-acidic
transition metal salts are used as catalysts for activation of
triple bonds and therefore subsequent cyclizations or skele-
tal rearrangement processes become possible and thus
propargylic amides are able to cyclize to give oxazolines or
oxazines (Scheme 1).1 The regioselectivity of metal-mediat-
ed cyclization processes usually depends upon the nature of
the starting materials or the character of the Lewis acid.
Inga Čikotienė was born in Vilnius, Lithuania in 1979. She graduated
with honors from Vilnius University in 2003 and obtained her Ph.D. in
chemistry at Vilnius University in 2006. After the postdoctoral work at
the Institute of Biotechnology, Lithuania, she returned to her alma ma-
ter as a lecturer, eventually being promoted to associate professor in
2009 and then to full professor in 2014. Her research interests include
organic synthesis, investigations of reaction mechanisms, and medici-
nal chemistry. She has received several awards including a Young Scien-
tist awards and scholarships from the Lithuanian Research Council, the
Lithuanian Academy of Science and the Rector of Vilnius University.
R1
N
R2
R3
[M]
a
O
R1
NH
R2
5-exo-dig
R1
R3
b
a
b
O
N
carboxylates (Scheme 2)4 led us to propose that N-(3-aryl-
prop-2-ynyl)amides should also be able to undergo electro-
phile-mediated 6-endo-dig rearrangements. The regioselec-
tivity of the process could be directed via the participation
of aryl group in stabilization of the intermediate vinylic car-
bocation formed during the first stage of electrophilic acti-
vation (Figure 1).
R3
6-endo-dig
O
R2
Scheme 1 Metal-mediated 5-exo-dig or 6-endo-dig cyclizations of
propargylic amides
However, although electrophilic cyclization of alkynes
bearing an internal nucleophile has emerged as a very effi-
cient process to obtain a variety of pre-functionalized cyclic
structures,2 to the best of our knowledge, there are only a
few reports of iodine-mediated cyclization of propargylic
amides leading exclusively to 5-exo-dig ring closure pro-
cesses3 and, to the best of our knowledge, there has been no
disclosure of 6-endo-dig cyclizations. Our recent work on
electrophile-mediated rearrangements of 3-arylprop-2-ynyl
E+
O
Ar
E
Ar
O
R
O
Scheme 2 Previous work on electrophile-mediated rearrangements of
propargylic esters4
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 479–483

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R. Bukšnaitienė, I. Čikotienė
Letter
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E
To explore this proposal we chose N-[3-(4-methoxyphe-
nyl)prop-2-ynyl]benzamide (1a) as a starting material and
tested its reactivity towards different electrophiles. Indeed,
in all cases the starting material underwent electrophile-
mediated 6-endo-dig cyclization and oxazoline derivatives
were not observed (Scheme 3, Table 1).
E
Ar
or
6-endo-dig
Ar
NH
R
O
5-exo-dig
O
NH
R
II
I
unstabilized
stabilized by
conjugation
Figure 1 Structures of two possible intermediates in electrophile-
mediated rearrangements of N-(3-arylprop-2-ynyl)amides
Table 1 Data on Reaction between N-[3-(4-Methoxyphenyl)prop-2-ynyl]benzamide (1a) and Electrophilic Reagents
Entry E+
Reaction conditions
Cyclization producta
Side product (Ar = 4-MeOC6H4)
Yield (%)
1
2
3
4
I+
I2 (1 equiv), K3PO4 (1 equiv), CH2Cl2, r.t., 2 h
ICl (1 equiv), K3PO4 (1 equiv), CH2Cl2, r.t., 1 h
Py2IBF4 (1.1 equiv), CH2Cl2, r.t., 2 h
2aa
2aa
2aa
2aa
-
-
-
-
57%
53%
74%
72%
I+
I+
I+
NIS (1.1 equiv), CH2Cl2, r.t., 30 min
O
O
Ar
HN
27% (2aa),
41% (3)
5
6
I+
I2 (1 equiv), PhI(OAc)2 (1 equiv), CH2Cl2, r.t., 1 h
I2 (1 equiv), PhI(OAc)2 (2 equiv), CH2Cl2, r.t., 1 h
2aa
Ph
I
3
I
I
N
I+
-
37%
AcO
O
Ph
Ar
4
O
O
Ar
HN
7
8
9
-
PhI(OAc)2 (1.5 equiv), AcOH, r.t., 12 h
-
67%
64%
Ph
AcO
5
O
O
Ar
HN
HN
H+
p-TSA·H2O (1 equiv), CH2Cl2, r.t., 1 week
-
Ph
6
Cl
O
Ar
5% (2ab),
15% (7ab)
PhSe+
PhSeCl (1.5 equiv), CH2Cl2, r.t., 1.5 h
2ab
2ab
Ph
Ph Se
7ab
24% (2ab),
32% (7ab)
10
11
PhSe+
PhSe+
PhSeCl (1 equiv), K3PO4 (1 equiv), CH2Cl2, r.t., 15 min
7ab
7ab
66% (2ab),
13% (7ab)
PhSeCl (1 equiv), t-BuOK (1 equiv), CH2Cl2, r.t., 15 min 2ab
E =
O
12
13
2ac
-
78%
O
OMe
(1 equiv), TMSOTf (1 equiv), CH2Cl2, r.t., 30 min
O
O
Ar
Ph
HN
Ph
Ph
6 and
Ph
Ph
Ph
22% (6),
31% (8)
-
Cl
(1 equiv), InCl3 (10 mol%), CH2Cl2, r.t., 48 h
Ph
8
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 479–483

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R. Bukšnaitienė, I. Čikotienė
Letter
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E+
E
In 2011, the group of Hashmi reported gold-catalyzed
cyclizations of non-terminal propargylic amides.9 They also
described a single example of iodine-mediated 5-exo-dig
cyclization of N-(3-phenylprop-2-ynyl)benzamide leading
to a iodooxazoline derivative. This result is contrary to our
proposal (Figure 1) and our previous4,10 and present find-
N
MeO
NH
Ph
O
Ph
O
MeO
2
1a
Scheme 3 Electrophile-mediated ring-closure reactions of N-[3-(4-me-
thoxyphenyl)prop-2-ynyl]benzamide (1a)
ings. However, it should be recognized that 1H NMR and 13
C
NMR spectroscopic and mass spectrometric analysis of the
cyclized products would permit unambiguous differentia-
tion between the cyclization processes. To confirm the 6-
endo-dig cyclization process, we performed a Sonagashira
coupling reaction between 5-iodo-6-(4-methoxyphenyl)-2-
phenyl-4H-1,3-oxazine (2aa) and phenylacetylene leading
to the formation of the phenylethynyl-containing product 9
(Scheme 4).
Initially, we studied iodine electrophiles such as molec-
ular iodine or iodine monochloride under basic conditions
(Table 1, entries 1 and 2) or N-iodosuccinimide or Barluen-
ga’s reagent in neutral media (Table 1, entries 3 and 4) to
initiate cyclization. However, when we tried to improve the
electrophilicity using iodine in conjunction with a hyperva-
lent iodine oxidant,5 no desired improvement was achieved.
Thus, treating of 1a with equivalent amounts of iodine and
phenyliodine(III) diacetate (PIDA), gave 27% of 2aa and 41%
of side product 3 (Table 1, entry 5). Using of an excess of
PIDA resulted in the formation of 5,5-diiodo-6-(4-methoxy-
phenyl)-2-phenyl-5,6-dihydro-4H-1,3-oxazin-6-yl acetate
(4; Table 1, entry 6). When we tried to apply the method of
Saito et al for PIDA-mediated cyclization,6 we only succeed-
ed in isolating 3-benzamido-1-(4-methoxyphenyl)-1-oxo-
propan-2-yl acetate (5) and no cyclization product was ob-
served (Table 1, entry 7).
HMBC
cross-peak
Ph
H
H
I
N
i
N
Ar
O
Ph
no
HMBC
cross-peak!
Ar
O
Ph
2aa
9 (60%)
H
H
N
Ph
Ph
O
Ar
Next, we explored the scope and limitation of the cy-
clization with p-toluenesulfonic acid, phenyl hypochlo-
roselenoite, 1-methoxyisochroman and chloromethylenedi-
benzene. While use of p-TSA led to slow hydration of the
ethynyl functionality and formation of only product 6 (Ta-
ble 1, entry 8), phenyl hypochloroselenoite gave more
promising results. After the treatment of starting material
with an equivalent of phenyl hypochloroselenoite, two
products were isolated. The yield of the desired compound
2ab was very low, and it was observed that concomitant ad-
dition to the triple bond occurred giving compound 7ab in
15% yield (entry 9). However, performing the same reaction
under basic conditions resulted in an improvement of over-
all yields (Table 1, entries 10 and 11); moreover, when po-
tassium tert-butoxide was used, 2ab became the major
product (Table 1, entry 11).
Acetals in the presence of one equivalent of trimethylsi-
lyltriflate are known to be powerful sources of oxocarbeni-
um ions;7 thus they can be used in electrophile-mediated
reactions. Indeed, when we used 1-methoxyisochroman
(Table 1, entry 12), a very smooth and efficient formation of
5-(isochroman-1-yl)-6-(4-methoxyphenyl)-2-phenyl-4H-
1,3-oxazine (2ac) was observed in 30 minutes. Finally we
evaluated chloromethylenedibenzene as a source of the di-
phenylmethylium ion.8 Unfortunately, reaction of 1a and
chloromethylenedibenzene in the presence of indium(III)
chloride did not lead to cyclization. Instead, after prolonged
stirring, only the hydration product 6 and the hydration–
alkylation adduct 8 were isolated (entry 13).
Scheme 4 Sonogashira coupling between compound 2aa and phenyl-
acetylene. Ar = 4-MeOC6H4. Reagents and conditions: (i) PdCl2(PPh3)2 (4
mol%), CuI (2 mol%), TEA (2 equiv), DMF, Ar, r.t.
After isolation and purification of compound 9, in the
HMBC spectrum we observed a cross peak between C(5)H2
and one of the Csp nuclei present, thus indicating a six-
membered system. In the case of a phenylethynylisoxazo-
line derivative, the Csp and C(4)H2 nuclei would be separat-
ed by four bonds and so no cross peak in HMBC spectrum
would be expected. In an analogous manner the HMBC
spectrum of 2ac showed a cross peak between C(5)H2 and
C(1) of the isochromane unit, confirming the six-mem-
bered structure of 2ac.
The optimized reaction conditions (Table 1, entries 4, 11
and 12) were applied to the general synthesis of 5-substi-
tuted 6-aryl-2-phenyl-4H-1,3-oxazines 2 (Scheme 5 and
Table 2).11 All electron-rich substrates 1a–e underwent effi-
cient and exclusive 6-endo-dig cyclization (Table 2, entries
1–15). However, when the starting material contained a 4-
chlorophenyl group on the triple bond, the activation of
alkynyl functionality was less efficient, resulting in an ex-
tended reaction time (entry 16). Moreover, besides the ex-
pected 6-endo-dig cyclization product 2fa, (4-chlorophe-
nyl)(2-phenyloxazol-5-yl)methanone 10fa was also isolat-
ed. Terminal propargylamide 1g did not cyclize to 5-iodo-2-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 479–483

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R. Bukšnaitienė, I. Čikotienė
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Table 2 Data on Reaction between N-(3-Substituted-prop-2-ynyl)benzamides 1 and Electrophilic Reagents
Entry
Starting material
Reaction
6-endo-dig cyclization
product
Side product
Yields (%)
72%
conditionsa
1
1a (R = 4-MeOC6H4)
A
B
C
A
B
C
A
B
C
A
B
C
A
B
C
2aa
2ab
2ac
2ba
2bb
2bc
2ca
2cb
2cc
2da
2db
2dc
2ea
2eb
2ec
-
2
1a
7ab
66% (2ab), 13% (7ab)
3
1a
-
78%
4
1b (R = 4-MeC6H4)
-
58%
5
1b
7bb
80% (2bb), 18% (7bb)
6
1b
-
81%
7
1c (R = 4-EtOC6H4)
-
58%
8
1c
7cb
65% (2cb), 12% (7cb)
9
1c
-
53%
10
11
12
13
14
15
1d [R = 3,4-(MeO)2C6H3]
-
52%
1d
7db
68% (2db), 19% (7db)
1d
-
-
-
-
70%
60%
63%
54%
1e [R = 3,4,5-(MeO)3C6H2]
1e
1e
N
O
Cl
Ph
16
17
1f (R = 4-ClC6H4)
Ab
2fa
16% (2fa), 37% (10fa)
16% (10ga), 41% (11)
O
10fa
N
I
Ph
NHCOPh
H
O
1g (R = H)
A
-
I
O
10ga
11
a Reaction conditions: A: NIS (1.1 equiv), CH2Cl2, r.t., 30 min. B: PhSeCl (1 equiv), t-BuOK (1 equiv), CH2Cl2, r.t., 15 min. C: 1-methoxyisochroman (1 equiv),
TMSOTf (1 equiv), CH2Cl2, r.t., 30 min.
b Reaction time was 12 h.
phenyl-4H-1,3-oxazine; instead 2-phenyloxazole-5-carbal-
dehyde 10ga and (E)-N-(2,3-diiodoallyl)benzamide 11 were
isolated (Table 2, entry 17).
can be explained by stabilization of an incipient cationic
species in intermediates I (Figure 1). It was also found that
regioselectivity can be lost or even switched when the tri-
ple bond is not sufficiently activated. Further studies into
the scope and limitations of these transformations are un-
derway in our laboratory.
E
E+
N
R
O
HN
R
O
2
Ph
Ph
1
Acknowledgment
Scheme 5 Electrophile-mediated ring-closure reactions of N-(3-substi-
tuted prop-2-ynyl)benzamides 1
The project was supported by the European Social Fund under the
Global Grant measure (Grant No. VP1-3.1-ŠMM-07-K-01-002).
In summary, we have shown that cyclization of propar-
gylic amides can be mediated by electrophilic reagents,
such as NIS, phenyl hypochloroselenoite or 1-methoxyiso-
chroman. The presence of an electron-rich aryl group next
to the triple bond is crucial for the smooth and highly regio-
selective 6-endo-dig cyclization reaction. The regiocontrol
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378614. Included are spectro-
scopic data of synthesized compounds and copies of NMR spectra.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
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R. Bukšnaitienė, I. Čikotienė
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Synlett
References and Notes
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phenyl-4H-1,3-oxazines 2: To the solution of the correspond-
ing N-[(3-substituted)prop-2-ynyl]benzamide 1 (1 mmol) in
CH2Cl2 (5 mL) N-iodosuccinimide (0.23 g, 1 mmol; method A) or
phenyl hypochloroselenoite (95.96 mg, 0.5 mmol) together with
potassium tert-butanoate (0.5 mmol; method B), or 1-methoxy-
isochromane (90.2 mg, 0.55 mmol) followed by trimethylsilyl
triflate (0.09 mL, 0.5 mmol; method C) were added. The
mixture was stirred at r.t. When reaction was complete (TLC),
the solution was quenched with aq sodium thiosulfate. The
organic layer was separated, washed with aq sodium thiosulfate
(2 × 20 mL), and H2O (2 × 20 mL), and dried over anhyd Na2SO4.
After filtration and evaporation of the solvent under reduced
pressure, the residue was purified by flash column chromatog-
raphy eluting with hexane–EtOAc mixtures.
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5-Iodo-6-(4-methoxyphenyl)-2-phenyl-4H-1,3-oxazine
(2aa): white solid; mp 119–120 °C; yield: 72%. 1H NMR (400
MHz, CDCl3): δ = 3.86 (s, 3 H, OMe), 4.56 (s, 2 H, CH2), 6.96 (d, 3J
= 8.8 Hz, 2 H, ArH), 7.40 (t, 3J = 7.6 Hz, 2 H, ArH), 7.48 (tt, 3J = 7.6
Hz, 4J = 2.4 Hz, 1 H, ArH), 7.63 (d, 3J = 8.8 Hz, 2 H, ArH), 7.95–
7.97 (m, 2 H, ArH). 13C NMR (100 MHz, CDCl3): δ = 55.2 (CH2),
55.4 (OMe), 69.8 (CI), 113.6 (ArC), 126.6 (ArC), 127.4 (ArC),
128.4 (ArC), 130.5 (ArC), 131.1 (ArC), 131.7 (ArC), 147.7 (Csp2),
153.7 (Csp2), 160.6 (ArC). HRMS (ESI): m/z [M + H+] calcd for
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C
17H15INO2: 392.0142; found: 392.0148.Compounds 1–11 were
also fully characterized by IR, 1H NMR, 13C NMR spectroscopic
and microanalytical data.
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