Nucleophilic addition of tertiary propargylic amines to arynes followed by a [2,3]-sigmatropic rearrangement

Article abstract of DOI:10.1039/c8cc02176g

In the presence of 2-(trimethylsilyl)aryl triflates as aryne precursors under mild conditions, a range of tertiary propargylic amines bearing electron-withdrawing groups were converted to quaternary propargylic ammonium ylides followed by a [2,3]-sigmatropic rearrangement to afford structurally diverse amino-substituted allenes or conjugated dienes, depending on their structure, in moderate to good yields.

Full text of DOI:10.1039/c8cc02176g

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Nucleophilic addition of tertiary propargylic amines to arynes
followed by a [2,3]-sigmatropic rearrangement
Received 00th January 20xx,
Accepted 00th January 20xx
Meng-Guang Zhou, Rui-Han Dai and Shi-Kai Tian*
DOI: 10.1039/x0xx00000x
www.rsc.org/
(a) Previous work:
In the presence of 2-(trimethylsilyl)aryl triflates as aryne
precursors under mild conditions, a range of tertiary propargylic
amines bearing electron-withdrawing groups were converted to
quaternary propargylic ammonium ylides followed by a [2,3]-
sigmatropic rearrangement to afford structurally diverse amino-
substituted allenes or conjugated dienes, depending on their
structure, in moderate to good yields.
R1 R5
N
R5
N
R2
R3
A: 1) R4X; 2) base
[2,3]
R1
R1
C
N
R6
EWG
B: N2=CHEWG
Rh (Ru, Fe, or Cu)
R6
R1
EWG
EWG = electron-withdrawing group
R5
N
EWG
R6
Owing to charge acceleration, conversion of tertiary
propargylic amines to quaternary propargylic ammonium
ylides permits a [2,3]-sigmatropic rearrangement under mild
conditions to afford amino-substituted allenes and/or
conjugated dienes depending on their structure and reaction
conditions (Scheme 1, a).1 It is noteworthy that such type of
amino-substituted allenes and conjugated dienes serve as
versatile building blocks in chemical synthesis through
transformations such as carbonylation and cycloaddition.2
There are two approaches reported previously to access
quaternary propargylic ammonium ylides for the [2,3]-
sigmatropic rearrangement: (1) N-alkylation of tertiary amines
followed by treatment with bases;3 and (2) metal carbenoid-
mediated coupling between tertiary propargylic amines and
diazo compounds.4 These approaches rely on the introduction
of alkyl groups to the nitrogen atom of tertiary amines to
access quaternary propargylic ammonium ylides. To expand
the scope for the [2,3]-sigmatropic rearrangement of
quaternary propargylic ammonium ylides, we have developed
a new strategy to execute the rearrangement through N-
arylation of tertiary propargylic amines without the presence
of strong bases and metals (Scheme 1, b).
(b) This work:
R
R
R1
N
R
N
N
R1
R1
R2
R2
R2
EWG
EWG
EWG
R
R
R1
R1
N
N
[2,3]
C
EWG
EWG
R2
R2
Scheme 1 [2,3]-Sigmatropic rearrangement of quaternary propargylic
ammonium ylides.
Recently, we5 and others6 reported that arynes and tertiary
allylic amines can participate in
a
[2,3]-sigmatropic
rearrangement under mild conditions. Inspired by this
discovery, alongside our interest in synthetic exploration of
C─N bond cleavage,7,8 we envisioned that addition of tertiary
propargylic amines to arynes9 followed by proton transfer
would lead to the formation of quaternary propargylic
ammonium ylides, which would undergo a [2,3]-sigmatropic
rearrangement to afford amino-substituted allenes (Scheme 1,
b). In exposure to bases, some of the allene products would
further isomerize to conjugated dienes.3
Using 2-(trimethylsilyl)phenyl triflate (2a) as a benzyne
precursor,10 we surveyed a few readily available fluoride
sources in the model reaction of tertiary propargylic amine 1a
in acetonitrile at room temperature and found that the
combined use of KF and 18-crown-6 afforded conjugated diene
4a in the best yield, 49%, with >99:1 Z/E selectivity (Table 1,
entry 5). Allene 3a was not obtained probably due to its ready
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isomerization to diene 4a in exposure to the remaining
fluoride source, a basic salt. We then examined a number of
solvents, and to our delight, found that performing the
reaction in ethylene glycol diethyl ether enhanced the yield to
65% without erosion of stereoselectivity (Table 1, entry 10).
Increasing the reaction scale from 0.20 mmol to 11.6 mmol
gave a slightly lower yield (58%). When the temperature was
Entry
1
R
EWG
4
Yieldb (%) Z/Ec
1
1a Me
1b Me
1c Me
1d Me
1e Me
CO2Et
CO2Bn
4a 65
4b 61
4c 62
4d 60
4e 52
>99:1
>99:1
>99:1
>99:1
70:30e
2
3d
elevated to 60 °C, the reaction gave a comparable yield, 66%
(Table 1, entry 15).
t
CO2 Bu
4
COPh
CN
Table 1 Optimization of the reaction conditionsa
5
6
1f Me
1g nBu
4f 49
>99:1
7
8
9
a
CO2Et
4g 70
4h 62
>99:1
95:5
96:4
1h propargyl CO2Et
1i CH2CO2Et CO2Et
4i
43
Entry F- source
Solvent
MeCN
Yieldb (%)
47
Z/Ec
Reaction conditions:
1 (0.20 mmol), 2a (0.24 mmol), KF (0.40 mmol),
b
18-crown-6 (0.40 mmol), EtOCH2CH2OEt (1.0 mL), rt, 6 h. Isolated
1
Bu4NFd
>99:1
-
yield. c Determined by H NMR spectroscopic analysis. d KF/18-crown-6
1
e
(0.60 mmol) was used and the reaction was run for 12 h. The two
stereoisomers are separable on silica gel chromatography.
2
CsF
MeCN
Trace
38
3
CsF/18-crown-6
KF
MeCN
>99:1
-
4
MeCN
0
In sharp contrast, allenes rather than conjugated dienes
were obtained from the reaction of tertiary internal
5
KF/18-crown-6
KF/18-crown-6
KF/18-crown-6
KF/18-crown-6
KF/18-crown-6
KF/18-crown-6
KF/18-crown-6
KF/18-crown-6
KF/18-crown-6
KF/18-crown-6
KF/18-crown-6
MeCN
49
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
-
6
DMF
28
propargylic amines with 2-(trimethylsilyl)phenyl triflate (2a
)
7
THF
55
under the same conditions (Table 3). In these cases, the allene
products were stable under the standard reaction conditions
and obviated isomerization to conjugated dienes. The
electron-withdrawing group in a suitable internal tertiary
propargylic amine could be an ester group, an amide group or
8
Dioxane
Et2O
46
9
10
10
11
12
13
14
15e
a
EtOCH2CH2OEt
Diglyme
CH2Cl2
65
56
42
a
benzoxazole group. Although amides were reported
ClCH2CH2Cl
PhMe
17
previously to undergo addition11 or insertion12 to arynes, in
our case they were well tolerated due to their much lower
nucleophilicity relative to tertiary amines. We also examined
the reaction with the corresponding substrate having a ketone
group or a cyano group, but unfortunately, observed a
complex mixture. Interestingly, very high site selectivity was
observed in the reaction with amine 1n, wherein the N-(3-
phenylprop-2-yn-1-yl) group participated in the [2,3]-
sigmatropic rearrangement and the N-(prop-2-yn-1-yl) group
was kept untouched (Table 3, entry 5).
0
EtOCH2CH2OEt
66
>99:1
Reaction conditions: 1a (0.20 mmol), 2a (0.24 mmol), F- source (0.40
b
mmol), 18-crown-6 (if any, 0.40 mmol), solvent (1.0 mL), rt, 6 h.
Isolated yield. Determined by 1H NMR spectroscopic analysis.
A
c
d
solution of Bu4NF (1.0 M) in THF was used. e The reaction was run at 60
C.
°
A range of tertiary terminal propargylic amines bearing
various electron-withdrawing groups were examined in the
reaction with 2-(trimethylsilyl)phenyl triflate 2a in the
(
)
Table 3 Benzyne-mediated [2,3]-sigmatropic rearrangement of tertiary
internal propargylic aminesa
presence of KF/18-crown-6 at room temperature, and the
corresponding conjugated dienes were obtained in moderate
to good yields (Table 2, entries 1-6). While excellent
stereoselectivity was observed for a substrate having an ester
group, a ketone group, or a benzoxazole group, the reaction
with
a substrate having a cyano group exhibited low
stereoselectivity. We also examined the reaction with a
substrate having an amide group but observed a complex
mixture. Other than a simple alkyl group, a propargyl group or
an ethoxycarbonylmethyl group was also successfully
introduced as a functionalized N-substituent, which did not
participate in the rearrangement (Table 2, entries 8 and 9).
Yieldb
(%)
Entry
1
R1
R2
EWG
3
1
2c
1j
Me
Me
Ph
Ph
CO2Et
3b 70
1k
3c 62
O
3
1l
Me
Ph
Ph
3d 47
N
4
5
1m nBu
CO2Et
3e 75
3f 64
Table 2 Benzyne-mediated [2,3]-sigmatropic rearrangement of tertiary
terminal propargylic aminesa
1n propargyl Ph
CO2Et
2 | J. Name., 2012, 00, 1-3
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6
7
8
9
10
a
1o CH2CO2Et Ph
CO2Et
CO2Et
3g 63
3h 75
3i 72
3j 70
3k 43
Table 4 Aryne-mediated [2,3]-sigmatropic rearrangement of amine 1ja
1p Me
1q Me
4-MeOC6H4
4-EtO2CC6H4 CO2Et
1r
1s
Me
Me
2-MeC6H4
Me
CO2Et
CO2Me
Reaction conditions: 1 (0.20 mmol), 2a (0.24 mmol), KF (0.40 mmol),
b
18-crown-6 (0.40 mmol), EtOCH2CH2OEt (1.0 mL), rt, 6 h. Isolated
c
yield. The structure of compound 3c was confirmed by single crystal
X-ray analysis (CCDC 1534313).
The benzyne-mediated [2,3]-sigmatropic rearrangement
was successfully extended to some N-propargylic cyclic amines
(Scheme 2). Although an elevated temperature (60
required in the reaction of an N-propargylic piperazin-2-one
1t or 1u), the amide group was kept untouched. We further
°C) was
(
applied the chemistry to optically active tertiary propargylic
amines, L-pipecolinic acid derivatives 1v and 1w, and observed
significant erosion of enantiopurity in the construction of
nitrogen-substituted
quaternary
stereocenters.
The
unsatisfactory efficiency of chirality transfer was attributable
to the low diastereoselective attack of the cyclic tertiary amine
on the benzyne intermediate, generated in situ from 2-
Entry
2
3
Yieldb (%)
(trimethylsilyl)phenyl triflate
configuration was determined by catalytic hydrogenation of
allene product 3n to afford α-amino ester , which was also
prepared from a known chiral compound, unsaturated α-
amino ester 6 5
(2a). The inversion of
1
2
3
4
5
a
2b
2c
2d
2e
2f
3p
62
47
42
57
45
3q/3q' (56:44)c
5
3r
3s
3t
.
Reaction conditions: 1j (0.20 mmol),
2
(0.24 mmol), KF (0.40 mmol),
b
18-crown-6 (0.40 mmol), EtOCH2CH2OEt (1.0 mL), rt, 6 h. Isolated
yield. c Determined by 1H NMR spectroscopic analysis.
In summary, we have established a new strategy for the
[2,3]-sigmatropic rearrangement of quaternary propargylic
ammonium ylides via nucleophilic addition of tertiary
propargylic amines to arynes under mild conditions. In the
presence of 2-(trimethylsilyl)aryl triflates as aryne precursors,
a range of tertiary propargylic amines bearing electron-
withdrawing groups were converted to quaternary propargylic
N
CO2Me
C
KF/18-crown-6 (1:1)
THF, rt, 6 h
2a
+
R
N
MeO2C
R
Ph
1v, R = H, >99% ee
1w, R = Me, >99% ee
3n, R = H, 42%, 72% ee
3o, R = Me, 74%, 73% ee
ammonium ylides followed by
a
[2,3]-sigmatropic
rearrangement to afford structurally diverse amino-
substituted allenes or conjugated dienes, depending on their
structure, in moderate to good yields. It is noteworthy that the
reaction proceeds in the absence of strong bases and metals, is
compatible with moisture and air, and tolerates a wide variety
of functional groups.
Scheme 2 N-Propargylic cyclic amines.
We are grateful for the financial support from the National
Natural Science Foundation of China (21772182 and
21472178), the National Key Basic Research Program of China
(2014CB931800), and the Strategic Priority Research Program
of the Chinese Academy of Sciences (XDB20000000).
A few 2-(trimethylsilyl)aryl triflates bearing either electron-
donating groups or electron-withdrawing groups were
demonstrated to serves as suitable aryne precursors in the
reaction of tertiary propargylic amine 1j (Table 4). The
regioselectivity highly depends on the position of substituents
in the in situ generated unsymmetrical arynes. While the
reaction with 4-methylbenzyne gave poor regioselectivity
(Table 4, entry 2), a single regioisomer was obtained from the
reaction with 3-methoxybenzyne (Table 4, entry 1).
Conflicts of interest
There are no conflicts to declare.
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8
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