Synthesis of Halogenated Cyclic Enamines from Cyclic N-2-En-4-ynyl-N-1-ynylamides and N-Propargyl-N-1-ynylamides via a Tandem Iron Halide Promoted N-to-C Shift-Aza-Prins Cyclization Sequence

Article abstract of DOI:10.1002/adsc.201801469

A facile and efficient N-to-C allyl shift-aza-Prins cyclization sequence of cyclic N-2-en-4-ynyl-N-1-ynylamides is promoted by iron(III) chloride, generating chloro-containing bridged bicyclic enamines in minutes and in high yields. This reaction involves an unprecedented formation of a ketenimine via Fe(III)-mediated N-to-C allyl rearrangement, followed by aza-Prins cyclization. This sequence can also be applied to the generation of brominated cyclobutenamine derivatives using Fe(III) bromide and N-propargyl-N-1-ynylamides. (Figure presented.).

Full text of DOI:10.1002/adsc.201801469

Title: Synthesis of Halogenated Cyclic Enamines from Cyclic N-2-
En-4-ynyl-N-1-ynylamides and N-Propargyl-N-1-ynylamides via a
Tandem Iron Halide Promoted N-to-C Shift–Aza-Prins Cyclization
Sequence
Authors: Ming-Chang Yeh, Hsin-Hui Lin, Tai-Ching Chiang, Rong-Xuan
Wu, Yi-Mei Chang, Hao-Wen Wong, and Ssu-Ting Liu
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using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
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the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801469
Link to VoR: http://dx.doi.org/10.1002/adsc.201801469

10.1002/adsc.201801469
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Synthesis of Halogenated Cyclic Enamines from Cyclic N-2-En-
4-ynyl-N-1-ynylamides and N-Propargyl-N-1-ynylamides via a
Tandem Iron Halide Promoted N-to-C Shift–Aza-Prins
Cyclization Sequence
Hsin-Hui Lin,a Tai-Ching Chiang,a Rong-Xuan Wu,a Yi-Mei Chang,a Hao-Wen Wang,a
Ssu-Ting Liu,a and Ming-Chang P. Yeh a*
a
Department of Chemistry, National Taiwan Normal University, 88 Ding-Jou Road, Sec. 4, Taipei 11677, Taiwan, R.O.C.
Fax: (+886)-2-29324249; e-mail: cheyeh@ntnu.edu.tw.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
of N-allyl ynamides would be to employ a simple
Abstract. A facile and efficient N-to-C allyl shift–aza-
Prins cyclization sequence of cyclic N-2-en-4-ynyl-N-1-
ynylamides is promoted by iron(III) chloride, generating
chloro-containing bridged bicyclic enamines in minutes and
in high yields. This reaction involves an unprecedented
formation of a ketenimine via Fe(III)-mediated N-to-C allyl
rearrangement, followed by aza-Prins cyclization. This
sequence can also be applied to the generation of
brominated cyclobutenamine derivatives using Fe(III)
bromide and N-propargyl-N-1-ynylamides.
Lewis acid. Here we report a facile synthesis of
chlorinated
bridged
bicyclic
enamines
in
stereoselective fashion via a novel iron(III) chloride
promoted N-to-C allyl shift–aza-Prins cyclization
sequence. Moreover, this strategy can be applied to
the synthesis of brominated cyclobutenamine
derivatives from N-propargyl-N-1-ynylamides and
iron(III) bromide.
Previous work:
Keywords: Rearrangement; Cyclization; Halogenation
(a) Palladium-catalyzed N-to-C allyl shift of N-allyl ynamides
(Hsung’s group[4]
)
Ynamides are versatile and useful building blocks for
the synthesis of biologically important molecules.[1]
In the presence of activating reagents, ynamides
deliver reactive keteniminium ion intermediates,
which upon trapping with a tethered π-nucleophile at
the α-position lead to nitrogen-containing cyclic
compounds.[2] Alternatively, reactive ketenimines can
be generated from ynamides by thermal aza-Claisen
rearrangement of N-allyl ynamides[3] or palladium-
catalyzed N-to-C allyl shift of N-allyl ynamides[4] or
decarboxylative allyl rearrangement of N-alloc
ynamides (Scheme 1).[5] These reactive ketenimines[6]
can further be trapped by enamines intermolecularly
(b) Palladium-catalyzed decarboxylative allyl rearrangement of
N-alloc ynamides (Cook’s group[5]
)
This work:
to give amidines[4a–b] or
a
tethered olefin
Iron halide promoted N-to-C shift of cyclic N-2-en-4-ynyl-N-1-
ynylamides
intramolecularly to afford cyclic imines.[4c–e] The key
step of the palladium-catalyzed rearrangement of N-
allyl ynamides starts with an oxidative addition of
Pd(0) to the C–N bond to form an ynamido-Pd-π-allyl
complex, which undergoes an N-to-C allyl migration
followed by reductive elimination to form
ketenimines.[3a] However, these palladium-catalyzed
allylic migrations normally requires heating the
reaction mixture up to 80 °C for 5–8 h.[4b] Moreover,
in some cases, the transformations need additional
phosphine ligands such as xantphos or BINAP.[4e] We
envisioned that an easier route for N-to-C allyl shift
Scheme 1. Synthesis of ketenimines from ynamides
1
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10.1002/adsc.201801469
Advanced Synthesis & Catalysis
b)
b)
6
7
8
9
10
11
12
FeCl3
FeCl3
AlCl3
FeBr3
FeCl2
InCl3
1.5
1.5
1.5
1.5
1.5
1.5
THF
ether
30
24
24
0
40
24
30
30
12 h
–
–
The synthesis of the parent six-membered ring N-2-
en-4-ynyl-N-1-ynylamide 1a was achieved starting
from cyclohexane-1,3-dione using the known
procedures (see Supporting Information for details).
First, a screen of Lewis acids was undertaken, while
CH2Cl2 was employed as the solvent under an
atmosphere of N2 (Table 1). Upon treatment with 1.1
equiv of FeCl3 at rt for 1 min, 1a was transformed
into the chlorine-containing bicyclo[3.2.1]octenamine
2a in 40% yield (Table 1, entry 1). The structure and
relative stereochemistry of 2a were confirmed by X-
ray diffraction analysis.[7] Upon increasing the
loading of FeCl3 from 1.1 to 1.5 equiv, the yield of 1a
increased from 40 to 65% (Table 1, entry 2).
Pleasingly, the yield of 2a could be considerably
improved to 83% when the reaction temperature was
lowered to 0 °C (Table 1, entry 3). The reaction
completed in 5 min at –10 °C. However, the yield of
2a did not increase (Table 1, entry 4). The use of
FeCl3 in several solvents such as toluene, THF or
ether did not result in better yields (Table 1, entries
5–7).
Other Lewis acids, for example, AlCl3, FeBr3, FeCl2,
TMSCl, and InCl3 were also screened. Among them,
only AlCl3 and FeBr3 gave low conversions to the
cyclized product 2a and the corresponding
brominated bridged bicyclic enamine, respectively
(Table 1, entries 8 and 9). In the presence of FeCl2
and InCl3, 1a underwent decomposition (Table 1,
entries 10 and 11). Treatment of 1a with TMSCl in
CH2Cl2 resulted in recovery of the starting substrate
(Table 1, entry 12). Subjection of 1a to ZnCl2 (1.5
equiv) in CH2Cl2 at r.t. for 2 h gave a mixture of
unidentified compounds (Table 1, entry 13).
Moreover, when the five-membered ring analogue 3a
was treated with 6 M aq HCl (9 equiv), a mixture of
the E and Z isomers of the corresponding -chloro
enamides was isolated.[8] Therefore, the use of 1.5
equiv of FeCl3 in CH2Cl2 at 0 °C is considered to be
the optimal reaction conditions for the transformation
of 1a to 2a (Table 1, entry 3).
20 min
5 min
1 min
12 h
1 min
15 h
CH2Cl2
CH2Cl2
THF
CH2Cl2
CH2Cl2
CH2Cl2
26
16c)
b)
–
–
–
–
b)
d)
TMSCl 1.5
ZnCl2 1.5
b)
13
2 h
a)
b)
Isolated yields from column chromatography over silica gel.
Not detected. The corresponding bromide was isolated. d)1a
c)
was recovered quantitatively.
With optimum reaction conditions established, the
scope of the FeCl3-promoted N-to-C allyl shift–aza-
Prins cyclization sequence was explored. Table 2
summarized the results that were obtained with a
variety of cyclic N-2-en-4-ynyl-N-1-ynylamides. The
scope with respect to the substitution on the ynamide
fragment was first investigated. Ynamides 1a–e,
bearing an electron-neutral aryl group on the ynamide
terminus, smoothly delivered the corresponding
products 2a–e in good yields (71–83%, Table 2,
entries 1–5). Substrate 1f, featuring a fluorine atom
on the phenyl ring, was unaffected and delivered the
desired product 2f in 74% yield (Table 1, entry 6).
Other halogen substituents like Cl (1g) and Br (1h)
were less efficient and afforded the corresponding
products 2g and 2h in 45 and 44% yield, respectively
(Table 2, entries 7–8). Adding an electron-
withdrawing ester group to the phenyl group, 1i, gave
the expected product 2i in 54% yield (Table 2, entry
9), whereas placing an electron-donating methoxy
group at C4 of the phenyl ring, 1j, (Table 2, entry 10)
failed to deliver any cyclized product. When 3-
thienyl-substituted ynamide 1k was treated with
FeCl3 (Table 2, entry 11), a 49% yield of the desired
product 2k was achieved. Alkyl substituents at the
ynamide terminus, 1l–o, were suited for the
transformation, furnishing the corresponding
chlorinated bicyclic enamines 2l–o in good yields
(65–82%, Table 2, entries 12–15). The influence of
the substituent (R2) at the alkyne fragment was next
surveyed while keeping the phenyl group at the
ynamide terminus fixed. As can be seen from Table 2,
entries 16–18, both aryl (1p, 1q) and alkyl (1r)
substituents at the alkyne terminus are efficient and
produced the expected chlorinated bridged bicyclic
enamines (2p[7]–r) in high yields (73–82%).
Moreover, five-membered ring substrates 3a–e
(Table 2, entries 19–23) also underwent the N-to-C
allyl shift–aza-Prins cyclization effectively to give
the corresponding bicyclic enamines 4a–e in good
yields (54–75%).
Table 1. Optimization of the Iron-Promoted Chlorinated
Bridged Bicyclic Enamines Formation
entry
Lewis
acid
equiv
solvent
t
time
yield
(%)a)
(°C)
1
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
1.1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
26
27
0
-10
25
1 min
1 min
1 min
5 min
3 min
40
65
83
75
16
2
3
4
5
1.5
1.5
1.5
1.5
2
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10.1002/adsc.201801469
Advanced Synthesis & Catalysis
Table 2. Substrate Scope
(path b). Miller reported the formation of 8-
chlorobicyclo[3.2.1]oct-6-ene derivatives by zinc
chloride catalyzed [3+2] cycloaddition of cyclic
allylic chlorides to alkynes.[10] It must be noted that
the stabilization by the conjugated π systems of the
phenylalkyne at C3 of the six-membered ring was
critical since the substrate with a simple methyl group
at C3 did not undergo the N-to-C allyl shift reaction
path.[11]
To further prove the proposed intermolecular N-to-
C allyl shift, a crossover experiment in which an
equimolar mixture of ynamides 1l and 1q was
subjected to the optimal reaction conditions and the
ratio of the products was examined by NMR
spectroscopy (Scheme 3). The analysis of the spectra
clearly indicates that four possible products 2l (22%)
and 2q (18%), 2a (11%), and 2m (14%) were
obtained. This result consists with an intermolecular
allyl transfer process, which involves a detachment–
re-addition sequence of iron-ketenimine moiety 7 to
the allylic carbon center depicted in path a, Scheme 2.
entry subs-
n
R1
R2
prod- yield
uct
trate
(%)a)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2ab)
2b
2c
2d
2e
2f
2g
2h
2i
83
82
71
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
1
3-MeC6H4
4-MeC6H4
4-PhC6H4
naphth
4-FC6H4
4-ClC6H4
4-BrC6H4
75
76
74
45
44
54
9
10
11
3-CO2MeC6H4 Ph
4-OMeC6H4 Ph
c)
1j
1k
1l
2j
–
3-thienyl
n-hexyl
3-Cl-propyl
n-hexyl
n-hexyl
Ph
Ph
Ph
Ph
4-MeC6H4
4-ClC6H4
n-hexyl
3-Cl-propyl
Ph
Ph
Ph
4-ClC6H4
2k
2l
2m
2n
49
82
82
12
13
14
15
16
17
18
19
20
21
22
1m
1n
1o
1p
1q
1r
3a
3b
3c
3d
77
65
82
73
73
64
57
54
65
3-CO2EtC6H4 2o
3-CO2EtC6H4 2pb)
4-ClC6H4
n-hexyl
Ph
Ph
Ph
Ph
Ph
2q
2r
4a
4b
4c
4d
1
1
1
1
23
3e
4eb)
75
a) Isolated yields from column chromatography over silica gel. b)
The structure was confirmed by X-ray diffraction analysis. c) Not
detected.
Scheme 2. Proposed Mechanism for the Formation of 2a
from 1a
A postulated mechanism for the transformation of
cyclic
N-2-en-4-ynyl-N-1-ynylamide
1a
to
chlorinated bridged bicyclic enamine 2a is outlined in
Scheme 2. Activation of the ynamide moiety in 1a by
FeCl3 leads to keteniminium ion 5 (path a).
Subsequently, detachment of the iron-ketenimine
moiety generates the stable allylic carbonium ion 6.
Re-addition of the iron-ketenimine 7 at the allylic
carbon followed by activation of the resulting
ketenimine with iron chloride gives intermediate 8,
which undergoes an aza-Prins cyclization[9] to furnish
the chlorinated bridged bicyclic enamine 2a.
However, an alternative mechanism can also be
considered (path b). Complexation of FeCl3 to the
NTs group may cause the detachment of iron-
Scheme 3. Crossover Experiment
The synthesis of brominated cyclobut-1-en-1-
amine derivatives from N-propargyl-N-1-ynylamides
can also be demonstrated using the same approach.[12]
The N-propargyl-N-1-ynylamides 9a was easily
prepared starting from commercially available 2-
methyl-3-butyn-2-amine (see Supporting Information
for details). First, 9a was subjected to various
reaction parameters (Lewis acid, solvent, and
temperature). The survey revealed that treatment of
9a with 4.0 equiv of FeBr3 in CH2Cl2 at 0 °C under
an atmosphere of nitrogen for 1 min gave the best
complexed
ynamide/ketenimine
from
the
cyclohexene ring to give allylic carbonium ion 6. A
formal [3+2] cycloaddition between the allylic cation
and the double bond of the ketenimine together with
trapping of the resulting secondary carbocation by a
chloride ion affords an imine intermediate, which
after hydrolysis and tautomerization furnishes 2a
3
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10.1002/adsc.201801469
Advanced Synthesis & Catalysis
12
13
14
15
16
17
9l
3-CO2MeC6H4 Ph
10l
37
33
result (See Supporting Information for details). Thus,
under this optimum reaction conditions, a major
product, identified as the brominated cyclobut-1-en-
1-amine 10a, was obtained in 68% yield (Table 3,
entry 1). The structure of 10a, possessing the Z-
configuration at the exocyclic olefin, was determined
9m
9n
9o
9p
9q
3-OMeC6H4
2-OMeC6H4
4-OMeC6H4
n-hexyl
Ph
Ph
Ph
Ph
Ph
10m
10n
10o
10p
10q
c)
–
–
c)
33
40
3-Cl-propyl
a) Isolated yields from column chromatography over silica gel. b)
The structure was confirmed by X-ray diffraction analysis. c) Not
detected.
1
with H NMR measurements and further confirmed
by X-ray crystallography.[7] With the optimal reaction
conditions in hand, the scope of this transformation
with respect to substitutions of both ynamide and
alkyne termini was explored. Results of the formation
of brominated cyclobut-1-en-1-amine derivatives
from N-propargyl-N-1-ynylamides are shown in
Table 3. In general, electron-neutral aryls on both
ynamide and alkyne termini were accommodated,
affording the desired products 10a–e in good yields
(51–68%, Table 3, entries 1–5). The halogen-
containing substrates, 9f–k, were also tolerated,
generating the anticipated brominated cyclic
enamines 10f–k in 46–83% isolated yields (Table 3,
entries 6–11). However, a lower yield of 10l was
obtained in the reaction of 9l, which is substituted
with an electron-withdrawing ester group at C3 of the
phenyl group on the ynamide terminus (37%, Table 3,
entry 12). The low yield was also found with
substrate 9m bearing an electron-donating methoxy
group at C3 of the phenyl ring on the ynamide
terminus (33%, Table 1, entry 13). Unfortunately,
running the reaction with substrates bearing a
methoxy group at C2 or C4 of the phenyl ring on the
ynamide moiety led to complete decomposition upon
treatment with FeBr3 (Table 3, entries 14–15).
Moreover, substrates with an alkyl substitution at the
ynamide terminus, 9p and 9q, were also reactive,
providing the desired compounds 10p and 10q, albeit
with diminished yields (33–40%, Table 3, entries 16–
17).
A formal alkyne aza-Prins cyclization reaction
path[13] is suggested for the formation of
cyclobutenamine 10a (Scheme 4). An N-to-C
propargyl shift of 9a with FeBr3 leads to ketenimine
11. Coordination of the iron center to both the alkyne
and the nitrogen atom provides intermediate 12,
which enables a syn-carbobromination of the alkyne,
furnishing cyclobut-1-en-1-amine[14] 10a possessing
the Z-configuration at the newly formed exocyclic
olefin after aqueous workup. It must be mentioned
that Fe(III) halides are known to promote alkynes
aza-Prins-type cyclization.[9a] Alternatively, an iron
bromide assisted SN2' type attack of a bromide on the
phenylacetylene affords a bromoallene and an iron-
complexed ynamide/ketenimine. A formal [2+2]
cycloaddition of the allene with the ketenimine gives
an imine, which then undergoes hydrolysis and
tautomerization to generate 10a (path b, Scheme 4).[15]
Table 3. Substrate Scope
Scheme 4. Proposed Mechanism for the Formation of 10a
from 9a
entry
substrate R1
R2
product yield
(%)a)
Six-membered ring N-propargyl-N-1-ynylamides
13 also reacts with FeBr3 under the same reaction
conditions to produce spiro compounds 14 and 15
(Scheme 5). Thus, treatment of 13a with 2.2 equiv of
FeBr3 at 0 °C in CH2Cl2 for 1 min gave a 44% yield
of spiro imine[16] 15a,[7] which was formed after an
endo to exo double-bond migration of the initial
formed spiro enamine 14a. Moreover, while
compounds 13b–d gave only spiro enamines 14b[7]–d
(51–75%), substrate 13e afforded both spiro-enamine
14e[7] and -imine 15e in 40 and 33% yield,
respectively.
1
2
3
4
5
6
7
8
9
10
11
9a
9b
9c
9d
9e
9f
9g
9h
9i
Ph
Ph
Ph
Ph
10ab)
10bb)
10c
68
55
51
2-MeC6H4
4-MeC6H4
Ph
2-MeC6H4
2-BrC6H4
4-ClC6H4
2-BrC6H4
Ph
2-MeC6H4 10d
65
57
57
75
60
46
60
83
2-MeC6H4 10eb)
Ph
Ph
10f
10g
2-MeC6H4 10h
4-ClC6H4
4-ClC6H4
4-ClC6H4
10i
10j
10k
9j
9k
2-MeC6H4
4-ClC6H4
4
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10.1002/adsc.201801469
Advanced Synthesis & Catalysis
1
Spectroscopic characterization and copies of H/13C NMR
spectra of compounds 1a–r, 2a–r, 3a–e, 4a–e, 9a–q, 10a–
q, 13a–e, 14b–e, 15a, 15e and X-ray crystallographic
information files for compounds 2a, 2p, 4e, 10a, 10b, 10e,
14b, 14e and 15a are available as supporting information.
Acknowledgements
The authors thank the Ministry of Science and Technology of the
Republic of China (MOST 106-2113-M-003-001) for financial
support.
Scheme 5. Synthesis of 14 and 15
References
In conclusion, we have developed a new approach
of N-to-C shift–aza-Prins cyclization tandem process
from cyclic N-2-en-4-ynyl-N-1-ynylamides and N-
propargyl-N-1-ynylamides. The reactions convert a
wide range of π-tethered ynamides to halogenated
cyclic enamines with iron(III) halides. This method is
advantageous as it employs inexpensive iron halides
under mild reaction conditions in short reaction times
and in good to high yields.
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Experimental Section
Synthesis of N-((1R*,5R*,8R*)-8-Chloro-7-phenyl-5-
(phenylethynyl)bicyclo[3.2.1]oct-6-en-6-yl)-4-methyl-
benzenesulfonamide (2a).
To a fire-dried 2-neck-round flask with a stir bar were
added FeCl3 (0.06 g, 0.375 mmol, 1.5 equiv) and CH2Cl2
(20.0 mL); the mixture was then cooled to 0 °C. A solution
of 1a (0.11 g 0.250 mmol, 1.0 equiv) in CH2Cl2 (5.0 mL)
was added to the mixture. After complete consumption of
the starting material (TLC, 1 min), the reaction mixture
was quenched with NEt3 (3.0 mL). The resulting mixture
was filtered thought a pad of Celite/silica gel/Celite and
concentrated under reduced pressure. Purification of the
residue by flash column chromatography (silica gel, ethyl
acetate/hexanes 1:10) gave 2a as a white solid; yield: 0.10
g (0.208 mmol. 83%).
Synthesis of (Z)-N-(4-(Bromo(phenyl)methylene)-3,3-
dimethyl-2-phenylcyclobut-1-en-1-yl)-4-
methylbenzenesulfonamide (10a) .
To a flame-dried 2-neck-round flask with a stir bar were
added FeBr3 (0.33 g, 1.00 mmol) and CH2Cl2 (4.0 mL).
The mixture was cooled to 0 °C. Ynamide 9a (0.10 g, 0.25
mmol) in CH2Cl2 (1.0 mL) was added to the mixture. After
complete consumption of the starting material (monitored
by TLC), the reaction mixture was quenched with NEt3
(5.0 mL). The resulting mixture was filtered thought a pad
of Celite/silica gel/Celite and concentrated under reduced
pressure. Purification of the residue by flash column
chromatography (ethyl acetate/hexanes 1:20) gave
compound 10a as a white solid; yield: 0.08 g (0.17 mmol,
68%).
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Supporting Information
5
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10.1002/adsc.201801469
Advanced Synthesis & Catalysis
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(10b), CCDC-1860504 (10e), CCDC-1553020 (14b),
CCDC-1862840 (14e), and CCDC-1551553 (15a)
contain the supplementary crystallographic data for
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6
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10.1002/adsc.201801469
Advanced Synthesis & Catalysis
COMMUNICATION
Synthesis of Halogenated Cyclic Enamines from
Cyclic N-2-En-4-ynyl-N-1-ynylamides and N-
Propargyl-N-1-ynylamides via a Tandem Iron
Halide Promoted N-to-C Shift–Aza-Prins
Cyclization Sequence
Adv. Synth. Catal. Year, Volume, Page – Page
Hsin-Hui Lin, Tai-Ching Chiang, Rong-Xuan Wu,
Yi-Mei Chang, Hao-Wen Wang, Ssu-Ting Liu, and
Ming-Chang P. Yeh*
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