Iron-Catalyzed Synthesis of α-Dienyl Five- and Six-Membered N-Heterocycles

Article abstract of DOI:10.1002/ejoc.201700977

The iron-catalyzed synthesis of α-dienyl N-heterocycles is reported. The method is cost-effective, atom-economic, and led to a range of substituted α-dienyl heterocycles in moderate to good yields and diastereoselectivities. The α-dienyl piperidines are key synthetic intermediates as demonstrated by the preparation of a panel of α-polyenyl N-heterocycles.

Full text of DOI:10.1002/ejoc.201700977

DOI: 10.1002/ejoc.201700977
Full Paper
Iron Catalysis
Iron-Catalyzed Synthesis of α-Dienyl Five- and Six-Membered
N-Heterocycles
Laurine Gonnard,[a] Amandine Guérinot*[a] and Janine Cossy*[a]
Abstract: The iron-catalyzed synthesis of α-dienyl N-heterocy- erate to good yields and diastereoselectivities. The α-dienyl
cles is reported. The method is cost-effective, atom-economic, piperidines are key synthetic intermediates as demonstrated by
and led to a range of substituted α-dienyl heterocycles in mod- the preparation of a panel of α-polyenyl N-heterocycles.
Introduction
the construction of α-polyenyl-substituted piperidines. Intramo-
lecular Mannich reaction of iminoacetals that already incorpo-
rate a protected diene has been used to access α-dienyl piper-
idines.[7] These cyclization reactions generally required relatively
harsh acidic conditions and high temperatures. One example of
double amination between a keto-aldehyde with the coordi-
nated diene motif and a primary amine were also reported to
synthesize the substituted N-heterocycles.[8,9] In most synthe-
ses, the polyenic fragment is introduced at a late stage gener-
ally from piperidino-aldehydes D. Wittig, Horner–Wadsworth–
Emmons (HWE), and Julia olefination reactions are commonly
employed but mixtures of (E,E)- and (E,Z)-dienes are often
observed.[10,11] This lack of stereocontrol associated with the
formation of stoichiometric amounts of by-products generally
result in moderate yields and troublesome purifications
(Scheme 1).
Five- and six-membered ring N-heterocycles are present in a
myriad of bioactive natural products[1] and among them, α-
polyenyl-substituted piperidines constitute an important class of
alkaloids. For example, corydendramine A and B,[2] micro-
grewiapine A,[3] and microcosamine A and B[4] are trisubstituted
piperidines that only differ by the nature of the N- and polyenyl
substituents. Microgrewiapine A is an antagonist of some
nicotinic receptors, whereas microcosamine A and B display in-
secticidal activity. Alkaloid (–)-SS20846A is another example of
bioactive α-dienyl piperidine that possesses antibacterial and
anticonvulsant properties.[5] (+)-Dienomycin C is a α-dienyl
trisubstituted piperidine that exhibits a moderate antibiotic ac-
tivity against Mycobacteria (Figure 1).[6]
Figure 1. Bioactive α-polyenyl piperidines.
Scheme 1. Access to α-polyenyl piperidines.
As a result of their biological and pharmacological proper-
ties, these α-polyenyl-substituted piperidines have attracted or-
ganic chemists and numerous syntheses of these compounds
have been described over the last decades. However, examina-
tion of the literature does not bring out a general method for
Consequently, the development of synthetic methods to ac-
cess α-polyenyl-substituted N-heterocycles is still desirable. In
the field of N-heterocycle synthesis by construction of the C–N
bond, metal-catalyzed cyclization of amino allylic alcohol deriv-
atives of type E is particularly attractive in terms of atom-econ-
omy and eco-compatibility. Thus, Pd0-,[12] PdII-,[13] Ir-[14] and
Au-[15]catalyzed cyclization reactions have been used as key
steps in the synthesis of several N-heterocyclic alkaloids.[16] In
2010, our group reported the FeCl3-catalyzed synthesis of piper-
idines from intermediates E (Scheme 2).[17a] The reaction gener-
ally proceeds smoothly with good diastereocontrol and was
[a] Laboratoire de Chimie Organique, Institute of Chemistry, Biology and
Innovation (CBI)-UMR 8231, ESPCI Paris, CNRS, PSL Research University,
10 rue Vauquelin, 75231 Paris Cedex 05, France
E-mail: amandine.guerinot@espci.fr
janine.cossy@espci.fr
www.lco.espci.fr
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201700977.
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then extended to the formation of various heterocycles.[17b] The facilitate the cyclization of conjugated diene 1a′ to 2a. Work
presence of the pendant double bond on cyclized products F realized at higher temperatures (75 and 100 °C) in 1,2-dichloro-
offers functionalization opportunities. Notably, some α-polyenyl ethane did not improve the yield of 2a (Table 1, Entries 4 and
piperidines were prepared from this intermediate after ozonoly- 5).[20] The influence of the solvent was then examined and, to
sis or oxidative cleavage of the alkene followed by olefin- our delight, the reaction carried out at room temp. in CH3CN
ation.[18] In contrast, to our knowledge, no direct metal-cata- gave an excellent yield of 93 % of 2a (Table 1,
lyzed formation of α-dienyl-substituted N-heterocycles from Entry 6).[21] From all these results, CH2Cl2 and CH3CN were se-
amino dienes H has been reported so far. Herein, we report a lected and the scope of the iron-catalyzed cyclization was ex-
FeCl3-catalyzed synthesis of α-dienyl-substituted N-heterocycles amined.
(Scheme 2). The synthetic utility of the method is highlighted
by the subsequent formation of various α-polyenyl N-hetero-
Table 1. Optimization studies for the cyclization of 1a.
cycles.
Entry
t
T [°C]
Solvent
2a (yield)
1a′ (yield)
1
2
3
4
5
6
17 h
r.t.
r.t.
50
75
100
r.t.
CH2Cl2
CH2Cl2
CH2Cl2
(CH2)2Cl2
(CH2)2Cl2
CH3CN
61 %
0 %
20 %, 0 %
0 %
0 %
0 %
10 min
10 min
10 min
10 min
17 h
62 %, 73 %[a]
73 %
57 %
69 %
93 %
0 %
[a] Anhydrous FeCl3 was used.
Scheme 2. Metal-catalyzed cyclization of amino allylic alcohol derivatives E
and H.
Various dienes differing by their substitution pattern on the
C9–C10 double bond were subjected to the cyclization condi-
tions that have been tuned previously. The cyclization was not
restricted to terminal diene as a methyl substituent (R1 = Me,
R2 = H) was well tolerated (Table 2, Entry 1). The corresponding
piperidine was isolated in good to excellent yield depending
on the solvent with an unchanged (E)/(Z) ratio for the C9–C10
double bond. When the methyl was replaced by a phenyl
group, the yield remained satisfying in CH2Cl2 (73 %) but
dropped in CH3CN (58 %; Table 2, Entry 2).[22] Pleasingly, func-
tionalized α-dienyl piperidines that possess either an alkenyl
iodide or an alkenyl tributylstannane could be accessed upon
cyclization of the corresponding dienes (Table 2, Entries 3 and
Results and Discussion
The formation of α-dienyl monosubstituted piperidines from
diene 1a was first investigated to establish the optimized condi-
tions. Based on our previous work, the reaction was carried out
with a catalytic amount of FeCl3·6H2O (5 mol-%) in CH2Cl2.[19]
After 17 h at room temp., the cyclized product was isolated in
a moderate yield of 61 % and only the (E)-isomer was observed
(Table 1, Entry 1). Monitoring the reaction by GC/MS revealed
that complete conversion of 1a could be obtained after just
10 min (Table 1, Entry 2). The desired product was formed in a
similar yield to the one obtained after 17 h at room temp.
(62 %). Interestingly, diene 1a′ that resulted from an isomeriza-
tion of the starting material was also isolated (20 %). When 1a′
was treated with FeCl3·6H2O at room temp., the cyclization reac-
tion was sluggish and produced substituted piperidine 2a in
46 % yield after 2 h (data not shown). Even if 1a′ can led to
piperidine 2a, its formation appears detrimental to the cycliza-
tion process, hypothetically upon coordination of the amino-
alcohol moiety to the iron center and subsequent poisoning of
the catalyst. Because the formation of diene 1a′ from 1a could
result from the presence of water in the reaction medium, the
cyclization was performed with anhydrous FeCl3 (Table 1, En-
try 2). Pleasingly, α-dienyl piperidine 2a was obtained in a good
yield of 73 %. Interestingly, the same yield of 73 % could be
reached in the presence of easy-to-handle FeCl3·6H2O by in-
creasing the temperature to 50 °C (Table 1, Entry 3). Under
these conditions, no conjugated diene 1a′ was detected after
10 min. We hypothesized that heat may either accelerate the
cyclization of 1a, which would avoid its isomerization to 1a′, or
Table 2. Synthesis of α-dienyl monosubstituted piperidines.
Entry
1
1
R1
R2
H
t
Solvent
2 (yield)
1b[a]
Me
17 h
17 h
17 h
17 h
1 h
18 h
2 h
2 h
CH2Cl2
CH3CN
CH2Cl2
CH3CN
CH2Cl2
CH3CN
CH2Cl2
CH3CN
CH2Cl2
CH3CN
2b (74 %)[b]
2b (95 %)[b]
2c (73 %)
2c (58 %)
2d (78 %)
2d (59 %)
2e (56 %)
2e (66 %)
2f (70 %)
2f (88 %)
2
3
4
5
1c
1d
1e
1f
Ph
H
I
H
SnBu3
H
H
Me
17 h
17 h
[a] Prepared as a 1:1 (E)/(Z) mixture for the C9–C10 double bond. [b] Obtained
as a 1:1 (E)/(Z) mixture for the C9–C10 double bond.
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4). These products could be considered as key intermediates cis-piperidine was produced as a unique diastereomer albeit in
toward the formation of α-polyenyl piperidines (vide infra). In- a low yield of 40 % (Table 3, Entry 4). It appears that a compro-
terestingly, in all cases (Table 2, Entries 2–4), the reaction was mise had to be found between high yield and good diastereo-
selective toward the formation of the (E,E)-isomer. In the pres- selectivity and, thus, mixtures of solvents were tested. When
ence of a C9 substituent (R2 = Me), the cyclization proceeded the reaction was carried out in a 1:1 mixture of CH2Cl2 and
smoothly to deliver the corresponding piperidine in 88 % yield CH3CN, after 17 h at room temp. and 17 h at 50 °C, a 55:45
in CH3CN (Table 2, Entry 5).
mixture of cis- and trans-piperidines was observed, which con-
firmed the detrimental role of CH3CN on the diastereoselectivity
of the cyclization. Additional heating at 50 °C for 17 h did not
improve the ratio (Table 3, Entry 5). A mixture of CH2Cl2 with
TFE (1:1) delivered the cis-piperidine with perfect dia-
stereocontrol and with a slightly improved yield relative to
those obtained with CH2Cl2 alone (66 % versus 63 %) (Table 3,
Entry 6). However, as the increase of the yield was not outstand-
ing, simple experimental conditions were favored and the gen-
erality of the reaction was investigated by using either CH2Cl2
or CH3CN.
With the objective of accessing valuable synthons that could
be transformed into α-polyenyl piperidines, diene 1g, which
features an N-methyliminoacetic acid (MIDA) boronate, was pre-
pared. As a result of synthetic concerns the conjugated diene
was prepared.[23] When 1g was treated with FeCl3·6H2O in
CH3CN at room temp., the reaction was slow and did not go to
completion after 12 h.[24] However, by heating the reaction at
50 °C for an additional 5 h, total consumption of the starting
diene occurred and the desired piperidine was isolated in a
good yield of 88 % (Scheme 3).
Table 3. Optimization study for the synthesis of 2,6-disubstituted piperidine
4a.
Scheme 3. Access to a BMIDA-containing α-dienyl piperidine.
Encouraged by these positive results, we then turned our
attention toward the synthesis of 2,6-disubstituted piperidines.
The reactivity of amino-dienol 3a was examined and, as the
diastereoselectivity of the cyclization came into play, optimiza-
tion of the conditions proved to be necessary. The previous
study on the formation of monosubstituted α-dienyl piper-
idines showed that the solvent has an important influence on
the outcome of the reaction and, consequently, a range of sol-
vents was evaluated. In CH2Cl2, after 17 h at room temp., the
expected piperidine was obtained in an excellent diastereo-
meric ratio of 96:4 in favor of the cis product albeit in a moder-
ate yield of 63 % (Table 3, Entry 1).[25] The use of CH3CN instead
of CH2Cl2 completely modified the diastereoselectivity of the
cyclization. After 17 h at room temp., an equimolar ratio of cis-
and trans-piperidine 4a was observed. Interestingly, by heating
the reaction mixture, the diastereomeric ratio improved and
after additional 52 h at 50 °C, cis-4a was formed as the major
product (dr = 83:17) in a good yield of 84 % (Table 3, Entries 2
and 3). To account for this observation, we hypothesized that
the increased temperature may facilitate an iron-induced equili-
bration process between the cis- and trans-piperidine, which
might be inhibited at room temp. in CH3CN. The equilibrium
favors the formation of the most stable cis-diastereomer (vide
supra). Worthy of note, when the mixture of cis-4a and trans-
4a (cis/trans = 83:17) previously obtained in CH3CN was treated
again with FeCl3·6H2O in CH2Cl2, a significant increase of the
diastereomeric ratio was observed (dr > 97:3 after 12 h at room
temp.). Unfortunately, this improved diastereoselectivity went
along with a drop in isolated yield (51 %, see Supporting Infor-
mation for details). As the formation of cationic intermediates
Entry
Solvent
t
T [°C]
dr[a]
4a (yield)
1
2
3
CH2Cl2
CH3CN
CH3CN
17 h
17 h
17 h
+ 52 h
17 h
17 h
+ 17 h
17 h
r.t.
r.t.
96:4
55:45
83:17
63 %
nd
84 %
r.t. then
50 °C
r.t.
r.t. then
50 °C
r.t.
4
5
TFE
> 95:5
55:45
40 %
65 %
CH2Cl2/CH3CN
6
CH2Cl2/TFE
> 95:5
66 %
[a] cis/trans ratio determined by using GC/MS analysis.
Various precursors of α-dienyl disubstituted piperidines were
treated with FeCl3·6H2O (5 mol-%) in CH2Cl2 or CH3CN. The evo-
lution of the diastereomeric ratio was monitored by GC/MS and
the reactions were quenched when a constant value was
reached. In some cases, heat was required to favor the cis/trans
equilibration and increase the diastereomeric ratio. The pres-
ence of a phenyl substituent was tolerated and the correspond-
ing 2,6-disubstituted piperidine was isolated with a satisfying
yield of 66 % and an excellent cis/trans ratio (90:10) (Table 4,
Entry 1). In the presence of a methyl group, after 17 h at room
temp., a moderate 69:31 cis/trans ratio was obtained in CH2Cl2.
The use of heat at 50 °C for 2 h was necessary to reach a good
diastereoselectivity (cis/trans = 94:6; Table 4, Entry 2). Disap-
pointingly, the cyclized product was produced in a moderate
53 % yield. When the same reaction was carried out in CH3CN,
after 17 h at room temp. and 31 h at 50 °C, a moderate dia-
stereomeric ratio was reached (80:20). However, further heating
led to decomposition, which prevented the isolation of the ex-
pected piperidine (Table 4, Entry 3).
The influence of the N-substituent was next investigated. As
was hypothesized (vide infra), the reaction was tested in highly a nosyl group is generally easier to cleave than a tosyl group,
ionizing 2,2,2-trifluoroethanol (TFE). Under these conditions, the cyclization of 3d was attempted. In CH2Cl2 the reaction yielded
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Table 4. Variation of the C2 substituent R4.
were produced in moderate yield (55 and 61 %, respectively)
with acceptable diastereomeric ratio (80:20; Table 5, Entries 3,
5, and 6). In contrast, when CH3CN was used, good yields were
obtained (87 and 80 %) together with poor diastereoselectivity
(70:30 and 65:35) (Table 5, Entries 4 and 7). The presence of
an acetyl group on the nitrogen atom was detrimental to the
cyclization as a mixture of products was formed from 3g in
both CH2Cl2 and CH3CN, probably as a result of poor nucleo-
philicity of the amide moiety (Table 5, Entries 8 and 9).
Entry
3
R4
Solvent
t
T
[°C]
dr[a]
4
(yield)
This iron-catalyzed cyclization of amino-dienols was not re-
stricted to the synthesis of piperidines. It was also suitable to
access α-dienyl tetrahydroquinoline frameworks as attested by
the formation of 6 from 5 in high yield in CH3CN (Scheme 4,
Equation 1). However, the developed conditions did not allow
the preparation of six-membered ring lactams because a com-
plex mixture of products was obtained upon treatment of 7
with FeCl3·6H2O whichever solvent was used. As a result of poor
nucleophilicity of the nitrogen atom, the cyclization did not
proceed and resulted in the formation of several non-identified
by-products (Scheme 4, Equation 2).
1
2
3b Ph
3c Me
CH2Cl2
CH2Cl2
19 h
r.t.
90:10[b]
94:6[b]
4b
(66 %)
4c
17 h
+ 2 h
r.t.
then
50 °C
r.t.
then
50 °C
(53 %)
3[d]
3c Me
CH3CN
17 h
+ 31 h
80:20[c]
nd
[a] cis/trans ratio. [b] Ratio determined by analysis of the crude 1H NMR spec-
trum. [c] Ratio determined by analysis of GC/MS. [d] Decomposition was ob-
served.
the piperidine in 70 % yield with moderate diastereocontrol
(cis/trans = 85:15), whereas an equimolar mixture of cis- and
trans-isomers was obtained in CH3CN even after 22 h at 50 °C
(Table 5, Entries 1 and 2). We hypothesized that the nosyl group
could interfere with the iron-induced equilibration process
upon coordination of the nitro group with the metal catalyst.
Carbamates are compatible with the reaction conditions but
once again a compromise has to be found between good yield
and good diastereoselectivity. In CH2Cl2, piperidines 4e and 4f
Table 5. Variation of the N-substituent.
Scheme 4. Synthesis of other six-membered ring N-heterocycles.
In addition, α-dienyl pyrrolidine 10 was successfully synthe-
sized from the corresponding precursor 9. Nevertheless, as in
the case of 2,6-disubstituted piperidines, we were not able to
find conditions to produce both high yield and diastereoselect-
ivity. In CH2Cl2, the cyclization proceeded in modest yield
(51 %) and great diastereocontrol (dr = 97:3), whereas in CH3CN
the five-membered ring was obtained in an improved yield
(70 %) but without any diastereoselectivity (Scheme 5, Equa-
tion 1). Finally, indoline 12 could be formed by cyclization of
11 (Scheme 5, Equation 2).
Entry
1
3
R3
Solvent
CH2Cl2
t
T
[°C]
dr[a]
4
(yield %)
3d Ns
3d Ns
18 h
+ 5 h
r.t.
85:15
4d (70 %)
4d (46 %)
then
50 °C
r.t.
2
CH3CN
18 h
+ 22 h then
50 °C
50:50
Under iron catalysis, the reactivity of bis-allylic alcohols ap-
pears similar to the reactivity of mono-allylic alcohols or
acetates previously studied for the synthesis of alkenyl piper-
idines.[26] Thus, based on our observations and previous results,
the mechanism depicted in Scheme 6 for the formation of α-
dienyl piperidines can be proposed. The iron catalyst may acti-
vate the bis-allylic alcohol to provide a carbocation, which
could be stabilized by the presence of the diene moiety.[27] In-
tramolecular nucleophilic attack of the nitrogen atom on the
carbocation intermediate may occur at the position that led to
the six-membered ring substituted by a conjugated diene. This
initial nucleophilic attack may proceed in a non-diastereoselec-
tive fashion as confirmed by the low to moderate diastereo-
3
4
5
3e Boc
3e Boc
CH2Cl2
CH3CN
CH2Cl2
17 h
24 h
17 h
+ 2 h
r.t.
r.t.
r.t.
then
50 °C
r.t.
80:20
70:30
60:40
4e (55 %)
4e (87 %)
4f (58 %)
3f
3f
3f
CBz
CBz
CBz
6
7
CH2Cl2
CH3CN
17 h
+ 67 h then
50 °C
17 h
+ 52 h then
50 °C
80:20
65:35
4f (61 %)
4f (80 %)
r.t.
8[b]
9[b]
3g Ac
3g Ac
CH2Cl2
CH3CN
26 h
18 h
r.t.
r.t.
nd
nd
nd
nd
[a] cis/trans ratio determined by analysis of the crude 1H NMR spectrum.
[b] Decomposition was observed.
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Scheme 5. Synthesis of five-membered ring N-heterocycles.
Scheme 7. Heck coupling between 2a and (hetero)aryl iodides. DMF = di-
methylformamide.
meric ratio obtained after a short reaction time. The evolution
of the diastereomeric ratio with time and temperature sug-
gested an iron-induced ring opening/closure of the N-hetero-
cycle to allow a thermodynamic equilibrium to be established.
This equilibration may result in the formation of the most stable
cis-isomer as the major compound. We hypothesized that the
low to moderate diastereoselectivities obtained in CH3CN could
result from coordination of the nitrile to the iron center, which
decreases its ability to mediate the re-opening of the piper-
idine.
enyl iodide. For instance, when 2g, which results from the cycli-
zation of 1g, was treated with alkenyl iodide 17 in the presence
of Pd(OAc)2, SPhos, and NaOH, expected triene 18 was isolated
in a satisfying yield of 59 % (Scheme 8).[29]
Scheme 8. Suzuki coupling on a BMIDA containing α-dienyl piperidine. THF =
tetrahydrofuran.
Piperidines 2d and 2e, that feature an alkenyl iodide and an
alkenyl stannane, respectively, could also be good partners in
metal-catalyzed cross-coupling reactions. A palladium-catalyzed
Suzuki coupling between 2d and alkenyl boronate 19 delivered
triene 20 in 81 % yield. When alkenyl stannane 2e was reacted
in a Stille coupling with alkenyl iodide 17, the corresponding
triene was formed efficiently (60 %) (Scheme 9).[30]
Scheme 6. Hypothetical mechanism.
To demonstrate that the method could be an attractive syn-
thetic tool to access functionalized α-dienyl and α-polyenyl N-
heterocycles, several transformations were performed on a few
cyclized products. The functionalization of the diene moiety
was first examined and a Heck coupling was performed on ter-
minal diene 2a. Treatment of 2a with aryl iodide 13 under palla-
dium catalysis, in the presence of a base, led to the expected
substituted diene in 61 % yield. The reaction was more
problematic with heteroaromatic iodide 15 as the Heck product
was formed with a low yield of 46 %. We hypothesized that the
nitrogen atom of the pyridine may cause the catalyst poisoning
in spite of the presence of the C2 chlorine atom that may re-
duce the Lewis basicity of the pyridine[28] (Scheme 7).
The formation of α-trienyl piperidines was then investigated.
The α-dienyl piperidines that incorporated the MIDA vinyl
boronate could be engaged in a Suzuki coupling with an alk-
Scheme 9. Access to α-trienyl piperidines by using metal-catalyzed coupling.
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The Heck coupling between a terminal diene and an alkenyl
iodide is an alternative approach towards the formation of tri-
ene frameworks. Disappointingly, the reaction between 2a and
alkenyl iodide 17 only delivered traces of the Heck product
under two sets of conditions. However, the use of conditions
recently developed in our group allowed the Heck coupling
between 2a and alkenyl iodo MIDA boronate 21 in good yield
(77 %) (Scheme 10).[31]
Scheme 12. Diels–Alder reactions.
Conclusions
An iron-catalyzed cyclization reaction to access α-dienyl-substi-
tuted N-heterocycles has been developed. The method displays
several advantages, such as low-toxicity, low-cost, and atom
economy, with water being the only waste product. A range of
mono- and disubstituted N-heterocycles that incorporate a di-
enic substituent were prepared with moderate to excellent yield
and diastereoselectivity. The synthetic utility of the method was
demonstrated by the formation of several α-polyenyl piper-
idines from α-dienyl piperidines by using various metal-cata-
lyzed coupling reactions. In addition, a one-pot cyclization/
Diels–Alder process was successfully performed and delivered
an original tricyclic scaffold.
Scheme 10. Heck coupling between 2a and alkenyl iodides.
Trienyl MIDA boronate 22 is a potent intermediate towards
the synthesis of various α-polyenyl piperidines. For example, it
could react with alkenyl iodide 17 under palladium catalysis to
afford tetraene 23 in moderate yield (Scheme 11).
Experimental Section
General Remarks: All reactions were carried out under an argon
atmosphere unless otherwise noted. THF, Et2O, CH2Cl2, and toluene
were dried by using a MBraun SPS800 purificator. FeCl3·6H2O was
purchased from ACROS as 96 % pure. All Grignard reagents for
which the preparation is not described were purchased from Sigma
Aldrich and used as simple Grignard reagents (RMgX without LiCl).
All other commercially available chemicals were used as received
without further purification. TLC was performed with silica gel
plates visualized either with a UV lamp (254 nm) or by using a
Scheme 11. Access to an α-tetraenyl piperidine.
By taking advantage of the presence of the diene, Diels–
Alder
cycloadditions
were
performed.[32,33]
α-Dienyl
piperidine 2a was heated with diethyl but-2-ynedioate to give
the corresponding Diels–Alder adduct 25 in a yield of 60 %.[34]
An excess of the alkyne partner as well as a prolonged reaction staining solution (p-anisaldehyde or KMnO4) followed by heating.
Purification was performed with silica gel (Merck-Kieselgel 60, 230–
400). NMR spectra were recorded with a Bruker AVANCE 400. 1H
NMR spectra were recorded at 400 MHz and proton chemical shifts
are reported relative to residual solvent peak [CDCl3 at δ =
7.26 ppm; (CD3)2CO at δ = 2.05 ppm; (CD3)2SO at δ = 2.50 ppm].
Data are reported as follows: chemical shift, multiplicity (s = singlet,
d = doublet, t = triplet, q = quartet, quint = quintuplet, sext =
sextuplet, hept = heptuplet, oct = octuplet, m = multiplet or over-
lap of non-equivalent resonances), integration. 13C NMR spectra
were recorded at 100 MHz and carbon chemical shifts are reported
relative to residual solvent peaks [CDCl3 at δ = 77.16 ppm; (CD3)2CO
time at 110 °C were necessary to reach complete conversion of
the diene. The reaction between 2a and N-methylmaleimide
proceeded smoothly to deliver tricyclic compound 27 in 81 %
yield.[35] It is worth nothing that a one-pot process that includes
the iron-catalyzed cyclization and the Diels–Alder reaction
could be developed for this transformation. When dienic amino
alcohol 1a was treated with FeCl3·6H2O in the presence of N-
methylmaleimide in (CH2)2Cl2 for 1 h at room temp. and 48 h
at 80 °C, a cascade reaction took place and desired product 27
was isolated in quantitative yield (Scheme 12).[36]
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Synlett 2011, 2053; c) B. Olszewska, B. Kryczka, A. Zawisza, Tetrahedron
Lett. 2012, 53, 6826; d) B. Olszewska, B. Kryczka, A. Zawisza, Tetrahedron
2013, 69, 9551.
at 29.84 or 206.26 ppm; (CD3)2SO at δ = 39.52 ppm]. Data are re-
ported as follows: chemical shift in ppm, coupling constants. Infra-
red (IR) spectra were recorded with a Bruker TENSORTM 27 (IRFT).
Mass spectra with Electronic Impact (MS-EI) were recorded with a
Shimadzu GC–MS-QP2010S Gas Chromatograph/Mass Spectrome-
ter. High-resolution mass spectra (HRMS) were realized at the Labo-
ratoire de Spectrométrie de Masse SM3E de l'Université Pierre et
Marie Curie, Paris. Melting points were determined with a Kofler
bench or a Büchi melting point apparatus in open capillaries.
[13]
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Supporting Information (see footnote on the first page of this
article): Further details can be found in supporting information.
Acknowledgments
One of us (L. G.) thanks the French Ministère de l'Enseignement
Supérieure et de la Recherche for a grant.
[14]
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Keywords: Earth-abundant metals · Iron · Synthetic
methods · Piperidine · Nitrogen heterocycles · Cyclization
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See ref.[10] and ref.[11a]
[18]
[19]
See the supporting information for the evaluation of some other Lewis
acids in the same transformation.
[20]
[21]
[22]
By working at 0 °C the reaction slowed and, after 10 min, the cyclized
product was isolated in a low yield of 39 %.
The cyclization also proceeded smoothly in TFE (96 %,) whereas a mix-
ture of products was produced in hexafluoroisopropanol.
The use of TFE proved really beneficial and allowed the formation of 2c
in 94 % yield.
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[23]
[24]
[25]
See the experimental details for the synthesis of 1g.
Compound 1g was not soluble in CH2Cl2.
When 3a was treated with InCl3 (5 mol-%) in CH2Cl2 at room temp., after
17 h, a cis/trans ratio of 60:40 was observed, which emphasizes the cru-
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through its ability to induce an epimerization process.
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[26]
[27]
Alkenyl piperidines were obtained from mono-allylic alcohols or acetates
at room temp. in CH2Cl2 in the presence of FeCl3·6H2O (5–10 mol-%) in
61–99 % yield with a dr > 90:10 (see ref.[17]). The lower yields obtained
for the formation of α-dienyl piperidines than for α-alkenyl piperidines
may result from problems of stability of the diene under the reaction
conditions.
During the synthesis of alkenyl piperidines, the formation of a cationic
intermediate was confirmed by using an optically active mono allylic
acetate. A racemic piperidine was isolated and the absence of chirality
transfer supported the hypothetical carbocationic intermediate (see
ref.[17a]).
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[30]
[31]
[34] The relative configuration of the major diastereomer has not been deter-
mined.
[35] The cis relationship between the three protons on the tertiary carbon
atoms of the cyclohexene was proposed by assuming an endo approach.
The relative configuration of the stereocenter at C2 of the piperidine in
the major diastereomer has not been determined.
[36] This result may confirm that the moderate yields obtained for the cycli-
zation of bis-allylic alcohols may result from a stability issue of the result-
ing diene moiety under the reaction conditions. In this tandem process,
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yield is obtained for the formation of the Diels–Alder adduct.
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Received: July 12, 2017
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