Synergistic effect of the TiCl4/p-TsOH promoter system on the aza-Prins cyclization

Article abstract of DOI:10.1021/acs.joc.5b02342

A novel aza-Prins cyclization promoted by a synergistic combination between a Lewis acid and a Br?nsted acid to efficiently afford piperidines is described. Contrary to what has been previously reported in the literature, the generality of the reaction employing N-alkyl, N-aryl, and nonprotected homoallylamines has been demonstrated. The reaction is highly diastereoselective depending on the homoallylic amine used, N-PMP homoallyl amine leading preferentially to the trans diastereomer, and free homoallylamine affording the deprotected piperidine as single cis diastereomer.

Full text of DOI:10.1021/acs.joc.5b02342

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Article
Synergistic effect of the TiCl4/p-TsOH
promoter system on the Aza-Prins cyclization
Vianney Durel, Claudia Lalli, Thierry Roisnel, and Pierre van de Weghe
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02342 • Publication Date (Web): 06 Jan 2016
Downloaded from http://pubs.acs.org on January 11, 2016
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Synergistic effect of the TiCl4/p-TsOH promoter system on the Aza-Prins cyclization
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Vianney Durel, Claudia Lalli,* Thierry Roisnel and Pierre van de Weghe*
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Université de Rennes 1, UMR CNRS 6226, Institut des Sciences Chimiques de Rennes, Equipe
PNSCM, UFR des Sciences Biologiques et Pharmaceutiques, 2 avenue du Prof Léon Bernard, Fꢀ
35043 Rennes Cedex, France
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*Eꢀmail: pierre.vanꢀdeꢀweghe@univꢀrennes1.fr
*Eꢀmail: claudia.lalli@univꢀrennes1.fr
Table of Contents artwork
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Abstract A novel azaꢀPrins cyclization promoted by a synergistic combination between a Lewis acid
and a Brønsted acid to efficiently afford piperidines is described. Contrary to what has been previously
reported in the literature, the generality of the reaction employing Nꢀalkyl, Nꢀaryl and nonꢀprotected
homoallylamines has been demonstrated. The reaction is highly diastereoselective depending on the
homoallylic amine used, NꢀPMP homoallyl amine leading preferentially to the trans diastereomer, and
free homoallylamine affording the deprotected piperidine as single cis diastereomer.
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Introduction
Nowadays there are many routes to prepare piperidines, among them the azaꢀPrins cyclization reaction
involving aldehydes and homoallylic amines, appears to be a straightforward method that provides
direct access to sixꢀmembered azacycles.1 Despite the great interest and the recent advances
concerning the Prins cyclization, a feasible nitrogenꢀbased version of this reaction knows only
moderate success. Indeed this reaction is restricted in most cases to Nꢀsulfonyl homoallylic amines,
which may limit the interest in this process and its development. Several Lewis acids are reported to
promote the reaction of Nꢀsulfonyl homoallylic amines with aldehydes, among them, Fe(III) halides in
5
stoichiometric or subꢀstoichiometric amount,2 BiCl3,3 BF3.Et2O, 4 InCl3 and TMSX.6 Brønsted acids
are also reported to catalyze the cyclization, as in the case of phosphomolybdic acid,7 HBF4.Et2O8 and
TfOH.9 It has to be pointed out that there are only a very few examples reported in the literature
concerning aliphatic or primary amines.10 They concern mainly the use of the azaꢀPrins cyclization as
key step in the total synthesis of biologically active alkaloids. To the best of our knowledge to date a
detailed study devoted to the development of an effective azaꢀPrins cyclization involving nonꢀ
sulfonylated homoallylic amines has not been undertaken. We wish herein to fill this gap by reporting
our results on the azaꢀPrins cyclization reaction with Nꢀaryl, ꢀalkyl homoallylic amines and even with
nonꢀprotected ones.
Results & Discussion
We began our investigations by studying the reaction between Nꢀalkyl homoallylic amine as model
substrate, namely Nꢀmethyl butꢀ3ꢀenꢀ1ꢀylglycinate (1), and pꢀbromobenzaldehyde (2a), in CH2Cl2 at
60 °C in a sealed vial overnight (table 1). In the first attempts different Lewis acids known to promote
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the azaꢀPrins cyclization were screened, such as FeCl3, AlCl3 or Bi(OTf)3 (entries 1ꢀ3), unfortunately
without any conversion of the starting materials, in some cases only the degradation of the reagents
after a prolonged reaction time was observed. Only with 3 equiv. of MgBr2 or TiCl4 (entry 4ꢀ5) trace
amounts of the desired product were detected in the crude NMR. The use of pꢀTsOH.H2O, TFA and pꢀ
nitrobenzoic acid as Brønsted acids (entries 6ꢀ8) also failed to convert the starting materials into the
desired product.
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Table 1. Reaction conditions optimization.[a]
Lewis Acid
(equiv.)
Brønsted Acid
(equiv.)
Cis:trans
X
Entry
Yield (%)[b]
(d.r.)[d]
1
2
FeCl3 (3)
AlCl3 (3)
Bi(OTf)3 (3)
MgBr2 (3)
TiCl4 (3)
ꢀ
ꢀ
n.r.[c]
n.r.[c]
n.r.[c]
traces
traces
n.r.[c]
n.r.[c]
n.r.[c]
98
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
3
ꢀ
ꢀ
ꢀ
4
ꢀ
ꢀ
Br
Cl
ꢀ
5
ꢀ
ꢀ
6
pꢀTsOH.H2O (3)
TFA (3)
ꢀ
7
ꢀ
ꢀ
ꢀ
8
ꢀ
pꢀNO2ꢀC6H4CO2H
pꢀTsOH.H2O (1)
pꢀTsOH.H2O (0.1)
pꢀTsOH.H2O (0.1)
pꢀTsOH.H2O (0.1)
pꢀTsOH.H2O (0.1)
pꢀTsOH.H2O (0.1)
ꢀ
ꢀ
9
TiCl4
57:43
57:43
50:50
45:55
50:50
50:50
Cl
Cl
Br
Cl
Cl
Cl
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11
12
13
14
TiCl4(1)
MgBr2 (1)
AlCl3 (1)
FeCl3 (1)
ZnCl2 (1)
99
55
43
28
20
[a] General conditions: 1 (1 equiv.), 2a (1 equiv.), CH2Cl2 (0.05 M) at 60 °C 16 h. [b] Yields refer to
isolated products. [c] n.r.: no reaction. [d] 1H NMR determination on the crude mixture.
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Within our recent investigations on the Prins cyclization,11 we reported a remarkable synergistic effect
between nonꢀreactive Brønsted and Lewis acids that lack the ability to catalyze the reaction if used
alone.11b The benefit of this synergistic effect in the Prins cyclization was then confirmed when we
disclosed the first enantioselective Prins cyclization by combining a chiral BINOLꢀderived bisꢀ
phosphoric acid and CuCl.11c
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Based on our findings and on the previous observations by Aubé and coworkers,10 a,b we decided to
combine TiCl4 with pꢀTsOH.H2O, the Lewis acid playing the role also of the nucleophile source. Thus
1, and 2a were reacted in the presence of 3 equiv. of TiCl4 and 1 equiv. of pꢀTsOH.H2O, in CH2Cl2 at
60 °C in a sealed vial overnight (table 1, entry 9). To our delight the desired product was recovered in
98% yield, as a mixture of two diastereomers (cis:trans = 57:43). The variation of the Lewis and
Brønsted acid amounts didn’t affect the reactivity (see supporting information for details) and
gratifyingly the expected piperidine was recovered in quantitative yield even with only 1 equiv. of
TiCl4 and catalytic amount (10 mol%) of pꢀTsOH.H2O and in the same diastereomeric ratio (table 1,
entry 10). A screening of different Brønsted and Lewis acid combinations revealed TiCl4 to be
superior to MgBr2, AlCl3, FeCl3 and ZnCl2 (table 1, entries 11ꢀ14). On the contrary, the use of TFA,
MeSO3H, camphorsulfonic acid, as well as pꢀnitro benzoic acid with TiCl4 didn't affect the outcome of
the reaction (see Supporting Information for details). Decreasing the reaction temperature to 40 °C
was detrimental for the reactivity, moreover when the reaction was performed at 60 °C in 1,2ꢀ
dichloroethane a slight drop of the yield was observed.
With the optimized conditions in hand we next examined the scope of the synergism between TiCl4
and pꢀTsOH.H2O with respect to different aldehydes, and the results are summarized in Table 2.
Table 2. Scope of the azaꢀPrins cyclization with the Nꢀalkyl homoallylic amine 1.a
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Cis:trans
Entry
1
Aldehyde 2 R=
Product 3
Yield (%)[b]
98
(d.r.)[c]
pꢀBrꢀC6H4 2a
C6H5 2b
57:43
57:43
86:14
42:58
38:62
45:55
50:50
3a
3b
3c
3d
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94
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oꢀClꢀC6H4 2c
pꢀCNꢀC6H4 2d
pꢀNO2ꢀC6H4 2e
mꢀNO2ꢀC6H4 2f
pꢀN(CH3)2ꢀC6H4 2g
3e
3f
3g
8
2,5ꢀ(OCH3)2ꢀC6H3 2h
92
87:13
3h
9
oꢀOCH3ꢀC6H4 2i
pꢀOCH3ꢀC6H4 2j
pꢀCH3ꢀC6H4 2k
(CH3)2CH 2l
65
60[d]
74
85:15
62:38
62:38
43:57
3i
10
11
12
3j
3k
3l
86
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13[e]
14[e]
C6H4ꢀ(CH2)2 2m
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78
62:38
62:38
3m
(CH3)(CH2)6 2n
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3n
[a] General conditions: 1 (1 equiv.), 2 (1 equiv.), TiCl4 (1 equiv.), pꢀTsOH.H2O (10 mol%), in CH2Cl2
(0.1 M) at 60 °C in a sealed vial 16 h. [b] Yields refer to isolated products. [c] 1H NMR determination
on the crude mixture. [d] 62% conversion. [e] Performed with 2 (1.5 equiv).
Gratifyingly benzaldehyde 2b (entry 2) smoothly participated to the reaction leading to the desired
product 3b in 94% yield, and the same cis:trans selectivity (d.r. 57:43). The aromatic ring substitution
in the ortho, meta or para position with electronꢀwithdrawing groups (entries 3ꢀ6) is well tolerated as
in all the cases the piperidines 3c-f were obtained in 86ꢀ97% yields. The reaction proved to be less
efficient for aromatic aldehydes substituted with an electronꢀdonating group especially in the para
position (entries 7, 10 and 11), leading to the products 3g, j and k in 60%, 60% and 74% yield
respectively. It’s interesting to note that in the presence of an ortho substituent on the aromatic ring,
the cisꢀproduct was obtained as major diastereomer (entries 3, 8 and 9) affording the desired
piperidines with up to 87:13 d.r. probably because of the steric hindrance.12 Aliphatic aldehydes
undergo azaꢀPrins cyclization in high yields (entries 12ꢀ14), however in the case of 3ꢀ
phenylpropionaldehyde (2m) and nꢀoctanal (2n) a slight excess of aldehyde was needed (1.5 equiv) to
have a complete conversion of 1; these aldehydes reacting with themselves leading to small amount of
the aldolꢀcrotonization products.
The scope of the reaction was then extended to other protected homoallylic amines. Contrarily to the
scarce previously reported results,13,3,10c our reaction conditions are not compatible with the use of
carbamates as protecting group on the nitrogen atom. Both the Bocꢀ and Cbzꢀ are cleaved in the
presence of the combination of TiCl4 and pꢀTsOH.H2O and no trace of the azaꢀPrins product was
observed. Otherwise the azaꢀPrins reaction with homoallylic amine protected by the widely used pꢀ
methoxyphenyl (PMP) group 4 was also carried out and the results are reported in Table 3.
Table 3. Scope of the azaꢀPrins cyclization with PMPꢀprotected homoallylic amine 4.a
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Cis/trans
Entry
1
Aldehyde 2 R=
Product 5
Yield (%)[b]
99
(d.r.)[c]
pꢀBrꢀC6H4 2a
12:88
5a
5b
5c
2
3
C6H5 2b
93
99
23:77
28:72
oꢀClꢀC6H4 2c
4
pꢀNO2ꢀC6H4 2e
92
14:86
5d
5e
5
6
7
pꢀOCH3ꢀC6H4 2j
pꢀCH3ꢀC6H4 2k
(CH3)2CH 2l
40[d]
90
20:80
22:78
9:91
5f
98
5g
[a] General conditions: 4 (1 equiv.), 2 (1 equiv.), TiCl4 (1 equiv.), pꢀTsOH.H2O (10 mol%), in CH2Cl2
(0.1 M) at 60 °C in a sealed vial 16 h. [b] Yields refer to isolated products. [c] 1H NMR determination
on the crude mixture. [d] 49% conversion.
In the presence of aromatic aldehydes substituted on the ortho or para positions with electron
withdrawing groups 2a-c and e the azaꢀPrins products 5a-d, were isolated in up to 99% yields, this
time surprisingly, with a good diastereoselection in favor of the trans isomer (d.r. up to 86:14).
Aliphatic isobutyraldehyde 2l also provided the desired piperidine 5g in very good yield and as single
diastereomer (trans:cis = 91:9). The substitution on the aromatic ring with strong electron donating
groups is less tolerated. Indeed, while pꢀtolualdehyde (2k) smoothly reacted to give the desired
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piperidine in 90% yield (entry 6), pꢀanisaldehyde (2j) gave the product in only 40% yield (entry 5) and
2,5ꢀdimethoxy benzaldehyde (2h) did not react at all. This is probably due to electronic effects, since
the iminium intermediate is too electron enriched due to the donating PMP and methoxy groups. To
illustrate the synthetic utility of this methodology we deprotected the PMP group in standard reaction
conditions, in the presence of ceric ammonium nitrate CAN, in order to obtain the NH free piperidine
as the single trans 7a diastereomer in 73% yield (Scheme 1), thus with an overall yield of 66% over
two steps.
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Scheme 1. Deprotection of the PMP group of the piperidine trans 5a.
We next wondered about the possibility to carry out the azaꢀPrins cyclization with the butꢀ3ꢀenꢀ1ꢀ
amine (6). Indeed very few examples are reported in the literature using a free homoallyl amine or an
imine. To our delight, although the reaction time was longer (90 h instead of overnight) the synergistic
combination of TiCl4 with pꢀTsOH.H2O allowed isolation of the expected piperidines 7 in good yields
and gratifyingly as the single cisꢀstereoisomer (d.r. > 95/5) (Table 4).
Table 4. Scope of the azaꢀPrins yclization with homoallyl amine 6.a
Entry
1
Aldehyde 2 R=
pꢀBrꢀC6H4 2a
Product 7
Yield (%)[b]
77
7a
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C6H5 2b
86
80
7b
7c
oꢀClꢀC6H4 2c
pꢀNO2ꢀC6H4 2e
pꢀOCH3ꢀC6H4 2j
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5
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7d
34[c]
7e
7f
6
7
pꢀCH3ꢀC6H4 2k
(CH3)2CH 2l
70[c]
88
7g
[a] General conditions: 6 (1 equiv.), 2 (1 equiv.), TiCl4 (1 equiv.), pꢀTsOH.H2O (10 mol%), in CH2Cl2
(0.1 M) at 60 °C in a sealed vial 90 h. [b] Yields refer to isolated products. [c] Reaction time
prolonged to 160 h.
Again the only exception in this trend concerns the electron rich aldehydes; the reaction with 2k
afforded the piperidine 7f in 70% yield after a longer reaction time (160 h) and 2j afforded 7g in only
32% yield after 160 h.
The structure of compounds trans 3e and cis 7a and their relative configurations were determined by
NOESY experiments14 and confirmed by single crystal Xꢀray analysis14 (Figure 1).
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Figure 1 ORTEP representation of the piperidines products transꢀ3e and cisꢀ7a. The thermal
ellipsoids are shown at 50% probability.
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H
H
H
H
H
Br
Cl
H
HN
H
H
Noesy
It is worth noting that the cis/trans ratio is strongly dependent on the feature of the nitrogen atom
substituent, as depicted in Table 5. To determine the trend of the selectivity dependence, the reactions
between benzaldehyde (2b) and different substituted homoallylic amines were performed.
Table 5. Selectivity dependence.
Cl
Cl
TiCl4 (1 equiv)
R
p-TsOH.H2O (10 mol%)
N
2b
+
+
H
CH2Cl2, 60 °C
(sealed tube)
N
Ph
N
Ph
R
R
trans
cis
Cis/trans
(d.r.)[b]
Entry
R=
CH2CO2Me (1)
Product (Yield %)[a]
1
2
3
4
5
6
3b (94)
5b (93)
7b (86)
11 (93)
12 (66)
13 (90)
57:43
23:77
>95:5
>5:95
50:50
50:50
PMP
H
(4)
(6)
Ts
(8)
Bn
(9)
nꢀPr
(10)
[a] Yields refer to isolated products. [b] 1H NMR determination on the crude mixture.
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With Nꢀtosyl homoallyl amine (8) only the product trans 11 was recovered in 95% yield (entry 4).
Next we employed Nꢀalkyl homoallylic amines such as Nꢀbenzyl (9) and Nꢀpropyl (10) (entries 5 and
6): both delivered an equimolar mixture of cis and trans isomers 12 and 13 in good yield. We can
therefore conclude that whereas the free amine 6 led to the piperidine cis 7b as unique stereoisomer
(entry 3), the arylamine 4 and the tosylamine 8 gave the trans isomer as major product (entries 2 and
4), finally no selectivity was observed with the alkylamines 1, 9 and 10 (entries 1, 5 and 6).
These results could be explained as follow (Figure 2). According to the common reaction mechanism
of the azaꢀPrins cyclization, the reaction starts by the formation of an iminium whose A and B forms
are in equilibrium and then the nucleophilic attack (here the chloride anion) occurs on the equatorial
position. As mentioned by Padrón et al.,2a in the case of R1=Ts, ab-initio calculations showed that the
iminium B is more stable than the isomer A. This is probably due to the strong steric repulsion
between the groups R1 and R in comparison to the lower energy cost of the allylic strain between R
and H. Obviously, this comment can also explain the transꢀ selectivity with R1=PMP. When R1=H,
only the allylic strain remains,15 favoring thus the formation of the iminium A and consequently the
formation of the cisꢀpiperidine. The observed lack of selectivity when the amine bears an alkyl chain
(homoallylic amine 1) is certainly due to an equivalent energy cost between the steric repulsion for the
iminium A and the allylic strain for B. This last case helps us to better understand the high cisꢀ
selectivity when the reaction was carried out with orthoꢀsubstituted aryl aldehydes (Table 2, entries 3ꢀ
8ꢀ9). These orthoꢀsubstituents could contribute to increase the steric hindrance detrimental to the
iminium B by reinforcing the negative contribution of the allylic strain versus the steric repulsion
between the residue CH2CO2Me (R1) and the aryl group (R).
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Figure 2. Comparison of possible transition structures for the cyclization reaction.
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In conclusion, we have demonstrated that the synergism between TiCl4 and pꢀTsOH.H2O can promote
the azaꢀPrins cyclization with Nꢀaryl, ꢀalkyl and even non protected homoallylic amines. The
piperidine derivatives are obtained in good yields and with a cis/trans ratio dependent on the group
borne by the nitrogen atom. The transꢀisomer was obtained as major compound when tosyl and PMP
are used as protecting groups, while the cisꢀisomer was formed in the absence of protecting group.
This methodology can be useful for preparing either cis- or trans- piperidines and could be later used
for the synthesis of valuable piperidine scaffolds found in natural and bioactive products.
Experimental section
General information
All the reactions were performed in dried glassware, under argon atmosphere and with dry solvents.
Reagents were obtained from commercial suppliers and used without further purification unless
otherwise noted. TLC analyses were performed using precoated Merck TLC Silica Gel 60 F254 plates.
Purifications by column chromatography on silica gel were performed using Merck Silica Gel 60 (70ꢀ
230 mesh) and purifications by preparative thin layer chromatography on silica gel using Merck Silica
Gel 60 PF254. Petroleum ether (PE) used for purifications was the low boiling point fraction (40ꢀ60
1
°C). H NMR and 13C spectra were recorded on a 300 Mhz instrument using TMS and CDCl3
respectively as internal standards. Chemical shifts (δ) are reported in parts per million (ppm). The
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following abbreviations are used for multiplicities: s, singlet; d, doublet; t, triplet; dd, doublet of
doublets; q, quadruplet; quint, quintuplet; td, triplet of doublets; dt, doublet of triplets; tt, triplet of
triplets, m, multiplet. Carbon multiplicities were determined by Jmod experiments. Coupling constants
(J) are reported in Hertz (Hz). ꢀ HRMS analyses were obtained using MaXis 4G or a TOF Q for ESI.
Xꢀray crystallographic data were collected on a crystal diffractometer. Melting points were obtained
on a hot bench.
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Preparation of
N-methyl but-3-en-1-ylglycinate (1): To a solution of methyl glycinate
hydrochloride (11.12 g, 2 equiv., 88.6 mmol) in acetonitrile (220 mL) was added K2CO3 (18.36 g, 3
equiv., 133 mmol). The mixture was stirred 1 h at room temperature, then 4ꢀbromoꢀ1ꢀbutene (4.5 mL,
1 equiv., 44.9 mmol) was added and the stirring continued at 45 °C for 48 h. The insoluble material
was filtered off and the filtrate concentrated under reduced pressure. CH2Cl2 (60 mL) and H2O were
added, the twoꢀphase mixture was separated, and the aqueous phase was extracted twice with CH2Cl2.
The combined organic phases were dried over MgSO4, filtered, and evaporated in vacuo. Compound 1
1
was isolated as colorless oil (6.01 g, 90% yield) after distillation (70 °C, to reduced pressure). H
NMR (CDCl3, 300 MHz):
δ = 5.85ꢀ5.75 (m, 1 H), 5.14ꢀ5.04 (m, 2 H), 3.73 (s, 3 H), 3.43 (s, 2 H), 2.68
(t, J = 6.7 Hz, 2 H), 2.26 (q, J = 6.7 Hz, 2 H), 1.66 (bs, NH). 13C NMR (CDCl3, 75 MHz):
δ
= 173.0
(C=O), 136.2 (=CH), 116.7 (=CH2), 51.9 (CH3), 50.8 (CH2), 48.6 (CH2), 34.4 (CH2). ESIꢀHRMS
calculated for C7H14NO2 [M+H]+ 144.1024, found 144.1022.
Preparation of
N-(but-3-en-1-yl)-4-methoxyaniline (4): To a solution of pꢀanisidine (6.16 g, 5
equiv., 49.2 mmol) and 4ꢀbromoꢀ1ꢀbutene (1.33 g, 1 equiv., 9.85 mmol) in EtOH (20 mL) was added
NaI (147 mg, 0.1 equiv., 0.98 mmol). The mixture was stirred to reflux for 4 h, and then the solvent
was removed in vacuo. CH2Cl2 (20 mL) followed by KOH (1 M, 20 mL) were added. The twoꢀphase
mixture was separated, and the organic phase was washed with water (2 × 20 mL) and brine (2 × 20
mL), dried over MgSO4, filtered, and evaporated in vacuo. The compound 4 was isolated as brown oil
1
(1.58 g, 90% yield) after purification by flash chromatography (10% EtOAc in petroleum ether). H
NMR (CDCl3, 300 MHz):
δ = 6.78 (d, J = 8.8 Hz 2 H), 6.58 (d, J = 8.8 Hz, 2 H), 5.86ꢀ5.75 (m, 1 H),
5.16ꢀ5.08 (m, 2 H), 3.73 (s, 3 H), 3.27 (bs, NH), 3.13 (t, J = 6.7 Hz, 2 H), 2.36 (q, J = 6.7 Hz, 2 H).
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13C NMR (CDCl3, 75 MHz):
δ
= 152.2 (C), 142.6 (C), 136.0 (=CH), 117.1 (=CH2), 115.0 (2 × CH),
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114.4 (2 × CH), 55.9 (CH3), 43.9 (CH2), 33.8 (CH2). ESIꢀHRMS calculated for C11H16NO [M+H]+
178.1232, found 178.1232.
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Preparation of
N-but-3-en-1-yl-4-methylbenzenesulfonamide (8): This substrate was synthesized
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according to a described procedure.16 To a solution of 3ꢀbutenꢀ1ꢀamine (662 mg, 1 equiv., 9.3 mmol),
NEt3 (1.9 mL, 1.5 equiv., 13.9 mmol) and dimethylaminopyridine (341 mg, 0.3 equiv., 2.79 mmol) in
CH2Cl2 (30 mL), at 0 °C tosyl chloride (2.13 g, 11.2 mmol, 1.2 eq) was added. The reaction was
warmed to r.t., stirred for 3 h, quenched with water and the aqueous layer was extracted three times
with CH2Cl2. The combined organic phases were dried over MgSO4, filtered, and evaporated in vacuo.
The residue was purified by flash chromatography (EP/EtOAc 4:1) to afford the corresponding
tosylamine 15 (2.08 g, 99% yield) as colourless oil. 1H NMR (CDCl3, 300 MHz):
δ = 7.75 (d, J = 8.4
Hz, 2 H), 7.32 (d, J = 8.4 Hz 2 H), 5.69ꢀ5.56 (m, 1 H), 5.09ꢀ5.01 (m, 2 H), 4.42 (s, NH), 3.02 (q J =
6.6 Hz, 2 H), 2.43 (s, 3 H), 2.20 (q, J = 6.6 Hz, 2 H). 13C NMR (CDCl3, 75 MHz) :
δ
= 143.6 (C),
137.1 (C), 134.3 (=CH), 129.9 (2 × CH), 127.3 (2 × CH),118.4 (=CH2), 42.2 (CH2), 33.7 (CH2) 21.7
(CH3).
Preparation of
N-benzylbut-3-en-1-amine (9): This substrate was synthesized according to a
described procedure.17 To a solution of benzylamine (5.25 g, 5 equiv., 49.0 mmol) and 4ꢀbromoꢀ1ꢀ
butene (1 mL, 1 equiv., 9.85 mmol) in EtOH (20 mL), NaI (150 mg, 0.1 equiv., 0.98 mmol) was
added. The mixture was stirred to reflux for 4 h. Then the solvent was removed in vacuo, CH2Cl2 (20
mL) followed by KOH (1 M, 20 mL) were added and the twoꢀphase mixture was separated. The
organic phase was washed with water (2 × 20 mL) and brine (2 × 20 mL), dried over MgSO4, filtered,
and evaporated in vacuo. The residue was purified by flash chromatography (10 % EtOAc in
petroleum ether) to give pure product 17 (Nꢀbenzylbutꢀ3ꢀenꢀ1ꢀamine) as a yellow oil (1.51 g, 95%
yield). 1H NMR (CDCl3, 300 MHz):
3.81 (s, 2 H), 2.71 (t, J = 6.8 Hz, 2 H), 2.31 (qt, J = 6.8, 1.3 Hz, 2 H), 1.84 (br s, 1 H). 13C NMR
δ = 7.33–7.22 (m, 5 H), 5.85ꢀ5.72 (m, 1 H), 5.12–5.02 (m, 2 H),
(CDCl3, 75 MHz):
δ = 140.1 (C), 136.5 (=CH), 128.6 (2 × CH), 128.3 (2 × CH), 127.1 (CH), 116.6
(=CH2), 53.9 (CH2), 48.3 (CH2), 34.3 (CH2).
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Preparation of
N-propylbut-3-en-1-amine (10): To a solution of butꢀ3ꢀenꢀ1ꢀamine (0.77 mL, 1.0
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equiv., 8.4 mmol) in MeOH (10 mL) was added propanal (0.74 mL, 1.2 equiv., 10.1 mmol). The
mixture was stirred at room temperature for 2 h. Solid NaBH4 (794 mg, 2.5 equiv., 21 mmol) was then
added portionwise over 1 h. The reaction was stirred at room temperature overnight, quenched with
2.0 M aq. NaOH (10 mL) and extracted with Et2O (3 × 30 mL). The organic layers were combined,
dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by distillation (70 °C
under reduce pressure) to give compound 19 (900 mg, 95% yield) as a colorless oil. 1H NMR (CDCl3,
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300 MHz):
δ = 5.86ꢀ5.72 (m, 1 H), 5.12–5.02 (m, 2 H), 2.67 (t, J = 6.8 Hz, 2 H), 2.57 (t, J = 7.3 Hz, 2
H), 2.28 (qt, J = 6.8, 1.2 Hz, 2 H), 1.51 (q, J = 7.3 Hz, 2 H), 0.91 (t, J = 7.3 Hz, 3 H). 13C NMR
(CDCl3, 75 MHz):
11.9 (CH3).
δ = 136.7 (=CH), 116.4 (=CH2), 51.9 (CH2), 48.9 (CH2), 34.5 (CH2), 23.3 (CH2),
4-Methoxyphenyl deprotection: To a solution of trans 5a (114.2 mg, 1.0 equiv., 0.3 mmol) in
MeCNꢀH2O (4:1, 6 mL) was added ceric ammonium nitrate Ce(NH4)2(NO3)6 (987 mg, 6 equiv., 1.8
mmol) at 0 °C. The mixture was stirred at the same temperature for 3 h. Solid NaBH4 (794 mg, 2.5
equiv., 21 mmol) was then added portionwise over 1 h. Then water (12 mL) was added and extracted
with EtOAc (90 mL). The aqueous layer was basified with K2CO3, filtered through a pad of celite and
extracted with EtOAc (2 × 30 mL). The organic layers were combined, dried over MgSO4, filtered,
and evaporated in vacuo. The residue was purified by flash chromatography (100% EtOAc) to give
1
pure product trans 7a (60 mg, 73% yield) as a black solid. Black solid, M.p. 78ꢀ80 °C H NMR
(CDCl3, 300 MHz):
δ = 7.45 (d, J = 8.3 Hz, 2 H), 7.26 (d, J = 8.3 Hz, 2 H), 4.60 (quint, J = 3.0 Hz, 1
H), 4.15 (dd, J = 10.7, 3.0 Hz, 1 H), 3.31 (td, J = 12.1, 3.0 Hz, 1 H), 3.08 (bs, NH), 3.01(ddd, J = 12.1,
4.4, 2.6 Hz, 1 H), 2.13ꢀ1.91 (m, 4 H). 13C NMR (CDCl3, 75 MHz):
δ
= 142.7 (C), 131.7 (2 × CH),
128.7 (2 × CH), 121.3 (C), 57.9 (CH), 54.8 (CH), 42.0 (CH2), 41.2 (CH2), 33.2 (CH2). ESIꢀHRMS
calculated for C11H14NClBr [M+H]+ 273.9993, found 273.9993.
General procedure
To a solution of homoallylic amine (1 equiv., 0.4 mmol) and aldehyde (1 equiv*., 0.4 mmol) in
CH2Cl2 (4 mL) p-TSA.H2O (0.1 equiv., 0.04 mmol) was added. The mixture was stirred for 15 min
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then a solution of TiCl4 (1 M in CH2Cl2, 1 equiv., 0.4 mmol) was added. The solution was stirred at 60
°C for 16 h (with amine 1, 4, 15, 17 and 19), 90 h (with amine 6**) or 160 h (with amine 8, 10 and
12), quenched with NaHCO3 and extracted with CH2Cl2. The combined organic layers were dried with
MgSO4, solvent was removed, and the residue was purified by flash chromatography on silica gel
(10% EtOAc in petroleum ether) to give the pure piperidine products.
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* 1.5 eq for aldehyde 2m and 2n
** For amine 6 reaction with 2j and 2k has been extended for 160 h
Methyl 2-(2-(4-bromophenyl)-4-chloropiperidin-1-yl)acetate 3a (98%, 136 mg, dr: 57:43)
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Cis 3a: Orange oil H NMR (CDCl3, 300 MHz):
δ = 7.45 (d, J = 8.4 Hz, 2 H), 7.22 (d, J = 8.4 Hz, 2
H), 3.94 (tt, J = 11.7, 4.3 Hz, 1 H), 3.63 (dd, J = 12.1, 2.2 Hz, 1 H), 3.61 (s, 3 H), 3.08 (ddd, J = 12.1,
4.1, 2.8 Hz, 1 H), 3.07 (ABq, 2 H), 2.66 (td, J = 12.1, 2.2 Hz, 1 H), 2.24ꢀ2.15 (m, 2 H), 2.06 (qd, J =
12.1, 4.1 Hz, 1 H), 1.89 (q, J = 12.1 Hz, 1 H). 13C NMR (CDCl3, 75 MHz):
δ = 171.1 (C), 141.1 (C),
132.1 (2 × C), 129.5 (2 × C), 121.7 (C), 64.9 (C), 56.5 (C), 54.9 (C), 52.4 (C), 51.5 (C), 45.9 (C), 36.8
(C). ESIꢀHRMS calculated for C14H17NO2ClBrNa [M+Na]+ 368.0029, found 368.0032. Trans 3a:
Yellow oil 1H NMR (CDCl3, 300 MHz):
δ = 7.45 (d, J = 8.5 Hz, 2 H), 7.25 (d, J = 8.5 Hz, 2 H), 4.53
(quint, J = 3.0 Hz, 1 H), 3.95 (dd, J = 10, 3.8 Hz, 1 H), 3.64 (s, 3 H), 3.11 (ABq, 2 H), 3.05ꢀ2.92 (m, 2
HꢀH), 2.32ꢀ2.21 (m, 1 H), 2.10ꢀ1.95 (m, 3 H). 13C NMR (CDCl3, 75 MHz):
δ
= 171.3 (C), 141.6 (C),
132.1 (2 × C), 129.7(2 × C), 121.5 (C), 60.0 (C), 57.0 (C), 56.0 (C), 51.6 (C), 47.4 (C), 43.1 (C), 33.4
(C). ESIꢀHRMS calculated for C14H17NO2ClBrNa [M+Na]+ 368.0028, found 368.0028.
Methyl 2-(4-chloro-2-phenylpiperidin-1-yl)acetate 3b (94%, 100 mg, dr: 57:43)
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Cis 3b: Yellow oil H NMR (CDCl3, 300 MHz):
δ = 7.33ꢀ7.26 (m, 5 H), 3.96 (tt, J = 11.7, 4.3 Hz, 1
H), 3.62 (dd, J = 10.9, 2.6 Hz, 1 H), 3.60 (s, 3 H), 3.10 (ddd, J = 11.9, 4.1, 2.9 Hz, 1 H), 3.08 (ABq, 2
H), 2.66 (td, J = 12.0, 2.6 Hz, 1 H), 2.21 (m, 2 H), 2.07 (qd, J = 12.0, 4.2 Hz, 1 H), 1.96 (q, J = 12.0
Hz, 1 H). 13C NMR (CDCl3, 75 MHz):
δ = 171.3 (C), 142.0 (C), 128.9 (2 × CH), 128.0 (CH), 127.7 (2
× CH), 65.7 (CH), 56.9 (CH), 55.0 (CH2), 52.5 (CH2), 51.4 (CH3), 46.0 (CH2), 36.9 (CH2). ESIꢀHRMS
calculated for C14H18NO2ClNa [M+Na]+ 290.0924, found 290.0922. Trans 3b: Yellow oil H NMR
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(CDCl3, 300 MHz):
δ
= 7.38ꢀ7.25 (m, 5 H), 4.54 (quint, J = 2.9 Hz, 1 H), 3.94 (dd, J = 10.8, 3.0 Hz, 1
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H), 3.63 (s, 3 H), 3.11 (ABq, 2 H), 3.01ꢀ2.91 (m, 2 H), 2.30ꢀ2.28 (m, 1 H), 2.17ꢀ1.96 (m, 3 H). 13C
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NMR (CDCl3, 75 MHz):
δ = 171.4 (C), 142.4 (C), 128.9 (2 × CH), 127.9 (2 × CH), 127.8 (CH), 60.7
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(CH), 57.3 (CH), 56.1 (CH2), 51.5(CH3), 47.5 (CH2), 43.1(CH2), 33.5 (CH2). ESIꢀHRMS calculated
for C14H18NO2ClNa [M+Na]+ 290.0924, found 290.0926.
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Methyl 2-(4-chloro-2-(2-chlorophenyl)piperidin-1-yl)acetate 3c (86%, 103 mg, dr: 86:14)
Cis 3c: Orange oil 1H NMR (CDCl3, 300 MHz):
δ = 7.61 (dd, J = 7.6, 1.7 Hz, 1 H), 7.33 (dd, J = 7.9,
1.3 Hz, 1 H), 7.28 (td, J = 7.6, 1.3 Hz, 1 H), 7.18 (td, J = 7.9, 1.7 Hz, 1 H), 4.10 (dd, J = 11.2, 3.1 Hz,
1 H), 3.97 (tt, J = 11.7, 4.3 Hz, 1 H), 3.63 (s, 3 H), 3.18 (dt, J = 11.8, 3.5 Hz, 1 H), 3.08 (ABq, 2 H),
2.60 (td, J = 12.0, 2.5 Hz, 1 H), 2.32ꢀ2.19 (m, 2 H), 2.06 (qd, J = 12.1, 4.1 Hz, 1 H), 1.79 (q, J = 12.1
Hz, 1 H). 13C NMR (CDCl3, 75 MHz):
δ = 171.1 (C), 139.2 (C), 133.2 (C), 129.8(CH), 128.8 (CH),
128.6 (CH), 127.7 (CH), 61.2 (CH), 56.4 (CH), 55.3 (CH2), 52.8 (CH2), 51.6 (CH3), 44.5 (CH2), 36.7
(CH2). ESIꢀHRMS calculated for C14H17NO2Cl2Na [M+Na]+ 324.0534, found 324.0536. Trans 3c:
Yellow oil 1H NMR (CDCl3, 300 MHz):
δ = 7.62 (dd, J = 7.6, 1.7 Hz, 1 H), 7.33 (dd, J = 7.9, 1.3 Hz,
1 H), 7.26 (td, J = 7.6, 1.3 Hz, 1 H), 7.17 (td, J = 7.9, 1.7 Hz, 1 H), 4.53 (quint, J = 4.5 Hz, 1 H), 4.46
(dd, J = 11.0, 2.9 Hz, 1 H), 3.66 (s, 3 H), 3.09 (ABq, 2 H), 3.01ꢀ2.96 (m, 2 H), 2.29ꢀ2.22 (m, 1 H),
2.13ꢀ2.08 (m, 1 H), 2.02ꢀ1.87 (m, 2 H). 13C NMR (CDCl3, 75 MHz):
δ = 171.4 (C), 139.9 (C), 133.6
(C), 129.9 (CH), 128.9 (CH), 128.5 (CH), 127.6 (CH), 56.8 (CH), 56.4 (CH), 56.4 (CH2), 51.7 (CH3),
47.7 (CH2), 41.7 (CH2), 33.4 (CH2). ESIꢀHRMS calculated for C14H17NO2Cl2Na [M+Na]+ 324.0534,
found 324.0535.
Methyl 2-(4-chloro-2-(4-cyanophenyl)piperidin-1-yl)acetate 3d (96%, 112 mg, dr: 42:58)
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Cis 3d: Orange oil H NMR (CDCl3, 300 MHz):
δ = 7.64 (d, J = 8.3 Hz, 2 H), 7.47 (d, J = 8.3 Hz, 2
H), 3.95 (tt, J = 11.7, 4.2 Hz, 1 H), 3.78 (dd, J = 12.1, 2.4 Hz, 1 H), 3.62 (s, 3 H), 3.10 (ddd, J = 11.9,
3.9, 2.9 Hz, 1 H), 3.06 (ABq, 2 H), 2.70 (td, J = 12.1, 2.3 Hz, 1 H), 2.26ꢀ2.16 (m, 2 H), 2.04 (qd, J =
12.1, 4.2 Hz, 1 H), 1.86 (q, J = 11.7 Hz, 1 H). 13C NMR (CDCl3, 75 MHz):
δ = 170.8 (C), 147.6 (C),
132.8 (2 × CH), 128.5 (2 × CH), 118.7 (C), 111.8 (C), 65.0 (CH), 56.2 (CH), 54.8 (CH2), 52.2 (CH2),
51.5 (CH3), 45.7 (CH2), 36.6 (CH2). ESIꢀHRMS calculated for C15H17N2O2ClNa [M+Na]+ 315.0876,
found 315.0877. Trans 3d: Orange oil 1H NMR (CDCl3, 300 MHz):
δ = 7.64 (d, J = 8.6 Hz, 2 H), 7.51
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(d, J = 8.6 Hz, 2 H), 4.53 (quint, J = 2.9 Hz, 1 H), 4.07 (t, J = 6.8 Hz, 1 H), 3.65 (s, 3 H), 3.07 (ABq, 2
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H), 3.02 (td, J = 11.6, 3.0 Hz, 1 H), 2.98ꢀ2.93 (m, 1 H), 2.27ꢀ2.22 (m, 1 H), 2.02ꢀ1.98 (m, 3 H). C
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NMR (CDCl3, 75 MHz): δ = 171.0 (C), 148.3 (C), 132.7 (2 × CH), 128.6 (2 × CH), 117.7 (C), 111.6
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(C), 60.1 (CH), 56.5 (CH), 56.0 (CH2), 51.6 (CH3), 47.1 (CH2), 43.0 (CH2), 33.2 (CH2). ESIꢀHRMS
calculated for C15H17N2O2ClNa [M+Na]+ 315.0876, found 315.0876.
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Methyl 2-(4-chloro-2-(4-nitrophenyl)piperidin-1-yl)acetate 3e (90%, 111 mg, dr: 38:62)
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Cis 3e: Orange oil H NMR (CDCl3, 300 MHz):
δ = 8.20 (d, J = 8.8 Hz, 2 H), 7.53 (d, J = 8.6 Hz, 2
H), 3.96 (tt, J = 11.7, 4.3 Hz, 1 H), 3.86 (dd, J = 11.4, 2.5 Hz, 1 H), 3.62 (s, 3 H), 3.11 (ddd, J = 11.9,
4.1, 3.0 Hz, 1 H), 3.07 (ABq, 2 H), 2.72 (td, J = 12.2, 2.5 Hz, 1 H), 2.28ꢀ2.17 (m, 2 H), 2.07 (qd, J =
12.2, 4.1 Hz, 1 H), 1.88 (q, J = 11.9 Hz, 1 H). 13C NMR (CDCl3, 75 MHz):
δ = 170.8 (C), 149.6 (C),
147.7 (C), 128.6 (2 × CH), 124.3 (2 × CH), 64.7 (CH), 56.1 (CH), 54.8 (CH2), 52.2 (CH2), 51.6 (CH3),
45.8 (CH2), 36.7 (CH2). ESIꢀHRMS calculated for C14H17N2O4ClNa [M+Na]+ 335.0775, found
335.0775. Trans 3e: Orange solid M.p. 112ꢀ114 °C. 1H NMR (CDCl3, 300 MHz):
δ = 8.20 (d, J = 8.8
Hz, 2 H), 7.59 (d, J = 8.6 Hz, 2 H), 4.54 (quint, J = 3.0 Hz, 1 H), 4.15 (t, J = 7.0 Hz, 1 H), 3.65 (s, 3
H), 3.08 (ABq, 2 H), 3.05ꢀ2.94 (m, 2 H), 2.28ꢀ2.22 (m, 1 H), 2.04ꢀ2.00 (m, 3 H). 13C NMR (CDCl3, 75
MHz):
δ = 171.0 (C), 150.4 (C), 147.6 (C), 128.7 (2 × CH), 124.2 (2 × CH), 59.9 (CH), 56.5 (CH),
56.0 (CH2), 51.6 (CH3), 47.1 (CH2), 43.1 (CH2), 33.2 (CH2). ESIꢀHRMS calculated for
C14H17N2O4ClNa [M+Na]+ 335.0775, found 335.0775.
Methyl 2-(4-chloro-2-(3-nitrophenyl)piperidin-1-yl)acetate 3f (97%, 122 mg, dr: 45:55)
Cis 3f: Yellow solid M.p. 98ꢀ100 °C. 1H NMR (CDCl3, 300 MHz):
δ = 8.21 (s, 1 H), 8.15 (d, J = 8.1
Hz, 1 H), 7.71 (d, J = 7.6 Hz, 1 H), 7.53 (t, J = 7.9 Hz, 1 H), 3.97 (tt, J = 11.7, 4.3 Hz, 1 H), 3.86 (dd,
J = 11.4, 2.3 Hz, 1 H), 3.62 (s, 3 H), 3.11 (ddd, J = 11.7, 3.9, 2.6 Hz, 1 H), 3.09 (ABq, 2 H), 2.72 (td, J
= 12.2, 2.3 Hz, 1 H), 2.26ꢀ2.22 (m, 2 H), 2.06 (qd, J = 12.2, 4.1 Hz, 1 H), 1.90 (q, J = 11.9 Hz, 1 H).
13C NMR (CDCl3, 75 MHz):
δ = 170.8 (C), 148.7 (C), 144.4 (C), 133.8 (CH), 130.0 (CH), 123.1 (CH),
122.8 (CH), 64.5 (CH), 56.1 (CH), 54.8 (CH2), 52.2 (CH2), 51.5 (CH3), 46.0 (CH2), 36.7 (CH2). ESIꢀ
HRMS calculated for C14H17N2O4ClNa [M+Na]+ 335.0775, found 335.0777. Trans 3f: Orange oil H
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δ
= 8.26 (t, J = 1.1 Hz, 1 H), 8.14 (qd, J = 8.1 , 1.1 Hz, 1 H), 7.75 (d, J = 7.7
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Hz, 1 H), 7.52 (d, J = 7.9 Hz, 1 H), 4.55 (quint, J = 2.9 Hz, 1 H), 4.17 (t, J = 7.0 Hz, 1 H), 3.65 (s, 3
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H), 3.09 (dt, J = 11.9, 2.5 Hz, 1 H), 3.08 (ABq, 2 H), 2.98ꢀ2.92 (m, 1 H), 2.33ꢀ2.23(m, 1 H), 2.07ꢀ2.03
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(m, 3 H). C NMR (CDCl3, 75 MHz):
δ
= 170.9 (C), 148.7 (C), 145.0 (C), 134.1 (CH), 129.9 (CH),
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129.9 (CH), 122.9 (CH), 59.7 (CH), 56.6 (CH), 56.0 (CH2), 51.6 (CH3), 47.1 (CH2), 43.2 (CH2), 33.3
(CH2). ESIꢀHRMS calculated for C14H17N2O4ClNa [M+Na]+ 335.0775, found 335.0775.
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Methyl 2-(4-chloro-2-(4-(dimethylamino)phenyl)piperidin-1-yl)acetate 3g (60%, 75 mg, dr: 50:50)
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Cis 3g: White solid M.p. 88ꢀ90 °C. H NMR (CDCl3, 300 MHz):
δ = 7.17 (d, J = 8.7 Hz, 2 H), 6.68
(d, J = 8.7 Hz, 2 H), 3.95 (tt, J = 11.7, 4.4 Hz, 1 H), 3.60 (s, 3 H), 3.48 (dd, J = 11.4, 2.4 Hz, 1 H),
3.10 (ABq, 2 H), 3.09 (dt, J = 11.8, 3.4 Hz, 1 H), 2.94 (s, 6 H), 2.61 (td, J = 12.0, 2.4 Hz, 1 H), 2.22ꢀ
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2.17 (m, 2 H), 2.12ꢀ1.93 (m, 2 H). C NMR (CDCl3, 75 MHz):
δ = 171.5 (C), 150.3 (C), 129.5 (C),
128.5 (2 × CH), 112.7 (2 × CH), 65.2 (CH), 57.2 (CH), 54.9 (CH2), 52.5 (CH2), 51.3 (CH3), 45.8
(CH2), 40.7 (2 × CH3), 36.9 (CH2). ESIꢀHRMS calculated for C16H23N2O2ClNa [M+Na]+ 333.1346,
found 333.1345. Trans 3g: Brown solid M.p. 60ꢀ62 °C. 1H NMR (CDCl3, 300 MHz):
δ = 7.20 (d, J =
8.8 Hz, 2 H), 6.68 (d, J = 8.8 Hz, 2 H), 4.54 (quint, J = 2.9 Hz, 1 H), 3.80 (dd, J = 10.9, 2.8 Hz, 1 H),
3.62 (s, 3 H), 3.11 (ABq, 2 H), 2.94ꢀ2.89 (m, 8 H), 2.32ꢀ2.22 (m, 1 H), 2.17ꢀ2.08 (m, 1 H), 2.02ꢀ1.93
(m, 2 H). 13C NMR (CDCl3, 75 MHz):
δ = 171.7 (C), 150.2 (C), 129.9 (C), 128.7 (2 × CH), 112.7 (2 ×
CH), 60.0 (CH), 57.8 (CH), 56.1 (CH2), 51.4 (CH3), 47.6 (CH2), 42.9 (CH2), 40.7 (2 × CH3), 33.6
(CH2). ESIꢀHRMS calculated for C16H23N2O2ClNa [M+Na]+ 333.1346, found 333.1348.
Methyl 2-(4-chloro-2-(2,5-dimethoxyphenyl)piperidin-1-yl)acetate 3h (92%, 120 mg, dr: 87:13)
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Cis 3h: Yellow solid M.p. 78ꢀ80 °C. H NMR (CDCl3, 300 MHz):
δ = 7.10 (d, J = 2.85 Hz, 1 H),
6.81ꢀ6.73 (m, 2 H), 3.98ꢀ3.92 (m, 2 H), 3.77 (s, 3 H), 3.76 (s, 3 H), 3.62 (s, 3 H), 3.16 (dt, J = 11.7, 3.5
Hz, 1 H), 3.07 (ABq, 2 H), 2.52 (td, J = 12.0, 2.0 Hz, 1 H), 2.26ꢀ2.17 (m, 2 H), 2.08 (qd, J = 12.0, 4.0
Hz, 1 H), 1.87 (q, J = 12.0 Hz, 1 H). 13C NMR (CDCl3, 75 MHz):
δ = 171.4 (C), 154.3 (C), 151.0 (C),
130.9 (C), 113.9 (CH), 112.9 (CH), 112.2 (CH), 58.1 (CH), 56.9 (CH), 56.1(CH3), 55.8 (CH3), 55.6
(CH2), 53.2 (CH2), 51.5 (CH3), 44.6 (CH), 36.7 (CH). ESIꢀHRMS calculated for C16H22NO4ClNa
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[M+Na]+ 350.1135, found 350.1139. Trans 3h: Yellow solid M.p. 72ꢀ74 °C. H NMR (CDCl3, 300
MHz):
δ
= 7.11 (d, J = 3.00 Hz, 1 H), 6.81ꢀ6.75 (m, 2 H), 4.53 (quint, J = 2.9 Hz, 1 H), 4.32 (dd, J =
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7.7, 5.9 Hz, 1 H), 3.78 (s, 3 H), 3.76 (s, 3 H), 3.64 (s, 3 H), 3.10 (ABq, 2 H), 2.99ꢀ2.86 (m, 2 H), 2.29ꢀ
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2.24 (m, 1 H), 2.03ꢀ2.01 (m, 3 H). C NMR (CDCl3, 75 MHz):
δ = 171.8 (C), 154.3 (C), 151.5 (C),
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131.6 (C), 113.7 (CH), 113.1 (CH), 112.5 (CH), 57.5 (CH), 56.6 (CH2), 56.5 (CH), 55.9 (CH3), 53.0
(CH3), 51.6 (CH3), 48.1 (CH2), 41.7 (CH2), 33.5 (CH2). ESIꢀHRMS calculated for C16H22NO4ClNa
[M+Na]+ 350.1135, found 350.1144.
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Methyl 2-(4-chloro-2-(2-methoxyphenyl)piperidin-1-yl)acetate 3i (65%, 78 mg, dr: 85:15)
Cis 3i: Orange oil 1H NMR (CDCl3, 300 MHz):
δ = 7.50 (dd, J = 7.5, 1.7 Hz, 1 H), 7.22 (ddd, J = 8.2,
7.5, 1.7 Hz, 1 H), 6.97 (td, J = 8.2, 1.0 Hz, 1 H), 6.85 (dd, J = 8.2, 1.0 Hz, 1 H), 4.00ꢀ3.95 (m, 2 H),
3.80 (s, 3 H), 3.61 (s, 3 H), 3.18 (dt, J = 11.8, 3.4 Hz, 1 H), 3.06 (Abq, 2 H), 2.52 (td, J = 12.0, 2.5 Hz,
1 H), 2.23ꢀ2.13 (m, 2 H), 2.08 (qd, J = 12.1, 4.0 Hz, 1 H), 1.89 (q, J = 12.1 Hz, 1 H). 13C NMR
(CDCl3, 75 MHz):
δ = 171.5 (C), 156.8 (C), 129.8 (C), 128.4 (CH), 128.0 (CH), 121.2 (CH), 110.7
(CH), 57.9 (CH), 57.0 (CH), 55.6 (CH2), 55.5 (CH3), 53.2 (CH2), 51.5 (CH3), 44.6 (CH2), 36.8 (CH2).
ESIꢀHRMS calculated for C15H21NO3Cl [M+H]+ 298.1210 , found 298.1211. Trans 3i: Orange oil H
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NMR (CDCl3, 300 MHz):
δ = 7.50 (dd, J = 7.5, 1.7 Hz, 1 H), 7.22 (ddd, J = 8.2, 7.5, 1.7 Hz, 1 H),
6.95 (td, J = 8.2, 1.0 Hz, 1 H), 6.86 (dd, J = 8.2, 1.0 Hz, 1 H), 4.54 (quint, J = 2.8 Hz, 1 H), 4.35 (m, 1
H), 3.82 (s, 3 H), 3.63 (s, 3 H), 3.09 (ABq, 2 H), 3.02ꢀ2.86 (m, 2 H), 2.34ꢀ2.26 (m, 1 H), 2.06ꢀ1.95 (m,
3 H). 13C NMR (CDCl3, 75 MHz):
δ = 171.7 (C), 157.3 (C), 130.3 (C), 128.3 (CH), 128.3 (CH), 121.2
(CH), 110.8 (CH), 57.5 (CH), 56.5 (CH2), 55.7 (CH3), 52.8 (CH), 51.6 (CH3), 48.2 (CH2), 41.5 (CH2),
33.5 (CH2). ESIꢀHRMS calculated for C15H21NO3Cl [M+H]+ 298.1210 , found 298.1209.
Methyl 2-(4-chloro-2-(4-methoxyphenyl)piperidin-1-yl)acetate 3j (60%, 71 mg, dr: 62:38)
Cis 3j: Orange oil 1H NMR (CDCl3, 300 MHz):
δ = 7.23 (d, J = 8.6 Hz, 2 H), 6.85 (d, J = 8.6 Hz, 2
H), 3.95 (tt, J = 11.8, 4.3 Hz, 1 H), 3.80 (s, 3 H), 3.60 (s, 3 H), 3.56 (dd, J = 11.3, 2.3 Hz, 1 H), 3.09
(dt, J = 11.7, 3.4 Hz, 1 H), 3.08 (ABq, 2 H), 2.67 (td, J = 12.1, 2.4 Hz, 1 H), 2.22ꢀ2.17 (m, 2 H), 2.05
(qd, J = 12.1, 4.2 Hz, 1 H), 1.95 (q, J = 12.1 Hz, 1 H). 13C NMR (CDCl3, 75 MHz):
δ = 171.4 (C),
159.3 (C), 134.0 (C), 128.8 (2 × CH), 114.2 (2 × CH), 65.0 (CH), 57.0 (CH), 55.4 (CH3), 54.9 (CH2),
52.5 (CH2), 51.4 (CH3), 46.0 (CH2), 36.9 (CH2). ESIꢀHRMS calculated for C15H20NO3ClNa [M+Na]+
320.1029, found 320.1028. Trans 3j: Orange oil 1H NMR (CDCl3, 300 MHz):
δ = 7.27 (d, J = 8.7 Hz,
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2 H), 6.86 (d, J = 8.7 Hz, 2 H), 4.54 (quint, J = 3.0 Hz, 1 H), 3.87 (dd, J = 11.0, 2.4 Hz, 1 H), 3.79 (s,
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3 H), 3.63 (s, 3 H), 3.10 (ABq, 2 H), 2.98ꢀ2.94 (m, 2 H), 2.32ꢀ2.21 (m, 1 H), 2.15ꢀ1.94 (m, 3 H). C
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NMR (CDCl3, 75 MHz): δ = 171.6 (C), 159.2 (C), 134.4 (C), 129.0 (2 × CH), 114.2 (2 × CH), 59.9
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(CH), 57.6 (CH), 56.1 (CH2), 55.4 (CH3), 51.5 (CH3), 47.6 (CH2), 43.1 (CH2), 33.6 (CH2). ESIꢀHRMS
calculated for C15H20NO3ClNa [M+Na]+ 320.1029, found 320.1027.
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Methyl 2-(4-chloro-2-p-tolylpiperidin-1-yl)acetate 3k (74%, 83 mg, dr: 62:38)
Cis 3k: Orange oil 1H NMR (CDCl3, 300 MHz):
δ = 7.23 (d, J = 7.9 Hz, 2 H), 7.15 (d, J = 7.9 Hz, 2
H), 3.94 (tt, J = 11.7, 4.4 Hz, 1 H), 3.61 (s, 3 H), 3.60 (d, J = 7.7 Hz, 1 H), 3.12 (dt, J = 11.8, 3.4 Hz, 1
H), 3.10 (ABq, 2 H), 2.67 (td, J = 12.0, 2.1 Hz, 1 H), 2.34 (s, 3 H), 2.25ꢀ2.18 (m, 2 H), 2.09 (qd, J =
11.9, 4.0 Hz, 1 H), 2.00 (q, J = 12.1 Hz, 1 H). 13C NMR (CDCl3, 75 MHz):
δ = 171.3 (C), 138.8 (C),
137.7 (C), 129.6 (2 × CH), 127.6 (2 × CH), 65.4 (CH), 56.9 (CH), 54.9 (CH2), 52.5 (CH2), 51.4 (CH3),
45.9 (CH2), 36.8 (CH2), 21.2 (CH3). ESIꢀHRMS calculated for C15H21NO2Cl [M+H]+ 282.1261 , found
282.1264. Trans 3k: Orange oil 1H NMR (CDCl3, 300 MHz):
δ = 7.24 (d, J = 7.9 Hz, 2 H), 7.13 (d, J
= 7.9 Hz, 2 H), 4.54 (quint, J = 2.9 Hz, 1 H), 3.87 (dd, J = 10.8, 2.9 Hz, 1 H), 3.63 (s, 3 H), 3.11 (ABq,
2 H), 2.95ꢀ2.90 (m, 2 H), 2.32 (s, 3 H), 2.29ꢀ2.21 (m, 1 H), 2.15ꢀ2.06 (m, 1 H), 2.02ꢀ1.95 (m, 2 H). 13C
NMR (CDCl3, 75 MHz):
δ = 171.6 (C), 139.5 (C), 137.4 (C), 129.5 (2 × CH), 127.8 (2 × CH), 60.3
(CH), 57.5 (CH), 56.2 (CH2), 51.5 (CH3), 47.5 (CH2), 43.1 (CH2), 33.5 (CH2), 21.2 (CH3). ESIꢀHRMS
calculated for C15H21NO2Cl [M+H]+ 282.1261 , found 282.1264.
Methyl 2-(4-chloro-2-isopropylpiperidin-1-yl)acetate 3l (86%, 80 mg, dr: 43:57)
Cis 3l: Yellow oil 1H NMR (CDCl3, 300 MHz):
δ = 3.87 (tt, J = 11.8, 4.3 Hz, 1 H), 3.69 (s, 3 H), 3.41
(ABq, 2 H), 2.91 (ddd, J = 12.0, 4.6, 2.5 Hz, 1 H), 2.77 (td, J = 12.1, 2.6 Hz, 1 H), 2.55 (ddd, J = 11.4,
3.9, 2.0 Hz, 1H), 2.11ꢀ2.01 (m, 2 H), 1.96ꢀ1.79 (m, 2 H), 1.50 (q, J = 11.9 Hz, 1 H), 0.91 (d, J = 6.8
Hz, 3 H), 0.85 (d, J = 6.8 Hz, 3 H). 13C NMR (CDCl3, 75 MHz):
δ = 171.6 (C), 63.4 (CH), 58.4 (CH),
53.1 (CH2), 52.9 (CH2), 51.5 (CH3), 36.6 (CH2), 35.5 (CH2), 27.9 (CH), 20.0 (CH3), 15.2 (CH3). ESIꢀ
HRMS calculated for C11H21NO2Cl [M+H]+ 234.1261, found 234.1263. Trans 3l: Yellow oil 1H NMR
(CDCl3, 300 MHz):
δ = 4.50 (quint, J = 3.6 Hz, 1 H), 3.72 (s, 3 H), 3.42 (ABq, 2 H), 3.09 (td, J =
11.8, 2.8 Hz, 1 H), 2.85 (ddd, J = 9.8, 4.9, 3.0 Hz, 1 H), 2.76 (dt, J = 12.0, 4.1 Hz, 1 H), 2.05ꢀ1.97 (m,
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2 H), 1.87ꢀ1.81 (m, 2 H), 1.76 (qd, J = 9.8, 3.4 Hz, 1 H), 0.90 (d, J = 6.8 Hz, 3 H), 0.84 (d, J = 6.8 Hz,
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3 H). 13C NMR (CDCl3, 75 MHz):
δ = 171.9 (C), 58.9 (CH), 57.9 (CH), 54.3 (CH2), 51.6 (CH3), 47.9
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(CH2), 33.1 (CH2), 32.1 (CH2), 27.3 (CH), 19.9 (CH3), 15.9 (CH3). ESIꢀHRMS calculated for
C11H21NO2Cl [M+H]+ 234.1261, found 234.1259.
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Methyl 2-(4-chloro-2-phenethylpiperidin-1-yl)acetate 3m (52%, 61 mg, dr: 62:38)
Cis 3m: Orange oil 1H NMR (CDCl3, 300 MHz):
δ = 7.31ꢀ7.26 (m, 2 H), 7.21ꢀ7.16 (m, 3 H) 3.89 (tt, J
= 11.7, 4.4 Hz, 1 H), 3.68 (s, 3 H), 3.42 (ABq, 2 H), 2.96 (ddd, J = 12.2, 4.2, 2.9 Hz, 1 H), 2.77ꢀ2.52
(m, 4 H), 2.22 (dquint, J = 12.6, 2.2 Hz, 1 H), 2.09 (dsex, J = 12.6, 2.2 Hz, 1 H), 1.93ꢀ1.86 (m, 2 H),
1.77ꢀ1.65 (m, 2 H). 13C NMR (CDCl3, 75 MHz):
δ = 171.4 (C), 142.0 (C), 128.6 (2 × CH), 128.4 (2 ×
CH), 126.1 (CH), 58.5 (CH), 57.5 (CH), 53.2 (CH2), 52.9 (CH2), 51.6 (CH3), 41.3 (CH2), 36.2 (CH2),
34.9 (CH2), 31.0 (CH2). ESIꢀHRMS calculated for C16H23NO2Cl [M+H]+ 296.1417 , found 296.1425.
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Trans 3m: Orange oil H NMR (CDCl3, 300 MHz):
δ = 7.31ꢀ7.26 (m, 2 H), 7.21ꢀ7.16 (m, 3 H), 4.43
(quint, J = 4.2 Hz, 1 H), 3.70 (s, 3 H), 3.40 (ABq, 2 H), 3.06ꢀ2.95 (m, 2 H), 2.80ꢀ2.56 (m, 3 H), 2.09ꢀ
2.02 (m, 2 H), 1.97ꢀ1.89 (m, 3 H), 1.77ꢀ1.70 (m, 1 H). 13C NMR (CDCl3, 75 MHz):
δ
= 171.6 (C),
142.1 (C), 128.6 (2 × CH), 128.5 (2 × CH), 126.0 (CH), 57.0 (CH), 54.8 (CH), 54.8 (CH2), 51.8 (CH3),
47.8 (CH2), 38.1 (CH2), 33.5 (CH2), 33.0 (CH2), 31.6 (CH2). ESIꢀHRMS calculated for C16H23NO2Cl
[M+H]+ 296.1417 , found 296.1414.
Methyl 2-(4-chloro-2-heptylpiperidin-1-yl)acetate 3n (78%, 90 mg, dr: 62:38)
Cis 3n: Orange oil 1H NMR (CDCl3, 300 MHz):
δ = 3.88 (tt, J = 11.7, 4.3 Hz, 1 H), 3.70 (s, 3 H), 3.41
(s, 2 H), 2.94 (dt, J = 12.1, 3.0 Hz, 1 H), 2.69 (ddd, J = 12.1, 4.2, 2.8 Hz, 1 H), 2.66ꢀ2.62 (m, 1 H),
2.18ꢀ2.04 (m, 2 H), 1.89 (qd, J = 12.2, 4.3 Hz, 1 H), 1.60 (q, J = 11.9 Hz, 1 H), 1.26 (s, 12 H), 0.88 (t,
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J = 6.6 Hz, 3H). C NMR (CDCl3, 75 MHz):
δ = 171.5 (C), 59.1 (CH), 57.7 (CH), 53.4 (CH2), 53.0
(CH2), 51.6 (CH3), 41.4 (CH2), 36.3 (CH2), 33.2 (CH2), 31.9 (CH2), 30.0 (CH2), 29.3 (CH2), 24.9
(CH2), 22.8 (CH2), 14.2 (CH3). ESIꢀHRMS calculated for C15H28NO2ClNa [M+Na]+ 312.1706, found
312.1714. Trans 3n: Orange oil 1H NMR (CDCl3, 300 MHz):
δ = 4.42 (quint, J = 4.0 Hz, 1 H), 3.73
(s, 3 H), 3.42 (ABq, 2 H), 3.05ꢀ2.98 (m, 2 H), 2.77 (dt, J = 11.9, 4.3 Hz, 1H), 2.11ꢀ2.07 (m, 1 H), 1.96ꢀ
1.85 (m, 3 H), 1.26 (s, 12 H), 0.88 (t, J = 6.6 Hz, 3H). 13C NMR (CDCl3, 75 MHz):
δ = 171.5 (C), 57.1
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(CH), 55.1 (CH), 54.8 (CH2), 51.8 (CH3), 47.8 (CH2), 38.2 (CH2), 33.6 (CH2), 31.9 (CH2), 31.2 (CH2),
30.0 (CH2), 29.4 (CH2), 25.5 (CH2), 22.8 (CH2), 14.2 (CH3). ESIꢀHRMS calculated for
C15H28NO2ClNa [M+Na]+ 312.1706, found 312.1706.
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Cis 5a: Orange oil H NMR (CDCl3, 300 MHz):
δ = 7.27 (d, J = 8.9 Hz, 2 H), 7.10 (d, J = 8.9 Hz, 2
H), 6.86 (d, J = 8.3 Hz, 2 H), 6.64 (d, J = 8.3 Hz, 2 H), 4.02 (tt, J = 11.7, 4.3 Hz, 1 H), 3.91 (dd, J =
11.1, 2.6 Hz, 1 H), 3.67 (s, 3 H), 3.36 (dt, J = 12.4, 3.6 Hz, 1 H), 2.79 (td, J = 12.1, 3.0 Hz, 1 H), 2.37ꢀ
2.18 (m, 2 H), 2.17 (qd, J = 12.1, 4.1 Hz, 1 H), 1.96 (q, J = 12.1 Hz, 1 H). 13C NMR (CDCl3, 75
MHz):
δ = 156.0 (C), 144.5 (C), 142.2 (C), 131.5 (2 × CH), 129.3 (2 × CH), 125.7 (2 × CH), 120.5
(C), 114.0 (2 × CH), 64.6 (CH), 57.5 (CH2), 56.8 (CH), 55.3 (CH3), 46.9 (CH2), 37.5 (CH2). ESIꢀ
HRMS calculated for C18H20NOClBr [M+H]+ 380.0417 , found 380.0418. Trans 5a: Black solid M.p.
106ꢀ108 °C. 1H NMR (CDCl3, 300 MHz):
δ = 7.29 (d, J = 8.5 Hz, 2 H), 7.13 (d, J = 8.5 Hz, 2 H), 6.92
(d, J = 9.0 Hz, 2 H), 6.68 (d, J = 9.0 Hz, 2 H), 4.51ꢀ4.47 (m, 2 H), 3.70 (s, 3 H), 3.35 (td, J = 10.9, 2.8
Hz, 1 H), 3.16 (dt, J = 12.3, 4.1 Hz, 1 H), 2.36ꢀ2.26 (m, 1 H), 2.17ꢀ2.14 (m, 2 H), 2.03 (dd, J = 14.0,
3.0 Hz, 1 H). 13C NMR (CDCl3, 75 MHz):
δ = 155.4 (C), 145.2 (C), 142.3 (C), 131.5 (2 × CH), 129.4
(2 × CH), 124.4 (2 × CH), 120.4 (C), 114.1 (2 × CH), 58.7 (CH), 56.9 (CH), 55.4 (CH3), 50.7 (CH2),
43.4 (CH2), 34.5 (CH2). ESIꢀHRMS calculated for C18H20NOClBr [M+H]+ 380.0417 , found 380.0416.
4-chloro-1-(4-methoxyphenyl)-2-phenylpiperidine 5b (93%, 113 mg, dr: 23:77)
Cis 5b: Yellow solid M.p. 78ꢀ80 °C. 1H NMR (CDCl3, 300 MHz):
δ = 7.26ꢀ7.06 (m, 5 H), 6.89 (d, J =
9.0 Hz, 2 H), 6.63 (d, J = 9.0 Hz, 2 H), 4.01 (tt, J = 11.4, 4.5 Hz, 1 H), 3.93 (dd, J = 11.1, 2.7 Hz, 1 H),
3.65 (s, 3 H), 3.39 (dt, J = 12.4, 3.5 Hz, 1 H), 2.81 (td, J = 12.1, 3.1 Hz, 1 H), 2.40ꢀ2.34 (m, 1 H),
2.25ꢀ2.16 (m, 2 H), 2.02 (q, J = 11.9 Hz, 1 H). 13C NMR (CDCl3, 75 MHz):
δ = 155.8 (C), 144.9 (C),
143.1 (C), 128.3 (2 × CH), 127.6 (2 × CH), 126.9 (CH), 125.7 (2 × CH), 113.9 (2 × CH), 65.3 (CH),
57.6 (CH2), 57.1 (CH), 55.3 (CH3), 47.1 (CH2), 37.6 (CH2). ESIꢀHRMS calculated for C18H21NOCl
[M+H]+ 302.1306, found 302.1305. Trans 5b: Orange oil 1H NMR (CDCl3, 300 MHz):
δ = 7.27ꢀ7.08
(m, 5 H), 6.92 (d, J = 9.0 Hz, 2 H), 6.67 (d, J = 9.0 Hz, 2 H), 4.57 (dd, J = 8.5, 3.9 Hz , 1 H), 4.46
(quint, J = 4.1 Hz , 1 H), 3.66 (s, 3 H), 3.39 (td, J = 11.3, 2.9 Hz, 1 H), 3.18 (dt, J = 12.6, 4.4 Hz, 1 H),
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2.35ꢀ2.14 (m, 3 H), 2.06ꢀ1.99 (m, 1 H). 13C NMR (CDCl3, 75 MHz):
δ = 154.9 (C), 145.4 (C), 142.8
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(C), 128.4 (2 × CH), 127.6 (2 × CH), 126.7 (C), 123.6 (2 × CH), 114.1 (2 × CH), 59.2 (CH), 57.0
(CH), 55.4 (CH3), 50.1 (CH2), 43.1 (CH2), 34.6 (CH2). ESIꢀHRMS calculated for C18H21NOCl [M+H]+
302.1306, found 302.1306.
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4-chloro-2-(2-chlorophenyl)-1-(4-methoxyphenyl)piperidine 5c (99%, 130 mg, dr: 28:72)
Cis 5c: Yellow oil 1H NMR (CDCl3, 300 MHz):
δ = 7.45ꢀ7.41 (m, 1 H), 7.23ꢀ7.20 (m, 1 H), 7.04ꢀ6.95
(m, 2 H), 6.87 (d, J = 9.0 Hz, 2 H), 6.65 (d, J = 9.0 Hz, 2 H), 4.50 (dd, J = 11.0, 2.7 Hz, 1 H), 4.06 (tt,
J = 11.6, 4.5 Hz, 1 H), 3.67 (s, 3 H), 3.45 (dt, J = 12.4, 3.6 Hz, 1 H), 2.79 (td, J = 12.2, 3.0 Hz, 1 H),
2.48ꢀ2.43 (m, 1 H), 2.27ꢀ2.24 (m, 1 H), 2.19 (qd, J = 12.0, 4.2 Hz, 1 H), 1.85 (q, J = 12.0 Hz, 1 H). 13C
NMR (CDCl3, 75 MHz):
δ = 155.8 (C), 144.8 (C), 140.1 (C), 132.2 (C), 129.3 (CH), 129.2 (CH),
127.9 (CH), 127.2 (CH), 124.9 (2 × CH), 114.1 (2 × CH), 59.7 (CH), 58.0 (CH2), 56.8 (CH), 55.3
(CH3), 44.8 (CH2), 37.6 (CH2). ESIꢀHRMS calculated for C18H20NOCl2 [M+H]+ 336.0922 , found
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336.0923. Trans 5c: Yellow solid M.p. 96ꢀ98 °C. H NMR (CDCl3, 300 MHz):
δ = 7.42ꢀ7.38 (m, 1
H), 7.23ꢀ7.20 (m, 1 H), 7.01ꢀ6.97 (m, 2 H), 6.92 (d, J = 9.0 Hz, 2 H), 6.66 (d, J = 9.0 Hz, 2 H), 5.00
(dd, J = 10.4, 2.9 Hz, 1 H), 4.55 (quint, J = 3.2 Hz, 1 H), 3.65 (s, 3 H), 3.32ꢀ3.26 (m, 2 H), 2.37ꢀ2.23
(m, 2 H), 2.08ꢀ1.92 (m, 2 H). 13C NMR (CDCl3, 75 MHz):
δ = 155.5 (C), 145.5 (C), 140.7 (C), 132.5
(C), 129.3 (CH), 129.3 (CH), 127.7 (CH), 127.0 (CH), 124.5 (2 × CH), 114.1 (2 × CH), 56.9 (CH),
55.3 (CH3), 54.3 (CH), 52.1 (CH2), 41.9 (CH2), 34.4 (CH2). ESIꢀHRMS calculated for C18H20NOCl2
[M+H]+ 336.0922 ,found 336.0919.
4-chloro-1-(4-methoxyphenyl)-2-(4-nitrophenyl)piperidine 5d (92%, 131 mg, dr: 14:86)
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Trans 5d: Black solid M.p. 106ꢀ108 °C. H NMR (CDCl3, 300 MHz):
δ = 8.02 (d, J = 8.7 Hz, 2 H),
7.45 (d, J = 8.7 Hz, 2 H), 6.94 (d, J = 8.9 Hz, 2 H), 6.68 (d, J = 8.9 Hz, 2 H), 4.62 (dd, J = 9.6, 3.7 Hz,
1 H), 4.56 (quint, J = 3.3 Hz, 1 H), 3.68 (s, 3 H), 3.34 (td, J = 11.9, 2.7 Hz, 1 H), 3.19 (dt, J = 12.3, 3.9
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Hz, 1 H), 2.39ꢀ2.30 (m, 1 H), 2.18ꢀ2.05 (m, 3 H). C NMR (CDCl3, 75 MHz):
δ = 155.9 (C), 151.3
(C), 146.8 (C), 144.9 (C), 128.5 (2 × CH), 125.0 (2 × CH), 123.7 (2 × CH), 114.2 (2 × CH), 58.8
(CH), 56.6 (CH), 55.4 (CH3), 51.2 (CH2), 43.5 (CH2), 34.2 (CH2). ESIꢀHRMS calculated for
C18H20N2O3Cl [M+H]+ 347.1157, found 347.1160.
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4-chloro-1,2-bis(4-methoxyphenyl)piperidine 5e (40%, 52 mg, dr: 20:80)
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Trans 5e: Orange solid M.p. 98ꢀ100 °C. H NMR (CDCl3, 300 MHz):
δ = 7.16 (d, J = 8.8 Hz, 2 H),
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H), 2.05ꢀ1.99 (m, 1 H). C NMR (CDCl3, 75 MHz):
δ = 155.3 (C), 155.0 (C), 145.5 (C), 134.8 (C),
128.7 (2 × CH), 123.7 (2 × CH), 114.0 (2 × CH), 113.7 (2 × CH), 58.6 (CH), 57.1 (CH), 55.4 (CH3),
55.2 (CH3), 50.0 (CH2), 43.1 (CH2), 34.7 (CH2). ESIꢀHRMS calculated for C19H23NO2Cl [M+H]+
332.1417, found 332.1417.
4-chloro-1-(4-methoxyphenyl)-2-p-tolylpiperidine 5f (90%, 113 mg, dr: 22:78)
Cis 5f: Orange oil 1H NMR (CDCl3, 300 MHz):
δ = 7.10 (d, J = 7.9 Hz, 2 H), 6.95 (d, J = 7.9 Hz, 2
H), 6.89 (d, J = 9.0 Hz, 2 H), 6.63 (d, J = 9.0 Hz, 2 H), 4.03 (tt, J = 11.4, 4.7 Hz, 1 H), 3.89 (dd, J =
11.1, 2.7 Hz, 1 H), 3.66 (s, 3 H), 3.38 (dt, J = 12.3, 3.5 Hz, 1 H), 2.79 (td, J = 12.0, 3.1 Hz, 1 H), 2.38ꢀ
2.32 (m, 1 H), 2.24ꢀ2.15 (m, 5 H), 2.01 (q, J = 12.0 Hz, 1 H). 13C NMR (CDCl3, 75 MHz):
δ = 155.8
(C), 145.0 (C), 140.1 (C), 136.4 (C), 129.1 (2 × CH), 127.4 (2 × CH), 125.7 (2 × CH), 113.8 (2 × CH),
64.9 (CH), 57.6 (CH2), 57.2 (CH), 55.3 (CH3), 47.2 (CH2), 37.6 (CH2), 21.2(CH3). ESIꢀHRMS
calculated for C19H23NOCl [M+H]+ 316.1468, found 316.1465. Trans 5f: Orange solid M.p. 102ꢀ104
°C. 1H NMR (CDCl3, 300 MHz):
δ = 7.14 (d, J = 7.9 Hz, 2 H), 6.98 (d, J = 7.9 Hz, 2 H), 6.92 (d, J =
9.0 Hz, 2 H), 6.68 (d, J = 9.0 Hz, 2 H), 4.55 (dd, J = 8.5, 3.7 Hz, 1 H), 4.44 (quint, J = 4.7 Hz, 1 H),
3.66 (s, 3 H), 3.38 (td, J = 10.0, 3.0 Hz, 1 H), 3.18 (dt, J = 12.6, 4.6 Hz, 1 H), 2.29ꢀ2.13 (m, 6 H),
2.04ꢀ2.00 (m, 1 H). 13C NMR (CDCl3, 75 MHz):
δ = 155.8 (C), 145.5 (C), 139.7 (C), 136.2 (C), 129.1
(2 × CH), 127.5 (2 × CH), 123.4 (2 × CH), 114.1 (2 × CH), 58.9 (CH), 57.0 (CH), 55.4 (CH3), 49.9
(CH2), 43.1 (CH2), 34.7 (CH2), 21.1 (CH3). ESIꢀHRMS calculated for C19H23NOCl [M+H]+ 316.1468,
found 316.1468.
4-chloro-2-isopropyl-1-(4-methoxyphenyl)piperidine 5g (98%, 105 mg, dr: 9:91)
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Cis 5g: Orange oil H NMR (CDCl3, 300 MHz):
δ = 7.07 (d, J = 8.9 Hz, 2 H), 6.84 (d, J = 8.9 Hz, 2
H), 3.99 (tt, J = 11.5, 4.3 Hz, 1 H), 3.79 (s, 3 H), 3.07 (dt, J = 12.2, 3.6 Hz, 1 H), 2.75ꢀ2.67 (m, 2 H),
2.15ꢀ2.13 (m, 2 H), 1.99 (qd, J = 12.0, 4.3 Hz, 1 H), 1.71 (q, J = 11.5 Hz, 1 H), 1ꢀ70ꢀ1.65 (m, 1 H),
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0.78 (t, J = 7.2 Hz, 6 H). 13C NMR (CDCl3, 75 MHz):
δ
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(2 × CH), 65.0 (CH), 58.7 (CH), 56.9 (CH2), 55.5 (CH3), 37.5 (CH2), 35.7 (CH2), 28.2 (CH), 19.7
(CH3), 15.1 (CH3). ESIꢀHRMS calculated for C15H23NOCl [M+H]+ 268.1468, found 268.1465. Trans
5g: Orange oil 1H NMR (CDCl3, 300 MHz):
δ = 6.93 (d, J = 9.1 Hz, 2 H), 6.82 (d, J = 9.1 Hz, 2 H),
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4.37 (sp, J = 4.1 Hz 1 H), 3.76 (s, 3 H), 3.44 (dt, J = 13.8, 4.7 Hz, 1 H), 3.30 (m, 1 H), 3.03 (m, 1 H),
2.13ꢀ2.07 (m, 2 H), 1.96ꢀ1.86 (m, 3 H), 0.89 (d, J = 6.7 Hz, 3 H), 0.85 (d, J = 6.7 Hz, 3 H). 13C NMR
(CDCl3, 75 MHz):
δ = 153.8 (C), 145.3 (C), 120.4 (2 × CH), 114.6 (2 × CH), 62.5 (CH), 56.7 (CH),
55.7 (CH3), 46.0 (CH2), 34.7 (CH2), 34.5 (CH2), 27.5 (CH), 20.4 (CH3), 18.6 (CH3). ESIꢀHRMS
calculated for C15H23NOCl [M+H]+ 268.1468, found 268.1466.
2-(4-bromophenyl)-4-chloropiperidine cis 7a Yellow solid (77%, 84 mg)
M.p. 64ꢀ66 °C. 1H NMR (CDCl3, 300 MHz):
δ = 7.45 (d, J = 8.4 Hz, 2 H), 7.23 (d, J = 8.4 Hz, 2 H),
3.99 (tt, J = 11.7, 4.3 Hz, 1 H), 3.61 (dd, J = 11.4, 2.5 Hz, 1 H), 3.23 (ddd, J = 12.2, 2.5, 1.7 Hz, 1 H),
2.79 (td, J = 12.2, 2.5 Hz, 1 H), 2.30ꢀ2.17 (m, 2 H), 1.84 (ddd, J = 12.2, 4.6, 2.3 Hz, 1 H), 1.82 (s,
NH), 1.76 (q, J = 12.0 Hz, 1 H). 13C NMR (CDCl3, 75 MHz):
δ = 142.4 (C), 131.8 (2 × CH), 128.5 (2
× CH), 121.4 (C), 61.0 (CH), 57.4 (CH), 46.4 (CH2), 45.3 (CH2), 36.8 (CH2). ESIꢀHRMS calculated
for C11H14NClBr [M+H]+ 273.9998, found 273.9998.
4-chloro-2-phenylpiperidine cis 7b10a Yellow solid (86%, 68 mg)
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M.p. 60ꢀ62 °C. H NMR (CDCl3, 300 MHz):
δ = 7.37ꢀ7.29 (m, 5 H), 4.04 (tt, J = 11.8, 4.4 Hz, 1 H),
3.66 (dd, J = 11.4, 2.4 Hz, 1 H), 3.26 (ddd, J = 12.2, 4.4, 2.4 Hz, 1 H), 2.66 (td, J = 12.2, 2.4 Hz, 1 H),
2.34 (dquint, J = 12.6, 2.3 Hz, 1 H), 2.22 (dsex, J = 12.6, 2.3 Hz, 1 H), 1.90ꢀ1.88 (m, 3 H). 13C NMR
(CDCl3, 75 MHz):
δ = 143.4 (C), 128.7 (2 × CH), 127.7 (CH), 126.7 (2 × CH), 61.6 (CH), 57.7 (CH),
46.5 (CH2), 45.4 (CH2), 37.0 (CH2). ESIꢀHRMS calculated for C11H15NCl [M+H]+ 196.0893 , found
196.0897.
4-chloro-2-(2-chlorophenyl)piperidine cis 7c Orange oil (80%, 74 mg)
1H NMR (CDCl3, 300 MHz):
δ = 7.62 (dd, J = 7.7, 1.7 Hz, 1 H), 7.36ꢀ7.17 (m, 3 H), 4.14 (dd, J =
11.3, 2.0 Hz, 1 H), 4.03 (tt, J = 11.7, 4.3 Hz, 1 H), 3.41 (bs, NH), 3.26 (ddd, J = 12.2, 4.1, 2.5 Hz, 1
H), 2.85 (td, J = 12.2, 2.5 Hz, 1 H), 2.40 (dquint, J = 12.6, 2.1 Hz, 1 H), 2.22 (dsex, J = 12.6, 2.1 Hz, 1
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H), 1.93 (qd, J = 12.1, 4.3 Hz, 1 H), 1.76 (q, J = 12.1 Hz, 1 H). 13C NMR (CDCl3, 75 MHz):
δ = 139.7
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43.1 (CH2), 36.4 (CH2). ESIꢀHRMS calculated for C11H14NCl2 [M+H]+ 230.0503 , found 230.0503.
4-chloro-2-(4-nitrophenyl)piperidine cis 7d10a Orange solid (82%, 79 mg)
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M.p. 100ꢀ102 °C. 1H NMR (CDCl3, 300 MHz):
δ = 8.20 (d, J = 8.6 Hz, 2 H), 7.56 (d, J = 8.6 Hz, 2 H),
4.02 (tt, J = 11.8, 4.4 Hz, 1 H), 3.79 (dd, J = 11.3, 2.4 Hz, 1 H), 3.28 (ddd, J = 12.2, 4.3, 2.6 Hz, 1 H),
2.84 (td, J = 12.2, 2.6 Hz, 1 H), 2.35ꢀ2.20 (m, 2 H), 1.94 (bs, NH), 1.87 (qd, J = 12.2, 4.5 Hz, 1 H),
1.77 (q, J = 12.2 Hz, 1 H). 13C NMR (CDCl3, 75 MHz):
δ = 150.8 (C), 147.5 (C),127.6 (2 × CH),
124.0 (2 × CH), 61.0 (CH), 57.0 (CH), 46.3 (CH2), 45.3 (CH2), 36.7 (CH2). ESIꢀHRMS calculated for
C11H14N2O2Cl [M+H]+ 241.0744 , found 241.0747.
4-chloro-2-(4-methoxyphenyl)piperidine cis 7e10a White solid (34%, 31 mg)
M.p. 74ꢀ76 °C. 1H NMR (CDCl3, 300 MHz):
δ = 7.26 (d, J = 8.6 Hz, 2 H), 6.86 (d, J = 8.6 Hz, 2 H),
3.99 (tt, J = 11.7, 4.4 Hz, 1 H), 3.79 (s, 3 H), 3.59 (dd, J = 11.2, 2.3 Hz, 1 H), 3.22 (ddd, J = 12.2, 4.4,
2.6 Hz, 1 H), 2.79 (td, J = 12.3, 2.5 Hz, 1 H), 2.28 (dquint, J = 12.5, 2.3 Hz, 1 H), 2.19 (dsex, J = 12.6,
2.3 Hz, 1 H), 1.91ꢀ1.74 (m, 3 H). 13C NMR (CDCl3, 75 MHz):
δ = 159.1 (C), 135.6 (C), 127.8 (2 ×
CH), 114.0 (2 × CH), 61.1 (CH), 57.8 (CH), 55.4 (CH3), 46.5 (CH2), 45.5 (CH2), 37.0 (CH2). ESIꢀ
HRMS calculated for C12H17NOCl [M+H]+ 226.0998, found 226.0998.
4-chloro-2-p-tolylpiperidine cis 7f White solid (70%, 58 mg)
M.p. 78ꢀ80 °C. 1H NMR (CDCl3, 300 MHz):
δ = 7.23 (d, J = 8.0 Hz, 2 H), 7.13 (d, J = 8.0 Hz, 2 H),
3.98 (tt, J = 11.7, 4.4 Hz, 1 H), 3.58 (dd, J = 11.3, 2.3 Hz, 1 H), 3.21 (ddd, J = 12.2, 4.3, 2.6 Hz, 1 H),
2.77 (td, J = 12.3, 2.5 Hz, 1 H), 2.32 (s, 3 H), 2.27 (dquint, J = 12.5, 2.2 Hz, 1 H), 2.17 (dsex, J = 12.5,
2.3 Hz, 1 H), 1.90ꢀ1.74 (m, 2 H), 1.67 (s, 1 H). 13C NMR (CDCl3, 75 MHz):
δ = 140.5 (C), 137.2 (C),
129.3 (2 × CH), 126.5 (2 × CH), 61.3 (CH), 57.8 (CH), 46.5 (CH2), 45.5 (CH2), 37.0 (CH2), 21.1
(CH3). ESIꢀHRMS calculated for C12H17NCl [M+H]+ 210.1049, 210.1051.
4-chloro-2-isopropylpiperidine cis 7g Orange oil (88%, 57 mg)
1H NMR (CDCl3, 300 MHz):
δ = 3.90 (tt, J = 11.7, 4.3 Hz, 1 H), 3.17 (ddd, J = 12.6, 4.5, 2.5 Hz, 1 H),
2.64 (td, J = 12.6, 2.5 Hz, 1 H), 2.30 (ddd, J = 11.3, 5.8, 2.2 Hz, 1H), 2.21ꢀ2.10 (m, 2 H), 1.82 (bs,
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NH), 1.70 (qd, J = 11.9, 4.5 Hz, 1 H), 1.64ꢀ1.58 (m, 1 H), 1.42 (q, J = 11.9 Hz, 1 H), 0.94 (d, J = 2.6
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Hz, 3 H), 0.92 (d, J = 2.6 Hz, 3 H). 13C NMR (CDCl3, 75 MHz):
δ = 62.6 (CH), 58.6 (CH), 46.3
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(CH2), 40.6 (CH2), 37.7 (CH2), 33.1 (CH), 19.0 (CH3), 18.8 (CH3). ESIꢀHRMS calculated for
C8H17NCl [M+H]+ 162.1049 , found 162.1049.
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4-chloro-2-phenyl-1-tosylpiperidine trans 112a Yellow solid (93%, 130 mg)
M.p. 104ꢀ106 °C. 1H NMR (CDCl3, 300 MHz):
δ = 7.78 (d, J = 8.2 Hz, 2 H), 7.35ꢀ7.26 (m, 7 H), 5.40
(d, J = 5.0 Hz, 1 H), 3.99ꢀ3.86 (m, 2 H), 3.09ꢀ2.99 (m, 1 H), 2.73 (dquint, J = 13.6, 1.9 Hz, 1 H), 2.46
(s, 3 H), 1.94ꢀ1.83 (m, 2 H), 1.64ꢀ1.50 (m, 1 H). 13C NMR (CDCl3, 75 MHz):
δ
= 143.7 (C), 138.1 (C),
137.4 (C), 130.1 (2 × CH), 129.1 (2 × CH), 127.5 (C), 127.0 (2 × CH), 126.6 (2 × CH), 56.1 (CH),
52.9 (CH), 41.5 (CH2), 37.7 (CH2), 35.3 (CH2), 21.7 (CH2). ESIꢀHRMS calculated for
C18H20NO2ClNaS [M+Na]+ 372.0801 , found 372.0802.
1-benzyl-4-chloro-2-phenylpiperidine 12 (64%, 73 mg, dr: 52:48)
Cis 12: White solid M.p. 134ꢀ136 °C. 1H NMR (CDCl3, 300 MHz):
δ = 7.44 (d, J = 7.1 Hz, 2 H), 7.36ꢀ
7.19 (m, 8 H), 3.92 (tt, J = 11.6, 4.2 Hz, 1 H), 3.26 (ABq, 2 H), 3.20 (dd, J = 11.3, 2.7 Hz, 1 H), 3.00
(dd, J = 11.2, 3.0 Hz, 1 H), 2.30ꢀ2.23 (m, 1 H), 2.12ꢀ1.87 (m, 4 H). 13C NMR (CDCl3, 75 MHz):
δ
=
143.5 (C), 139.2 (C), 128.9 (2 × CH), 128.7 (2 × CH), 128.3 (2 × CH), 127.6 (CH), 127.5 (2 × CH),
126.9 (CH), 68.5 (CH), 58.8 (CH2), 57.3 (CH), 52.1 (CH2), 46.7 (CH2), 36.8 (CH2). ESIꢀHRMS
calculated for C18H21NCl [M+H]+ 286.1362, found 286.1361. Trans 12: White solid M.p. 126ꢀ128 °C.
1H NMR (CDCl3, 300 MHz):
δ = 7.47 (d, J = 7.1 Hz, 2 H), 7.35ꢀ7.19 (m, 8 H), 4.51 (t, J = 2.9 Hz, 1
H), 3.70 (dd, J = 8.5, 5.5 Hz, 1 H), 3.34 (ABq, 2 H), 2.78 (dt, J = 11.9, 3.5 Hz, 1 H), 2.54 (td, J = 12.1,
2.6 Hz, 1 H), 2.10ꢀ2.06 (m, 3 H), 1.88 (d, J = 14.2 Hz, 1 H). 13C NMR (CDCl3, 75 MHz):
δ
= 144.2
(C), 139.6 (C), 128.8 (2 × CH), 128.7 (2 × CH), 128.2 (2 × CH), 127.7 (2 × CH), 127.4 (CH), 126.8
(CH), 62.5 (CH), 59.4 (CH2), 57.8 (CH), 46.3 (CH2), 43.8 (CH2), 33.6 (CH2). ESIꢀHRMS calculated
for C18H21NCl [M+H]+ 286.1362, found 286.1361.
4-chloro-2-phenyl-1-propylpiperidine 13 (90%, 85 mg, dr: 57:43)
Cis 13: Yellow oil 1H NMR (CDCl3, 300 MHz):
δ = 7.32ꢀ7.24 (m, 5 H), 3.92 (tt, J = 11.7, 4.3 Hz, 1
H), 3.20 (dt, J = 11,3, 3.2 Hz, 1 H), 3.08 (dd, J = 11.3, 2.5 Hz, 1 H), 2.37ꢀ2.30 (m, 1 H), 2.24ꢀ2.16 (m,
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2 H), 2.10ꢀ1.79 (m, 4 H), 1.36 (q, J = 7.6 Hz, 2 H), 0.71 (t, J = 7.3 Hz, 3 H). 13C NMR (CDCl3, 75
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MHz):
δ = 143.6 (C), 128.7 (2 × CH), 127.6 (2 × CH), 127.4 (CH), 68.5 (CH), 57.4 (CH), 56.2 (CH2),
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52.0 (CH2), 46.6 (CH2), 37.0 (CH2), 19.5 (CH2), 11.8 (CH3). ESIꢀHRMS calculated for C14H21NCl
1
[M+H]+ 238.1362, found 238.1359. Trans 13: Yellow oil H NMR (CDCl3, 300 MHz):
δ = 7.35ꢀ7.23
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(m, 5 H), 4.51 (quint, J = 2.9 Hz, 1 H), 3.59 (dd, J = 8.9, 4.7 Hz, 1 H), 2.97 (dt, J = 11.9, 3.2 Hz, 1 H),
2.64 (td, J = 12.0, 2.1 Hz, 1 H), 2.44ꢀ2.34 (m, 1 H), 2.18 (t, J = 13.1 Hz 1 H), 2.01ꢀ1.97 (m, 4 H),
1.44ꢀ1.37 (m, 2 H), 0.72 (t, J = 7.4 Hz, 3 H). 13C NMR (CDCl3, 75 MHz):
δ = 144.1 (C), 128.6 (2 ×
CH), 127.8 (2 × CH), 127.2 (CH), 62.2 (CH), 57.9 (CH), 56.8 (CH2), 46.3 (CH2), 43.6 (CH2), 33.7
(CH2), 19.4 (CH2), 11.9 (CH3). ESIꢀHRMS calculated for C14H21NCl [M+H]+ 238.1362, found
238.1362.
Supporting Information
Copies of 1H NMR and 13C NMR spectra for products 1ꢀ4ꢀ8ꢀ9ꢀ10, for all piperidines 3ꢀ5ꢀ7ꢀ11ꢀ12ꢀ13
and Xꢀray crystallographic data, and crystal structure of compounds trans 3e and cis 7a are provided.
The Supporting Information is available free of charge on the ACS Publications website at DOI:
Author information
Corresponding author
*Eꢀmail: pierre.vanꢀdeꢀweghe@univꢀrennes1.fr
*Eꢀmail: claudia.lalli@univꢀrennes1.fr
The authors declare no competing financial interest.
Acknowledgments
We thank Université de Rennes 1, CNRS, Rennes Métropole and Région Bretagne for financial
support. The CRMPO de l’Institut des Sciences Chimiques de Rennes is gratefully acknowledged for
mass measurement.
References
1. (a) Pastor, I. M.; Yus, M. Curr. Org. Chem. 2012, 16, 1277. (b) Olier, C.; Kaafarini, M.; Gastaldi,
S.; Bertrand, M. P. Tetrahedron 2010, 66, 413.
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