On the scope of Pd-catalyzed carboamination reactions - Synthesis of 2,4-disubstituted pyrrolidines and 2-substituted piperidines and morpholines

Article abstract of DOI:10.1016/j.tet.2010.06.004

The scope of the palladium-catalyzed carboamination reaction for the synthesis of 2-substituted pyrrolidines, piperidines, and morpholines was investigated. Formation of a 2,4-disubstituted pyrrolidine proceeded in high yield but with a diastereoisomeric ratio of only 2:5, favoring the cis-isomer. The diastereoselectivity is hence significantly smaller than that observed previously in the formation of 2,3- and 2,5-disubstituted pyrrolidines. The yields of substituted piperidines and morpholines were lowered by competing Heck arylation reactions. Both the N-substituent and the choice of phosphine ligand for the palladium-catalyzed reaction were determining for the outcome. The scope of the palladium-catalyzed carboamination reaction for the synthesis of 2-substituted pyrrolidines, piperidines, and morpholines was investigated.

Full text of DOI:10.1016/j.tet.2010.06.004

Tetrahedron 66 (2010) 6133e6137
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Tetrahedron
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On the scope of Pd-catalyzed carboamination reactionsdsynthesis of 2,4-
disubstituted pyrrolidines and 2-substituted piperidines and morpholines
,
,
a,
Tue Heesgaard Jepsen a b, Mogens Larsen b , Mogens Brøndsted Nielsen
*
*
a Department of Chemistry, University of Copenhagen, Universitetsparken 5, DK-2100, Copenhagen Ø, Denmark
b Department of Medicinal Chemistry, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Copenhagen, Denmark
a r t i c l e i n f o
a b s t r a c t
Article history:
The scope of the palladium-catalyzed carboamination reaction for the synthesis of 2-substituted pyr-
rolidines, piperidines, and morpholines was investigated. Formation of a 2,4-disubstituted pyrrolidine
proceeded in high yield but with a diastereoisomeric ratio of only 2:5, favoring the cis-isomer. The di-
astereoselectivity is hence significantly smaller than that observed previously in the formation of 2,3-
and 2,5-disubstituted pyrrolidines. The yields of substituted piperidines and morpholines were lowered
by competing Heck arylation reactions. Both the N-substituent and the choice of phosphine ligand for the
palladium-catalyzed reaction were determining for the outcome.
Received 15 February 2010
Received in revised form 7 May 2010
Accepted 1 June 2010
Available online 9 June 2010
Keywords:
Carboamination
Diastereoselectivity
Morpholine
Ó 2010 Elsevier Ltd. All rights reserved.
Piperidine
Pyrrolidine
1. Introduction
2,3- and 2,5-disubstituted pyrrolidines were prepared with excellent
diastereoselectivities of dr >1:20 corresponding to trans-2,3-pyrro-
Numerous biologically active molecules incorporate a frame-
work of substituted pyrrolidines, piperidines, and morpholines.1
These heterocyclic compounds are often used as drug targets, and
development of new ways for their synthesis and functionalization
is therefore of significant interest. There are two general methods of
functionalizing these aliphatic heterocycles. The first method is di-
rect functionalization of the parent heterocycle. This approach is
neither very easy nor very stereoselective, and a more convenient
method is the intramolecular cyclization of a suitably functionalized
aliphatic chain. Several methods for CeN forming intramolecular
reactions are found in literature,2 but often they require harsh re-
action conditions or lack the opportunity for further functionaliza-
tion of the molecule. Few methods exist that allow a simultaneous
intramolecular CeN bond formation and an intermolecular CeC
bond formation in the 2-position of the heterocycle.3
lidines and cis-2,5-pyrrolidines as the favored products.4a In addition,
Wolfe and Bertrand4a have reported one example of formation of
a 2,4-disubstituted pyrrolidine, for which an unspecified (in regard to
cis/trans isomers) diastereoselectivity of dr¼1:3 was observed. Mi-
chael and Cochran7 have prepared 2,4-disubstituted pyrrolidines in
cis/trans ratios of 7:3, but the exact carboamination conditions were
different from those of Wolfe and co-workers.
We became interested in further investigating the diaster-
eoselective synthesis of N-protected 2,4-disubstituted pyrrolidines
by carboamination of suitable g
-aminoalkenes.8 Further, we pres-
ent here the synthesis of N-substituted 2-benzylpiperidines and 2-
benzylmorpholines via the carboamination protocol. It should be
noted that an alternative palladium-catalyzed carboamination re-
action between aminoalkenes and unactivated arenes (i.e., without
a halide group) promoted by N-fluorobenzenesulfonimide was re-
cently reported by Michael and co-workers.9 In fact, halobenzenes
were also subjected to this method without breaking the
arylehalide bond.
Wolfe and co-workers have developed an efficient method of
synthesizing 2-substituted pyrrolidines,4 piperazines,5 and mor-
pholines6 via palladium-catalyzed carboamination. This reaction is
particularly attractive because it proceeds under relatively mild re-
action conditions and because biologically active molecules often
contain substituents in the 2-position of the heterocycle. N-Protected
2. Results and discussion
2.1. Synthesis of pyrrolidines
Using the method of Wolfe, a Pd-catalyzed carboamination re-
* Corresponding authors. E-mail addresses: mola@lundbeck.com (M. Larsen),
mbn@kiku.dk (M.B. Nielsen).
action between p-bromoanisole and (pent-4-enyl) carbamic acid
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.004

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T.H. Jepsen et al. / Tetrahedron 66 (2010) 6133e6137
tert-butyl ester (14a) in the presence of the phosphine bis(2-
diphenylphosphinophenyl) ether (dpe-phos) furnished quantita-
tively 2-(p-methoxybenzyl)pyrrolidine-1-yl-carboxylic acid tert-
butyl ester (4) (Scheme 1, Table 1dentry 1). The Boc-protected
compound 4 was subsequently deprotected using HCl in methanol,
generating the ammonium salt 5 in a yield of 70% (Scheme 1).
Changing the phosphine ligand to the racemic 2,20-bis(diphenyl-
phosphino)-1,10-binaphthyl (BINAP, entry 2) provided a signifi-
cantly lower yield of 4. The chiral nature of BINAP was found to play
ratio obtained is similar to the one reported by Wolfe and Ber-
trand4a for the formation of 2-benzyl-4-allylpyrrolidine (dr¼1:3).
Yet, the preferred stereoisomer (cis or trans) was not determined in
this previous work.
2.2. Synthesis of piperidines
In order to develop a method for synthesizing N-protected 2-
substituted piperidines, the reaction conditions were screened and
Boc
N
H2
N
H
H
H
Cl
Boc
N
H
R
H
R
H
R
R
R = H: 1
R = Ph: 2
MeO
MeO
MeO
MeO
i)
ii)
+
+
Boc
N
H2
N
H
Cl
+
Br
R
H
H
MeO
R = H: 4
R = Ph: cis/ trans-
R = H: 5
R = Ph: cis/ trans-
3
6
7
Scheme 1. Conditions: (i) Pd2(dba)3, NaOt-Bu, phosphine ligand (Table 1), toluene, 105 ꢀC, 15 h; (ii) HCl, MeOH. dba¼dibenzylidene acetone.
different N-protective groups were used, such as Boc, phenyl, tosyl,
and mesyl according to the reactants 8,7 9,10 10,11 and 11 (prepared
Table 1
by treating 10 with MsNH2 and NaH in DMSO) (Scheme 2, Table 2).
Generally the piperidine synthesis was complicated on account of
a competing Heck reaction.12 The monodentate phosphine ligand P
(2-furyl)3 was the best choice of ligand for accomplishing the pi-
peridine. It was not possible to convert the Boc-protected precursor
8 by using the bidentate ligand dpe-phos (entry 1), but with use of
Products from carboamination of precursors 1 and 2
Entry
R
Liganda
Conversionb (%) Product
Yieldb (Isolated)
1
2
3
4
H
H
H
dpe-phos 100
4
4
4
100% (99%)
BINAP
70
69
70% (45%c)
(R)-BINAP
69% (45%c)
Ph dpe-phos 100
cis/trans-6
cis-6 trans-6
100% (93%) 71%d 29%d
a
dpe-phos
(2 mol %)¼bis(2-diphenylphosphinophenyl)
ether,
2 mol %
R
N
BINAP¼2,20-bis(diphenylphosphino)-1,10-binaphthyl.
R
b
According to LC-MS.
Racemic mixture (1:1).
N
c
H
A
8
d
R = Boc:
The ratio between cis-6 and trans-6 was evaluated after Boc deprotection and
isolation of pure cis-7 and trans-7.
R = Ph:
R = Ts:
R = Ms:
9
MeO
10
11
i)
R
NH
+
no role for the stereochemical outcome; thus, with (R)-BINAP the
same 1:1 racemic mixture of 4 was obtained (entry 3).
+
The next objective was to elucidate the stereochemistry in the
formation of N-protected 2,4-disubstituted pyrrolidines. Subjecting
(2-phenylpent-4-enyl) carbamic acid tert-butyl ester (27) to the
carboamination reaction provided cis/trans-2-(p-methoxybenzyl)-
4-phenylpyrrolidine-1-yl-carboxylic acid tert-butyl ester (cis/trans-
6) (Scheme 1, Table 1dentry 4). A 100% conversion was observed by
LC-MS, and a total yield of 93% of the two diastereoisomers was
isolated. Deprotection of the mixture of cis/trans-6 using HCl in
methanol gave the two diastereoisomeric ammonium salts cis-7
and trans-7 in an overall yield of 83% (Scheme 1). According to 1H
NMR spectroscopy as well as analytical HPLC using a chiral column,
the two isomers were present in a ratio of 29:71z2:5. Fortunately,
these salts could be separated by preparative Supercritical Fluid
Chromatography (SFC) using a chiral column (eluent: 0.5% dieth-
ylamine in ethanol), and the stereochemistry was determined by
2D NOESY NMR. The isomer trans-7 was isolated in a yield of 14%,
while cis-7 was isolated in a yield of 29%. Thus, the cis-isomer was
isolated in majority, and the carboamination reaction forming cis/
trans-6 can now be characterized by a dr of 2:5 in favor of the cis-
isomer. The diastereoisomer selectivity for formation of 2,4-di-
substituted pyrrolidines is therefore significantly smaller than that
for formation of 2,3- and the 2,5-disubstituted pyrrolidines. The
Br
B
MeO
MeO
12
R = Boc:
R = Ph: 14
3
15
R = Ts:
16
R = Ms:
H2
N
Cl
ii)
12A
MeO
13A
NH3
Cl
ii)
12b
MeO
13B
Scheme 2. Conditions: (i) Pd2(dba)3, NaOt-Bu, phosphine ligand (Table 2), toluene,
105 ꢀC, 15 h; (ii) HCl, MeOH. dba¼dibenzylidene acetone.

T.H. Jepsen et al. / Tetrahedron 66 (2010) 6133e6137
6135
Table 2
Table 3
Products from carboamination of precursors 8-11
Products from carboamination of precursors 17e20
Entry
R
Liganda
Conversion Product Yieldb (Isolated)
(%)
Entry R Liganda
Conversion Product Yieldb (Isolated)
(%)
A
B
A
B
1
2
3
Boc dpe-phos
Boc P(2-furyl)3
Boc P(2-furyl)3
0
50
6c
12
12
12
d
d
1
2
3
4
Boc dpe-phosc or P(2-furyl)3
Bn P(2-furyl)3
Ph P(2-furyl)3
Ts P(2-furyl)3
0
0
100
100
21
22
23
24
d
d
d
d
24% (13%) 26% (9%)
35% (17%) 30%
100% (69%) 0%
0% 95% (39%)
4
5
6
Ph P(2-furyl)3
Ts dpe-phosd
Ts P(2-furyl)3
80
10
70
14
15
15
75% (51%) 0%
0%
0%
a
dpe-phos (2 mol %)¼bis(2-diphenylphosphinophenyl) ether, 8 mol % P(2-fur-
100%
70% (41%)
yl)3¼tris(2-furyl)phosphine.
b
According to LC-MS.
Using either 2 or 4 mol % dpe-phos.
7
Ms dpe-phos or P(2-furyl)3 0%
16
d
d
c
a
dpe-phos (2 mol %)¼bis(2-diphenylphosphinophenyl) ether, 8 mol % P(2-fur-
yl)3¼tris(2-furyl)phosphine.
b
According to LC-MS.
Pd(OAc)2 was used instead of Pd2(dba)3.
dpe-phos (4 mol %) was used instead of 2 mol %.
arylation. We also attempted to prepare the N-tosyl-protected
morpholine 24A, but the conditions gave instead 95% of the Heck
product 24B (entry 4) according to LC-MS analysis. In addition, 5%
of a product corresponding to two subsequent Heck reactions was
observed. Changing the solvent from toluene to dioxane resulted in
an increase of two-fold Heck arylation products to 31% (using dpe-
phos). Using Cs2CO3 instead of NaOt-Bu as base still only gave Heck
coupling products.
c
d
P(2-furyl)3 (entries 2 and 3) it was possible to obtain 35% of the
piperidine 12A according to LC-MS. The N-Boc-protected com-
pounds 12A and 12B (Heck product) were deprotected using HCl in
methanol, and the products 13A and 13B were isolated in yields of
78% and 81%, respectively (Scheme 2).
Carboamination of the N-phenyl-substituted substrate 9 gave an
LC-MS based yield of 75% of the N-phenyl-substituted piperidine
14A (entry 4). When the N-protecting group was changed to a tosyl
group (compound 10), a 70e100% conversion of the starting ma-
terial was observed (entries 5 and 6). Yet, only the Heck product
15B was now obtained. Subjecting instead the N-mesyl precursor
11 to the reaction conditions resulted in no conversion; neither 16A
nor 16B was formed no matter the choice of phosphine ligand
(entry 7).
3. Conclusions
In conclusion, we have found that 2,4-disubstituted pyrroli-
dines are formed from an N-Boc-protected precursor in a di-
astereoisomeric trans/cis ratio of 2:5 via the palladium-catalyzed
carboamination route. The diastereoselectivity is hence signifi-
cantly smaller than that observed previously4a in the formation of
2,3- and 2,5-disubstituted pyrrolidines (Fig. 1). The phosphine li-
gand dpe-phos was superior to BINAP in the pyrrolidine synthesis.
The carboamination reaction was successfully extended to the
synthesis of 2-substituted N-phenylpiperidines and N-phenyl-
morpholines. In contrast, it was not possible to obtain 2-
substituted N-Boc-morpholines, while we managed to prepare 2-
substituted N-Boc-piperidines by changing the phosphine ligand
from dpe-phos to P(2-furyl)3, the yields were only moderate ow-
ing to competing Heck arylation. The Heck arylation products
completely dominated in efforts to prepare N-tosyl-substituted
piperidines and morpholines.
2.3. Synthesis of morpholines
Finally, we turned to the synthesis of N-protected 2-substituted
morpholines from precursors 17,13 18,14 19 (prepared from 2-anili-
noethanol, allylbromide, NaH, and Bu4NI in THF), and 20 (prepared
by tosylation of the corresponding amine13) (Scheme 3, Table 3).
Attempts of synthesizing the N-Boc-protected morpholine 21 (en-
try 1) and N-benzyl-protected morpholine 22 (entry 2) failed, with
no conversion of the starting material. In contrast, the N-phenyl-
Boc
N
Boc
N
Boc
N
R
N
O
R
N
H
R
A
Ar
Ar
Ar
17
R = Boc:
R = Bn: 18
MeO
O
R
R
19
R = Ph:
i)
20
R = Ts:
trans-2,3
cis-2,4
d.r. = 2:5
cis-2,5
d.r. > 1:20
R
NH
+
d.r. > 1:20
+
O
Figure 1. Summary of the diastereoselectivity in pyrrolidine formation by palladium-
Br
catalyzed carboamination (favored products are shown), including the work of Wolfe4a
B
MeO
MeO
21
R = Boc:
4. Experimental
R = Bn: 22
3
23
R = Ph:
24
R = Ts:
4.1. General experimental procedures
Scheme 3. Conditions: (i) Pd2(dba)3, NaOt-Bu, phosphine ligand (Table 3), toluene,
105 ꢀC, 15 h. dba¼dibenzylidene acetone.
Chemicals were purchased from Aldrich, Across, Merck, or Fluka
and used without further purification. Carboamination reactions
were carried out under an argon atmosphere in dried glassware
and using dry HPLC grade solvent. NMR spectra were recorded at
either a 500 MHz Bruker Spectrospin instrument or a 600 MHz
Bruker Ultrashield 600 Plus instrument, and deuterated solvents
from Cambridge Isotope Labs and Aldrich were used. Proton
chemical shifts are reported in parts per million with TMS as an
substituted morpholine 23A was successfully obtained in almost
quantitative yield (entry 3). Conversion of N-aryl precursors to
morpholines by the carboamination reaction was also very recently
reported in parallel work by Wolfe and co-workers.6 In the same
paper, efforts to couple an N-Boc-protected substrate with 1-
bromo-4-tert-butylbenzene are mentioned to afford only Heck

6136
T.H. Jepsen et al. / Tetrahedron 66 (2010) 6133e6137
internal reference, and carbon chemical shifts are reported in parts
per million relative to chemical shifts for the deuterated solvents
(CDCl3: 77.16 ppm, DMSO-d6: 39.52 ppm). Stereochemistry was
assigned on the basis of 1H NMR and 2D COSY experiments, as well
as APT, HSQC/HMBC, and 2D NOESYexperiments. All reactions were
analyzed by LC-MS and TLC (Merck 5554), and the ratios of the
regioisomers, enantiomers and diastereoisomers were determined
by LC-MS with either a reversed phase column or a chiral column.
LC-MS data were obtained from a UPLC equipped with an ESI mass
spectrometer and UV- and ELSD-detectors. The system consists of
an API300ex instrument with a Waters Acuity UPLC system and an
APPI ion source (ESI). Column chromatography was used for puri-
fication of the products, using Merck silica gel (0.040e0.063 mm)
as the stationary phase. Diastereoisomers were separated by Su-
percritical Fluid Chromatography (SFC) using a chiral column.
Melting points were determined on a Büchi apparatus and are
uncorrected. Elemental analyses were performed at the De-
partment of Chemistry, University of Copenhagen.
4.4. cis/trans-2-(p-Methoxybenzyl)-4-phenylpyrrolidinium
chloride (cis/trans-7)
4.4.1. Carboamination. Pd-source: 1% Pd2(dba)3, Phosphine ligand:
2% dpe-phos. According to the general procedure, p-bromoanisole
(1.12 g, 6.00 mmol) was treated with
Pd2(dba)3 (45.8 mg, 0.0500 mmol),
2
(1.31 g, 5.00 mmol),
dpe-phos (53.8 mg,
0.100 mmol), and NaOt-Bu (0.56 g, 6.00 mmol) in toluene (30 mL).
Yield of cis/trans-6 (Rf¼0.58; 30% EtOAc/heptane): 1.71 g (93%); LC-
MS yield: 100%. LC-MS: RT (UV-detector): 1.02 min, m/z¼268.1
[MHþꢂBoc]. Boc deprotection: According to the procedure de-
scribed above, cis/trans-6 (1.18 g, 3.21 mmol) was dissolved in
a saturated solution of HCl in MeOH. The product precipitated as
white flakes as a mixture of the two diastereoisomers in the ratio
(cis/trans)¼5:2, judged by LC-MS and NMR. Yield: 0.80 g (83%). The
two diastereoisomers were separated by preparative Supercritical
Fluid Chromatography (SFC) using a chiral column (eluent: 0.5%
diethylamine in ethanol, flow: 3 mL/min, UV: 230 nm, temp 40 ꢀC).
Compound trans-7 (Rf¼0.38; NEt3/MeOH/EtOAc 5:10:85): Yield:
130 mg (14%). Mp 49e51 ꢀC. LC-MS: RT (UV-detector): 1.95 min, m/
4.2. General procedure for carboamination reactions
z¼268.2 [MꢂCl]þ. 1H NMR (600 MHz, DMSO-d6):
¼9.75 (s, 2H),
d
7.35 (m, 4H), 7.30 (d, J¼8.1 Hz, 2H), 7.25 (m, 1H), 6.91 (d, J¼8.1 Hz,
2H), 3.93 (m, 1H), 3.73 (s, 3H), 3.71 (m, 1H), 3.67 (m, 1H), 3.14 (m,
1H), 3.11 (m, 1H), 2.93 (m, 1H), 2.15 (m, 1H), 2.01 (m, 1H). 13C NMR
A Schlenk tube was dried with a heat gun under an argon at-
mosphere. Dry solvent (usually toluene) was added and degassed
under an argon atmosphere. The Pd-source (Pd(OAc)2 (2 mol %) or
Pd2(dba)3 (1 mol % complex, 2 mol % Pd)) was added along with ei-
ther a monodentate phosphine ligand (4 mol % or 8 mol %) or
a bidentate phosphine ligand (2 mol % or 4 mol %). Then p-bro-
moanisole (1.2 M equiv), an aminoalkene (1.0 M equiv), and a base
consisting of NaOt-Bu (1.2 M equiv) or Cs2CO3 (2.3 M equiv) were
added. The mixture was degassed under an argon atmosphere,
whereafter the tube was sealed and stirred at 105 ꢀC for 15 h. The
reaction mixture was analyzed by LC-MS and TLC, and then
quenched with a saturated aqueous solution of NH4Cl (50 mL). The
toluene layer was separated, and the aqueous layer was extracted
with EtOAc (3ꢁ50 mL). The combined organic layers were washed
with brine, dried over MgSO4, and filtered through a short column of
silica gel. The solution was concentrated in vacuo to a brownish oil
that was purified further using column chromatographyon silica gel.
(151 MHz, DMSO-d6):
d
¼158.6, 141.3, 130.6, 129.6, 129.1, 127.8,
127.4, 114.5, 60.7, 55.5, 50.7, 41.3, 37.2, 36.9. Anal. Calcd for
C18H22ClNO: C, 71.16; H, 7.30; N, 4.61. Found: C, 71.09; H, 7.35; N,
4.60.
Compound cis-7 (Rf¼0.38; NEt3/MeOH/EtOAc 5:10:85) Yield:
280 mg (29%). Mp 50e52 ꢀC. LC-MS: RT (UV-detector): 1.93 min,
m/z¼268.1 [MꢂCl]þ. 1H NMR (600 MHz, DMSO-d6)
¼9.87 (s, 1H),
d
9.64 (s, 1H), 7.39 (m, 2H), 7.35 (m, 2H), 7.28 (d, J¼8.2 Hz, 2H), 7.26
(m, 1H), 6.91 (d, J¼8.2 Hz, 2H), 3.77 (m, 1H), 3.74 (s, 3H), 3.59 (m,
1H), 3.49 (m, 1H), 3.24 (m, 1H), 3.19 (m, 1H), 3.02 (m, 1H), 2.30 (m,
1H), 1.83 (m, 1H). 13C NMR (151 MHz, DMSO-d6)
130.5, 129.6, 129.1, 127.8, 127.5, 114.5, 61.9, 55.5, 50.1, 42.6, 39.4,
36.6. Anal. Calcd for C18H22ClNO: C, 71.16; H, 7.30; N, 4.61. Found: C,
71.11; H, 7.36; N, 4.59.
d
¼158.6, 140.7,
4.5. 2-(p-Methoxybenzyl)piperidinium chloride (13A) and 6-
(p-Methoxyphenyl)-hex-5-en-1-ammonium chloride (13B)
4.3. 2-(p-Methoxybenzyl)pyrrolidinium chloride (5)
4.5.1. Carboamination. Pd-source: 1% Pd2(dba)3, Phosphine ligand:
8% P(2-furyl)3. According to the general procedure, p-bromoanisole
4.3.1. Carboamination. Pd-source: 1% Pd2(dba)3; Phosphine ligand:
2% dpe-phos. According to the general procedure, p-bromoanisole
(1.12 g, 6.00 mmol) was treated with
8 (1.00 g, 5.00 mmol),
(2.24 g, 12.0 mmol) was treated with
1
(1.85 g, 10.0 mmol),
Pd2(dba)3 (45.8 mg, 0.0500 mmol), P(2-furyl)3 (92.9 mg,
0.400 mmol), and NaOt-Bu (1.15 g, 12.0 mmol) in toluene (30 mL).
After column chromatography (SiO2, EtOAc/heptane 1:10), com-
pounds 12A and 12B were isolated as yellow oils containing minor
impurities. Compound 12A (Rf¼0.51; 30% EtOAc/heptane): Yield:
0.21 g (ca. 13%), LC-MS yield: 24%. 12B (Rf¼0.58; EtOAc/heptane):
Yield: 0.15 g (ca. 9%), LC-MS yield: 26%. LC-MS: 12A: RT (UV-de-
tector): 3.24 min, m/z¼205.7 [MHþꢂBoc]. LC-MS: 12B: RT (UV-
detector): 3.12 min, m/z¼205.8 [MHþꢂBoc]. Using Pd(OAc)2
(22.45 mg, 0.100 mmol) instead of Pd2(dba)3, but otherwise iden-
tical conditions, 12A was isolated in a yield of 026 g (17%).
Pd2(dba)3 (92.0 mg, 0.100 mmol), dpe-phos (108 mg, 0.200 mmol),
and NaOt-Bu (1.15 g, 12.0 mmol) in toluene (50 mL). LC-MS of the
mixture indicated quantitative conversion to the product 4 that was
isolated as a yellow oil (Rf¼0.53; 30% EtOAc/heptane). Yield: 2.87 g
(99%); LC-MS yield: 100%. LC-MS: RT (UV-detector): 3.14 min, m/
z¼191.7 [MHþ-Boc]. Boc deprotection: MeOH (50 mL) was poured
into a flask and HCl was bubbled through with cooling, generating
a saturated solution of HCl in MeOH. Compound 4 (2.87 g,
9.85 mmol) was dissolved in the solution. After stirring for 60 min
at rt, the mixture was concentrated in vacuo to a yellow oil. Re-
crystallization from acetone/diethyl ether gave the salt 5 as a white
solid (Rf¼0.31; NEt3/MeOH/EtOAc 5:10:85). Yield: 1.56 g (70%). Mp
50e53 ꢀC. LC-MS: RT (UV-detector): 1.37 min, m/z¼191.9 [MꢂCl]þ.
4.5.2. Boc deprotection of 12A. According to the procedure de-
scribed above, compound 12A (0.26 g, 0.85 mmol) was dissolved in
a saturated solution of HCl in MeOH. The product 13A precipitated
as white flakes (Rf¼0.32; NEt3/MeOH/EtOAc 5:10:85). Yield: 0.16 g
(78%). Mp 91e92 ꢀC; litt.2c 92 ꢀC. LC-MS: RT (UV-detector):
1.45 min, m/z¼205.9 [MꢂCl]þ. 1H NMR (600 MHz, DMSO-d6):
1H NMR (600 MHz, DMSO-d6):
d
¼9.43 (s, 1H), 9.34 (s, 1H), 7.24 (d,
J¼8.6 Hz, 2H), 6.90 (d, J¼8.6 Hz, 2H), 3.73 (s, 3H), 3.63e3.51 (m, 1H),
3.20 (m, 1H), 3.12e3.07 (m, 1H), 3.08e3.02 (m, 1H), 2.85 (m, 1H),
2.00e1.93 (m, 1H), 1.94e1.88 (m, 1H), 1.87e1.77 (m, 1H), 1.63e1.54
(m, 1H). 13C NMR (151 MHz, DMSO-d6):
d
¼158.6, 130.5, 129.7, 114.5,
d
¼9.11 (s, 1H), 9.05 (s, 1H), 7.16 (d, J¼8.6 Hz, 2H), 6.90 (d, J¼8.6 Hz,
61.2, 55.5, 44.5, 36.6, 29.9, 23.2. Anal. Calcd for C12H18ClNO: C,
63.29; H, 7.97; N, 6.15. Found: 62.94; H, 7.96; N, 6.15.
2H), 3.74 (s, 3H), 3.21 (m, 1H), 3.15 (m, 1H), 3.04 (m, 1H), 2.82 (m,
1H), 2.68 (m, 1H), 1.70 (m, 2H), 1.62 (m, 2H), 1.38 (m, 2H). 13C NMR

T.H. Jepsen et al. / Tetrahedron 66 (2010) 6133e6137
6137
(151 MHz, DMSO-d6):
38.4, 27.7, 22.2, 22.0. Anal. Calcd for C13H20ClNO: C, 64.59; H, 8.34;
N, 5.79. Found: C, 64.34; H, 8.34; N, 5.81.
d
¼158.6, 130.8, 128.5, 114.5, 57.4, 55.5, 44.3,
(m, 1H), 2.59 (m, 1H). 13C NMR (151 MHz, CDCl3):
131.3, 130.3, 129.5, 119.3, 115.4, 114.0, 67.2, 67.0, 57.9, 55.3, 43.0, 30.1.
Anal. Calcd for C18H21NO2: C, 76.29; H, 7.47; N, 4.94. Found: C,
76.27; H, 7.51; N, 4.93.
d
¼158.0, 149.6,
4.5.3. Boc deprotection of 12B. According to the procedure de-
scribed above, 12B (0.15 g, 0.49 mmol) was dissolved in a saturated
solution of HCl in MeOH. The product 13B precipitated as white
flakes (Rf¼0.35; NEt3/MeOH/EtOAc 5:10:85). Yield: 94 mg (81%).
Mp 83e84 ꢀC. LC-MS: RT (UV-detector): 1.76 min, m/z¼205.8
4.9. N-{2-[3-(p-Methoxyphenyl)prop-2-enyl-oxy]ethyl}
tosylamide (24B)
4.9.1. Carboamination. Pd-source: 1% Pd2(dba)3, Phosphine ligand:
8% P(2-furyl)3. According to the general procedure, p-bromoanisole
(1.12 g, 6.00 mmol) was treated with 20 (1.28 g, 5.00 mmol),
Pd2(dba)3 (45.8 mg, 0.0500 mmol), P(2-furyl)3 (92.9 mg,
0.400 mmol), and NaOt-Bu (1.15 g, 12.0 mmol) in toluene (50 mL).
Yield of 24B (yellow oil, Rf¼0.47; 30% EtOAc/heptane): 0.69 g (39%);
LC-MS yields: 95% (24B), 5% (product from two Heck coupling re-
actions). LC-MS: 24B: RT (UV-detector): 2.76 min, m/z¼384.0
[MNaþ]; product from two Heck coupling reactions: RT (UV-de-
tector): 3.01 min, m/z¼468.4 [MHþ], m/z¼490.0 [MNaþ]. Com-
[MꢂCl]þ. 1H NMR (600 MHz, DMSO-d6):
¼8.15 (s, 3H), 7.32 (d,
d
J¼7.8 Hz, 2H), 6.87 (d, J¼7.8 Hz, 2H), 6.35 (d, J¼15.8 Hz, 1H), 6.11 (dt,
J¼15.8, 6.7 Hz, 1H), 3.74 (s, 3H), 2.77 (m, 2H), 2.17 (m, 2H), 1.61 (m,
2H), 1.47 (m, 2H). 13C NMR (151 MHz, DMSO-d6):
129.9, 128.1, 127.5, 114.4, 55.5, 39.0, 32.3, 27.0, 26.2. Anal. Calcd for
C13H20ClNO: C, 64.59; H, 8.34; N, 5.79. Found: C, 64.61; H, 8.45; N,
5.86.
d
¼158.8, 130.4,
4.6. N-Phenyl-2-(p-methoxybenzyl)piperidine (14A)
pound 24B: 1H NMR (600 MHz, CDCl3):
d
¼7.77 (d, J¼8.0 Hz, 2H),
4.6.1. Carboamination. Pd-source: 1% Pd2(dba)3, Phosphine ligand:
8% P(2-furyl)3. According to the general procedure, p-bromoanisole
7.31 (d, J¼8.0 Hz, 2H), 7.29 (d, J¼7.7 Hz, 2H), 6.86 (d, J¼7.7 Hz, 2H),
6.47 (d, J¼15.8 Hz, 1H), 6.05 (dt, J¼15.8, 7.0 Hz, 1H), 4.87 (t, J¼13.4,
1H), 4.02 (d, J¼7.0 Hz, 2H), 3.82 (s, 3H), 3.49 (t, J¼6.7 Hz, 2H), 3.13
(dt, J¼13.4, 6.7 Hz, 2H), 2.42 (s, 3H). 13C NMR (151 MHz, CDCl3):
(2.24 g, 12.0 mmol) was treated with
9 (1.75 g, 10.0 mmol),
Pd2(dba)3 (91.6 mg, 0.100 mmol), P(2-furyl)3 (186 mg, 0.800 mmol),
and NaOt-Bu (1.15 g,12.0 mmol) in toluene (50 mL). Theproduct was
recrystallized from MeOH, affording the product 14A as a white solid
(Rf¼0.54; 30% EtOAc/heptane). Yield: 1.44 g (51%); LC-MS yield: 75%.
Mp 57e60 ꢀC. LC-MS: RT (UV-detector): 1.91 min, m/z¼282.0
d
¼159.4, 143.6, 136.9, 132.9, 130.0, 129.0, 127.8, 127.1, 122.8, 113.9,
71.9, 67.8, 55.2, 42.8, 21.5. Anal. Calcd for C19H23NO4S: C, 63.14; H,
6.41; N, 3.87. Found: C, 63.01; H, 6.25; N, 3.67.
[MHþ].1H NMR (600 MHz, CDCl3):
d
¼7.31 (m, 2H), 7.06 (m, 2H), 7.01
Supplementary data
(m, 2H), 6.84 (m, 3H), 3.99 (m,1H), 3.80 (s, 3H), 3.40 (m,1H), 3.07 (m,
1H), 2.78 (m, 1H), 2.64 (m, 1H), 1.74 (m, 6H). 13C NMR (151 MHz,
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.06.004.
CDCl3)
d
¼157.8, 147.2, 132.2, 130.0, 129.2, 121.7, 116.7, 113.8, 58.3,
55.3, 43.9, 32.1, 26.3, 25.7, 19.1. Anal. Calcd for C19H23NO: C, 81.10; H,
8.24; N, 4.98. Found: C, 81.03; H, 8.33; N, 4.95.
References and notes
4.7. N-[6-(p-Methoxyphenyl)hex-5-enyl]tosylamide (15B)
1. (a) Herndon, J. L.; Ismaiel, A.; Ingher, S. P.; Teitler, M.; Glennon, R. A. J. Med.
Chem. 1992, 35, 4903; (b) Guzikowski, A. P.; Tamitz, A. P.; Acosta-Burruel, M.;
Hong-Bae, S.; Cai, S. X.; Hawkinson, J. E.; Keana, J. F. W.; Kesten, S. R.; Shipp, C.
T.; Tran, M.; Whittemore, E. R.; Woodward, R. M.; Wright, J. L.; Zhou, Z.-L. J. Med.
Chem. 2000, 43, 984; (c) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435; (d) Lewis, J. R.
Nat. Prod. Rep. 2001, 18, 95; (e) De Lucca, G. V.; Kim, U. T.; Johnson, C.; Vargo, B.
J.; Welch, P. K.; Covington, M.; Davies, P.; Solomon, K. A.; Newton, R. C.; Trainor,
G. L.; Decicco, C. P.; Ko, S. S. J. Med. Chem. 2002, 45, 3794; (f) Wijtmans, R.; Vink,
M. K. S.; Schoemaker, H. E.; van Delft, F. L.; Blaauw, R. H.; Rutjes, F. P. J. T.
Synthesis 2004, 641; (g) Slater, M. J.; Amphlett, E. M.; Andrews, D. M.; Bravi, G.;
Burton, G.; Cheasty, A. G.; Corfield, J. A.; Ellis, M. R.; Fenwick, R. H.; Fernandes,
S.; Guidetti, R.; Haigh, D.; Hartley, C. D.; Howes, P. D.; Jackson, D. L.; Jarvest, R. L.;
Lovegrove, V. L. H.; Withhurst, K. J.; Parry, N. R.; Price, H.; Shah, P.; Singh, O. M.
P.; Stocker, R.; Thommes, P.; Wilkinson, C.; Wonacott, A. J. Med. Chem. 2007, 50,
897; (h) Kuettel, S.; Zambon, A.; Kaiser, M.; Brun, R.; Scapozza, L.; Perozzo, R. J.
Med. Chem. 2007, 50, 5833.
4.7.1. Carboamination. Pd-source 1% Pd2(dba)3, Phosphine ligand:
8% P(2-furyl)3. According to the general procedure, p-bromoanisole
(1.12 g, 6.00 mmol) was treated with 10 (1.27 g, 5.00 mmol),
Pd2(dba)3 (45.8 mg, 0.0500 mmol), P(2-furyl)3 (92.9 mg,
0.400 mmol), and NaOt-Bu (1.15 g, 12.0 mmol) in toluene (30 mL).
Yield of 15B (colorless oil, Rf¼0.45; 30% EtOAc/heptane): 0.73 g
(41%); LC-MS yield: 70%. LC-MS: RT (UV-detector): 0.87 min, m/
z¼360.2 [MHþ]. 1H NMR (600 MHz, CDCl3):
¼7.77 (d, J¼8.0 Hz,
d
2H), 7.31 (d, J¼8.0 Hz, 2H), 7.26 (d, J¼7.7 Hz, 2H), 6.86 (d, J¼7.7 Hz,
2H), 6.29 (d, J¼15.8 Hz, 1H), 5.99 (dt, J¼15.8, 7.0 Hz, 1H), 4.64 (t,
J¼13.4, 1H), 3.82 (s, 3H), 2.98 (dt, J¼13.4, 6.7 Hz, 2H), 2.43 (s, 3H),
2.15 (m, 2H), 1.53 (m, 2H), 1.46 (m, 2H). 13C NMR (151 MHz, CDCl3):
2. (a) Pichon, M.; Figadère, B. Tetrahedron: Asymmetry 1996, 7, 927; (b) Mitch-
inson, A.; Nadin, A. J. Chem. Soc., Perkin Trans. 1 2000, 2862; (c) Weissermel, K.;
Arpe, H. J.; Lindley, C. R.; Hawkins, S. S. Industrial Organic Chemistry; Wiley:
Weinheim, 2003, pp 159e161; (d) Ágai, B.; Proszenyák, Á; Tárkányi, G.; Vida, L.;
Faigl, F. Eur. J. Org. Chem. 2004, 3623.
d
¼158.7, 143.4, 136.9, 130.4, 129.9, 129.7, 127.8, 127.1, 127.0, 113.9,
55.3, 43.1, 32.3, 29.0, 26.3, 21.5. Anal. Calcd for C20H25NO3S: C,
66.82; H, 7.01; N, 3.90. Found: C, 66.77; H, 7.05; N, 3.88.
3. (a) Larock, R. C.; Yang, H.; Weinreb, S. M.; Herr, R. J. J. Org. Chem. 1994, 59, 4172;
(b) Tamaru, Y.; Kimura, M. Synlett 1997, 749.
4.8. N-Phenyl-2-(p-methoxybenzyl)morpholine (23A)
4. (a) Bertrand, M. B.; Wolfe, J. P. Tetrahedron 2005, 61, 6447; (b) Bertrand, M. B.;
Leathen, M. L.; Wolfe, J. P. Org. Lett. 2007, 9, 457; (c) Bertrand, M. B.; Neukom, J.
D.; Wolfe, J. P. J. Org. Chem. 2008, 73, 8851.
5. (a) Nakhla, J. S.; Wolfe, J. P. Org. Lett. 2007, 9, 3279; (b) Nakhla, J. S.; Schultz, D.
M.; Wolfe, J. P. Tetrahedron 2009, 65, 6549.
6. Leathen, M. L.; Rosen, B. R.; Wolfe, J. P. J. Org. Chem. 2009, 74, 5107.
7. Michael, F. E.; Cochran, B. M. J. Am. Chem. Soc. 2006, 128, 4246.
8. For a recent review on intramolecular aminopalladation of alkenes, see: Min-
atti, A.; Muñiz, K. Chem. Soc. Rev. 2007, 36, 1142.
9. Rosewall, C. F.; Sibbald, P. A.; Liskin, D. V.; Michael, F. E. J. Am. Chem. Soc. 2009,
131, 9488.
10. Curran, D. P.; Liu, H. J. Chem. Soc., Perkin Trans. 1 1994, 11, 1377.
11. Morino, Y.; Hidaka, I.; Oderaotoshi, Y.; Komatsu, M.; Minakata, S. Tetrahedron
2006, 62, 12247.
12. Heck, R. F. Acc. Chem. Res. 1979, 12, 146.
13. Moree, W. J.; Sears, P.; Kawashiro, K.; Witte, K.; Wong, C. H. J. Am. Chem. Soc.
4.8.1. Carboamination. Pd-source: 1% Pd2(dba)3, Phosphine ligand:
8% P(2-furyl)3. According to the general procedure, p-bromoanisol
(2.24 g, 12.0 mmol) was treated with 19 (1.77 g, 10.0 mmol),
Pd2(dba)3
(91.6 mg,
0.100 mmol),
P(2-furyl)3
(186 mg,
0.800 mmol), and NaOt-Bu (1.15 g, 12.0 mmol) in toluene (50 mL).
Recrystallization from MeOH afforded the product 23A as white
needles (Rf¼0.43; 30% EtOAc/heptane). Yield: 1.96 g (69%); LC-MS
yield: 100%. Mp 102e103 ꢀC. LC-MS: RT (UV-detector): 2.61 min, m/
z¼283.8 [MHþ]. 1H NMR (600 MHz, CDCl3):
d
¼7.37 (dd, J¼8.7,
7.3 Hz, 2H), 7.13 (d, J¼8.5 Hz, 2H), 6.99 (d, J¼8.7 Hz, 2H), 6.91 (t,
J¼7.3 Hz, 1H), 6.87 (d, J¼8.5 Hz, 2H), 4.09 (m, 1H), 3.84 (m, 1H), 3.82
(s, 3H), 3.77 (m, 2H), 3.65 (m, 1H), 3.30 (m, 1H), 3.23 (m, 1H), 3.04
1997, 119, 3942.
14. Dobrov, A. Synthesis 1989, 12, 963.