A new sequential intramolecular cyclization based on the boekelheide rearrangement

Article abstract of DOI:10.1002/ejoc.201000936

Pyrrolidines and piperidines were synthesized from (aminoalkyl)pyridine N-oxides with a general and quite efficient method developed by using di-tert-butylsilyl bis(trifluoromethanesulfonate) as a new promoter for a Boekelheide-type reaction. The use of a

Full text of DOI:10.1002/ejoc.201000936

FULL PAPER
DOI: 10.1002/ejoc.201000936
A New Sequential Intramolecular Cyclization Based on the Boekelheide
Rearrangement
Assunta Massaro,[a] Alessandro Mordini,*[b] Anna Mingardi,[c] Jens Klein,[c] and
Daniele Andreotti*[c]
Keywords: Pyridine N-oxides / Boekelheide rearrangement / Cyclization / Intramolecular reactions / Nitrogen heterocycles /
Synthetic methods
Pyrrolidines and piperidines were synthesized from (amino-
alkyl)pyridine N-oxides with a general and quite efficient
method developed by using di-tert-butylsilyl bis(trifluoro-
methanesulfonate) as a new promoter for a Boekelheide-type
reaction. The use of a new Boekelheide promoter, which is
compatible with amino groups, opens new perspectives in
view of its application in intramolecular cyclizations.
oxide 1 to the corresponding 2-pyridone 2 with acetic an-
hydride (Scheme 1, path a) was the first example reported
in this field.[3–5]
Introduction
The development of new synthetic methodologies has
reached a level, which allows organic chemists to plan and
perform almost any kind of functional-group transforma-
tion. Nevertheless, despite such an achievement, investi-
gations in this field are still highly desirable and required to
solve problems, which we are now facing with respect to
sustainable development. Multistep syntheses are now less
desirable in view of the needs for economically and ecologi-
cally justifiable processes. Modern syntheses must deal care-
fully with our resources and must be designed in a way that
allows easy and short access to diversified substance lib-
raries. A general way to improve synthetic efficiency and
also to give access to a multitude of diversified molecules is
the development of sequential reactions, which allow the
formation of complex compounds, starting from simple
substrates in a single transformation consisting of several
steps.[1] In this respect, we decided to investigate in detail
the Boekelheide rearrangement[2] as a tool for a new one-
step intramolecular cyclization to give heterocycles.
Scheme 1.
A few years later, Boekelheide[6–8] established a different
procedure, which allowed oxygen functionalities to be
transferred onto alkyl groups in the 2-position of pyridine
rings. It was also clearly established that oxygen migration
could occur on the alkyl chain of substituents attached to
position 4 of the heteroaromatic ring. This process, which
is now known as Boekelheide reaction, requires the acti-
vation of pyridine N-oxides[9] by electrophilic agents such
as Ac2O, as in the original example, or others like P2O5,
TFAA, or TsCl. Despite many efforts, the mechanism[10–16]
of this rearrangement is not completely understood, and its
interpretation has evolved with time. At present, the gen-
erally accepted explanation involves an ion-pair mecha-
nism[17,18] as shown in Scheme 2 for the rearrangement oc-
curring in position 2.
Results and Discussion
Since the late 1940s, the reactivity of pyridine N-oxide,
mediated by N-oxide activators, has attracted the interest of
several research groups. The transformation of pyridine N-
[a] Dipartimento di Chimica “U. Schiff”, Università di Firenze,
Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy
[b] Istituto di Chimica dei Composti Organometallici
Via della Lastruccia 13, 50019 Sesto Fiorentino, FI, Italy
E-mail: alessandro.mordini@unifi.it
[c] GlaxoSmithKline,
Via Fleming 2, 37135 Verona, Italy
E-mail: daniele.andreotti@aptuit.com
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000936.
Scheme 2.
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A. Massaro, A. Mordini, A. Mingardi, J. Klein, D. Andreotti
FULL PAPER
Although it has potential, the Boekelheide reaction has
found only a limited number of applications so far, mainly
due to the need for protection of other functional groups in
the molecule that cannot tolerate the use of highly reactive
promoters such as Ac2O, P2O5, TFAA and TsCl. The Boek-
elheide rearrangement can be formally considered as an ac-
tivation of the pyridine ring followed by a nucleophilic at-
tack; but only a few nucleophiles, other than acetate, are
compatible with the activation conditions usually em-
ployed. The resulting lack of extensive studies on nucleo-
philic reactions induced by the Boekelheide rearrangement
coupled with our interest in developing new efficient syn-
thetic procedures, were the driving force to initiate the in-
vestigation described here.
Scheme 3.
An early observation by Cohen demonstrated that
Boekelheide reactions carried out in benzonitrile[19] lead to
the formation of products derived from trapping the Boek-
elheide cationic intermediate with the nitrile species, albeit
in minor amounts (7 and 8). In our experiments on classical
Boekelheide rearrangements, when tosyl chloride was used
as promoter, we isolated the product derived from nucleo-
philic attack of the chloride (9b) as well as the expected
Scheme 4.
In this paper we report our initial systematic investiga-
transposition product 9a. On the other hand, upon subjec- tion on these new intramolecular Boekelheide reactions as
tion of the tosylate derivative to microwave (MW) irradia- a function of the reaction conditions, the length and the
tion in DMF, the nucleophilic attack of formate occurred, position of the lateral chain (i.e. the size of the newly
leading to compound 10 (Scheme 3).
formed ring), and the promoter. The choice of the latter is
These results clearly demonstrated that a nucleophile crucial, because the usual promoters greatly limit the scope
present in the reaction medium during the rearrangement, of this strategy, which – in order to become synthetically
other than the oxygenated species derived from the pyridine useful – needs to be free from these limitations. For this
N-oxide, could be trapped by the Boekelheide intermediate. reason, we have also envisaged a new possible promoter,
This allowed us to plan a new strategy in which the nucleo- which would allow a broader range of nucleophiles to be
phile would be bonded to the pyridine ring (as in 11), and employed. Several (aminoalkyl)pyridine N-oxides were pre-
could then lead to heterocyclic compounds 12 through an pared for this purpose according to the procedure outlined
intramolecular telescopic process (Scheme 4).
in Scheme 5.
Scheme 5.
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A New Sequential Intramolecular Cyclization
We synthesized the intermediates 20a–e according to two
This is, to the best of our knowledge, the first intra-
possible routes. Route A involved a PdII-catalyzed cross- molecular cyclization induced by a Boekelheide reaction re-
coupling[21] between 2-bromopyridine and the required ported so far, and opens interesting synthetic perspectives.
iodoalkanenitrile 13c,e (obtained from the commercially
Upon monitoring the reaction course by NMR spec-
available chloroalkyl cyanide by chlorine/iodine ex- troscopy, we observed a very fast activation of the pyridine
change[20]) to give the intermediates 14c,e, which – after re- N-oxide indicated by downfield shifts of all proton and car-
duction of the nitrile functionality, protection with Boc an- bon chemical shifts of the aromatic ring. In addition, the
hydride, and substitution with benzyl bromide – led to the 1H NMR spectra showed that the amine nitrogen atom was
[(benzylamino)alkyl]pyridines 20c,e. Route B consited of a quaternarized – probably due to protonation by the triflic
Sonogashira coupling[22] of 2- or 4-bromopyridine with the acid deriving from the promoter. Addition of TEA restored
commercially available alkynol 17 to give the intermediates the original nucleophilicity. Subsequent aqueous quench led
18a,b,d, which – by oxidation, reductive amination with to the formation of two major identifiable species: the ex-
benzylamine, and Boc protection – led to 20a,b,d. The pyr- pected cyclised product 23a and compound 24, derived
idine rings of these intermediates were then oxidized with from a simple Boekelheide rearrangement, which was iso-
mCPBA[23] (21a–e), and final deprotection with TFA af- lated in about 30% yield (Figure 1).
forded 22a–e, starting materials for the cyclization reac-
tions.
Due to the incompatibility of the traditional promoters
with amino groups, we envisaged the possibility of using
silyl derivatives as activators for the Boekelheide reaction.
Their oxophilic nature was deemed compatible with the
presence of unprotected basic amines that could participate
Figure 1. Side product obtained during cyclization of 22a.
by intramolecular reaction with the activated pyridine N-
oxide. Our reagent of choice for testing the intramolecular
rearrangements was di-tert-butylsilyl bis(trifluoromethanes-
ulfonate) (tBu2SiOTf2), which is commercially available and
features the presence of a non-nucleophilic counterion. We
were pleased to find that when the amino pyridine N-oxide
22a was treated with tBu2SiOTf2 and triethylamine in
The analogous quinoline N-oxide 25 (prepared according
to a procedure similar to that reported in Scheme 5,
route A) behaves in the same way giving, after treatment
with tBu2SiOTf2 and triethylamine in dichloromethane, the
corresponding 2-(N-benzylpyrrolidin-2-yl)quinoline 26 in
comparable yield (Scheme 7).
dichloromethane,
the
2-(N-benzylpyrrolidin-2-yl)pyr-
idine[24] 23a was obtained as planned.
A careful screening of all the parameters involved in the
reaction was done on the cyclization of 22a to 23a (see Sup-
porting Information), from which some clear conclusions
can be drawn: (i) there are no differences among the bases
used [triethylamine, (dimethylamino)pyridine, diisopropyl-
ethylamine]; (ii) all the solvents used [dichloromethane,
N,N-dimethylformamide (DMF), acetonitrile, tetra-
hydrofuran, toluene] except acetonitrile lead to the cycliza-
tion, although the yields are lower with DMF; (iii) at least
2 equiv. of promoter are required, but an additional amount
does not improve the yields; (iv) 2 equiv. of base are re-
quired per equivalent of promoter; (v) increasing the tem-
perature does not increase the yields. The cyclized product
23a was obtained in 52% yield, which could be increased
up to 78% by MW irradiation (50 °C, 250 W, 20 min)
(Scheme 6).
Scheme 7.
We also investigated the length of the chain carrying the
amino group, and we obtained similar results with the
amino pyridine N-oxides 22c having one more carbon atom.
The corresponding 2-(N-benzylpiperidin-2-yl)pyridine 23c
was obtained under the same reaction conditions as de-
scribed above, although with lower yield (38%), which was
increased to 60% by MW irradiation (Scheme 8).
Scheme 8.
The longer analogue 22e, which would give the corre-
sponding azepine, did not cyclize under the same reaction
conditions.
Scheme 6.
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A. Massaro, A. Mordini, A. Mingardi, J. Klein, D. Andreotti
FULL PAPER
In order to extend the scope of our intramolecular
Boekelheide reaction, we decided to investigate some ad-
ditional (aminoalkyl)pyridine N-oxides. Our aim was to
better understand some features of this new process. We
chose substrates 22b,d to verify the possibility of inducing
an intramolecular cyclization at position 4 of the pyridine
ring, and amines 27a–e to investigate the effect of substitu-
ents on the lateral chain both on the chemical and stereo-
chemical behaviour. Compounds 22b,d were synthesized as
described for the analogues with the lateral chain in the 2-
position (22a), whereas the fully protected precursors of
27a–e are commercially available. Both compounds 22b and
22d behave in the same manner as the analogue with substi-
tution in position 2 (22a,c), giving the corresponding pyr-
rolidine 23b and piperidine 23d (Scheme 9). Although the
yields were lower (45 and 35%, respectively), they were Scheme 9.
again slightly increased by MW irradiation (62% and 48%,
respectively). Indeed, in our experiments we have found that
Conclusions
the Boekelheide rearrangement to alkyl chains in position
4 generally occurrs with lower yields than the one in posi-
tion 2.
We have developed a general and quite efficient method
to synthesize pyrrolidines and piperidines from (amino-
alkyl)pyridine N-oxides using di-tert-butylsilyl bis(trifluoro-
methanesulfonate) as a new promoter for a Boekelheide-
type reaction.
The use of a new Boekelheide promoter, which is com-
patible with amino groups, opens new perspectives in view
of its application in intramolecular cyclizations.
The presence of substituents on the alkyl chain in posi-
tion 2 has some effect on the yield of the cyclised products
(Scheme 10). As a general trend, we have observed that the
closer the methyl group is with respect to the picoline car-
bon atom, the lower is the yield. In the case of 27e, the
methyl group attached to carbon atom 2 of the chain for-
bids the attack of the amino group, leaving unreacted start-
ing material.
In all other cases, the reaction takes place with unopti-
mized moderate yields (25–50%) and diastereoselectivities
(from 2:1 up to 3:1) that could be improved by using the
microwave irradiation.
Experimental Section
General Procedures: Air- and moisture-sensitive compounds were
stored in Schlenk tubes or in Schlenk burettes. They were protected
by and handled under 99.99% pure nitrogen. Purifications by flash
Scheme 10.
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A New Sequential Intramolecular Cyclization
column chromatography were performed using glass columns (10–
50 mm wide); silica gel (230–400 mesh) was chosen as stationary
phase, with an elution rate of 5 cm/min. 1H NMR spectra were
recorded at 200, 400 and 500 MHz. Chemical shifts were deter-
mined relative to the residual solvent peak (CHCl3: δ = 7.26 ppm).
Coupling constants (J) were measured in Hz. Coupling patterns
are described by abbreviations: s (singlet), d (doublet), t (triplet), q
(quartet), quint (quintet), dd (doublet of a doublet), m (multiplet),
br. s (broad singlet). 13C NMR spectra were recorded at 50.4 and
100.6 MHz. Chemical shifts were determined relative to the resid-
ual solvent peak (CHCl3: δ = 77.0 ppm). Mass spectra were ob-
tained at a 70 eV ionization potential. LC-MS analyses were per-
formed by operating in ESI positive or negative mode. The phases
used were: (A) 10 mm aqueous solution of NH4HCO3 (adjusted to
pH = 10 with ammonia); (B) acetonitrile. The gradient was: t =
0 min, 97% A, 3% B; t = 1.06 min, 1% A, 99% B; t = 1.45 min,
1% A, 99% B; t = 1.46 min 97% A, 3% B, followed by 1 min of
reconditioning. Retention times are indicated in min. Protections
of amines with Boc2O, oxidations of pyridines with mCPBA and
deprotection of N-Boc-amines with TFA have been described in
detail only for one example; the others were almost identical.
= 25.80, 32.06, 37.43, 62.26, 76.69, 77.32, 121.05, 122.91, 136.48,
148.95, 161.92 ppm. LC-MS: tR = 0.46 min; m/z = 152 [MH+].
4-(2-Pyridinyl)-butanal (19a): To a solution of oxalyl chloride
(546 mg, 4.30 mmol) in CH2Cl2 (10 mL) cooled to –78 °C, DMSO
(672 mg, 8.6 mmol) was added, and the mixture was stirred for
30 min. A solution of 4-(pyridin-2-yl)butan-1-ol (18a, 500 mg,
3.31 mmol) in CH2Cl2 (2 mL) was then added, and the reaction
mixture was stirred at –78 °C for 1 h. TEA (1.7 mL) was added,
and the reaction mixture was stirred for an additional 30 min. The
reaction was quenched with water and the mixture extracted with
EtOAc. The organic layer was concentrated to give crude product
19a (460 mg, 95%) as a yellow oil, which was used as such without
further purification. The spectroscopic data are in full agreement
with the literature data.[25] 1H NMR (400 MHz, CDCl3, 25 °C): δ
= 2.00–2.17 (m, 2 H), 2.50 (td, J = 7.30, 1.51 Hz, 2 H), 2.84 (t, J
= 7.50 Hz, 2 H), 7.01–7.21 (m, 2 H), 7.50–7.69 (m, 1 H), 8.53 (d,
J = 5.04 Hz, 1 H), 9.77 (d, J = 1.51 Hz, 1 H) ppm. LC-MS: tR
=
0.48 min; m/z = 150 [MH+].
1,1-Dimethylethyl
(Phenylmethyl)[4-(2-pyridinyl)butyl]carbamate
(20a): (1) To a solution of benzylamine (2.63 mL, 24.13 mmol) in
MeOH (160 mL) stirred under nitrogen at room temp., a solution
of 4-(2-pyridinyl)butanal (19a) (3.6 g, 24.13 mmol) in MeOH
(20 mL) was added dropwise over 15 min. Acetic acid (4.14 mL,
72.4 mmol) was then added, and the mixture was stirred for 3 h.
After this time, sodium cyanoborohydride (1.516 g, 24.13 mmol)
was added, and the stirring was continued for 4 h. (2) The methanol
was evaporated, and the crude (phenylmethyl)[4-(2-pyridinyl)butyl]-
amine (6.60 g, 27.5 mmol) was dissolved in a mixture of THF
(75 mL) and a saturated solution (1 m) of NaHCO3. Boc2O
(17.98 g, 82 mmol) was then added, and the reaction mixture was
vigorously stirred overnight, then extracted with EtOAc
(3ϫ40 mL). The organic phase was washed with brine, dried with
Na2SO4, and the solvent was evaporated to give the crude product
(6.66 g) as yellow oil. The product was purified by flash chromatog-
raphy on silica gel (cyclohexane/EtOAc, 2:1) to give pure 20a
Materials: Starting materials were commercially available unless
otherwise stated. All commercial reagents were used without fur-
ther purification except triethylamine, which was distilled from cal-
cium hydride. Anhydrous tetrahydrofuran was distilled from so-
dium diphenylketyl. DMF was distilled from calcium hydride and
then stored over molecular sieves (4 Å). Dichloromethane was
dried with calcium chloride and stored over molecular sieves (4 Å).
Petroleum ether, unless specified, was the fraction with boiling
range 40–70 °C.
Preparation of the (Benzylamino)pyridines
Synthesis of [4-(1-Oxido-2-pyridinyl)butyl](phenylmethyl)amine
(22a): Scheme 5, route B.
4-(2-Pyridinyl)-3-butyn-1-ol: To a solution of 2-bromopyridine
(6.04 mL, 63.3 mmol), CuI (0.603 g, 3.16 mmol), TEA (13.23 mL,
95 mmol), and (PPh3)2PdCl2 (1.3 g, 1.852 mmol) in 1,4-dioxane
(100 mL) stirred under nitrogen at room temp., 3-butyn-1-ol
(5.75 mL, 76 mmol) was added dropwise during 15 min. Upon ad-
dition of the alcohol, the yellow solution became first red, then
orange with a white precipitate. The reaction mixture was stirred
at room temp. overnight, then the solvent was evaporated, and the
crude reaction mixture was dissolved in EtOAc and washed with
water (pH = 6). The water phase was extracted with EtOAc
(4ϫ30 mL), and the combined organic phases were washed with
brine and dried (Na2SO4). The crude product was purified on silica
gel (EtOAc/cyclohexane, 70:30) to give pure product (7.97 g, 85%)
as a red oil. The spectroscopic data are in full agreement with lit-
erature data.[22] 1H NMR (400 MHz, CDCl3, 25 °C): δ = 2.72 (t, J
= 6.30 Hz, 2 H), 3.36 (br. s, 1 H), 3.87 (t, J = 6.30 Hz, 2 H), 7.18–
7.22 (m, 1 H), 7.38 (d, J = 7.78 Hz, 1 H), 7.63 (td, J = 7.72,
1
(2.05 g, 25% over two steps) as a yellow oil. H NMR (400 MHz,
CDCl3, 25 °C): δ = 1.48 (br. s, 9 H), 1.54–1.64 (m, 4 H), 1.70 (d, J
= 7.91 Hz, 2 H), 2.79 (t, J = 7.59 Hz, 2 H), 4.44 (s, 2 H), 7.10–7.18
(m, 2 H), 7.23–7.31 (m, 3 H), 7.32–7.39 (m, 2 H), 7.58–7.65 (m, 1
H), 8.49–8.54 (m, 1 H) ppm. 13C NMR (50.4 MHz, CDCl3, 25 °C):
δ = 26.96, 27.72, 28.15, 37.80, 44.80, 46.95, 84.60, 120.86, 122.63,
126.93, 128.32, 128.45, 136.14, 136.37, 148.95, 154.29, 161.67 ppm.
LC-MS: tR = 1.00 min; m/z = 341 [MH+]. C28H28N2O2 (424.54):
calcd. C 74.08, H 8.29, N 8.23, O 9.40; found C 74.04, H 8.31, N
8.25, O 9.38.
1,1-Dimethylethyl
[4-(1-Oxido-2-pyridinyl)butyl](phenylmethyl)-
carbamate (21a): To a solution of 1,1-dimethylethyl (phenylmeth-
yl)[4-(2-pyridinyl)butyl]carbamate (20a) (1.845 g, 5.42 mmol) in
CH2Cl2 (25 mL), mCPBA (1.47 g, 5.46 mmol) was added, and the
reaction mixture was stirred at room temp. for 2 h. A saturated
solution of Na2S2O3 was added, and the CH2Cl2 was evaporated.
EtOAc was added, and the organic phase was washed with
1.88 Hz, 1 H), 8.51 (dd, J = 4.80, 1.5 Hz, 1 H) ppm. LC-MS: tR
=
0.46 min; m/z = 148 [M + H+].
4-(2-Pyridinyl)-1-butanol (18a): To a solution of 4-(2-pyridinyl)-3- Na2S2O3 (4ϫ30 mL), NaHCO3 (2ϫ30 mL), and brine. The or-
butyn-1-ol (7.97 g, 54.2 mmol) in ethanol (108 mL), palladium on
carbon (2.6 g, 2.443 mmol) was added, and the reaction mixture
was stirred under hydrogen at room temp. for 18 h. The mixture
was filtered through a pad of Celite, and the solvent was evaporated
to give 18a (7.618 g, 93%) as a yellow oil. 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 1.52–1.73 (m, 2 H), 1.76–1.89 (m, 2 H), 2.01–
2.57 (br. s, 1 H), 2.84 (t, J = 7.40 Hz, 2 H), 3.69 (t, J = 6.40 Hz, 2
H), 7.04–7.21 (m, 2 H), 7.60 (td, J = 7.58, 1.52 Hz, 1 H), 8.50 (d,
ganic phase was then dried (Na2SO4), and the solvent was evapo-
rated to give crude 21a (1.92 g, 99%) as a yellow oil. 1H NMR
(500 MHz, CDCl3, 25 °C): δ = 1.40–1.51 (m, 9 H), 1.57–1.81 (m, 4
H), 2.92 (br. s, 2 H), 3.19 (br. s, 1 H), 3.29 (br. s, 1 H), 4.44 (d, J
= 16.45 Hz, 2 H), 7.16 (d, J = 5.82 Hz, 1 H), 7.21 (br. s, 2 H), 7.23–
7.28 (m, 3 H), 7.29–7.35 (m, 2 H), 8.27 (d, J = 6.26 Hz, 1 H) ppm.
13C NMR (50.4 MHz, CDCl3, 25 °C): δ = 23.10, 27.63, 27.89,
29.92, 45.96, 49.96, 79.29, 123.14, 125.30, 126.74, 128.08, 128.17,
J = 4.80 Hz, 1 H) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ 137.46, 138.16, 139.22, 151.77, 154.38 ppm. LC-MS: tR = 0.81 min;
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m/z = 357 [MH+]. C21H28N2O3 (356.46): calcd. C 70.76, H 7.92, N
7.86, O 13.47; found C 70.79, H 8.01, N 7.84, O 13.45.
[M+]. C10H12N2 (160.22): calcd. C 74.97, H 7.55, N 17.48; found
C 74.95, H 7.53, N 17.51.
5-(2-Pyridinyl)-1-pentanamine (15c): Lithium aluminium hydride
(231 mg, 6.09 mmol) was suspended in dry THF (8 mL) and cooled
to 0 °C. A solution of 5-(2-pyridinyl)pentanenitrile (14c) (650 mg,
4.06 mmol) in THF (4 mL) was added, and the mixture was stirred
at 0 °C for 2 h, then warmed to room temp. and filtered through
Celite. The solvent was evaporated to give 15c (619 mg, 93%) as
a red oil, which was used without further purification. 1H NMR
(200 MHz, CDCl3, 25 °C): δ = 1.21–1.95 (m, 6 H), 2.40 (br. s, 2
H), 2.61–2.79 (m, 4 H), 7.02–7.26 (m, 2 H), 7.54 (dt, J = 7.80,
1.60 Hz, 1 H), 8.48 (d, J = 4.00 Hz, 1 H) ppm. 13C NMR
(50.4 MHz, CDCl3, 25 °C): δ = 26.58, 29.29, 29.66, 38.29, 42.08,
120.79, 122.59, 136.12, 137.36, 149.04 ppm. C10H16N2 (164.25):
calcd. C 73.13, H 9.82, N 17.06; found C 73.10, H 9.79, N 17.03.
[4-(1-Oxido-2-pyridinyl)butyl](phenylmethyl)amine (22a): To a solu-
tion of 1,1-dimethylethyl [4-(1-oxido-2-pyridinyl)butyl](phen-
ylmethyl)carbamate (21a) (500 mg, 1.403 mmol) in CH2Cl2
(14 mL), stirred under nitrogen at room temp., TFA (1.081 mL,
13.03 mmol) was added, and the reaction mixture was stirred at
room temp. for 4 h. The solvent and the excess TFA were evapo-
rated, and the crude mixture was dissolved in EtOAc and washed
with NaHCO3 containing some NaOH pellets. The organic phase
was dried with Na2SO4, filtered, and the solvent was evaporated to
afford 22a (355 mg, 99%) as a yellow oil. 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 1.61–1.68 (m, 2 H), 1.76–1.84 (m, 2 H), 1.92
(br. s, 1 H), 2.72 (t, J = 6.84 Hz, 2 H), 2.93–2.97 (m, 2 H), 3.81 (s,
2 H), 7.13–7.17 (m, 1 H), 7.19–7.30 (m, 3 H), 7.31–7.38 (m, 4 H),
8.26 (d, J = 6.41 Hz, 1 H) ppm. 13C NMR (50.4 MHz, CDCl3,
25 °C): δ = 23.66, 28.87, 30.18, 48.38, 53.48, 123.38, 125.43, 125.86,
1,1-Dimethylethyl [5-(2-Pyridinyl)pentyl]carbamate (16c): 5-(2-Pyr-
idinyl)-1-pentanamine (15c) (1.21 g, 7.38 mmol) was dissolved in
CH2Cl2 (50 mL), and Boc2O (1.93 g, 8.85 mmol) was added. The
solution was cooled to 0 °C, and TEA (1.54 mL, 11.07 mmol) and
DMAP (catalytic amount) were added. The mixture was stirred
overnight, then the reaction was quenched with NaHCO3 and the
mixture extracted several times with CH2Cl2. The organic layers
were dried (Na2SO4), and the solvent was evaporated to give the
crude product (2.80 g), which was was purified by flash chromatog-
raphy on silica gel (CH2Cl2/EtOAc, 2:1) to afford pure 16c (1.40 g,
74%) as a yellow oil. 1H NMR (200 MHz, CDCl3, 25 °C): δ = 1.40
(s, 9 H), 1.24–1.56 (m, 4 H), 1.63–1.68 (m, 2 H), 2.74 (t, J =
7.60 Hz, 2 H), 3.02–3.12 (m, 2 H), 3.52 (br. s, 1 H), 7.02–7.11 (m,
2 H), 7.54 (dt, J = 7.40, 2.00 Hz, 1 H), 8.46–8.49 (m, 1 H) ppm.
13C NMR (50.4 MHz, CDCl3, 25 °C): δ = 26.38, 28.38, 29.37,
29.80, 38.11, 40.37, 78.85, 120.82, 122.61, 136.15, 149.03, 155.85,
161.90 ppm. C15H24N2O2 (264.37): calcd. C 68.15, H 9.15, N 10.60,
O 12.10; found C 68.13, H 9.18, N 10.57, O 12.08.
127.17, 128.31, 128.38, 138.57, 139.52, 152.04 ppm. LC-MS: tR
=
0.46 min; m/z = 257 [MH+]. C16H20N2O (256.35): calcd. C 74.97,
H 7.86, N 10.93, O 6.24; found C 75.00, H 7.84, N 10.91, O 6.21.
Synthesis of 5-(1-Oxido-2-pyridinyl)-N-(phenylmethyl)-1-pentan-
amine (22c): Scheme 5, route A. 5-Iodopentanenitrile (13c), neces-
sary for this synthesis, was prepared according to a literature pro-
cedure:[20] 5-Chloropentanenitrile (1.34 mL, 13.52 mmol) and NaI
(6.08 g, 40.55 mmol) were stirred and refluxed in acetone (130 mL)
under N2 for 2 d. After distilling off the solvent, the residue was
diluted with water and extracted with ethyl acetate (200 mL +
100 mL). The organic extracts were successively washed with 1 m
Na2S2O3 and saturated NaHCO3, dried (Na2SO4), concentrated,
and distilled under reduced pressure to give 6-iodopentanenitrile
(13c) (2.60 g, 99%) as a colourless liquid. 1H NMR (200 MHz,
CDCl3, 25 °C): δ = 1.54–2.12 (m, 4 H), 2.24–2.49 (m, 2 H), 3.07–
3.31 (m, 2 H) ppm.
1,1-Dimethylethyl (Phenylmethyl)[5-(2-pyridinyl)pentyl]carbamate
(20c): 1,1-Dimethylethyl [5-(2-pyridinyl)pentyl]carbamate (16c)
(315 mg, 1.19 mmol) was dissolved in dry DMF (6 mL) and added
to a suspension of NaH (70 mg, 1.43 mmol, 50% in mineral oil) in
DMF (6 mL) at 0 °C. The mixture was stirred at 0 °C for 2 h and
at room temp. for 2 h, then benzyl bromide (118 μL, 0.99 mmol)
and tetrabutylammonium iodide (catalytic amount) were added.
The mixture was stirred at room temp. overnight, then the reaction
was quenched with saturated aq. NH4Cl and the mixture extracted
with EtOAc (3ϫ20mL). The organic phase was dried with
Na2SO4, and the solvent was evaporated to give the crude product,
which was purified by flash chromatography on silica gel (petro-
leum ether/EtOAc, 2:1) to afford pure 20c (255 mg, 60%) as a yel-
5-(2-Pyridinyl)pentanenitrile (14c): A known procedure[21] was used
for the synthesis of 14c. To a round-bottom flask containing Zn
dust (1.30 g, 20.0 mmol), dibromoethane (305.2 mg, 1.62 mmol)
was added, and the resulting mixture was warmed to 60 °C and
then allowed to cool for 1 min. This heating/cooling process was
repeated three more times, and then the flask was allowed to cool
for an additional 3 min. Trimethylsilyl chloride (26.5 mg,
0.24 mmol) in THF (20 mL) was then added. The resulting mixture
was warmed to 60 °C, and a solution of 5-iodopentanenitrile (13c)
(6.5 mmol) in THF (1 mL) was added. The mixture was stirred at
60 °C until all the alkyl iodide had been consumed (ca. 4 h, TLC
control). The resulting solution of alkylzinc iodide was transferred
by a syringe fitted with a 0.45 μm filter to a second flask charged
with 2-bromopyridine (1.3 mmol) and (Ph3P)2PdCl2 (45 mg,
0.06 mmol). The resulting mixture was stirred at 60 °C under N2
for 18 h, cooled to room temperature, and the reaction quenched
with saturated aqueous NH4Cl solution (5 mL). The resulting mix-
ture was stirred at room temp. for 20 min and diluted with ethyl
acetate (200 mL). The organic phase was washed with saturated
aqueous NH4Cl (50 mL), brine (50 mL), and dried with Na2SO4.
The organic phase was concentrated, and the crude product was
purified by flash column chromatography on silica gel using petro-
leum ether/EtOAc (3:1), then EtOAc as eluent to afford 14c
(416 mg, 40%) as a yellow oil. 1H NMR (200 MHz, CDCl3, 25 °C):
δ = 1.52–1.98 (m, 2 H), 2.22–2.48 (m, 2 H), 2.80 (t, J = 6.96 Hz, 4
1
low oil. H NMR (200 MHz, CDCl3, 25 °C): δ = 1.24–1.53 (m, 4
H), 1.50 (s, 9 H), 1.62–1.78 (m, 2 H), 2.74 (t, J = 7.60 Hz, 2 H),
3.05–3.25 (m, 2 H), 4.39 (s, 2 H), 7.04–7.33 (m, 7 H), 7.55 (dt, J =
7.60, 1.80 Hz, 1 H), 8.49 (d, J = 4.20 Hz, 1 H) ppm. 13C NMR
(50.4 MHz, CDCl3, 25 °C): δ = 26.58, 27.91, 28.42, 29.55, 38.25,
46.43, 50.36, 79.42, 120.81, 122.59, 126.92, 127.10, 128.29, 136.14,
138.58, 149.06, 154.30, 161.96 ppm. GC-MS: m/z (%) = 57 (100)
[tBu], 91 (31) [py-CH2], 106 (86) [pyCH2CH2], 148 (13)
[py(CH2)5], 163 (36) [py(CH2)5NH], 253 (14) [py(CH2)5NBn], 354
(3) [M+]. C22H30N2O2 (354.49): calcd. C 74.54, H 8.53, N 7.90, O
9.03; found C 74.52, H 8.49, N 7.87, O 9.06.
1,1-Dimethylethyl
[5-(1-Oxido-2-pyridinyl)pentyl](phenylmethyl)-
H), 7.02–7.20 (m, 2 H), 7.49–7.66 (m, 1 H), 8.49 (d, J = 4.76 Hz, carbamate (21c): See the procedure used for 21a. The product ob-
1 H) ppm. 13C NMR (50.4 MHz, CDCl3, 25 °C): δ = 16.99, 24.90,
28.55, 37.17, 121.15, 122.64, 136.31, 137.33, 149.15, 160.73 ppm.
tained as a yellow oil (98%) was used as such without further puri-
fication. 1H NMR (200 MHz, CDCl3, 25 °C): δ = 1.47 (s, 9 H),
GC-MS: m/z (%) = 51 (76), 78 (100) [Py], 106 (2), 159 (26), 160 (2) 1.35–1.83 (m, 6 H), 2.92 (t, J = 7.60 Hz, 2 H), 3.12–3.32 (m, 2 H),
276
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 271–279

A New Sequential Intramolecular Cyclization
4.45 (s, 2 H), 7.12–7.38 (m, 8 H), 8.25 (d, J = 5.80 Hz, 1 H) ppm.
13C NMR (50.4 MHz, CDCl3, 25 °C): δ = 25.49, 26.36, 28.18,
CDCl3, 25 °C): δ = 27.46, 28.46, 28.47, 34.81, 46.15, 50.34, 79.69,
123.79, 127.09, 127.50, 128.40, 138.39, 146.64, 149.54, 151.10 ppm.
29.38, 30.20, 46.07, 50.12, 79.08, 122.95, 124.94, 125.13, 126.54, GC-MS: m/z (%) = 41 (36), 57 (100) [tBu], 91 (67) [Bz], 106 (50)
127.55, 127.91, 130.16, 138.03, 139.05, 151.70 ppm. GC-MS: m/z
(%) = 57 (100) [tBu], 91 (53) [pyCH2], 106 (25) [pyCH2CH2], 148
[pyCH2CH2], 120 (28) [py(CH2)3], 240 (6) [M+ – Boc], 340 (1) [M+].
C21H28N2O2 (340.46): calcd. C 74.08, H 8.29, N 8.23, O 9.40; found
(11) [py(CH2)5], 163 (9) [py(CH2)5NH], 253 (33) [py(CH2)5NBn], C 74.10, H 8.32, N 8.21, O 9.38.
354 (3). 370 (1) [M+]. C22H30N2O3 (370.49): calcd. C 71.32, H 8.16,
N 7.56, O 12.96; found C 71.29, H 8.14, N 7.59, O 12.99.
1,1-Dimethylethyl
[4-(1-Oxido-4-pyridinyl)butyl](phenylmethyl)-
carbamate (21b): See procedure used for 21a. The product obtained
as a yellow oil (80%) was used without further purification. 1H
NMR (200 MHz, CDCl3, 25 °C): δ = 1.45 (s, 9 H), 1.40–1.58 (m,
4 H), 2.50–2.62 (m, 2 H), 3.10–3.32 (m, 2 H), 4.40 (br. s, 2 H), 7.04
(d, J = 6.20 Hz, 2 H), 7.18–7.38 (m, 5 H), 8.13 (d, J = 7.00 Hz, 2
H) ppm. 13C NMR (50.4 MHz, CDCl3, 25 °C): δ = 27.44, 27.86,
28.54, 34.00, 46.12, 50.49, 79.81, 125.81, 127.08, 127.09, 128.35,
132.05, 138.67, 141.40, 154.17 ppm. GC-MS: m/z (%) = 57 (100)
[tBu], 91 (76) [Bz], 106 (54) [pyCH2CH2], 120 (27) [py(CH2)3], 240
(7) [M+ – Boc], 284 (8) [M+ – tBuBoc], 340 (1%). C21H28N2O3
(356.46): calcd. C 70.76, H 7.92, N 7.86, O 13.47; found C 70.74,
H 7.89, N 7.83, O 13.45.
5-(1-Oxido-2-pyridinyl)-N-(phenylmethyl)-1-pentanamine (22c): See
the procedure used for 22a. The product obtained as a yellow oil
(63%) was used without further purification. 1H NMR (200 MHz,
CDCl3, 25 °C): δ = 1.29–1.84 (m, 6 H), 2.41–2.72 (m, 3 H), 2.87 (t,
J = 7.60 Hz, 2 H), 3.76 (s, 2 H), 6.98–7.43 (m, 8 H), 8.20 (d, J =
6.23 Hz, 1 H) ppm. 13C NMR (50.4 MHz, CDCl3, 25 °C): δ =
25.96, 27.04, 29.59, 30.42, 49.03, 53.84, 123.28, 125.32, 125.68,
126.93, 128.13, 128.33, 139.56, 139.78, 152.38 ppm. GC-MS: m/z
(%) = 91 (100) [Bz], 119 (30), 120 (6), 158 (56), 193 (3), 253 (2).
C17H22N2O (270.37): calcd. C 75.52, H 8.20, N 10.36, O 5.92;
found C 75.49, H 8.17, N 10.33, O 5.96.
[4-(1-Oxido-4-pyridinyl)butyl](phenylmethyl)amine (22b): See pro-
cedure used for 22a. The product obtained as a yellow oil (99%)
was used without further purification. 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 1.50–1.57 (m, 2 H), 1.63–1.70 (m, 3 H), 2.60 (t,
J = 7.60 Hz, 2 H), 2.65 (t, J = 6.80 Hz, 2 H), 3.77 (s, 2 H), 7.06
(d, J = 6.80 Hz, 2 H), 7.22–7.38 (m, 5 H), 8.11 (d, J = 6.80 Hz, 2
H) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 27.87, 29.48,
34.22, 48.84, 54.03, 125.96, 126.98, 128.07, 128.42, 138.77, 140.27,
142.14 ppm. GC-MS: m/z (%) = 91 (100) [Bz], 106 (8) [pyCH2CH2],
120 (22) [py(CH2)3], 240 (1). C16H20N2O (256.35): calcd. C 74.97,
H 7.86, N 10.93, O 6.24; found C 75.00, H 7.83, N 10.90, O 6.21.
Synthesis of [4-(1-Oxido-4-pyridinyl)butyl](phenylmethyl)amine
(22b): Scheme 5, route B.
4-(Pyridin-4-yl)but-3-yn-1-ol: See procedures used for 18a, but
starting from 4-bromopyridine. The crude product was purified by
flash chromatography on silica gel [from EtOAc/petroleum ether
(2:1) to EtOAc 100%, then EtOAc/MeOH (10:1)] to afford the pure
product (77%) as an orange oil. The spectroscopic data are in com-
plete agreement with the literature’s data.[26] 1H NMR (200 MHz,
CDCl3, 25 °C): δ = 1.91 (br. s, 1 H), 2.71 (t, J = 6.6 Hz, 2 H), 3.78–
3.95 (m, 2 H), 7.24 (dd, J = 4.40, 1.40 Hz, 2 H), 8.51 (dd, J = 4.40,
1.40 Hz, 2 H) ppm. 13C NMR (50.4 MHz, CDCl3, 25 °C): δ =
23.98, 60.81, 79.84, 92.23, 125.73, 128.26, 149.37 ppm. GC-MS:
m/z (%) = 31 (63), 63 (41), 90 (57), 117 (100) [pyCϵCCH3], 147
(53) [M+].
Synthesis of [5-(1-Oxido-4-pyridinyl)pentyl](phenylmethyl)amine
(22d): In this case a different procedure for the preparation of the
alcohol 18d was used.
5-(4-Pyridinyl)-1-pentanol: To a cooled (0 °C) solution of 4-penten-
1-ol (1.0 g, 11.61 mmol) in THF (10 mL), 9-BBN (0.5 m in THF,
34.83 mmol) was slowly added. The mixture was slowly warmed to
25 °C and then stirred over a weekend to give a solution of the B-
alkyl-9-BBN derivative. This solution was transferred into a sepa-
rate flask containing 4-bromopyridine hydrochloride (2.71 g,
13.93 mmol), Pd(PPh3)4 (1.26 g, 1.16 mmol), and potassium car-
bonate (32 mL, 3 m in H2O, 92.90 mmol) in DMF (80 mL). The
mixture was stirred at 70 °C for 24 h, and then it was diluted with
EtOAc and poured into water. The aqueous layer was extracted
with EtOAc (3ϫ50 mL). The combined organic layers were washed
with brine, dried (Na2SO4) and concentrated to afford the crude
product, which was then purified by flash chromatography on silica
gel (EtOAc 100%) to give the pure alcohol (870 mg, 45%) as a
yellow oil. The spectroscopic data are in complete agreement with
the literature’s data.[27] 1H NMR (200 MHz, CDCl3, 25 °C): δ =
1.40–1.75 (m, 7 H), 2.65 (t, J = 7.70 Hz, 2 H), 3.66 (t, J = 6.50 Hz,
2 H), 7.09 (d, J = 5.80 Hz, 2 H), 8.48 (d, J = 5.80 Hz, 2 H) ppm.
13C NMR (50.4 MHz, CDCl3, 25 °C): δ = 25.19, 29.78, 32.28,
34.87, 61.78, 123.79, 149.00, 151.77 ppm.
4-(Pyridin-4-yl)butan-1-ol (18b): See procedure used for 18a. The
product obtained as a yellow oil (90%) was used without further
purification. The spectroscopic data are in complete agreement
with the literature’s data.[26] 1H NMR (200 MHz, CDCl3, 25 °C): δ
= 1.46–1.79 (m, 4 H), 1.93 (br. s, 1 H), 2.64 (t, J = 7.0 Hz, 2 H),
3.66 (t, J = 7.00 Hz, 2 H), 7.10 (dd, J = 4.40, 1.40 Hz, 2 H), 8.44
(dd, J = 4.40, 1.40 Hz, 2 H) ppm. 13C NMR (50.4 MHz, CDCl3,
25 °C): δ = 26.57, 32.22, 35.01, 62.40, 123.77, 149.35, 151.20 ppm.
GC-MS: m/z (%) = 31 (29), 65 (24), 93 (22) [pyCH3], 105 (100)
[pyCH2CH3], 151 (10) [M+].
4-(Pyridin-4-yl)butanal (19b): See procedure used for 19a The prod-
uct obtained as a red oil (99%) was used without further purifica-
tion. The spectroscopic data are in complete agreement with the
literature’s data.[25] 1H NMR (200 MHz, CDCl3, 25 °C): δ = 1.95
(t, J = 7.60 Hz, 2 H), 2.47 (dt, J = 8.00, 1.00 Hz, 2 H), 2.64 (t, J
= 7.60 Hz, 2 H), 7.09 (d, J = 5.80 Hz, 2 H), 8.48 (dd, J = 4.40,
1.40 Hz, 2 H), 9.76 (t, J = 1.40 Hz, 1 H) ppm. 13C NMR
(50.4 MHz, CDCl3, 25 °C): δ = 22.51, 34.30, 42.95, 149.50, 150.05,
150.20, 201.02 ppm. GC-MS: m/z (%) = 51 (24), 65 (32), 78 (18)
[Py], 92 (24) [pyCH2], 106 (100) [pyCH2CH2], 149 (14) [M+].
5-(4-Pyridinyl)pentanal (19d):[28] See procedure used for 19a. The
1,1-Dimethylethyl (Benzyl)[4-(pyridin-4-yl)butyl]carbamate (20b): product obtained as a yellow oil (96%) was used without further
See procedure used for 20a. The crude product was purified by
flash chromatography on silica gel [petroleum ether/EtOAc (3:1 Ǟ
1:1)] to give the pure product (27% over two steps) as a yellow oil.
purification. 1H NMR (200 MHz, CDCl3, 25 °C): δ = 1.55–1.75
(m, 4 H), 2.38–2-45 (m, 2 H), 2.46–2.62 (m, 2 H), 7.02 (d, J =
6.00 Hz, 2 H), 8.38 (dd, J = 4.40, 1.60 Hz, 2 H), 9.67 (t, J =
1H NMR (200 MHz, CDCl3, 25 °C): δ = 1.44 (s, 9 H), 1.40–1.50 1.60 Hz, 1 H) ppm. 13C NMR (50.4 MHz, CDCl3, 25 °C): δ =
(m, 2 H), 1.61–1.73 (m, 2 H), 2.58 (t, J = 6.80 Hz, 2 H), 3.05–3.25
(m, 2 H), 4.40 (br. s, 2 H), 7.06 (d, J = 5.80 Hz, 2 H), 7.18–7.38
(m, 5 H), 8.46 (d, J = 5.20 Hz, 2 H) ppm. 13C NMR (50.4 MHz,
21.38, 29.47, 34.78, 43.36, 123.48, 149.29, 150.37, 201.45 ppm. GC-
MS: m/z (%) = 106 (100) [pyCH2CH2], 92 (31) [pyCH2], 120 (7)
[py(CH2)3].
Eur. J. Org. Chem. 2011, 271–279
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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277

A. Massaro, A. Mordini, A. Mingardi, J. Klein, D. Andreotti
FULL PAPER
N-(Phenylmethyl)-5-(4-pyridinyl)-1-pentanamine:
5-(4-Pyridinyl)- phase was dried with Na2SO4, and the solvent was evaporated to
pentanal (19d) (680 mg, 4.17 mmol) was dissolved in dry MeOH
(40 mL) and benzylamine (0.54 mL, 5.00 mmol). Acetic acid
(0.71 mL, 12.51 mmol) and sodium cyanoborohydride (1 m, THF
solution, 4.17 mmol) were then added. The mixture was stirred at
room temp. overnight, and then the solvent was evaporated. The
crude product was dissolved in EtOAc and washed with NaHCO3.
The organic phase was dried with Na2SO4, filtered and the solvent
was evaporated to give the product (864 mg, 82%) as a yellow oil,
give the crude product as orange oil, which was purified by flash
chromatography on silica gel (cyclohexane/EtOAc, 5:1) to give pure
23a (144 mg, 52%) as a yellow oil. The same reaction was repeated
under microwave irradiation (50 °C, 250 W, 20 min) in a closed ves-
sel to give 23a with 78% yield after purification. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 1.68–1.99 (m, 3 H), 2.25–2.38 (m, 2
H), 3.10–3.17 (m, 1 H), 3.24 (d, J = 10.40 Hz, 1 H), 3.66 (t, J =
6.40 Hz, 1 H), 3.85 (d, J = 10.00 Hz, 1 H), 7.13–7.18 (m, 1 H),
7.19–7.35 (m, 5 H), 7.62–7.72 (m, 2 H), 8.52–8.57 (m, 1 H) ppm.
13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 22.78, 33.76, 53.58,
1
which was used without further purification. H NMR (200 MHz,
CDCl3, 25 °C): δ = 1.20–1.62 (m, 6 H), 2.40–2.78 (m, 5 H), 3.74 (s,
2 H), 7.03 (d, J = 5.40 Hz, 2 H), 7.18–7.40 (m, 5 H), 8.40 (d, J = 58.52, 70.65, 121.11, 121.92, 126.74, 128.10, 128.67, 136.78, 139.42,
5.60 Hz, 2 H) ppm. 13C NMR (50.4 MHz, CDCl3, 25 °C): δ = 148.86, 164.14 ppm. LC-MS: tR = 0.89 min; m/z = 239 [MH+].
2-[1-(Phenylmethyl)-2-piperidinyl]pyridine (23c):[29] See procedure
used for 23a. The crude product was purified by flash chromatog-
26.78, 29.79, 30.10, 35.19, 49.09, 53.89, 123.77, 126.78, 127.89,
128.17, 140.08, 149.29, 151.56 ppm. C17H22N2 (254.37): calcd. C
80.27, H 8.72, N 11.01; found C 80.24, H 8.69, N 10.98.
raphy on silica gel [petroleum ether/EtOAc (3:1) Ǟ EtOAc 100%]
1
to afford pure 23c (38%; 60% by MW) as a yellow oil. H NMR
(400 MHz, CDCl3, 25 °C): δ = 1.55–1.64 (m, 4 H), 1.76–1.90 (m, 3
H), 2.92–3.02 (m, 2 H), 3.33–3.40 (m, 1 H), 3.66 (app. d, J =
12.00 Hz, 1 H), 7.11–7.22 (m, 2 H), 7.25–7.27 (m, 4 H), 7.59–7.69
(m, 2 H), 8.51–8.54 (m, 1 H) ppm. 13C NMR (100.6 MHz, CDCl3,
25 °C): δ = 24.76, 25.78, 35.37, 53.03, 60.03, 70.46, 121.57, 121.95,
126.65, 128.05, 128.72, 136.76, 140.46, 148.88, 165.02 ppm. GC-
MS: m/z (%) = 91 (100) [Ph – CH2], 106 (89) [py(CH2)3], 147 (22)
[py(CH2)5], 161 (79) [M – Bz], 174 (11) [M – Py], 252(1) [M+].
1,1-Dimethylethyl (Phenylmethyl)[5-(4-pyridinyl)pentyl]carbamate
(20d): See procedure used for 16c. The crude product was purified
by flash chromatography on silica gel (petroleum ether/EtOAc, 2:1)
to afford pure 20d (25%) as a yellow oil. 1H NMR (200 MHz,
CDCl3, 25 °C): δ = 1.22–1.38 (m, 2 H), 1.46 (s, 9 H), 1.42–1.65 (m,
2 H), 1.80–1.98 (m, 2 H), 2.57 (t, J = 7.20 Hz, 2 H), 3.09–3.18 (m,
2 H), 4.41 (br. s, 2 H), 7.07 (d, J = 5.80 Hz, 2 H), 7.19–7.38 (m, 5
H), 8.47 (d, J = 5.80 Hz, 2 H) ppm. 13C NMR (50.4 MHz, CDCl3,
25 °C): δ = 26.39, 27.78, 28.46, 29.89, 35.08, 46.37, 50.40, 79.48,
123.67, 126.89, 127.88, 128.19, 138.28, 149.29, 149.78, 151.20 ppm.
GC-MS: m/z (%) = 175 (10) [M+ – Ph – Boc], 174 (100), 91 (95)
[Ph – CH2]. C22H30N2O2 (354.49): calcd. C 74.54, H 8.53, N 7.90,
O 9.03; found C 74.51, H 8.49, N 7.94, O 9.00.
4-[1-(Phenylmethyl)pyrrolidin-2-yl]pyridine (23b): See procedure
used for 23a. The crude product was purified by flash chromatog-
raphy on silica gel [petroleum ether/EtOAc (3:1) Ǟ petroleum
ether/EtOAc (1:1)] to afford pure 23b (45%; 62% by MW) as a
1
yellow oil. H NMR (400 MHz, CDCl3, 25 °C): δ = 1.38–1.43 (m,
1,1-Dimethylethyl
[5-(1-Oxido-4-pyridinyl)pentyl](phenylmethyl)-
1 H), 1.55–1.90 (m, 2 H), 2.18–2.34 (m, 2 H), 3.10–3.18 (m, 2 H),
3.42 (t, J = 8.00 Hz, 1 H), 3.80 (d, J = 13.20 Hz, 1 H), 7.21–7.31
(m, 5 H), 7.39 (d, J = 5.20 Hz, 2 H), 8.55 (m, 2 H) ppm. 13C NMR
(100.6 MHz, CDCl3, 25 °C): δ = 23.74, 35.02, 53.44, 58.24, 68.16,
122.67, 127.13, 128.18, 128.60, 134.93, 149.82, 155.01 ppm. ESI-
MS: m/z = 239.17 [M + H+]. C16H18N2 (238.33): calcd. C 80.63, H
7.61, N 11.75; found C 80.61, H 7.58, N 11.78.
carbamate (21d): See procedure used for 21a. The product obtained
as a yellow oil (99%) was used without further purification. 1H
NMR (200 MHz, CDCl3, 25 °C): δ = 1.38–1.64 (m, 15 H), 2.58 (t,
J = 7.20 Hz, 2 H), 3.05–3.13 (m, 2 H), 4.20 (br. s, 2 H), 7.08 (d, J
= 6.60 Hz, 2 H), 7.20–7.38 (m, 5 H), 8.17 (d, J = 6.60 Hz, 2 H)
ppm. 13C NMR (50.4 MHz, CDCl3, 25 °C): δ = 21.08, 26.27, 28.48,
29.78, 34.37, 46.29, 50.38, 79.89, 125.78, 126.86, 128.27, 134.38,
135.89, 138.56, 153.67, 161.18 ppm. GC-MS: m/z (%) = 57 (100)
[tBu], 91 (95) [Ph – CH2], 106 (30), 253 (33) [M+ – BocO], 354 (2)
[M+ – O]. C22H30N2O3 (370.49): calcd. C 71.32, H 8.16, N 7.56, O
12.96; found C 71.29, H 8.14, N 7.53, O 13.00.
4-[1-(Phenylmethyl)-2-piperidinyl]pyridine (23d): See procedure used
for 23a. The crude product was purified by flash chromatography
on silica gel [petroleum ether/EtOAc (3:1) Ǟ petroleum ether/
EtOAc (1:1)] to afford pure 23d (35%; 48% by MW) as a yellow
1
oil. H NMR (400 MHz, CDCl3, 25 °C): δ = 1.25–1.64 (m, 4 H),
[5-(1-Oxido-4-pyridinyl)pentyl](phenylmethyl)amine (22d): See pro-
cedure used for 22a. The product obtained as a yellow oil (69%)
was used without further purification. 1H NMR (200 MHz,
CDCl3, 25 °C): δ = 1.12–1.65 (m, 7 H), 2.58 (app. q, J = 7.00 Hz,
4 H), 3.76 (s, 2 H), 7.03 (d, J = 7.00 Hz, 2 H), 7.17–7.34 (m, 5 H),
8.07 (d, J = 7.00 Hz, 2 H) ppm. 13C NMR (50.4 MHz, CDCl3,
25 °C): δ = 26.73, 29.82, 30.03, 34.26, 49.09, 54.01, 125.68, 126.68,
127.80, 128.14, 138.49, 140.07, 141.80 ppm. GC-MS: m/z (%) = 32
(100), 91 (78) [Ph – CH2], 106 (25), 120 (12), 254 (2) [M+ – O].
C17H22N2O (270.37): calcd. C 75.52, H 8.20, N 10.36, O 5.92;
found C 75.49, H 8.18, N 10.38, O 5.89.
1.73–1.82 (m, 2 H), 1.95 (dt, J = 11.60, 3.60 Hz, 1 H), 2.87 (d, J =
13.60 Hz, 1 H), 2.94–3.10 (m, 1 H), 3.14 (dd, J = 11.20, 2.80 Hz,
1 H), 3.68 (d, J = 13.60 Hz, 1 H), 7.25–7.32 (m, 5 H), 7.41 (d, J =
6.00 Hz, 2 H), 8.55 (d, 6.00 Hz, 2 H) ppm. 13C NMR (100.6 MHz,
CDCl3, 25 °C): δ = 24.78, 25.67, 36.56, 52.89, 59.88, 68.10, 122.70,
126.78, 128.10, 128.47, 138.78, 149.78, 155.00 ppm. GC-MS: m/z
(%) = 252 (9) [M+], 175 (17) [M+ – Ph], 174 (100), 161 (15) [M+
–
Bn], 91 (72) [Bn], 65 (15). C17H20N2 (252.36): calcd. C 80.91, H
7.99, N 11.10; found C 80.89, H 7.97, N 11.14.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterization data of all in-
termediates and final compounds not reported here; 1H and 13C
NMR of compounds 22a–d and 23a–d.
Intramolecular Ring Closures
2-[1-(Phenylmethyl)-2-pyrrolidinyl]pyridine (23a):[24] To a solution
of
[4-(1-oxido-2-pyridinyl)butyl](phenylmethyl)amine
(22a)
(300 mg, 1.170 mmol) in CH2Cl2 (10 mL) bis(1,1-dimethylethyl)sil-
anediyl bis(trifluoromethanesulfonate) (0.758 mL, 2.341 mmol)
was added, and the reaction mixture was stirred at room temp. for
30 min. Then TEA (0.652 mL, 4.68 mmol) was added (the yellow
solution became orange), and the mixture was stirred for an ad-
ditional 2 h. The reaction was quenched by adding saturated aq.
NH4Cl to the red mixture and extracting with CH2Cl2. The organic
Acknowledgments
We acknowledge GlaxoSmithKline of Verona for its financial sup-
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Received: July 2, 2010
Published Online: November 25, 2010
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