The aza-silyl-Prins reaction: A novel method for the synthesis of trans-2,6-tetrahydropyridines

Article abstract of DOI:10.1055/s-2003-41434

Reaction of 4-trimethylsilyl-3-butenyl-1-amines with aldehydes under mild Lewis acid conditions gives substituted tetrahydropyridines in excellent yields and with excellent trans diastereoselectivity.

Full text of DOI:10.1055/s-2003-41434

1740
LETTER
The Aza-Silyl-Prins Reaction: A Novel Method for the Synthesis of Trans-2,6-
Tetrahydropyridines
A
za-Silyl-Prins Re
d
action rian P. Dobbs,*a Sebastien J. J. Guesné,a Michael B. Hursthouse,b Simon J. Colesb
a
School of Chemistry, University of Exeter, Stocker Road, Exeter, EX4 4QD, UK
Fax +44(1392)263434; E-mail: A.Dobbs@exeter.ac.uk
b
EPSRC National Crystallography Service, University of Southampton, Highfield, Southampton. SO17 1BJ, UK
Received 15 May 2003
Abstract: Reaction of 4-trimethylsilyl-3-butenyl-1-amines with
aldehydes under mild Lewis acid conditions gives substituted
tetrahydropyridines in excellent yields and with excellent trans
diastereoselectivity.
R
O
InCl3
OH R1
H
R
O
R1
CH2Cl2
TMS
Scheme 1 The silyl-Prins reaction
Key words: Prins reaction, aldehydes, indium trichloride
there are no examples of Lewis acid mediated Prins-type
cyclisations to give tetrahydropyridines. The acid-pro-
moted cyclisation reaction of vinylsilanes to give tetrahy-
dropyridines, however, continues to be of considerable
interest, and the recent work reported by Tanner4 prompts
us to report our findings in this area.
The piperidine ring is widespread in nature and there have
been numerous accounts of the synthesis of piperidines
and their wide range of biological activities. Nevertheless,
synthetic methodologies for the synthesis of nitrogen con-
taining heterocycles continue to be of immense impor-
tance.
The desired substrates for our initial studies were a range
of N-substituted Z-4-trimethylsilyl-3-buten-1-ylamines 1
(Scheme 2). Initially these were prepared via a four step
sequence starting from either 3-butyn-1-ol or 4-pentyn-2-
ol. Silylation using n-butyllithium/trimethylsilyl chloride
followed by DIBAL-H reduction gave 4-trimethylsilyl-3-
buten-1-ol in 85–90% overall yield. Tosylation of the al-
cohol and displacement with a range of amines gave the
desired cyclisation precursors 1a–f.
Initially a range of Lewis acids were screened.5 No reac-
tion was observed for the reaction of 1b with either ben-
zaldehyde or hexanal using any Lewis acid in dry
dichloromethane at low or room temperature (Table 1, en-
tries 1, 3 and 5). Increasing the temperature to refluxing
dichloromethane did, however, by GC-analysis, suggest
traces of product formation. The solvent therefore was
switched to a higher boiling solvent – acetonitrile. Several
Lewis acids now proceeded to promote the reaction and
The use of silanes in the termination of cyclisation reac-
tions is now a popular synthetic methodology, and the
area has been extensively reviewed.1 Furthermore, there
are now many examples of natural product total syntheses
that have incorporated this methodology as a key step.1
We have recently added to this wealth of methodology by
reporting the facile indium trichloride mediated cyclisa-
tion of Z-4-trimethylsilyl-3-buten-1-ols with aldehydes or
epoxides to give good yields of substituted dihydropyrans
– the silyl-Prins reaction (Scheme 1).2 The reaction de-
monstrates exclusive cis-diastereoselectivity across the
oxygen atom.
It occurred to us that it would be interesting to explore the
application of the silyl-Prins reaction to the synthesis of
the tetrahydropyridine ring. Despite Overman’s impres-
sive work on the acid-catalysed vinylsilane-iminium ion
cyclisation to azacycles,3 to the best of our knowledge,
1. TsCl, DMAP, Et3N
CH2Cl2, 0 °C, >90%
R
R
1. 2n-BuLi, –78 °C, THF
2. 2TMS-Cl, –78 °C to r.t.
OH
NHR1
R
OH
2. R1NH2, EtOH, reflux
3. DIBAL-H, Et2O, reflux
1
TMS
TMS
85–90%
a) R = H, R1 = Ph 40% d) R = Me, R1 = Ph 70%
b) R = H, R1 = Bn 62% e) R = Me, R1 = Bn 68%
c) R = H, R1 = n-Pr 89% f) R = Me, R1 = n-Pr 62%
Scheme 2 Synthesis of 4-trimethylsilyl-3-butenyl-1-amines
Synlett 2003, No. 11, Print: 02 09 2003. Web: 25 08 2003.
Art Id.1437-2096,E;2003,0,11,1740,1742,ftx,en;D10903ST.pdf.
DOI: 10.1055/s-2003-41434
© Georg Thieme Verlag Stuttgart · New York

LETTER
Aza-Silyl-Prins Reaction
1741
yield tetrahydropyridine products (Table 1, entries 2, 4, 6, The methyl-substituted analogues 1d–f were then pre-
and 7). Of these, indium trichloride soon became the pared, in order to investigate any diastereoselectivity dur-
Lewis acid of choice, consistently giving superior yields ing the cyclisation process. Reaction with indium
to alternative promoters (Tables 1 and 2).
trichloride and a range of aldehydes, under the same reac-
tion conditions gave, in each case, only a single diastereo-
mer product in good yields (Table 3).
Table 1 Results of Lewis Acid Screening
O
Table 3 Synthesis of Disubstituted Tetrahydropyridines
N
Ph
Lewis Acid
H
Me
TMS
N
R
R
H
O
R1
InCl3
N
Ph
H
Me
N
R1
R
R
H
MeCN
Reflux
TMS
Entry
R
Lewis Acid Conditions
%Yield
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
InCl3
CH2Cl2, r.t.
0
64
0
Entry
R1
R
% Yield
70
InCl3
MeCN, reflux
CH2Cl2, –78 °C to
r.t.MeCN, reflux
1
2
3
4
5
6
7
8
9
Bn
Bn
Bn
Ph
Ph
n-C5H11
TMSOTf
TMSOTf
BF3·OEt2
BF3·OEt2
AlCl3
PhCH2
Ph
68
36
0
33
CH2Cl2, –78 °C to r.t.
MeCN, reflux
n-C5H11
Ph
22
37
37
62
27
0
MeCN, reflux
n-Pr
n-Pr
n-Pr
CBz
n-C5H11
PhCH2
Ph
73
n-C5H11
n-C5H11
InCl3
MeCN, reflux
85
TMSOTf
MeCN, reflux
40
n-C5H11
70
The preferred conditions of indium trichloride at reflux in
acetonitrile were then applied to the synthesis of a range
of simple tetrahydropyridines (Table 2). Good to excel-
lent yields were obtained for three different substituents
on the amine, these being alkyl (n-Pr), aryl (Ph) and ben-
zyl. The reaction is also tolerant of a range of aldehydes,
although in a similar manner to our original work on oxy-
genated heterocycles, the reaction with benzaldehyde is
less successful than with non-aromatic aldehydes.2
In our original work on the silyl-Prins reaction, we report-
ed exclusive cis-selectivity across the oxygen in the new
heterocycle.2 Interestingly, NOE data suggested that a
trans relationship existed between the two substituents at
the 2 and 6 positions: a small 2.2% enhancement of the
C6-methyl group was observed on irradiation of the pro-
ton at C2; no enhancement of the C6 proton was observed.
We were however unable to determine which substituent
was orientated axial or equatorial in these compounds.
Fortunately, we were able to crystallise several of these
compounds, and the structure of ( )-1-benzyl-2-methyl-6-
phenyl-1,2,3,6-tetrahydropyridine is shown (Figure 1).7
This not only confirmed the findings from the NOE exper-
iments, but also clearly illustrates the methyl group orien-
tated axial in the 2-position and the phenyl group
equatorial. The origin of the trans selectivity is believed
to be unfavourable A1,3 interactions between the N-alkyl
group, the methyl group and the R group from the alde-
hyde.
Table 2 Synthesis of Simple Tetrahydropyridines
R1
O
InCl3
N
H
TMS
N
R1
R
R
H
MeCN
Reflux
1 a–c
Entry
R1
R
% Yield
62
1
2
3
4
5
6
7
8
Bn
Bn
Bn
Ph
n-C5H11
PhCH2
Ph
95
Hydrogenation of the N-benzyltetrahydropyridines simul-
taneously removed both the N-benzyl group to give the
free amine and also hydrogenated the olefin to give the
trans-2,6-piperidine in good yield (76%, Scheme 3).3a
64
n-C5H11
PhCH2
Ph
95
Not wishing to be limited to these three groups on nitro-
gen, the cyclisation of the free amine was examined (pre-
pared by azide displacement of the tosyl group in Scheme
2 followed by lithium aluminium hydride reduction); this
unfortunately failed to give any cyclised product with any
aldehyde. A more versatile amine protecting group, the
Ph
84
Ph
0
n-Pr
n-Pr
PhCH2
Ph
55
22
Synlett 2003, No. 11, 1740–1742 ISSN 1234-567-89 © Thieme Stuttgart · New York

1742
A. P. Dobbs et al.
LETTER
( )-1-Benzyl-2-methyl-6-phenyl-1,2,3,6-tetrahydropyridine
White solid; Mp 77–78 °C. IR (nujol)/cm–1: 3084, 3060, 2992,
1869, 1603; dH (400 MHz; CDCl3) 7.49–7.47 (2 H, m, ArH), 7.36–
7.25 (8 H, m, ArH), 5.79 (1 H, m, H4), 5.63 (1 H, m, H5), 4.12 (1
H, m, H6), 3.62 (1 H, d, J = 13.8 Hz, H7), 3.48 (1 H, d, J = 13.8 Hz,
H7), 3.12 (1 H, m, H2), 2.45 (1 H, m, H3), 1.88 (1 H, m, H3), 1.10
(3 H, d, J = 6.6 Hz, CH3); dC (100 MHz; CDCl3) 144.1 (CPh), 140.5
(Ar), 129.4 (C5), 128.6 (Ar), 128.5 (Ar), 128.4 (Ar), 128.2 (Ar),
127.1 (Ar), 126.7 (Ar), 123.2 (C4), 61.6 (C6), 53.0 (C7), 46.2 (C2),
31.9 (C3), 1.13 (C8); m/z 264 (MH+, 100), 248 (47), 186 (45), 134
(95), 130 (19); Found C 86.23%, H 7.87%, N 5.08%; calcd for
C19H21N requires C 86.65%, H 8.04%, N 5.32%. Found: (M + H)+
264.1752. C18H19N requires (M + H)+ 264.1765.
Acknowledgement
We wish to thank the University of Exeter for financial support; the
EPSRC X-ray Crystallographic Service (Southampton, UK) for
structure determination and the EPSRC Mass Spectrometry Service
(Swansea, UK) for some mass spectral data.
Figure 1 NOE and X-ray crystallographic structure7 for ( )-1-
benzyl-2-methyl-6-phenyl-1,2,3,6-tetrahydropyridine
References
(1) (a) Silane-terminated reactions: Blumenkopf, T. A.;
Overman, L. E. Chem. Rev. 1986, 86, 857. (b) Silicon in
total synthesis: Langkopf, E.; Schinzer, D. Chem. Rev. 1995,
95, 1375.
H2
Me
N
n-Pn
Me
N
n-Pn
Pd/C
EtOH
H
(2) Dobbs, A. P.; Martinović, S. Tetrahedron Lett. 2002, 43,
7055.
(3) (a) Overman, L. E.; Malone, T. C.; Meier, G. P. J. Am. Chem.
Soc. 1983, 105, 6993. (b) Overman, L. E.; Burk, R. M.
Tetrahedron Lett. 1984, 25, 5739. (c) Flann, C.; Malone, T.
C.; Overman, L. E. J. Am. Chem. Soc. 1987, 109, 6097.
(d) Daub, G. W.; Heerding, D. A.; Overman, L. E.
Tetrahedron 1988, 44, 3919. (e) Application in total
synthesis: Overman, L. E.; Robichaud, A. J. J. Am. Chem.
Soc. 1989, 111, 300.
(4) Kværnø, L.; Norrby, P.-O.; Tanner, D. Org. Biomol. Chem.
2003, 1, 1041.
(5) Carlson, R.; Lundstedt, T.; Nordahl, A.; Prochazka, M. Acta
Chem. Scand. 1986, 522.
(6) Leading references to recent alternative methods for the
preparation of 2,6-trans substituted tetrahydropyridines:
(a) Using ring closing metathesis: Felpin, F.-X.; Lebreton, J.
Tetrahedron Lett. 2003, 44, 527. (b) Also see:
Kumareswaran, R.; Hassner, A. Tetrahedron: Asymmetry
2001, 12, 2269. (c) Via a [3+2] nitrone cycloaddition
reaction: Chackalamannil, S.; Wang, Y. Tetrahedron 1997,
53, 11203. (d) Via organolithium/allylboration: Bubnov, Y.
N.; Klimkina, E. V.; Ignatenko, A. V.; Gridnev, I. D.
Tetrahedron Lett. 1997, 38, 4631. (e) From an ene-iminium
ion cyclisation: Agami, C.; Comesse, S.; Kadouri-Puchot, C.
J. Org. Chem. 2002, 67, 2424.
Scheme 3
CBz group, could readily be incorporated on to the free
amine (CBzCl, sodium hydrogen carbonate, 90%). This
also gave the corresponding tetrahydropyridine in good
yield (Table 3, entry 9) and now offers the potential for
deprotection and further elaboration. This result is partic-
ularly interesting in light of the only previous related ex-
ample, where the acid catalysed cyclisation of a N-CO2Et
substituted amine gave a 1:1 mixture of the cis- and trans-
products.3b
In summary, we have developed an efficient Lewis acid
mediated cyclisation reaction of 4-trimethylsilyl-3-bute-
nyl-1-amines with aldehydes to give trans-tetrahydropy-
ridines in good yields.6 Given the current interest in the
postulated mechanism for the related vinylsilane-ketimin-
ium cyclisation reaction,3,4 we are currently investigating
the mechanism and stereocontrol of this reaction, as well
as its application in a range of natural product syntheses
and these findings will be reported in due course.
(7) Crystal data for ( )-1-benzyl-2-methyl-6-phenyl-1,2,3,6-
tetrahydropyridine: C19H21N, Triclinic space group P-1, a =
7.5440 (3) Å, b = 10.0139 (4) Å, c = 11.6666 (6) Å, a =
97.125 (2)°, b = 107.223 (2)°, g = 107.925 (2)°, Volume =
778.20 (6) Å3, Z = 2, Density (calculated) = 1.124 Mg / m3,
F(000) = 284. 6346 reflections were collected, 3446
independent reflections [Rint = 0.0475], which were used in
all calculations. Diffractometer: Nonius KappaCCD area
detector. Structure solution: SHELXS97 and structure
refinement: SHELXL97. The deposition number at the
Cambridge Crystallography Data Centre, CCDC, is
CCDC214999.
Typical experimental procedure for the indium trichloride me-
diated reaction:8 The secondary amine (1.0 mmol) was added
dropwise to a solution of indium trichloride (221 mg, 1.0 mmol) and
an aldehyde (1.0 mmol) in anhydrous acetonitrile (20 mL) at reflux
temperature. Once the reaction was completed (monitored by TLC)
the solution was cooled, concentrated and the residue obtained par-
titioned between dichloromethane (20 mL) and 1 M NaOH (20 mL).
The aqueous layer was extracted with dichloromethane. The com-
bined organic layers were washed with 1 M NaOH, water, dried
(magnesium sulfate) and concentrated under reduced pressure. The
residue obtained was then purified by flash chromatography to give
the corresponding tetrahydropyridine.
(8) All compounds gave satisfactory analytical and
spectroscopic data.
Synlett 2003, No. 11, 1740–1742 ISSN 1234-567-89 © Thieme Stuttgart · New York