Microwave-assisted aza-Prins reaction. Part 1: Facile preparation of natural-like 3-azabicyclo[3.3.1]non-6-enes

Article abstract of DOI:10.1016/j.tetlet.2011.10.123

A facile and operationally simple route to diastereomerically pure, natural-like 3-azabicyclo[3.3.1]non-6-enes via microwave-assisted, BF ₃·OEt₂-promoted aza-Prins reaction has been developed. Complexity-generating transformations based on these products involving reactive functionalities introduced during the aza-Prins step have been developed.

Full text of DOI:10.1016/j.tetlet.2011.10.123

Tetrahedron Letters 52 (2011) 7157–7160
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted aza-Prins reaction. Part 1: facile preparation
of natural-like 3-azabicyclo[3.3.1]non-6-enes
Vladislav Parchinsky a, Alexei Shumsky a, Mikhail Krasavin a,b,
⇑
a Chemical Diversity Research Institute, 2a Rabochaya St., Khimki, Moscow Reg., 141400, Russia
b Science and Education Center ‘‘Innovative Research’’, Yaroslavl State Pedagogical University, Yaroslavl 150000, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and operationally simple route to diastereomerically pure, natural-like 3-azabicyclo[3.3.1]non-6-
enes via microwave-assisted, BF3ÁOEt2-promoted aza-Prins reaction has been developed. Complexity-
generating transformations based on these products involving reactive functionalities introduced during
the aza-Prins step have been developed.
Received 13 August 2011
Revised 12 October 2011
Accepted 21 October 2011
Available online 28 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Microwave-assisted organic synthesis
aza-Prins reaction
Diastereoselective synthesis
Bicyclic piperidines
Lycopodium alkaloids
Complexity-generating synthesis
Intramolecular cyclization of electrophilic iminium species onto
an appropriately positioned olefin moiety (the aza-Prins reaction1)
as a simple entry into pharmaceutically useful piperidines has
been the subject of intense synthetic methodology research. From
a review of the current literature, it appears that in most cases the
cyclization is limited, with some exceptions, to N-sulfonyl homoal-
lylic amines,2 or requires activation of the olefin moiety by a tri-
methylsilyl substituent (the so-called aza-silyl-Prins reaction
furnishing tetrahydropyridines3). The aza-Prins cyclization of N-to-
syl homoallylamines with aldehydes (Scheme 1) has been cata-
lyzed efficiently by a variety of Lewis [FeIII halides,2a,g BiCl3,2b
GaI3/I2,2c I2,2f Me3SiI,2h BF3ÁOEt2,2i Sc(OTf)32k] or Brønsted (phos-
phomolybdic acid,2e HBF4ÁOEt2,2j TfOH2l) acids, and the initially
generated carbocation has been trapped by the catalyst counter-
ion,2b,c,h,j nucleophilic solvent molecule,2i,l water2e or even by a ha-
lide transferred from a halogenated solvent.2a,d,g A thorough
investigation of the scope, mechanism, and limitations of the
aza-Prins reaction has been undertaken by Dobbs.4
cyclization onto silyl enol ether. Inspired by these examples and
motivated by the widespread presence of bicyclic piperidine moie-
ties in natural products (Fig. 1),7 we became interested in exploring
the scope of this reaction using a model 3-cyclohexenylmethyl-
amine 1.
Compound 1 was easily synthesized in multigram quantities as
shown in Scheme 2. Although the nitrile precursor to 1 can, in prin-
ciple, be obtained directly from the cycloaddition of isoprene with
acrylonitrile,8 the same reaction with acrolein led to a greater yield
and easier purification and therefore justified the two additional
functional group interconversions.
After substantial experimentation on the reaction conditions
(reaction medium as well as temperature regimens) and acid
promoters, we discovered that pre-condensation of 1 with aromatic
aldehydes or ethyl glyoxylate followed by microwave irradiation at
180 °C for 1 h in the presence of an equimolar amount of BF3ÁOEt2 in
1,4-dioxane furnished, cleanly and efficiently (as judged by the LC–
MSanalyses of thereaction mixtures), hithertoundescribed3-azabi-
cyclo[3.3.1]non-6-enes 2a–k (Scheme 3). Notably, the same reaction
performed under conventional reflux in 1,4-dioxane led only to a
slow conversion of 1 into a complex mixture of products. Similarly,
an unsatisfactory result was obtained when the microwave-assisted
cyclization was attempted in the presence of other Lewis acid pro-
moters [InCl3, Sc(OTf)3, FeCl3] that had been used by others2 to pro-
mote the aza-Prins reaction of N-tosyl homoallylamine. This result
appears to be in accordance with the failure of non-sulfonylated
homoallylamines to give the aza-Prins cyclization products under
InCl3 catalysis as previously observed by Dobbs.4
In an elegant total synthesis of (+)-nankakurines A and B, Over-
man demonstrated the utility of the aza-Prins cyclization involving
cyclic unsaturated amines for constructing polycyclic piperidine-
containing frameworks.5 The skeletally related Lycopodium alkaloid,
luciduline, has been constructed by Waters6 via aza-Prins
⇑
Corresponding author at present address: Eskitis Institute, Griffith University,
Brisbane, QLD 4111, Australia. Tel.: +61 (0) 7 3735 6053; fax: +61 (0) 7 3735 6078.
E-mail
addresses:
mkrasavin@hotmail.com,
m.krasavin@griffith.edu.au
(M. Krasavin).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.123

7158
V. Parchinsky et al. / Tetrahedron Letters 52 (2011) 7157–7160
SO2Tol
SO2Tol
RCHO
SO2Tol
R
N+
N
NHTs
N
+
acid catalyst
R
R
X
X = Hal, OH
Scheme 1. aza-Prins cyclization involving N-tosyl homoallylamines.2
N
N
N
O
O
luciduline
N
H
N
N
R
N
N
Ac
N
Ac
dihydrolycolucine
spirolucidine
nankakurine A (R = H)
nankakurine B (R = Me)
Figure 1. Examples of natural products containing bicyclic piperidine moieties.
Table 1
3-Azabicyclo[3.3.1]non-6-enes 3a–k prepared in this work
CHO
CHO
CN
a
Product
R
Yielda (%)
46
+
3a
4-FC6H4
O
*
3b
67
b
3c
3d
3e
3f
4-MeOC6H4
4-ClC6H4
4-MeOOCC6H4
EtOOC
80
72
64
58
32
39
70
81
c
NH2
3g
3h
3i
2-HOC6H4
3-Py
Ph
1
3j
4-MeC6H4
S
EtOOC
Scheme 2. Synthesis of ( )-[(4-methylcyclohex-3-en-1-yl)methyl]amine (1).
Reagents and conditions: (a) ZnCl2 (5 mol %), neat, 40 °C, 18 h (76% after distilla-
tion); (b) NH2OH/EtOH, rt, then POCl3/CH2Cl2, reflux (81%); (c) LAH, 1,4-dioxane,
reflux, 3 h (69%).
*
3k
64
a
Yield after chromatography and conversion into the hydrochloride salt.
Compounds 2a–k were isolated chromatographically and con-
verted, for easier handling, into the respective hydrochloride salts
3a–k (Table 1).9 All the products were obtained as a single endo-
diastereomer, as confirmed by characteristic through-space
interactions observed in their NOESY spectra (Fig. 2). Also notable
double-bond regioisomer. This, as proposed earlier by Overman,5
could be due to participation of the nitrogen atom in regiospecific
intramolecular deprotonation of the initially formed carbocation
intermediate 4 (Scheme 4).
Compounds 2, albeit in lower yield, also formed on microwave
irradiation of equimolar amounts of 1, an aldehyde and BF3ÁOEt2 in
was the fact that each product
2
was formed as a single
RCHO
NH2
N
R
benzene
reflux, 30 min
1
BF3·OEt2 (1 equiv.)
H
R
N
1,4-dioxane, MW
180 oC, 1 h
2a-k (free base)
3a-k (HCl salt)
4M HCl/
1,4-dioxane
(~quant.)
Scheme 3. Microwave-promoted aza-Prins reaction toward 3-azabicyclo[3.3.1]non-6-enes.

V. Parchinsky et al. / Tetrahedron Letters 52 (2011) 7157–7160
7159
H
N
· HCl
R
H
H
EtOOC
H
HN
O
H
RNCO
N+
EtOOC
N
H
pyridine, r.t., 2 h
83%
H
H
3f
H
7
R
Cl
O
N
Figure 2. Through-space interactions observed in the NOESY spectrum of 3dÁHCl.
1,4-dioxane
N
O
MW, 180 oC, 2 h
64%
R = 4-MeC6H4
1,4-dioxane (i.e., without pre-formation of the Schiff base). In this
reaction, the major products 2 were accompanied by a small
(<10%) amount of 1-azaadamantane by-products 5, presumably
formed via a second aza-Prins reaction of 2 with unreacted alde-
hyde (Scheme 5). A similar access to the 1-azaadamantane frame-
work was reported by Khuong-Huu.10 Our further results
describing the synthetic potential of double aza-Prins cyclization
involving 1 as a facile entry into 1-azaadamantanes 5 are disclosed
in the following communication.11
6
Scheme 6. Synthesis of tricyclic hydantoin 6.
Compounds 2(3) are of interest not only from the standpoint of
their resemblance to naturally occurring alkaloids,7 as well as fully
synthetic, biologically active compounds (e.g., the recently de-
OH
scribed12 carba-cytisine partial antagonists of the
a4b2 neuronal
O
O
O
nicotinic acetylcholine receptor which are potentially useful in
smoking cessation). They contain a reactive nitrogen atom and
can be viewed as a starting point en route to medicinally relevant
scaffolds of increased complexity. This is exemplified by the syn-
thesis of hydantoin compound 6 obtained via microwave-assisted
cyclization of urea 7, which was in turn obtained by carbamoyla-
tion of 3f (Scheme 6). Another interesting example was provided
by the acylation of 3b with maleic anhydride which gave, on spon-
taneous intramolecular Diels–Alder (IMDA) reaction,13,14 the struc-
turally complex, polycyclic lactam carboxylic acid 8 (Scheme 7).
In conclusion, we have described the microwave-assisted,
BF3ÁOEt2-promoted aza-Prins reaction as a simple and diastereo-
specific entry to natural-like 3-azabicyclo[3.3.1]non-6-enes. With
judicious choice of the peripheral groups, these compounds can
O
H
N
· HCl
O
O
O
N
Et3N, 1,4-dioxane
40 oC
3b
COOH
H
O
O
IMDA
N
H
serve
as
templates
for
further
complexity-generating
transformations.
Typical procedure—synthesis of compounds 3a–k . Equimolar
amounts (2 mmol scale) of amine 1 and an aldehyde were com-
bined in benzene and heated at reflux for 30 min. The mixture
8
Scheme 7. Acylation of 3b with maleic anhydride.
R
LA
LA
N+
R
N
..
R
N
2
H
+
4
Scheme 4. Possible nitrogen atom contribution to the regioselective formation of 2.
H
R
N
RCHO (1 equiv.)
N
R
R
BF3·OEt2 (1 equiv.)
NH2
+
1,4-dioxane, MW
180 oC, 1 h
1
2, major
5, minor
Scheme 5. Formation of 1-azaadamantane by-products in the aza-Prins reaction of 1 with various aldehydes.

7160
V. Parchinsky et al. / Tetrahedron Letters 52 (2011) 7157–7160
Ramesh, K.; Narayana Kumar, G. G. K. S.; Gree, R. Tetrahedron Lett. 2010, 51,
1578–1581; (k) Subba Reddy, B. V.; Borkar, P.; Pawan Chakravarthy, P.; Yadav,
J. S.; Gree, R. Tetrahedron Lett. 2010, 51, 3412–3416; (l) Subba Reddy, B. V.;
Ramesh, K.; Ganesh, A. V.; Narayana Kumar, G. G. S. K.; Yadav, J. S.; Gree, R.
Tetrahedron Lett. 2011, 52, 495–498.
was evaporated to dryness, the residue dissolved in anhydrous 1,4-
dioxane (5 mL) and transferred into a microwave reactor tube.
BF3ÁOEt2 (1.0 equiv) was added, the reaction tube was capped with
a septum and irradiated using a Biotage Initiator™ microwave
reactor at 180 °C for 1 h. The solvent was evaporated and the res-
idue was partitioned between CHCl3 (10 mL) and 1 M aqueous
NaOH solution. The organic layer was separated, dried over anhy-
drous MgSO4, filtered, concentrated, and chromatographed on sil-
ica gel using an appropriate gradient of MeOH in CH2Cl2 as
eluent. Fractions containing 2 (as verified by LC–MS analysis) were
combined and concentrated in vacuo to give a viscous oil. This was
dissolved in a minimum amount of 1,4-dioxane and treated with
excess 4 M HCl in 1,4-dioxane. The resulting white crystalline pre-
cipitate was collected by filtration, washed with 1,4-dioxane and
air-dried to provide analytically pure 3.
3. (a) Dobbs, A. P.; Guesne, S. J. J.; Hursthouse, M. B.; Coles, S. J. Synlett 2003,
1740–1742; (b) Dobbs, A. P.; Guesne, S. J. J. Synlett 2005, 2101–2103; (c) Dobbs,
A. P.; Parker, R. J.; Skidmore, J. Tetrahedron Lett. 2008, 49, 827–831.
4. Dobbs, A. P.; Guesne, S. J. J.; Parker, R. J.; Skidmore, J.; Stephenson, R. A.;
Hursthouse, M. B. Org. Biomol. Chem. 2010, 8, 1064–1080.
5. Altman, R. A.; Nilsson, B. L.; Overman, L. E.; de Alaniz, J. R.; Rohde, J. M.; Taupin,
V. J. Org. Chem. 2010, 75, 7519–7534.
6. Cheng, X.; Waters, S. Org. Lett. 2010, 12, 205–207.
7. Barbe, G.; Fiset, D.; Charette, A. B. J. Org. Chem. 2011, 76, 5354–5362.
8. Petrov, A. A.; Sapozhnikova, A. F. Zh. Obshch. Khim. 1948, 18, 424–429.
9. Characterization data for selected compounds: 3d: 1H NMR (400 MHz, 90 °C,
DMSO-d6) d 10.60 (d, J = 11.0 Hz, 1H), 8.54 (d, J = 11.6 Hz, 1H), 7.45 (ABq,
J = 10.9 Hz, 4H), 5.60 (s, 1H), 4.55 (d, J = 15.9 Hz, 1H), 3.13–3.38 (m, 3H), 2.33 (s,
2H), 2.20 (s, 1H), 2.09 (d, J = 16.0 Hz, 1H), 1.70 (d, J = 16.0 Hz, 1H), 0.98 (s, 3H);
13C NMR (100 MHz, 90 °C, DMSO-d6) d 135.6, 132.3, 129.9, 127.6, 127.5, 126.8,
59.5, 39.0, 29.6, 29.4, 23.2, 23.1; LC–MS (MÀCl) m/z 248.3. Anal. Calcd for
C
15H19Cl2N: C, 63.39; H, 6.74; N, 4.93; found: C, 63.42; H, 6.78; N, 4.99; 3e: 1H
Acknowledgment
NMR (400 MHz, 90 °C, DMSO-d6) d 10.61 (br s, 1H), 8.47 (br s, 1H), 7.95 (d,
J = 10.7 Hz, 2H), 7.65 (d, J = 10.7 Hz, 2H), 5.65 (s, 1H), 4.61 (s, 1H), 3.87 (s, 3H),
3.09–3.35 (m, 3H), 2.20–2.40 (m, 3H), 2.12 (d, J = 16.6 Hz, 1H), 1.76 (d,
J = 16.6 Hz, 1H), 0.95 (s, 3H); 13C NMR (100 MHz, 90 °C, DMSO-d6) d 165.5,
142.0, 130.1, 129.0, 128.5, 127.0, 126.0, 59.8, 51.4, 50.5, 39.0, 29.7, 23.2, 23.1;
LC–MS (MÀCl) m/z 272.6. Anal. Calcd for C17H22ClNO2: C, 66.33; H, 7.20; N,
4.55; found: C, 66.40; H, 7.27; N, 4.61; 3i: 1H NMR (400 MHz, 90 °C, DMSO-d6) d
10.46 (br s, 1H), 8.52 (br s, 1H), 7.47 (m, 2H), 7.29–7.37 (m, 3H), 5.58 (s, 1H),
4.52 (d, J = 15.1 Hz, 1H), 3.14–3.38 (m, 3H), 2.34 (br s, 2H), 2.18 (s, 1H), 2.10 (d,
J = 15.8 Hz, 1H), 1.70 (d, J = 15.8 Hz, 1H), 0.91 (s, 3H); 13C NMR (100 MHz, 90 °C,
DMSO-d6) d 137.2, 130.7, 128.1, 127.5, 126.9, 125.9, 60.1, 50.6, 29.9, 29.7, 23.9,
23.5; LC–MS (MÀCl) m/z 214.5. Anal. Calcd for C15H20ClN: C, 72.13; H, 8.07; N,
14.19; found: C, 72.02; H, 8.08; N, 14.09.
This research was supported by the Federal Agency for Science
and Innovation (Russian Federation Government Contract
02.740.11.0092).
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