Dearomatization of N-phenyl-2,6-dialkylpiperidines: Practical synthesis of (±)-solenopsin A and (±)-dihydropinidine

Article abstract of DOI:10.1055/s-2004-830884

The fire ant venom alkaloid (±)-solenopsin A was prepared in 4 steps (34%) starting from the N-phenyl-2-undecyl piperidine (1c). The key step in this synthesis involved the dearomatization of the phenyl group of N-phenyl-2-methyl-6-undecyl-piperidine (9c), which was carried out under Birch conditions.

Full text of DOI:10.1055/s-2004-830884

LETTER
2005
Dearomatization of N-Phenyl-2,6-dialkylpiperidines: Practical Synthesis of
±)-Solenopsin A and (±)-Dihydropinidine
(
a
a
a
a
a
b
Dearomatization
N
o
i
f
N
-Phe
c
nyl-2,6-dia
o
lkylpiperidin
l
es as Girard, Cyrille Gautier, Richard Malassene, Jean-Pierre Hurvois,* Claude Moinet, Loic Toupet
a
Laboratoire d’Electrochimie, UMR 6509, Institut de Chimie, Université de Rennes I, Campus de Beaulieu, 35042 Rennes Cedex, France
Fax +33(223)235967; E-mail: Jean-Pierre.Hurvois@univ-rennes1.fr
b
Groupe Matière Condensée et Matériaux, Université de Rennes I, Campus de Beaulieu, 35042 Rennes Cedex, France
Received 12 May 2004
diate bifunctional cyanoamine III, allowed the synthesis
of several N-phenyl-2-alkylpiperidines IV. It is worth
noting that in this sequence, the phenyl group, easily add-
Abstract: The fire ant venom alkaloid (±)-solenopsin A was pre-
pared in 4 steps (34%) starting from the N-phenyl-2-undecyl pipe-
ridine (1c). The key step in this synthesis involved the
8
dearomatization of the phenyl group of N-phenyl-2-methyl-6-unde- ed, should be considered as an effective activator for the
9
cyl-piperidine (9c), which was carried out under Birch conditions.
elaboration of I to IV. Moreover, since numerous meth-
ods are now available for the synthesis of aniline deriva-
Key words: alkaloids, carbanions, diastereoselectivity, lithium, pi-
peridines
1
0
tives, this approach makes I a useful building block for
the construction of natural piperidine-type compounds.
Thus, to synthesize V, conditions were needed for a clean
removal of the phenyl group from IV. To this end,
dearomatization11 of IV via single electron transfer
seemed to us a valuable synthetic approach. In this paper,
we report the synthesis of mono- and disubstituted piperi-
dine derivatives, including three piperidine alkaloids, as
well as the course of the reactions.
1
Due to their interesting biological properties, piperidine
12
alkaloids and related analogs have been the subject of nu-
2
merous synthetic approaches. These synthetic routes in-
3
volve: i) alkylation of a-lithiated piperidine derivatives,
4
ii) reduction of imines or masked iminium ions, iii) aza-
Diels–Alder reactions with imines, iv) alkylation of ami-
5
6
nonitrile systems. This latest approach is based on the uti- We set mono-substituted amines 4a–f as initial synthetic
lization of cyano-stabilized carbanions which proved targets of this study. With this aim in mind, it was felt that
efficient intermediates for the elaboration of new carbon Birch reduction of the aromatic ring of amines 1a–f could
to carbon bonds. To this end, the development in our lab- lead to the expected secondary amines 4a–f after hydro-
oratory of a one step synthesis of new aminonitrile sys- lysis of the intermediate enamines 2 and 3.
tems (II) starting from aromatic amines of the type of (I)
7
seemed to us a promising possibility (Scheme 1).
5'
4'
Ph
N
Ph
N
Ph
N
CN
3'
3'
CN
2'
1)
+
N
R
N
R
N
R
R
2
II
I
III
2a–f
3a–f
1a–f
Ph
N
2)
H
N
R
R
a: R = H
b: R = C3H7
c: R = C11H23
d: R = C5H11
e: R = C7H15
f : R = C9H19
g: R = CH3
H
N
R
V
IV
Scheme 1
4a–f
Scheme 2 Synthesis of 2-substituted piperidines 4a–f from N-phe-
Subsequent studies have shown that the sequence of lithi-
ation (lithium diisopropylamide, tetrahydrofuran, –30 °C)
of these aminonitriles, electrophilic substitution (R-Br),
nylpiperidines 1a–f. Conditions: 1) Li, liq. NH –THF–EtOH or t-
3
BuOH, –35 °C, 2) 10% HCl, EtOH, 60 °C, 10 min.
and reductive decyanation (NaBH , EtOH) of the interme-
4
Model studies were carried out for screening the reduction
conditions by using various N-phenylpiperidines substi-
tuted at C-2 by aliphatic side chains of an increasing
length. As shown in Table 1, reduction of 1a occurred in
liquid ammonia in the presence of lithium and t-BuOH as
SYNLETT 2004, No. 11, pp 2005–2009
0
6
.0
9
.2
0
0
4
Advanced online publication: 04.08.2004
DOI: 10.1055/s-2004-830884; Art ID: G17304ST
©
Georg Thieme Verlag Stuttgart · New York

2
006
N. Girard et al.
LETTER
proton donor to afford 2a (90%), which was obtained as should be used for the reduction of 1c to be complete (en-
1
an oil without purification (entry 1). In the H NMR spec- try 5). Hydrolysis of the enamine moiety was made during
trum (C D ) of this oil, characteristic resonance multiplet acid workup, leading after column chromatography to 2-
6
6
signals attributed to H-3¢, H-4¢ and H-5¢ were found at undecylpiperidine 4c in 90% yield. We were pleased to
d = 4.97, 6.13 and 5.43 ppm, respectively. In addition, find that this protocol could be done cleanly and reproduc-
spectroscopic features for this form include a set of four ibly on anilines 1d,f to yield the corresponding secondary
1
3
13
low-field C resonance lines, two of these are due to the amines 4d,f (entries 6–8). It should be noted that when
C-2¢ and C-3¢ carbon atoms found at d = 148.8 and 97.8 ethanol was used as proton donor over-reduction oc-
ppm. Collectively, these results indicate that reduction of curred. A more detailed examination of the spectrum of
the phenyl group readily occurred to give the conjugated 2d revealed the presence of an additional triplet absorp-
dienamine 2a.
tion (d = 4.6 ppm), which was further attributed to the vi-
nylic proton of 3d. Interestingly, both enamines 2 and 3
were readily hydrolyzed into the corresponding amines 4.
Table 1 Synthesis of 2-Substituted Piperidines 4a–f According to
Scheme 2
Having these data in hands, we envisaged that the present
methodology could have applications for the preparation
of the trans-alkaloid (±)-solenopsin A (9c), and the cis-al-
Entry
Products
4a
Method
Time (h)
1.5
Yielda,b (%)
1
2
3
4
5
6
7
8
A
A
A
B
C
B
B
B
80c
70c
14,15
kaloid (±)-dihydropinidine (9b).
4b
3.0
Ph
d
4c
8.0
£5
R
N
CN
1)
2)
2
4c
2.0
44
90
84
81
77
1b–c
4c
4.0
5b–c
Ph
Ph
N
4d
2.0
CN
R
N
R
R
CH3
CH3
3
)
4e
2.0
6
CH3
4f
2.0
6
b–c
9b–c
Method A: Reduction with Li (5 equiv) at –35 °C in the mixture liq.
NH –THF–t-BuOH (30:10:5). Method B: Li (10 equiv), liq. NH –
3
3
H
H
N
THF–EtOH (20:10:4). Method C: Li (150 equiv), liq. NH –THF–
R
N
CH3
3
4
)
1
3
EtOH (20:10:8). For a complete description see ref.
+
6
2
a
All products were isolated and characterized by IR, H NMR, 13C
1
NMR and HRMS.
Yields were determined after chromatography over silica (Et O sat-
b
(±)-dihydropinidine
cis-10b)
(±)-isosolenopsin A
cis-10c)
(±)-epidihydropinidine
(trans-10b)
(±)-solenopsin A
(trans-10c)
2
(
urated with gaseous NH ).
3
c
Amines 4a,b were obtained as their Boc derivatives.
Starting compound was recovered in 90% yield.
(
d
Scheme 3 Synthesis of (±)-solenopsin A and (±)-dihydropinidine
–
+
from anilines 1b,c. Conditions: 1) –2e , –H , MeOH, NaCN, (5b,
7%, c:t = 37:63, 5c, 78%, c:t = 40:60); 2) LDA (1 equiv), THF,
CH I, –78 °C to r.t.; (6b, 88%, 6c, 96%); 3) NaBH (4 equiv), EtOH,
Under this methodology, (±)-coniine, the poisonous hem-
lock alkaloid, can be easily prepared. Conversion of the
7
3
4
N-phenyl-2-propylpiperidine (1b) was made as described r.t., (9b, 90%, c:t = 40:60, 9c, 96%, c:t = 35:65); 4) Li (30 equiv), liq.
NH –THF–EtOH (20:10:4), 10% HCl, EtOH, 60 °C, 15 min, (cis-
above to give 2b in nearly quantitative yield. The resulting
oil was then refluxed (10 min) in EtOH in the presence of
3
1
0b, 24%, trans-10b, 32%, cis-10c, 25%, trans-10c, 47%).
1
0% HCl to give (±)-coniine as its chlorohydride salt. The
Boc group was then introduced under standard conditions Thus, the electrolysis of a methanolic solution of 1b was
to provide 4b in an overall 70% yield from 2b. Converse- performed (Ep = +0.75 V/ECS, NaCN, 2.2 F/mol) in a
ly, little conversion (£5%) was determined when 1c was batch cell equipped with a glassy carbon electrode as an-
reduced under similar reaction conditions. Moreover, in ode to afford 5b as a single regioisomer. It should be noted
1
this experiment, starting material was recovered almost that the H NMR spectrum of this aminonitrile revealed
entirely (entry 3). This observation is consistent with the the presence of an inseparable mixture of epimers at C-6.
prediction that with substrates that bear hydrophobic side The exposure of a THF solution of 5b to a stoichiometric
chains, the intermediate radical anions are formed in con- amount of LDA at –78 °C, followed by the introduction of
centrations that are too low to allow protonation by the CH I onto the resulting anion solution, led to the clean for-
3
16
1
tertiary alcohol which itself has a low solubility in liquid mation of 6b in 88% yield (Scheme 3). The H NMR
ammonia. In contrast, primary alcohols (EtOH) dissolve spectrum of 6b revealed the presence of a single dia-
readily in liquid ammonia and protonate the intermediate stereomer (de 99%), and showed H-6 as a multiplet
radical anion more rapidly. Indeed, when increasing signal at d = 3.3 ppm with a width at half-height of about
amounts of EtOH were used, reduction of 1c readily oc- 20 Hz, which is more consistent with an axial rather
curred (entry 4 and 5). Note that 150 equivalents of Li than an equatorial orientation. However, the relative
Synlett 2004, No. 11, 2005–2009 © Thieme Stuttgart · New York

LETTER
Dearomatization of N-Phenyl-2,6-dialkylpiperidines
2007
stereochemistry of 6b could not be determined at this
stage, but was presumed to be as drawn in Scheme 3. This
stereochemical assignment was verified in the spiro-
piperidine derivative 8g, which could be simply prepared
from the N-phenyl-2-cyano-6-methylpiperidine (1g)
according to a protocol reported in a former paper
8
b
(
Scheme 4). Fortunately, a slow crystallization of a
solution of 8g gave single crystals. A further X-ray study
performed on these crystals indicated that both the alkyl
1
7
chains were in a cis configuration (Figure 1).
CH3
CH3
Ph
Ph
1)
2)
N
N
(CH2)4Cl
CN
CN
1g cis:trans, 30/70
6g
Figure 1 ORTEP drawing of spiropiperidine 8g in the solid state.
CH3
CH3
Ph
N
Ph
5
). These results were in keeping with previous observa-
3)
N
(CH2)4CN
tions, which clearly indicate that hydride reduction of
aminonitriles of the type of 6b proceeded with inversion
of configuration, and that an intermediate iminium species
with ring inversion is involved during the reductive pro-
cess. We and others observed that this ring inversion was
at the root of the lack of stereoselectivity during the reduc-
tive process.20 Finally, we effected the deprotection of
both isomers by reduction of 9b with Li in a mixture of
THF and liquid ammonia in the presence of ethanol
CN
H2N
7g
CN
8g
Scheme 4 Synthesis of spiropiperidine 8g: 1) LDA (1 equiv), THF,
Br(CH ) Cl, –78 °C to r.t., 80%; 2) NaCN (4 equiv), DMSO, n-Bu NI
2
4
4
(
5 mol%), r.t., 100 h, 85%; 3) LDA, THF, –78 °C to r.t., 12 h, 88%.
(
Scheme 3). Work up13 gave an oily residue, which was
For the preparation of (±)-dihydropinidine, conditions
were needed to effect the reduction of aminonitrile 6b
while retaining the configuration at C-2. To this end, sev-
eral reducing reagents including hydride anions and dis-
solving metals were used, and selected results are reported
in Table 2. In all cases, the reductive decyanation afforded
the expected piperidine 9b with good to excellent yields
but with little diastereoselectivity. It is noteworthy that
purified over a silica column. The less polar (±)-dihydro-
pinidine (cis-10b, 24%) eluted first, followed by the more
polar (±)-epidihydropinidine (trans-10b, 32%). At this
point, it was clear that this sequence was found more con-
venient for the preparation of trans-2,6-dialkylpiperidines
rather than for their cis counterparts. Therefore, synthesis
of (±)-solenopsin A, a representative example of the trans
series was undertaken. As depicted beyond, the key inter-
mediate 6c was prepared with an overall 75% yield start-
ing from 1c. Next, treatment of 6c with an excess of
when an excess of NaBH was used (entries 1, 2), trans-
4
1
8
9
b predominated, while reductions with solvated
1
9
electrons yielded cis-9b as the major product (entries 4,
NaBH yielded the cis and trans piperidines 9c as an in-
4
Table 2 Synthesis of N-Phenylpiperidines 9b,c
b
Entry
Products
9b
Reducing agent (equiv) Yield (%)a
dr , c:t
30:70
40:60
50:50
65:35
55:45
35:65
Conditions
1
2
3
4
5
NaBH (4.0)
70
90
46
80
70
96
EtOH, r.t., 5 h
4
9b
NaBH (4.0)
EtOH, –90 °C to r.t., 12 h
CH Cl , –30 °C to r.t., 4 h
4
9b
DIBALH (1.2)
Na (5.0)
2
2
9b
NH –THF (20:5), –70 °C, 4 hc
3
9b
Na (5.0)
NH –THF–t-BuOH (50:25:3), –70 °C, 4 h
3
6
9c
NaBH (4.0)
EtOH, r.t., 5 h
4
a
Yields were determined after column chromatography over silica (Et O–petroleum ether = 5:95.
Diastereomeric ratios were determined by H NMR and GC.
The solution was worked up after the slow addition of a THF solution of t-BuOH at –70 °C.
2
b
c
1
Synlett 2004, No. 11, 2005–2009 © Thieme Stuttgart · New York

2
008
N. Girard et al.
LETTER
separable mixture (Table 2, entry 6). This product distri-
bution and the identity of each isomer were confirmed
after the removal of the phenyl group by the separation
and characterization of pure (±)-solenopsin A (trans-10c,
(12) (a) Birch, A. J.; Hutchinson, E. G.; Rao, G. S. J. Chem. Soc.,
Chem. Commun. 1970, 657. (b) Leonard, N. J.; Steinhardt,
C. K.; Lee, C. J. Org. Chem. 1962, 27, 4027. (c) Rabideau,
P. W.; Marcinov, Z. In Organic Reactions, Vol. 42;
Paquette, L. A., Ed.; John Wiley: New York, 1992, 1; and
references therein.
2
1
4
8%).
(
13) General Procedure (Method B) for the Preparation of
In summary, an effective and practical procedure that al-
lows the preparation of 2,6-dialkylpiperidines has been
developed. The advantages of the present synthesis lie in
its simplicity and conciseness. Attempts to develop an
enantioselective variant of this approach are currently un-
der investigation in our laboratory and results will be re-
ported in due course.
Amines 4c–f: To 20 mL of liquid NH 2 mL of anhyd. EtOH
3
and 10 mL of THF containing 350 mg (1.35 mmol) of N-
phenyl-2-heptylpiperidine (1e) were successively added.
Under a stream of Ar, Li (0.1 g, 10 equiv) was added in small
pieces, upon which the solution became blue. The resulting
solution was stirred at –40 °C for 2 h. After the blue color
had disappeared, the mixture was diluted with 10 mL of
EtOH. To this mixture H O (100 mL) was added, and the
2
aqueous phase was extracted with Et O. The combined
organic phases were dried and concentrated in vacuo. The
residue was dissolved in 10 mL of EtOH containing 1 mL of
2
Acknowledgment
N. G. would like to thank the MENRT for a grant.
37% HCl and refluxed for 10 min. EtOH was distilled, and
the solid residue was stirred in a 20% KOH (5 mL) solution
and extracted several times with Et O. The ethereal layers
2
References
were combined and dried over MgSO . The crude product
4
(
1) (a) Fodor, G. B.; Colasanti, B. In Alkaloids: Chemical and
Biological Perspectives, Vol. 3; Pelletier, S. W., Ed.; John
Wiley: New York, 1985, 1. (b) Schneider, M. J. In
was chromatographed on silica column eluting with Et O
2
saturated with gaseous NH to give 200 mg (81%) of 2-
3
1
heptylpiperidine(4e) as a slightly yellow oil: H NMR (300
Alkaloids: Chemical and Biological Perspectives, Vol. 10;
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3
H), 1.20–1.65 (m, 17 H), 1.70–1.80 (m, 1 H), 2.23–2.42 (m,
(
(
1 H), 2.10 (td, 1 H, J = 11.70 Hz and 2.85 Hz), 3.05 (dm, 1
1
3
(
b) Jeyaraman, R.; Chandrasekaran, L. Chem. Rev. 1983, 83,
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H, J = 10.50 Hz). C NMR (75 MHz, CDCl ): d = 14.06,
3
3
22.63, 24.94, 25.88, 26.69, 29.25, 29.78, 31.80, 33.04,
37.53, 47.27, 56.91. HRMS: m/z calcd for C H N [M ]:
+
1
2
25
(
183.1987; found: 183.1987.
R. J. Am. Chem. Soc. 1984, 106, 3270. (c) Gawley, R. E.;
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K. Tetrahedron Lett. 2000, 41, 7779.
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H. Eur. J. Org. Chem. 1998, 63; and references therein.
(17) Further details of the crystal structure analysis of compound
8g are available on request from the Cambridge
3344.
(
4) (a) Matsumura, Y.; Maruoka, K.; Yamamoto, H.
Tetrahedron Lett. 1982, 23, 1929. (b) Dhavale, D. D.; Saha,
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(
6
c) Reding, M. T.; Buchwald, S. L. J. Org. Chem. 1998, 63,
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3
369.
5) (a) Grieco, P. A.; Kaufman, M. D. J. Org. Chem. 1999, 64,
041. (b) Kranke, B.; Hebrault, D.; Schultz-Kukula, M.;
Crystallographic Data Centre as supplementary publication
no: 237635. Copies of the data can be obtained free of charge
on application to the director CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44 (1223)336033, e-mail:
deposit@ccdc.cam.ac.uk].
(
(
(
(
6
Kunz, H. Synlett 2004, 671.
6) For a review on nitrile anions chemistry see: (a)Fleming, F.
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A.; Uriac, P.; Sinbandhit, S.; Toupet, L. Liebigs Ann. Recl.
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4
e
(
9) (a) Caubère, P.; Derozier, N. Bull. Soc. Chim. Fr. 1969,
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1
737. (b) Bhaskar Kanth, J. V.; Periasamy, M. J. Org. Chem.
(21) Preparation of (±)-Solenopsin A: To 20 mL of liquid NH3
4 mL of anhyd EtOH and 10 mL of THF containing 250 mg
(0.76 mmol) of N-phenyl-2-methyl-6-undecylpiperidine (9c,
c:t, 35:65) were successively added. Under a stream of Ar,
Li (60 mg, 30 equiv) was added in small pieces, upon which
the solution became blue. The resulting solution was stirred
1993, 58, 3156.
(
(
10) (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.; Buchwald, S. L.
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11) (a) Kolis, S. P.; Gonzales, J.; Bright, L. M.; Harman, W. D.
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K. P.; Kündig, E. P. Chem. Rev. 2000, 100, 2917.
1
3
at –40 °C for 2 h. Workup gave an oily residue, which was
chromatographed on silica (eluent: Et O saturated with
2
gaseous NH ) to afford cis-10c (48 mg, 25%) and trans-10c
3
1
(
90 mg, 47%). (±)-Solenopsin A: H NMR (300 MHz,
Synlett 2004, No. 11, 2005–2009 © Thieme Stuttgart · New York

LETTER
Dearomatization of N-Phenyl-2,6-dialkylpiperidines
2009
CDCl ): d = 0.85 (t, 3 H, J = 6.30 Hz), 1.04 (d, 3 H, J = 6.60
CDCl ): d = 0.87 (t, 3 H, J = 6.04 Hz), 0.94–1.05 (m, 1 H),
3
3
Hz), 1.16–1.66 (m, 27 H), 2.80–2.88 (m, 1 H), 2.97–3.08 (m,
1.05 (d, 3 H, J = 6.30 Hz), 1.20–1.65 (m, 25 H), 1.70–1.80
H). 13C NMR (75 MHz, CDCl ): d = 14.07 (CH -), 19.56,
(m, 1 H), 2.42–2.50 (m, 1 H), 2.55–2.66 (m, 1 H). C NMR
13
1
2
3
3
3
1.24 (CH -), 22.63, 26.45, 29.33, 29.62, 29.64 (2 C), 29.78,
(75 MHz, CDCl ): d = 14.09, 22.67, 23.10, 24.88, 25.99,
3
3
0.80, 31.89, 33.00, 34.07, 45.78 (CH-), 50.80 (CH-).
29.34, 29.60, 29.62, 29.66, 29.84, 31.90, 32.28, 34.44,
+
+
HRMS: m/z calcd for C H N [M ]: 253.2769; found:
37.47, 52.46, 57.13. HRMS: m/z calcd for C H N [M ]:
1
7
35
17 35
1
253.2760. (±)-Isosolenopsin A: H NMR (300 MHz,
253.2769; found: 253.2767.
Synlett 2004, No. 11, 2005–2009 © Thieme Stuttgart · New York