Direct access to functionalized cyclic enones using Mannich, Morita-Baylis-Hillman and elimination reactions

Article abstract of DOI:10.1055/s-2006-942539

A series of highly functionalized cyclic enones were obtained from Mannich, Morita-Baylis-Hillman and elimination reaction with cyclic enones. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942539

PAPER
3025
Direct Access to Functionalized Cyclic Enones Using Mannich,
Morita–Baylis–Hillman and Elimination Reactions
D
irec
t
A
ccess toF
c
unctionaliz
h
edCyclic
E
n
i
ones m Porzelle, Craig M. Williams*
School of Molecular and Microbial Sciences, University of Queensland, Brisbane, 4072, Queensland, Australia
Fax +61(0)733654299; E-mail: c.williams3@uq.edu.au
Received 16 March 2006; revised 29 May 2006
Abstract: A series of highly functionalized cyclic enones were ob-
tained from Mannich, Morita–Baylis–Hillman and elimination re-
action with cyclic enones.
H
Key words: Morita–Baylis–Hillman, cyclic enones, aminals, Man-
nich reactions, concavine
N
H
H
O
1
Our ongoing interest in the synthesis of natural products
using the Morita–Baylis–Hillman1 reaction (MBH)2 re-
sulted in the recent discovery that surfactants improve
MBH yields when using cyclic enones.3 Considering
many natural products contain nitrogen, we embarked on
a quest to investigate methods that might allow an aza-
variation of the MBH-reaction.4 A survey of current liter-
ature reveals a number of reports detailing the aza-MBH
reaction using stabilized imines (two steps overall),5–11
but the more traditional aza-MBH (one-step) has only
been reported twice.12,13 It was this type of one-step pro-
tocol we were most interested in utilizing as it introduces
masked, unsubstituted methylene functionality which is
seen, for example, in concavine (1) (Figure 1).14 The one-
step aza-MBH reaction, described by Kozlov and Koval-
eva,12 between formaldehyde, secondary amines and
enones, however, could not be repeated and produced in-
stead the normal type MBH product (4 from 2 and form-
aldehyde) (Scheme 1). Kalinin13 reports that treating
aminals such as 6 with acetyl chloride, forms Schiff base
chlorides (i.e. 7) which, when reacted with methyl vinyl
ketone, results in the formation of the aza-MBH products.
Again we were unable to reproduce these results or apply
the protocol to the corresponding cyclic enone system of
5. Instead, however, the Mannich15 product 8 was ob-
tained in moderate yield. Although Schiff base salts like 7
have been utilized previously in Mannich reactions of cy-
clic ketones,16,17 cyclic enones have yet to be exposed to
these salts.
Figure 1 Structure of concavine 1
The Mannich reaction was demonstrated by the applica-
tion of aminals di(N-piperidinyl)methane (6) and di(N-
morpholinyl)methane (9), which were prepared according
to a slightly modified procedure reported by Wilkins,18 to
a range of cyclic enones (Table 1). Generating aminals
which allow the introduction of a free amine, for example
bis(N,N-hexamethyldisilazan)methane, have so far failed.
To establish a reaction protocol, aminals and cyclic
enones were dissolved in anhydrous acetonitrile under an
argon atmosphere, freshly distilled acetyl chloride was
then added and the reaction mixture was stirred at room
temperature for 4–14 hours.
Fortuitously, this protocol was found to be superior to
those involving trichloromethylsilane (Cl3MeSi) or chlo-
rotrimethylsilane (ClMe3Si), used to generate Schiff bases
from aminoethers,17,18 as neither of the latter reagents
gave any improvement in either yield or purity. A further
advantage of this protocol was that the product, in most
cases, precipitated out of the reaction mixture and was
simply collected by filtration. Interestingly, the reaction
was found to be somewhat substrate specific. For exam-
ple, only half the cases gave monosubstitution (Entries 1,
2, 5, 9, 10, Table 1) whereas the remainder gave disubsti-
tuted products (Entries 3, 4, 6, 7, 8, Table 1), irrespective
of the number of equivalents used.
It is noteworthy that, contrary to Kalinin et al.,13 the Man-
nich products were obtained exclusively. In no cases were
products of a aza-Morita–Baylis–Hillman type reaction
detected. Sequential MBH reactions on the Mannich prod-
ucts were undertaken using surfactants (i.e. SDS), accord-
ing to the protocol described previously. MBH reactions
with the Mannich products turned out to be capricious. In
accordance with previous results, no product formation
was observed with the b-substituted cyclic enones 16 and
20.3 All other substrates were totally consumed, but af-
forded complex mixtures. Conversely, good results were
This observation encouraged us to investigate sequential
Mannich and MBH reactions, as this strategy may also be
useful for the synthesis of natural products of type 1 that
contain nitrogen. Results of this study are discussed here-
in.
SYNTHESIS 2006, No. 18, pp 3025–3030
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x.
x
x
.
2
0
0
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Advanced online publication: 02.08.2006
DOI: 10.1055/s-2006-942539; Art ID: T04206SS
© Georg Thieme Verlag Stuttgart · New York

3026
A. Porzelle, C. M. Williams
PAPER
O
O
O
2
R
H
H
N
H
3
4 R = OH
5 R = N(CH2)5
O
X
O
AcCl
2
X
X
N
N
N
N
X
Cl
6, 9
7, 10
8, 11
O
X = CH2 6, 7, 8, 12
X = O 9, 10, 11, 13
N
+
X
12, 13
Scheme 1 Initial studies of the aza-MBH reaction
X
O
O
N
AcCl, 9
AcO
AcO
N
MeCN
r.t.
X
14 h
23 (76%)a
22
X
O
O
N
AcCl, 9
AcO
AcO
N
MeCN
r.t.
X
14 h
25 (63%)a
24
O
O
O
O
N
OAc
H+
AcCl, 9
O
O
MeCN
r.t.
14 h
28
26
27 (65%)
Scheme 2 Mannich reaction of MBH acetates; a yields based on aminal
obtained when the methylene hydroxyl functionality was the substrate 26 underwent cyclization to 28 due to cata-
introduced first, followed by acetyl protection with acetyl lytic amounts of HCl present in acetyl chloride. Such a cy-
chloride. The MBH-acetate of cyclopentenone 22, when clization to tricycle 28 is known from previous studies in
reacted with 9, gave the double alkylated product 23, as our lab.2 For authentication, 28 was reacted with 6 to give
did enone 24, (a rare example of a Morita–Baylis–Hill- tricycle 29 in high yield (Scheme 3). Interestingly, it
mann reaction with a C-3 substituted cyclic enone) turned out that 26 could not be alkylated at the C-6 posi-
(Scheme 2).19 Cyclopentenone and 3-methylcyclohex- tion. All reactions with excess aminal or triethylamine, to
enone (Entries 3, 4, 7, 8, Table 1) also underwent double trap HCl, resulted in total recovery of starting material.
alkylation. Alcohol protection (i.e. acetates 22, 24, 26)
was essential in order to avoid side reactions. In the case
of 26, the tricyclic compound 27 was exclusively ob-
tained, instead of the expected acetate. It is believed that
MBH-acetates 30 and 31 gave, after standard Mannich re-
actions, 32 and 33 in good yields. Elimination of the ami-
no group to form the exocyclic double bond was achieved
Synthesis 2006, No. 18, 3025–3030 © Thieme Stuttgart · New York

PAPER
Direct Access to Functionalized Cyclic Enones
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Table 1 Mannich Reaction of Aminals with Cyclic Enonesa
O
O
N
Entry Enone
Product
Yield (%)b
O
AcCl, 6
O
O
MeCN
r.t.
14 h
O
80c
N
1
28
X
29 (85%)
8; X = CH2
11; X = O
Scheme 3 Mannich reaction with tricycle 28
2
85c
OAc
O
OAc O
OAc
O
AcCl
6 or 9
X
AcCl
N
O
O
N
MeCN
r.t., 4 h
MeCN
r.t., 4 h
3
87c,d
X
N
R
R
R
R
R
R
X
R = Me 30
R = H 31
R = Me, X = O 32 (86%)
R = H, X = CH2 33 (82%)
R = Me 34 (71%)
R = H 35 (63%)
14; X = CH2
18; X = O
4
89d
58e
O
R = Me, 6, AcCl (3 equiv), MeCN, r.t., 17 h; R = Me, 34 (62%)
R = H, 9, AcCl (3 equiv), MeCN, r.t., 17 h; R = H, 35 (55%)
O
N
5
Scheme 4 Mannich reaction of MBH acetates
15
slightly diminished yields (62% and 55%) as compared to
the two-step procedure (Scheme 4). As expected, the
products 34 and 35 were found to be heat sensitive, which
possibly contributed to the moderate yields of products
obtained.
O
N
O
6
82d
N
O
In conclusion, simple cyclic enones can become highly
functionalized, expediently, using the sequential MBH–
Mannich protocol; methodology we believe is applicable
to a range of applications. Attempts to amalgamate the
MBH–Mannich–elimination sequence into a one-pot pro-
tocol are in progress.
19
X
O
O
N
7
83d
N
X
16; X = CH2
20; X = O
Boiling and melting points are uncorrected. 1H and 13C NMR spec-
tra were recorded on a Bruker AC 300 (300 MHz, 75MHz) or Bruk-
er 400 (400 MHz, 100 MHz) in CDCl3. Coupling constants are
given in Hz and chemical shifts are expressed as d values in ppm.
High and low EI mass spectral data were obtained on a Kratos
MS25 RFA. Column chromatography was conducted on silica gel
(Flash Silica Gel 230–400 mesh), with distilled solvents. Petroleum
ether (PE) used had boiling range 40–60 °C.
8
9
82d,e
53c
O
O
N
X
17; X = CH2
21; X = O
10
90c
Synthesis of Aminals; General Procedure
To formalin (10–30 mmol) was added the corresponding amine (2
equiv) at 0 °C. After 30 min at 0 °C, the mixture was allowed to
come to r.t. over 2 h. The pure aminals were obtained by distillation
directly from the reaction mixture.
a Reactions were performed at 1 mmol in anhyd MeCN (3 mL) under
Ar at r.t. for 4–14 h.
b Yields of isolated product.
c Product precipitates from the reaction mixture and collected by fil-
Di(N-piperidinyl)methane (6)18
Yield: 5 g (90%); colorless liquid; bp 60 °C (0.1 mmHg).
1H NMR (300 MHz, CDCl3): d = 2.79 (s, 2 H), 2.35 (br t, 8 H),
1.52–1.47 (m, 8 H), 1.41–1.36 (m, 4 H).
tration.
d Based on aminal.
e Yield of title compound obtained as a mixture with amide (12–13)
by-product.
13C NMR (75 MHz, CDCl3): d = 82.73, 53.04, 25.89, 24.87.
MS (EI): m/z (%) = 98 (100) [M+ – NC5H10], 84 (20), 56 (14), 41
using acetyl chloride in acetonitrile at room temperature,
affording good yields of products 34 and 35 (71% and
63% respectively). Attempts at a more practical, one-pot
protocol, i.e. Mannich reaction and sequential elimination
to introduce the double bond was successful, giving only
(23).
Di(N-morpholinyl)methane (9)18
Yield: 1.7 g (92%); colorless liquid; bp 65 °C (0.1 mmHg).
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A. Porzelle, C. M. Williams
PAPER
1H NMR (300 MHz, CDCl3): d = 3.63 (m, 8 H), 2.85 (s, 2 H), 2.43
(m, 8 H).
MS (EI): m/z (%) = 207 (2) [M+], 182 (2), 124 (8), 98 (100), 84 (8),
81 (11), 69 (10), 55 (18), 41 (14).
13C NMR (75 MHz, CDCl3): d = 81.60, 66.94, 51.94.
HRMS (EI): m/z calcd for C13H21NO: 207.1623; found: 207.1627.
MS (EI): m/z (%) = 186 (2) [M+], 100 (100) [M+ – NC4H8O], 56
(20), 42 (12).
6,6-[Bis(piperidin-1-yl)methyl]-3-methylcyclohex-2-en-1-one
(16)
Yield: 128 mg (83%); slightly pale-yellow oil; Rf = 0.23 (EtOAc–
PE, 1:1).
1H NMR (300 MHz, CDCl3): d = 5.75 (s, 1 H), 3.1 (m, 1 H), 2.60–
2.02 (m, 18 H), 1.55–1.38 (m, 8 H), 1.32–1.27 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 201.18, 161.76, 126.31, 58.08,
54.75, 43.71, 26.64, 25.97, 25.92, 24.33, 24.14.
ESI-MS: m/z = 327 [M + Na+].
Mannich Reaction; General Procedure
To a solution of aminal (1 mmol) and cyclic enone (1.2 mmol) in
anhyd MeCN (3 mL) under argon at r.t., was added freshly distilled
AcCl (0.78 mL, 1 mmol). A white precipitate formed after 10–30 s.
The mixture was then stirred for a further 4–14 h, after which the
precipitate was collected, dissolved in CH2Cl2 (5 mL) and washed
with sat. NaHCO3 (5 mL) and brine (5 mL). When no precipitate
was formed, the reaction mixture was diluted with CH2Cl2 (10 mL)
and washed with sat. NaHCO3 (5 mL) and brine (5 mL). Pure prod-
ucts were obtained after column chromatography (EtOAc–PE).
4,4-Dimethyl-6-[(piperidin-1-yl)methyl]cyclohex-2-en-1-one
(17)
Yield: 117 mg (53%); pale-yellow oil; Rf = 0.75 (EtOAc–PE, 2:1).
6-[(Piperidin-1-yl)methyl]cyclohex-2-en-1-one (8)
1H NMR (300 MHz, CDCl3): d = 6.57 (d, J = 7.5 Hz, 1 H), 5.78 (d,
J = 7.5 Hz, 1 H), 2.83 (dd, J = 9.5, 3.1 Hz, 1 H), 2.64–2.58 (m, 1 H),
2.40–2.20 (m, 5 H), 2.05–2.02 (m, 1 H), 1.60–1.52 (m, 5 H), 1.41–
1.36 (m, 2 H), 1.16 (s, 3 H), 1.13 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 201.18, 158.87, 126.73, 58.22,
54.76, 41.10, 40.59, 33.52, 30.52, 25.98, 25.32, 24.40.
Yield: 155 mg (80%); pale-yellow oil; Rf = 0.42 (EtOAc–PE, 2:1).
1H NMR (300 MHz, CDCl3): d = 6.91 (dt, J = 7.5, 1.5 Hz, 1 H),
5.95 (dt, J = 7.5, 1.5 Hz, 1 H), 2.73 (dd, J = 9.4, 3.4 Hz, 1 H), 2.53–
2.49 (m, 1 H), 2.43–2.20 (m, 8 H), 1.81–1.78 (m, 1 H), 1.58–1.53
(m, 4 H), 1.43–1.38 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 201.34, 149.98, 129.54, 57.96,
54.78, 44.59, 26.89, 25.85, 25.06, 24.26.
MS (EI): m/z (%) = 221 (10) [M+], 177 (2), 162 (2), 136 (11), 121
(4), 98 (100), 93 (13), 84 (11), 77 (9), 55 (9), 41 (14).
MS (EI): m/z (%) = 192 (3), 180 (2), 176 (100), 148 (11), 133 (21),
118 (6), 105 (6), 98 (17), 91 (21), 65 (8), 55 (8), 41 (7).
HRMS (EI): m/z [M+ – H] calcd for C12H18NO: 192.1388; found:
192.1386.
HRMS (EI): m/z calcd for C14H23NO: 221.1780; found: 221.1781.
5,5-[Bis(morpholinomethyl)]cyclopent-2-en-1-one (18)
Yield: 140 mg (89%); white solid; mp 78 °C (subl.); Rf = 0.19
(EtOAc–PE, 2:1).
6-(Morpholinomethyl)cyclohex-2-en-1-one (11)
1H NMR (300 MHz, CDCl3): d = 7.77 (dt, J = 5.8, 2.8 Hz, 1 H),
6.12 (dt, J = 5.8, 2.1 Hz, 1 H), 3.55–3.50 (m, 8 H), 2.78 (s, 2 H),
2.50 (d, J = 13.3 Hz, 2 H), 2.40–2.28 (m, 10 H).
13C NMR (75 MHz, CDCl3): d = 213.77, 165.30, 133.53, 67.06,
63.11, 55.45, 52.80, 38.17.
Yield: 165 mg (85%); pale-yellow oil; Rf = 0.38 (EtOAc–PE, 1:1).
1H NMR (300 MHz, CDCl3): d = 6.93–6.87 (m, 1 H), 5.94 (ddd,
J = 5.2, 5.2, 4.1 Hz, 1 H), 3.66–3.62 (m, 4 H), 2.74 (dd, J = 12.3, 4.5
Hz, 1 H), 2.51–2.29 (m, 8 H), 2.25–2.17 (m, 1 H), 1.85–1.76 (m,
1 H).
13C NMR (75 MHz, CDCl3): d = 200.77, 149.77, 129.54, 66.94,
ESI-MS: m/z = 303 [M + Na+].
57.67, 53.86, 44.24, 26.55, 24.92.
Anal. Calcd for C15H24N2O3: C, 64.26; H, 8.63; N, 9.99. Found: C,
64.06, H, 8.70; N, 9.97.
MS (EI): m/z (%) = 195 (4), 126 (1), 100 (100), 68 (5), 56 (12), 42
(11).
7,7-[Bis(morpholinomethyl)]cyclohept-2-en-1-one (19)
Yield: 152 mg (82%); pale-yellow oil; Rf = 0.31 (EtOAc–PE, 2:1).
HRMS (EI): m/z calcd for C11H17NO2: 195.1259; found: 195.1256.
1H NMR (300 MHz, CDCl3): d = 6.61–6.53 (m, 1 H), 6.02–5.97 (m,
1 H), 3.65–3.61 (m, 8 H), 2.90–2.70 (m, 2 H), 2.60–2.30 (m, 8 H),
2.05–1.38 (m, 8 H).
13C NMR (75 MHz, CDCl3): d = 204.71, 145.72, 132.71, 66.97,
59.55, 53.89, 49.35, 29.84, 27.78, 25.21.
5,5-[Bis(piperidin-1-yl)methyl]cyclopent-2-en-1-one (14)
Yield: 145 mg (87%); pale-yellow oil; Rf = 0.22 (EtOAc–PE, 1:1).
1H NMR (300 MHz, CDCl3): d = 7.76–7.73 (m, 1 H), 6.12–6.10 (m,
1 H), 2.76 (t, J = 1.8 Hz, 2 H), 2.42 (d, J = 10.0 Hz, 2 H), 2.34–225
(m, 10 H), 1.44–1.37 (m, 8 H), 1.32–1.27 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 214.66, 165.35, 133.23, 63.40,
56.56, 53.48, 37.82, 26.28, 24.00.
ESI-MS: m/z = 331 [M + Na+].
MS (EI): m/z (%) = 276 (2) [M+], 191 (4), 178 (4), 98 (100), 84 (11),
55 (6).
3-Methyl-6,6-bis(morpholinomethyl)cyclohex-2-en-1-one (20)
Yield: 153 mg (82%); slightly yellow oil; Rf = 0.22 (EtOAc–PE,
2:1).
1H NMR (300 MHz, CDCl3): d = 5.74 (s, 1 H), 3.60–3.53 (m, 8 H),
2.53–2.05 (m, 16 H), 1.86 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 200.49, 161.79, 126.27, 66.92,
57.79, 53.84, 43.05, 30.05, 26.41, 24.10.
ESI-MS: m/z = 331 [M + Na+].
HRMS (EI): m/z calcd for C17H28N2O: 276.2202; found: 276.2205.
7-[(Piperidin-1-yl)methyl]cyclohept-2-en-1-one (15)
Yield: 110 mg (58%); pale-yellow oil; Rf = 0.21 (EtOAc–PE, 2:1).
1H NMR (300 MHz, CDCl3): d = 6.60–6.52 (m, 1 H), 601–5.97 (m,
1 H), 2.83–2.70 (m, 2 H), 2.40–2.25 (m, 8 H), 2.05–1.95 (m, 1 H),
1.90–1.87 (m, 1 H), 1.66–1.33 (m, 7 H).
13C NMR (75 MHz, CDCl3): d = 205.17, 145.85, 132.78, 59.74,
54.77, 49.66, 29.70, 28.15, 25.91, 25.26, 24.25.
4,4-Dimethyl-6-(morpholinomethyl)cyclohex-2-enone (21)
Yield: 200 mg (90%); pale-yellow oil; Rf = 0.64 (EtOAc–PE, 2:1).
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Direct Access to Functionalized Cyclic Enones
3029
1H NMR (300 MHz, CDCl3): d = 6.52 (dd, J = 10.0, 2.2 Hz, 1 H),
5.72 (d, J = 10.0 Hz, 1 H), 3.65–3.55 (m, 4 H), 2.83–2.78 (dd,
J = 12.6, 4.3 Hz, 1 H), 2.58–2.51 (m, 1 H), 2.43–2.22 (m, 5 H),
2.01–1.94 (m, 1 H), 1.55 (t, J = 13.7 Hz, 1 H), 1.10 (s, 3 H), 1.08 (s,
3 H).
13C NMR (75 MHz, CDCl3): d = 200.44, 158.81, 126.51, 66.77,
57.75, 53.72, 40.85, 40.13, 33.34, 30.36, 25.16.
Yield: 21 mg (65%); white solid; mp 85 °C (subl.); Rf = 0.76
(EtOAc–PE, 1:1).
1H NMR (300 MHz, CDCl3): d = 4.35 (d, J = 11.8 Hz, 1 H), 3.60 (t,
J = 4.61 Hz, 4 H), 3.36 (d, J = 11.8 Hz, 1 H), 2.50–2.48 (m, 1 H),
2.41–2.35 (m, 6 H), 2.23–2.21 (m, 2 H), 2.05 (dt, J = 13.38, 3.15
Hz, 1 H), 1.63–1.46 (m, 2 H), 1.33–1.20 (m, 7 H), 1.05 (s, 3 H),
0.95 (s, 3 H).
MS (EI): m/z (%) = 223 (10) [M+], 208 (2), 176 (2), 136 (10), 121
(6), 100 (100), 93 (4), 56 810), 41 (10).
13C NMR (75 MHz, CDCl3): d = 212.48, 73.37, 67.18, 62.85, 62.75,
55.62, 51.61, 50.87, 42.13, 38.93, 37.11, 34.92, 34.41, 30.88, 27.36,
22.66, 20.96.
HRMS (EI): m/z calcd for C13H21NO2: 223.1572; found: 223.1570.
MS (EI): m/z (%) = 321 (4) [M+], 293 (3), 222 (4), 208 (5), 197 (7),
[4,4-Bis(morpholinomethyl)-5-oxocyclopent-1-enyl]methyl
Acetate (23)
Yield: 134 mg (76%); pale-brown oil; Rf = 0.16 (EtOAc–PE, 1:1).
1H NMR (300 MHz, CDCl3): d = 7.57–7.55 (m, 1 H), 4.62–4.60 (m,
2 H), 3.52–3.58 (m, 8 H), 2.7 (br s, 2 H), 2.51–2.48 (m, 2 H), 2.38–
2.26 (m, 10 H), 2.05 (s, 3 H).
177 (2), 164 (3), 149 (4), 140 (6), 100 (100).
HRMS (EI): m/z calcd for C19H31NO3: 321.2304; found: 321.2306.
Anal. Calcd. for C19H31NO3: C, 70.99; H, 9.72. Found: C, 71.02; H,
9.85.
[4-Methyl(N-piperidinyl)]-1,7,7-trimethyl-6-oxatricy-
clo[6.2.2.04,9]dodecan-3-one (29)
Yield: 122 mg (85%); white solid; mp 89 °C (subl.); Rf = 0.85
13C NMR (75 MHz, CDCl3): d = 210.99, 170.41, 161.71, 140.18,
66.97, 63.06, 57.77, 55.36, 53.07, 36.53, 20.69.
(EtOAc–PE, 1:1).
ESI-MS: m/z = 375 [M + Na+].
1H NMR (300 MHz, CDCl3): d = 4.26 (d, J = 11.8 Hz, 1 H), 3.38 (d,
J = 11.8 Hz, 1 H), 2.50–2.48 (m, 1 H), 2.41–2.35 (m, 5 H), 2.23–
2.05 (m, 4 H), 1.63–1.43 (m, 7 H), 1.33–1.17 (m, 8 H), 1.05 (s,
3 H), 0.95 (s, 3 H).
[2-Methyl-5,5-bis(morpholinomethyl)-6-oxocyclohex-1-
enyl]methyl Acetate (25)
Reaction scale: 0.2 mmol.
Yield: 26 mg (63%); pale-brown oil; Rf = 0.19 (EtOAc–PE, 1:1).
13C NMR (75 MHz, CDCl3): d = 213.02, 73.38, 62.69, 62.57, 56.96,
51.72, 51.39, 42.22, 39.06, 37.15, 34.26, 30.92, 27.41, 26.54, 22.80,
21.00.
1H NMR (300 MHz, CDCl3): d = 4.83–4.65 (m, 2 H), 3.82–3.55 (m,
8 H), 2.70 (br s, 1 H), 2.48–2.22 (m, 15 H), 2.05 (s, 3 H), 1.94 (s,
3 H).
ESI-MS: m/z = 342 [M + Na+].
13C NMR (75 MHz, CDCl3): d = 197.70, 170.96, 162.62, 130.01,
68.86, 57.96, 53.87, 46.63, 43.19, 41.73, 31.96, 21.19, 20.96.
Anal. Calcd. for C20H33NO2: C, 75.19; H, 10.41. Found: C, 75.02;
H, 10.65.
ESI-MS: m/z = 403 [M + Na+].
Amino-Group Elimination; General Procedure
To a solution of amine (1 mmol) in anhyd MeCN (3 mL) under ar-
gon at r.t., was added freshly distilled AcCl (1.6 mL, 2 mmol). The
mixture was kept under argon and stirred for a further 17 h. CH2Cl2
(10 mL) was added and the mixture was washed with sat. NaHCO3
(5 mL) and brine (5 mL). The pure products were obtained after col-
umn chromatography (EtOAc–PE) on silica.
[3,3-Dimethyl-5-(morpholinomethyl)-6-oxocyclohex-1-
enyl]methyl Acetate (32)
Yield: 253 mg (86%); colorless oil; Rf = 0.7 (EtOAc–PE, 1:1).
1H NMR (300 MHz, CDCl3): d = 6.53 (s, 1 H), 4.62–4.57 (m, 2 H),
3.69–3.64 (m, 4 H), 2.90 (dd, J = 9.5, 3.3 Hz, 1 H), 2.70–2.61 (m,
1 H), 2.50–2.45 (m, 2 H), 2.38–2.31 (m, 3 H) 2.05–2.00 (m, 1 H),
2.01 (s, 3 H), 1.61 (t, J = 10.3 Hz, 1 H), 1.16 (s, 3 H), 1.13 (s, 3 H).
3,3-Dimethyl-5-methylene-6-oxocyclohex-1-enyl)methyl Ace-
tate (34)
Yield: 148 mg (71%); colorless oil; Rf = 0.7 (EtOAc–PE, 1:1).
13C NMR (75 MHz, CDCl3): d = 198.85, 170.55, 156.73, 131.09,
66.65, 61.33, 57.75, 53.72, 40.87, 40.25, 33.15, 30.57, 25.16, 20.89.
1H NMR (300 MHz, CDCl3): d = 6.71 (s, 1 H), 6.03 (br q, 1 H), 5.27
(br q, 1 H), 4.72 (d, J = 1.14 Hz, 2 H), 2.54 (s, 2 H), 2.05 (s, 3 H),
1.12 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 186.89, 170.58, 157.52, 140.79,
132.08, 121.80, 61.33, 45.11, 34.25, 28.15, 20.92.
MS (EI): m/z(%) = 295 (4) [M+], 235 (9), 220 (5), 182 (3), 100
(100), 81 (5), 69 (6), 56 (6), 43 (5).
HRMS (EI): m/z calcd for C16H25NO4: 295.1784; found: 295.1773.
{6-Oxo-5-[(piperidin-1-yl)methyl]cyclohex-1-enyl}methyl Ace-
tate (33)
Yield: 218 mg (82%); pale-yellow oil; Rf = 0.6 (EtOAc–PE, 1:1).
ESI-MS: m/z = 203 [M + Na+].
1H NMR (300 MHz, CDCl3): d = 6.91 (br t, J = 3.6 Hz, 1 H), 4.73–
4.61 (m, 2 H), 2.71 (dd, J = 12.5, 4.6 Hz, 1 H), 2.54–2.46 (m, 1 H),
2.45–2.15 (m, 8 H), 2.02 (s, 3 H), 1.85–1.70 (m, 1 H), 1.57–1.45
(m, 4 H), 1.42–1.35 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 199.63, 170.66, 147.89, 134.00,
61.47, 57.85, 54.75, 44.57, 26.76, 25.88, 24.83, 24.24, 20.91.
(5-Methylene-6-oxocyclohex-1-enyl)methyl Acetate (35)
Yield: 114 mg (63%); colorless oil; Rf = 0.8 (EtOAc–PE, 1:1).
1H NMR (300 MHz, CDCl3): d = 7.02 (t, J = 3.23 Hz, 1 H), 5.99 (d,
J = 1.05 Hz, 1 H), 5.30–5.28 (m, 1 H), 4.78 (d, J = 1.05 Hz, 2 H),
2.71 (t, J = 4.74 Hz, 2 H), 2.49–2.44 (m, 2 H), 2.06 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 187.24, 170.70, 148.28, 142.34,
135.14, 120.67, 61.45, 30.71, 25.80, 20.94.
ESI-MS: m/z = 231 [M + Na+].
ESI-MS: m/z = 298 [M + Na+].
[4-Methyl(N-morpholino)]-1,7,7-trimethyl-6-oxatricy-
clo[6.2.2.04,9]dodecan-3-one (27)
Reaction scale: 0.1 mmol.
Mannich Reaction Followed by Elimination; General Proce-
dure
To a solution of aminal (1 mmol) and cyclic enone (1.2 mmol) in
anhyd MeCN (3 mL) under argon at r.t. was added freshly distilled
Synthesis 2006, No. 18, 3025–3030 © Thieme Stuttgart · New York

3030
A. Porzelle, C. M. Williams
PAPER
AcCl (2.4 mL, 3 mmol). The mixture was kept under argon and
stirred for a further 17 h. The reaction mixture was diluted with
CH2Cl2 (10 mL) and washed with sat. NaHCO3 (5 mL) and brine (5
mL). The pure products were obtained after column chromatogra-
phy (EtOAc–PE) on silica.
(5) Sun, S.; Zhang, Q.; Liu, Q.; Kang, J.; Yin, Y.; Li, D.; Dong,
D. Tetrahedron Lett. 2005, 46, 6271.
(6) (a) Zhao, L.-J.; He, H. S.; Shi, M.; Toy, P. H. J. Comb.
Chem. 2004, 6, 680. (b) Ribiere, P.; Enjalbal, C.; Aubagnac,
J.-L.; Yadav-Bhatnagar, N.; Martinez, J.; Lamaty, F. J.
Comb. Chem. 2004, 6, 464.
3,3-Dimethyl-5-methylene-6-oxocyclohex-1-enyl)methyl Ace-
tate (34)
Yield: 129 mg (62%); colorless oil; 19% of starting enone was re-
(7) Balan, D.; Adolfsson, H. Tetrahedron Lett. 2003, 44, 2521.
(8) Ribiere, P.; Yadav-Bhatnagar, N.; Martinez, J.; Lamaty, F.
QSAR Comb. Sci. 2004, 23, 911.
covered.
(9) Shi, M.; Xu, Y.-M.; Shi, Y.-L. Chem. Eur. J. 2005, 11, 1794;
and literature therein.
(5-Methylene-6-oxocyclohex-1-enyl)methyl Acetate (35)
Yield: 99 mg (55%); colorless oil; 20% of starting enone was recov-
ered.
(10) Shi, M.; Zhao, G.-L. Adv. Synth. Catal. 2004, 346, 1205.
(11) Liu, X.; Chai, Z.; Zhao, G.; Zhu, S. J. Fluorine Chem. 2005,
126, 1215.
(12) Kozlov, N. S.; Kovaleva, V. N. Vestsi Akad. Navuk B. SSR,
Ser. Khim. Navuk 1979, 118; Chem. Abstr. 1979, 91, 56428s.
(13) Koldobsky, A. B.; Milyutin, I. A.; Kalinin, V. N. Dokl. Akad.
Nauk 1992, 324, 1015.
(14) Arnone, A.; Bava, A.; Fronza, G.; Nasini, G.; Ragg, E.
Tetrahedron Lett. 2005, 46, 8037.
Acknowledgment
The authors thank The University of Queensland for financial sup-
port.
(15) For a general review, see: Arend, M.; Westermann, B.;
Risch, N. Angew. Chem. Int. Ed. 1998, 37, 1044.
(16) (a) Kinast, G.; Tietze, L.-F. Angew. Chem. Int. Ed. Engl.
1976, 15, 239. (b) Sielemann, D.; Keuper, R.; Risch, N. J.
Prakt. Chem. 1999, 341, 487.
(17) For the reaction of bis(aminol) ethers under the same
conditions, see: Buckley, B. R.; Bulman Page, P. C.;
Heaney, H.; Sampler, E. P.; Carley, S.; Brocke, C.; Brimble,
M. A. Tetrahedron 2005, 61, 5876.
References
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(19) 2-(Hydroxymethyl)-3-methylcyclohex-2-enone was
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Synthesis 2006, No. 18, 3025–3030 © Thieme Stuttgart · New York