Intramolecular prins reactions of vinylcyclopropanes with aldehydes and ketones: A new synthesis of semicyclic conjugated dienes

Article abstract of DOI:10.1055/s-2005-922752

Carbonyl compounds bearing pendant vinylcyclopropanes react with sulfonic acids to produce semicyclic conjugated dienes. These functionalized dienes can be readily elaborated into complex polycyclic compounds. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-922752

LETTER
3075
Intramolecular Prins Reactions of Vinylcyclopropanes with Aldehydes and
Ketones: A New Synthesis of Semicyclic Conjugated Dienes
I
ntramolecular Prin
i
s
Reac
n
tionsof
V
in
g
ylcyclopropa
h
nes ui Liu, Nabi A. Magomedov*
Department of Chemistry, University of Rochester, Rochester, New York 14627-0216, USA
Fax +1(585)2760205; E-mail: magomedov@chem.rochester.edu
Received 25 August 2005
intermediate then undergoes cyclopropane ring opening
Abstract: Carbonyl compounds bearing pendant vinylcyclopro-
panes react with sulfonic acids to produce semicyclic conjugated
dienes. These functionalized dienes can be readily elaborated into
complex polycyclic compounds.
with tosylate followed by dehydration of the resulting al-
cohol 3 to furnish the final diene. Notably, while sulfonic
acids were found to result in clean reactions,5 other protic
acids such as trifluoroacetic acid or hydrobromic acid
produced complex mixtures of products.
Key words: vinylcyclopropane, cyclizations, ring opening, elimi-
nations, conjugated diene
An attractive feature of the diene products of type 4 is the
presence of a strategically positioned leaving group,
which can be used as a handle to introduce a dienophile
moiety for subsequent cycloaddition chemistry. Realizing
that this operationally simple synthesis of functionalized
dienes may serve as a useful method for the preparation of
complex compounds, we decided to explore it in more
detail.
Conjugated dienes are important building blocks for or-
ganic synthesis. In particular, semicyclic dienes, in which
one of the olefins is endocyclic, are useful starting mate-
rials for the rapid assembly of complex polycyclic archi-
tectures.1,2 Herein we demonstrate a new synthesis of
semicyclic conjugated dienes proceeding through a one-
pot sequence of an acid-mediated Prins cyclization of a vi-
nylcyclopropane onto a carbonyl group, nucleophilic ring
opening of the cyclopropane ring, and a regioselective
dehydration reaction.
The utility of this cyclization for the preparation of vinyl-
cyclohexenes was examined as outlined in Scheme 2.
Aldehyde 8, prepared from bromide 56 using standard
chemistry, cleanly reacted with p-toluenesulfonic acid to
furnish the mixture of the expected diene 9 and alcohol 10
in 42% and 55% yields, respectively. Interestingly, when
10 was resubmitted to the reaction conditions, no dehy-
dration was observed. This indicated that trans-10 was not
the precursor of 9. Presumably diene 9 was produced from
the diastereomer of 10 in which the vinyl and hydroxy
groups are in the cis arrangement.
In the course of our investigation of acid-catalyzed in-
tramolecular reactions of imines with nucleophilic al-
kenes,3 we serendipitously discovered that aldehyde 1
reacted with p-toluenesulfonic acid in refluxing toluene to
produce conjugated diene 4 in 58% yield as the only isol-
able product (Scheme 1).
Presumably, the reaction commences with a nucleophilic
attack of the electron-rich alkene onto the acid-activated
carbonyl to generate cyclopropylcarbenium ion 2.4 This
a, b
c
NC
Br
Br
TsOH·H2O
5
6
7
toluene, ∆
d
O
58%
TsO
1
4
e
+
1
OTs
Prins
cyclization
OTs
TsOH
HO
O
–H2O
H
10
9
8
H
H
Scheme 2 Reagents and conditions: a) Mg, Et2O, then (CH2O)n,
78%; b) PPh3, Br2, pyridine, 85%; c) LDA/Me2CHCN, 78%; d)
DIBAL-H, 84%; e) TsOH, PhMe, 110 °C, 30 min.
OTs
OH
OH
TsO
3
2
These results can be rationalized on the basis of confor-
mational analysis of the diastereomeric homoallylic alco-
hols formed upon Prins cyclization of 8 (Scheme 3).
Scheme 1
Each of the diastereomeric cyclohexanols can exist in two
chair conformations. One of the conformers of cis-10
bears a hydroxy group antiperiplanar to the allylic proton,
thereby satisfying the stereoelectronic requirement for an
SYNLETT 2005, No. 20, pp 3075–3078
Advanced online publication: 28.11.2005
DOI: 10.1055/s-2005-922752; Art ID: S08005ST
© Georg Thieme Verlag Stuttgart · New York
1
9
.1
2
.2
0
0
5

3076
Y. Liu, N. A. Magomedov
LETTER
Ts
N
H
H
H
5, K2CO3
H
R
TsHN
OMe
OEt
O
H
–H2O
HO
O
cis-10
OH
19
20, 67%
R
DIBAL
OTs
H
R = CH2CH2OTs
Ts
N
TsOH,
PhMe
9
OH
H
R
O
NTs
H
2
H
R
OTs
OH
2
22, 73%
21, R = H, 80%
H
trans-10
R
Scheme 5
Scheme 3
molecular variant of this reaction might be successful.
When the methyl ketone 21 (R = Me) was reacted with
p-toluenesulfonic acid, a complex mixture of products
was produced containing no desired diene. However, the
derivatives of b-ketoesters possessing more electrophilic
carbonyl groups were reasonably reactive (Scheme 6 and
Scheme 7).
E2 elimination reaction.7 In contrast, trans-10 cannot at-
tain a chair conformation with the antiperiplanar arrange-
ment of the hydroxy group and allylic hydrogen at C-2
and, as a consequence, survives under the reaction condi-
tions.
We then applied this strategy for the preparation of het-
erocyclic dienes, which could be of use for the synthesis
of polycyclic nitrogen heterocycles. The substrate alde-
hydes 15 and 16 were readily prepared from a-amino acid
derivatives 11 and 12 as outlined in Scheme 4.
COOEt
5, K2CO3, DMSO
COOEt
O
O
23
24, 76%
TsOH, PhMe, ∆
R
R
OR1
OR1
5, K2CO3/DMSO
COOEt
TsHN
N
COOEt
O
Ts
O
+
TsO
11, R = H, R1 = Et
12, R = Me, R1 = Me
13, R = H, R1 = Et, 87%
14, R = Me, R1 = Me, 80% (97% ee)
O
OTs
26, 45%
25, 42%
DIBAL-H
Scheme 6
R
TsOH, PhMe
Ts
H
OTs
N
COOEt
N
Ts
EtOOC
O
5, K2CO3, DMSO
O
O
R
17, R = H, 42%
18, R = Me, 38% (46% ee)
15, R = H, 65%
16, R = Me, 70% (72% ee)
72%
27
28
Scheme 4
TsOH, PhMe, ∆
Treatment of these aldehydes with p-toluenesulfonic acid
in refluxing toluene produced the corresponding piperi-
dine derivatives 17 and 18 in moderate yields. The reac-
tion of the chiral non-racemic alanine derivative 16 was of
particular interest, because enolizable a-amino aldehydes
are exceptionally prone to racemization.8 The cyclization
of 16 (72% ee) occurred with partial racemization produc-
ing diene 18 with 46% ee. The formation of chiral non-ra-
cemic 18 suggests that the rate of the cyclization of 16 is
faster than the rate of racemization. The reaction of b-ami-
no acid derivative 21 was more efficient than reactions of
substrates derived from the a-amino acids, producing
azepane 22 in 73% isolated yield (Scheme 5).
H
EtOOC
+
EtOOC
OTs
OTs
OH
29, 40%
30, 40%
Burgess reagent, PhMe, ∆
83%
Scheme 7
Thus, cyclization of 24 yielded the desired diene 26 in ad-
dition to acyclic compound 25. Evidently, 25 results from
the direct reaction of vinylcyclopropane with sulfonic
acid. In case of the less reactive carbonyl compounds, this
process appears to compete with the cyclization reaction.
The use of ketones as carbonyl components in this reac-
tion would significantly expand the scope of the process.
Although Oshima found that ketones were not reactive in
the intermolecular reactions of vinylcyclopropanes with
ketones,4 we hoped that under our conditions the intra-
The cyclohexanone derivative 28 was more reactive in the
cyclization process, producing an equimolar mixture of
bicyclic diene 29 and alcohol 30 (Scheme 7).
Synlett 2005, No. 20, 3075–3078 © Thieme Stuttgart · New York

LETTER
Intramolecular Prins Reactions of Vinylcyclopropanes
3077
H
Interestingly, while alcohol 30 failed to undergo dehydra-
tion to 29 when resubmitted to the reaction conditions,
this transformation was readily accomplished by treat-
ment with the Burgess reagent. These observations can be
rationalized by the conformational analysis outlined in
Scheme 8. The sterically favored nucleophilic attack of
the alkene onto the activated ketone carbonyl can produce
two diastereomeric cis-hydrindanes 30 and 31
(R = CH2CH2OTs). The cis-hydrindane system is con-
formationally flexible, thereby enabling the two dia-
stereomeric alcohols to exist as a pair of conformers.9
Compound 31 can attain a conformation with the anti-
periplanar arrangement between the leaving group and al-
lylic hydrogen (31b), and, as a consequence, readily
forms diene 29 under acidic catalysis. This stereoelectron-
ic requirement for an E2-like elimination reaction cannot
be satisfied for isomer 30.10 Interestingly, although an
axial OH group in conformer 30a is antiperiplanar to the
C-5 proton on the cyclohexane ring, no cyclohexene for-
mation is observed under these reaction conditions. Evi-
dently, the reaction conditions are sufficiently mild such
that only regioselective dehydration involving elimination
of the activated allylic proton occurs. Transformation of
30 to 29 was instead affected by reaction with the Burgess
reagent via a syn-elimination mechanism.11
a, b
NTs
NTs
O
77% (2 steps)
OTs
H
H
O
22
32
Scheme 9 Reagents and conditions: a) potassium acrylate, DMF,
100 °C, 30 min; b) toluene, 150 °C, 17 h.
In summary, we have demonstrated the synthesis of semi-
cyclic dienes involving sulfonic acid-mediated intramo-
lecular Prins reactions of vinylcyclopropanes with
aldehydes and ketones followed by regioselective
dehydration reactions. The products of these reactions
bear a primary alkyl sulfonate group, which can be em-
ployed to introduce an internal dienophile for the prepara-
tion of complex polycyclic compounds by cycloaddition
chemistry.
Representative Procedure; Synthesis of 22
To a solution of 84 mg (0.26 mmol) of aldehyde 21 (R = H) in 50
mL of toluene was added 46 mg (0.24 mmol) of p-toluenesulfonic
acid monohydrate. The reaction mixture was refluxed for 30 min,
after which time TLC indicated complete consumption of starting
aldehyde. The reaction mixture was cooled down to r.t., and washed
with 10 mL of sat. aq NaHCO3. The organic layer was separated,
dried over MgSO4, and concentrated in vacuo. The residue was
flash-chromatographed over silica gel (EtOAc–hexane, 1:2) to pro-
vide 83 mg (73%) of diene 22 as thick colorless oil. IR (neat): 2924,
O
OEt
OH
O
OH
1597, 1452, 1358, 1336, 1174, 1159, 1095 cm–1. H NMR (400
1
H
OEt
R
29
MHz, CDCl3): d = 2.34–2.45 (m, 6 H), 2.42 (s, 3 H), 2.45 (s, 3 H),
3.25–3.29 (m, 4 H), 4.02 (t, J = 6.6 Hz, 2 H), 5.33 (dt, J = 15.7, 6.9
Hz, 1 H), 5.70 (t, J = 6.2 Hz, 1 H), 5.97 (d, J = 15.7 Hz, 1 H), 7.90
(d, J = 8.2 Hz, 2 H), 7.33 (d, J = 8.2 Hz, 2 H), 7.65 (d, J = 8.2 Hz, 2
H), 7.77 (d, J = 8.2 Hz, 2 H). 13C NMR (100 MHz, CDCl3): d = 21.6,
21.7, 28.4, 28.6, 32.3, 46.8, 47.5, 69.9, 121.1, 127.2, 127.9, 129.8,
129.9, 130.6, 133.1, 135.8, 136.8, 140.1, 143.4, 144.9. HRMS (EI):
m/z calcd for C24H29NO5S2 [M+]: 475.1487; found: 475.1485.
anti-elimination
H
H
R
31a
31b
O
OEt
OH
O
OH
Burgess
reagent
29
OEt
5
syn-elimination
H
H
Synthesis of 32
R
R
To a solution of 67 mg of diene 22 (0.14 mmol) in 2 mL of dry DMF
was added 77 mg (0.70 mmol) of potassium acrylate. The mixture
was heated at 100 °C for half an hour, after which time TLC indi-
cated complete consumption of starting tosylate. The reaction mix-
ture was cooled down to r.t., diluted with 10 mL of a 1:1 mixture of
EtOAc and hexane, and washed with four 3-mL portions of H2O.
The organic layer was dried over MgSO4, filtered, and concentrated
in vacuo. The residue was dissolved in 2 mL of toluene, hydro-
quinone (1 mg) was added, and the mixture was heated at 150 °C in
a sealed tube for 17 h. The reaction mixture was cooled down to r.t.,
concentrated in vacuo, and the residue was flash-chromatographed
over silica gel (EtOAc–hexane 1:1, then 2:1) to provide 40 mg (77%
yield) of tricycle 32 as thick colorless oil. IR (neat): 2960, 2920,
2852, 1724, 1259, 1157, 1091 cm–1. 1H NMR (400 MHz, CDCl3):
d = 1.58–1.76 (m, 3 H), 1.82–1.93 (m, 2 H), 2.00 (ddd, J = 12.9, 4.5,
4.5 Hz, 1 H), 2.33–2.58 (m, 4 H), 2.42 (s, 3 H), 2.79 (ddd, J = 10.9,
6.8, 4.1 Hz, 1 H), 3.10 (ddd, J = 11.2, 10.3, 3.2 Hz, 1 H), 3.21 (ddd,
30a
30b
Scheme 8
Finally, we briefly examined the synthetic utility of the
diene products for the preparation of polycyclic com-
pounds. The cycloaddition reactions of unactivated semi-
cyclic dienes sometimes suffer from poor reactivity and
low regioselectivity.12 However, employing the primary
alkyl tosylate as a point of attachment of a dienophile fol-
lowed by intramolecular cycloaddition would address the
issues of reactivity and regioselectivity.13 With this in
mind, tosylate 22 was reacted with potassium acrylate
(Scheme 9). Subsequent heating of the resulting ester to
150 °C cleanly produced tricycle 32 in 77% overall yield.
The efficiency of this cycloaddition reaction is note- J = 12.8, 10.8, 2.0 Hz, 1 H), 3.26–3.35 (m, 2 H), 4.24 (ddd, J = 11.2,
10.3, 3.2 Hz, 1 H), 4.37 (ddd, J = 11.2, 4.1, 4.1 Hz, 1 H), 5.32 (s, 1
worthy because ester-tethered intramolecular Diels–Alder
H), 7.30 (d, J = 8.2 Hz, 2 H), 7.64 (d, J = 8.2 Hz, 2 H). 13C NMR
cycloadditions are often problematic due to the unfavor-
(100 MHz, CDCl3): d = 21.7, 27.9, 32.0, 32.9, 33.9, 37.1, 38.0, 39.6,
able conformation of the ester moiety.14
47.7, 48.2, 68.8, 125.5, 127.3, 129.9, 136.1, 141.8, 143.4, 173.9.
HRMS (EI): m/z calcd for C20H25NO4S [M+]: 375.1504; found:
375.1501.
Synlett 2005, No. 20, 3075–3078 © Thieme Stuttgart · New York

3078
Y. Liu, N. A. Magomedov
LETTER
(8) Myers, A. G.; Zhong, B.; Movassaghi, M.; Kung, D. W.;
Lanman, B. A.; Kwon, S. Tetrahedron Lett. 2000, 41, 1359.
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(10) It is commonly accepted that acid-catalyzed dehydrations of
tertiary alcohols occur via an E1 mechanism:
Acknowledgment
We thank the University of Rochester for support of this work.
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Synlett 2005, No. 20, 3075–3078 © Thieme Stuttgart · New York