Thermal intramolecular [2 + 2] cycloaddition: Synthesis of 3-azabicyclo[3.1.1]heptanes from morita-baylis-hillman adduct-derived 4,4-diaryl-1,3-dienes

Article abstract of DOI:10.1002/adsc.201400571

Various 3-azabicyclo[3.1.1]heptane derivatives were synthesized from Morita-Baylis-Hillman adduct-derived 1,3-dienes bearing a 4,4-diaryl moiety through a thermal intramolecular [2+2] cycloaddition approach. By using the same approach, bicyclo[3.1.1]heptane, 3-azabicyclo[3.2.0]heptane, and 3-oxabicyclo[3.1.1]heptane derivatives could also be synthesized. A structurally similar dimethyl-Gallyl derivative underwent an intramolecular ene reaction to afford the pyrrolidine derivative.

Full text of DOI:10.1002/adsc.201400571

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DOI: 10.1002/adsc.201400571
Thermal Intramolecular [2+2]Cycloaddition: Synthesis of
3-Azabicyclo[3.1.1]heptanes from Morita–Baylis–Hillman
G
Adduct-Derived 4,4-Diaryl-1,3-dienes
Ko Hoon Kim,a Jin Woo Lim,a Junseung Lee,a Min Jeong Go,a
and Jae Nyoung Kima,*
a
Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Korea
Fax : (+82)-62-530-3389; e-mail: kimjn@chonnam.ac.kr
Received: June 12, 2014; Published online: October 16, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400571.
Abstract: Various 3-azabicyclo
G
The intramolecular variant of this reaction can also
be utilized for the synthesis of fused cyclobutane de-
rivatives.[5] Three representative intramolecular
[2+2]cycloaddition approaches are shown in Figure 1.
Ihara and co-workers used silyl enol ether as an elec-
tron-rich alkene partner [Eq. (1)].[5a] Hsung and co-
workers used Gassmanꢀs cationic [2+2]cycloaddition
approach involving in-situ generated alkenyl oxocar-
benium ion intermediate as an electron-deficient
alkene moiety [Eq. (2)].[5b] Very recently, Hamada re-
ported the synthesis of cyclobutane by the reaction
between unactivated alkene and electron-deficient ar-
ylidenemalonate [Eq. (3)].[5g]
atives were synthesized from Morita–Baylis–Hill-
man adduct-derived 1,3-dienes bearing a 4,4-diaryl
moiety through a thermal intramolecular [2+2]cy-
cloaddition approach. By using the same approach,
bicyclo
and 3-oxabicyclo
also be synthesized. A structurally similar dimethyl-
allyl derivative underwent an intramolecular ene re-
action to afford the pyrrolidine derivative.
A
3-azabicycloACTHNGUTERNNU[G 3.2.0]heptane,
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
Keywords:
bicyclo[3.2.0]heptanes; intramolecular [2+2] cyclo-
addition; Morita–Baylis–Hillman adducts
3-azabicyclo
N
A
ACHTUNGTRENNUNG
A
Recently, we reported the synthesis of hexahydro-
AHCTUNGTREGiNNUN soindole-3a-carboxylate 2a via an intramolecular
[4+2]cycloaddition reaction of trisubstituted diene 1a,
as shown in Scheme 1.[6] We did not observe the for-
mation of an intramolecular [2+2]cycloaddition prod-
The cyclobutane scaffold is an important structural uct, 3-azabicycloACTHNUGRTNEUNG[3.1.1]heptane, presumably due to the
motif incorporated into a large number of natural more facile [4+2]cycloaddition reaction to form 2a.
products and biologically interesting substances.[1] In Thus, as a continuing study, we decided to examine
addition, the cyclobutanes can be used for the synthe-
sis of complex molecules by ring-opening and/or ring-
expansion reactions driven by the relief of the ring
strain.[2] Thus the synthetic methods for cyclobutanes
have been studied extensively.[3–5] The [2+2]cycload-
dition is one of the most straightforward approaches
for the construction of cyclobutanes.[4,5] The [2+2]cy-
cloaddition can be categorized into two types. The
first approach is a reaction between electron-rich al-
kenes and a,b-unsaturated carbonyl compounds or ni-
troalkenes.[4a–o] Electron-rich alkenes include ketene
dithioacetals,[4a–c] enol ethers/silyl enol ethers,[4d–h,5a]
and enamines/dienamines.[4i–o] The second approach
uses a combination of simple alkenes and electron-de-
ficient alkenes such as alkenyl oxocarbenium
ions,[4p,q,5b–f] N-alkenyliminium ions,[4r,s] allyl cation,[4t]
quinones,[4u,5i] and alkylidenemalonates.[4v,5g]
Figure 1. Examples of intramolecular [2+2]cycloaddition.
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equivocally confirmed by its crystal structure (see the
Supporting Information).[9]
The reported intramolecular [2+2]cycloadditions
have been carried out in the presence of an acid cata-
lyst. Thermally-driven [2+2]cycloadditions have been
reported in a limited case.[5i,j] However, the use of an
acid catalyst in the reaction of 1b was ineffective. As
an example, the reaction of 1b in the presence of
CF3COOH (3.0 equiv.)[5e,f,h] in 1,2-dichloroethane
(1208C, 20 h) in a sealed tube did not produce 3b/4b
in any trace amount. No reaction was observed in the
presence of ScACTHNUTRGNEUNG
(OTf)3 (5 mol%)[5g] in 1,2-dichloro-
ethane (reflux, 20 h), and severe decomposition of 1b
was observed in the presence of FeCl3.[5b,h]
Based on the interesting result and the importance
of 3-azabicycloACTHNUTRGNEUNG
[3.1.1]heptane derivatives,[10] we pre-
pared some representative starting materials 1b–
i from MBH adducts,[6,11,12] as shown in Scheme 2 (see
the Supporting Information for details). The reactions
of 1c–g were examined under the same reaction con-
ditions, and the results are summarized in Table 1.
The reaction of bis(para-chlorophenyl) derivative 1c
(entry 2) showed the same pattern as that with 1b,
and a major product 3c was isolated in good yield
(71%). The formation of a diastereomer 4c was ob-
served at the right position on TLC; however, we
could not isolate 4c in an appreciable amount in the
Scheme 1. Synthesis of 3-azabicycloACHTUNTRGNEUNG[3.1.1]heptane 3b and its
epimer 4b. Conditions: 1b (0.3 mmol), toluene, BHT
(10 mol%), sealed tube, 1608C, 80 h.
the reaction with tetrasubstituted diene derivative 1b.
The additional phenyl group of 1b, as compared to
1a, would facilitate the formation of a zwitterionic in-
termediate I. The diphenylmethyl cation part could
be further stabilized by the favorable dipolar interac-
tion by the ester enolate moiety. In addition, the re-
quired s-cis conformation for the [4+2]cycloaddition
would be difficult due to the presence of a phenyl
group.[7] Thus the starting material was prepared from
the Morita–Baylis–Hillamn (MBH) adduct of b-phe-
nylcinnamaldehyde and methyl acrylate (vide infra),
and the reaction of 1b was carried out in the presence
of butyrated hydroxytoluene (BHT) in toluene in
a sealed tube at 1608C as in our previous paper.[6,8]
As expected, 3-azabicycloACTHNUTRGNEUGN[3.1.1]heptane 3b was ob-
tained in good yield (72%) along with its C-6 epimer
4b (13%). The formation of a [4+2]cycloaddition
product 2b was not observed at all.
A plausible [2+2]cycloaddition mechanism for the
formation of 3b/4b is suggested in Scheme 1. A ther-
mal 6-endo-trig cyclization of 1b would form the zwit-
terionic intermediate I, and the following 4-exo-trig
cyclization of I produced the [2+2]cycloaddition
products 3b and 4b. The formation of a stable diphe-
nylmethyl cation and the presence of an electron sink
(an acrylate moiety) made the first carbon-carbon
Scheme 2. Preparation of starting materials: a) methyl acry-
late, DABCO, PhOH, room temperature; b) PBr3, CH2Cl2,
room temperature; c) K2CO3, DMF, room temperature; d)
dimethyl malonate, K2CO3, DMF, room temperature;
bond-formation possible. The structure of 3b was un- e) K2CO3, DMF, room temperature.
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Thermal Intramolecular [2+2]Cycloaddition
Table 1. Synthesis of 3-azabicycloACTHNUTRGNEUNG[3.1.1]heptanes and
yl) derivative 1g (entry 6) also afforded 3g (59%) and
4g (32%).
bicyclo
ACHTUNGTRENNUNG
The [2+2]cycloaddition reaction did not occur for
the substrates 1h, 1i and 1j[12] under the same reaction
conditions, as shown in Scheme 3. The reaction of 1h
failed on account of the steric hindrance around the
Michael acceptor position of the intermediate II due
to the phenyl group. The reaction of allyl derivative
1i failed, presumably due to the absence of an elec-
tron-withdrawing ester moiety at the acceptor alkene.
The reason for the failure of 1j might be the instabili-
ty of the zwitterionic intermediate III.
As a next entry, we examined the reaction of dime-
thylallyl derivative 1k,[12] as shown in Scheme 4. Two
reaction pathways could be feasible leading to 3-
azabicycloACTHNUGRTNEUNG[3.1.1]heptane 5 via the [2+2]cycloaddition
process and/or 3,4-disubstituted pyrrolidine 6a via the
intramolecular ene reaction.[14] Actually, the reaction
Scheme 3. Attempted [2+2]cycloadditions of 1h–j. Condi-
tions: 1h–j (0.3 mmol), toluene, BHT (10 mol%), sealed
tube, 1608C, 40 h.
[a]
Conditions: Substrate
(10 mol%), sealed tube, 1608C, 80 h, and E is COOMe.
Ar is para-chlorophenyl.
Isolation failed.
1 (0.3 mmol), toluene, BHT
[b]
[c]
[d]
E is COOMe.
pure state due to the presence of unidentified side
products near the spot. The reaction of fluorene de-
rivative 1d (entry 3) also gave 3d (78%) and 4d (5%).
The reaction of 1e bearing a phenyl group at the allyl-
ic position (entry 4) afforded 3e (54%) and 4e (38%).
The stereochemistry of 3e and 4e was confirmed by
NOE experiments (see the Supporting Information).
Similarly, the reaction of 1f having a dimethylmalo-
nate
ACHTUNGTRENNUNG
tether
(entry 5)
produced
bicyclo-
Scheme 4. Synthesis of pyrrolidine 6a. Conditions: 1k
(0.3 mmol), toluene, BHT (10 mol%), sealed tube, 1608C,
[3.1.1]heptanes,[13] 3f (69%) and 4f (21%), in good
combined yield. The reaction of bis(para-chlorophen- 40 h.
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Scheme 6. Synthesis of 3-azabicycloACHTUNTRGNEUNG[3.2.0]heptane 9. Condi-
tions: 1o (0.3 mmol), toluene, BHT (10 mol%), 2008C,
120 h.
As a next entry, we prepared 1o[12] bearing a croto-
nate moiety in order to examine the feasibility for the
synthesis of 3-azabicycloACHTNUGRTNEUNG
[3.2.0]heptane derivative 9,[17]
as shown in Scheme 6. The reaction of 1o at 1608C
did not produce the product 9 in an appreciable
amount (20 h), whereas, product 9 was obtained in
moderate yield (46%) at elevated temperature for
a long time (2008C, 120 h) along with recovered 1o
(25%). Consecutive 5-exo-trig and 4-exo-trig cycliza-
tions via the zwitterionic intermediates VII and VIII
Scheme 5. Ene reactions of 1l–n. Conditions: 1l–n
(0.3 mmol), toluene, BHT (10 mol%), sealed tube.
afforded pyrrolidine 6a in good yield (81%) as could produce the product. The possibility for the for-
a single isomer,[14,15] and the formation of a six-mem- mation of other stereoisomers could not be excluded
bered cyclization product piperidine was not observed completely at this stage; however, we could not iso-
in any trace amount (vide infra). The stereochemistry late them in appreciable amount. The stereochemistry
of 6a was confirmed by NOE experiments. The result of 9 was confirmed by NOE experiments.
indicated that an intramolecular ene reaction pro-
ceeds preferentially over the [2+2]cycloaddition in oxabicyclo
this case. rivative 1p, as shown in Scheme 7. The starting mate-
As a last entry, we examined the synthesis of 3-
AHCTUNGTRENNUNG
In order to examine the scope of the ene reaction rial 1p-E (30%) was prepared from the corresponding
briefly, the reactions of 1l–n[12] were carried out, as MBH bromide and allylic alcohol derivative in the
shown in Scheme 5. The secondary phenyl derivative presence of silver oxide.[12,18] In the reaction, double
1l produced pyrrolidine 6b (65%) along with piperi- bond-isomerized 1p-Z (35%) was also formed pre-
dine derivative 7 (20%).[15d,16] The piperidine 7 might sumably via a pentadienyl cation intermediate IX.[18d]
be formed via the transition state IV. However, the The reaction of 1p-E at 1608C was sluggish, and the
piperidine could also be formed via the [2+2]cycload- reaction was performed at 2008C for 140 h in the
dition process of 1l to form V and the following 1,5- presence of BHT (20 mol%). 3-Oxabicyclo-
hydrogen abstraction.[14g,h] The structures of 6b and 7
[3.1.1]heptane derivative 10[19] was obtained in a rea-
ACHTUNGTRENNUNG
were confirmed by NOE experiments. However, no sonable yield (43%) along with recovered starting
reaction was observed with 1m under the same reac- material 1p-E (19%) and a trace amount of 1p-Z (<
tion conditions. The activation energy leading to 5%). The formation of the other stereoisomer was
a transition state VI might be high due to the pres- not observed. The same product 10 was obtained in
ence of a phenyl group at the enophile. Similarly, 1,2- a similar yield (41%) from the reaction of 1p-Z.
disubstituted cyclopentane 8 was synthesized in high Hsung and co-workers have also observed an identical
yield (90%) from the malonate derivative 1n.[12] How- stereocheimcal outcome in their intramolecular
ever, the reaction of 1n required a higher temperature [2+2]cycloaddition irrespective of the stereochemistry
(2008C, 40 h) than N-tosyl derivatives 1k (Scheme 4) of the starting material.[5b,c] It is interesting to note
and 1l (Scheme 5).
that 1p-E (21%) was recovered in the reaction of 1p-
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Thermal Intramolecular [2+2]Cycloaddition
Experimental Section
Typical Procedure for the Synthesis of 3-Aza-
bicyclo[3.1.1]heptane 3b/4b
AHCTUNGTRENNUNG
A mixture of 1b (164 mg, 0.3 mmol) and BHT (7 mg,
10 mol%) in dry toluene (5.0 mL) in a sealed tube was
heated to 1608C for 80 h in an oil bath. After removal of
toluene and a column chromatographic purification process
(hexanes/ether, 2:1) compounds 3b (yield: 118 mg, 72%)
and 4b (yield: 21 mg, 13%) were obtained as white solids.
Acknowledgements
This research was supported by Basic Science Research Pro-
gram through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science and
Technology (2012R1A1B3000541). Spectroscopic data were
obtained from the Korea Basic Science Institute, Gwangju
branch.
Scheme 7. Synthesis of 3-oxabicycloACTHNUTRGNEUNG[3.1.1]heptane 10. Con-
ditions: a) Ag2O (2.0 equiv.), Et2O, reflux, 24 h; b) BHT
(20 mol%), toluene, sealed tube, 2008C, 140 h.
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moiety through a thermal [2+2] cycloaddition ap-
proach. Similarly, bicyclo
oxabicyclo[3.1.1]heptane derivatives could be synthe-
sized. A slight modification of the Michael acceptor
ACHTUNGTREN[NUNG 3.1.1]heptane and 3-
ACHTUNGTRENNUNG
moiety produced 3-azabicyclo
tive in moderate yield.
ACHTUNGERTN[NUNG 3.2.0]heptane deriva-
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absence of BHT under the same conditions. Along this
line, we examined the reaction of 1b in the presence of
AcOH, phenol, para-nitrophenol, and picric acid. The
yield of product and reaction time was not changed
much when we used acetic acid or phenol; however,
the reaction time for completion was shortened to 40–
48 h by using para-nitrophenol or picric acid as an acid
catalyst.
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