DMAP-Catalyzed [4 + 2] Cycloaddition of α,β-Unsaturated Carboxylic Acids with Ketones for Synthesis of α,β-Unsaturated δ-Lactones

Article abstract of DOI:10.1002/cjoc.201600929

The DMAP-catalyzed [4 + 2] cycloaddition of α,β-unsaturated carboxylic acids with ketones furnishing α,β-unsaturated δ-lactones in good yields (up to 80%) is described, which is the first example of remote γ-C(sp³)-H activation of α,β-unsaturated carboxylic acids facilitated by DMAP, a pyridine-based catalyst. Copyright

Full text of DOI:10.1002/cjoc.201600929

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DOI: 10.1002/cjoc.201600929
DMAP-Catalyzed [4＋2] Cycloaddition of α,β-Unsaturated Carboxylic
Acids with Ketones for Synthesis of α,β-Unsaturated δ-Lactones
Jinghai Jin, Qinchang Xu, and Weiping Deng*
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and
Technology, Shanghai 200237, China
The DMAP-catalyzed [4＋2] cycloaddition of α,β-unsaturated carboxylic acids with ketones furnishing
α,β-unsaturated δ-lactones in good yields (up to 80%) is described, which is the first example of remote γ-C(sp3)-H
activation of α,β-unsaturated carboxylic acids facilitated by DMAP, a pyridine-based catalyst.
Keywords DMAP, cycloaddition, α,β-unsaturated carboxylic acids, α,β-unsaturated δ-lactones
Introduction
successfully employed in the organocatalyzed [4＋2]
annulation for the direct asymmetric synthesis of
α,β-unsaturated δ-lactone derivatives. For example,
Peters and co-workers reported a chiral cinchona alka-
loid derivative-catalyzed enantioselective [4＋2] cy-
cloaddition of α,β-unsaturated acid chlorides with the
aldehyde to offer synthetic versatile α,β-unsaturated
δ-lactones (Scheme 1a).[8] In 2011, Ye’s group devel-
oped an N-heterocyclic carbene (NHC)-catalyzed for-
mation of chiral dienolates from α,β-unsaturated acid
chlorides, and the subsequent formal [4＋2] annulation
with ketones gained corresponding α,β-unsaturated
δ-lactones (Scheme 1b).[9] In 2012, Chi’s group demon-
strated a chiral NHC-catalyzed generation of the same
α,β-Unsaturated δ-lactones are serving as important
structural motifs existing in a variety of natural products
that display different biological activities, such as anxi-
ety-treating[1] (Figure 1a), anti-inflammation[2] (Figure
1b), or anti-tumor[3] (Figure 1c) agents, etc. Notably, it
has been shown in several studies[4] that the
α,β-unsaturated moiety plays an important role in the
anti-tumor activity due to its electrophilicity as a Mi-
chael acceptor in the presence of nucleophilic functional
groups of protein.[4,5c] Consequently, lots of synthetic
methods, most of which often involve multistep proce-
dures, have been developed for their construction.[5] The
most direct synthetic route to α,β-unsaturated δ-lactones
is based on metal-catalyzed hetero-Diels-Alder (HDA)
reactions.[6]
Scheme 1 γ-Functionalization of dienolates for the synthesis of
α,β-unsaturated δ-lactones
Figure 1 Representative natural products containing α,β-un-
saturated δ-lactone moiety.
Recently, dienolates derived from α,β-unsaturated
carbonyl compounds via γ-deprotonation have been
*
E-mail: weiping_deng@ecust.edu.cn
Received December 28, 2016; accepted February 15, 2017; published online XXXX, 2017.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201600929 or from the author.
Dedicated to Professor Xikui Jiang on the occasion of his 90th birthday.
Chin. J. Chem. 2017, XX, 1—4
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Jin, Xu & Deng
COMMUNICATION
intermediates from enals in the presence of an oxidant
for the synthesis of α,β-unsaturated δ-lactones in excel-
lent yields and enantioselectivities (Scheme 1c).[10] In
2013, Yao et al. disclosed a chiral NHC/Lewis acid-
catalyzed cycloaddition of α-bromo-α,β-unsaturated
aldehydes with isatin derivatives to access desired
δ-lactone derivatives (Scheme 1d).[11] Although a lot of
synthetic approaches of δ-lactone derivatives have been
reported, the development of new methodologies using
stable and readily available starting materials is still
highly desired.
Based on our recent developments in organocataly-
sis,[13] we envisioned that pyridine-based DMAP, bear-
ing sp2-hybridized nucleophilic nitrogen atom, would be
a potential nucleophilic catalyst[14] to facilitate the gen-
eration of dienolates from α,β-unsaturated acids[15] via a
similar γ-deprotonation promoted by cinchona alkaloid,
and the following formal [4＋2] cycloaddition with ke-
tones to directly produce α,β-unsaturated δ-lactones.
result, a quick screening (see Supporting Information
for the details) of the ratio of 1a and 2a showed that 2.0
equivalents of 1a gave the highest yield in 71% (Table 1,
entries 1－3). Next, we examined the influence of bases
on the reaction (Table 1, entries 4－10). Compared with
NHC catalysis, inorganic bases were found not suitable
for this reaction (Table 1, entries 9 and 10), and the 4.0
equivalents of Et3N used in step 2 was the optimal
choice (Table 1, entry 4). Further screening of solvents
indicated that the reaction could proceed efficiently with
moderate yields in most tried solvents (Table 1, entries
11－16), and DCM was the best choice to afford corre-
sponding cycloadduct 3aa in 80% yield (Table 1, entry
4).
With the optimized reaction conditions in hand, the
substrate scope of this formal [4＋2] annulation was
then explored (Table 2). The reaction was found to be
tolerant of both electron-donating or -withdrawing sub-
stitutions on phenyl group of α,β-unsaturated acids. To
begin with, carboxylic acids with electron-donating
groups (Me, MeO) offered α,β-unsaturated δ-lactones
3ba－3fa in good yields (62%－73%) (Table 2, entries
2－6). In the case of electron-withdrawing groups (F, Cl,
Br), the corresponding products were also obtained in
moderate to good yields (45%－77%) (Table 2, entries 7
－12). Likewise, other aryl substrates containing naph-
thyl, thienyl, and furyl groups also worked efficiently in
Results and Discussion
Initially, commonly used electrophile ethyl 3,3,3-tri-
fluoro-2-oxopropanoate 2a (1.0 equiv.) and (E)-3-phe-
nylbut-2-enoic acid 1a (1.2 equiv.) were chosen as the
model substrate to test the reaction feasibility in the
presence of catalytic amount of DMAP using Et3N as
base in DCM at room temperature under nitrogen at-
mosphere. To our delight, the reaction proceeded
smoothly and gave the desired α,β-unsaturated δ-lactone
3aa in 42% yield (Table 1, entry 1). Encouraged by this
Table 2 α,β-Unsaturated acids 1 with 2a in the synthesis of
α,β-unsaturated δ-lactonesa
Table 1 Optimization of reaction conditionsa
Entry
1
2
3
4
5
6
7
8
R
3
t/h
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
Yieldb/%
80
Ph (1a)
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
3ja
3ka
3la
3ma
3na
3oa
3pa
3qa
3ra
o-MePh (1b)
p-MePh (1c)
o-OMePh (1d)
m-OMePh (1e)
p-OMePh (1f)
o-BrPh (1g)
m-BrPh (1h)
p-BrPh (1i)
71
73
62
70
72
62
66
77
70
68
45
72
75
63
76
68
Entry 1a/2a Solvent
Base (equiv.)b
Et3N (3.0)
Et3N (3.0)
Et3N (3.0)
Et3N (4.0)
Et3N (5.0)
Et3N (2.0)
DIPEA (4.0)
t/h Yieldc/%
1
2
1.2/1
2/1
1/2
2/1
2/1
2/1
2/1
2/1
2/1
2/1
2/1
2/1
2/1
2/1
2/1
2/1
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
CHCl3
DCE
16
16
16
16
16
16
16
42
71
21
80
67
3
4
5
6
7
8
9
52
62
9
10
11
12
13
14
15
16
17
18
p-ClPh (1j)
p-FPh (1k)
2,6-lutidine (4.0) 16
trace
20
trace
65
48
51
66
63
67
Cs2CO3 (4.0)
t-BuOK (4.0)
Et3N (4.0)
Et3N (4.0)
Et3N (4.0)
Et3N (4.0)
Et3N (4.0)
Et3N (4.0)
16
16
16
16
16
16
16
16
2,4-diClPh (1l)
1-naphthyl (1m)
2-naphthyl (1n)
2-furyl (1o)
2-thienyl (1p)
PhCH2CH2 (1q)
Me (1r)
10
11
12
13
14
15
16
Et2O
THF
CH3CN
Tol
53
a Conditions: All reactions were carried out with 1 (0.4 mmol), 2a
(0.2 mmol), Et3N (0.4 mmol), PivCl (0.4 mmol), DCM (1 mL);
then Et3N (0.8 mmol), DMAP (0.04 mmol), 4Å MS, under a N2
atmosphere, at room temperature; b Isolated yield.
a Conditions: All reactions were carried out in 1 mL of solvent,
under a N2 atmosphere, at room temperature; b The base was used
in the step two; c Isolated yield.
2
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Synthesis of α,β-Unsaturated δ-Lactones
termediate III undergoes intramolecular cyclization to
afford the desired α,β-unsaturated δ-lactone 3 (Figure
2).
this transformation, providing the desired cycloadducts
in 63%－76% yields (Table 2, entries 13－16). Addi-
tionally, 3-alkylbut-2-enoic acids also showed good re-
activity to obtain 3qa (68%) and 3ra (53%) (Table 2,
entries 17 and 18).
Next, we further explored the reaction of the sub-
strates 1 with vicinal tricarbonyl compound 2b (Table 3).
Substrates 1 bearing either electron-donating (Me, MeO)
or -withdrawing (F, Cl, Br) groups on phenyl both re-
acted with 2b to offer the desired products in moderate
to good yields (44%－67%) (Table 3, entries 1－8).
Moreover, heterocyclic or alkyl substituted 1 also gave
the cycloadducts in moderate yields (50%－59%) (Ta-
ble 3, entries 9－12).
Table 4 The exploration of enantioselective synthesis of
α,β-unsaturated δ-lactone 3aaa
Table 3 α,β-Unsaturated acids 1 with 2b in the synthesis of
α,β-unsaturated δ-lactonesa
Entry
Cat.
t/h
16
16
16
16
eeb/%
Yieldc/%
1
2
3
4
Fc-PIP
Np-PIQ
An-PIQ
C-1
6
7
8
67
62
66
70
11
a Conditions: The same reaction conditions as noted in Table 2;
b Determined by Chiral HPLC analysis; c Isolated yield.
Entry
1
2
3
4
5
6
7
8
R
3
t/h
16
16
16
16
16
16
16
16
16
16
16
16
Yieldb/%
64
Ph (1a)
3ab
3cb
3eb
3gb
3hb
3ib
p-MePh (1c)
m-OMePh (1e)
o-BrPh (1g)
m-BrPh (1h)
p-BrPh (1i)
p-ClPh (1j)
p-FPh (1k)
1-naphthyl (1m)
2-naphthyl (1n)
2-thienyl (1p)
Me (1r)
67
60
44
47
50
48
55
50
3jb
3kb
3mb
3nb
3pb
3rb
9
10
11
12
59
51
51
a Conditions: The same reaction conditions as noted in Table 2;
b Isolated yield.
Considering stereoselectivity, we envisioned that
enantioselective [4＋2] annulation could be catalyzed
by a chiral nucleophilic catalyst. Therefore, we tested
the in-house designed amidine-based catalysts (Table 4,
entries 1－3) and a chiral 4-(pyrrolidino)-pyridine de-
rivative C-1 (Table 4, entry 4).
Disappointingly, all of them gave the products in
good yields but with low ee (6%－11%) presumably
due to relatively remote stereocontrol from chiral cata-
lyst.
Figure 2 Proposed catalytic cycle.
Conclusion
In summary, the DMAP-catalyzed direct γ-func-
tionalization of α,β-unsaturated acids for [4＋2] cy-
cloaddition to ketones was developed, providing the
α,β-unsaturated δ-lactones in good yields (up to 80%).
Notably, the key dienolate intermediates involved in this
reaction are generated in situ from α,β-unsaturated car-
boxylic acids facilitated by DMAP, which represented
the first example of sp2-hybridized nucleophilic nitrogen
atom for γ-deprotonation of α,β-unsaturated acids. Fur-
ther exploration of the chiral amidine derivatives for
stereo-controlled synthesis of δ-lactones is underway in
our laboratory.
Similar to the Ye’s and Yao’s results,[15] a catalytic
cycle of this reaction was proposed. The nucleophilic
attack of DMAP to the mixed anhydride 1’ formed in
situ from the α,β-unsaturated acid 1 gives the α,β-un-
saturated acyl ammonium intermediate I. The γ-depro-
tonation of the α,β-unsaturated acyl ammonium inter-
mediate I in the presence of base offers the key dieno-
late intermediate II, which reacts with ketone 2a via
Aldol addition to generate intermediate III. Finally, in-
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Jin, Xu & Deng
COMMUNICATION
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General Procedure
To an oven-dried 25 mL Schlenk tube equipped with
a stir bar was charged with the unsaturated carboxylic
acid 1 (2.0 equiv., 0.4 mmol) and Et3N (2.0 equiv., 0.4
mmol) in dry DCM under N2. Then, pivaloylchloride
(2.0 equiv., 0.4 mmol) was added dropwise at 0 ℃. Af-
ter stirring at 0 ℃ for 30 min, Et3N (4.0 equiv., 0.8
mmol), DMAP (20 mmol%, 0.04 mmol) and ketone 2
(1.0 equiv., 0.2 mmol) were added. The reaction mixture
was stirred at room temperature until the complete con-
sumption of the ketone (monitored by TLC). Then, the
solvent was removed under reduced pressure and the
residue was purified by chromatography on silica gel to
give the desired cycloaddition product 3.
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Acknowledgement
This work is supported by the National Natural Sci-
ence Foundation of China (No. 21372074).
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