Regiospecific 6-endo-annulation of in situ generated 3,4-dienamides/acids: Synthesis of δ-lactams and δ-lactones

Article abstract of DOI:10.1021/ol4007772

A novel and efficient method for the construction of α-(1,3- dithiolan-2-ylidene) δ-lactam and δ-lactone rings has been developed. It involves the regiospecific 6-endo-annulation of in situ generated 2-(1,3-dithiolan-2-ylidene)-3,4-dienamides/acids from the dehydrative coupling of α-oxo ketene dithioacetals with tertiary propargyl alcohols promoted by BF₃·Et₂O. A range of α-(1,3-dithiolan-2- ylidene) δ-lactams and δ-lactones are obtained in good to high yields. In addition, indenes are prepared by using α-acetyl ketene dithioacetal as the precursor.

Full text of DOI:10.1021/ol4007772

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Regiospecific 6-Endo-Annulation of
in Situ Generated 3,4-Dienamides/Acids:
Synthesis of δ‑Lactams and δ‑Lactones
Ying Liu,† Badru-DeenBarry,† Haifeng Yu,§ Jianquan Liu,† Peiqiu Liao,*,† and Xihe Bi*,†,‡
Department of Chemistry, Northeast Normal University, Changchun 130024,
P. R. of China, State Key Laboratory of Elemento-Organic Chemistry, Nankai
University, Tianjin 300071, P. R. of China, and School of Chemistry and Life Science,
Anshan Normal University, Anshan, Liaoning 114007, P. R. of China
bixh507@nenu.edu.cn; liaopq774@nenu.edu.cn
Received March 22, 2013
ABSTRACT
A novel and efficient method for the construction of R-(1,3-dithiolan-2-ylidene) δ-lactam and δ-lactone rings has been developed. It involves the
regiospecific 6-endo-annulation of in situ generated 2-(1,3-dithiolan-2-ylidene)-3,4-dienamides/acids from the dehydrative coupling of R-oxo
ketene dithioacetals with tertiary propargyl alcohols promoted by BF3 Et2O. A range of R-(1,3-dithiolan-2-ylidene) δ-lactams and δ-lactones are
3
obtained in good to high yields. In addition, indenes are prepared by using R-acetyl ketene dithioacetal as the precursor.
δ-Lactone and δ-lactam rings are often found as the core
structural motif in naturally occurring bioactive compounds
and synthetic drugs.1 R-Alkylidene δ-lactones and δ-lactams
are special subclasses of δ-lactone/δ-lactam derivatives with a
characteristic exoalkylidene moiety conjugated with a carbo-
nyl group, the distinct feature believed to be crucial for their
biological activities.2 R-Alkylidene δ-lactones have been iden-
tifiedin a variety of natural products (Crassin,3 Artemisitene,4
Teucrium Lactone,5Pentalenolactone E,6 etc.) (Figure 1).
These compounds show significant biological activities such
as cytotoxicity against human pharyngeal carcinoma (KB)
cells as well antibiotic and antimalarial properties. Natural
R-alkylidene δ-lactams, on the other hand, were almost
unknown until the very recent isolation of a new humante-
nine-type alkaloid, Gelegamine B, from Gelsemium elegan.7
In recent years, the growing interest in the biolog-
ical activities of R-alkylidene δ-lactams/δ-lactones has
† Northeast Normal University.
§ Anshan Normal University.
‡ Nankai University.
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r
10.1021/ol4007772
XXXX American Chemical Society

the synthetic potency of gem-dialkylthio vinylallenes15and
develop novel cyclization reactions,16 we report herein
a straightforward method for the divergent synthesis of
R-alkylidene δ-lactams and δ-lactones by the tandem dehy-
drative coupling/intramolecular cyclization of ketene dithio-
acetals and tertiary propargyl alcohols (Scheme 1).
Scheme 1. Strategies for the Construction of R-Alkylene
δ-Lactams/δ-Lactones
Figure 1. Natural compounds containing a R-alkylidene δ-lactone
or δ-lactam unit.
inspired the development of several synthetic approaches
(Scheme1), including the intramolecular cyclizations based
on BaylisꢀHillman acetates (pathways 1, 2, and 3),8
tandem carbonylation/radical cyclization of pent-4-yn-
1-imine derivatives (pathway 4),9 and HornerꢀWadsworthꢀ
Emmons reaction of R-(dialkoxyphosphoryl)-δ-lactams/
-lactones (pathways 5)10 and synthetic transformations of
sugar derivatives (pathway 6).11 However, the broad ap-
plications of these methods have been impeded by several
drawbacks such as nonreadily available substrates, multi-
step reactions, longer reaction times, and/or lower yields.9ꢀ11
As a result, the development of efficient and practical meth-
ods to access these important heterocyclic frameworks re-
mains imperative. Allenes12 and ketene dithioacetals13 are
two classes of synthons with respectively unique structural
characters and reactivities. Reports on the synthesis of
δ-lactams and δ-lactones from allenoic amides/acids
are relatively rare,14 while the formation of R-alkylidene
δ-lactams and δ-lactones from functionalized allenes re-
mains elusive.12 As part of our continuing efforts to explore
In our initial search for optimal conditions, the reaction
of2-(1,3-dithiolan-2-ylidene)acetamide(1a) and propargyl
alcohol (2a) was evaluated in the presence of BF3 Et2O
3
(1.1 equiv) in 1,2,3-trichloropropane (1,2,3-TCP),17 and as
envisioned, 2-(1,3-dithiolan-2-ylidene)-3,5-diphenylhexa-
3,4-dienamide (Int-1a) was exclusively obtained in 93%
yield within 20 min. Treatment of this intermediate with
4 equiv of trifluoroacetic acid (TFA) for another 20 min
afforded 88% of R-(1,3-dithiolan-2-ylidene) δ-lactams
(3a). Notably, TFA was crucial for the cyclization step,
as formation of 3a was never achieved even by increasing
the amount of BF3 Et2O (4 equiv). Next solvent screening
3
showed 1,2,3-TCP to be absolute, as other solvents such as
DMSO, 1,4-dioxane, and CH3CN were unfit for the
transformation. Intrigued by this successful synthesis of
R-alkylidene-δ-lactams in 1,2,3-TCP solvent, we imagined
that 2-(1,3-dithiolan-2-ylidene)acetic acid (1b) will simi-
larly react with 2a to afford R-(1,3-dithiolan-2-ylidene)
δ-lactone (4a) under the same reaction conditions. To our
dismay, the reaction did not proceed and 1b was almost
recovered completely in 1,2,3-TCP. In our persistent ex-
ploration for possibilities we discovered that 1b and 2a
could efficiently interact at room temperature in the pre-
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8525. (e) Ramana, C. V.; Nagarajan, M. Synlett 1997, 763.
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Wiley-VCH: Weinheim, Germany, 2004. (b) Sydnes, L. K. Chem. Rev. 2003,
103, 1133. (c) Ma, S. Chem. Rev. 2005, 105, 2829. (d) Krause, N.; Winter,
C. Chem. Rev. 2011, 111, 1994.
sence of 1.1 equiv of BF3 Et2O in toluene to afford 4a in
3
91% isolated yield within 20 min. It is worth mentioning
that, unlike Int-1a, the intermediate Int-1b cannot be
isolated under the reaction conditions.
(13) Pan, L.; Bi, X.; Liu, Q. Chem. Soc. Rev. 2013, 42, 1251.
(14) (a) Wan, Z.; Nelson, S. G. J. Am. Chem. Soc. 2000, 122, 10470.
(b) Liu, G.; Lu, X. Tetrahedron Lett. 2003, 44, 127. (c) Liu, Z.; Wasmuth,
A. S.; Nelson, S. G. J. Am. Chem. Soc. 2006, 128, 10352. (d) Piera, J.;
(16) (a) Wang, Z.; Bi, X.; Liao, P.; Liu, X.; Dong, D. Chem. Commun.
2013, 49, 1309–1311. (b) Xiong, T.; Li, Y.; Bi, X.; Lv, Y.; Zhang, Q.
Angew. Chem. 2011, 123, 7278–7281. Angew. Chem., Int. Ed. 2011, 50,
7140–7143. (c) Wang, Y.; Bi, X.; Li, W.; Li, D.; Zhang, Q.; Liu, Q.;
Ondon, B. S. Org. Lett. 2011, 13, 1722.
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Bi, X.; Liu, Q. Org. Lett. 2011, 13, 6536.
€
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B. D.; Liu, J.; Liao, P.; Zhang, J.; Liu, Q.; Bi, X. Chem. Commun. 2012,
48, 8802. (b) Li, Q.; Wang, Y.; Fang, Z.; Liao, P.; Barry, B. D.; Che, G.;
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B
Org. Lett., Vol. XX, No. XX, XXXX

the six-membered structures of products 3 and 4 were
further established by the HSQC and HMBC studies of 3h
and 4a. As shown in Scheme 2, δ-lactam derivatives 3i and
3j, bearing a 1,3-dithian-2-ylidene unit, were obtained in 69
and 60% yields, respectively, by using substrates 1ab. Delight-
fully, 6-spiro-δ-lactams 3k and 3l could be also produced in
good yields by varying the propargyl alcohols 2.
Table 1. Synthesis of R-(1,3-Dithiolan-2-ylidene)
δ-Lactams 3/δ-Lactones 4
time
Ca product (min)
yieldb
(%)
entry
1
2
Scheme 2. Synthesis of δ-Lactam Derivatives 3iꢀ3ja
2a
R1 = Ph
R2 = Ph
R3 = Me
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
3a
4a
3b
4b
3c
4c
3d
4d
3e
4e
3f
20
20
20
45
20
40
20
60
20
50
20
30
20
120
20
70
88
91
88
95
83
96
79
88
86
80
61
45
67
61
75
65
2
3
2b R1 = Ph
R2 = 2-ClC6H4
4
R3 = Me
5
2c
R1 = Ph
R2 = 3-ClC6H4
R3 = Me
6
7
2d R1 = Ph
R2 = 4-ClC6H4
8
R3 = 4-ClC6H4
9
2e
2f
R1 = Ph
R2 = Ph
R3 = Ph
10
11
12
13
14
15
16
a Isolated yields.
R1 = Ph
R2 = Ph
Further studies disclosed that when the carboxyl group
of 1b was changed to an acetyl group (1c), the R-acetyl
ketene dithioacetals 1c reacted with phenyl-substituted
tertiary propargyl alcohols 2 to rapidly produce function-
alized gem-dialkylthio vinylallenes (Int-c) under FeBr3
catalysis.15a Interestingly, when TFA was added to this
reaction mixture, which was allowed to sit for an addi-
tional 30 min, a series of indene derivatives were generated
in moderate to good yields (Table 2).18 The structure of 5a
R3 = Ethyl
4f
2g
R1 = 4-FC6H4
R2 = Ph
R3 = Me
3g
4g
3h
4h
2h R1 = 4-MeOC6H4
R2 = Ph
R3 = Me
1
was resolved from H NMR, 13C NMR, HMBC, and
a Conditions A: 1a (1.0 mmol), 2 (1.2 mmol), BF3 Et2O (1.1 mmol),
1,2,3-TCP (2.0 mL), and TFA (4.0 mmol) at room temperature. Condi-
3
HRMS spectral data, and that for 5e was unambiguously
confirmed from X-ray diffraction analysis (Figure 2).
tions B: 1b (1.0 mL), 2 (1.2 mmol), BF3 Et2O (1.1 mmol), and toluene
(2.0 mL) at room temperature. b Isolated yields.
3
Next, the reaction scope of the ketene dithioacetal 1a or
1b was explored with respect to the propargylic alcohols
2aꢀh under the optimal reaction conditions (Conditions A
for R-alkylidene δ-lactams 3; Conditions B for R-alkylidene
δ-lactones 4). The results as summerized in Table 1 showed
that 1a/1b reacted efficiently with 2aꢀe to afford the corres-
ponding R-(1,3-dithiolan-2-ylidene) δ-lactams 3aꢀe/δ-lactones
4aꢀe in good yields (entries 1ꢀ10). However, when ethyl
was introduced to the C3-position of 2 (e.g., 2f), only a
moderate yield of 3f/4f could be obtained, which might be
due to the steric effect of the ethyl group (entries 11, 12). It is
worth noting that the yields of 3gꢀh/4gꢀhwere significantly
lower than those of 3aꢀc/4aꢀc (entries 13ꢀ16). This is
indicative of the remarkable influence of substituent groups
linking the phenyl at the C1 position of 2 on the synthesis of
R-(1,3-dithiolan-2-ylidene) δ-lactams/δ-lactones. Notably,
Table 2. Synthesis of Indenes 5
entry
R2
R3
Ar
5
yield (%)a
1
2
3
4
5
Ph
4-ClC6H4
4-MeC6H4 CH3
CH3
Ph
Ph
Ph
5a
5b
5c
78
75
70
61
67
CH3
Ph
CH3
4-MeOC6H4 5d
5e
4-ClC6H4
4-ClC6H4 Ph
a Isolated yields.
Org. Lett., Vol. XX, No. XX, XXXX
C

by the interaction with a Lewis acid [LA], so that the
incipient propargylic carbocation B is formed by the loss of
[LA]OH which would subsequently accept a Hþ to regen-
erate the [LA]. A resonance balance between propargylic
carbocation B and allenic carbocation B0 exists,19 and
here the latter is preferably attacked by the electron-rich
R-carbon of ketene dithioacetals (1), leading to the allenic
amides, acids, and ketonesC (Int-a, -b, -c), withthe conseq-
uent loss of Hþ at this stage. For the allenic amides,
protonation takes place on the central carbon of the allenic
system, and the nitrogen atom of the amino group attacks
the tertiary carbocation in an intramolecular nucleophilic
additionfashion toproduce the δ-lactams3. Forthe allenic
acids, the allene is activated by coordination to a Lewis acid
prior to the subsequent intramolecular nucleophilic attack
by the carbonyl oxygen of the acid group to form the
δ-lactones 4. Analogous to the δ-lactams, the formation
of indene 5 also involves the initial protolactonization of the
central carbon of the allenic system to give intermediate D
which then undergoes cyclization through electrophilic
aromatic substitution to yield the target 5.
Figure 2. Crystal structure of compound 5e.
Scheme 3. A Plausible Reaction Mechanism
In summary, we have developed a novel route to gen-
erate δ-lactams and δ-lactones from in situ generated 3,4-
dienamides and acids under mild acid-mediated reaction
conditions. Further studies disclosed that indenes can be
prepared by choosing R-acetyl ketene dithioacetal. Efforts
are ongoing in extending the scope of this methodology.
Acknowledgment. This work was supported by the NSFC
(21172029, 21202016), FRFCU (10JCXK005), and Research
Fund for the Doctoral Program of Higher Education of China
(RFDP 20100043120008).
Supporting Information Available. Experimental pro-
cedures; 1H NMR, 13C NMR, HSQC, and HMBC spec-
troscopic data for all compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
On the basis of these experimental findings and our
previous work,14,15 plausible reaction mechanisms for the
formation of δ-lactams (3), δ-lactones (4), and indenes (5)
are proposed (Scheme 3). First, the ꢀOH of 2 is polarized
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The authors declare no competing financial interest.
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D
Org. Lett., Vol. XX, No. XX, XXXX