Intramolecular Keto Lactam Condensation: A Convenient and Straightforward Approach to Bicyclic Vinylogous Lactams

Article abstract of DOI:10.1002/ejoc.201701060

Although the aldol condensation is a well-known reaction, the aza-type aldol condensation, namely, the intramolecular condensation of common keto lactams leading to bicyclic vinylogous lactams, is a highly demanding transformation, with potential applicat

Full text of DOI:10.1002/ejoc.201701060

A Journal of
Accepted Article
Title: Intramolecular Keto-lactam Condensation: A Convenient and
Straightforward Approach to Bicyclic Vinylogous Lactams
Authors: Pei-Qiang Huang and Ting Fan
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10.1002/ejoc.201701060
European Journal of Organic Chemistry
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Intramolecular Keto-lactam Condensation: A Convenient and
Straightforward Approach to Bicyclic Vinylogous Lactams
Pei-Qiang Huang,* [a,b] and Ting Fan[a]
Abstract: While aldol condensation is a well-known reaction, the aza-
type aldol condensation, namely, intramolecular condensation of
common keto-lactams leading to bicyclic vinylogous lactams is a
highly demanding yet challenging transformation in both organic
synthesis and medicinal chemistry. The known methods for this type
of cyclization require several steps. We disclose in this paper a
straightforward approach that consists of the in situ formation of silyl
enol ether with tert-butyldimethylsilyl trifluoromethanesulfonate
(TBDMSOTf), lactam activation with triflic anhydride (Tf2O), and
tandem cyclocondensation reaction. The reaction can run in a one-
pot manner or in a two-step fashion both under mild conditions. The
yields for the one-pot version are 52-80%. In some cases, the two-
step version afforded higher overall yields (44-85%) as compared with
those of the one-pot version.
Figure 1. Structures of bicyclic vinylogous lactams and structurally related
medicinal agents
Introduction
Bicyclic vinylogous lactams of types A and B (Fig. 1) are found as
key structural features in medicinal agents,[1-3] and serve as
versatile intermediates for the synthesis of alkaloids.[4,5] For
example, benzo[c]quinolizin-3-ones of generic structure 1,[2a-c] 19-
nor-10-azasteroids such as 2,[2d] phenanthridin-3-one derivatives
3,[3a] and 6-azasteroids 4[3b] represent four classes of potent and
selective non-steroidal inhibitors of the type 1 human isozyme of
5-reductase (5R-1).
Retrosynthetically,
a
straightforward approach for the
construction of the structural motifs A and B would be the
intramolecular keto-amide condensation reaction of keto-lactams
C and D, respectively (Fig. 2). However, this attractive route is
hampered by the low electrophilicity of amide carbonyl. For
example, to bring about the cyclization of keto-lactam 5 to
vinylogous lactam 8 (Scheme 1), about two dozen different
methods have been investigated, but all were unsuccessful.[6]
To tackle this problem, two stepwise alternatives have been
developed. The first one was developed by Heathcock and co-
workers during the first total synthesis of a Daphniphyllum alkaloid,
methyl homodaphniphyllate.[4] This method involves the pre-
conversion of lactam 5 to thiolactam 7 with Lawesson's reagent 6,
followed by in situ S-ethylation with Meerwein's reagent, and
NEt3-promoted cyclization to give vinylogous
Figure 2. One-step retrosynthetic analysis of bicyclic vinylogous lactam.
lactam 8 (Scheme 1, eq. 1). The second approach, developed by
Danishefsky and co-workers, is based on the diazo-thioamide
coupling reaction.[5] This method consists of thionation of lactams
9,
aza-conjugate
addition
of
thiolactams
10
with
diazomethylvinylketone 11, rhodium acetate promoted
cyclocondensation, and desulfurization with Raney-Nickel to
generate bicyclic vinylogous lactams 13 (Scheme 1, eq. 2). A
longer but more general version of the Danishefsky’s method[5]
involves the stepwise incorporation of the diazoketone moiety by
aza-conjugate addition with methy acrylate, followed by
saponification, mixed anhydride formation, and conversion to the
diazoketone 12. Danishefsky’s method has been applied to the
synthesis of iso-A58365A[5a] and indolizomycin.[5b,c] By replacing
Meerwein's reagent with dimethyl sulfate, Heathcock’s method
has been applied to the synthesis of phenanthridin-3-one
derivatives,[3a] and extended by Guarna and co-workers[2b] to allow
the syntheses of a series of benzo[c]quinolizin-3-ones.[2b,c]
[a]
Prof. Dr. P.–Q. Huang, T. Fan
Department of Chemistry and The Key Laboratory for Chemical
Biology of Fujian Province, iChEM (Collaborative Innovation Center
of Chemistry for Energy Materials), College of Chemistry and
Chemical Engineering, Xiamen University, Xiamen, Fujian 361005
(P.R. China)
[b]
State Key Laboratory of Elemento-Organic Chemistry, Nankai
University, Tianjin 300071, P. R. China
E-mail: pqhuang@xmu.edu.cn; Homepage URL:
http://121.192.177.81:90/huangpeiqiang/en/Index.asp
Supporting information for this article is given via a link at the end of
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15a in 56% yield. Next, effects of base additives were examined.
While yield was not improved by the introduction of Hünig base (i-
Pr2NEt) or 2-fluoropyridine as a base additive, running the
reaction in the presence of 1.2 equiv of triethylamine or 2,6-di-tert-
butyl-4-methylpyridine (DTBMP)[12,9u] furnished the tricyclic
vinylogous lactam 15a in 74% and 82% isolated yield,
respectively. Thus, DTBMP was employed as the base additive
for the subsequent investigations.
Scheme 1. Heathcock’s and Danishefsky’s methods.
Both Heathcock’s and Danishefsky’s methods as well as the
extended version, although robust, require the pre- transformation
of lactams to thiolactams. Moreover, all of those methods use
hazardous reagents such as Lawesson's reagent, dimethyl
sulfate, diazo compounds, and Raney-Nickel. Thus, it is highly
desirable to develop convenient methods for the direct
transformation of keto-lactams to bicyclic vinylogous lactams.
In recent years, the direct transformation of amides/ lactams
has emerged as an active research area.[7] Among the many
methods developed so far,[8-10] the strategy based on the
activation of amides/ lactams with triflic anhydride (Tf2O) is quite
Scheme 2. Two-step cyclization reaction of 14a.
Encouraged by these results,
a one-pot reaction was
attractive for its versatility and chemoselectivity.[9,10] In this context, envisaged. Thus 14a was successively treated with TBDMSOTf
Bélanger and co-workers reported the Tf2O-mediated two-step
aldehyde-amides/ lactams cyclization to afford β-
(1.5 equiv)/ trimethylamine (3.0 equiv) and Tf2O (1.1 equiv) at 0
C to r.t. In this one-pot manner, 15a was obtained in 72% yield
(80% based on the recovered starting material) (Table 1, entry 1).
Screening six bases other than TEA showed that the use of TEA
as a base gave the highest yield (Table 1, entry 1 versus entries
2-7). A quick examination of effects of equivalents of both TEA
and TBDMSOTf on the reaction (Table 1, entries 8-11) allowed
identifying the optimal conditions, consisting of using 2.0 equiv of
TEA and 1.5 equiv of TBDMSOTf. Under the optimized conditions,
15a was obtained in 76% yield (Table 1, entry 9). It is worth noting
that when DTBMP or 4-t-Bu-pyridine was used as a base in
combination with TBDMSOTf, the formation of silyl enol ether was
not observed. The observation implicated that silyl enol ether is
the reactive intermediate for the subsequent cyclization reaction.
The intramolecular condensation reaction was extended to the
higher homologue 14b. Thus, under the optimal conditions, 14b
was converted to the desired vinylogous lactam 15b in 72% yield
(78% based on the recovered starting material, BRSM) (Table 2,
entry 2). By the two-step version SEE2 and lactam 15b were
obtained in yields of 86% and 83%, respectively.
formylenamines (vinylogous formamides).[9u,v] In one case, a
phenyl keto-amide was employed as the substrate affording a
monocyclic vinylogous amide.[9u] Our group[10] also developed, on
one hand, a Tf2O/ halogen-source-mediated cyclization of keto-
lactams to generate halo-tropinone derivatives,[10a] and on the
other hand, the amide/ lactam-based aza-Knovenagel-type
condensation reaction of both tert- and sec-amides/ lactams.[10b,h]
The reported results included three examples of intermolecular
condensation of methyl ketones with N-benzyl-γ-lactam.[10h] In
spite of these progresses, the intramolecular keto-lactam
condensation reaction remains elusive. In this article, we report
the Tf2O-mediated one-pot
intramolecular keto-lactam
condensation reaction for the synthesis of bicyclic vinylogous
lactams.
Results and Discussion
We opted for the known keto-lactam 14a[11] as the first substrate
for our initial investigation. For the cyclocondensation of keto-
lactam 14a, a two-step cyclization method was first investigated
(Scheme 2). For this purpose, keto-lactam 14a was converted to
the corresponding silyl enol ether SEE1 by reacting with
TBDMSOTf/ trimethylamine (TEA), which afforded silyl enol ether
SEE1 in 86% yield. Pleasantly, simple exposure of SEE1 to Tf2O
in CH2Cl2 at 0 °C ~ r.t. produced the desired cyclization product
Next, we focused on the cyclization of common keto-lactams
14c – 14f. Under the one-pot cyclization conditions [TEA (2.0
equiv), TBDMSOTf (1.5 equiv), CH2Cl2; Tf2O (1.1 equiv), 0 C, to
r.t.], the reaction of 14c afforded the desired vinylogous lactam
15c in 48% yield (55% BRSM) (Table 2, entry 3).
Alternatively, the two-step procedure was also examined,
which afforded silyl enol ether SEE3a,b and the cyclization
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Table 1. Optimization of conditions for the one-pot cyclization
reaction of 14a.
Entry
Base (equiv)
TBDMSOTf
(equiv)
Yield[a]
1
2
TEA (3.0)
DABCO (3.0)
DTBMP (3.0)
4-t-Bu-pyridine (3.0)
2,4,6-Collidine (3.0)
2,6-lutidine (3.0)
DBU (3.0)
2.0
2.0
2.0
3.0
2.0
2.0
2.0
2.5
1.5
1.5
1.0
72%
48%
0[b]
3
4
0[b]
5
68%
70%
65%
73%
76%
63%
53%
6
7
8
TEA (3.0)
9
TEA (2.0)
10
11
TEA (2.0)
TEA (2.0)
[a] Isolated yield. [b] Silyl enol ether was not formed.
product 15c in 83%, and 68% yield, respectively. Similarly,
following the one-pot procedure, the cyclization of keto-
lactam 14d gave vinylogous lactam 15d in 42% yield (52%
BRSM) (Table 2, entry 4). The yields of the two-step method
were 85% (for silyl enol ether SEE4a,b) and 65% (for 15d),
respectively. Comparing with the reactions described in entry
4 (Table 2), where the products could be coined as aza-
Robinson annulation products,[13] the cyclization of keto-
lactam 14e is interesting. Indeed, when subjecting 14e to the
one-pot cyclization conditions, two regioisomeric non-aza-
Robinson annulation products 15e-a (30%) and 15e-b (23%),
resulted from terminal SEE5a and internal silyl enol ethers
SEE5b, respectively, were obtained in a combined yield of
53% (Table 2, entry 5). In this case, the two-step protocol
resulted in a lower overall yield. Finally, the cyclization
reactions of phenyl keto-lactams 14f and 14g were examined.
By the one-pot procedure, the reaction of 14f afforded 15f in
65% yield (Table 2, entry 6). In this case, the two-step
method afforded a higher overall yield (85%). Similarly, the
direct cyclization of 14g provided 15g in 63%yield (Table 2,
entry 7), while the two-step method afforded 15g in an overall
yield of 73%.
[a] Isolated yield of the one-pot method: i) TBDMSOTf, Et3N, r.t., CH2Cl2; ii)
Tf2O 0 C to r.t. [b] Yield based on the recovered starting materials. [c] Isolated
yield of the two-step method: (1) TBDMSOTf, Et3N, CH2Cl2, r.t.; (2) DTBMP,
Tf2O, 0 C to r.t. [d] Combined isolated yield of SEEa (terminal) and SEEb
(internal), regioisomeric ratio determined by 1H NMR. [e] Yield based on the
recovered starting materials of the two-step method.
Mechanistic considerations
A plausible mechanism of the keto-lactam condensation is
depicted in Scheme 3. The first step of the reaction involves the
formation of silyl enol ether. In the case where the starting ketone
contains two kind of acidic –hydrogen, two regioisomeric silyl
enol ethers, terminal (SEEa) and internal (SEEb) are formed.
Then the lactam carbonyl reacts with Tf2O to generate highly
electrophilic O-triflyl imidate salts E and F, which undergo a rapid
intramolecular addition with nucleophilic silyl enol ether partners
to generate N,O-acetals G and H. Then, the nitrogen lone pair-
assisted elimination of ¯OTf occurs spontaneously generating
iminium triflate intermediates I and J. Finally, base-promoted
tautomerization affords the corresponding vinylogous lactams 15.
Table 2. Intramolecular keto-lactam condensation leading to bicyclic
vinylogous lactams.
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General method: Melting points were determined on a Büchi M560
Automatic Melting Point apparatus and are uncorrected. Infrared spectra
were measured with a Nicolet Avatar 360 FT-IR spectrometer using film/
KBr pellet techniques. 1H NMR and 13C NMR spectra were recorded in
CDCl3 or CD3OD on an instrument at 500/125 MHz or 400/100 MHz,
respectively. Chemical shifts () are reported in ppm and respectively
referenced to internal standard Me3Si. Mass spectra were recorded on a
Bruker Dalton ESquire 3000 plus LC-MS apparatus (ESI direct injection).
HRMS spectra were recorded on a 7.0T FT-MS apparatus. Tf2O was
distilled over phosphorus pentoxide and used within a week. THF was
distilled over sodium benzophenone ketyl under N2. Dichloromethane was
distilled over calcium hydride under N2.
Comparing the yield of 15c (48%) with that of 15g (63%) obtained
by the one-pot method allows concluding that the difference of
15% corresponds to the minor regioisomer SEE3b (SEE3a:
SEE3b = 85:15) that is unable to undergo a 4-(enolexo)-endo-trig
cyclization,[14] and yields back, after workup, the starting keto-
lactam 14c. It is also worthy of mention that silyl enol ethers SEE
are mixtures of geometric isomers.[15]
General procedure for intramolecular condensation of keto-lactams
14 (the one-pot method: General procedure A).
To a dried 10-mL round-bottom flask were added successively a tertiary
keto-lactams (0.25 mmol), dichloromethane (5 mL) and triethylamine (0.5
mmol) under an argon atmosphere. After being cooled to 0 °C, tert-
butyldimethylsilyl trifluoromethanesulfonate (TBDMSOTf) (0.375 mmol)
was added and the mixture was stirred at r.t. until the complete
consumption of starting material as indicated by TLC monitoring (ca. 15 h;
for 14g,h, overnight). To the resulting mixture, trifluoromethanesulfonic
anhydride (Tf2O) (0.275 mmol) were added at 0 °C. The mixture was
allowed warming-up and stirred at r.t. for 15 min. The reaction was
quenched with sat. NaHCO3, and the mixture was extracted with
dichloromethane (3× 5 mL). The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was
concentrated under reduced pressure. The residue was purified by flash
chromatography on silica gel to afford the desired vinylogous lactam 15.
General procedure for intramolecular condensation of keto-lactams
14 (the two-step method: General procedure B).
To a dried 10-mL round-bottom flask were added successively a tertiary
keto-lactams (0.5 mmol), dichloromethane (10 mL) and triethylamine (1.0
mmol) under an argon atmosphere. After being cooled to 0 °C, tert-
butyldimethylsilyl trifluoromethanesulfonate (TBDMSOTf) (0.75 mmol) was
added and the mixture was stirred at r.t. until the complete consumption of
starting material as indicated by TLC monitoring. The reaction was
quenched with sat. NaHCO3, and the mixture was extracted with
dichloromethane (3× 10 mL). The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was
concentrated under reduced pressure. The residue was purified by flash
chromatography on silica gel to afford the desired silyl enol ether. To a
dried 10-mL round-bottom flask containing silyl enol ether (0.25 mmol)
were added 4-methyl-2,6-di-tert-butylpyridine (DTBMP) (0.3 mmol) and
trifluoromethanesulfonic anhydride (Tf2O) (0.275 mmol) at 0 °C. The
mixture was allowed warming-up and stirred at r.t. for 15 min. The reaction
was quenched with sat. NaHCO3, and the mixture was extracted with
dichloromethane (3× 5 mL). The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was
concentrated under reduced pressure. The residue was purified by flash
chromatography on silica gel to afford the desired vinylogous lactam 15.
Scheme 3. Plausible mechanisms for the intramolecular keto-lactam
condensation leading to vinylogous lactams.
Conclusions
In summary, one-pot O-silylation - amide activation - cyclization
method has been developed for the direct cyclization to yield
bicyclic vinylogous lactams. In addition, a complementary two-
step version of the one-pot method has also been developed. The
method provides a ready access to diverse tricyclic and bicyclic
vinylogous lactams, which are as key structural features found in
medicinal agents, and versatile blocks for the synthesis of
alkaloids. We believe that this convenient solution to the
longstanding problem of the direct intramolecular condensation
reactions of common keto-lactams would find applications in
organic synthesis and medicinal chemistry.
2,3-Dihydropyrrolo[1,2-a]quinolin-5(1H)-one (15a). Following general
procedure A, the one-pot reaction of tertiary amide 14a (101 mg, 0.5 mmol)
afforded 15a (70 mg, yield: 76%) and the recovered starting material 14a
(ca. 5%). Following general procedure B, the two-step reaction afforded
silyl enol ether SEE1 and 15a in 86% and 82% yield, respectively. In
addition, about 2% of starting material was observed. 15a: beige solid, Rf
= 0.4 (10% MeOH/ethyl acetate). Mp: 173-174 °C (lit.11 167-173 °C). IR
(film)max: 3468, 3378, 2958, 2842, 1626, 1599, 1555, 1497, 1469, 1427,
1306, 1262, 1152, 1066, 959, 835, 757, 620 cm-1; 1H NMR (500 MHz,
Experimental Section
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CD3OD) δ 8.12 (d, J = 8.2 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.34 – 7.22 (m,
2H), 6.03 (s, 1H), 4.09 (t, J = 7.3 Hz, 2H), 3.04 (t, J = 7.7 Hz, 2H), 2.28 –
2.18 (m, 2H) ppm; 13C NMR (1 25 MHz, CD3OD) δ 179.4, 158.9, 139.6,
133.2, 126.3, 125.9, 124.8, 117.5, 105.0, 51.8, 32.6, 21.5 ppm; HRMS
(ESI) m/z calcd for [C12H11NONa]+ (M + Na)+: 208.0733; found: 208.0731.
15e-b: pale yellow oil, Rf = 0.3 (10% MeOH/ethyl acetate). IR (film) max:
2932, 2858, 1635, 1545, 1268, 1170, 925, 678 cm-1; 1H NMR (500 MHz,
CDCl3) δ 3.43 (t, J = 9.9 Hz, 2H), 3.07 (t, J = 6.0 Hz, 2H), 2.89 (t, J = 6.4
Hz, 2H), 2.78 (t, J = 9.9 Hz, 2H), 2.06 (s, 3H), 1.83 – 1.77 (m, 2H), 1.68 –
1.62 (m, 2H) ppm; 13C NMR (125 MHz, CDCl3) δ 190.6, 162.3, 106.3, 52.9,
46.6, 28.6, 27.1, 25.5, 22.6, 19.6 ppm; HRMS (ESI) m/z calcd for
[C10H15NONa]+ (M + Na)+: 188.1046; found: 188.1040.
1,2,3,4-Tetrahydro-6H-pyrido[1,2-a]quinolin-6-one (15b). Following
general procedure A, the one-pot reaction of tertiary amide 14b (109 mg,
0.5 mmol) afforded 15b (72 mg, yield: 72%) and the recovered starting
material 14b (ca. 8%). Following general procedure B, the two-step
reaction afforded silyl enol ether SEE2 and 15b in 86% and 83% yield,
respectively. In addition, about 2% of starting material was observed. 15b:
beige solid, Rf = 0.4 (10% MeOH/ethyl acetate). Mp: 189-190 °C. IR (film)
(2,3,5,6-Tetrahydro-1H-pyrrolizin-7-yl)(phenyl)methanone
(15f).
Following general procedure A, the one-pot reaction of tertiary amide 14f
(58 mg, 0.25 mmol) afforded 15c (35 mg, yield: 65%) and the recovered
starting material 14f (ca. 15%). Following general procedure B, the two-
step reaction afforded silyl enol ether SEE6 and 15f in 89% and 95% yield,
respectively. 15f: Rf = 0.3 (10% MeOH/ethyl acetate). IR (film) max: 3053,
2925, 2854, 1680, 1445, 1260, 1049, 876, 704, 658 cm-1; 1H NMR (500
MHz, CD3OD) δ 7.41 – 7.36 (m, 5H), 3.58 (t, J = 9.2 Hz, 2H), 3.35 – 3.32
(m, 2H), 3.22 (t, J = 9.2 Hz, 2H), 2.22 – 2.15 (m, 2H), 2.09 – 1.98 (m, 2H)
ppm; 13C NMR (125 MHz, CD3OD) δ 189.0, 178.0, 143.7, 130.2, 129.2
(2C), 128.2 (2C), 104.9, 32.8, 28.6 (2C), 26.7 (2C) ppm; HRMS (ESI) m/z
calcd for [C14H15NONa]+ (M + Na)+: 236.1046; found: 236.1049.

max: 3410, 3098, 3068, 2939, 1619, 1596, 1567, 1494, 1470, 1313, 1173,
1075, 1036, 845, 763 cm-1; 1H NMR (500 MHz, CD3OD) δ 8.19 (d, J = 8.1
Hz, 2H), 7.63 – 7.57 (m, 2H), 7.37 – 7.31 (m, 1H), 6.00 (s, 1H), 4.01 (t, J
= 6.4 Hz, 2H), 2.86 (t, J = 6.5 Hz, 2H), 2.00 – 2.00 (m, 2H), 1.82 – 1.75 (m,
2H) ppm; 13C NMR (125 MHz, CD3OD) δ 178.1, 155.5, 142.4, 133.3, 127.0,
126.3, 125.1, 116.9, 110.0, 47.3, 31.1, 23.7, 19.4 ppm; HRMS (ESI) m/z
calcd for [C13H13NONa]+ (M + Na)+: 222.0889; found: 222.0883.
2,3,5,6-Tetrahydroindolizin-7(1H)-one
(15c).
Following
general
(2,3,5,6,7,8-Hexahydroindolizin-1-yl)(phenyl)methanone
(15g).
procedure A, the one-pot reaction of tertiary amide 14c (39 mg, 0.25 mmol)
afforded 15c (16 mg, yield: 48%) and the recovered starting material 14c
(ca. 13%). Following general procedure B, the two-step reaction afforded
silyl enol ether SEE3 and 15c in 83% and 68% yield, respectively. In
addition, about 11% of starting material was observed. 15c: Rf = 0.3 (10%
MeOH/ethyl acetate). IR (film) max: 2933, 2843, 1668, 1575, 1418, 1264,
1171, 1098 cm-1; 1H NMR (500 MHz, CDCl3) δ 5.00 (s, 1H), 3.46 (t, J = 7.9
Hz, 2H), 3.38 (t, J = 6.9 Hz, 2H), 2.69 (t, J = 7.7 Hz, 2H), 2.51 (t, J = 7.9
Hz, 2H), 2.01 – 2.04 (m, 2H) ppm; 13C NMR (125 MHz, CDCl3) δ 190.9,
169.2, 93.3, 53.3, 45.4, 35.1, 31.8, 21.3 ppm; HRMS (ESI) m/z calcd for
[C8H11NONa]+ (M + Na)+: 160.0733; found: 160.0733.
Following general procedure A, the one-pot reaction of tertiary amide 14g
(58 mg, 0.25 mmol) afforded 15c (35 mg, yield: 65%) and the recovered
starting material 14g (ca. 15%). Following general procedure B, the two-
step reaction afforded silyl enol ether SEE7 and 15g in 83% and 88% yield,
respectively. 15g: Rf = 0.3 (10% MeOH/ethyl acetate). IR (film) max: 3056,
2920, 2843, 1503, 1501, 1444, 1269, 1175, 1088, 707 cm-1; 1H NMR (500
MHz, CD3OD) δ 7.40 – 7.31 (m, 5H), 3.58 (t, J = 9.6 Hz, 2H), 3.23 (t, J =
6.1 Hz, 2H), 2.85 (t, J = 9.6 Hz, 2H), 2.28 – 2.19 (m, 2H), 1.80 – 1.75 (m,
2H), 1.52 – 1.47 (m, 2H) ppm; 13C NMR (126 MHz, CD3OD) δ 188.7, 169.1,
144.9, 130.0, 129.3 (2C), 128.0 (2C), 108.8, 54.1, 47.2, 27.4, 27.3, 23.0,
20.0 ppm; HRMS (ESI) m/z calcd for [C15H17NONa]+ (M + Na)+: 250.1202;
found: 250.1198.
3,4,6,7,8,9-Hexahydro-2H-quinolizin-2-one (15d). Following general
procedure A, the one-pot reaction of tertiary amide 14d (43 mg, 0.25 mmol)
afforded 15c (16 mg, yield: 42%) and the recovered starting material 14d
(ca. 19%). Following general procedure B, the two-step reaction afforded
silyl enol ether SEE4 and 15d in 85% and 65% yield, respectively. In
addition, about 12% of starting material was observed. 15d: Rf = 0.3 (10%
MeOH/ethyl acetate). IR (film)max: 2939, 2846, 1617, 1552, 1501, 1312,
1245, 1168, 1114, 803, 630 cm-1; 1H NMR (500 MHz, CDCl3) δ 5.00 (s,
1H), 3.40 (t, J = 7.7 Hz, 2H), 3.21 (t, J = 6.1 Hz, 2H), 2.47 – 2.42 (m, 4H),
1.90 – 1.84 (m, 2H), 1.70 – 1.63 (m, 2H) ppm; 13C NMR (125 MHz, CDCl3)
δ 190.6, 163.7, 98.5, 50.5, 50.3, 35.2, 29.8, 23.2, 19.7 ppm; HRMS (ESI)
m/z calcd for [C9H13NONa]+ (M + Na)+: 174.0889; found: 174.0883.
Acknowledgements
The authors are grateful for financial support from the National
Natural Science Foundation of China (21332007 and 21672176)
and the Program for Changjiang Scholars and Innovative
Research Team in University of Ministry of Education, China.
Keywords: Cyclization Reaction • Keto-lactams • Condensation
Reaction • Heterocycles • Amides
1,2,3,4,7,8-Hexahydropyrido[1,2-a]azepin-9(6H)-one (15e-a) and 1-
(2,3,5,6,7,8-Hexahydroindolizin-1-yl)ethan-1-one (15e-b). Following
general procedure A, the one-pot reaction of tertiary amide 14e (46 mg,
0.25 mmol) afforded 15e-a (13 mg, yield: 30%) and 15e-b (10 mg, yield:
23%) in a combined yield of 53%. Following general procedure B, the two-
step reaction afforded silyl enol ether SEE5, 15e-a and 15e-b in 70%, 38%
and 24% yield, respectively.
[1]
a) S. Aggarwal, S. Thareja, A. Verma, T. R. Bhardwaj, M. Kumar,
Steroids 2010, 75, 109-153; b) S. M. Geddis, L. Carro, J. T. Hodgkinson,
D. R. Spring, Eur. J. Org. Chem. 2016, 5799-5802; c) F. Salvaggio, J. T.
Hodgkinson, L. Carro, S. M. Geddis, W. R. J. D. Galloway, M. Welch, D.
R. Spring, Eur. J. Org. Chem. 2016, 434-437; d) D. A. Heredia, E. L.
Larghi, T. S. Kaufman, Eur. J. Org. Chem. 2016, 1397-1404.
15e-a: pale yellow oil, Rf = 0.27 (10% MeOH/ethyl acetate). IR (film) max
:
2920, 2850, 1543, 1444, 1349, 1285, 1235, 1139 cm-1; 1H NMR (500 MHz,
CDCl3) δ 4.95 (s, 1H), 3.45 – 3.41 (m, 2H), 3.30 (t, J = 6.2 Hz, 2H), 2.57 (t,
J = 6.7 Hz, 2H), 2.42 (t, J = 6.5 Hz, 2H), 2.02 –1.96 (m, 2H), 1.83 – 1.78
(m, 2H), 1.68 – 1.63 (m, 2H) ppm; 13C NMR (125 MHz, CDCl3) δ 198.3,
158.1, 101.8, 56.7, 52.0, 41.4, 32.5, 23.6, 23.2, 19.8 ppm; HRMS (ESI)
m/z calcd for [C10H15NONa]+ (M + Na)+: 188.1046; found: 188.1045.
[2]
a) A. Guarna, F. Machetti, E. G. Occhiato, D. Scarpi, A. Comerci, G.
Danza, R. Mancina, M. Serio, K. Hardy, J. Med. Chem. 2000, 43, 3718-
3735; b) A. Guarna, E. Lombardi, F. Machetti, E. G. Occhiato, D. Scarpi,
J. Org. Chem. 2000, 65, 8093-8095; c) E. G. Occhiato, A. Ferrali, G.
Menchi, A. Guarna, G. Danza, A. Comerci, R. Mancina, M. Serio, G.
Garotta, A. Cavalli, M. De Vivo, M. Recanatini, J. Med. Chem. 2004, 47,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701060
European Journal of Organic Chemistry
FULL PAPER
3546-3560; d) A. Guarna, E. G. Occhiato, F. Machetti, A. Marrucci, G.
Bechara, G. Pelletier, A. B. Charette, Nat. Chem. 2012, 4, 228-234; r) S.-
L. Cui, J. Wang, Y.-G. Wang, J. Am. Chem. Soc. 2008, 130, 13526-
13527; s) Q.-L. Dong, G.-S. Liu, H.-B. Zhou, L. Chen, Z.-J. Yao,
Tetrahedron Lett. 2008, 49, 1636-1640; t) M. Movassaghi, M. D. Hill, O.
K. Ahmad, J. Am. Chem. Soc. 2007, 129, 10096-10097; u) G. Bélanger,
R. Larouche-Gauthier, F. Menard, M. Nantel, F. Barabe, J. Org. Chem.
2006, 71, 704-712; (v) G. Bélanger, R. Larouche-Gauthier, F. Ménard,
M. Nantel, F. Barabé, Org. Lett. 2005, 7, 4431-4434; (w) P. Magnus, L.
Gazzard, L. Hobson, A. H. Payne, T. J. Rainey, N. Westlund, V. Lynch,
Tetrahedron 2002, 58, 3423-3443.
Danza, M. Serio, P. Paoli, J. Med. Chem. 1997, 40, 3466-3477.
[3]
a) R. A. Mook, K. Lackey, C. Bennett, Tetrahedron Lett. 1995, 36, 3969-
3972; b) S. V. Frye, C. D. Haffner, P. R. Maloney, R. A. Mook, G. F.
Dorsey, R. N. Hiner, C. M. Cribbs, T. N. Wheeler, J. A. Ray, J. Med.
Chem. 1994, 37, 2352-2360.
[4]
[5]
a) C. H. Heathcock, S. K. Davidsen, S. G. Mills, M. A. Sanner, J. Org.
Chem. 1992, 57, 2531-2544; b) C. H. Heathcock, S. K. Davidsen, S. Mills,
M. A. Sanner, J. Am. Chem. Soc. 1986, 108, 5650-5651.
a) F. G. Fang, M. Prato, G. Kim, S. J. Danishefsky, Tetrahedron Lett.
1989, 30, 3625-3628; b) G. Kim, M. Y. Chu-Moyer, S. J. Danishefsky, J.
Am. Chem. Soc. 1990, 112, 2003-2005; c) G. Kim, M. Y. Chu-Moyer, S.
J. Danishefsky, G. K. Schulte, J. Am. Chem. Soc. 1993, 115, 30-39.
See reference/ note 24 in ref. 4a.
[10] a) S.-Y. Huang, Z. Chang, S.-C. Tuo, L.-H. Gao, A.-E Wang, P.-Q. Huang,
Chem. Commun. 2013, 49, 7088-7090; b) P.-Q. Huang, W. Ou, K.-J.
Xiao, A.-E Wang, Chem. Commun. 2014, 50, 8761–8763.; c) P.-Q.
Huang, H. Geng, Y.-S. Tian, Q.-R. Peng, K.-J. Xiao, Sci. China Chem.
2015, 58, 478-482; d) J.-F Zheng, Z.-X. Xie, X. Chen, P.-Q. Huang, Acta
Chim. Sinica 2015, 73, 705-715; e) P.-Q. Huang, Y. Wang, K.-J. Xiao,
Y.-H. Huang, Tetrahedron 2015, 71, 4248-4254; f) P.-Q. Huang, Y.-H.
Huang, H. Geng, J.-L. Ye, Sci. Rep. 2016, 6, 28801; g) Q.-W. Lang, X.-
N. Hu, P.-Q. Huang, Sci. China Chem. 2016, 59, 1638-1644; h) P.-Q.
Huang, W. Ou, Eur. J. Org. Chem. 2017, 582-592.
[6]
[7]
For reviews on the direct transformation of amides, see: a) T. Sato, N.
Chida, J. Syn. Org. Chem. Jap. 2016, 74, 599-610; b) D. Kaiser, N.
Maulide, J. Org. Chem. 2016, 81, 4421-4428; c) V. Pace, S. Monticelli,
K. de la Vega-Hernandez, L. Castoldi, Org. Biomol. Chem. 2016, 14,
7848-7854; d) V. Pace, W. Holzer, B. Olofsson, Adv. Synth. Catal. 2014,
356, 3697-3736; e) T. Sato, N. Chida, Org. Biomol. Chem. 2014, 12,
3147-3150; f) S. A. Ruider, N. Maulide, Angew. Chem. Int. Ed. 2015, 54,
13856-13858.
[11] C. P. Jones, K. W. Anderson, S. L. Buchwald, J. Org. Chem. 2007, 72,
7968-7973.
[8]
a) T. Slagbrand, G. Kervefors, F. Tinnis, H. Adolfsson, Adv. Synth. Catal.
2017, 359, 1990-1995; b) T. Slagbrand, A. Volkov, P. Trillo, F. Tinnis, H.
Adolfsson, ACS Cat. 2017, 7, 1771-1775; c) Á. L. Fuentes de Arriba, E.
Lenci, M. Sonawane, O. Formery, D. J. Dixon, Angew. Chem., Int. Ed.
2017, 56, 3655-3659; d) P. W. Tan, J. Seayad, D. J. Dixon, Angew.
Chem., Int. Ed. 2016, 55, 13436-13440; e) P.-Q. Huang, W. Ou, F. Han,
Chem. Commun. 2016, 52, 11967-11970; f) S. Katahara, S. Kobayashi,
K. Fujita, T. Matsumoto, T. Sato, N. Chida, J. Am. Chem. Soc. 2016, 138,
5246-5249; g) M. Nakajima, T. Sato, N. Chida, Org. Lett. 2015, 17, 1696-
1699; h) A. W. Gregory, A. Chambers, A. Hawkins, P. Jakubec, D. J.
Dixon, Chem. Eur. J. 2015, 21, 111-114; i) M. Nakajima, Y. Oda, T. Wada,
R. Minamikawa, K. Shirokane, T. Sato, N. Chida, Chem. Eur. J. 2014, 20,
17565-17571; j) M. Yoritate, T. Meguro, N. Matsuo, K. Shirokane, T. Sato,
N. Chida, Chem. Eur. J. 2014, 20, 8210-8216; k) K. Shirokane, T. Wada,
M. Yoritate, R. Minamikawa, N. Takayama, T. Sato, N. Chida, Angew.
Chem., Int. Ed. 2014, 53, 512-516; l) Y. Yanagita, H. Nakamura, K.
Shirokane, Y. Kurosaki, T. Sato, N. Chida, Chem. Eur. J. 2013, 19, 678-
684; m) K. Shirokane, Y. Kurosaki, T. Sato, N. Chida, Angew. Chem., Int.
Ed. 2010, 49, 6369-6372; n) Y. Oda, T. Sato, N. Chida, Org. Lett. 2012,
14, 950-953. For amide activation in form of imides, see: (o) V. Barbier,
J. Marrot, F. Couty, O. R. P. David, Eur. J. Org. Chem. 2016, 549–555;
p) R. M. de Figueiredo, R. Fröhlich, M. Christmann, Angew. Chem. Int.
Ed. 2007, 46, 2883-2886.
[12] a) L.-y. Chen, L. Ghosez, Tetrahedron Lett. 1990, 31, 4467-4470; b) A.
G. Anderson, P. J. Stang, J. Org. Chem. 1976, 41, 3034-3036.
[13] Danishefsky’s and Heathcock’s methods have been coined aza-Robinson
annulation.[5,2b,c]
[14] J. E. Baldwin, M. J. Lusch, Tetrahedron 1982, 38, 2939-2947.
[15] N. E. Pratt, K. F. Albizati, J. Org. Chem. 1990, 55, 770-773.
[9]
a) A. de la Torre, D. Kaiser, N. Maulide, J. Am. Chem. Soc. 2017, 139,
6578-6581; b) D. Kaiser, A. de la Torre, S. Shaaban, N. Maulide, Angew.
Chem. Int. Ed. 2017, 56, 5921-5925; c) V. Tona, B. Maryasin, A. de la
Torre, J. Sprachmann, L. Gonzalez, N. Maulide, Org. Lett. 2017, 19,
2662-2665; d) C. Hauduc, G. Bélanger, J. Org. Chem. 2017, 82, 4703-
4712; e) C. A. B. Rodrigues, A. Misale, F. Schiel, N. Maulide, Org. Biomol.
Chem. 2017, 15, 680-683; f) S. Regnier, W. S. Bechara, A. B. Charette,
J. Org. Chem. 2016, 81, 10348-10356; g) V. Pace, K. de la Vega-
Hernandez, E. Urban, T. Langer, Org. Lett. 2016, 18, 2750-2753; h) P.
Cyr, S. Regnier, W. S. Bechara, A. B. Charette, Org. Lett. 2015, 17, 3386-
3389; i) K. L. White, M. Mewald, M. Movassaghi, J. Org. Chem. 2015, 80,
7403-7411; j) W. S. Bechara, I. S. Khazhieva, E. Rodriguez, A. B.
Charette, Org. Lett. 2015, 17, 1184-1187; k) M. Mewald, J. W. Medley,
M. Movassaghi, Angew. Chem. Int. Ed. 2014, 53, 11634-11639; l) B.
Peng, D. Geerdink, C. Farès, N. Maulide, Angew. Chem. Int. Ed. 2014,
53, 5462-5466; m) B. Peng, D. Geerdink, N. Maulide, J. Am. Chem. Soc.
2013, 135, 14968-14971; n) G. Pelletier, A. B. Charette, Org. Lett. 2013,
15, 2290-2293; o) V. Valerio, D. Petkova, C. Madelaine, N. Maulide,
Chem. Eur. J. 2013, 19, 2606-2610; p) B. Peng, D. H. O'Donovan, I. D.
Jurberg, N. Maulide, Chem. Eur. J. 2012, 18, 16292-16296; q) W. S.
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By pass thioamides: Intramolecular
keto-lactam condensation leading to
bicyclic vinylogous lactams has been
achieved in either one-pot or in a two-
step manner. The method consists of
silyl enol ether formation and in situ
amide activation with triflic anhydride.
Synthetic Method
Pei-Qiang Huang,* and Ting Fan
Page No. – Page No.
Intramolecular Keto-lactam Condensation: A Convenient and
Straightforward Approach to Bicyclic Vinylogous Lactams

Heterocycles, synthetic method
This article is protected by copyright. All rights reserved.