Multifaceted α-Enaminone: Adaptable Building Block for Synthesis of Heterocyclic Scaffolds Through Conceptually Distinct 1,2-, 1,3-, 1,4-, and C-O Bond Forming Annulations

Article abstract of DOI:10.1021/acs.joc.7b00516

The new reactivity of α,β-unsaturated enaminones driven by their dual electronic attitude is reported. We introduce unexplored, α-enaminone synthones and reveal the unusual functionalities of these building blocks. The feasibility of this new concept is demonstrated in the direct functionalization of enaminone precursors, such as alkylation; 1,2- 1,3-, or 1,4-addition; and C-O bond formation. The general and potential applicability is presented through the collective synthesis of several important classes of heterocycles via controlled cyclizations of easily accessible common precursors. The rapid composition of novel key α-enaminone synthones yields an assembly of oxazines, azaspirones, quinolinones, and quinolinols in a regio- and chemoselective fashion.

Full text of DOI:10.1021/acs.joc.7b00516

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Article
A Multifaceted #-Enaminone - Adaptable Building Block for
Synthesis of Heterocyclic Scaffolds Through Conceptually
Distinct 1,2-, 1,3-, 1,4- and C-O Bond Forming Annulations
David Lankri, Ghassan Albarghouti, Mohamed Mahameed, and Dmitry Tsvelikhovsky
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 19 Jun 2017
Downloaded from http://pubs.acs.org on June 19, 2017
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A Multifaceted
α-Enaminone - Adaptable Building Block for Synthesis of
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Heterocyclic Scaffolds Through Conceptually Distinct 1,2-, 1,3-, 1,4- and C-O
Bond Forming Annulations
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David Lankri,† Ghassan Albarghouti,† Mohamed Mahameed and Dmitry Tsvelikhovsky*
The Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem,
Jerusalem 91120, Israel
dmitryt@ekmd.huji.ac.il
The new reactivity of
α,βꢀunsaturated enaminones driven by their "dual electronic attitude" is
reported. We introduce unexplored, αꢀenaminone synthones and reveal the unusual functionalities
of these building blocks. The feasibility of this new concept is demonstrated in the direct
functionalization of enaminone precursors, such as alkylation, 1,2ꢀ 1,3ꢀ or 1,4ꢀaddition, and CꢀO
bond formation. The general and potential applicability is presented through the collective synthesis
of several important classes of heterocycles via controlled cyclizations of easily accessible common
precursors. The rapid composition of novel key
αꢀenaminone synthones yields an assembly of
oxazines, azaspirones, quinolinones, and quinolinols in a regioꢀ and chemoselective fashion.
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INTRODUCTION
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Enaminoketones have attracted increased interest, particularly cyclic βꢀenaminones, which are
known as important intermediates and have proven to be versatile building blocks for the synthesis
of various heterocycles and natural products.1 The Nꢀ and βꢀpositions are their most reactive sites.2
Acting as bisnucleophiles, βꢀenaminones are suitable platforms for construction of heterocyclic
compounds, such as pyridine, pyrimidine, indolizidine, quinolizidine, and pyrrole derivatives,
which are common motifs in alkaloid structures.3
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Little is known about
αꢀenaminones, apparently because they are often not directly accessible from
the corresponding diketones.4 Compared with βꢀenaminones, the chemical behaviour of the
α
ꢀketo
,βꢀunsaturated
ketones (electrophiles). Although many strategies are available for utilizing βꢀenaminones as
derivatives differs (Figure 1). They can react as enamines (nucleophiles), as well as
α
building blocks, methods for the preparation of heterocycles using
α
ꢀketoenamines are limited.5ꢀ8
Figure 1. Dual electronic attitude of α-Enaminone
O
O
O
R1
N
NR1R2
NR1R2
R2
enamine
nucleophilic attitude
enone
electrophilic nature
α
-enaminone
limited reactivity
In this study, we report novel reactivity of
α,βꢀenaminones driven by their "dual electronic
attitude". We introduce unexplored, stable αꢀenaminone synthones, radically different from other
known ꢀ or βꢀcounterparts by their chemical behaviour, and unlock unusual functionalities of these
α
building blocks. We demonstrate general synthesis of several important classes of heterocycles via
controlled cyclizations of an easily accessible αꢀenaminone common key precursors.
Oxazine, azaspirone, quinolines, quinolinone and quinolinol structures are frequently observed as
scaffold segments in various biochemical compounds. These architectures have been identified as
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building blocks of a numerous alkaloids, as well as other families of diverse, and often remotely
related metabolites.9 Unfortunately, access to a large number of these target molecules, and their
structural analogues, is either unknown or hindered by the multistep syntheses.10 An inꢀdepth
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analysis of the introduced cores suggests that αꢀenaminone scaffold of Typeꢀ1 (Scheme 1) has the
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potential to serve as an operational, collective key unit for their construction via controlled
intramolecular cyclizations.4c,11 This would be the first attempt to link simple and single enaminone
core with such a diverse, heterocyclic architectures. With this in mind, we developed a novel
streamlined synthetic methodology that allows the rapid and collective composition of multiple
targets using a single common precursor.
As we contemplate the possible approaches for delivering the desired targets, we first consider a
1,4ꢀaddition, generating quinolinone scaffolds (Scheme 1). Inevitably, to obtain bicyclic
quinolinols, the 1,2ꢀcyclization pathway must be constructed. In addition, if 1,2ꢀ and 1,4ꢀadditions
are possible, the 1,3ꢀcycloꢀaddition becomes a plausible outcome, which would afford heterocyclic
systems, such as azaspirones. We also illustrate a CꢀO bond formation pathway that allows for
direct synthesis of benzoꢀ and methyleneꢀoxazines. Intriguingly, designing a method to differentiate
between these cyclization pathways would elegantly allow for the regioꢀ and chemoselective
collective delivery of a broad spectrum of conceptually different heterocycles. To the best of our
knowledge, synthesis of all the previously mentioned scaffolds (and their structural analogues)
using our approach has never been attempted.
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Scheme 1. Collective synthesis of heterocycles via controlled cyclization of α-enaminone precursor.
4
5
6
7
8
9
OH
Unprecedented 1,2-, 1,3-, 1,4- or C-O bond forming annulations
R2 = Alk
Regio-, Stereo-, and Chemoselective
N
R2
R1
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quinolinols
1,2-addition
R2 = Ar
N
R2
New Synthone
R1
R1
R1
(n)
(n) = C2
O
quinoline
1 Precursor
N
1 Methodology
7 Heterocycles
4 Transformations
X
O
N
R2
1
R2 = Alk
(n) = C1
X =Br, I
R2
O
N
azaspirones
1,3-addition
R1
R2
O
R2 = Ar
or Alk
R2 = Alk
R1
N
oxazines
C-O bond formation
R2
O
azaspirones
R2 = Ar
N
R1
R2
R1
O
R
2 = H
benzoxazines
N
1,4-addition
quinolinones
Natural products from diverse biological origins share oxazine, quinoline and azaspirone heterocyclic cores
O
O
Me
O
NH
O
O
O
Me
HN
Me
Me
Me
Me
Me
Me
O
Me
O
N
OH
O
N
Me
R1
N
Me
Me
HO
Me
O
O
O
O
N
R2
O
OMe
N
N
N
Me
H
OH
Me
Me
ansalactam A
Me
O
R1 = OH, R2 = H flabelliformine
R1 = H, R2 = OH lycodoline
alalakine
communesin F
benzoxazomycin
RESULTS AND DISCUSSION
1,4-Addition. To test our hypothesis, a simple building block of Typeꢀ2 was prepared (Scheme 2;
R1 = Et; see Experimental section) and selected as the model precursor. αꢀEnaminone 4 was
obtained by reacting 2 with 1,3ꢀdibromopropane in the presence of K3PO4 (1st equivalent of base).
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Surprisingly, an unexpected direct cyclization was observed. During the preparation of 4, the
alkylation of 2 with dibromopropane led to the isolation of a stable bicyclic quinolinone system 3
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rather than the anticipated αꢀenaminone. We assumed that subsequent fast cyclization of 4 yields
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compound 3 as an exclusive single product. Presumably, an equilibrium between 5 and 4 is
established due to prevailing enamineꢀtype electronic behaviour, suppressing the enoneꢀdriven
resonance. Subsequent nucleophilic attack leads to favourable 6ꢀmembered ring 6. In the presence
of a second equivalent of base, the deprotonation of 6 occurs, generating product 3. No hydrolysis
of 6 was detected, and only 3 was observed, which suggests that a very fast deprotonation may have
occurred. This deprotonation allows formation of the thermodynamically favourable product,
preserving its α,βꢀunsaturated functionality.
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Scheme 2. 1,4-Addition: rapid access Quinolinones from α-enaminone precursor (the mechanism)
A
preserved α,β-unsaturated functionality
R1
NH
R1
O
2
O
(10 equiv.)
Br
Br
single-step
composition
N
Base (2.0 equiv.), TBAB (0.5 equiv.)
MS, solvent, 100 °C, 16 h.
H
3
1,4-addition
Base (1st equiv.)
fast
enamine electronic attitude
no hydrolysis
R1
R1
Br
R1
O
6
O
4
O
Br
N
N
H
N
fast
Br
H
H
5
B
not isolated (not stable)
Base (2nd equiv.)
An efficient system for the desired transformation involves a combination of 2 with 10 equivalents
of 1,3ꢀdibromopropane, 0.5 equivalents of TBAB, and 2 equivalents of K3PO4 at 100 °C in toluene
(entry 10, Table 1). Control experiments were performed and demonstrated that no cyclization
occurred in the absence of base. It is important to mention, that all attempts to decrease the amount
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of 1,3ꢀdibromopropane resulted in incomplete conversion, and slow decomposition of starting
material. To confirm the hypothesis and expand the scope of the substrates and targets employed,
we conducted additional experiments with various αꢀenaminone precursors bearing different R1
groups (compounds 2aꢀ2d; Table 2) under the optimized cyclization conditions. We detected
exclusive 1,4ꢀselectivity, which led to the generation of quinolinone scaffolds 3aꢀd.12
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Table 1. Conditions evaluation for synthesis of Quinolinones: 2 → 3 [R1 = Et]
Entry
Base
Solvent
Additive
Yield (%) 3:2a
1
K2CO3
THF
ꢀ
29:44
2
3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
tꢀBuOK
K3PO4
K3PO4
K3PO4
K3PO4
K2CO3
DMF
ꢀ
No reaction
No reaction
0:93
MeCN
ꢀ
4
Pyridine
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
ꢀ
5
ꢀ
29:65
6
ꢀ
26:51
7
ꢀ
5:76
8
ꢀ
9:87
9
MS, TBAB 20%
MS, TBAB 50%
MS, TBAB 100%
MS, TBAB 50%
13:81
10
11
12
80:10b
70:15
13:41c
b
aGC yields: 0.2 mmol scale. All attempts to increase the conversion rate by elevating the temperature or
c
prolonging the reaction time resulted in decomposition of starting materials. The decline in mass balance
was due to the degradation of starting precursor during the reaction course.
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Table 2. 1,4-Addition (access to Quinolinones)a
7
R1
NH
8
9
R1
O
2
O
(10 equiv.)
Br
Br
N
K3PO4 (2.0 equiv.), TBAB (0.5 equiv.)
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MS, toluene, 100 °C, 16 h.
3
Precursors
Me
Me
Me
OTBS
O
O
O
O
NH
NH
NH
NH
2a
2b
2c
2d
O
Quinolinones
Me
Me
Me
OTBS
O
O
O
N
N
N
N
3a 78%
3b 58%
3c 57%
3d 54% [X-ray]
aIsolated yields: 0.5 mmol scale. Starting materials (in a range of 5ꢀ10%) were isolated. Prolonging the
reaction time resulted in decomposition of 2.
In principle, the reaction of precursor 2 with dibromopropane could produce other possible reactive
intermediate, 4a (instead of 4; Scheme 3A), that could give rise to quinolinone 3. In order to
differentiate among the pathways, the reaction of 2a was carried out under the standard conditions
but in the presence of 1ꢀiodoꢀ3ꢀchloropropane (Scheme 3B). Compound 7 was then isolated as the
only observable stable intermediate, and the structure was assigned on the basis of its NMR spectra
and the results of GCMS analysis. No evidence for the presence of Cꢀalkylated (1,4ꢀtype addition)
product 8 was detected. It should be also noted that no cyclization outcome 3a, or any other sideꢀ
product, were formed in the reaction mixture.
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Scheme 3. Selective N-alkylation pathway
7
8
9
R1
Br
A
O
N
4
Proposed N-alkylation pathway
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3
Br
Br
R1
NH
2
O
unlikely
C-alkylation pathway
Br
4a
B Reaction with iodochloropropane underlying selective N-alkylation pathway
Me Me
I
Cl
O
O
NH
N
H
Cl
optimized conditions
H
7
2a
N-alkylation
stable (NMR, GCMS)
Me
x
O
No C-alkylation
pathway detected
NH
no cyclization product (3a) detected
no hydrolysis product detected
Cl
8
not detected
C-O Bond formation. An unexpected cyclization caught our attention when precursor 9 (R2 ≠ H;
Scheme 4) was subjected to 1,2ꢀdibromoethane. During the preparation of αꢀenaminone 11, the
rapid cyclization led to the unforeseen isolation of stable oxazine ꢀ 10 (general structure).
Surprisingly, 11 delivers two different outcomes (i.e., 10aꢀmethyleneꢀoxazine or 10bꢀbenzoxazine)
depending on the nature of the R2 substituent (see Scheme 4). The best system for CꢀO bond
formation involves a combination of 9 with 2 equivalents of 1,2ꢀdibromoethane, 0.2 equivalents of
TBAB, and 2 equivalents of base at 100 °C. Table 3 lists the conditions evaluated for αꢀenaminone
integrated with the aliphatic R2 group (with DIEA as optimal base; entry 6). Then, the same set of
variables was applied to the starting material, bearing an aromatic R2 residue. For this setting,
K2CO3 has been determined to be the best base. We believe that in the presence of base, the
deprotonation of 11 is established (Scheme 4; two variants are possible depending on the R2
substituent). The subsequent nucleophilic attack of the oxygen, which was driven by the enone
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transient attitude, leads further to more favourable 6ꢀmembered ring scaffolds that bear a conjugated
double bond system (i.e., 10a) or fully aromatized oxazine (i.e., 10b). Representative examples of
methyleneꢀ and benzoxazines, that were synthesized through CꢀO bond formation, shown in the
Table 4. For this transformation, compounds with a variety of R1ꢀ and R2ꢀsubstituted Typesꢀ14 and
16 cores were prepared (precursors 14aꢀd, 16aꢀb; see Experimental section) and subjected to the
optimized conditions. It is also imperative to mention the exclusive Eꢀselectivity was observed for
cyclization products 15a-d and 17aꢀd. The critical stereochemical assignment of the bicyclic targets
has been confirmed by NMR analysis (see SI spectral data).13
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Scheme 4. Annulation of α-enaminone via C-O bond formation: synthesis of methylene- and
benzoxazines.
single-step
composition
enone prevailing charge transfer
R1
NH
O
9
Br
O
N
C-O bond
formation
(2 equiv.)
Br
base (2.0 equiv.), TBAB (0.2 equiv.)
THF, 100 °C, 16 h
R2
R2
R1
10
Base (1st equiv.)
Br
O
12
O
O
N
R2 = CH2R
DIEA
R1
N
Br
R
O
R
R1
10a
N
R1
Base
nd equiv.
+ traces of 10b
2
R2
Br
11
O
N
R2 = Ar
K2CO3
R1
N
not isolated (not stable)
R2
R2
R1
13
10b
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Table 3. Conditions evaluation for synthesis of Oxazines: 9 → 10 [R1 = Ph, R2 = Et]
6
7
8
9
Entry
Base
Solvent
Yield (%) 12:11a
1
K2CO3
Acetone
62:25
10
11
12
13
14
15
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2
3
Na2CO3
Cs2CO3
K3PO4
DIEA
DIEA
DIEA
DIEA
DIEA
DIEA
DIEA
Acetone
Acetone
Acetone
Acetone
THF
67:5
17:51
55:9
4
5
74:3
6
85:0
7
Toluene
DMF
76:9
8
13:0b
9
1,4ꢀDioxane
Pyridine
MeCN
64:18
No reaction
43:8b
10
11
b
aGC yields: 0.2 mmol scale. The decline in mass balance was due to the degradation of starting precursor
during the reaction course.
As shown in Table 4, the isolated yields of compounds 17a-b were significantly lower than of those
of 15a-d. We attribute the apparent difference between these two groups to the nature of their R2
residue. As proposed in the Scheme 5, an aromatic R2 (in the presence of base) enables formation of
a stable resonance form (19) of starting precursor 18, which dramatically slows down the alkylation
step towards αꢀenaminone 20. This result is confirmed by our ability to recover a vast amount of
unreacted starting materials. In contrast, the compounds integrated with aliphatic R2 groups did not
transform into the resonance form, and most likely undergo the desired alkylations to generate
bicyclic products.
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Table 4. Scope: C-O Bond formation (synthesis of Methylene- and Benzoxazines)a
6
7
8
9
R1
Br
O
N
(2 equiv.)
O
Br
NH
DIEA (2.0 equiv.), TBAB (0.2 equiv.)
10
11
12
13
14
15
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THF, 100 °C, 16 h
Me
R1
14
O
15
Me
E-stereoselective
O
Br
(2 equiv.)
Br
Me
NH
K2CO3 (2.0 equiv.), TBAB (0.2 equiv.)
N
THF, 100 °C, 16 h
16
Me
R
17
R
Precursors
O
Me
O
O
OTBS
NH
NH
NH
Me
14a
O
14b
O
14c
O
Me
Me
NH
S
Me
Me
NH
NH
Me
14d
16a
16b
Cl
Oxazines
O
N
O
N
O
N
Me
Me
Me
Me
OTBS
15a 80%
15b 75%
15c 71%
O
O
N
17a R = H 26% [X-ray]
17b R = Cl 17%
N
Me
starting materials (16a-b)
recovered in both cases
Me
S
15d 71%
R
aIsolated yields: 0.5 mmol scale.
Scheme 5. Resonance contribution to alkylation rate of enaminone precursor
Aromatic group enables formation of stable resonance form, which dramatically
slows down the rate of alkylation step towards enaminone
R1
R1
R1
O
O
O
Br
SLOW
Base
NH
N
N
(1st equiv.)
Br
Br
18
19
20
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1,3-Addition. With suitable access to quinolinones and oxazines in hand, we next experimented
with other cyclizations. The reaction scope was extended to the synthesis of more challenging
heterocycles using the same precursor (9) as a starting material (Table 5A). An interesting result
was observed when 9 (R2 ≠ H) was subjected to 1,3ꢀdibromopropane rather than 1,2ꢀdibromoꢀ
ethane (as in the previously discussed transformation). In contrast to αꢀenaminones 4 (Scheme 2)
and 11 (Scheme 4), the typeꢀ21 enaminones were stable (for various R1 and R2). Following the
exposure of enaminone 21 to basic conditions (the optimized reaction protocol is provided in Table
6, entry 12), we detected another unexpected and novel cyclization.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 5. 1,3-Addition: synthesis of Azaspirones. Plausible mechanism and the substrate scopea
stable for various R1 and R2
A
D
R1
R1
Br
R1
NH
O
Br
Br
O
O
Br
O
O
(10 equiv.)
R1
NaOMe (2.0 equiv.)
MeCN, 100 °C, 1 h
N
N
both formed
and
separated
N
N
R1
K2CO3 (2.0 equiv.)
R2
R2
THF, 80 °C, 16 h
Me
Me
Me
21
25
26 endo
27 exo
OTBS
9
α
-Enaminones
OMe
B
Me
R1
R1
O
S
O
O
O
O
O
O
endo
termination
N
N
N
N
N
N
N
R2 = Ar or CH2R
R2 Br
R2
(major)
Me Br
Me Br
25c
Me Br
Me Br
Me Br
22a
24
25a
25b
25d
25e
21
NaOMe (2.0 equiv.), MeCN, 100 °C, 1 h
1,3-addition
endo-azaspirones
OMe
Me
OTBS
R1
R1
O
O
S
exo
termination
O
O
N
O
N
O
O
N
N
N
N
N
Br
R2 = CH2R
22b
23
R
R
Me
Me
26b 71%
Me
Me
Me
26d 60%
E-stereoselective
(always minor)
26a 54%
26c 63%
26d 50%
exo-azaspirones
C
21
24
Br
OMe
α
-Enaminones
Me
OTBS
S
Me
Me
Br
S
Br
O
O
O
N
O
N
O
O
O
O
N
N
N
N
N
N
Me
Me
27b 16%
Me
Me
Me
27b 3%
Cl
21a
21b
21c
27b 5%
27b 15%
27b 15%
Azaspirone products
Me
E
Effect of steric hindrance on selectivity: Inversion of the endo and exo products ratio
Me
Me
Me
S
O
O
N
O
Br
N
O
N
O
O
N
N
N
NaOMe (2.0 equiv.)
MeCN, 100 °C, 1 h
Me
+
Me
separated
Me
29 17%
Cl
24a 73%
24b 72%
24c 75%b
28 (R1 = Et, R2 = Me)
30 46%
aIsolated yields: 0.5 mmol scale. bCs2CO3 was used as base (20h).
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The derivatives of 21 were synthesized (see experimental section) and further subjected to the
optimized cyclization conditions to generate products 24a-c, 26a-d and 27a-d (Tables 5C and 5D
respectively). Interestingly, of the two intermediates (22a and 22b; Table 5B), deprotonation
primarily occurs at 22a regardless of the nature of R2 group (aliphatic CH2R or Aromatic).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
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36
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41
42
43
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
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Table 6. Conditions evaluation for 1,3-addition: 21 → 24 [R1 = Et, R2 = Ph]
Entry
Base
Solvent
Yield (%) 12:11a
1
Cs2CO3
1,4ꢀDioxane
No reaction
2
3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
K2CO3
THF
17
DMF
29
4
Toluene
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
No reaction
5
55
6
No reaction
7
10
8
K3PO4
6
9
NaOH
11
No reaction
77
10
11
12
DIEA
NaOMe
NaOMe (2 equiv.)
96
aGC yields: 0.2 mmol scale.
The endoꢀterminated cyclizations (24) were consistently observed as the dominant products for this
transformation. We postulated that the formation of 25 (minor outcome) is suppressed due to the
steric intramolecular hindrance from the Rꢀgroup, and the alkylbromide chain (23; Table 5B). To
test this hypothesis, enaminone 28 (integrated with the Me group as R2) was prepared and subjected
to the optimized cyclization conditions (Table 5E). The ratio of endoꢀ and exoꢀproducts (29 and 30
repectively) inverts with exo 30 being a major product, which further strengthens our core
assumption.
Additionally, we investigated the effect of the temperature on selectivity of this reaction (1,3ꢀ
addition). Therefore, we subjected enaminone 25b (with R1 and R2 being Et groups; Scheme 6) to
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cyclization conditions at a lower temperature of 50 °C, utilizing NaOtꢀBu as a base.14 We detected a
similar ratio for products 26b and 27b (67:18).
6
7
8
9
Notwithstanding the lack of selectivity, the successful construction of azaspirones via 1,3ꢀ
cyclization of enaminone is remarkable. All pairs of exoꢀ and endoꢀ products were successfully
separated, providing access to two conceptually different heterocycles. It should be also mentioned,
that the exclusive Eꢀselectivity observed for all exoꢀterminated products 26a-e. The critical
stereochemical assignment was confirmed by NMR analysis.13
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
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Scheme 6. Effect of temperature on the selectivity
Me
Me
Me
NaOtBu (2.0 equiv.)
MeCN, 50 °C, 1 h
O
O
O
N
N
N
elimination
15%
+
26b
67%
27b
18%
21
Me Br
Me
Me
1,2-Addition. To complete the picture, we executed additional cyclizations to investigate the final
1,2ꢀaddition of the ꢀenaminone system. We followed the protocols designed for the radical
α
cyclization of classical enones.15 Our attempts were carried out using the SmI2/HMPA system.16
Here, typeꢀ31 αꢀenaminones (see Experimental section for preparation) were subjected to radical
cyclization conditions to provide bicyclic quinolinols 32 or quinoline 33, however, both were
obtained in low yields (Table 7). The two transformations were confirmed to undergo the desired
termination, even though reduction and other side products were detected in the reaction mixtures
(quinoline was obtained if R2 = aromatic). Despite our goal of enhancing the outcome of this
transformation by varying the temperature, solvent, concentration, amount of SmI2 or HMPA
alternation, and order of reagent addition, our efforts were not successful. Nevertheless, radical
reactions of 31a-c afforded the desired products 32a, 32b and 33a (Table 7). To the best of our
knowledge, these results represent the first examples of intramolecular cyclizations that incorporate
quinolinols and quinolines from a simple enaminone. In these less effective cyclizations, the
formation of 32 and 33 required 4 equivalents of the Sm reagent, 10 equivalents of HMPA, and 10
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equivalents of tertꢀbutyl alcohol. Regardless of the mentioned drawbacks, the successful
construction of the reported heterocycles via this type of transformation is unprecedented and
unique.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 7. Radical 1,2-cyclization: direct access to Quinolines and Quinolinols
OH
I
R2 = CH2R
N
SmI2 (4 equiv.)
HMPA (10 equiv.)
t-BuOH (10 equiv.)
O
32
stable
R1
R
R1
N
1,2-addition
THF
0 °C → rt, 1 h
R2
31
R2 = Ar
N
isolated
stable for various R1 and R2
aromatization
R1
R
33
I
Precursors
I
I
O
O
O
N
N
N
Me
Cl
Me
31a
Me
31b
31c
Me
Scope
elimination and reduction products isolated in all reactions
OH OH
N
N
N
Me
Me
Me
Me
32a 43%
32b 37%
33a 30%
Cl
CONCLUSION
We have reported the unprecedented reactivity of α,βꢀunsaturated enaminones driven by their "dual
electronic attitude". We introduced novel, stable αꢀenaminone synthones and discovered the
unusual and novel functionalities of these building blocks. We have demonstrated that readily
available αꢀenaminone precursors undergo facile cyclizations under basic conditions to afford a
broad spectrum of heterocycles, such as azaspirones, quinolinones, quinolines, quinolinols and
oxazines. Accurate design of the starting material allows for specific and selective functionalization
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reactions across the unsaturated scaffold, enabling the preparation of diverse products. We believe
that our methodology is groundꢀbreaking in the field of basic chemical research, paves the way for
novel retrosynthetic pathways, and may reasonably find potential application for the construction of
highly complex systems.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
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Experimental Section
General Information. Unless otherwise noted, all reagents were purchased from commercial
suppliers and used without further purification. Solvents used in the reactions were distilled from
appropriate drying agents prior to use. Reactions were monitored by thinꢀlayer chromatography
(TLC) on silica gel 60 F254 aluminium plates (Merck) and/or gas chromatographyꢀmass
spectrometry (GCMS). Visualization of compounds on TLC was accomplished by irradiation with
UV light at 254 nm, iodine or vanillin stain. GCMS Analysis was performed with ‘Agilent 7820A’
gas chromatograph equipped with ‘Agilent 5975’ quadrupole mass selective detector, using Agilent
HPꢀ5MS capillary column (30 m, 0.25 mm, 0.25 ꢁm film). Column chromatography was
performed using silica gel 60 (particle size 0.040ꢀ0.063 mm) purchased from SigmaꢀAldrich or
aluminium oxide 90 active basic (particle size 0.063ꢀ0.200 mm) purchased from Merck. Proton
and carbon NMR spectra were recorded on Varian Mercury 300 MHz or Varian Mercury 500
MHz spectrometer in deuterated solvent. Proton chemical shifts are reported in ppm (δ) relative to
tetramethylsilane with the solvent resonance employed as the internal standard (CDCl3, δ 7.26
ppm). 13C chemical shifts are reported in ppm from tetramethylsilane with the solvent resonance as
the internal standard (CDCl3, δ 77.0 ppm). Data are reported as follows: chemical shift, multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), integration and coupling constants
(Hz). High resolution mass spectra were determined on a Thermo Scientific LTQ Orbitrap XL
(FTMS). Infrared spectra (IR) were recorded on a Thermo Fischer Scientific NICOLETꢀiS10
spectrometer.
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General procedure A: Synthesis of Quinolinones (1,4-addition): To a flameꢀdried 15.0 mL
reaction tube flushed with nitrogen, fitted with a magnetic stirring bar and rubber septum, were
added imminone (1.0 equiv.), K3PO4 (2.0 equiv.), dibromopropane (10.0 equiv.), TBAB (0.5
equiv.) and molecular sieves (4Ǻ, 500 mg, 1.0 mmol) in dry toluene (0.1M) at room temperature.
The reaction mixture was refluxed at 100 °C for 16 h. The mixture was then concentrated in vacuo,
and the crude mixture was purified by flash chromatography to yield the desired product.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
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36
37
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44
45
46
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48
49
50
51
52
53
54
55
56
57
58
59
60
1-Propyl-1,3,4,5,6,7-hexahydroquinolin-8(2H)-one (3a): General procedure A was applied. αꢀ
Iminone 2a (77 mg, 0.5 mmol) prepared according to General Procedure E, K3PO4 (212 mg, 1.0
mmol), dibromopropane (1.01 g, 5.0 mmol), TBAB (83 mg, 0.25 mmol) and molecular sieves (4Ǻ,
250 mg) were mixed in dry toluene (5.0 mL) at room temperature. The reaction mixture was
refluxed at 100 °C for 16 h. The mixture was then concentrated in vacuo and the crude product was
purified by flash chromatography (Silica gel, 4/96% MeOH/DCM) to yield 3a in 78% yield (75 mg)
1
as yellow liquid. H NMR (300 MHz, CDCl3): δ 2.93ꢀ2.87 (m, 2H), 2.72ꢀ2.63 (m, 2H), 2.46ꢀ2.35
(m, 2H), 2.27 (t, J = 6.2 Hz, 2H), 2.11 (t, J = 6.6 Hz, 2H), 1.89 (p, J = 6.3 Hz, 2H), 1.71ꢀ1.52 (m,
4H), 0.85 (t, J = 7.4 Hz, 3H).13C NMR (75 MHz, CDCl3): δ 196.2, 141.1, 139.2, 54.6, 47.6, 39.3,
31.1, 29.7, 22.5, 22.0, 18.5, 11.5. IR (neat): 2930, 2868, 2824, 1671, 1603, 1184 cmꢀ1. HRMS m/z:
([M+Na]+) calcd for C12H19NONa 216.1359; found 216.1356.
1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1,3,4,5,6,7-hexahydroquinolin-8(2H)-one (3b):
General procedure A was applied. αꢀIminone 2b (135 mg, 0.5 mmol) prepared according to General
Procedure E, K3PO4 (212 mg, 1.0 mmol), dibromopropane (1.01 g, 5.0 mmol),TBAB (83 mg, 0.25
mmol) and molecular sieves (4Ǻ, 250 mg) were mixed in dry toluene (5.0 mL) at room temperature.
The reaction mixture was refluxed at 100 °C for 16 h. The mixture was then concentrated in vacuo
and the crude product was purified by flash chromatography (Silica gel, 5/95% ether/hexane) to
yield 3b in 58% yield (90 mg) as yellow liquid. 1H NMR (300 MHz, CDCl3): δ 3.82 (t, J = 6.7 Hz,
2H), 3.00ꢀ2.93 (m, 2H), 2.87 (t, J = 6.7 Hz, 2H), 2.44ꢀ2.36 (m, 2H), 2.26 (t, J = 6.2 Hz, 2H), 2.11
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(t, J = 6.6 Hz, 2H), 1.89 (p, J = 6.3 Hz, 2H), 1.67 (p, J = 6.3 Hz, 2H), 0.87 (s, 9H), 0.05 (s, 6H).13C
NMR (75 MHz, CDCl3): δ 196.2, 140.7, 138.8, 62.9, 54.8, 49.3, 39.2, 31.0, 29.6, 25.9, 22.5, 18.9,
18.3, ꢀ5.3. IR (neat): 2927, 2855, 1673, 1251, 1099, 832, 774 cmꢀ1. HRMS m/z: ([M+Na]+) calcd
for C17H31NO2SiNa 332.2016; found 332.2019.
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11
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13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1-Isobutyl-1,3,4,5,6,7-hexahydroquinolin-8(2H)-one (3c): General procedure A was applied. αꢀ
Iminone 2c (84 mg, 0.5 mmol) prepared according to General Procedure E, K3PO4 (212 mg, 1.0
mmol), dibromopropane (1.01 g, 5.0 mmol), TBAB (83 mg, 0.25 mmol) and molecular sieves (4Ǻ,
250 mg) were mixes in dry toluene (5 mL) at room temperature. The reaction mixture was refluxed
at 100 °C for 16 h. The mixture was then concentrated in vacuo and the crude product was purified
by flash chromatography (Silica gel, 20/80% ethyacetate/hexane) to yield 3c in 57% yield (59 mg)
1
as yellow liquid. H NMR (300 MHz, CDCl3): δ 2.95ꢀ2.86 (m, 2H), 2.56 (d, J = 7.3 Hz, 2H), 2.40
(t, J = 7.4 Hz, 2H), 2.27 (t, J = 6.2 Hz, 2H), 2.12 (t, J = 6.6 Hz, 2H), 2.02ꢀ1.84 (m, 3H), 1.73ꢀ161
(m, 2H), 0.93 (d, J = 6.7 Hz, 6H).13C NMR (75 MHz, CDCl3): δ 196.1, 141.5, 138.7, 59.8, 47.6,
39.5, 31.2, 29.8, 27.7, 22.4, 20.6, 18.3. IR (neat): 2951, 2866, 2822, 1671, 1602, 1435, 1184, 1121,
978 cmꢀ1. HRMS m/z: ([M+Na]+) calcd for C13H21NONa 230.1515; found 230.1519.
1-Benzyl-1,3,4,5,6,7-hexahydroquinolin-8(2H)-one (3d): General procedure A was applied. αꢀ
Iminone 2d (101 mg, 0.5 mmol) prepared according to General Procedure E, K3PO4 (212 mg, 1.0
mmol), dibromopropane (1.01 g, 5.0 mmol), TBAB (83 mg, 0.25 mmol) and molecular sieves (4Ǻ,
250 mg) were mixed in dry toluene (5 mL) at room temperature. The reaction mixture was refluxed
at 100 °C for 16 h. The mixture was then concentrated in vacuo and the crude product was purified
by flash chromatography (Silica gel, 20/80% ether/hexane) to yield 3d in 54% yield (66 mg) as pale
yelloe solid (M.p. 86ꢀ89 °C). 1H NMR (300 MHz, CDCl3): δ 7.48ꢀ7.43 (m, 2H), 7.34ꢀ7.19 (m, 3H),
3.93 (s, 2H), 2.80ꢀ2.76 (m, 2H), 2.50ꢀ2.44 (m, 2H), 2.31 (t, J = 6.2 Hz, 2H), 2.12 (t, J = 6.5 Hz,
2H), 1.95 (p, J = 6.3 Hz, 2H), 1.67ꢀ1.57 (m, 2H).13C NMR (75 MHz, CDCl3): δ 196.1, 140.7,
140.5, 139.8, 129.1, 128.1, 126.9, 55.7, 46.5, 39.4, 31.2, 29.8, 22.5, 17.8. IR (neat): 2943, 2928,
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2864, 1661, 1611, 1161, 946, 746, 702 cmꢀ1. HRMS m/z: ([M+H]+) calcd for C16H20NO 242.1539;
found 242.1538.
6
7
8
General procedure B: Synthesis of Oxazines (C-O formation): To a flameꢀdried 15 mL reaction
9
tube, fitted with a magnetic stirring bar and a rubber septum connected to a nitrogen source,
αꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
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49
50
51
52
53
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56
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58
59
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iminone (1.0 equiv.), base (2.0 equiv.), TBAB (0.2 equiv.), dibromoethane (2.0 equiv.) were mixed
in dry THF (0.5M) at room temperature. The reaction mixture was refluxed at 100 °C for 16 h. The
mixture was then concentrated in vacuo and the crude mixture was purified by flash
chromatography to yield the desired product.
5-Ethylidene-4-propyl-3,4,5,6,7,8-hexahydro-2H-benzo[b][1,4]oxazine (15a): General procedure
B was applied. αꢀIminone 14a (91 mg, 0.5 mmol) prepared according to General Procedure E,
Hunig's base (130 mg, 1.0 mmol), TBAB (33 mg, 0.1 mmol) and dibromoethane (188 mg, 1.0
mmol) were mixed in dry THF (1.0 mL) at room temperature. The reaction mixture was refluxed at
100 °C for 16 h. The mixture was then concentrated in vacuo and the crude mixture was purified by
flash chromatography (basic alumina, 5/95% ether/hexane) to yield 15a in 80% yield 84 mg) as
yellow liquid. 1H NMR (300 MHz, CDCl3): δ 5.48 (q, J = 7.1 Hz, 1H), 3.97ꢀ3.90 (m, 2H), 2.94 (t,
J = 4.3 Hz, 2H), 2.56ꢀ2.47 (m, 2H), 2.22 (q, J = 6.6 Hz, 4H), 1.62ꢀ1.74 (m, 5H), 1.54 (h, J = 7.4
13
Hz, 2H), 0.88 (t, J = 7.4 Hz, 3H). C NMR (75 MHz, CDCl3): δ 140.0, 132.5, 122.0, 112.0, 59.5,
55.0, 45.7, 27.9, 25.3, 22.4, 21.8, 13.2, 11.5. IR (neat): 2958, 2929, 2869, 1624, 1455, 1353, 1143,
700 cmꢀ1. HRMS m/z: ([M+H]+) calcd for C13H22NO 208.1696; found 208.1690.
4-Benzyl-5-ethylidene-3,4,5,6,7,8-hexahydro-2H benzo[b][1,4]oxazine (15b): General procedure
B was applied. αꢀ|Iminone 14b (115 mg, 0.5 mmol) prepared according to General Procedure E,
Hunig's base (130 mg, 1mmol), TBAB (33 mg, 0.1mmol) and dibromoethane (188 mg, 1.0 mmol)
were mixed in dry THF (1.0 mL) at room temperature. The reaction mixture was refluxed at 100 °C
for 16 h. The mixture was then concentrated in vacuo and the crude product was purified by flash
chromatography (basic alumina, 5/95% ether/hexane) to yield 15b in 75% yield (95 mg) as yellow
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liquid. 1H NMR (300 MHz, CDCl3): δ 7.43 (d, J = 7.6 Hz, 2H), 7.35 (t, J = 7.4 Hz, 2H), 7.31ꢀ7.23
(m, 1H), 5.70 (q, J = 7.2 Hz, 1H), 3.99ꢀ3.95 (m, 2H), 3.93 (s, 2H), 2.90 (t, J = 4.4 Hz, 2H), 2.30 (q,
J = 6.7 Hz, 4H), 1.77 (q, J = 6.4 Hz, 2H), 1.69 (d, J = 6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
141.0, 139.4, 132.2, 128.4, 127.8, 126.9, 121.3, 112.0, 59.4, 56.4, 45.7, 28.0, 25.4, 22.5, 13.3. IR
(neat): 2957, 2928, 2864, 1642, 1624, 1194, 1146, 731, 696 cmꢀ1. HRMS m/z: ([M+H]+) calcd for
C17H22NO 256.1696; found 256.1693.
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5-Ethylidene-4-propyl-3,4,5,6,7,8-hexahydro-2H-benzo[b][1,4]oxazine (15c): General procedure
B was applied. αꢀIminone 14c (149 mg, 0.5 mmol) prepared according to General Procedure E,
Hunig's base (130 mg, 1.0 mmol), TBAB (33 mg, 0.1 mmol) and dibromoethane (188 mg, 1.0
mmol) were mixed in dry THF (1.0 mL) at room temperature. The reaction mixture was refluxed at
100 °C for 16 h. The mixture was then concentrated in vacuo and the crude mixture was purified by
flash chromatography (basic alumina, 5/95% ether/hexane) to yield 15c in 71% yield 95 mg) as
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yellow liquid. H NMR (300 MHz, CDCl3): δ 5.54 (q, J = 7.2 Hz, 1H), 3.96 (t, J = 4.4 Hz, 2H),
3.76 (t, J = 6.3 Hz, 2H), 3.03 (t, J = 4.4 Hz, 2H), 2.73 (t, J = 6.4 Hz, 2H), 2.26ꢀ2.17 (m, 4H), 1.63ꢀ
1.75 (m, 5H), 0.90 (s, 9H), 0.07 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 140.1, 132.4, 121.7, 112.4,
62.6, 59.7, 55.2, 47.1, 27.9, 25.9, 25.3, 22.4, 18.3, 13.2, ꢀ5.4 . IR (neat): 2957, 2930, 2859, 1456,
1249, v1098, 837, 770 cmꢀ1. HRMS m/z: ([M+H]+) calcd for C18H34NO2Si 324.2353; found
324.2354.
5-Ethylidene-4-(thiophen-2-ylmethyl)-3,4,5,6,7,8-hexahydro-2H-benzo[b][1,4]oxazine (15d):
General procedure B was applied. αꢀIminone 14d (118 mg, 0.5 mmol) prepared according to
General Procedure E, Hunig's base (130 mg, 1.0 mmol), TBAB (33 mg, 0.1 mmol) and
dibromoethane (188 mg, 1.0 mmol) were mixed in dry THF (1.0 mL) at room temperature. The
reaction mixture was refluxed at 100 °C for 16 h. The mixture was then concentrated in vacuo and
the crude product was purified by flash chromatography (basic alumina, 5/95% ether/hexane) to
yield 15d in 71% yield (93 mg) as yellow liquid. 1H NMR (300 MHz, CDCl3): δ 7.27ꢀ7.22 (m, 1H),
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6.99ꢀ6.91 (m, 2H), 5.77 (q, J = 7.1 Hz, 1H), 4.01 (s, 2H), 3.95 (t, J = 4.4 Hz, 2H), 3.00ꢀ2.92 (m,
2H), 2.36ꢀ2.23 (m, 4H), 1.82ꢀ1.67 (m, 5H).13C NMR (75 MHz, CDCl3): δ 143.7, 141.1, 132.0,
126.5, 124.8, 124.6, 120.9, 112.3, 59.6, 51.8, 45.7, 27.9, 25.3, 22.4, 13.3. IR (neat): 2955, 2928,
2858, 1455, 1246, 1094, 830, 771 cmꢀ1. HRMS m/z: ([M+H]+) calcd for C15H20NOS 262.1260;
found 262.1251.
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5-Phenyl-4-propyl-3,4,5,6,7,8-hexahydro-2H-benzo[b][1,4]oxazine (17a): General procedure B
was applied. αꢀIminone 16a (115 mg, 0.5 mmol) prepared according to General Procedure E,
K2CO3 (138 mg, 1.0 mmol), TBAB (33 mg, 0.1 mmol) and dibromoethane (188 mg, 1.0 mmol)
were mixed in dry THF (1.0 mL) at room temperature. The reaction mixture was refluxed at 100 °C
for 16 h. The mixture was then concentrated in vacuo and the crude product was purified by flash
chromatography (Silica gel, 2/98% ether/hexane) to yield 17a in 26% yield (32 mg) as yellow
liquid. 1H NMR (300 MHz, CDCl3): δ 7.57ꢀ7.52 (m, 2H), 7.41 (dd, J = 8.2, 6.6 Hz, 2H), 7.36ꢀ7.31
(m, 1H), 6.98ꢀ6.86 (m, 2H), 6.82 (dd, J = 7.1, 2.0 Hz, 1H), 4.13 (t, J = 4.4 Hz, 2H), 3.17 (t, J = 4.5
Hz, 2H), 2.54ꢀ2.46 (m, 2H), 1.26ꢀ1.07 (m, 2H), 0.47 (t, J = 7.4 Hz, 3H).13C NMR (75 MHz,
CDCl3): δ 147.7, 141.1, 136.0, 134.2, 129.1, 128.1, 126.7, 123.6, 121.9, 116.4, 60.3, 57.7, 45.6,
20.7, 11.1. IR (neat): 2964, 2860, 1580, 1461, 1433, 1240, 1006, 871, 775, 702 cmꢀ1. HRMS m/z:
([M+Na]+) calcd for C17H19NONa 276.1357; found 276.1360.
5-(4-Chlorophenyl)-4-propyl-3,4,5,6,7,8-hexahydro-2H-benzo[b][1,4]oxazine (17b): General
procedure B was applied. αꢀIminone 16b (132 mg, 0.5 mmol) prepared according to General
Procedure E, K2CO3 (138 mg, 1.0 mmol), TBAB (33 mg, 0.1 mmol) and dibromoethane (188 mg,
1.0 mmol) were mixed in dry THF (1.0 mL) at room temperature. The reaction mixture was
refluxed at 100 °C for 16 h. The mixture was then concentrated in vacuo and the crude product was
purified by flash chromatography (Silica gel, 2/98% Ether/hexane) to yield 17b in 17% yield (49
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mg) as yellow liquid. H NMR (300 MHz, CDCl3): δ 7.50ꢀ7.45 (m, 2H), 7.38ꢀ7.33 (m, 2H), 6.96ꢀ
6.83 (m, 2H), 6.74 (dd, J = 7.2, 1.9 Hz, 1H), 4.10 (t, J = 4.5 Hz, 2H), 3.14 (t, J = 4.5 Hz, 2H), 2.50ꢀ
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2.42 (m, 2H), 1.23ꢀ1.10 (m, 2H), 0.49 (t, J = 7.4 Hz, 3H).13C NMR (75 MHz, CDCl3): δ 139.4,
132.5, 130.4, 128.3, 123.4, 122.1, 116.7, 60.2, 57.7, 45.4, 20.7, 11.1. IR (neat): 2964, 2930, 2860,
1580, 1461, 1433, 1240, 1134, 1006, 871, 763, 702 cmꢀ1. HRMS m/z: ([M+H]+) calcd for
C17H19ClNO 288.1150; found 288.1152.
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General procedure C: Synthesis of azaspiro-decanones (1,3 addition): To a flameꢀdried 15 mL
reaction tube flushed with nitrogen, fitted with a magnetic stirring bar and rubber septum, were
added αꢀenaminone (1.0 equiv., 0.5 mmol) and NaOMe (2.0 equiv., 1 mmol) in dry MeCN (1M) at
room temperature. The reaction mixture was refluxed at 100 °C for 1 h. The mixture was then
concentrated in vacuo and the crude product was purified by flash chromatography to yield the
desired product.
10-(4-Chlorophenyl)-1-propyl-1-azaspiro[4.5]dec-9-en-6-one (24a): General procedure C was
applied. αꢀEnaminone 21a (192 mg, 0.5 mmol) prepared according to General Procedure F and
NaOMe (54 mg, 1.0 mmol) were mixed in dry MeCN (0.5 mL) at room temperature. The reaction
mixture was refluxed at 100 °C for 1 h. The mixture was then concentrated in vacuo and the crude
product was purified by flash chromatography (Silica gel, 5/95% ether/hexane) to yield 24a in 73%
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yield (111 mg) as pale yellow oil. H NMR (300 MHz, CDCl3): δ 7.47 (d, J = 6.6, 3.0 Hz, 2H),
7.22 (d, J = 4.9, 1.9 Hz, 2H), 6.13 (t, J = 4.2 Hz, 1H), 3.12ꢀ3.26 (m, 1H), 2.79 (q, J = 8.2 Hz, 1H),
2.64ꢀ2.36 (m, 6H), 1.88ꢀ1.77 (m, 3H), 1.69ꢀ1.50 (m, 2H), 1.45ꢀ4.32 (m, 1H), 0.84 (t, J = 7.4 Hz,
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3H). C NMR (75 MHz, CDCl3): δ 213.1, 142.1, 139.3, 132.8, 130.7, 130.5, 127.5, 72.9, 51.1,
50.3, 39.5, 34.4, 24.3, 22.6, 22.5, 12.1. IR (neat): 2958, 2931, 2871, 2846, 1704, 1486, 1174, 1089,
1015, 822 cmꢀ1. HRMS m/z: ([M+H]+) calcd for C18H23ClNO 304.1463; found 304.1467.
10-Phenyl-1-propyl-1-azaspiro[4.5]dec-9-en-6-one (24b): General procedure C was applied. αꢀ
Enaminone 21b (175 mg, 0.5 mmol) prepared according to General Procedure F and NaOMe (54
mg, 1.0 mmol) were mixed in dry MeCN (0.5 mL) at room temperature. The reaction mixture was
refluxed at 100 °C for 1 h. The mixture was then concentrated in vacuo and the crude product was
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purified by flash chromatography (Silica gel, 5/95% ether/hexane) to yield 24b in 72% yield (97
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mg) as pale yellow oil. H NMR (300 MHz, CDCl3): δ 7.48 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.1
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Hz, 3H), 6.12 (t, J = 4.2 Hz, 1H), 3.18 (td, J = 8.1, 2.7 Hz, 1H), 2.78 (q, J = 7.4 Hz, 1H), 2.67ꢀ2.58
(m, 2H), 2.54ꢀ2.38 (m, 4H), 1.90ꢀ1.69 (m, 3H), 1.68ꢀ1.62 (m, 1H), 1.59ꢀ1.49 (m, 1H), 1.45ꢀ1.39
(m, 1H), 0.83 (t, J = 7.4 Hz, 3H).13C NMR (75 MHz, CDCl3): δ 213.4, 143.1, 141.0, 130.3, 129.3,
127.4, 126.9, 73.1, 51.2, 50.3, 39.5, 34.4, 24.4, 22.6, 22.5, 12.1. IR (neat): 2957, 2930, 2846, 1704,
1442, 1174, 1075, 759, 698 cmꢀ1. HRMS m/z: ([M+H]+) calcd for C18H24NO 270.18524; found
270.18506.
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10-Phenyl-1-(thiophen-2-ylmethyl)-1-azaspiro[4.5]dec-9-en-6-one (24c): General procedure C
was applied. αꢀEnaminone 21c (202 mg, 0.5 mmol) prepared according to General Procedure F,
Cs2CO3 (326 mg, 1.0 mmol) were mixed in dry MeCN (0.5 mL) at room temperature. The reaction
mixture was refluxed at 100 °C for 20 h. The mixture was then concentrated in vacuo and the crude
product was purified by flash chromatography (Silica gel, 5/95% ether/hexane) to yield 24c in 75%
yield (122 mg) as yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.62ꢀ7.54 (m, 2H), 7.40ꢀ7.28 (m, 3H),
7.16 (d, J = 5.1, 1.3 Hz, 1H), 6.93ꢀ6.86 (m, 1H), 6.81 (d, J = 3.4 Hz, 1H), 6.20 (t, J = 4.3 Hz, 1H),
4.05ꢀ3.86 (m, 2H), 3.10ꢀ2.99 (m, 1H), 2.89 (q, J = 8.0 Hz, 1H), 2.80ꢀ2.68 (m, 1H), 2.60ꢀ2.46 (m,
13
3H), 2.14ꢀ2.01 (m, 1H), 2.01ꢀ1.78 (m, 2H), 1.77ꢀ1.56 (m, 1H). C NMR (75 MHz, CDCl3): δ
212.9, 144.2, 143.1, 140.6, 130.8, 129.4, 127.6, 127.1, 126.1, 125.2, 124.5, 73.2, 50.7, 48.0, 39.1,
35.2, 24.5, 22.5. IR (neat): 2958, 2845, 1704, 1444, 1169, 758, cmꢀ1. HRMS m/z: ([M+Na]+) calcd
for C20H21NOSNa 346.1236; found 346.1236.
26a (endo) and 27a (exo): General procedure C was applied. αꢀEnaminone 25a (178 mg, 0.5
mmol) prepared according to General Procedure F and NaOMe (54 mg, 1.0 mmol), were mixes in
dry MeCN (0.5 mL) at room temperature. The reaction mixture was refluxed at 100 °C for 1 h. The
mixture was then concentrated in vacuo and the crude product was purified by flash
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chromatography (Silica gel, 5/95% ether/hexane) to yield 54% of 26a and 5% of 27a (65 mg and 7
mg respectively).
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49ꢀ51 °C). H NMR (300 MHz, CDCl3): δ 7.17 (d, J = 5.0, 1.3 Hz, 1H), 6.92ꢀ6.84 (m, 2H), 5.88ꢀ
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5.79(m, 1H), 3.96 (d, J = 14.1 Hz, 1H), 3.72 (d, J = 14.0 Hz, 1H), 3.17ꢀ3.07 (m, 1H), 2.92 (q, J =
7.8 Hz, 1H), 2.72ꢀ2.58 (m, 1H), 2.44ꢀ2.30 (m, 4H), 2.24ꢀ2.11 (m, 1H), 2.06ꢀ1.94 (m, 1H), 1.90ꢀ1.78
(m, 3H), 1.12 (t, J = 7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 213.6, 145.6, 143.9, 126.2, 124.1
(2C) 123.7, 74.0, 50.7, 47.9, 38.7, 35.4, 24.9, 22.6, 22.1, 13.3. IR (neat): 2957, 2924, 2848, 1703,
1177, 722 cmꢀ1. HRMS m/z: ([M+Na]+) calcd for C16H21NOSNa 298.1236; found 298.1237.
10-Ethylidene-1-(thiophen-2-ylmethyl)-1-azaspiro[4.5]decan-6-one (27a): pale yellow solid
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(M.p. 53ꢀ55 °C). H NMR (300 MHz, CDCl3): δ 7.19 (dd, J = 4.8, 1.6 Hz, 1H), 6.93 (d, J = 5.2
Hz, 2H), 6.07 (q, J = 7.0 Hz, 1H), 4.14 (d, J = 14.5 Hz, 1H), 3.72 (d, J = 14.5 Hz, 1H), 3.22ꢀ3.10
(m, 1H), 2.95ꢀ2.84 (m, 1H), 2.79ꢀ2.68 (m, 1H), 2.54ꢀ2.47 (m, 2H), 2.27ꢀ2.10 (m, 2H), 1.97ꢀ1.71 (m,
3H), 1.70ꢀ1.56(m, 5H).13C NMR (75 MHz, CDCl3): δ 213.8, 145.8, 139.2, 126.3, 124.1, 123.9,
118.5, 79.5, 50.9, 48.6, 39.9, 38.1, 25.9, 22.9, 21.7, 13.3. IR (neat): 2926, 2841, 1702, 1454, 1134,
851, 696 cmꢀ1. HRMS m/z: ([M+Na]+) calcd for C16H21NOSNa 298.1236; found 298.1236.
26b (endo) and 27b (exo): General procedure C was applied. αꢀEnaminone 25b (151 mg, 0.5
mmol) prepared according to General Procedure F and NaOMe (54 mg, 1.0 mmol) were mixed in
dry MeCN (0.5 mL) at room temperature. The reaction mixture was refluxed at 100 °C for 1 h. The
mixture was then concentrated in vacuo and the crude product was purified by flash
chromatography (Silica gel, 5/95% ether/hexane) to yield 71% of 26b and 16% of 27b (78 mg and
18 mg respectively) as pale yellow oils.
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10-Ethyl-1-propyl-1-azaspiro[4.5]dec-9-en-6-one (26b): H NMR (300 MHz, CDCl3): δ 5.81ꢀ
5.72 (m, 1H), 3.20ꢀ3.08 (m, 1H), 2.84ꢀ2.73 (m, 1H), 2.60ꢀ2.46 (m, 1H), 2.45ꢀ2.21 (m, 5H), 2.18ꢀ
1.96 (m, 2H), 1.90ꢀ1.69 (m, 4H), 1.54ꢀ1.19 (m, 2H), 1.03 (t, J = 7.5 Hz, 3H), 0.81 (t, J = 7.4 Hz,
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3H).13C NMR (75 MHz, CDCl3): δ 214.5, 144.2, 123.1, 73.6, 50.7, 50.4, 39.3, 34.7, 24.3, 22.7,
22.6, 21.9, 13.2, 11.8. IR (neat): 2958, 2931, 2872, 2847, 1712, 1458, 1180, 1085 cmꢀ1. HRMS m/z:
([M+Na]+) calcd for C14H23NONa 244.1672; found 244.1679.
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10-Ethylidene-1-propyl-1-azaspiro[4.5]decan-6-one (27b): 1H NMR (300 MHz, CDCl3): δ 5.81ꢀ
5.70 (m, 1H), 3.25ꢀ3.17 (m, 1H), 2.93ꢀ2.83 (m, 1H), 2.75ꢀ2.55 (m, 2H), 2.47ꢀ2.38 (m, 2H), 2.33ꢀ
2.25 (m, 1H), 2.18ꢀ2.03 (m, 2H), 1.89ꢀ1.82 (m, 1H), 1.76ꢀ1.70 (m, 3H), 1.64 (d, J = 6.9 Hz, 3H),
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1.57ꢀ1.39 (m, 3H), 0.86 (t, J = 7.4 Hz, 3H). C NMR (75 MHz, CDCl3): δ 214.4, 139.6, 117.8,
51.7, 51.0, 40.1, 38.1, 29.7, 25.8, 22.9, 22.7, 21.6, 13.2, 12.0. IR (neat): 2956, 2928, 2668, 1707,
1456, 1197, 1153, 1096 cmꢀ1. HRMS m/z: ([M+H]+) calcd for C14H24NO 222.1852; found
222.1855.
26c (endo) and 27c (exo): General procedure C was applied. αꢀEnaminone 25c (175 mg, 0.5 mmol)
prepared according to General Procedure F and NaOMe (54 mg, 1.0 mmol) were mixed in dry
MeCN (0.5 mL) at room temperature. The reaction mixture was refluxed at 100 °C for 1 h. The
mixture was then concentrated in vacuo and the crude product was purified by flash
chromatography (Silica gel, 5/95% ether/hexane) to yield 63% of 26c and 15% of 27c (85 mg and
20 mg respectively).
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1-Benzyl-10-ethyl-1-azaspiro[4.5]dec-9-en-6-one (26c): pale yellow solid (M.p. 52ꢀ55 °C). H
NMR (300 MHz, CDCl3): δ 7.34ꢀ7.16 (m, 5H), 5.90ꢀ5.82 (m, 1H), 3.76ꢀ3.51 (m, 2H), 3.04ꢀ2.93
(m, 1H), 2.85 (h, J = 6.5 Hz, 1H), 2.73ꢀ2.57 (m, 1H), 2.49ꢀ2.28 (m, 4H), 2.25ꢀ2.14 (m, 1H), 2.05ꢀ
1.76 (m, 4H), 1.11 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 214.0, 143.9, 140.5, 128.1,
128.0, 126.5, 123.8, 73.9, 52.8, 50.5, 39.0, 35.0, 24.7, 22.8, 22.1, 13.3. IR (neat): 2961, 2847, 1709,
1494, 1452, 1153, 733, 697 cmꢀ1. HRMS m/z: ([M+H]+) calcd for C18H24NO 270.1852; found
270.1857.
1-Benzyl-10-ethylidene-1-azaspiro[4.5]decan-6-one (27c): pale yellow solid (M.p. 57ꢀ58° C). 1H
NMR (300 MHz, CDCl3): δ 7.38 (d, J = 7.0 Hz, 2H), 7.32 (t, J = 7.5 Hz, 2H), 7.26ꢀ7.17 (m, 1H),
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5.97 (q, J = 7.0 Hz, 1H), 3.88 (d, J = 14.4 Hz, 1H), 3.65 (d, J = 14.6 Hz, 1H), 3.11ꢀ3.02 (m, 1H),
2.90ꢀ2.79 (m, 1H), 2.77ꢀ2.67 (m, 1H), 2.57ꢀ2.48 (m, 2H), 2.30ꢀ2.13 (m, 2H), 1.97ꢀ1.68 (m, 4H),
1.67ꢀ1.59 (m, 4H).13C NMR (75 MHz, CDCl3): δ 214.1, 140.9, 139.6, 128.1, 128.0, 126.3, 118.3,
79.7, 53.1, 50.7, 40.0, 37.7, 25.9, 22.9, 21.7, 13.3. IR (neat): 2926, 2849, 1703, 1492, 1453, 1209,
1152, 1136, 735, 697 cmꢀ1. HRMS m/z: ([M+Na]+) calcd for C18H23NONa 292.1672; found
292.1676.
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26d (endo) and 27d (exo): General procedure C was applied. αꢀEnaminone 25d (190 mg, 0.5
mmol) prepared according to General Procedure F and NaOMe (54 mg, 1.0 mmol) were mixed in
dry MeCN (0.5 mL) at room temperature. The reaction mixture was refluxed at 100 °C for 1 h. The
mixture was then concentrated in vacuo and the crude product was purified by flash
chromatography (Silica gel, 5/95% EtOAc/hexane) to yield 50% of 26d and 15% of 27d (75 mg
and 22 mg respectively).
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10-ethyl-1-(4-methoxybenzyl)-1-azaspiro[4.5]dec-9-en-6-one (26d): pale yellow oil. H NMR
(300 MHz, CDCl3): δ 7.19 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 5.88ꢀ5.80 (m, 1H), 3.79 (s,
3H), 3.68ꢀ3.47 (m, 2H), 2.99ꢀ2.91 (m, 1H), 2.88ꢀ2.79 (m, 1H), 2.69ꢀ2.59 (m, 1H), 2.55ꢀ2.30 (m,
4H), 2.23ꢀ2.12 (m, 1H), 2.01ꢀ1.77 (m, 4H), 1.11 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
214.0, 158.3, 143.9, 132.6, 129.1, 123.7, 113.5, 73.7, 55.2, 52.1, 50.4, 39.1, 35.0, 24.6, 22.7, 22.1,
13.3. IR (neat): 2960, 2834, 1709, 1510, 1241, 1168, 1036, 810 cmꢀ1. HRMS m/z: ([M+Na]+) calcd
for C19H25NO2Na 322.1778 ; found 322.1777.
(E)-10-ethylidene-1-(4-methoxybenzyl)-1-azaspiro[4.5]decan-6-one (27d): yellow oil. 1H NMR
(300 MHz, CDCl3): δ 7.29 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 5.97 (q, J = 6.9 Hz, 1H),
3.85ꢀ3.76 (m, 4H), 3.57 (d, J = 13.9 Hz, 1H), 3.07ꢀ2.96 (m, 1H), 2.88ꢀ2.68 (m, 2H), 2.57ꢀ2.47 (m,
2H), 2.30ꢀ2.14 (m, 2H), 1.97ꢀ1.70 (m, 5H), 1.66 (d, J = 5.7 Hz, 3H.13C NMR (75 MHz, CDCl3): δ
214.1, 158.2, 143.8, 139.6, 133.0, 129.1, 118.3, 115.0, 113.5, 79.5, 67.5, 55.2, 52.5, 50.6, 40.0,
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37.7, 25.9, 22.9, 21.6, 13.3. IR (neat): 2923, 2853, 1693, 1490, 1457, 1243, 1202, 1158, 1146, 742,
690 cmꢀ1. HRMS m/z: ([M+Na]+) calcd for C19H25NO2Na 322.1778; found 322.1777.
26e (endo) and 27e (exo): General procedure C was applied. αꢀEnaminone 25e (209 mg, 0.5 mmol)
prepared according to General Procedure F and NaOMe (54 mg, 1.0 mmol) were mixed in dry
MeCN (0.5 mL) at room temperature. The reaction mixture was refluxed at 100 °C for 1 h. The
mixture was then concentrated in vacuo and the crude product was purified by flash
chromatography (Silica gel, 5/95% ether/hexane) to yield 60% of 26e and 3% of 27e (101 mg and 5
mg respectively) as pale yellow oils.
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1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-10-ethyl-1-azaspiro[4.5]dec-9-en-6-one
(26e):
1H
NMR (300 MHz, CDCl3): δ 5.78ꢀ5.72 (m, 1H), 3.65ꢀ3.51 (m, 2H), 3.22ꢀ3.13 (m, 1H), 2.99ꢀ2.88
(m, 1H), 2.70ꢀ2.47 (m, 3H), 2.42ꢀ2.11 (m, 4H), 2.05ꢀ1.91 (m, 1H), 1.90ꢀ1.64 (m, 4H), 1.03 (t, J =
7.4 Hz, 3H), 0.87 (s, 9H), 0.02 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 214.0, 144.1, 123.2, 74.2,
62.7, 51.6, 51.5, 38.8, 34.8, 26.0, 24.7, 23.0, 21.9, 18.4, 12.9, ꢀ5.3. IR (neat): 2956, 2928, 2845,
1714, 1253, 1103, 832, 774 cmꢀ1. HRMS m/z: ([M+Na]+) calcd for C19H35NO2SiNa 360.2329;
found 360.2329.
1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-10-ethylidene-1-azaspiro[4.5]decan-6-one (27e): 1H
NMR (300 MHz, CDCl3): δ 5.81 (q, J = 6.4 Hz, 1H), 3.77ꢀ3.65 (m, 2H), 3.26ꢀ3.18 (m, 1H), 3.00ꢀ
2.78 (m, 2H), 2.76ꢀ2.65 (m, 1H), 2.58ꢀ2.47 (m, 1H), 2.45ꢀ2.38 (m, 2H), 2.20ꢀ2.01 (m, 2H), 1.94ꢀ
1.66 (m, 3H), 1.68ꢀ1.45 (m, 5H), 0.89 (s, 9H), 0.05 (s, 6H).13C NMR (75 MHz, CDCl3): δ 214.0,
139.5, 118.2, 80.1, 62.8, 52.4, 51.9, 40.0, 37.8, 26.0, 25.8, 22.9, 21.8, 18.4, 13.2, ꢀ5.31, ꢀ5.27. IR
(neat): 2954, 2928, 2856, 1709, 1254, 1104, 834, 775 cmꢀ1. HRMS m/z: ([M+Na]+) calcd for
C19H35NO2SiNa 360.2329; found 360.2327.
29 (endo) and 30 (exo): General procedure C was applied. αꢀEnaminone 28 (144 mg, 0.5 mmol)
prepared according to General Procedure F and NaOMe (54 mg, 1.0 mmol) were mixed in dry
MeCN (0.5 mL) at room temperature. The reaction mixture was refluxed at 100 °C for 1 h. The
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mixture was then concentrated in vacuo and the crude product was purified by flash
chromatography (Silica gel, 5/95% ether/hexane) to yield 17% of 29 and 46% of 30 (18 mg and 48
mg respectively) as pale yellow oils.
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10-Methyl-1-propyl-1-azaspiro[4.5]dec-9-en-6-one (29):
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1H NMR (300 MHz, CDCl3): δ 5.82ꢀ5.71 (m, 1H), 3.21ꢀ3.09 (m, 1H), 2.88ꢀ2.78 (m, 1H), 2.61ꢀ2.50
(m, 1H), 2.48ꢀ2.37 (m, 1H), 2.38ꢀ2.21 (m, 4H), 1.99ꢀ1.72 (m, 4H), 1.71 (s, 3H), 1.55ꢀ1.28 (m, 2H),
0.84 (t, J = 7.4 Hz, 3H).13C NMR (75 MHz, CDCl3): δ 214.3, 138.9, 125.7, 73.3, 50.5, 50.4, 39.3,
34.4, 24.4, 22.7, 22.6, 17.7, 11.9. IR (neat): 2957, 2930, 2848, 1711, 1448, 1184, 1083, 807 cmꢀ1.
HRMS m/z: ([M+H]+) calcd for C13H22NO 208.1696; found 208.1697.
10-Methylene-1-propyl-1-azaspiro[4.5]decan-6-one (30): 1H NMR (300 MHz, CDCl3): δ 5.19ꢀ
5.13 (m, 1H), 4.89ꢀ4.84 (m, 1H), 3.32ꢀ3.22 (m, 1H), 3.00ꢀ2.89 (m, 1H), 2.72ꢀ2.62 (m, 1H), 2.55 (dt,
J = 14.0, 4.3 Hz, 1H), 2.48ꢀ2.29 (m, 4H), 2.17ꢀ2.03 (m, 1H), 1.95ꢀ1.72 (m, 4H), 1.64ꢀ1.50 (m, 2H),
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1.46ꢀ1.36 (m, 1H), 0.86 (t, J = 7.4 Hz, 3H). C NMR (75 MHz, CDCl3): δ 213.5, 150.1, 109.4,
79.7, 51.8, 51.2, 40.5, 38.7, 33.6, 23.6, 22.9, 21.7, 11.9. IR (neat): 2955, 2934, 2870, 2843, 1708,
1457, 1100, 1082, 905 cmꢀ1. HRMS m/z: ([M+H]+) calcd for C13H22NO 208.1696; found 208.1696.
General procedure D: Synthesis of Quinolines and Quinolinols (1,2-addition). In a flameꢀdried
100 mL reaction flask flushed with nitrogen, fitted with a magnetic stirring bar and rubber septum a
solution of SmI2 in THF (0.1 M, 4.0 equiv.) was added dropwise (1 mL/min) to a solution of αꢀ
enaminone (1.0 equiv, 0.5 mmol), HMPA (10.0 equiv., 5.0 mmol) and tꢀBuOH (10.0 equiv., 5.0
mmol) in dry THF (0.05 M) at 0 °C. The reaction mixture was then stirred under inert atmosphere
for 1 h at room temperature and quenched with aqueous saturated NH4Cl. The mixture was
extracted with EtOAc, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude
mixture was purified by flash chromatography to yield the desired product.
1-Benzyl-8-ethyl-1,3,4,5,6,7-hexahydroquinolin-4a(2H)-ol (32a): General procedure D was
applied. A solution of SmI2 in THF (20.0 mL, 0.1 M, 2.0 mmol) was added dropwise to a solution
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of αꢀenaminone 31a prepared according to General Procedure G, (199 mg, 0.5 mmol), HMPA (895
mg, 5.0 mmol), and tꢀBuOH (370 mg, 5.0 mmol) in dry THF (10.0 mL) at 0 °C. The reaction
mixture was stirred under inert atmosphere for 1 h at room temperature and quenched with aqueous
saturated NH4Cl. The mixture was then dried over anhydrous Na2SO4, filtered and concentrated in
vacuo. The crude product was purified by flash chromatography (Silica gel, 10/90% EtOAc/hexane)
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to yield 32a in 43% yield (58 mg) as mixture of 2 diastereomers as yellow liquid. H NMR (300
MHz, CDCl3): δ 7.42ꢀ7.29 (m, 4H), 7.28ꢀ7.21 (m, 1H), 4.39 (d, J = 14.5 Hz, 1H), 3.83 (d, J = 14.3
Hz, 1H), 2.79ꢀ2.90 (m, 1H), 2.60 (t, J = 12.8, 2.9 Hz, 1H), 2.28 (q, J = 7.5 Hz, 2H), 2.17ꢀ2.02 (m,
2H), 2.01ꢀ1.79 (m, 2H), 1.79ꢀ1.71 (m, 1H), 1.59ꢀ1.70 (m, 2H), 1.56ꢀ1.38 (m, 2H), 1.29ꢀ1.14 (m,
1H), 0.99 (t, J = 7.6 Hz, 3H).13C NMR (75 MHz, CDCl3): δ 142.4, 141.0, 130.1, 128.3, 128.1,
126.7, 69.4, 60.3, 48.1, 39.4, 39.3, 29.3, 24.8, 18.4, 18.1, 12.8. IR (neat): 2930, 2872, 1710, 1459,
942, 734, 697 cmꢀ1. HRMS m/z: ([M+Na]+) calcd for C18H25NONa 294.1828; found 294.1824.
8-Ethyl-1-propyl-1,3,4,5,6,7-hexahydroquinolin-4a(2H)-ol (32b): General procedure D was
applied. A solution of SmI2 in THF (20mL, 0.1 M, 2.0 mmol) was added dropwise to a solution of
αꢀenaminone 31b prepared according to General Procedure G, (175 mg, 0.5 mmol), HMPA (895
mg, 5.0 mmol), and tꢀBuOH (370 mg, 5.0 mmol) in dry THF (10.0 mL) at 0 °C. The reaction
mixture was stirred under inert atmosphere for 1 h at room temperature and quenched with aqueous
saturated NH4Cl. The mixture was then dried over anhydrous Na2SO4, filtered and concentrated in
vacuo. The crude product was purified by flash chromatography (Basic alumina, 5/95%
EtOAc/hexane) to yield 32b in 37% yield (41 mg) as mixture of 2 diastereomers as yellow liquid.
1H NMR (300 MHz, CDCl3): Mixture of diastereomers: δ 3.09ꢀ2.92 (m, 2H), 2.70ꢀ2.58 (m, 2H),
2.16ꢀ2.06 (m, 3H), 2.04ꢀ1.95 (m, 2H), 1.86ꢀ1.71 (m, 2H), 1.61ꢀ1.53 (m, 2H), 1.52ꢀ1.38 (m, 4H),
1.34ꢀ1.24 (m, 2H), 0.95 (t, J = 7.6 Hz, 3H), 0.87 (t, J = 7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3):
Major diastereomer: δ 142.7, 127.7, 69.3, 58.4, 49.2, 39.6, 38.9, 29.5, 25.1, 23.0, 19.6, 18.7, 13.0,
11.6. Minor diastereomer, characteristic signals: δ 79.9, 57.9, 53.6, 42.4, 34.7, 34.1, 23.6, 21.0,
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