Synthesis of Polycyclic δ-Lactams with Bridged Benzomorphan Skeleton: Selectivity and Diversity Driven by Substituents

Article abstract of DOI:10.1021/acs.joc.7b02509

An efficient synthesis of bromofunctionalized 2,6-methano- and 1,5-methano-benzomorphanones, starting from easily available 6-benzyl-3,6-dihydropyridin-2(1H)-ones, is described. Furthermore, the synthesis of bridged benzomorphanones with hitherto not know

Full text of DOI:10.1021/acs.joc.7b02509

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Article
Synthesis of Polycyclic #-Lactams with Bridged Benzomorphan
Skeleton: Selectivity and Diversity Driven by Substituents
Jacek G. So#nicki, Tomasz J. Idzik, Aleksandra Borzyszkowska, Gabriela Maciejewska, and #ukasz Struk
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02509 • Publication Date (Web): 16 Jan 2018
Downloaded from http://pubs.acs.org on January 16, 2018
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Synthesis of Polycyclic δꢀLactams with Bridged Benzomorphan Skeleton:
Selectivity and Diversity Driven by Substituents
,
†
†
†
‡
Jacek G. Sośnicki,* Tomasz J. Idzik, Aleksandra Borzyszkowska, Gabriela Maciejewska,
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†
Łukasz Struk
†
West Pomeranian University of Technology, Szczecin, Faculty of Chemical Technology and Engineering,
Department of Organic and Physical Chemistry, Al. Piastów 42, Szczecin, 71ꢀ065, Poland,
‡
Wrocław University of Technology, Faculty of Chemistry, Wybrzeże Wyspiańskiego 27, 50ꢀ370 Wrocław,
Poland
Corresponding author’s eꢀmail address: sosnicki@zut.edu.pl
Abstract
An efficient synthesis of bromofunctionalized 2,6ꢀmethanoꢀ and 1,5ꢀmethanoꢀ
benzomorphanones, starting from easily available 6ꢀbenzylꢀ3,6ꢀdihydropyridinꢀ2(1H)ꢀones, is
described. Furthermore, the synthesis of bridged benzomorphanones with hitherto not known
polycyclic systems containing 2ꢀ or 3ꢀazabicyclo[4.1.0]heptane units is developed upon treatment of
both 2,6ꢀ and 1,5ꢀmethanobromobenzomorphans with t-BuOK. The effects of substituents on the
diversity and stereoselectivity of both transformations are studied.
Introduction
Polycyclic organic compounds with piperidine core constitute useful drugs or their naturally
occurring precursors. A couple of synthetic benzomorphan and natural morphine (as an archetype)
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are prominent examples. The main interest in benzomorphans 1 (1,2,3,4,5,6ꢀhexahydroꢀ2,6ꢀ
methanoꢀ3ꢀbenzazocine, Figure 1), which have the ring system matching the part of morphine
3
skeleton and which could be represented by (R)ꢀpentazocine – clinically used drug (Figure 1),
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results from their structural simplicity and new profiles of analgesic activity giving hope for
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nonaddictive medication that could replace morphine. Apart from the opioid receptor activity,
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benzomorphans have also been recognized as sodium channel blockers for the treatment of stroke
6
and as potential drugs for the treatment of cocaine addiction and overdose. The construction of
benzomorphan analogues in terms of positional variation of nitrogen have been also carried out to
2
determine their pharmacological utility. Amongst a few ringꢀconnections variants, benzomorphan
analogues based on the skeleton of 2 (1,2,3,4,5,6ꢀhexahydroꢀ1,5ꢀmethanoꢀ3ꢀbenzazocine, Figure 1)
have attracted attention as potential drugs supporting smoking cessation (similarly to natural cytisine,
7
8
Figure 1) and as tyrosine analogue, which could be used as a potential ligand for SH2 inhibition.
FIGURE 1. Naturally occurring morphine, cytisine and clinically used (R)ꢀpentazocine as
representative of synthetic benzomorphans
A number of methodologies have been developed for the synthesis of benzomorphans 1 and 2
2
(
2,6ꢀmethanoꢀ3ꢀbenzazocines and 1,5ꢀmethanoꢀ3ꢀbenzazocines, respectively). One of interesting
strategies comprises the cyclization of benzylꢀfunctionalized piperidines. Within this strategy, the
sequence with intramolecular FriedelꢀCrafts cyclization as a key step, involving benzylpiperidines
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with hydroxyl or C=C double moieties (capable to create carbocationic, electrophilic site) is a
2
,4a,5a,9
dominant approach.
Among other methods noteworthy is the cyclization of benzylꢀ
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piperidinones in the BuchwaldꢀHartwig reaction. Unsaturated benzylꢀδꢀlactams were sparingly
applied as substrates towards benzomorphans. Only recently 6ꢀbenzyl α,βꢀunsaturated δꢀlactams
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have been cyclized in acidic and radical conditions. It should be also emphasized that amongst the
reagents able to induce electrophilic site in the double C=C bond of unsaturated piperidines, only
acids gave benzomorphans as cyclization products, while the attempt to use bromine led to transꢀ
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dibromo adduct, not to bromoꢀsubstituted benzomorphans. Despite that failure, the investigation
toward the synthesis of bromoꢀsubstituted benzomorphans is a hot subject of research because these
compounds could reveal new pharmacological properties, as inferred from the properties of natural
1
4
bioactive compounds containing bromine atom in their structure. Besides, the introduction of
reactive bromine atom into benzomorphan skeleton could open new synthetic possibilities.
Therefore, the synthesis of halogenꢀfunctionalized benzomorphans is an ongoing challenge.
The past decades have witnessed great progress in the field of induced by halonium ions
15
stereoselective cyclofunctionalization of alkenes equipped with a nucleophilic arm. However,
halocarbocyclizations, in which halonium intermediate is quenched intramolecularly by πꢀelectrons
of the aromatic ring have been less studied. As representative examples, the treatment of 3ꢀbenzyl
1
6
cycloalkenes with bromine, providing bromoꢀcyclized product should be mentioned. Amongst
other reagents capable of forming halonium ion: N-halosuccinimide (NXS) in the presence of
1
7
18
Sm(OTf)
3
and IPy
2
BF
4
–HBF4,
has been used. BDSB (bromodiethylsulfonium
bromopentachloroantimonate) has been recently found as one of the most convenient reagent for
19
carbocyclization. Besides, catalytic enantioselective bromocyclization of aromatic polyenes has
20
also been successfully discovered.
Recently, we have developed a straightforward synthesis of 6ꢀbenzyl β,γꢀunsaturated δꢀ
21
lactams through the addition of lithium disecꢀbutylbenzylmagnesiate to 2ꢀpyridones and now we
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decided to use these adducts as starting material in the synthesis of bromobenzomorphans. Herein,
we report results of our effort towards the synthesis of bromoꢀbenzomorphans through the
halocarbocyclization process, starting from 6ꢀbenzyl β,γꢀunsaturated δꢀlactams and their further
transformation to the novel polycyclic systems which may be regarded as bridged benzomorphan
derivatives. Hitherto, 6ꢀbenzyl β,γꢀunsaturated δꢀlactams have not been used for the synthesis of
benzomorphans.
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Results and Discussion
The initial experiments to obtain cyclized product (via 6ꢀendo trig process) were started with
6ꢀbenzyl, Nꢀmethyl β,γꢀunsaturated δꢀlactam (1a), as well as BDSB and NBS as easy to use
electrophilic sources of bromine. As a result, the use of BDSB led to total failure, while the
application of NBS in THF premised success because it led to 11ꢀbromobenzomorphanone product
2a, unfortunately only in 30% yield (Table 1, entry 1). Because the yield of 2a was not satisfactory
and additional undesired product 3 was also formed in 28% yield, further optimization was required.
The relevant results are collected in Table 1. Happily, from among solvents tested nitromethane was
disclosed as the best one, allowing improvement of yield of 2a up to 66% (Table 1, entry 7).
Furthermore, triphenoxyphosphine (0.175 equiv.) was found as the best phosphineꢀderived additive.
It allowed enhancement of the productivity of 2a up to 97% yield and its use prevented the formation
of 3 (Table 1, entry 16). Successful use of phosphorous(III) additives, in particular
triphenylphosphite, indicated that reactive bromophosphonium ion (BPI) was formed, leading to
2
0c
product 2 as depicted in Scheme 1. Nitromethane as a polar solvent probably stabilized this ion
and subsequently formed a bromocarbonium ion, facilitating the cyclization instead of
dibromination.
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TABLE 1. Optimization at the reaction conditions for bromocarbocyclization of 1a using NBS.
The effect of varying solvents and R P as additives
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
3
3
3
3
4
4
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4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
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2
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a
a
Yields Yields
a
R
3
P additives
(equiv.)
Conv.
[%]
Entry Solvent
NBS (eqiv.) / Time (h)
[%]
2a
30
33
8
[%]
3
1
2
3
4
5
THF
MeCN
DMF
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
up to 5.8 / up to 96
up to 1.7 / up to 24
up to 2.2 / up to 59
2.2 / 48
>99
>99
89
28
4
b
ꢀ
e
CH Cl
98
17
35
42
66
26
63
81
85
88
92
76
85
97
84
48(48 )
2
2
acetone
~2.8 / 264
>99
98
12
16
3
c
6
7
8
9
PhCl
up to 2.2 / up to 96
up to 2.0 / up to 96
up to 1.8 / up to 92
1.2/3
c
c
c
MeNO
CH Cl
MeCN
2
>99
99
2
2
Ph
3
P (0.2)
26
0
Ph P (0.2)
89
3
c
1
1
1
0
1
2
MeNO
MeNO
2
Ph
Ph
Ph P (0.3)
3
P (0.2)
1.5/3
96
0
c
c
c
c
c
c
c
2
3
P (0.25)
1.5/3
96
0
MeNO2
1.5/3
95
0
3
d
13
MeNO
MeNO
2
2
Ph
Ph
3
3
P (0.3)
P (0.4)
1.5/3
94
0
1
4
5
1.5/3
1.5/3
1.5/3
1.5/3
86
0
1
MeNO2
MeNO
MeNO
(PhO) P (0.1)
86
0
3
16
2
(PhO)
3
P (0.175)
P (0.2)
98
0
17
2
(PhO)
3
98
0
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MeNO2 ((oꢀtol) P) (0.175)
1.5/3
1.5/3
1.5/3
97
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85
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84
0
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9
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MeNO
MeNO
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((oꢀtol)
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P) (0.2)
P) (0.3)
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((oꢀtol)
3
a
b
c
–
by GC-FID (calibration curve), – unidentified product was present, - the reactions were conducted in the
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dark; – the reaction was conducted at 0 C, – isolated yield
SCHEME 1. C4ꢀsubstituent dependent reactivity of 1 under bromocyclization conditions
(
results in Table 2)
At the next step, the influence of substituents at the nitrogen atom and at C4 of 6ꢀbenzyl β,γ
ꢀ
unsaturated ꢀlactams was tested under optimized bromocyclization conditions. As a result, C4ꢀ
δ
unsubstituted N-Me, N-Pr, N-Bn, and N-Ph derivatives gave sole bromobenzomorphans products 2 in
high isolated yields, while 4ꢀMe and 4ꢀPh derivatives led also to product 4 besides benzomorphans 2
(
Scheme 1, Table 2). Notably, the amounts of compound 4 were depended on the nature of 4ꢀ
substituent and were high for 4ꢀphenyl and low for 4ꢀmethyl derivatives. This result indicates that for
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4ꢀsubstituted substrates, in the transition state, carbocation formation at C4 is possible which is better
stabilized by C4ꢀPh in comparison to C4ꢀMe group, resulting in increasing the amounts of
elimination products 4. It is worth mentioning that compounds 2eꢀi and 4eꢀi were laboriously
separated using 120ꢀcm long chromatographic column and that 4ꢀmethyl derivatives of 4 were
unstable, making their analysis difficult.
1
1
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TABLE 2. Bromocarbocyclization of 6ꢀbenzyl, NR and C4ꢀR substituted β,γꢀunsaturated
δꢀlactams 1 under optimized conditions (Scheme 1)
Isolated
Isolated
1
2
a
Entry
Compounds
NR
C4ꢀR
Selectivity
2 : 4
yields [%]
yields [%]
1, 2, 4
2
4
ꢀ
1
2
a
b
c
d
e
f
Me
nPr
Bn
Ph
H
H
100 : 0
100 : 0
100 : 0
100 : 0
86 : 14
85 : 15
93 : 7
97
84
93
81
91
83
89
24
19
ꢀ
b
3
H
ꢀ
b
4
H
ꢀ
5
6
7
8
9
Me
Bn
Ph
Me
Me
Me
Ph
Ph
0
14
0
g
h
i
Me
Bn
19 : 81
21 : 79
75
76
a
1
b
-
assigned by H NMR of the crude reaction mixture; – PPh
3
(0.3 mole) was used.
We then evaluated the influence of substituents at Cꢀ3 of 6ꢀbenzylꢀ3,6ꢀdihydropyridinꢀ2(1H)ꢀ
one on bromocarbocyclization, at first using Cꢀ3 monosubstituted compounds, both trans and cis
derivatives, bearing benzyl substituent at Cꢀ6 and methyl or benzyl substituents at Cꢀ3 (Scheme 2
and 3). Surprisingly, only transꢀderivatives 1j, 1k gave benzomorphans 2j and 2k, respectively
(Scheme 2), while cisꢀderivatives 1l and 1m were unreactive (Scheme 3).
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SCHEME 2. Bromocarbocyclization of 3,6ꢀtrans substituted 3,6ꢀdihydropyridinꢀ2(1H)ꢀones 1j
and 1k
SCHEME 3. The attempts at bromocarbocyclization of 3,6ꢀcis substituted 3,6ꢀdihydropyridinꢀ
2(1 )ꢀones 1l and 1m
H
It should be emphasized that from the two transꢀoriented benzyl groups in 1k, only 6ꢀbenzyl group
was involved in the cyclization process (Scheme 2, path a), while the 3ꢀbenzyl group remained intact
(Scheme 2, path b). Next, 6ꢀbenzyl, 3,3ꢀdisubstituted derivatives were studied including 3,3ꢀ
dimethylꢀ (1n) (Scheme 4), 3,3ꢀdibenzylꢀ (1o), transꢀ3ꢀbenzylꢀ3ꢀmethylꢀ (1p) and transꢀ3,6ꢀ
dibenzylꢀ (1q) substituted derivatives (Scheme 5). As a result, bromine underwent an addition to 6ꢀ
benzylꢀ3,3ꢀdimethyl δ−lactam 1n yielding dibromolactam 5 (Scheme 4), instead of carbocyclized
product, while for 1oꢀq the 3ꢀbenzyl group (being in trans relation to benzyl group at Cꢀ6) was
involved in carbocyclization leading to 1,5ꢀmethanobenzomorphan 6oꢀ6q in good yields (Scheme 5,
path a). The above results indicated the steric hindrance of C6ꢀbenzyl group vs cisꢀoriented C3ꢀ
methyl/benzyl substituents in the transition state A for the lack of carbocyclization of 1lꢀ1n (Scheme
3
and 4) and reactivity of 1oꢀq towards 2,6ꢀmethanobenzomorphans (Scheme 5, path b).
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SCHEME 4. The attempts at bromocarbocyclization of 6ꢀbenzylꢀ3,3ꢀdimethylꢀ3,6ꢀdihydroꢀ
pyridinꢀ2(1H)ꢀone 1n
SCHEME 5. Bromocarbocyclization of 1o, 1p and 1q
In this context the preference of cyclization of 1k towards 2,6ꢀmethano derivative 2k with the
participation of C6ꢀBn instead of C3ꢀBn group (Scheme 2) could not be easily explained. It seemed
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that electron distribution in the transition state and conformational preference of C6ꢀBn and C3ꢀBn
groups determined by one substituent at Cꢀ3, enabling the 2,6ꢀmethanobenzomorphan formation,
while two substituents at Cꢀ3, could change the conformation of lactam ring thus allowing to cyclize
with the participation of Cꢀ3Bn leading do 1,5ꢀmethanobenzomorphan. However, in order to
completely clarify this issue, further research is required.
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It should be strongly emphasized that in all carbocyclizations showed above, only 6ꢀendo-trig
cyclization products were formed, even if Baldwin's rules permit both 5ꢀexo-trig and 6ꢀendo-trig
processes and even though both products are located at similar energetic levels, as suggested by heats
of formations calculated for obtained 2d and hypothetical 5ꢀexo-trigꢀ2d products, for example
(Scheme 6). The regioselectivity of cyclization observed can be easily explained on the basis of
22
stereoelectronic effect, which assumed axial attack relative to the electrophilic carbon atom, here
involved in bromonium ion. The axial approach of the benzene ring to Cꢀ4 of lactam is only possible
when 6ꢀbenzyl group takes the axial orientation, thus allowing 1,3ꢀbridge formation (Scheme 6, path
a).
SCHEME 6. Example of bromocarbocyclization of 1d through 6ꢀendo-trig vs 5ꢀexo-trig
processes
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Subsequently, we checked the behavior of bromobenzomorphans 2 upon treatment with
strong bases, expecting anion formation, which could react intramolecularly through substitution of
bromine, yielding cyclopropane ring. The anticipated transformation involving cyclopropanation was
successful because it led to the polycyclic lactam 7 by the connection of Cꢀ1 and Cꢀ11 atoms of the
corresponding benzomorphan (Scheme 7, Scheme 8 ꢀ lower part). The ring system obtained has been
hitherto unknown and may be considered as a novel bridged benzomorphan skeleton.
1
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SCHEME 7. Synthesis of bridged benzomorphans 7
In a more detailed study, we found that LDA and DBU was not effective and that in optimized
conditions the addition of 7eq. of t-BuOK to THF solution of bromobenzomorphan led to desired
product in high yields within 2ꢀ7 h, at room temperatures, however, only for N-alkyl substituted
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benzomorphans (Scheme 7), while N-Ph bromobenzomorphan 2d gave at these conditions
1ꢀcarboxyamidomethyloꢀsubstituted naphthalene 8 (Scheme 8). Switching solvent from THF to
DMF or HMPA allowed us to obtain also a novel N-phenyl bridged derivative 7f in 44% and 53 %
yields, respectively, however, still together with naphthalene 8 (Scheme 8).
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SCHEME 8. Effect of N-Ph substituent in 2d on distribution of product 8 and 7f
Although the formation of cyclopropane ring in 2 can be easily rationalized by the
geometrically defined approach of benzyl anion in B to C11ꢀBr from the opposite side with respect
to the living bromine atom (Scheme 8, lower part), the unexpected formation of naphthalene
derivative 8 prompted us to perform additional kineticꢀlike NMR study. Conducting the reaction in
8
an NMR tube in THFꢀd solution by mixing of 2d with different quantities of t-BuOK and recording
1
the H NMR spectra in equal time intervals allowed us to observe the formation of intermediate (intꢀ
1) and to establish the dependence of the rates of both elimination processes on the quantity of the
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base (see Supporting Information). A plausible mechanism of both transformation is depicted in
Scheme 8. The structure of intermediate intꢀ1 was evidenced by the recording of 1D NMR spectra at
their highest concentration reached during the reaction, conducted in an NMR tube (details see
Supporting Information).
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In further studies, we found that the procedure of cyclopropanation is more general because it
was also successfully applied for 1,5ꢀmethanobromobezomorphan 6oꢀq leading to corresponding
cyclopropaneꢀfused benzomorphans 9oꢀq in satisfactory yields (Scheme 9).
SCHEME 9. Synthesis of bridged benzomorphans 9
Next, we decided to apply the developed procedures in the synthesis of bridged 2,6ꢀmethanoꢀ
benzomorphan 15, having phenyl substituent in the cyclopropane ring at C3b. Synthesis of such
compound implies the formation of additional asymmetric center at C1 in bromobenzomorphan and
at C3b in bridged derivative (Scheme 10). Initially, 6ꢀ(diphenylmethyl)ꢀ4ꢀmethylꢀ3,6ꢀ
dihydropyridinꢀ2(1H)ꢀone (12) was prepared as a starting compound in the reaction between
23
diphenylmethyllithium (10Li) and 4ꢀmethylꢀ2ꢀpyridone in 45% yield (Scheme 10). Subsequently,
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carbocyclization led to product 13, isolable in 60% yields and byꢀproduct 14 which was difficult to
purify. Products 13 : 14 were obtained at the molar ratio 78 : 22. Cyclopropanation of 13 led to
product 15 in 96% yield.
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Despite incomplete regioselectivity of carbocyclization, the formation of lactams 13 was fully
stereoselective because the second isomer (13ꢀ1) possibly formed was not detected in the crude
1
reaction mixture (checked by H NMR) (Scheme 10). Judging by the heat of formation (
ꢀ
H),
calculated at PM3 level of theory for the structure of obtained isomer 13, which is less about 4.24
kcal/mol in relation to H of possibly formed structure 13ꢀ1, one could conclude that in transition
ꢀ
state the steric interaction between the phenyl group of benzhydryl substituent and N-Me moiety
determine the stereochemical course of this reaction, as depicted in Scheme 11.
SCHEME 10. Synthesis of bridged benzomorphans 15 with C3bꢀphenyl substituent
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SCHEME 11. Stereoselective carbocyclization of 12
As azabicyclo[4.1.0]heptane ring systems, present in both obtained bridged benzomorphans 7
and 9, consist of the central cores of some biologically active compounds, e.g. of piperidine:
(ꢀ)ꢀGSK1360707 (developed by GlaxoSmithKline as potent dopamine reuptake inhibitor for the
2
4
treatment of the major depressive disorder (MDD) and amidine: ONOꢀ1714 (acting as a potent
25
inhibitor of inducible nitric oxide synthase and as a potential neuroprotective agent in stroke
26
patients, (Figure 2), finally, we converted two representatives of bridged benzomorphans 7a and 9o
into amidine and piperidine derivatives, respectively, according to scheme 12. The results of not
optimized transformations indicate high stability of obtained ring systems present in compounds 16ꢀ
18 and designate starting lactams as prospect derivatives for further functionalizations toward
bridged benzomorphans.
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FIGURE 2. Biologically active compounds with azabicyclo[4.1.0]heptane ring systems
SCHEME 12. The attempts at derivatization of bridged benzomorphanones via
transformations of amide group
1
13
13
The structures of all compounds were elucidated with the aid of 1D NMR ( H, C, Cꢀ
1
1
13
1
1
1
1
13
DEPTꢀ135) and 2D NMR ( H, H DFQꢀCOSY, C, H COSY, H, H NOESY, H, C HMBC)
spectroscopy. The routine NMR spectra were taken in CDCl solutions, although perdeuterated
3
toluene was used in some cases in order to get a better separation of the signals. In the assignment of
structures, the conformational analysis was applied. It consisted in unequivocal assignment of the
1
maximum number of H NMR signals to the appropriate proton in the molecule (using correlation
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methods), refinement of JH,H(exp) coupling constants, and their comparison with theoretical values
27
of coupling constants [JH,H(calc)] calculated using Karplus like equations based on dihedral angles
28
found in PM3 optimized structures. The theoretical values of coupling constants matched the
coupling constants obtained from the spectra, confirming the correctness of the proposed structures.
Additionally, in order to be absolutely sure that 5ꢀexo-trig cyclization products were not formed,
theoretical values of coupling constants of hypothetical 5ꢀexo-trigꢀ2d (Scheme 6) were calculated for
the PM3 optimized structure for comparison. The results, included in Supplementary Information,
1
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showed a large difference between the coupling constants calculated and those refined from the H
NMR spectrum of 2d, thus unambiguously indicating benzomorphanone as the obtained product.
1
1
Finally, the refined structures were additionally supported by the H, H NOESY throughꢀspace
interactions between the juxtaposed hydrogen atoms. The observed NOE effects in NOESY spectra
for selected representatives are shown in Figure 3 and in Supplementary Information.
Conclusion
In conclusion, we have demonstrated that stereoselective carbocyclization of 6(3)ꢀbenzylꢀβ,γ
unsaturated ꢀlactams using NBS with P(OPh) as an additive, followed by treatment of the obtained
1ꢀbromobenzomorphanones (2,6ꢀmethanoꢀ and 1,5ꢀmethanoꢀ3ꢀbenzazocinones) with t-BuOK as a
ꢀ
δ
3
1
base, provides easy access to novel and unique benzomorphanones with internal
azabicyclo[4.1.0]heptane unit. In spite the fact that in both transformations the presence of
substituents at the 3,6ꢀdihydropyridinꢀ2ꢀone ring influenced the regioselectivity the high synthetic
potential of the proposed approach is pronounced by the possible farꢀreaching functionalization of
bromo and amide groups in the products. Besides, in the light of great interest in the synthesis of
piperidine derivatives as potential pharmaceuticals, the successful synthesis of
bromobenzomorphanones and its bridged derivatives, capable of further functionalization may gain
considerable importance in drug development area.
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FIGURE 3. Diagnostic NOE effects found in H, H NOESY spectra of representative
compounds
Experimental section
1
13
Melting points were determined on a Boetius hot stage apparatus. H, C NMR spectroscopic
measurements were performed on a Bruker DPX 400 Avance III HD spectrometer, operating at
400.1 and 100.6 MHz, respectively. TMS was used as internal reference and spectra were acquired in
5
1
mm probes. For NMR analyses ACD/SpecManager (version 12.01) and MestReNova (version
0.0.1) programs were used. For detailed peak assignments, 2D spectra were acquired using Bruker
1
1
13
1
1
1
1
13
1
1
software ( H, H DFQꢀCOSY, C, H COSY, H, H NOESY, H, C HMBC). In the H, H NOESY
1
13
spectra the optimized mixing time, varied from 0.65 s to 0.95 s, was used. The H, C HMBC longꢀ
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range correlations were acquired for JC,H=10 Hz. The standard abbreviation for multiplicities were
used (s = singlet, d = doublet, t = triplet, q =quartet, quint = quintet, m = multiplet, sxt = sextet, spt =
septet, etc.). Gas chromatographyꢀmass spectrometry (GCꢀMS) measurements were carried out on a
HewlettꢀPackard instrument model HP 6890 equipped with a mass detector HP 5973 and on an
Agilent 7820A GC system equipped with a mass (Agilent 5977E MSD) and FID detectors. Infrared
spectra were taken with a Specord M80 instrument and Alfa spectrometer with ATRꢀadapter
(Bruker). The standard abbreviation for IR band intensities description was used (s – strong, m –
medium, w – weak). HRMS analyses (ESI+) were performed on a Waters LCT premier XE (TOF)
using acetonitrile as solvent. Elemental analysis was performed on an Elementar model Vario EL III
analyzer.
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Reactions in tetrahydrofuran (THF) solution was performed under argon in flameꢀdried flasks and
liquid components were added from a syringe. THF was purified in argon atmosphere according to a
standard procedure prior to use. Products were purified by flash column chromatography on silica
gel (63ꢀ200 µm, Merck) using appropriate solvents. Nitromethane was used such as purchased. NBS
was recrystallized before use.
Syntheses of substrates used
21
Compounds 1c, 1d, 1e, 1h, 1i, 1n, 1q were obtained according to procedure described earlier.
Compounds 1e, 1h, 1i are new, their spectroscopic data are as follows:
(±)-6ꢀBenzylꢀ1,4ꢀdimethylꢀ3,6ꢀdihydropyridinꢀ2(1H)ꢀone (1e): Yield 80% (0.377g). The crude
product purified by column chromatography (SiO , nꢀhexane : ethyl acetate, 1 : 3) gave colorless oil.
2
1
o
H NMR (400 MHz, CDCl
CHHꢀ3), 2.47 (dd, J=21.3, 2.0 Hz, 1 H, CHHꢀ3), 2.82 (dd, J=13.3, 3.5 Hz, 1 H, 6ꢀCHH), 2.92 (dd,
J=13.3, 6.1 Hz, 1 H, 6ꢀCHH), 3.08 (s, 3 H, NCH ), 4.03ꢀ4.11 (m, 1 H, CHꢀ6), 5.37 (ddq, J=4.2, 2.7,
1.3 Hz, 1 H, =CHꢀ5), 7.01ꢀ7.05 (m, 2 H, C H ), 7.20ꢀ7.28 (m, 3 H, C H ). C NMR (100 MHz,
3 3
, 23 C): δ = 1.60 (t, J=1.3 Hz, 3 H, 4ꢀCH ), 1.95 (dt, J=21.3, 2.7 Hz, 1 H,
3
13
6
5
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o
CDCl
3
, 23 C): δ = 21.6 (4ꢀCH
3
), 32.9 (NCH
3 2 2
), 36.5 (CH ꢀ3), 39.7 (6ꢀCH ), 61.3 (CHꢀ6), 119.0
(=CHꢀ5), 126.7, 128.1, 130.0, 135.9 (C
6
H
5
), 132.3 (=CHꢀ4), 168.7 (C=O). GCꢀMS (EI, 70eV): m/z =
ꢀ1
+
1
24 (100), 91 (13). IR (ATR):
16.1388; found 216.1394.
ν = 1637 cm . HRMS (ESIꢀTOF): m/z calcd for C14H18NO[M+H] ,
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(
±)ꢀ6ꢀBenzylꢀ1ꢀmethylꢀ4ꢀphenylꢀ3,6ꢀdihydropyridinꢀ2(1H)ꢀone (1h): Yield 85% (0.517g). The crude
product purified by column chromatography (SiO
2
, nꢀhexane : ethyl acetate, 1 : 2) gave white solid,
1
o
m.p. 94ꢀ96 °C (petroleum ether : ethyl acetate). H NMR (400 MHz, CDCl
3
, 23 C): δ = 2.32 (dt,
J=20.5, 2.9 Hz, 1 H, CHHꢀ3), 2.95 (dd, J=13.3, 3.5 Hz, 1 H, 6ꢀCHH), 2.99 (d, J=20.5 Hz, 1 H, CHHꢀ
3
), 3.05 (dd, J=13.3, 6.1 Hz, 1 H, 6ꢀCHH), 3.16 (s, 3 H, NCH ), 4.27ꢀ4.34 (m, 1 H, CHꢀ6), 6.02 (dd,
3
13
J=4.8, 2.9 Hz, 1 H, =CHꢀ5), 7.03ꢀ7.07 (m, 2 H, ArH), 7.21ꢀ7.35 (m, 8 H, ArH). C NMR (100 MHz,
o
CDCl3, 23 C): δ = 32.8 (NCH
3
), 34.0 (CH
2
ꢀ3), 39.6 (6ꢀCH
2
), 61.7 (CHꢀ6), 120.6 (=CHꢀ5), 125.0,
1
26.9, 127.9, 128.2, 128.6, 130.0 (ArH), 134.7, 135.5, 138.4 (Ar, =Cꢀ4), 168.5 (C=O). GCꢀMS (EI,
ꢀ1
70eV): 186 (100), 91 (12). IR (ATR):
ν = 1635 cm . HRMS (ESIꢀTOF): m/z calcd for
+
C H NO[M+H] , 278.1545; found 278.1545.
19
20
(
±)ꢀ1,6ꢀDibenzylꢀ4ꢀphenylꢀ3,6ꢀdihydropyridinꢀ2(1H)ꢀone (1i): Yield 77% (0.601g). The crude
product purified by column chromatography (SiO
2
, nꢀhexane : ethyl acetate, 3 : 1) gave white solid,
1
o
m.p. 134ꢀ136 °C (petroleum ether : ethyl acetate). H NMR (400 MHz, CDCl
3
, 23 C): δ = 2.39 (ddd,
J=20.6, 3.3, 2.9 Hz, 1 H, CHHꢀ3), 2.90 (dd, J=13.5, 3.3 Hz, 1 H, 6ꢀCHH), 3.07 (dd, J=13.5, 6.5 Hz,
1 H, 6ꢀCHH), 3.11 (dd, J=20.6, 1.7 Hz, 1 H, CHHꢀ3), 4.07 (d, J=15.0 Hz, 1 H, NCHH), 4.25 (dqt,
J=6.5, 3.3, 2.9, 1.7 Hz, 1 H, CHꢀ6), 5.71 (d, J=15.0 Hz, 1 H, NCHH), 5.99 (dd, J=5.1, 2.9 Hz, 1 H,
13
o
=
=
CHꢀ5), 7.03ꢀ7.06 (m, 2 H, ArH), 7.21ꢀ7.37 (m, 13 H, ArH). C NMR (100 MHz, CDCl
3
, 23 C): δ
34.3 (CH ꢀ3), 39.2 (6ꢀCH ), 46.6 (NCH ), 57.7 (CHꢀ6), 120.9 (=CHꢀ5), 125.0, 126.9, 127.5,
2
2
2
1
27.95, 127.98, 128.3, 128.6, 128.8, 130.1 (ArH), 134.8, 135.6, 136.8, 138.2 (Ar, =Cꢀ4), 168.9
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ꢀ
1
(C=O). GCꢀMS (EI, 70eV): 262 (100), 91 (98); IR (ATR):
ν = 1633 cm . HRMS (ESIꢀTOF): m/z
+
calcd for C25
H
24NO[M+H] , 354.1858; found 354.1848.
Synthesis and spectroscopic data for compound 12
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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6
0
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9
0
A stirred solution of diphenylmethane (1.679g; 10mmol) in dry THF (20mL) in a Schlenk flask was
o
cooled to 0 C under argon, and nꢀBuLi (1.6 M in hexane; 6.55mL, 10.05mmol) was added by
o
syringe. The resulting solution was stirred for 30 min, at 0 C and then was slowly transferred by
o
syringe to a precooled (ꢀ80 C) solution of 1,4ꢀdimethylpyridinꢀ2(1H)ꢀone (0.819g; 6.65mmol) in
o
THF (50mL), prepared in another Schlenk flask. The resulting solution was stirred for 1h at ꢀ80 C.
After this time, the mixture was carefully quenched with saturated aqueous NH Cl (15mL), then it
4
was allowed to warm up to room temp and diluted with water (ca. 10 mL). The aqueous layer was
4
extracted with ethyl acetate (3 x 70mL), and the combined organic layers were dried with MgSO .
The mixture was filtered and the solvents were evaporated under reduced pressure. The crude
product was purified by column chromatography on silica gel using n-hexane : ethyl acetate (1: 3),
yielding 0.865g of pale yellow solid.
(
±)-6ꢀBenzhydrylꢀ1,4ꢀdimethylꢀ3,6ꢀdihydropyridinꢀ2(1H)ꢀone (12): Yield 45% (0.865g), m.p. 75ꢀ
1
o
7
8 °C (petroleum ether). H NMR (400 MHz, CDCl
3
, 23 C): δ = 1.59 (s, 3 H, 4ꢀCH
), 4.42 (d, J=4.7
), 4.62ꢀ4.68 (m, 1 H, CHꢀ6), 5.59 (ddq, J=4.7, 2.8, 1.4 Hz, 1 H, =CHꢀ5), 7.10ꢀ7.17
3
), 1.80 (d,
J=21.0 Hz, 1 H, CHHꢀ3), 2.44 (dd, J=21.0, 1.4 Hz, 1 H, CHHꢀ3), 2.98 (s, 3 H, NCH
Hz, 1 H, CHPh
3
2
13
(
m, 2 H, ArH), 7.22ꢀ7.36 (m, 8 H, ArH). C NMR (100.6 MHz, CDCl ): δ = 21.8 (4ꢀCH ), 33.7
3 3
3 2 2
(NCH ), 36.6 (CH ꢀ3), 54.2 (CHꢀPh ), 64.2 (CHꢀ6), 117.6 (=CHꢀ5), 126.7, 127.1, 128.0, 128.5,
128.5, 130.1 (one signal overlaps), 134.1 (=Cꢀ4), 138.8, 140.4 (Ar), 169.0 (C=O). GCꢀMS (EI,
ꢀ1
70eV): m/z = 124 (100). IR (ATR):
ν
= 1638 cm . HRMS (ESIꢀTOF): m/z calcd for
+
C H NO[M+H] , 292.1701; found 292.1709.
20
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Synthesis of compound 1k and 1m according to procedure described earlier
To a solution of 1a (0.510g, 2.53 mmol) in dry THF (20mL) in a Schlenk flask at ꢀ80°C
commercially available (Sigma Aldrich) 2.0M solution of LDA in THF/heptane/ethylbenzene
0
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2
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0
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6
7
8
9
0
(
1.30mL, 2.57 mmol) was added dropwise and stirred at that temperature for 1h. After this time,
benzyl bromide was added dropwise for about 5 minutes, and the reaction mixture was allowed to
slowly warm to 0°C for 1h. After completion of the reaction (GCꢀMS control) the mixture was
4
carefully quenched with saturated aqueous NH Cl (10 mL), then allowed to warm to rt and diluted
with water (ca. 10mL). The aqueous layer was extracted with ethyl acetate (3 x 70 mL), and the
combined organic layers were dried with MgSO . The mixture was filtered and the solvents were
4
evaporated under reduced pressure. The crude product was purified by column chromatography
(
column length 120cm) on silica gel using nꢀhexane:ethyl acetate (3:1) to give desired product 1k as
colorless oil with 80% yield (0.591g, 2.03mmol) and product 1m as pale yellow oil with 8% yield
0.059g, 0.2mmol).
(
3
0
(±)-transꢀ3,6ꢀDibenzylꢀ1ꢀmethylꢀ3,6ꢀdihydropyridinꢀ2(1H)ꢀone (1k) : Yield 80% (0.591g). The
crude product purified by column chromatography (SiO , nꢀhexane : ethyl acetate, 3 : 1; 1.2 m
2
1
o
column lenght) gave colourless oil. H NMR (400 MHz, CDCl
3
, 23 C): δ = 2.35ꢀ2.42 (m, 1 H, CHꢀ
3), 2.72 (dd, J=13.6, 9.4 Hz, 1 H, 3ꢀCHH), 2.83ꢀ2.92 (m, 2 H, 6ꢀCH
2
), 3.08 (s, 3 H, NCH ), 3.24 (dd,
3
J=13.6, 4.3 Hz, 1 H, 3ꢀCHH), 4.00 (ttd, J=4.8, 4.2, 0.8 Hz, 1 H, CHꢀ6), 5.50 (ddd, J=10.1, 2.3, 0.6
Hz, 1 H, CHꢀ4), 5.58 (ddd, J=10.1, 4.2, 2.7 Hz, 1 H, =CHꢀ5), 7.01ꢀ7.09 (m, 4 H, C H ), 7.14ꢀ7.19
6
5
13
o
(
m, 1 H, C H ), 7.20ꢀ7.26 (m, 5 H, C H ). C NMR (100 MHz, CDCl , 23 C): δ = 33.2 (NCH ),
6
5
6
5
3
3
37.5 (3ꢀCH
2
2
), 39.5 (6ꢀCH ), 41.4 (CHꢀ3), 61.4 (CHꢀ6), 124.6 (=CHꢀ5), 127.0 (=CHꢀ4), 126.1, 126.7,
1
13
1
6 5
28.15, 128.21, 129.3, 129.9, 135.8, 139.2 (2 x C H ); 170.5 (C=O). H and C NMR data for this
30
product matched those reported previously.
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(±)-cisꢀ3,6ꢀDibenzylꢀ1ꢀmethylꢀ3,6ꢀdihydropyridinꢀ2(1H)ꢀone (1m) : Yield 8% (0.059g) The crude
product purified by column chromatography (SiO
2
, nꢀhexane : ethyl acetate, 3 : 1; 1.2 m column
1
o
lenght) gave pale yellow oil. H NMR (400 MHz, CDCl
3
, 23 C): δ = 1.94 (dd, J=13.0, 9.3 Hz, 1 H,
3
ꢀCHH), 2.12 (dd, J=13.4, 7.6 Hz, 1 H, 6ꢀCHH), 2.70 (dd, J=13.4, 3.7 Hz, 1 H, 6ꢀCHH), 2.90 (dd,
1
1
1
1
1
1
1
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1
1
2
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2
2
2
2
2
2
3
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3
4
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5
5
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5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
J=13.0, 4.1 Hz, 1 H, 3ꢀCHH), 3.04ꢀ3.11 (m, 4 H, CHꢀ3, NCH ), 3.97 (dq, J=7.4, 3.6 Hz, 1 H, CHꢀ6),
3
5
.47 (dd, J=10.3, 3.3 Hz, 1 H, =CHꢀ4), 5.51 (dd, 1 H, J=10.3, 3.5 Hz, =CHꢀ5), 6.98ꢀ7.06 (m, 4 H,
13
o
C
6
H
5
), 7.15ꢀ7.33 (m, 6 H, C
6
H
5
). C NMR (100 MHz, CDCl
3 3
, 23 C): δ = 33.2 (NCH ), 39.6 (3ꢀ
CH
2
), 40.0 (6ꢀCH
2
), 43.4 (CHꢀ3), 61.6 (CHꢀ6), 124.5 (=CHꢀ5), 126.3 (=CHꢀ4), 126.3, 126.8, 128.1,
1
13
1
28.3, 129.6, 129.9, 136.2, 138.6 (2 x C H ); 170.2 (C=O). H and C NMR data for this product
6 5
30
matched those reported previously.
Synthesis of compound 1p
3
A stirred solution of BnMgCl (2.0 M in THF; 1.77cm , 2.95mmol) in dry THF (12mL) in a Schlenk
flask was cooled to 0°C under argon, and sꢀBuLi (1.4 M in cyclohexane, 5.06mL, 7.08mmola) was
added by syringe over 5 min. The resulting solution was stirred for 5 min, and then it was cooled to –
80°C. The solution containing lithium benzyldi(secꢀbutyl)magnesate and LiCl was then transferred
by syringe to a precooled (ꢀ80°C) solution of 1ꢀbenzylꢀ3ꢀmethylꢀ2ꢀpyridone (0.59g, 2.95mmol) in
THF (32mL) in another Schlenk flask. The resulting solution was stirred for 60 min at –80 °C. After
this time benzyl bromide (0.53mL; 0.757g; 4.426mmol) was added and the mixture was stirred 15
o
o
min at ꢀ80 C, then 2 h at 0 C and then 80 min at rt. After this time, saturated aqueous NH Cl (10mL),
4
was added and the aqueous layer was extracted with ethyl acetate (3 x 60mL), and the combined
4
organic layers were dried with MgSO . The mixture was filtered, and the solvents were evaporated
under reduced pressure. The crude product was purified by 1.2ꢀm long column chromatography on
silica gel using a mixture of nꢀhexane and ethyl acetate (9 : 1) to give the byꢀproduct 19 in 20% yield
(
0.224g) as thick oil and desired product 1p in 84:16 mixture of trans : cis products, in total yields of
50% as colourless oil (0.564g).
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(3SR,6SR)ꢀ1,3,6ꢀTribenzylꢀ3ꢀmethylꢀ3,6ꢀdihydropyridinꢀ2(1H)ꢀone (1p). Yield 50% (0.564g), H
o
NMR (400 MHz, CDCl
3
, 23 C, major isomer (trans) from 84:16 mixture of trans and cis isomers): δ
=
0.84ꢀ0.90 (m, 3 H, 3ꢀCH
3
), 2.51 (d, J=13.0 Hz, 1 H, 3ꢀCHH), 2.75ꢀ2.86 (m, 2 H, 6ꢀCH
2
), 3.30 (d,
J=13.0 Hz, 1 H, 3ꢀCHH), 3.70ꢀ3.76 (m, 1 H, CHꢀ6), 3.95 (d, J=15.2 Hz, 1 H, NCHH), 5.43 (dd,
J=10.1, 4.0 Hz, 1 H, =CHꢀ5), 5.58 (dd, J=10.1, 1.2 Hz, 1 H, =CHꢀ4), 5.71 (d, J=15.3 Hz, 1 H,
0
1
2
3
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9
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4
5
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8
9
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1
2
3
4
5
6
7
8
9
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2
3
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5
6
7
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9
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2
3
4
5
6
7
8
9
0
13
NCHH), 6.70ꢀ6.75 (m, 2 H, Ph), 6.96ꢀ7.01 (m, 2 H, Ph), 7.12ꢀ7.34 (m, 11 H, Ph). C NMR (100
o
MHz, CDCl
3
, 23 C): δ = 27.9 (3ꢀCH
3
), 39.5 (6ꢀCH
2
), 44.5 (Cꢀ3), 46.0 (NCH
2
), 46.7 (3ꢀCH
2
), 56.9
(CHꢀ6), 123.3 (=CHꢀ5), 126.1, 126.8, 127.1, 127.7, 127.8, 128.2, 128.5, 129.9, 130.6 (Ph), 132.0
(
=CHꢀ4), 136.1, 136.5, 138.2 (Ph), 172.8 (C=O). HRMS (ESIꢀTOF): m/z calcd for
+
C H NO[M+H] , 382.2171; found: 382.2161.
27
28
1
(
4SR,5RS)ꢀ1,3,4ꢀTribenzylꢀ3ꢀmethylꢀ3,4ꢀdihydropyridinꢀ2(1H)ꢀone (19). Yield 20% (0.224g), H
o
NMR (400 MHz, CDCl
3
, 23 C): δ = 1.28 (s, 3 H, 3ꢀCH
3
), 2.24 (t, J=12.5 Hz, 1 H, 4ꢀCHH), 2.37
(
ddd, J=12.5, 5.0, 3.9 Hz, 1 H, CHꢀ4), 2.76 (d, J=13.2 Hz, 1 H, 3ꢀCHH), 2.87 (dd, J=12.5, 3.9 Hz, 1
H, 4ꢀCHH), 3.29 (d, J=13.2 Hz, 1 H, 3ꢀCHH), 4.65 (d, J=14.9 Hz, 1 H, NCHH), 4.79 (d, J=14.9 Hz,
1 H, NCHH), 4.82 (dd, J=7.8, 4.9 Hz, 1 H, =CHꢀ5), 6.02 (d, J=7.8 Hz, 1 H, =CHꢀ6), 6.90ꢀ6.94 (m, 2
1
3
o
H, Ph), 7.12ꢀ7.37 (m, 13 H, 3 xPh). C NMR (100 MHz, CDCl
CH ), 40.3 (CHꢀ4), 42.0 (3ꢀCH ), 46.2 (Cꢀ3), 49.7 (NCH ), 109.3 (=CHꢀ5), 126.0, 126.6 (Ph), 126.0,
26.6 (Ph), 127.5 (=CHꢀ6), 127.8, 128.1, 128.1, 128.7, 129.2, 130.5, 137.1, 137.5, 139.8 (Ph), 174.0
3 3
, 23 C): δ = 19.1 (3ꢀCH ), 35.1 (4ꢀ
2
2
2
1
ꢀ1
(
C=O). GCꢀMS (EI, 70eV): m/z = 290 (70), 91 (100); IR (ATR): ν = 1656 cm . HRMS (ESIꢀTOF):
+
m/z calcd for C27H28NO[M+H] , 382.2171; found: 382.2169.
Synthesis and spectroscopic data of compound 1q
3
A stirred solution of BnMgCl (2.0 M in THF; 3.26 cm , 6.51 mmol) in dry THF (10 mL) in a
3
Schlenk flask was cooled to 0°C under argon, and s-BuLi (1.4 M in cyclohexane, 9.30 cm , 13.02
mmol) was added by syringe over 5 min. The resulting solution was stirred for 5 min, and then it was
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cooled to –80°C. The solution containing lithium benzyldi(secꢀbutyl)magnesate and LiCl was then
transferred by syringe to a precooled (ꢀ80 °C) solution of N-methylꢀ2ꢀpyridone (0.592 g, 5.43 mmol)
in THF (20 mL) in another Schlenk flask. The resulting solution was stirred for 60 min at ꢀ80 °C.
3
After this time, 2.5 fold excess of p-fluorobenzyl bromide (1.69cm , 2.564g, 13.56 mmol) was added
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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3
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4
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5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
o
and the mixture was stirred 15 minut at ꢀ80 C, then 4.5 h at 0 C. After this time, saturated aqueous
NH Cl (15 mL), was added and the aqueous layer was extracted with ethyl acetate (3 x 70 mL), and
the combined organic layers were dried with MgSO . The mixture was filtered, and the solvents were
4
4
evaporated under reduced pressure. The crude product was purified by column chromatography on
silica gel using a mixture of n-hexane and ethyl acetate in 6:1 ratio to give the desired product 1q
with 75% yield (1.699g) as white solid (crystalized from AcOEt : petroleum ether).
(±)ꢀ6ꢀBenzylꢀ3,3ꢀbisꢀ(4ꢀfluorobenzyl)ꢀ1ꢀmethylꢀ3,6ꢀdihydropyridinꢀ2(1H)ꢀone (1q). Yield 75%
1
(
1.699g), H NMR (400 MHz): δ = 1.12 (dd, J=13.0, 9.8 Hz, 1 H, 6ꢀCHH), 2.54 (d, J=13.0 Hz, 1 H,
3ꢀCHH), 2.59 (dd, J=13.0, 4.4 Hz, 1 H, 6ꢀCHH), 2.60 (d, J=13.0 Hz, 1 H, 3ꢀCHH), 2.82 (s, 3 H,
NCH ), 3.14 (d, J=13.0 Hz, 1 H, 3ꢀCHH), 3.42 (d, J=13.0 Hz, 1 H, 3ꢀCHH), 3.41ꢀ3.47 (m, 1 H, CHꢀ
3
6), 5.29 (dd, J=10.4, 3.5 Hz, 1 H, =CHꢀ5), 5.41 (dd, J=10.4, 1.0 Hz, 1 H, =CHꢀ6), 6.81ꢀ6.87 [m, 4 H,
2
2
xCHꢀ3’, 2xCH(Bn)], 6.96 ꢀ 7.05 (m, 4 H, 2xCHꢀ2’, 2xCHꢀ3’), 7.07ꢀ7.26 [m, 5 H, 2xCHꢀ2’,
13
o
xCH(Bn)] ppm. C NMR (100 MHz, CDCl3, 23 C): δ = 33.2 (NCH
3
2
), 41.1 (6ꢀCH ), 45.1 (2x3ꢀ
2
2
CH
2
), 50.6 (Cꢀ3), 61.4 (CHꢀ6), 114.4 (d, JCF=21.3 Hz, 2xCHꢀ3’), 114.7 (d, JCF=21.3 Hz, 2xCHꢀ3’),
3
1
25.3 (=CHꢀ5), 126.6 [ArH, (6ꢀBn)], 128.3 (=CHꢀ4), 128.4, 129.2 [ArH, (6ꢀBn)], 131.6 (d, J =7.9
CF
3
4
Hz, 2xCHꢀ2’), 132.1 (d, J =7.9 Hz, 2xCHꢀ2’), 133.3 (d, J =3.7 Hz, Cꢀ1’), 136.7 [Ar, (Bn)],
CF
CF
1
1
161.6 (d, JCF=243.6 Hz, CHꢀ4’), 162.9 (d, JCF=243.6 Hz, CHꢀ4’), 170.6 (C=O). GCꢀMS (EI,
ꢀ1
70eV): m/z = 326 (44), 109 (100), 91 (18). IR (ATR):
ν
= 1620 cm . HRMS (ESIꢀTOF): m/z calcd
+
for C27
H
26
F
2
NO[M+H] , 418.1982, found: 418.1990.
A typical procedure for the bromocarbocyclization of N-substituted 6-benzyl-3,6-dihydropyridin-
2(1H)-ones. Synthesis of bromobenzomorphans 2, 6, 13, bromolactams 4, 5, 14.
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To a stirred solution of N-substituted 6ꢀbenzylꢀ3,6ꢀdihydropyridinꢀ2(1H)ꢀone (1.7 mmol) in MeNO
2
(35 mL) triphenyl phosphite 0.175 equiv. (0.297 mmol, 0.092g,) and then N-bromosuccinimide 1.5
equiv (2.55 mmol, 0.454 g) were added. The resulting orange ꢀ yellow solution was stirred for 2ꢀ3h
(TLC control, products 2, 4, 13 and 14) or 24ꢀ100h (TLC control, products 5 and 6) at room
0
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temperature in the dark. After this time 2% solution of Na SO (10mL) and then saturated aqueous
2
3
solution of NaHCO
aqueous layer was extracted with ethyl acetate (3 x 70mL) and the combined organic layers were
dried over MgSO . The mixture was filtered and the solvents were evaporated under reduced
3
(10mL) were added and the mixture was stirred for additional 10 min. The
4
pressure. The crude product was purified by column chromatography on silica gel using a mixture of
appropriate solvents to give the desired product.
(
(
(
2RS,6SR,11SR)ꢀ11ꢀBromoꢀ3ꢀmethylꢀ2,3,5,6ꢀtetrahydroꢀ2,6ꢀmethanobenzo[d]azocinꢀ4(1H)ꢀone
2a): Yield 97% (0.462g, reaction time: 3h). The crude product purified by column chromatography
1
SiO
2
, nꢀhexane : ethyl acetate, 1 : 2 ) gave white solid, m.p. 149ꢀ151 °C (petroleum ether). H NMR
o
(400 MHz, CDCl
3
, 23 C): δ = 2.48 (ddd, J=17.8, ~1.8, ~1.5 Hz, 1 H, CHHꢀ5
α
), 3.02 (s, 3 H, NCH
3
),
3.15ꢀ3.17 (m, 2 H, CHHꢀ1), 3.24 (dd, J=17.8, 5.9 Hz, 1 H, CHHꢀ5
β
), 3.41 (dddd, J=5.9, 3.9, 1.8, 1.5
Hz, 1 H, CHꢀ6), 4.00 (tt, J=3.1, 3.1, 1.8, 1.8 Hz, 1 H, CHꢀ2), 4.70 (dt, J=3.9, 1.8, 1.8 Hz, 1 H, CHꢀ
13
1
3
8
1), 7.05ꢀ7.11 (m, 2 H, ArHꢀ7,10), 7.17ꢀ7.23 (m, 2 H, C
4.1 (NCH ), 35.4 (CH ꢀ1), 37.6 (CH
, Cꢀ9) 128.7, 129.5 (Cꢀ7, Cꢀ10), 129.7, 138.3 (Cꢀ6a, Cꢀ10a), 167.5 (C=O). GCꢀMS: (EI, 70eV): m/z
6
H
4
). C NMR (100.6 MHz CDCl
3
): δ =
3
2
2
ꢀ5), 40.1 (CHꢀ6), 48.6 (CHꢀ11), 61.4 (CHꢀ2), 127.3, 127.8, (Cꢀ
+
ꢀ1
= 281 (64), [M+2], 279 (64), [M ], 200 (100); IR (KBr pellet):
ν = 1638 cm . HRMS (ESIꢀTOF):
+
m/z calcd. for C13
H
15BrNO[M+H] , 280.0337, found: 280.0340.
(2RS,6SR,11SR)ꢀ11ꢀBromoꢀ3ꢀpropylꢀ2,3,5,6ꢀtetrahydroꢀ2,6ꢀmethanobenzo[d]azocinꢀ4(1H)ꢀone (2b):
Yield 84% (0.440g, reaction time: 3h). The crude product purified by column chromatography (SiO2,
1
nꢀhexane : ethyl acetate, 1 : 1 ) gave white solid, m.p. 93ꢀ95 °C (nꢀhexane : ethyl acetate). H NMR
o
(400 MHz, CDCl
3
, 23 C): δ = 0.96 (t, J=7.4 Hz, 3 H, CH
3
), 1.56ꢀ1.72 (m, 2 H, CH
2
CH
3
), 2.46 (ddd,
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J=17.7, ~1.8, ~1.5 Hz, 1 H, CHHꢀ5
α
), 2.63 (ddd, J=13.6, 8.6, 5.6 Hz, 1 H, NCHH), 3.08ꢀ3.19 (m, 2
H, m, 2 H, CHHꢀ1), 3.22 (dd, 1 H, J=17.7, 5.9 Hz, CHHꢀ5
β
), 3.38 (dddd, J=5.9, 3.9, 1.8, 1.5 Hz, 1 H,
CHꢀ6), 4.01 (ddd, J=13.6, 9.0, 6.7 Hz, 1 H, NCHH), 4.02ꢀ4.05 (m, 1 H, CHꢀ2), 4.71 (dt, J=3.9, 1.8,
13
1.8 Hz, 1 H, CHꢀ11), 7.04ꢀ7.09 (m, 2 H, ArHꢀ7,10), 7.16ꢀ7.21 (m, 2 H, ArHꢀ7,10). C NMR (100.6
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3 3 2 3 2 2
MHz CDCl ): δ = 11.4 (CH ), 20.2 (CH CH ), 36, 1 (CH ꢀ1), 37.9 (CH ꢀ5), 39.9 (CHꢀ6), 47.1
(NCH
2
), 48.8 (CHꢀ11), 58.5 (CHꢀ2), 127.2, 127.8, (Cꢀ8, Cꢀ9) 128.6, 129.5 (Cꢀ7, Cꢀ10), 129.9, 138.5
+
(Cꢀ6a, Cꢀ10a), 167.1 (C=O). GCꢀMS (EI, 70eV): m/z = 309 (52), [M+2], 307 (52), [M ], 228 (100);
ꢀ1
+
IR (ATR):
08.0661.
ν = 1633 cm . HRMS (ESIꢀTOF): m/z calcd for C15H19BrNO[M+H] , 308.0650, found:
3
(
(
(
2RS,6SR,11SR)ꢀ3ꢀBenzylꢀ11ꢀbromoꢀ3ꢀ2,3,5,6ꢀtetrahydroꢀ2,6ꢀmethanoꢀbenzo[d]azocinꢀ4(1H)ꢀone
2c): Yield 93% (0.563g, reaction time: 3h). The crude product purified by column chromatography
2
SiO , nꢀhexane : ethyl acetate, 5 : 1, then 3 : 1 ) gave white solid, m.p. 134ꢀ136 °C (nꢀhexane : ethyl
1
o
acetate). H NMR (400 MHz, CDCl
J=17.4, 3.9 Hz, 1 H, CHHꢀ1 ), 3.12 (dd, J=17.4, 2.2 Hz, 1 H, CHHꢀ1
H, CHHꢀ5 ), 3.39ꢀ3.43 (m, 1 H, CHꢀ6), 3.96 (dq, J=3.9, ~2.0, 2.0, 2.0 Hz, 1 H, CHꢀ2), 3.99 (d,
J=15.1 Hz, 1 H, NCHH), 4.65 (dt, J=3.9, 2.0, 2.0 Hz, 1 H, CHꢀ11), 5.39 (d, J=15.1 Hz, 1 H, NCHH),
.01ꢀ7.06 (m, 1 H, ArH), 7.06ꢀ7.11 (m, 1 H, ArH), 7.17ꢀ7.24 (m, 2 H, ArH), 7.26ꢀ7.36 (m, 5 H,
3
, 23 C): δ = 2.59 (br d, J=17.6 Hz, 1 H, CHHꢀ5
α
), 3.05 (dd,
β
α
), 3.35 (dd, J=17.6, 6.1 Hz, 1
β
7
1
3
ArH). C NMR (100.6 MHz CDCl
3
):
2 2 2
δ = 35.5 (CH ꢀ1), 38.0 (CH ꢀ5), 40.0 (CHꢀ6), 48.1 (NCH ),
4
1
8.6 (CHꢀ11), 57.6 (CHꢀ2), 127.3, 127.6, 127.9, 128.4, 128.5, 129.7, 129.5, (ArH), 130.0, 136.3,
+
38.4 (Ar), 167.6 (C=O). GCꢀMS (EI, 70eV): m/z = 357 (34), [M+2], 355 (33), [M ], 276 (16), 91
ꢀ1
+
(
100); IR (ATR): ν = 1634 cm . HRMS (ESIꢀTOF): m/z calcd for C19H19BrNO[M+H] , 356.0650;
found 356.0645.
(2RS,6SR,11SR)ꢀ11ꢀBromoꢀ3ꢀphenylꢀ2,3,5,6ꢀtetrahydroꢀ2,6ꢀmethanobenzo[d]azocinꢀ4(1H)ꢀone
(2d): Yield 81% (0.471g, reaction time: 3h). The crude product purified by column chromatography
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(SiO
2
, nꢀhexane : ethyl acetate, 5 : 1 then 3 : 1 ) gave white solid, m.p. 164ꢀ166 °C (petroleum ether).
1
o
H NMR (400 MHz, CDCl , 23 C): δ = 2.66 (ddd, J=18.0, 1.8, 1.4 Hz, 1 H, CHHꢀ5 ), 3.04 (dd,
3
α
J=17.6, 4.0 Hz, 1 H, CHHꢀ1
β
), 3.16 (dd, J=17.6, 2.2 Hz, 1 H, CHHꢀ1
α
), 3.39 (dd, J=18.0, 6.0 Hz, 1
H, CHHꢀ5 ), 3.52 (dddd, J=6.0, 3.9, 1.8, 1.4 Hz, 1 H, CHꢀ6), 4.40 (dq, J=4.0, ~2.0, 2.0, 2.0 Hz, 1 H,
β
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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CHꢀ2), 4.85 (dt, J=3.9, 1.8, 1.8 Hz, 1 H, CHꢀ11), 7.10ꢀ7.16 (m, 2 H, ArH), 7.18ꢀ7.22 (m, 2 H, ArH),
1
3
7.23ꢀ7.27 (m, 2 H, ArH), 7.31ꢀ7.36 (m, 1 H, ArH), 7.41ꢀ7.46 (m, 2 H, ArH). C NMR (100.6 MHz
CDCl ): = 36.0 (CH ꢀ1), 38.3 (CH ꢀ5), 40.1 (CHꢀ6), 49.0 (CHꢀ11), 63.3 (CHꢀ2), 127.5, 127.8,
28.0, 128.1, 128.9, 129.6, 129.8, 138.4, 141.5 (C H , C H ), 167.5 (C=O); (one signal is
3
δ
2
2
1
6
5
6
4
+
overlapped). GCꢀMS (EI, 70eV): m/z = 343 (72), [M+2], 341 (64), [M ], 262 (38), 234 (100), 77
ꢀ1
+
(54); IR (ATR):
ν = 1647 cm . HRMS (ESIꢀTOF): m/z calcd for C H BrNO[M+H] , 342.0494;
18 17
found: 342.0493.
(2SR,6RS,11RS)ꢀ11ꢀBromoꢀ3,6ꢀdimethylꢀ2,3,5,6ꢀtetrahydroꢀ2,6ꢀmethanobenzo[d]azocinꢀ4(1H)ꢀone
(
2e): Yield 91% (0.455g, reaction time: 2h). The crude product purified by column chromatography
SiO , nꢀhexane : ethyl acetate, 3 : 1 ) gave white solid, m.p. 128ꢀ130 °C (petroleum ether : ethyl
(
2
1
o
acetate). H NMR (400 MHz, CDCl
3
, 23 C): δ = 1.57 (s, 3 H, 4ꢀCH
ꢀ5), 2.87 (d, J=17.5 Hz, 1 H, CHH ꢀ5), 2.99 (s, 3 H, NCH ), 3.13 (dd, J=17.1, 2.2 Hz, 1 H,
ꢀ1), 3.22 (dd, J=17.1, 3.9 Hz, 1 H, CHH ꢀ1), 4.10 (ddd, J=3.9, 2.2, 2.0 Hz, 1 H, CHꢀ2), 4.59
3
), 2.42 (dd, J=17.5, 1.3 Hz, 1 H,
CHH
β
α
3
CHH
α
β
(dd, J=2.0, 1.3 Hz, 1 H, CHꢀ11), 7.04 (d, J=7.5 Hz, 1 H, CHꢀ10), 7.18 (tt, J=7.3, 1.4 Hz, 1 H, CHꢀ9),
13
o
7
.21ꢀ7.26 (m, 1 H, CHꢀ8), 7.37 (dd, J=7.9, 1.3 Hz, 1 H, CHꢀ7). C NMR (100 MHz, CDCl
), 33.7 (NCH ), 35.8 (CH ꢀ1), 39.4 (Cꢀ6), 44.5 (CH ꢀ5), 58.6 (CHꢀ11), 62.4 (CHꢀ2),
26.6 (CHꢀ7), 127.4 (CHꢀ8), 127.6 (CHꢀ9), 129.5 (CHꢀ10), 130.0 (Cꢀ10a), 140.7 (Cꢀ6a), 168.1
3
, 23 C):
δ = 25.9 (6ꢀCH
3
3
2
2
1
+
+
(C=O). GCꢀMS (EI, 70eV): m/z = 295 (27) [M +2], 293 (28) [M ], 280 (12), 278 (12), 214 (100). IR
ꢀ1
+
(ATR):
ν = 1638 cm . HRMS (ESIꢀTOF): m/z calcd for C14H17BrNO[M+H] , 294.0494, found:
294.0488.
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(2SR,6RS,11RS)ꢀ3ꢀBenzylꢀ11ꢀbromoꢀ6ꢀmethylꢀ2,3,5,6ꢀtetrahydroꢀ2,6ꢀmethanobenzo[d]azocinꢀ
4(1H)ꢀone (2f): Yield 83% (0.522g, reaction time: 3h). The crude product purified by column
chromatography (SiO
2
, nꢀhexane : ethyl acetate, 1 : 1 ) gave white solid, m.p. 145ꢀ147 °C (petroleum
1
o
ether : ethyl acetate). H NMR (400 MHz, CDCl
3
, 23 C): δ =2.53 (dd, J=17.6, 1.3 Hz, 1 H, CHHꢀ5
α
),
ꢀ1), 4.00ꢀ4.07 (m, 2 H, CHꢀ2, NCHH),
.55 (t, J=1.3 Hz, 1 H, CHꢀ11), 5.31 (d, J=15.0 Hz, 1 H, NCHH), 6.98 (d, J=7.5 Hz, 1 H, ArH), 7.18
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
4
β 2
.98 (d, J=17.6 Hz, 1 H, CHHꢀ5 ), 3.03ꢀ3.15 (m, 2 H, CH
13
(td, J=7.4, 1.3 Hz, 1 H, ArH), 7.22ꢀ7.35 (m, 7 H, ArH), 7.40 (dd, J=7.9, 1.0 Hz, 1 H, ArH). C NMR
o
(100 MHz, CDCl
3
, 23 C): δ = 25.9 (6ꢀCH
3
), 35.9 (CH
2
ꢀ1), 39.2 (Cꢀ6), 44.8 (CH
2
ꢀ5), 47.8 (NCH
2
),
5
1
2
8.6 (CHꢀ11), 58.7 (CHꢀ2), 126.7, 127.4, 127.5, 127.6, 128.3, 128.4, 129.4 (ArH), 130.2 (Cꢀ10a),
+
+
36.4(Ar), 140.8 (Cꢀ6a), 168.2 (C=O). GCꢀMS (EI, 70eV): m/z = 371 (35) [M +2], 369 (33) [M ],
ꢀ1
+
90 (31), 91 (100). IR (ATR):
ν = 1634 cm . HRMS (ESIꢀTOF): m/z calcd for C H BrNO[M+H] ,
20 21
370.0807, found: 370.0816.
(5SR,6RS)ꢀ1,6ꢀDibenzylꢀ5ꢀbromoꢀ4ꢀmethylꢀ5,6ꢀdihydropyridinꢀ2(1H)ꢀone (4f): Yield 14% (0.088g,
reaction time: 3h). The crude product purified by column chromatography (SiO , nꢀhexane : ethyl
2
acetate, 1 : 1) gave colorless solid, which during storage in a refrigerator converted itself into 6ꢀ
1
o
benzylꢀ4ꢀmethylpyridinꢀ2ꢀone. H NMR (400 MHz, CDCl
CH ), 2.65 (dd, J=13.8, 9.8 Hz, 1 H, 6ꢀCHH), 2.92 (dd, J=13.8, 5.4 Hz, 1 H, 6ꢀCHH), 3.79 (ddd,
J=9.9, 5.4, 1.3 Hz, 1 H, CHꢀ6), 3.97 (d, J=14.7 Hz, 1 H, NCHH), 4.23 (d, J=1.0 Hz, 1 H, CHꢀ5),
5.28 (d, J=14.8 Hz, 1 H, NCHH), 5.93 (q, J=1.3 Hz, 1 H, =CHꢀ3), 6.98ꢀ7.02 (m, 2 H, C ), 7.23ꢀ
), 47.3 (CHꢀ
), 63.5 (CHꢀ6), 123.2 (=CHꢀ3), 127.3, 127.8, 128.5, 128.9, 129.1, 129.2, 136.4, 136.4
), 146.5 (=Cꢀ4), 162.3 (C=O).
3
, 23 C): δ = 1.97 (d, J=1.3 Hz, 3 H, 4ꢀ
3
6
H
5
13
o
7.40 (m, 8 H, C
), 48.3 (NCH
2 x C
6 5 3 3 2
H ). C NMR (100 MHz, CDCl , 23 C): δ = 20.4 (4ꢀCH ), 38.4 (6ꢀCH
5
2
(
(
6 5
H
2SR,6RS,11RS)ꢀ11ꢀBromoꢀ6ꢀmethylꢀ3ꢀphenylꢀ2,3,5,6ꢀtetrahydroꢀ2,6ꢀmethanobenzo[d]azocinꢀ
4(1H)ꢀone (2g): Yield 89% (0.539g, reaction time: 3h). The crude product purified by column
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