Selective α-Methylation of Ketones

Article abstract of DOI:10.1021/acs.joc.1c00148

The convenient and scalable preparative approach for the two-step α-methylation of ketones is described. The optimized protocols for regioselective preparation of enaminones with further diastereoselective and functional groups tolerant hydrogenation to α-methylketones are developed. The scope and limitations of the proposed methodology are discussed. The advantages compared to known procedures are demonstrated. The unexpected role of acetone in the hydrogenation is suggested. The evaluation of the method for both early building block synthesis and late-stage CH-functionalization is shown. The elaborate procedures' preparability and scalability are demonstrated by the synthesis of several α-methyl ketones up to 100 g amount.

Full text of DOI:10.1021/acs.joc.1c00148

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Article
Selective α‑Methylation of Ketones
Andriy I. Frolov, Eugeniy N. Ostapchuk, Alexander E. Pashenko, Yaroslav O. Chuchvera,
Eduard B. Rusanov, Dmitriy M. Volochnyuk,* and Sergey V. Ryabukhin*
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ABSTRACT: The convenient and scalable preparative approach for the
two-step α-methylation of ketones is described. The optimized protocols
for regioselective preparation of enaminones with further diastereoselective
and functional groups tolerant hydrogenation to α-methylketones are
developed. The scope and limitations of the proposed methodology are
discussed. The advantages compared to known procedures are demon-
strated. The unexpected role of acetone in the hydrogenation is suggested.
The evaluation of the method for both early building block synthesis and
late-stage CH-functionalization is shown. The elaborate procedures’
preparability and scalability are demonstrated by the synthesis of several
α-methyl ketones up to 100 g amount.
Methylene ketones as structural fragments occur in many
drugs, drug candidates, and natural compounds; thus; the
interest in the reactions enabling their selective alkylation
grows increasingly over the past decades.
INTRODUCTION
■
The introduction of alkyl substituents into biologically active
molecules in many cases leads to significant changes in their
activity. Particularly, adding the simplest alkyl substituentthe
methyl groupto pharmacologically active molecules often
positively impacts their metabolic stability, solubility, selectiv-
ity, and binding affinity.1 Numerous examples showcasing this
phenomenon were given in the literature.1,2 By far, both the
most popular and the most impactful for derivatization of
bioactive molecules, the methyl substituent is also referred to
as “magic methyl”.1,2d
There are two fundamentally different approaches to the
preparation of alkylated biomolecules. The first approach is
“late-stage CH-functionalization”3 which implies alkylation as a
final step in the target compound synthesis. The other
approach suggests to introduce an alkyl substituent into
building blocks in the early stages. Both methodologies have
their advantages and drawbacks. Even though the selectivity of
late-stage CH-functionalization reactions is generally low, and
the versatile protocols that cover the large chemical space of
complex molecules have not yet been developed for such
transformations, this remains a promising strategy, which has
already seen some success in the past.3b,4 Alkylation in the
early stage of building blocks preparation requires the synthesis
of new modified intermediates on the basis of analogy with the
parent synthetic pathway. This implies de novo synthesis of the
target molecules,1 which might be viewed as a disadvantage in
many cases. On the other hand, functionalization of the
building blocks in early steps opens room for quick SAR
investigations, which makes it very attractive for pharmaceut-
ical companies.1,5 In this study, α-methylene ketones were
taken as the target substrates, and the efficient methyl group
introduction approaches to the α-position were investigated. α-
Typically, α-alkylation of ketones is performed by alkylation
of corresponding enolates with alkyl halides or sequential
chalcone reduction.6 Both these approaches have significant
limitations and suffer from low selectivity, poor scalability, and
a number of possible side reactions. Later on, metal-catalyzed
ketone methylation reactions,7 as well as metal-free approach-
es,7e,8 were developed. However, the drawbacks as the use of
the toxic reagents or harsh reaction conditions still remain.9
Kotick and co-workers2e have shown α-methylation of
dihydrocodeine via hydrogenation of the corresponding
enaminone intermediate (Scheme 1, A). One-pot Rh-catalyzed
direct α-methylation procedures for α-methyleneketones,
proposed by Li and co-workers,9 and Chan and co-workers,10
(Scheme 1, C) despite being fairly versatile, remain problem-
atic for scale-up synthesis due to the costly catalysts.
Regardless of the methylation via Bredereck-type reagents
being merely somewhat beneath the surface, only one record
describing the similar approach to α-monomethylation of
acetophenones has been published to date (Scheme 1, B).11
However, the noted method (B) leads mostly to alcohols
instead of targeted methyl ketones. It happens due to the
nonselective reduction step,11 which is not surprising,
Received: January 19, 2021
Published: May 27, 2021
https://doi.org/10.1021/acs.joc.1c00148
© 2021 American Chemical Society
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Scheme 1. Literature Examples of Ketones α-Alkylation (A−J) and Reaction Sequence Proposed in This Work (K)
considering that the reduction of aromatic carbonyls to
corresponding benzylic alcohols in Pd/C-catalyzed hydro-
genations is well-known in the literature.12 The alkylation
protocols that imply a hydrogen-borrowing strategy with
alcohols as alkyl source, and a variety of heterogeneous
(Scheme 1, H)13 and homogeneous (Scheme 1, D−G, I, J)14
metal catalysts, show promising results. Particularly, N-
methylation of amines,14a,d α-methylation of 1-aryl-1-prop-
anols,13 β-methylation of 2-arylethanols,13 3-methylation of
indoles,13 and α-alkylation of methylketones have been
described. Nevertheless, the listed approaches still have strong
limitations, showing poor selectivity or leading to poly-
methylated products.13,14 Recently developed iron-catalyzed
hydrogen-borrowing reactions show reasonable yields and
selectivity on α-alkylations of methylketones (Scheme 1, I, J).
However, they are still not applicable for mono-α-methyl-
ations, and use “custom”, commercially unavailable catalyst-
s.14e,f
In our ongoing efforts to adapt existing and developing new
effective approaches to the advanced building blocks for
medicinal chemistry,15 we propose the stepwise incorporation
of dialkylaminoacetal, followed by selective hydrogenation
(Scheme 1, K). Herein, we present the most general and
scalable (up to 100 g) method for chemo- and regioselective α-
methylation of ketones, tolerable toward many common
functional groups, and consequently applicable to both late-
stage and early BB functionalization. We have optimized the
literature16 conditions to achieve selective enaminones
formation by reacting ketones with Bredereck’s reagent
((CH3)3COCH[N(CH3)2]2, further BR),16a and, in some
cases, in a DMF-DMA system, which allowed us to prepare
mono-substituted products.16b It is also noteworthy that
enaminones, used as intermediates in this study, are valuable
starting materials for many important reactions.11,17
RESULTS AND DISCUSSION
■
Considering that the catalytic hydrogenation-hydrogenolysis
step looked the most challenging,11 we decided to find optimal
conditions for this transformation. We used a multidimensional
optimization scheme, which included temperature, hydrogen
pressure, substrate concentration, and catalyst content
optimization, as well as catalyst choice and solvent choice.
Herein, we present the best showcasing projections, partic-
ularly catalyst type and solvent type optimizations.
Enaminones readily react with dihydrogen in the presence of
Pd/C catalyst at ambient conditions;11 thus, in the first
optimization cycle, we used available Pt-group metals on
different beds. We chose N-Boc-4-piperidone as the model
compound, since it is a showcasing substrate for the family of
druglike and natural compounds, which are attractive targets
for molecular “tuning” via C-alkylation (Scheme 2).1,3b The
Scheme 2. Optimization of the Hydrogenation Protocol for
Enaminones 2 to Corresponding Methylketones 3, Using
Enaminone 2(13) as the Model Compound
course of reactions was monitored by GC/MS using the
column precalibrated to detect the substrate, and products,
with dodecane as an internal standard. In the summary of these
experiments, Pd/C (10%) had shown to provide both the best
yield and selectivity (Table 1).
Knowing the optimal hydrogenation catalyst, we decided to
study the influence of the solvent on the reaction course. For
this, we took the solvents, which are most commonly used for
heterogeneous catalytic hydrogenation, as i-PrOH, MeOH,
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Table 1. Optimization of the Catalyst for Hydrogenation on
the Model Enaminone 2(13)
Table 3. Comparison of Hydrogenation Step for
a
Characteristic Acetophenone Enaminones II(a−c), Known
from the Literature (A)11 and the Procedure Optimized in
This Work (B)
catalyst
time, h conversion, % yield, % selectivity, %
Pd/C (10%)
Pd/BaSO4 (5%)
Pd/Al2O3 (5%)
Pd/CaCO3 (5%)
Pt/C (5%)
Pt/C (5%)
Ru/C (5%)
Rh/C (5%)
24
24
24
24
24
24
24
24
85.9
0
6.3
85.1
0
3.7
0
15.2
44.8
0
99.0
0
58.3
0
26.6
50.4
0
0
57.3
88.9
58.7
74.3
0
0
a
Conditions: 1 atm H2, room temperature, acetone, 2−4% molar of
the catalyst used (based on the pure metal).
and THF, together with less popular AcOEt and acetone
(Table 2).18 The reaction progress was monitored by GC/MS
Table 2. Optimization of the Solvent for Hydrogenation on
a
the Model Enaminone 2(13)
solvent
time, h
conversion, %
yield, %
selectivity, %
composition, which might be a beneficial strategy for further
investigation toward selective methylation of aromatic ketones.
However, the nature behind the drastic increase of selectivity
in cases when acetone was used as the reaction media
remained unclear. It is known from the literature that alcohols
are the main byproducts when reducing acetophenones in our
conditions. We assumed the “kinetic shielding” of the
competing ketone reduction by acetone. The difference in
amounts of starting ketone and acetone is a lot (near 0.1 mol/
L). Correspondingly, the keto group of the latter can compete
with the keto group of the substrate during the reduction. To
evaluate the relevance of this hypothesis, we have conducted its
experimental proof. We used the standard GC/MS protocol
for solvents quality checks, to quantify the possibility of the
acetone reduction to isopropyl alcohol in our standard reaction
conditions. We used 4-((dimethylamino)methylene)-
dihydrofuran-3(2H)-one 2(10) as a test object. This is an
available compound with a low molecular weight, which does
not bind with the filler of the GC column irreversibly. As a
blank experiment, we next used the following: Acetone and
catalyst were taken in the same ratio and treated with hydrogen
gas under the same temperature and pressure parameters as a
test reaction mixture. The 5% solution of isopropyl alcohol in
acetone was used for instrument calibration. The series of
experiments resulted in the average concentration of
isopropanol of 1.6 g/L for 4-((dimethylamino)-methylene)-
dihydrofuran-3(2H)-one 2(10) reduction reaction mixtures
and 8.9 g/L for blank experiments. It indicates the possibility
of competing reduction reactions when the substrate was
present in the mixture. On the other hand, for the number of
saturated cyclic and heterocyclic enaminones, we found traces
of dimethylamino(methyl)-alcohols when analyzing crude
mixtures on GC/MS. We expected to observe a significantly
acetone
THF
AcOEt
i-PrOH
MeOH
8
8
8
8
8
34.7
41.6
65.3
84.9
100
34.5
36.0
37.5
42.3
35.5
99.4
86.6
57.4
49.8
35.5
a
Conditions: 1 atm H2, room temperature, Pd/C (10%), 4% molar of
the Pd used (based on the pure metal).
analysis in the same manner as above for the catalyst selection
iteration. THF and acetone showed the best selectivity (86.6%
and 99.4%, respectively) and yields close to those of the
“traditional” alcohols (Table 2). Summarizing the optimization
study on the hydrogenation step, the system acetone/Pd/
C(10%) has proven to be the most promising in terms of both
yield and selectivity.
We have compared the yields of the acetophenone
enaminones obtained via our optimized protocol for hydro-
genation (Scheme 3, Table 3, conditions B), with the yields
obtained using the original procedure published by Borah and
co-workers11 (Scheme 3, Table 3, conditions A). As it is shown
in Table 3, in the case of acetophenones I(a−c), the switch to
acetone as the media for the hydrogenation step allowed us to
inverse the regioselectivity to predominantly the formation of
desired methylketones III(a−c), instead of the formation of
benzylic alcohols IV(a−c). The overall conversion is also
significantly increased. Despite shifting the selectivity toward
desired methylated ketones, the content of the benzylic
alcohols in the reaction mixtures remained significant, which
could be attributed by conjugation between π-electrons of the
aromatic rings and carbonyl group, and consequently
prolonged exposure times with the catalyst for these molecules.
The latter gives space for optimization of the catalyst
Scheme 3. General Scheme for Methylation of Acetophenones I via Subsequent Enaminones II Formation and Their
Hydrogenation to Methylketones III
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Scheme 4. Proposed Reaction Schemes for Enaminones Reduction at Different Substrate Concentrations (0.1 and 0.5 M of
2(10) in Acetone)
higher yield of such product on increased substrate
concentration (Scheme 4).
we used toluene as a solvent (procedure C), which was
warmed to 55 °C to increase the solubility if necessary
(procedure D). These modifications allowed us to synthesize
the varied set of low molecular weight enaminones (Figure 2,
Table 4), including enaminone derivatives of natural
compounds (entries 20−22, Table 4). It is notable that our
optimized condition for the enaminones formation reactions,
besides high regioselectivity, showed remarkable tolerance to
the number of important functional groups, including fluorine
(entry 9, Table 4), lactone (entry 21, Table 4), lactam (entry
19, Table 4), amides (entries 13−17, Table 4), and amines
(entries 18, 20, Table 4). The methodology has shown poor
results for nonprotected functional groups with active
hydrogen, such as free amino, hydroxy, and carboxy functions,
due to the possibility of their reaction with BR or DMF-DMA.
Importantly, the introduction of one enaminone fragment
only occurs, even if there are two or more possibilities present.
The high diastereoselectivity (de > 90%) at the reduction step
is also observed in the cases of existent stereocenters in the
starting ketones 1. The cis-product formation is detected and
proven by X-ray study21 (Figure 3).
With these data in hand, we provided the reduction
experiment for the same test substrate. Its concentration in
acetone 5-fold increased, thus removing the “kinetic shielding”
assured by acetone. The reaction resulted in a mixture of
methylketone 3(10) and 4-((dimethylamino)methyl)-
tetrahydrofuran-3-ol 4(10) in close to a 2:1 ratio. The workout
gave a 45% isolated yield of 3(10) and 23% of aminoalcohol
4(10). The structure of 4-((dimethylamino)methyl)-
tetrahydrofuran-3-ol 4(10) was additionally confirmed by X-
ray (Figure 1).19
The transformation of ketones 1 to enaminones 2 proceeds
with high conversion. In most cases, enaminones were taken
for the reduction step without additional purification. The
analytically pure compounds were isolated via crystallization,
fraction distillation, column chromatography, or preparative
HPLC purification (see Table 4 for the details).
The adjusted protocols for subsequent enaminones prep-
aration, followed by reductive elimination of the dimethylami-
no function, using Pd/C(10%) as the catalyst in acetone media
at ambient conditions, resulted in regio- and diastereoselective
α-methylation of ketones with the conservation of a carbonyl
function. The developed hydrogenation procedure allowed the
use of crude starting materials from the enaminone preparation
step for a wide scope of substrates in up to 100 g scale with
overall two-step yields of the methylated ketones around 55−
60% on average. The given synthetic approach has proven to
be convenient and versatile for the wide variety of structural
types and chemotypes of ketones, comprising alicyclic 1(1−9)
and heterocyclic 1(10−19) compounds, acetophenones I(a−
c), aliphatic ketones 1(22,23), and natural compounds
1(21,22). Thus, it becomes an accessible instrument for
both de novo synthesis and late-stage functionalization.
Nevertheless, despite the versatility for functional classes,
some limitations of scope for the proposed ketones α-
methylation strategy were also determined. Sulfur-containing
ketones 1(24) and 1(25) reacted with BR, yielding 50% and
10% of enaminones 2(24) and 2(25), respectively. However,
Figure 1. Structure of 4-((dimethylamino)methyl)tetrahydrofuran-3-
ol 4(10) according to X-ray data.
The exclusive formation of cis-product overall supports the
hypothesis that the reduction of a carbonyl group happens due
to prolonged exposure of the substrate with catalyst, provided
in this case by increased substrate concentration. The
formation of N,N-dimethylaminoalcohols at higher substrate
concentrations, when the “kinetic shielding” role decreased,
indicates the carbonyl reduction competing with the main
reaction, which is Pd/C-induced retro-Michael-type elimina-
tion,20 followed by reduction to the respective methyl ketone
(Scheme 4).
The BR16a or DMF-DMA11 systems were used, depending
on the reactivity of the substrates. In general, using BR
(procedure B, Table 4) instead of DMF-DMA leads to better
yields. However, in cases of reactive fluid ketones, the
difference was a little, so we used DMA-DMF as a more
common and less expensive reagent (procedure A, Table 4). In
the case of applying insoluble in BR or DMA-DMF ketones,
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Table 4. Preparative Formation of α-Methylketones
Step I
procedures, purification techniques, yield of crude
Step II
a
b
b
starting
ketone 1
purification techniques, yield of pure
c d
,
c
entry
product 2
product
product 3
compound
1
2
1(1)
1(2)
2(1)
2(2)
B, E, 85%
A, F, 86%
B, F, 82%
A, F, 78%
B, F, 72%
B, F, 85%
A, F, 84%
A, G, 89%
B, G, 87%
A, F, 87%
B, F, 58%
B, F, 77%
A, F, 92%
B, F, 82%
A, E, 56%
C, E, 90%
A, E, 72%
C, E, 94%
C, E, 92%
A, E, 88%
C, E, 95%
A, E, 68%
C, E, 94%
C, E, 76%
A, E, 76%
C, E, 74%
A, G, 88%
B, G, 75%
A, G, 77%
C, G, 73%
A, E, 84%
B, E, 69%
A, G, 88%
C, G, 83%
D, E, 95%
A, F, 75%
A, F, 68%
3(1)
3(2)
H, 20%
H, 74%
3
1(3)
2(3)
3(3)
H, 67%
4
5
6
1(4)
1(5)
1(6)
2(4)
2(5)
2(6)
3(4)
3(5)
3(6)
H, 72%
H, 58%
F, 48%
7
1(7)
2(7)
3(7)
F, 44%
8
9
1(8)
1(9)
2(8)
2(9)
3(8)
3(9)
G, 32%
G, 52%
10
11
1(10)
1(11)
2(10)
2(11)
3(10)
3(11)
H, 73%
H, 73%
12
13
1(12)
1(13)
2(12)
2(13)
3(12)
3(13)
H, 78%
F, 84%
14
1(14)
2(14)
3(14)
F, 81%
15
16
1(15)
1(16)
2(15)
2(16)
3(15)
3(16)
F, 71%
F, 62%
17
18
19
20
1(17)
1(18)
1(19)
1(20)
2(17)
2(18)
2(19)
2(20)
3(17)
3(18)
3(19)
3(20)
F, 47%
F, 49%
F, 63%
F, 52%
21
22
23
1(21)
1(22)
1(23)
2(21)
2(22)
2(23)
3(21)
3(22)
3(23)
E, 96%
H, 69%
H, 78%
a
The preparative procedure (A−D) for compounds type 2 preparation is noted. The description of each procedure is in the Experimental Section.
The purification techniques (E−H) used for obtaining pure analytical samples of 2 and pure final compounds type 3 is noted. The description of
b
c
d
each technique is in the Experimental Section. All yields are preparative. The compounds type 2 were used in the next step without additional
purification as crude products with purity ∼85−90%. The yield for crude products was provided.
we could not isolate any reduction products after treating
2(24) and 2(25) with hydrogen on Pd/C, presumably due to
catalyst poisoning (Scheme 5).
On the other hand, despite proven efficiency as the tool for
late-stage functionalization on the example of some notable
natural compounds 1(20,21), the substrate differentiation
remains a strong factor in the case of complex structures
(Scheme 6). Camphor 1(26) can form respective enaminone
2(26), but through the reduction step, it transformed to
unexpected N,N-dimethylamino-derivative 5(26) at any
concentration of the substrate. It probably happens due to
the extremely high sterical hindrance of the camphor core. So,
the contact of the molecule with the catalyst is seriously
hampered, which prevents the retro-Michael step. Increasing
the steric restriction of the ketone can lead even to enaminone
formation failure. We observed such a situation on the attempt
utilizing the ketone 1(27) in our reaction conditions. The next
case is the loosing of regioselectivity in the reduction step. The
ketone 1(28) forms enaminone 2(28) in good yield, and the
reductive elimination of the N,N-DMA also went by the
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Scheme 5. Sulphur Heterocyclic Ketones 1(24) and 1(25) in
α-Methylation Reaction Sequence
reduction failed cases leaves us the possibility of utilizing them
in different reactions for the effective modification of natural-
like compounds in the late stage.
CONCLUSION
■
We have developed the preparatively convenient, tolerable to
many functional groups, inexpensive, and scalable approach for
two-step methylation of α-methylketones. The approach is
based on the efficient regioselective procedure for mono
introduction of an N,N-dialkylaminomethylene fragment into
the α-position of ketones in the first step, and the regio- and
diastereoselective, high yielded, and functional group tolerable
catalytic hydrogenation method based on Pd/C (10%) as
catalyst and acetone as reaction media in the second. The role
of acetone as the “kinetic shield” for avoiding keto group
reduction is proven.
The versatility of the proposed methods was demonstrated
on a wide scope of substrates, including some natural
compounds. It makes the approach viable for both early- and
late-stage ketones α-methylation. The overall simplicity of the
experimental protocols and equipment used (see Supporting
Information (SI) for the details) make the described synthetic
sequence an easily accessible and powerful chemical toolkit. It
is also noteworthy that preliminary experiments point toward
the potency of the listed procedures to be successfully applied
for the other alkylation reactions outside the methylation and
wide exploration of enaminones obtained in different synthetic
transformations.
Figure 2. α-Methylketones 3(1−23) synthesized in this study.
predicted way. However, another double bond occurred to be
also susceptible to catalytic hydrogenation even in mild
conditions, resulting in the inseparable mixture of 3(28) and
7(28) in a 2:1 ratio. The attempts to apply harsher conditions
for the exclusive formation of 7(28) at the hydrogenation step
led only to the carbonyl reduction product added to the
mixture above.
The limitations we faced, when probing our methylation
reactions as a late-stage functionalization tool for complex
molecules, however, show evident structure relation and leave
substantial chemical space of natural and drug-like compounds
to work with. Also, the formation of enaminones in the
Figure 3. X-ray crystal structures for α-methylketones 3(16), 3(20)dnph (as dinitrophenyl hydrazine derivative), and 3(21).
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Scheme 6. Limitations on α-Methylation of Natural-like Ketones 1(26−28)
with purity ∼85−90%. The crude product 2 was used in the
next step without additional purification. The analytical
samples were obtained according to the purification techniques
listed below.
EXPERIMENTAL SECTION
■
General Information. The solvents were purified according to
the standard procedures. All starting materials were obtained from
Enamine Ltd. Melting points were measured on an automated melting
1
D. A mixture of BR (1.1 mol; 1.1 equiv) and ketone 1 (1 mol; 1
equiv) in toluene (1 L, the concentration of ketone 1 in
toluene − 1 mol/L) was stirred at 55 °C on an air bath for 18
h. The mixture was concentrated in vacuo to give the crude
title compound 2 with purity ∼85−90%. The crude product 2
was used in the next step without additional purification. The
analytical samples were obtained according to the purification
techniques listed below.
point system. H, 13C, and 19F NMR spectra were recorded on a
Bruker 170 Avance 500 spectrometer (at 500 MHz for protons and
126 MHz for carbon-13) and a Varian Unity Plus 400 spectrometer
(at 400 MHz for protons, 101 MHz for carbon-13, and 376 MHz for
fluorine-19). Tetramethylsilane (1H, 13C) or C6F6 (19F) was used as a
standard. Elemental analyses were performed at the Laboratory of
Organic Analysis, Institute of Organic Chemistry, National Academy
of Sciences of Ukraine; their results were found to be in good
agreement ( 0.4%) with the calculated values. Preparative HPLC
analyses were done on an Agilent 1200. Mass spectra were recorded
on an Agilent 1100 LCMSD SL instrument (chemical ionization
(APCI)). X-ray diffraction studies were performed on an automatic
diffractometer (graphite monochromated Mo Kα radiation, CCD
detector, ω-scanning, 2θmax = 60°). CCDC-2027103 4(10), CCDC-
2027101 3(16), CCDC-2027102 3(20)dnph, and CCDC-2027100
3(21) contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
General Procedures for Step II. Enaminone 2 (0.5 mol, 1 equiv)
was dissolved in anhydrous acetone (1 L) under argon (the
concentration of enaminone 2 in acetone − 0.5 mol/L). Then the
10% Pd on charcoal (0.02 mol; 0.04 equiv; 4 mol % of pure Pd) was
added. The reaction mixture was purged with hydrogen and stirred
under 1 atm hydrogen gas for 2 days. The catalyst was filtered from
the reaction mixture and washed with acetone (2 × 100 mL). The
combined organic layer was concentrated in vacuo to form the crude
title compound. Then the crude compound was purified by one of the
purification techniques listed below to obtain target methylated
product 3.
General Procedures for Step I.
The Purification Techniques.
E. The crude product 3 was purified by the crystallization in an
appropriate solvent pointed out below in the compound
description section.
F. The crude product 2 or 3 was purified by the column
chromatography on silica gel in an appropriate system of
solvents pointed out below in the compound description
section.
G. The crude product 2 or 3 was purified by the preparative
HPLC on silica gel in an appropriate system of solvents
pointed out below in the compound description section.
H. The crude product 3 was purified by the vacuum distillation.
The temperature and the appropriate pressure are pointed out
below in the compound description section.
A. A mixture of DMF-DMA (1.2 mol; 1.2 equiv) and ketone 1 (1
mol; 1 equiv) in DMF (2 L, the concentration of ketone 1 in
DMF − 0.5 mol/L) was stirred at 100 °C on an oil bath for 18
h. The resultant mixture was concentrated in vacuo to give the
crude title compound 2 with purity ∼85−90%. The crude
product 2 was used in the next step without additional
purification. The analytical samples were obtained according to
the purification techniques listed below.
B. A mixture of BR (1.2 mol; 1.2 equiv) and ketone 1 (1 mol; 1
equiv) was stirred at 50 °C on an air bath for 18 h. The
mixture was concentrated in vacuo to give the crude title
compound 2 with purity ∼85−90%. The crude product 2 was
used in the next step without additional purification. The
analytical samples were obtained according to the purification
techniques listed below.
Experimental Data and Analytical Data for Synthesized
Compounds. Compounds type 2 and 3 were synthesized and
isolated according to general procedures A−D and purified according
to the purification techniques E−H listed above. The appropriate
procedure and purification technique, yields, and compounds
characterization data are indicated below. Yields of crude (for
C. A mixture of BR (1.1 mol; 1.1 equiv) and ketone 1 (1 mol; 1
equiv) in toluene (1 L, the concentration of ketone 1 in
toluene − 1 mol/L) was stirred at RT for 18 h. The mixture
was concentrated in vacuo to give the crude title compound 2
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compounds type 2) and pure (for 2 and 3) products are also noted in
Table 4.
C11H19NO: C, 72.88; H, 10.56; N, 7.73. Found: C, 72.86; H, 10.53;
N, 7.74.
(E)-2-((Dimethylamino)methylene)cyclobutanone (2(1)). The
compound was synthesized by the general procedure A. 106.4 g of
the crude compound was obtained as a yellowish viscous oil in 85%
yield. The analytical sample (63 mg) was acquired by the purification
method E (crystallization solvent MTBE).
(E)-7-((Dimethylamino)methylene)-1,4-dioxaspiro[4.5]-decan-8-
one (2(7)).22b The compound was synthesized by both general
procedures A (183.8 g, 87% yield) and B (122.5 g, 58% yield) as a
light brown oil. The analytical sample (64 mg) was acquired by the
purification method F (system of solvents MTBE/MeOH).
1H NMR (500 MHz, DMSO-d6) δ 7.49 (s, 1H), 4.05−3.90 (m,
4H), 3.06 (s, 6H), 2.91 (s, 2H), 2.50 (t, J = 7.1 Hz, 2H), 1.94 (t, J =
7.0 Hz, 2H). LCMS, positive mode, m/z:228 [M + H2O − H]+.
LCMS, negative mode, m/z: 183 [M − N(CH3)2 + OH − H]−. Anal.
Calcd for C11H17NO3: C, 62.54; H, 8.11; N, 6.63. Found: C, 62.58;
H, 7.81; N, 6.84.
(3aR,6aR,Z)-1-((Dimethylamino)methylene)tetrahydro-penta-
lene-2,5(1H,3H)-dione (2(8)).22c The compound was synthesized by
the general procedure B (148.8 g, 77% yield) as a gray viscous oil.
The analytical sample (59 mg) was acquired by the purification
method F (system of solvents MTBE/MeOH).
1H NMR (400 MHz, Chloroform-d) δ 6.87 (s, 1H), 2.93 (s, 6H),
2.74 (t, J = 5.6 Hz, 2H), 2.62 (t, J = 5.6 Hz, 2H). 13C{1H} NMR (126
MHz, Chloroform-d) δ 195.6, 138.7, 111.5, 44.1, 43.0, 20.1. EIMS, 70
eV, m/z (rel. int.): 126 [M + H]+ (5); 125 [M]+ (64); 110 (38); 97
(16); 96 (23); 82 (55); 81 (10); 69 (25); 68 (40); 53 (13); 43 (52);
42 (100); 41 (38); 39 (17). Anal. Calcd for C7H11NO: C, 67.17; H,
8.86; N, 11.19. Found: C, 67.18; H, 9.05; N, 11.27.
(E)-2-((Dimethylamino)methylene)cyclopentanone (2(2)). The
compound was synthesized by both general procedures A (119.7 g,
86% yield) and B (114.1 g, 82% yield) as a yellowish viscous oil. The
analytical sample (54 mg) was acquired by the purification method F
(system of solvents MTBE/MeOH).
1H NMR (500 MHz, Chloroform-d) δ 7.29 (s, 1H), 3.78 (q, J = 8.2
Hz, 1H), 3.07 (s, 6H), 2.99−2.87 (m, 1H), 2.68−2.48 (m, 3H),
2.36−2.19 (m, 2H), 2.11 (dd, J = 17.6, 8.7 Hz, 1H). EIMS, 70 eV, m/
z (rel. int.): 194 [M + H]+ (8); 193 [M]+ (63); 178 (11); 151 (12);
150 (100); 136 (17); 124 (16); 122 (19); 108 (14); 107 (16); 94
(13); 82 (29); 79 (13); 42 (21). Anal. Calcd for C11H15NO2: C,
68.37; H, 7.82; N, 7.25. Found: C, 68.22; H, 7.93; N, 7.18.
(E)-2-((Dimethylamino)methylene)-4,4-difluorocyclo-hexanone
(2(9)).22b The compound was synthesized by both general procedures
A (174.1 g, 92% yield) and B (155.2 g, 82% yield) as a light brown
viscous oil. The analytical sample (62 mg) was acquired by the
purification method F (system of solvents MTBE/MeOH).
1H NMR (500 MHz, Chloroform-d) δ 7.54 (s, 1H), 3.18 (t, J =
14.7 Hz, 2H), 3.10 (s, 6H), 2.52 (t, J = 7.2 Hz, 2H), 2.23 (tt, J = 13.8,
7.2 Hz, 2H). Anal. Calcd for C9H13F2NO: C, 57.13; H, 6.93; N, 7.40.
Found: C, 57.34; H, 7.02; N, 7.23.
1H NMR (400 MHz, DMSO-d6) δ 7.00 (s, 1H), 3.01 (s, 6H), 2.78
(t, J = 7.2 Hz, 2H), 2.00 (t, J = 7.9 Hz, 2H), 1.73 (p, J = 7.6 Hz, 2H).
13C{1H} NMR (126 MHz, Chloroform-d) δ 202.9, 146.0, 102.8, 42.0,
37.6, 27.2, 20.7. LCMS, positive mode, m/z: 140 [M + H]+. Anal.
Calcd for C8H13NO: C, 69.03; H, 9.41; N, 10.06. Found: C, 68.89; H,
9.39; N, 10.06.
(E)-2-((Dimethylamino)methylene)cyclohexanone (2(3)).17b The
compound was synthesized by both general procedures A (119.5 g,
78% yield) and B (110.3 g, 72% yield) as a gray viscous oil. The
analytical sample (67 mg) was acquired by the purification method F
(system of solvents MTBE/MeOH).
1H NMR (400 MHz, DMSO-d6) δ 7.29 (s, 1H), 3.03 (s, 6H), 2.64
(t, J = 6.2 Hz, 2H), 2.11 (t, J = 6.5 Hz, 2H), 1.70−1.52 (m, 4H).
EIMS, 70 eV, m/z (rel. int.): 154 [M]+ (9); 153 [M]+ (87); 152 [M
− H]+ (12); 138 (100); 136 (38); 124 (16); 110 (36); 97 (18); 96
(28); 94 (13); 84 (14); 82 (69); 81 (19); 79 (10); 68 (16); 44 (23);
42 (43); 41 (18); 38 (12). Anal. Calcd for C9H15NO: C, 70.55; H,
9.87; N, 9.14. Found: C, 70.87; H, 10.00; N, 9.52.
(E)-4-((Dimethylamino)methylene)dihydrofuran-3(2H)-one
(2(10)). The compound was synthesized by both general procedures
A (79.1 g, 56% yield) and C (127.1 g, 90% yield) as a yellowish
viscous oil. The analytical sample (85 mg) was acquired by the
purification method E (crystallization solvent MTBE).
(E)-2-((Dimethylamino)methylene)-5,5-dimethylcyclohexanone
(2(4)). The compound was synthesized by the general procedure B
(154.1 g, 85% yield) as a gray viscous oil. The analytical sample (64
mg) was acquired by the purification method F (system of solvents
MTBE/MeOH).
1H NMR (400 MHz, DMSO-d6) δ 7.14 (s, 1H), 4.99 (s, 2H), 3.85
(s, 2H), 3.00 (s, 6H). 13C{1H} NMR (126 MHz, Chloroform-d) δ
197.2, 146.2, 98.4, 71.5, 69.8, 45.9. LCMS, positive mode, m/z: 142
[M + H]+. Anal. Calcd for C7H11NO2: C, 59.56; H, 7.85; N, 9.92.
Found: C, 59.44; H, 7.76; N, 9.84.
1H NMR (400 MHz, DMSO-d6) δ 7.28 (s, 1H), 3.05 (s, 6H), 2.67
(t, J = 6.8 Hz, 2H), 1.92 (s, 2H), 1.42 (t, J = 6.7 Hz, 2H), 0.89 (s,
6H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 195.0, 150.0, 101.2,
52.4, 43.3, 36.3, 35.5, 30.7, 28.5, 22.3. LCMS, positive mode, m/z:
182 [M + H]+. Anal. Calcd for C11H19NO: C, 72.88; H, 10.56; N,
7.73. Found: C, 73.03; H, 10.80; N, 7.57.
(E)-3-((Dimethylamino)methylene)dihydro-2H-pyran-4(3H)-one
(2(11)). The compound was synthesized by both general procedures
A (111.8 g, 72% yield) and C (145.9 g, 94% yield) as a yellowish
viscous oil. The analytical sample (85 mg) was acquired by the
purification method E (crystallization solvent MTBE).
(E)-2-((Dimethylamino)methylene)cycloheptanone (2(5)).22a
The compound was synthesized by the general procedure A (140.5
g, 84% yield) as a gray viscous oil. The analytical sample (57 mg) was
acquired by the purification method F (system of solvents MTBE/
MeOH).
1H NMR (400 MHz, DMSO-d6) δ 7.41 (s, 1H), 3.86 (s, 2H), 3.68
(t, J = 5.7 Hz, 2H), 3.08 (s, 6H), 2.76 (t, J = 5.5 Hz, 3H). 13C{1H}
NMR (126 MHz, Chloroform-d) δ 191.9, 150.4, 99.4, 73.1, 65.5,
43.2, 25.9. LCMS, positive mode, m/z: 156 [M + H]+. Anal. Calcd for
C8H13NO2: C, 61.91; H, 8.44; N, 9.03. Found: C, 62.10; H, 8.60; N,
9.07.
1H NMR (400 MHz, DMSO-d6) δ 7.18 (s, 1H), 2.98 (s, 6H),
2.54−2.49 (m, 2H), 2.44−2.37 (m, 2H), 1.70−1.60 (m, 2H), 1.53 (h,
J = 6.0 Hz, 4H). EIMS, 70 eV, m/z (rel. int.): 168 [M + H]+. Anal.
Calcd for C10H17NO: C, 71.81; H, 10.25; N, 8.37. Found: C, 71.48;
H, 10.37; N, 8.09.
(E)-4-((Dimethylamino)methylene)dihydro-2H-pyran-3(4H)-one
(2(12)). The compound was synthesized by the general procedure C
(143.8 g, 92% yield) as a yellowish viscous oil. The analytical sample
(81 mg) was acquired by the purification method E (crystallization
solvent MTBE).
(E)-2-((Dimethylamino)methylene)cyclooctanone (2(6)).22a The
compound was synthesized by both general procedures A (161.3 g,
89% yield) and B (157.7 g, 87% yield) as a gray viscous oil. The
analytical sample (67 mg) was acquired by the purification method G
(system of solvents MeOH/H2O).
1H NMR (400 MHz, DMSO-d6) δ 7.41 (s, 1H), 3.86 (s, 2H), 3.68
(t, J = 5.7 Hz, 2H), 3.08 (s, 6H), 2.76 (t, J = 5.5 Hz, 2H). 13C{1H}
NMR (126 MHz, Chloroform-d) δ 191.9, 150.4, 99.4, 73.1, 65.8,
43.2, 25.9. LCMS, positive mode, m/z: 156 [M + H]+. Anal. Calcd for
C8H13NO2: C, 61.91; H, 8.44; N, 9.03. Found: C, 62.13; H, 8.31; N,
9.09.
1H NMR (400 MHz, DMSO-d6) δ 7.27 (s, 1H), 3.02 (s, 6H), 2.58
(t, J = 6.1 Hz, 2H), 2.42 (t, J = 6.1 Hz, 2H), 1.61−1.49 (m, J = 5.3
Hz, 2H), 1.52−1.43 (m, 4H), 1.41−1.32 (m, 2H). EIMS, 70 eV, m/z
(rel. int.): 182 [M]+ (6); 181 [M]+ (53); 138 (35); 124 (15); 110
(46); 98 (19); 97 (27); 96 (21); 85 (10); 84 (100); 82 (56); 71 (36);
68 (12); 58 (11); 55 (13); 44 (10); 42 (33); 41 (18). Anal. Calcd for
(E)-tert-Butyl 3-((Dimethylamino)methylene)-4-oxopiperidine-1-
carboxylate (2(13)). The compound was synthesized by both general
procedures A (223.8 g, 88% yield) and C (241.6 g, 95% yield) as a
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gray viscous oil. The analytical sample (79 mg) was acquired by the
purification method E (crystallization solvent MTBE).
Hz, 2H). LCMS, positive mode, m/z: 169 [M + H]+. Anal. Calcd for
C8H12N2O2: C, 57.13; H, 7.19; N, 16.66. Found: C, 56.86; H, 7.25;
N, 16.44.
(E)-tert-Butyl 2-((Dimethylamino)methylene)-3-oxo-8-aza-
bicyclo[3.2.1]octane-8-carboxylate (2(20)).23a The compound was
synthesized by both general procedures A (24.7 g, 88% yield) and C
(23.2 g, 83% yield) as a gray viscous oil. The analytical sample (67
mg) was acquired by the purification method G (system of solvents
MeCN/H2O).
1H NMR (400 MHz, Chloroform-d) δ 7.46 (s, 1H), 4.52 (s, 2H),
3.57 (t, J = 6.4 Hz, 2H), 3.08 (s, 6H), 2.41 (t, J = 6.4 Hz, 2H), 1.44 (s,
9H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 194.5, 154.8, 149.3,
101.1, 79.8, 43.5, 41.7, 41.3, 37.6, 28.4. EIMS, 70 eV, m/z (rel. int.):
253 [M − H]− (5); 109 (65); 80 (20); 67 (22); 56 (43); 55 (22); 54
(19); 53 (15); 50 (12); 45 (19); 44 (100); 42 (17); 41 (89); 40 (34);
39 (57); 38 (10). Anal. Calcd for C13H22N2O3: C, 61.39; H, 8.72; N,
11.01. Found: C, 61.38; H, 8.83; N, 10.91.
1H NMR (400 MHz, Chloroform-d) δ 7.47−7.28 (m, 1H), 5.53−
5.13 (m, 1H), 4.52−4.19 (m, 1H), 3.08 (s, 6H), 2.21 (s, 1H), 2.18−
2.06 (m, 2H), 1.88−1.78 (m, 1H), 1.69 (s, 2H), 1.42 (s, 9H). LCMS,
positive mode, m/z: 281 [M + H]+. Anal. Calcd for C15H24N2O3: C,
64.26; H, 8.63; N, 9.99. Found: C, 64.22; H, 9.02; N. 9,81.
(3S,3aS,5aS,9S,9aS,9bS,E)-7-((Dimethylamino)methylene)-
3,5a,9-trimethyloctahydronaphtho[1,2-b]-furan-2,8(3H,9bH)-
dione (2(21)). The compound was synthesized by the general
procedure D (0.29 g, 95% yield) as a gray viscous oil. The analytical
sample (21 mg) was acquired by the purification method E
(crystallization solvent MTBE).
(E)-tert-Butyl 3-((Dimethylamino)methylene)-4-oxopyrrolidine-
1-carboxylate (2(14)). The compound was synthesized by both
general procedures A (163.4 g, 68% yield) and C (225.9 g, 94% yield)
as a gray viscous oil. The analytical sample (87 mg) was acquired by
the purification method E (crystallization solvent MTBE).
1H NMR (400 MHz, DMSO-d6) δ 7.28 (s, 1H), 4.65 (d, J = 14.5
Hz, 1H), 4.33 (s, 1H), 3.63 (dd, J = 12.6, 5.9 Hz, 1H), 3.05 (s, 6H),
2.37 (q, J = 7.6, 7.0 Hz, 1H), 1.41 (s, 9H). 13C{1H} NMR (126 MHz,
Chloroform-d) δ 195.5, 154.2, 148.7, 100.0, 79.3, 47.8, 43.5, 36.1,
28.6. LCMS, negative mode, m/z: 240 [M]−. Anal. Calcd for
C12H20N2O3: C, 59.98; H, 8.39; N, 11.66. Found: C, 59.76; H, 8.34;
N, 11.27.
1H NMR (500 MHz, DMSO-d6) δ 7.33 (s, 1H), 4.07 (q, J = 5.4
Hz, 1H), 3.86 (t, J = 10.5 Hz, 1H), 3.01 (s, 6H), 2.47−2.35 (m, 2H),
1.97 (dq, J = 10.7, 7.1 Hz, 1H), 1.79−1.68 (m, 1H), 1.64−1.42 (m,
4H), 1.38−1.25 (m, 1H), 1.14 (d, J = 6.9 Hz, 3H), 1.05 (d, J = 7.0
Hz, 3H), 0.82 (s, 3H). 13C{1H} NMR (126 MHz, DMSO-d6) δ
197.7, 179.6, 151.3, 100.1, 84.3, 51.8, 51.6, 50.7, 43.4, 42.6, 42.0, 40.3,
35.3, 23.3, 19.5, 18.7, 12.7. LCMS, positive mode, m/z: 306 [M +
H]+. Anal. Calcd for C18H27NO3: C, 70.79; H, 8.91; N, 4.59. Found:
C, 70.99; H, 9.25; N, 4.79.
(E)-tert-Butyl 4-((Dimethylamino)methylene)-3-oxopiperidine-1-
carboxylate (2(15)).22d The compound was synthesized by the
general procedure C (193.3 g, 76% yield) as a gray viscous oil. The
analytical sample (54 mg) was acquired by the purification method E
(crystallization solvent MTBE).
1H NMR (400 MHz, DMSO-d6) δ 7.42 (s, 1H), 3.76 (s, 2H), 3.40
(t, J = 5.9 Hz, 2H), 3.08 (s, 6H), 2.71 (t, J = 6.0 Hz, 2H), 1.40 (s,
9H). LCMS, positive mode, m/z: 255 [M + H]+. Anal. Calcd for
C13H22N2O3: C, 61.39; H, 8.72; N, 11.01. Found: C, 61.78; H, 9.00;
N, 11.01.
(E)-1-(Dimethylamino)-4,4-dimethylpent-1-en-3-one (2(22)).23b
The compound was synthesized by the general procedure A (116.4
g, 75% yield) as a gray viscous oil. The analytical sample (55 mg) was
acquired by the purification method F (system of solvents EtOAc/
Hex).
(R,E)-tert-Butyl 3-((Dimethylamino)methylene)-5-methyl-4-oxo-
piperidine-1-carboxylate (2(16)).22e The compound was synthesized
by both general procedures A (203.9 g, 76% yield) and C (198.5 g,
74% yield) as a gray viscous oil. The analytical sample (61 mg) was
acquired by the purification method E (crystallization solvent
MTBE).
1H NMR (400 MHz, Chloroform-d) δ 7.71−7.52 (m, 1H), 5.34−
5.13 (m, 1H), 2.93 (br, 6H), 1.14 (s, 9H). EIMS, 70 eV, m/z (rel.
int.): 155 [M]+ (7); 98 (100). Anal. Calcd for C9H17NO: C, 69.63; H,
11.04; N, 9.02. Found: C, 69.97; H, 10.94; N, 9.35.
(E)-1-Cyclopropyl-3-(dimethylamino)prop-2-en-1-one (2(23)).23b
The compound was synthesized by the general procedure A (94.6 g,
68% yield) as a yellowish viscous oil. The analytical sample (57 mg)
was acquired by the purification method F (system of solvents
EtOAc/Hex).
1H NMR (400 MHz, DMSO-d6) δ 7.29 (s, 1H), 4.69−4.60 (m,
1H), 4.33 (s, 1H), 3.67−3.58 (m, 1H), 3.05 (s, 7H), 2.42−2.33 (m,
1H), 1.41 (s, 9H), 1.00−0.93 (m, 3H). LCMS, positive mode, m/z:
269 [M + H]+. Anal. Calcd for C14H24N2O3: C, 62.66; H, 9.01; N,
10.44. Found: C, 63.02; H, 8.91; N, 10.26.
1H NMR (400 MHz, Chloroform-d) δ 7.35 (d, J = 7.8 Hz, 1H),
5.80 (d, J = 7.8 Hz, 1H), 1.75 (m, 1H), 0.98 (m, 2H), 0.67 (m, 2H).
EIMS, 70 eV, m/z (rel. int.): 139 [M]+ (47); 98 (100). Anal. Calcd
for C8H13NO: C, 69.03; H, 9.41; N, 10.06. Found: C, 69.35; H, 9.33;
N, 10.35.
(Z)-tert-Butyl 3-((Dimethylamino)methylene)-2,4-dioxopiperi-
dine-1-carboxylate (2(17)).22f The compound was synthesized by
both general procedures A (236.1 g, 88% yield) and B (201.2 g, 75%
yield) as a gray viscous oil. The analytical sample (73 mg) was
acquired by the purification method G (system of solvents MeCN/
H2O).
(E)-3-((Dimethylamino)methylene)dihydro-2H-thiopyran-4(3H)-
one (2(24)). The compound was synthesized by the general
procedure C (85.6 g, 50% yield) as a yellowish viscous oil. The
analytical sample (48 mg) was acquired by the purification method E
(crystallization solvent MTBE).
1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 3.71 (t, J = 6.1 Hz,
2H), 3.39 (s, 3H), 3.03 (s, 3H), 2.37 (t, J = 6.1 Hz, 2H), 1.44 (s, 9H).
LCMS, positive mode, m/z: 269 [M + H]+. Anal. Calcd for
C13H20N2O4: C, 58.19; H, 7.51; N, 10.44. Found: C, 58.24; H, 7.77;
N, 10.74.
1H NMR (400 MHz, DMSO-d6) δ 7.29 (s, 1H), 3.75 (s, 2H), 3.05
(s, 6H), 2.80 (t, J = 6.4 Hz, 2H), 2.51−2.44 (m, 2H). 13C{1H} NMR
(151 MHz, Chloroform-d) δ 196.0, 149.2, 103.2, 43.7, 39.2, 34.8,
25.9. LCMS, negative mode, m/z: 143 [M − N(CH3)2 + OH − H].
Anal. Calcd for C8H13NOS: C, 56.11; H, 7.65; N, 8.18; S, 18.72.
Found: C, 55.93; H, 7.31; N, 7.85; S, 19.04.
(E)-3-((Dimethylamino)methylene)-1-methylpiperidin-4-one (2-
(18)).22g The compound was synthesized by both general procedures
A (129.5 g, 77% yield) and C (122.8 g, 73% yield) as a gray viscous
oil. The analytical sample (58 mg) was acquired by the purification
method G (system of solvents MeOH/H2O).
1H NMR (400 MHz, DMSO-d6) δ 7.23 (s, 1H), 3.02 (s, 6H),
2.52−2.46 (m, 2H), 2.27 (s, 3H), 2.19 (t, J = 6.2 Hz, 2H). LCMS,
positive mode, m/z: 169 [M + H]+. Anal. Calcd for C9H16N2O: C,
64.25; H, 9.59; N, 16.65. Found: C, 64.48; H, 9.83; N, 16.67.
(Z)-3-((Dimethylamino)methylene)piperidine-2,4-dione (2-
(19)).22h The compound was synthesized by both general procedures
A (141.3 g, 84% yield) and B (116.1 g, 69% yield) as a gray viscous
oil. The analytical sample (60 mg) was acquired by the purification
method E (crystallization solvent MTBE).
(E)-3-((Dimethylamino)methylene)dihydro-2H-thiopyran-4(3H)-
one 1,1-dioxide (2(25)). The compound was synthesized by the
general procedure C (2.3 g, 10% yield) as a yellowish viscous oil. The
analytical sample (46 mg) was acquired by the purification method F
(system of solvents MTBE/MeOH).
1H NMR (500 MHz, Chloroform-d) δ 7.63 (s, 1H), 4.22 (s, 2H),
3.34 (t, J = 6.7 Hz, 2H), 3.16 (s, 6H), 2.89 (t, J = 6.7 Hz, 2H).
13C{1H} NMR (151 MHz, Chloroform-d) δ 192.7, 151.8, 93.3, 51.1,
50.4, 44.0, 35.9. LCMS, positive mode, m/z: 204 [M + H]+. Anal.
Calcd for C8H13NO3S: C, 47.27; H, 6.45; N, 6.89; S, 15.77. Found: C,
47.45; H, 6.43; N, 6.71; S, 15.89.
1H NMR (400 MHz, DMSO-d6) δ 7.83 (s, 1H), 7.15 (s, 1H), 3.29
(s, 3H), 3.16 (td, J = 6.4, 3.3 Hz, 2H), 3.05 (s, 3H), 2.29 (t, J = 6.4
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Article
(1R,4S,E)-3-((Dimethylamino)methylene)-1,7,7-trimethyl-
bicyclo[2.2.1]heptan-2-one (2(26)). The compound was synthesized
by the general procedure A (4.2 g, 20% yield) as a gray viscous oil.
The analytical sample (34 mg) was acquired by the purification
method G (system of solvents Hexane/MTBE).
56 (47); 55 (46); 41 (26); 39 (12). Anal. Calcd for C9H16O: C,
77.09; H, 11.50. Found: C, 76.79; H, 11.15.
2-Methylcycloheptanone (3(5)).23c The crude compound was
purified by method F (system of solvents Hexane/MTBE). 36.6 g of
the target product obtained as a colorless viscous oil in 58% yield.
1H NMR (400 MHz, Chloroform-d) δ 2.65−2.52 (m, 1H), 2.51−
2.40 (m, 2H), 1.92−1.71 (m, 4H), 1.68−1.52 (m, 1H), 1.50−1.26
(m, 3H), 1.05 (d, J = 6.9 Hz, 3H). EIMS, 70 eV, m/z (rel. int.): 127
[M + H]+ (6); 126 (62); 111 (11); 98 (100); 97 (30); 93 (17); 84
(34); 83 (42); 82 (39); 70 (35); 69 (50); 68 (22); 67 (30); 56 (40);
55 (99); 43 (13); 42 (50); 41 (65); 39 (37). Anal. Calcd for C8H14O:
C, 76.14; H, 11.18. Found: C, 76.30; H, 11.11.
1H NMR (500 MHz, Chloroform-d) δ 6.95 (s, 1H), 2.97−2.83 (m,
7H), 2.02−1.86 (m, 1H), 1.60−1.48 (m, 1H), 1.43−1.33 (m, 1H),
1.34−1.24 (m, 1H), 0.98−0.68 (m, 9H). 13C{1H} NMR (126 MHz,
Chloroform-d) δ 207.2, 141.1, 111.0, 56.3, 48.2, 48.0, 42.2, 30.3, 28.4,
20.7, 19.0, 9.6. EIMS, 70 eV, m/z (rel. int.): 208 [M + H]+ (12); 207
[M]+ (83); 192 (14); 179 (48); 165 (24); 164 (100); 150 (10); 136
(32); 124 (10); 119 (12); 94 (10); 82 (16); 42 (13); 41 (11). Anal.
Calcd for C13H21NO: C, 75.32; H, 10.21; N, 6.76. Found: C, 75.54;
H, 9.96; N, 6.78.
2-Methylcyclooctanone (3(6)). The crude compound was purified
by method F (system of solvents Hexane/MTBE). 33.7 g of the target
product obtained as a colorless viscous oil in 48% yield.
(3S,8R,9S,10R,13S,14S,E)-16-((Dimethylamino)methylene)-3-hy-
droxy-10,13-dimethyl-3,4,7,8,9,10,11,12,13,14, 15,16-dodecahy-
dro-1H-cyclopenta[a]phenanthren-17(2H)-one (2(28)). The com-
pound was synthesized by the general procedure D (0.27 g, 80%
yield) as a gray viscous oil. The analytical sample (21 mg) was
acquired by the purification method G (system of solvents Hexane/
MTBE).
1H NMR (400 MHz, Chloroform-d) δ 2.64−2.53 (m, 1H), 2.45−
2.29 (m, 2H), 1.98−1.81 (m, 2H), 1.82−1.71 (m, 1H), 1.72−1.34
(m, 6H), 1.28−1.12 (m, 1H), 1.03 (dd, J = 6.8, 2.2 Hz, 3H). 13C{1H}
NMR (126 MHz, Chloroform-d) δ 220.0, 45.1, 40.3, 33.0, 26.9, 26.5,
25.6, 24.5, 16.7. EIMS, 70 eV, m/z (rel. int.): 141 [M + H]+ (3); 140
[M]+ (30); 112 (23); 111 (14); 98 (100); 97 (26); 96 (13); 93 (12);
84 (27); 83 (38); 81 (17); 70 (28); 69 (40); 68 (13); 67 (15); 56
(45); 55 (80); 54 (11); 43 (20); 42 (39); 41 (64); 39 (30). Anal.
Calcd for C9H16O: C, 77.09; H, 11.50. Found: C, 77.11; H, 11.35.
7-Methyl-1,4-dioxaspiro[4.5]decan-8-one (3(7)). The crude com-
pound was purified by method F (system of solvents Hexane/
MTBE). 37.4 g of the target product obtained as a colorless viscous
oil in 44% yield.
1H NMR (400 MHz, DMSO-d6) δ 6.99 (s, 1H), 5.30 (d, J = 4.6
Hz, 1H), 4.59 (d, J = 4.6 Hz, 1H), 3.31 (s, 6H), 2.73 (dd, J = 13.2, 6.3
Hz, 1H), 2.31−1.93 (m, 4H), 1.76 (d, J = 13.3 Hz, 1H), 1.72−1.52
(m, 5H), 1.48−1.28 (m, 3H), 1.22−1.03 (m, 2H), 0.97 (s, 5H), 0.74
(s, 3H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 206.8, 145.7, 142.0,
120.6, 102.0, 70.5, 51.3, 50.6, 45.9, 42.8, 42.0, 37.4, 36.8, 32.3, 32.0,
31.0, 27.4, 20.6, 19.7, 14.9. LCMS, positive mode, m/z: 344 [M +
H]+. Anal. Calcd for C22H33NO2: C, 76.92; H, 9.68; N, 4.08. Found:
C, 76.59; H, 9.89; N, 4.34.
1H NMR (400 MHz, Chloroform-d) δ 4.17−3.73 (m, 4H), 2.77−
2.52 (m, 2H), 2.33 (ddd, J = 14.3, 5.1, 2.9 Hz, 1H), 2.08−1.87 (m,
3H), 1.69 (t, J = 13.1 Hz, 1H), 0.99 (d, J = 6.6 Hz, 3H). 13C{1H}
NMR (126 MHz, Chloroform-d) δ 211.9, 107.4, 64.7, 64.6, 42.7,
41.3, 38.0, 34.6, 14.3. EIMS, 70 eV, m/z (rel. int.): 170 [M]+ (5); 114
(46); 100 (25); 99 (100); 55 (12). Anal. Calcd for C9H14O3: C,
63.51; H, 8.29. Found: C, 63.49; H, 8.69.
2-Methylcyclobutanone (3(1)). The crude compound was purified
by method H (bp = 40 °C, 50 mmHg). 8.4 g of the target product
obtained as a colorless liquid in 20% yield.
1H NMR (400 MHz, Chloroform-d) δ 3.29 (m, 1H), 3.03 (m,
1H), 2.89 (m, 1H), 2.20 (qd, J = 10.6, 5.0 Hz, 1H), 1.53 (m, 1H),
1.13 (d, J = 7.4 Hz, 3H). 13C{1H} NMR (126 MHz, Chloroform-d) δ
212.5, 54.9, 44.7, 18.6, 14.0. EIMS, 70 eV, m/z (rel. int.): 84 [M]+
(44); 56 (100); 55 (21); 43 (15); 42 (76); 41 (56); 39 (32). Anal.
Calcd for C5H8O: C, 71.39; H, 9.59. Found: C, 71.48; H, 9.60.
2-Methylcyclopentanone (3(2)). The crude compound was
purified by method H (bp = 38−40 °C, 10 mmHg). 36.3 g of the
target product obtained as a colorless liquid in 74% yield.
1H NMR (400 MHz, Chloroform-d) δ 2.32−2.14 (m, 2H), 2.14−
2.00 (m, 2H), 1.99−1.91 (m, 1H), 1.80−1.68 (m, 1H), 1.49−1.39
(m, 1H), 1.04 (d, J = 7.0 Hz, 3H). 13C{1H} NMR (126 MHz,
Chloroform-d) δ 221.9, 43.9, 37.6, 31.8, 20.6, 14.1. EIMS, 70 eV, m/z
(rel. int.): 98 [M]+ (80); 83 (21); 70 (28); 69 (46); 56 (24); 55 (80);
43 (12); 42 (100); 41 (44); 39 (34). Anal. Calcd for C6H10O: C,
73.43; H, 10.27. Found: C, 73.62; H, 10.24.
1-Methyltetrahydropentalene-2,5(1H,3H)-dione (3(8)). The
crude compound was purified by method G (system of solvents
MeCN/H2O). 24.4 g of the target product obtained as a colorless
viscous oil in 32% yield.
1H NMR (400 MHz, DMSO-d6) δ 3.04−2.52 (m, 2H), 2.44 (dtd, J
= 9.8, 8.4, 4.8 Hz, 3H), 2.32−1.79 (m, 4H), 0.98 (d, J = 7.0 Hz, 2H),
0.94 (d, J = 7.1 Hz, 1H). 13C{1H} NMR (126 MHz, Chloroform-d) δ
219.9, 219.7, 219.2, 218.3, 48.0, 47.6, 44.7, 44.3, 43.4, 43.4, 43.0, 42.3,
41.9, 38.7, 34.0, 33.9, 13.3. LCMS, positive mode, m/z: 153 [M +
H]+. Anal. Calcd for C9H12O2: C, 71.03; H, 7.95. Found: C, 71.14; H,
8.04.
4,4-Difluoro-2-methylcyclohexanone (3(9)). The crude com-
pound was purified by method F (system of solvents Hexane). 38.5
g of the target product obtained as a colorless viscous oil in 52% yield.
1H NMR (400 MHz, Chloroform-d) δ 2.65 (m, 2H), 2.42 (m,
3H), 2.30−2.03 (m, 1H), 1.88 (dtd, J = 31.4, 13.4, 3.9 Hz, 1H), 1.05
(d, J = 6.6 Hz, 3H). 13C{1H} NMR (126 MHz, Chloroform-d) δ
209.0, 121.5 (dd, J = 244.0, 239.3 Hz), 41.0 (dd, J = 25.9, 24.0 Hz),
40.1 (d, J = 9.5 Hz), 36.4 (d, J = 9.5 Hz), 33.4 (t, J = 26.1 Hz), 14.0.
19F NMR (376 MHz, Chloroform-d) δ −95.9 (d, J = 243.0 Hz),
−102.6 (d, J = 242.9 Hz). EIMS, 70 eV, m/z (rel. int.): 149 [M + H]+
(8); 148 [M]+ (100); 92 (37); 86 (58); 85 (40); 79 (15); 77 (63); 73
(48); 69 (68); 59 (18); 56 (17); 55 (71); 54 (13); 51 (22); 42 (29);
41 (32); 39 (27). Anal. Calcd for C7H10F2O: C, 56.75; H, 6.80.
Found: C, 57.03; H, 6.68.
4-Methyldihydrofuran-3(2H)-one (3(10)). The crude compound
was purified by method H (bp = 46−48 °C, 10 mmHg). 36.5 g of the
target product obtained as a colorless liquid in 73% yield.
1H NMR (400 MHz, Chloroform-d) δ 4.49 (t, J = 8.8 Hz, 1H),
4.07 (d, J = 17.1 Hz, 1H), 3.83 (d, J = 17.1 Hz, 1H), 3.71 (t, J = 9.3
Hz, 1H), 2.54 (h, J = 7.8 Hz, 1H), 1.16 (d, J = 7.1 Hz, 3H). 13C{1H}
NMR (126 MHz, Chloroform-d) δ 217.1, 73.7, 70.7, 42.0, 11.3.
EIMS, 70 eV, m/z (rel. int.): 100 [M]+ (19); 42 (100); 41 (48); 40
(13); 39 (31). Anal. Calcd for C5H8O2: C, 59.98; H, 8.05. Found: C,
60.32; H, 7.87.
2-Methylcyclohexanone (3(3)). The crude compound was purified
by method H (bp = 51−54 °C, 10 mmHg). 37.6 g of the target
product obtained as a colorless liquid in 67% yield.
1H NMR (400 MHz, Chloroform-d) δ 2.40−2.30 (m, 2H), 2.24
(m, 1H), 2.03 (m, 2H), 1.80 (m, 1H), 1.70−1.53 (m, 2H), 1.32 (qd, J
= 12.3, 4.0 Hz, 1H), 0.97 (d, J = 6.6 Hz, 3H). 13C{1H} NMR (101
MHz, Chloroform-d) δ 213.5, 45.3, 41.8, 36.1, 27.9, 25.1, 14.7. EIMS,
70 eV, m/z (rel. int.): 112 [M]+ (50); 84 (31); 83 (14); 69 (43); 68
(61); 67 (13); 56 (63); 55 (72); 53 (14); 44 (15); 42 (56); 41 (100);
40 (15); 39 (78). Anal. Calcd for C7H12O: C, 74.95; H, 10.78. Found:
C, 75.23; H, 10.52.
2,5,5-Trimethylcyclohexanone (3(4)). The crude compound was
purified by method H (bp = 69−72 °C, 10 mmHg). 50.5 g of the
target product obtained as a colorless liquid in 72% yield.
1H NMR (400 MHz, Chloroform-d) δ 2.27 (tt, J = 12.3, 6.0 Hz,
1H), 2.21−2.04 (m, 2H), 2.01−1.88 (m, 1H), 1.72−1.38 (m, 3H),
1.04−0.95 (m, 6H), 0.82 (s, 3H). 13C{1H} NMR (126 MHz,
Chloroform-d) δ 213.3, 54.7, 44.2, 38.2, 36.9, 31.7, 31.7, 25.4, 14.4.
EIMS, 70 eV, m/z (rel. int.): 141 [M + H]+ (4); 140 [M]+ (46); 125
(20); 98 (11); 97 (18); 96 (49); 84 (10); 83 (100); 69 (19); 57 (12);
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3-Methyldihydro-2H-pyran-4(3H)-one (3(11)). The crude com-
pound was purified by method H (bp = 58−61 °C, 10 mmHg). 41.7 g
of the target product obtained as a colorless liquid in 73% yield.
1H NMR (400 MHz, Chloroform-d) δ 4.20 (m, 1H), 4.12 (ddd, J =
11.2, 6.4, 1.7 Hz, 1H), 3.67 (td, J = 11.5, 3.1 Hz, 1H), 3.28 (t, J = 10.8
Hz, 1H), 2.70−2.53 (m, 2H), 2.35 (dt, J = 14.2, 2.8 Hz, 1H), 0.95 (d,
J = 6.7 Hz, 3H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 208.5,
74.1, 68.7, 46.1, 42.4, 9.8. EIMS, 70 eV, m/z (rel. int.): 114 [M]+
(46); 73 (100); 57 (11); 56 (40); 55 (15); 43 (15); 42 (56); 41 (22);
39 (14). Anal. Calcd for C6H10O2: C, 63.14; H, 8.83. Found: C,
62.76; H, 9.04.
tert-Butyl 3-Methyl-2,4-dioxopiperidine-1-carboxylate (3(17)).
The crude compound was purified by method G (system of solvents
MeCN/H2O). 53.4 g of the target product obtained as a white
powder in 47% yield (mp = 86−87 °C).
1H NMR (400 MHz, Chloroform-d) δ 4.55 (ddd, J = 14.4, 5.8, 2.3
Hz, 1H), 3.71 (ddd, J = 14.3, 12.1, 3.8 Hz, 1H), 3.56 (q, J = 6.6 Hz,
1H), 2.73−2.46 (m, 2H), 1.53 (s, 9H), 1.29 (d, J = 6.6 Hz, 3H).
13C{1H} NMR (126 MHz, Chloroform-d) δ 166.9, 166.3, 153.3,
102.3, 81.3, 42.2, 28.6, 28.3, 9.0. LCMS, negative mode, m/z: 227
[M]−; 226 [M − H]−. Anal. Calcd for C11H17NO4: C, 58.14; H, 7.54;
N, 6.16. Found: C, 58.52; H, 7.29; N, 6.12.
4-Methyldihydro-2H-pyran-3(4H)-one (3(12)). The crude com-
pound was purified by method H (bp = 67−68 °C, 10 mmHg). 44.5 g
of the target product obtained as a colorless liquid in 78% yield.
1H NMR (400 MHz, Acetonitrile-d3) δ 3.97−3.82 (m, 3H), 3.77
(td, J = 11.2, 3.3 Hz, 1H), 2.60 (m, 1H), 2.14 (m, 1H), 1.77−1.62 (m,
1H), 1.04 (d, J = 6.7 Hz, 3H). 13C{1H} NMR (126 MHz,
Acetonitrile-d3) δ 209.4, 74.1, 65.9, 41.7, 34.0, 13.5. EIMS, 70 eV,
m/z (rel. int.): 114 [M]+ (65); 69 (17); 56 (100); 55 (20); 42 (14);
41 (63); 39 (21). Anal. Calcd for C6H10O2: C, 63.14; H, 8.83. Found:
C, 63.50; H, 8.72.
1,3-Dimethylpiperidin-4-one (3(18)). The crude compound was
purified by method F (system of solvents Hexane/MTBE). 31.2 g of
the target product obtained as a yellow oil in 49% yield.
1H NMR (400 MHz, Chloroform-d) δ 3.06−2.95 (m, 2H), 2.69−
2.52 (m, 2H), 2.39−2.23 (m, 5H), 2.02 (t, J = 11.2 Hz, 1H), 0.95 (d,
J = 6.7 Hz, 3H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 210.5,
63.3, 56.2, 45.3, 44.2, 40.8, 11.9. EIMS, 70 eV, m/z (rel. int.): 128 [M
+ H]+ (5); 127 [M]+ (62); 84 (32); 71 (26); 70 (34); 57 (19); 56
(12); 55 (15); 44 (15); 43 (97); 42 (100); 41 (25); 39 (17). Anal.
Calcd for C7H13NO: C, 66.11; H, 10.30; N, 11.01. Found: C, 66.31;
H, 10.21; N, 11.23.
tert-Butyl 3-Methyl-4-oxopiperidine-1-carboxylate (3(13)). The
crude compound was purified by method F (system of solvents
Hexane). 89.6 g of the target product obtained as a white crystalline
solid in 84% yield (mp = 54−55 °C).
3-Methylpiperidine-2,4-dione (3(19)). The crude compound was
purified by method F (system of solvents MeCN/MeOH). 40.0 g of
the target product obtained as a white powder in 63% yield (mp =
125−126 °C).
1H NMR (400 MHz, Chloroform-d) δ 4.21−4.09 (m, 2H), 3.21
(ddd, J = 14.1, 10.3, 4.5 Hz, 1H), 2.80 (s, 1H), 2.57−2.31 (m, 3H),
1.45 (s, 9H), 1.00 (d, J = 6.6 Hz, 3H). 13C{1H} NMR (126 MHz,
Chloroform-d) δ 209.7, 154.5, 80.4, 49.8, 44.8, 43.8, 40.7, 28.4, 11.7.
EIMS, 70 eV, m/z (rel. int.): 213 [M]+ (2); 158 (17); 140 (14); 113
(14); 70 (11); 57 (100); 56 (25); 44 (11); 42 (14); 41 (34); 39 (13).
Anal. Calcd for C11H19NO3: C, 61.95; H, 8.98; N, 6.57. Found: C,
61.60; H, 8.93; N, 6.82.
1H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 8.09 (s, 1H), 6.78
(s, 1H), 3.62 (q, J = 6.8 Hz, 1H), 3.54 (dddd, J = 12.9, 10.5, 4.5, 2.0
Hz, 1H), 3.26 (dtd, J = 13.5, 6.0, 2.6 Hz, 1H), 3.13 (td, J = 7.2, 2.5
Hz, 2H), 2.58−2.53 (m, 1H), 2.44−2.29 (m, 3H), 1.56 (s, 2H), 1.04
(d, J = 6.8 Hz, 3H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 207.1,
170.4, 170.2, 161.6, 101.1, 52.4, 37.9, 37.7, 35.5, 28.5, 8.7, 8.2. (keto-
enol tautomerism was observed) EIMS, 70 eV, m/z (rel. int.): 128 [M
+ H]+ (7); 127 [M]+ (100); 99 (45); 98 (15); 85 (24); 83 (14); 72
(15); 71 (10); 57 (31); 56 (84); 55 (31); 53 (11); 43 (14); 42 (16);
41 (10). Anal. Calcd for C6H9NO2: C, 56.68; H, 7.14; N, 11.02.
Found: C, 56.65; H, 7.20; N, 11.25.
tert-Butyl 3-Methyl-4-oxopyrrolidine-1-carboxylate (3(14)). The
crude compound was purified by method F (system of solvents
Hexane). 80.7 g of the target product obtained as a colorless viscous
oil in 81% yield.
1H NMR (400 MHz, Chloroform-d) δ 4.09 (s, 1H), 3.85 (s, 1H),
3.63 (d, J = 19.4 Hz, 1H), 3.13 (dd, J = 11.1, 9.1 Hz, 1H), 2.59 (d, J =
10.5 Hz, 1H), 1.45 (s, 9H), 1.14 (d, J = 7.1 Hz, 3H). 13C{1H} NMR
(126 MHz, Chloroform-d) δ 209.1, 154.3, 80.3, 52.6, 49.7, 42.4, 28.4,
12.6. EIMS, 70 eV, m/z (rel. int.): 199 [M]+ (3); 144 (12); 143 (12);
126 (14); 71 (13); 57 (100); 56 (28); 43 (12); 42 (35); 41 (60); 39
(24). Anal. Calcd for C10H17NO3: C, 60.28; H, 8.60; N, 7.03. Found:
C, 60.36; H, 8.47; N, 7.41.
(2R)-tert-Butyl 2-Methyl-3-oxo-8-azabicyclo[3.2.1]octane-8-car-
boxylate (3(20)). The crude compound was purified by method F
(system of solvents Hexane/MTBE). 6.22 g of the target product
obtained as a yellow oil in 52% yield.
1H NMR (400 MHz, Chloroform-d) δ 4.66−4.07 (m, 2H), 2.82−
2.33 (m, 2H), 2.33−2.12 (m, 1H), 2.11−1.88 (m, 2H), 1.68−1.51
(m, 2H), 1.46 (d, J = 4.7 Hz, 9H), 1.15 (d, J = 7.3 Hz, 2H), 0.99 (d, J
= 6.8 Hz, 1H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 212.6,
208.4, 153.3, 79.9, 57.8, 53.1, 52.2, 46.4, 29.5, 28.4 (d, J = 4.0 Hz),
16.8. EIMS, 70 eV, m/z (rel. int.): 239 [M]+ (5); 166 (14); 124 (14);
82 (19); 69 (13); 68 (81); 67 (30); 57 (100); 56 (15); 55 (21); 41
(49); 39 (15). Anal. Calcd for C13H21NO3: C, 65.25; H, 8.85; N, 5.85.
Found: C, 65.41; H, 9.18; N, 5.50.
tert-Butyl 4-Methyl-3-oxopiperidine-1-carboxylate (3(15)). The
crude compound was purified by method F (system of solvents
Hexane). 75.7 g of the target product obtained as a colorless viscous
oil in 71% yield.
1H NMR (400 MHz, Chloroform-d) δ 4.05 (m, 1H), 3.86 (m,
2H), 3.35 (s, 1H), 2.42 (dp, J = 13.0, 6.6 Hz, 1H), 2.13−2.01 (m,
1H), 1.59 (qd, J = 12.1, 5.4 Hz, 1H), 1.42 (s, 9H), 1.09 (d, J = 6.7,
3H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 207.9, 154.5, 80.4,
54.1, 42.5, 41.7, 30.8, 28.3, 14.1. EIMS, 70 eV, m/z (rel. int.): 213
[M]+ (13); 157 [M − t-Bu]+ (31); 140 (26); 129 (18); 128 (10); 114
[M − Boc + H]+ (10); 85 (14); 84 (27); 57 (100); 56 (32); 55 (14);
43 (61); 42 (53); 41 (82); 39 (43). Anal. Calcd for C11H19NO3: C,
61.95; H, 8.98; N, 6.57. Found: C, 62.18; H, 9.27; N, 6.97.
tert-Butyl 3,5-Dimethyl-4-oxopiperidine-1-carboxylate (3(16)).
The crude compound was purified by method F (system of solvents
Hexane). 70.5 g of the target product obtained as a white crystalline
solid in 62% yield (mp = 75−77 °C).
(3S,3aS,5aS,7S,9S,9aS,9bS)-3,5a,7,9-Tetramethyloctahydro-
naphtho[1,2-b]furan-2,8(3H,9bH)-dione (3(21)). The crude com-
pound was purified by method E (solvent Hexane). 0.13 g of the
target product obtained as a white powder in 96% yield (mp = 34−37
°C).
1H NMR (500 MHz, Chloroform-d) δ 3.79 (td, J = 10.6, 2.8 Hz,
1H), 2.78−2.64 (m, 1H), 2.40−2.29 (m, 1H), 2.31−2.20 (m, 1H),
2.22−2.14 (m, 1H), 1.92 (td, J = 10.3, 2.8 Hz, 1H), 1.87−1.78 (m,
1H), 1.73−1.67 (m, 1H), 1.67−1.32 (m, 4H), 1.33−1.15 (m, 7H),
1.03 (dd, J = 6.6, 2.7 Hz, 3H), 0.85 (d, J = 2.7 Hz, 2H). 13C{1H}
NMR (126 MHz, DMSO-d6) δ 217.7, 179.5, 83.9, 51.6, 49.4, 48.1,
45.9, 41.1, 40.1, 36.7, 35.7, 23.1, 21.2, 18.4, 16.0, 12.7. LCMS, positive
mode, m/z: 265 [M + H]+. Anal. Calcd for C16H24O3: C, 72.69; H,
9.15. Found: C, 72.59; H, 8.76.
1H NMR (400 MHz, Chloroform-d) δ 4.31 (s, 1H), 2.75−2.42 (m,
2H), 1.46 (s, 9H), 0.98 (d, J = 6.2 Hz, 6H). 13C{1H} NMR (126
MHz, Chloroform-d) δ 210.9, 154.4, 80.4, 51.2, 44.5, 28.4, 11.1.
EIMS, 70 eV, m/z (rel. int.): 227 [M]+ (3); 172 (23); 170 (13); 154
(12); 127 (31); 112 (11); 71 (16); 70 (18); 57 (100); 56 (28); 44
(17); 43 (14); 42 (27); 41 (45); 40 (15). Anal. Calcd for
C12H21NO3: C, 63.41; H, 9.31; N, 6.16. Found: C, 63.45; H, 9.23;
N, 6.09.
2,2-Dimethylpentan-3-one (3(22)). The crude compound was
purified by method H (34−37 °C, 20 mmHg). 39.4 g of the target
product obtained as a colorless liquid in 69% yield.
1H NMR (400 MHz, Chloroform-d) δ 2.47 (q, J = 7.2 Hz, 2H),
1.10 (s, 9H), 0.99 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (126 MHz,
Chloroform-d) δ 216.6, 44.0, 29.6, 26.5, 8.1. EIMS, 70 eV, m/z (rel.
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Article
int.): 114 [M]+ (20); 57 (100); 41 (22). Anal. Calcd for C7H14O: C,
73.63; H, 12.36. Found: C, 73.45; H, 12.41.
Eugeniy N. Ostapchuk − Enamine Ltd, Kyiv 02094, Ukraine;
Taras Shevchenko National University of Kyiv, Kyiv 01033,
Ukraine
Alexander E. Pashenko − Enamine Ltd, Kyiv 02094,
Ukraine; Taras Shevchenko National University of Kyiv, Kyiv
01033, Ukraine
Yaroslav O. Chuchvera − Enamine Ltd, Kyiv 02094, Ukraine
Eduard B. Rusanov − Institute of Organic Chemistry,
National Academy of Sciences of Ukraine, Kyiv 02094,
Ukraine
1-Cyclopropylpropan-1-one (3(23)).23d The crude compound was
purified by method H (bp = 38−42 °C, 20 mmHg). 38.3 g of the
target product obtained as a colorless liquid in 78% yield.
1H NMR (400 MHz, Chloroform-d) δ 2.54 (q, J = 7.2 Hz, 2H),
1.88 (m, 1H), 1.06 (t, J = 7.2 Hz, 3H), 0.98 (m, 2H), 0.89 (m, 2H).
EIMS, 70 eV, m/z (rel. int.): 98 [M]+ (24); 69 (100); 41 (40). Anal.
Calcd for C6H10O: C, 73.43; H, 10.27. Found: C, 73.28; H, 10.33.
The compound 4(10) was obtained according to general procedure
for Step B. One mole (141.17 g) of starting enaminone 2(10) and 0.5
L of acetone were used. The mixture of 3(10) and 4(10) was
obtained in a ratio of 2:1 (0.5 and 0.25 mol of 3(10) and 4(10),
respectively) and was separated by distillation (4 is distilled at 77−78
°C, 5 mmHg). 31.9 g of the target product 4(10) obtained as a
colorless liquid in 22% total yield.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00148
Notes
(3R*,4R*)-4-((Dimethylamino)methyl)tetrahydrofuran-3-ol
The authors declare no competing financial interest.
1
(4(10)). H NMR (400 MHz, Chloroform-d) δ 5.61 (br, 1H), 4.52
(td, J = 6.0, 3.8 Hz, 1H), 4.03−3.93 (m, 1H), 3.87 (td, J = 8.0, 7.3, 1.6
Hz, 1H), 3.75 (dd, J = 9.5, 3.8 Hz, 1H), 3.52 (dd, J = 8.6, 6.1 Hz,
1H), 2.82 (t, J = 11.7 Hz, 1H), 2.51−2.39 (m, 1H), 2.38−2.32 (m,
1H), 2.31 (s, 6H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 74.7,
72.6, 70.6, 57.9, 44.8, 39.2. LCMS, positive mode, m/z: 146 [M +
H]+. Anal. Calcd for C7H15NO2: C, 57.90; H, 10.41; N, 9.65. Found:
C, 58.20; H, 10.49; N, 9.66.
The compound 5(26) was obtained using the similar method (Step
B in Table 4), but the H2 pressure in the autoclave was 10 atm. The
analytical sample was obtained by chromatography. The character-
istics of the compound were identical with those previously
reported.23e
ACKNOWLEDGMENTS
■
The work was supported by Enamine Ltd. Chromatographic
separation and purification was performed at the Preparative
Chromatography Department of Enamine Ltd. under the
supervision of Mrs. Olga Maksymenko. The authors thank the
Ministry of Education & Science of Ukraine for the grant
support (project 0120U102179), Prof. Andrey A. Tolmachev
for his encouragement and support, and Dr. Halyna Buvailo for
her help with manuscript preparation.
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00148.
Copies of NMR and GCMS spectra, X-ray crystallog-
raphy data descriptions (PDF)
Accession Codes
CCDC 2027100−2027103 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Authors
Dmitriy M. Volochnyuk − Enamine Ltd, Kyiv 02094,
Ukraine; Taras Shevchenko National University of Kyiv, Kyiv
01033, Ukraine; Institute of Organic Chemistry, National
Academy of Sciences of Ukraine, Kyiv 02094, Ukraine;
orcid.org/0000-0001-6519-1467;
Phone: +380967139494; Email: d.volochnyuk@
gmail.com
Sergey V. Ryabukhin − Enamine Ltd, Kyiv 02094, Ukraine;
Taras Shevchenko National University of Kyiv, Kyiv 01033,
Ukraine; orcid.org/0000-0003-4281-8268;
Phone: +380506424763; Email: s.v.ryabukhin@gmail.com
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X.; Stepan, A. F.; Plummer, M. S.; Zhang, Y. H.; Yu, J. Q. Divergent
C-H Functionalizations Directed by Sulfonamide Pharmacophores:
Authors
Andriy I. Frolov − Enamine Ltd, Kyiv 02094, Ukraine; Taras
Shevchenko National University of Kyiv, Kyiv 01033,
Ukraine
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