Michael additions involving amino acid esters with alkenyl N-heterocycles

Article abstract of DOI:10.1021/acs.joc.7b01724

Michael addition has been achieved with a variety of amino acid esters and 2- or 4-vinylpyridine. Similar reactions were accomplished with an alkenyl-substituted pyrimidine, pyrazine, thiazole, quinoxaline, benzoxazole, and quinolone. In reactions at a prochiral center, modest diastereoselectivities were observed with the formation of the new stereogenic carbon. NMR experiments indicate that the addition reaction is reversible under acidic conditions.

Full text of DOI:10.1021/acs.joc.7b01724

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Article
Michael additions involving amino acid esters with alkenyl N-heterocycles
Sean H Kennedy, and Douglas A. Klumpp
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01724 • Publication Date (Web): 28 Aug 2017
Downloaded from http://pubs.acs.org on August 29, 2017
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Michael additions involving amino acid esters with alkenyl N-
heterocycles
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Sean H. Kennedy and Douglas A. Klumpp*
Department of Chemistry and Biochemistry
Northern Illinois University, DeKalb, Illinois 60115
ABSTRACT: Michael addition has been achieved with a variety of amino acid esters
and 2- or 4-vinylpyridine. Similar reactions were accomplished with an alkenyl-
substituted pyrimidine, pyrazine, thiazole, quinoxaline, benzoxazole, and quinolone.
In reactions at a prochiral center, modest diastereoselectivities were observed with
the formation of the new stereogenic carbon. NMR experiments indicate that the
addition reaction is reversible under acidic conditions.
Introduction
Michael addition or conjugate addition has been an invaluable method of
synthesis for more than 125 years. In 1947, Weil and Doering reported the Michael
1
addition of a malonate ester with 2- and 4-vinylpyridine. Thereafter, it was
recognized that alkenyl-substituted N-heterocycles were useful Michael acceptors
and numerous synthetic methods were developed – utilizing a variety of ring
2
systems and nucleophile types. Among the nucleophile types, carbon, nitrogen,
oxygen, and sulfur nucleophile chemistry has all been described in the literature.
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Many transition metal-catalyzed reactions and asymmetric synthetic methods have
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also been reported. Despite its potential to give useful heterocyclic products, this
area of chemistry has not received the same attention as other types of Michael
addition (i.e., enone chemistry).
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A number of primary and secondary amines have been shown to undergo
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Michael addition with alkenyl-substituted N-heterocycles. This chemistry has been
used to prepare natural products, as well as, drug-like heterocyclic products.2
Among the amines used in these reactions, very little work has been done with
amino acids.5,6 One example has been reported with 2-vinylpyridine and similar
7
Michael acceptors. This chemistry involved the preparation of 3-vinylpyridine
derivatives for use in the synthesis of chiral polymers. Thus, 2,4-divinylpyridine (1)
reacts with the ethyl ester of L-proline in the presence of acetic acid to give the
Michael adduct 2 (eq 1). The vinyl group on the 4-carbon is less reactive than the
group in the 2-carbon, so product 2 is formed exclusively.
Both N-heterocycles and amino acids are privileged structures in the design of
biologically active compounds and medicinal agents. Consequently, a synthetic
method linking these two structures has a potentially high value. These two types of
structures have been previously linked using S 2 chemistry with amine-
N
functionalized heterocycles and bromoesters or reductive amination of amino acid
derivatives and heterocyclic aldehydes.8,9 In the following Article, we describe
Michael addition reactions involving these structures - alkenyl-substituted N-
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heterocycles and amino acid derivatives. A variety of amino acid derivatives and N-
heterocycles are utilized and modest diastereoselectivity is demonstrated in an
addition reaction.
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Results and Discussion
Our studies began with a survey of reaction conditions and catalysts for the
Michael addition of 2-vinylpyridine (3) and L-valine methyl ester (4, Table 1).
Acceptable yields of the addition product 5 are obtained with both Brønsted acids
and bases. The optimized conditions for this reaction involved the use of acetic acid
(Entry 2). A series of Lewis acids were also examined and Cu(OTf)
2
provided the
highest yield of product 5 – obtained in 78% isolated yield (Entry 4).
Using 2-vinylpyridine as a Michael acceptor, the addition reaction has been
accomplished with a variety of amino acid esters (Table 2). L-Proline ester gives the
addition product 6 in 59% yield. Likewise, glycine, phenylalanine, tyrosine,
methionine, and leucine esters provide the respective addition products (7-11). 4-
Vinylpyridine also undergoes addition chemistry, as valine, tyrosine, serine,
phenylalanine, and leucine esters provide the corresponding addition products (12-
16) in reasonable yields. The use of other N-heterocycles also provides Michael
addition products. Thus, the vinyl-substituted pyrimidine also gives product 17
with the valine methyl ester. Similar products (18 and 19) are obtained from the
pyrazine and thiazole substrates. Both the 2-vinylquinoxaline and 2-
vinylbenzoxazole
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Table 1. Yields of addition product 5 from reaction of 2-vinylpyridine
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(1 mmol) with valine methyl ester 4 (1 mmol). Yields determined
by NMR spectroscopy using internal standard.
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Table 2. Products with yields from addition reactions
with amino acid esters.a
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provide the respective addition products (20 and 21) from the proline ester.
Products 6-21 were obtained using several reaction conditions – see Experimental
Section for specific procedures. In most cases, addition products could be obtained
in acceptable yields using any of the three sets of reaction conditions. When 2-
vinylpyridine (3) is reacted with the L-glutamate diester (22), the pyrrolidinone
product (23) is isolated in 59% yield (eq 2). This product likely arises from initial
Michael addition – giving adduct 24 which undergoes further ring-closure to
provide the lactam ring.
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As chiral nucleophiles, amino acid derivatives could potentially give
stereoselective Michael addition products from achiral heterocyclic substrates.
Among the reported Michael additions with alkenyl-substituted N-heterocycles,
there are only several examples of stereoselective reactions and none of these
2
utilize nitrogen nucleophiles. As a substrate for addition, we examined the
quinoline derivative 25 (Scheme 1) - because it has a prochiral reaction center, and
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Scheme 1.
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moreover, the trifluoromethyl group should further activate the system by inductive
effects. When the L-valine (4) ester is reacted with quinolone 25 at 60 °C, the
diastereomeric addition products (26 and 27) are formed in a combined 75% yield.
A modest stereoselectivity is observed in the addition reaction, as the products are
formed in a 71:29 diastereomeric ratio. The two diastereomers were inseparable by
column chromatography, so it is not certain which stereoisomers is favored. When
the addition reaction is done at 25 °C, a comparable diastereoselectivity is observed.
A similar result is obtained with the phenylalanine methyl ester 28, leading to the
two diastereomeric compounds 29 in 54% yield and ca. 2:1 diastereomeric ratio.
In considering the results above, an obvious question arises: is the addition a
reversible process? A reversible or thermodynamic controlled reaction may explain
the relatively low yields obtained for some of the conversions and the significant
differences between some NMR determined reaction yields compared to isolated
product yields. A previous report described a reversible addition between a 1,3-
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dicarbonyl compound and 2-vinylpyridine and it was suggested that the Michael
addition product decomposed during silica gel chromatography.10 Katritzky and
coworkers had also developed a method of installing the 2-(2-pyridyl)-ethyl group
as a protecting group for thiols.11 The heterocyclic protecting group cleaves off in a
base-promoted elimination. In order to test for the reversibility of the amino acid
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ester addition, compound 12 was subjected to the reaction conditions using CD CN
3
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with catalytic CH
3
CO
2
H (eq 3). When the resulting mixture was analyzed by H
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NMR, the presence of 4-vinylpyridine was confirmed by well-resolved H signals
arising from the vinyl group (δ 5.5, 6.1, 6.8). After 24 hr at 60 °C, the ratio of 12 and
4
-vinylpyridine was found to be ca. 80:20 (Figure 1). Other conditions were
examined for the elimination of the amino acid fragment from 12. In the presence of
catalytic triethylamine in CD CN, compound 12 exhibited no elimination (25 ° and
0 °C). Compound 12 was also dissolved in D O solution containing 1 equivalent of
SO . At 25 °C, there was no elimination observed. However when the
temperature is raised to 38 ° or 60 °C, there is again some elimination observed
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2
H
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(12:4-vinylpyridine, ca. 95:5, 24 hr).
This observation has several important implications. First, there are
numerous reports of low to moderate yields from Michael addition reactions
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involving vinyl-substituted N-heterocycles. These results may be a consequence of
the equilibrium position for a given set of reaction conditions. Improved yields
might be obtainable by utilizing conditions favoring products and inhibiting the
reverse reactions.
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A.
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B.
Figure 1A. Compound 12 in CD
12 in CD CN with CH CO H (24 hrs, 60 °C).
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CN. Figure 1B. Product mixture from compound
3
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Indeed, our optimized conversions to products 6-9, 12-15, and 20-21 utilized non-
acidic conditions in the syntheses. Secondly, the reversibility of these reactions may
also impact the stereoselectivity of the addition reactions, where longer reaction
periods will yield mixtures reflecting thermodynamic control rather than kinetic
control. Finally, the potential for retro-Michael addition is considered a structure
alert for drug toxicity.12 Given the prevalence of N-heterocycles in pharmaceutical
substances, this aspect of heterocyclic chemistry should be considered in drug
design protocols – that pyridyl(2-ethyl) groups may cleave under some conditions
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to give 2-vinylpyridine. This type of slow equilibrium-based cleavage reaction is
also likely for other N-heterocycles.
In summary, we have developed convenient route to N-heterocyclic-
substituted amino acid derivatives. The synthetic methodology is based on the
Michael addition of amino acid esters to vinyl-substituted N-heterocycles. Modest
stereoselectivity is observed with the formation of a new stereocenter.
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EXPERIMENTAL SECTION
General. Reagents and solvent were purchased from commercial suppliers and
used as received. Addition reactions were done under an inert atmosphere using
thoroughly dried glassware. Products were isolated by flash chromatography using
1
13
60 Å silica gel. H and C NMR were done using either a 300 MHz or 500 MHz
spectrometer; chemical shifts were made in reference to NMR solvent signals. Low–
resolution mass spectra were obtained from a gas chromatography instrument
equipped with a mass–selective detector, high-resolution mass spectra were
obtained from a commercial analytical laboratory; time-of-flight (TOF) mass
analyzer was used the samples.
(S)-Methyl 3-methyl-2-((2-(pyridin-2-yl)ethyl)amino)butanoate (5). L-Valine methyl
ester hydrochloride (167 mg, 1 mmol, 1 equiv.), 2-vinylpyridine (126 mg, 1.2 mmol, 1.2
equiv.), and glacial acetic acid (57 µL, 1 mmol, 1 equiv.) were dissolved in 1 mL
methanol and stirred at 60 °C for 42 hours. The reaction was cooled to room temperature
and diluted with 5 mL of dichloromethane. Saturated sodium bicarbonate (2 mL) was
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added and the mixture was stirred for 10 minutes at room temperature. The mixture was
extracted with dichloromethane (2 x 5 mL), washed with brine, dried over Na SO , and
2
4
concentrated under vacuum. The residue was purified by column chromatography on
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silica gel to afford a yellow oil (161 mg, 0.68 mmol, 68 %); R = 0.36 (eluent = 2%
f
1
MeOH in EtOAc); H NMR (500 MHz, CDCl ): δ 8.51 (d, J = 4.5 Hz, 1H), 7.59-7.55
3
(m, 1H), 7.17 (d, J = 7.8 Hz, 1H), 7.11 - 7.07 (m, 1H), 3.67 (s, 3H), 3.03 - 2.96 (m, 2H),
2
.96 - 2.88 (m, 2H), 2.86 - 2.80 (m, 1H), 1.88 (sept, J = 6.7 Hz, 1H), 0.92 - 0.87 (m, 6H);
1
3
C NMR (125 MHz, CDCl ): δ 175.5, 160.1, 149.2, 136.2, 123.2, 121.2, 67.5, 51.4, 48.3,
3
3
8.7, 31.5, 19.1, 18.7. HRMS (EI-TOF) m/z: [M]+ Calcd for C H N O 236.1525;
1
3
20
2
2
found 236.1518.
(S)-Methyl 1-(2-(pyridin-2-yl)ethyl)pyrrolidine-2-carboxylate (6). L-Proline methyl ester
hydrochloride (166 mg, 1 mmol, 1 equiv.), 2-vinylpyridine (105 mg, 1 mmol, 1 equiv.),
and triethylamine (0.14 mL, 1 mmol, 1 equiv.) were dissolved in acetonitrile (3 mL) and
stirred at 80 °C for 48 hours. The reaction was cooled to room temperature and diluted
with 15 mL of dichloromethane. The mixture was washed with water (5 mL), brine, dried
over Na SO , and concentrated under vacuum. The residue was purified by column
2
4
chromatography on silica gel to afford an orange oil (138 mg, 0.59 mmol, 59 %); R =
f
1
0.37 (eluent = 4% MeOH in EtOAc); H NMR (300 MHz, CDCl ): δ 8.46 (d, J = 4.6 Hz,
3
1
3
2
H), 7.53 (t, J = 7.1 Hz, 1H), 7.15 (d, J =7.8 Hz, 1H), 7.08 - 7.02 (m, 1H), 3.66 (s, 3H),
.26 - 3.16 (m, 2H), 3.13 - 2.91 (m, 3H), 2.84 - 2.73 (m, 1H), 2.42 (q, J = 8.2 Hz, 1H),
1
3
.16 - 2.00 (m, 1H), 1.97 - 1.71 (m, 3H). C NMR (75 MHz, CDCl ): δ 174.6, 160.1,
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49.1, 136.3, 123.1, 121.2, 65.9, 54.6, 53.4, 51.8, 37.4, 29.4, 23.2. HRMS (EI-TOF) m/z:
[
M]+ Calcd for C H N O 234.1368; found 234.1362.
13 18 2 2
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Ethyl 2-((2-(pyridin-2-yl)ethyl)amino)acetate (7). Glycine ethyl ester hydrochloride (166
mg, 1.2 mmol, 1.2 equiv.) and 2-vinylpyridine (105 mg, 1 mmol, 1 equiv.) were
dissolved in acetonitrile (3 mL) and stirred at 90 °C for 42 hours. The reaction was
cooled to room temperature. Dichloromethane (3 mL) and saturated sodium bicarbonate
(2 mL) were added and the mixture was stirred for 10 minutes at room temperature. The
mixture was extracted with dichloromethane (2 x 15 mL), washed with brine, dried over
Na SO , and concentrated under vacuum. The residue was purified by column
2
4
chromatography on silica gel to afford a yellow oil (106 mg, 0.51 mmol, 51 %); R = 0.30
f
1
(eluent = 10% MeOH in EtOAc); H NMR (500 MHz, CDCl ): δ 8.52 (d, J = 4.8 Hz,
3
1
H), 7.61 - 7.56 (1H, m), 7.18 (d, J = 7.9 Hz, 1H), 7.13 - 7.09 (m, 1H), 4.16 (q, J = 5.4
Hz, 2H), 3.43 (d, J = 1.4 Hz, 2H), 3.06 - 3.01 (m, 2H), 3.00 - 2.95 (m, 2H), 2.31 (1H, br
13
s), 1.24 (t, J = 7.2 Hz, 3H); C NMR (125 MHz, CDCl ): δ 172.2, 159.9, 149.3, 136.4,
3
123.2, 121.3, 60.7, 50.9, 48.9, 38.3, 14.2. HRMS (EI-TOF) m/z: [M]+ Calcd for
C H N O 208.1212, found 208.1212.
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2
2
(S)-Methyl 3-phenyl-2-((2-(pyridin-2-yl)ethyl)amino)propanoate (8). L-phenyl-alanine
methyl ester hydrochloride (216 mg, 1 mmol, 1 equiv.) and 2-vinylpyridine (105 mg, 1
mmol, 1 equiv.) were dissolved in acetonitrile (3 mL) and stirred at 90 °C for 42 hours.
The reaction was cooled to room temperature. Dichloromethane (3 mL) and saturated
sodium bicarbonate (2 mL) were added and the mixture was stirred for 10 minutes at
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room temperature. The mixture was extracted with dichloromethane (2 x 5 mL), washed
with brine, dried over Na SO , and concentrated under vacuum. The residue was purified
2
4
by column chromatography on basic alumina to afford a yellow oil (148 mg, 0.52 mmol,
10
11
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48
49
50
51
52
53
54
55
56
57
58
59
60
1
2 %); R = 0.48 (basic alumina; eluent = 1:1 Hexanes/EtOAc); H NMR (500 MHz,
5
f
CDCl ): δ 8.48 - 8.45 (m, 1H), 7.55 (dt, J = 7.7, 1.7 Hz, 1H), 7.29 - 7.25 (m, 2H), 7.24 -
3
7
.19 (m, 1H), 7.17 - 7.14 (m, 2H), 7.11 - 7.07 (m, 2H), 3.64 (s, 3H), 3.58 (t, J = 6.8 Hz,
1
3
1
H), 3.07 - 3.01 (m, 1H), 3.00 - 2.87 (m, 5H); C NMR (125 MHz, CDCl ): δ 174.7,
3
159.8, 149.2, 137.2, 136.3, 129.2, 128.4, 126.7, 123.2, 121.2, 63.1, 51.7, 47.6, 39.5, 38.3.
HRMS (EI-TOF) m/z: [M]+ Calcd for C H N O 285.1603, found 285.1593.
1
7
21
2
2
(S)-Methyl 3-(4-hydroxyphenyl)-2-((2-(pyridin-2-yl)ethyl)amino)propanoate (9). L-
Tyrosine methyl ester hydrochloride (232 mg, 1 mmol, 1 equiv.) and 2-vinylpyridine
(
105 mg, 1 mmol, 1 equiv.) were dissolved in acetonitrile (3 mL) and stirred at 90 °C for
4
2 hours. The reaction was cooled to room temperature. Dichloromethane (3 mL) and
saturated sodium bicarbonate (2 mL) were added and the mixture was stirred for 10
minutes at room temperature. The mixture was extracted with dichloromethane (2 x 5
mL), washed with brine, dried over Na SO , and concentrated under vacuum. The
2
4
residue was purified by column chromatography on silica gel to afford a yellow oil (198
1
mg, 0.66 mmol, 66 %); R = 0.41 (eluent = 10% MeOH in CH Cl ); H NMR (500 MHz,
f
2
2
CDCl ): δ 8.43 (d, J = 4.3 Hz, 1H), 7.61 (dt, J = 7.7, 1.8 Hz, 1H), 7.16 - 7.13 (m, 2H),
3
6
.95 (d, J = 8.3 Hz, 2H), 6.71 (d, J = 8.5 Hz, 2H), 3.66 (s, 3H), 3.57 (t, J = 6.5 Hz, 1H),
1
.10 - 3.03 (m, 1H), 3.03 - 2.91 (m, 4H), 2.91 - 2.84 (m, 1H); C NMR (125 MHz,
3
3
CDCl ): δ 174.3, 159.5, 155.8, 148.7, 137.0, 130.3, 127.6, 123.6, 121.7, 115.7, 62.9, 51.9,
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7.6, 38.2, 37.4. HRMS (EI-TOF) m/z: [M]+ Calcd for C H N O 301.1552, found
3
1
7
21
2
3
01.1551.
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(S)-Methyl 4-(methylthio)-2-((2-(pyridin-2-yl)ethyl)amino)butanoate (10). L-methionine
methyl ester hydrochloride (200 mg, 1 mmol, 1 equiv.), 2-vinylpyridine (126 mg, 1.2
mmol, 1.2 equiv.), and glacial acetic acid (57 µL, 1 mmol, 1 equiv.) were dissolved in 1.5
mL methanol and stirred at 60 °C for 42 hours. The reaction was cooled to room
temperature and diluted with 5 mL of dichloromethane. Saturated sodium bicarbonate (2
mL) was added and the mixture was stirred for 10 minutes at room temperature. The
mixture was extracted with dichloromethane (2 x 5 mL), washed with brine, dried over
Na SO , and concentrated under vacuum. The residue was purified by column
2
4
chromatography on silica gel to afford an orange oil (121 mg, 0.45 mmol, 45 %); R =
f
1
0
.32 (eluent = 2% MeOH in EtOAc); H NMR (300 MHz, CDCl ): δ 8.48 (d, J = 4.4 Hz,
3
1
H), 7.59 - 7.50 (m, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.10 - 7.04 (m, 1H), 3.65 (s, 3H), 3.38
13
m, 1H), 3.05 - 2.78 (m, 4H), 2.50 (m, 1H), 2.02 (s, 3H), 1.94 - 1.70 (m, 2H)); C NMR
(
(75 MHz, CDCl ): δ 175.3, 160.0, 149.2, 136.2, 123.2, 121.2, 60.1, 51.8, 47.6, 38.6, 32.6,
3
3
2
0.4, 15.3. HRMS (EI-TOF) m/z: [M]+ Calcd for C H N O S 268.1246, found
13 20 2 2
68.1240.
(S)-Methyl 4-methyl-2-((2-(pyridin-2-yl)ethyl)amino)pentanoate (11). L-Leucine methyl
ester hydrochloride (182 mg, 1 mmol, 1 equiv.), 2-vinylpyridine (126 mg, 1.2 mmol, 1.2
equiv.), and glacial acetic acid (57 µL, 1 mmol, 1 equiv.) were dissolved in 1.5 mL
methanol and stirred at 60 °C for 42 hours. The reaction was cooled to room temperature
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and diluted with 5 mL of dichloromethane. Saturated sodium bicarbonate (2 mL) was
added and the mixture was stirred for 10 minutes at room temperature. The mixture was
extracted with dichloromethane (2 x 5 mL), washed with brine, dried over Na SO , and
2
4
10
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43
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46
47
48
49
50
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52
53
54
55
56
57
58
59
60
concentrated under vacuum. The residue was purified by column chromatography on
basic alumina to afford an orange oil (108 mg, 0.43 mmol, 43 %); R = 0.40 (basic
f
1
alumina, eluent = 5:1 Hexanes/EtOAc); H NMR (300 MHz, CDCl3): δ 8.49 (d, J = 4.8
Hz, 1H), 7.60 - 7.52 (m, 1H), 7.15 (d, J = 7.8 Hz, 1H), 7.12 - 7.05 (m, 1H), 3.66 (s, 3H),
3.29 (t, J = 7.2 Hz, 1H), 3.04 - 2.79 (m, 4H), 1.65 (septet, J = 6.7 Hz, 1H), 1.43 (t, J
13
7.2 Hz, 2H), 0.91 - 0.81 (m, 6H); C NMR (75 MHz, CDCl3): δ 176.2, 160.0, 149.2,
=
1
36.2, 123.2, 121.2, 60.0, 51.6, 47.1, 42.6, 38.6, 24.9, 22.6, 22.3. HRMS (EI-TOF) m/z:
[M]+ Calcd for C H N O 251.1760, found 251.1754.
2
14
23
2
(S)-Methyl 3-methyl-2-((2-(pyridin-4-yl)ethyl)amino)butanoate (12). L-valine methyl
ester hydrochloride (167 mg), 4-vinylpyridine (126 mg, 1.2 mmol, 1.2 equiv.), and
triethylamine (0.14 mL, 1 mmol, 1 equiv.) were dissolved in acetonitrile (3 mL) and
stirred at 80 °C for 48 hours. The reaction was cooled to room temperature and diluted
with 15 mL of dichloromethane. The mixture was washed with water (5 mL), brine, dried
over Na SO , and concentrated under vacuum. The residue was purified by column
2
4
chromatography on silica gel to afford a yellow oil (158 mg, 0.67 mmol, 67 %); R = 0.30
f
1
(
eluent = 4% MeOH in EtOAc); H NMR (500 MHz, CDCl ): δ 8.45 (d, J = 4.4 Hz, 2H),
3
7
-
.11 (d, J = 5.3 Hz, 2H), 3.01 (s, 3H), 2.96 (d, J = 6.1 Hz, 1H), 2.91 - 2.84 (m, 1H), 2.79
2.60 (m, 3H), 1.84 (septet, J = 6.7 Hz, 1H), 0.87 (d, J = 3.4 Hz, 3H), 0.86 (d, J = 3.4
13
Hz, 3H); C NMR (125 MHz, CDCl ): δ 175.5, 149.6, 149.1, 124.1, 67.3, 51.4, 48.7,
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5.9, 31.6, 19.2, 18.9. HRMS (EI-TOF) m/z: [M]+ Calcd for C H N O 236.1525,
1
3
20
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2
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(S)-Methyl 3-(4-hydroxyphenyl)-2-((2-(pyridin-4-yl)ethyl)amino)propanoate (13). L-
Tyrosine methyl ester hydrochloride (232 mg) and 4-vinylpyridine (105 mg, 1 mmol, 1
equiv.) were dissolved in acetonitrile (3 mL) and stirred at 90 °C for 42 hours. The
reaction was cooled to room temperature. Dichloromethane (3 mL) and saturated sodium
bicarbonate (2 mL) were added and the mixture was stirred for 10 minutes at room
temperature. The mixture was extracted with dichloromethane (2 x 5 mL), washed with
brine, dried over Na SO , and concentrated under vacuum. The residue was purified by
2
4
column chromatography on silica gel to afford a yellow oil (180 mg, 0.60 mmol, 60 %);
1
R = 0.36 (eluent = 10% MeOH in CH Cl ); H NMR (500 MHz, CDCl ): δ 8.43 - 840
f
2
2
3
(m, 2H), 7.07 - 7.04 (m, 2H), 6.96 - 6.92 (m, 2H), 6.78 - 6.73 (m, 2H), 3.69 (s, 3H), 3.48
1
dd, J = 8.0, 5.8 Hz, 1H), 2.98 - 2.90 (m, 2H), 2.81 - 2.68 (m, 4H); C NMR (125 MHz,
3
(
CDCl ): δ 174.8, 156.3, 149.4, 148.6, 130.2, 127.5, 124.6, 115.8, 62.9, 51.9, 47.9, 38.5,
3
35.3. HRMS (EI-TOF) m/z: [M]+ Calcd for C H N O 300.1474, found 300.1474.
1
7
20
2
3
(S)-Methyl 3-hydroxy-2-((2-(pyridin-4-yl)ethyl)amino)propanoate (14). L-Serine methyl
ester hydrochloride (156 mg, 1 mmol, 1 equiv.) and 4-vinylpyridine (105 mg, 1 mmol, 1
equiv.) were dissolved in acetonitrile (3 mL) and stirred at 90 °C for 42 hours. The
reaction was cooled to room temperature. Dichloromethane (3 mL) and saturated sodium
bicarbonate (2 mL) were added and the mixture was stirred for 10 minutes at room
temperature. The mixture was extracted with dichloromethane (2 x 5 mL), washed with
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brine, dried over Na SO , and concentrated under vacuum. The residue was purified by
2
4
column chromatography on silica gel to afford a yellow oil (114 mg, 0.51 mmol, 51 %);
1
R = 0.22 (eluent = 10% MeOH in EtOAc); H NMR (500 MHz, CDCl ): δ 8.48 (d, J =
f
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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28
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34
35
36
37
38
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43
44
45
46
47
48
49
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54
55
56
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58
59
60
4
.5 Hz, 2H), 7.15 (d, J = 5.5 Hz, 2H), 3.81 (dd, J = 10.9, 4.4 Hz, 1H), 3.74 (s, 3H), 3.64
(dd, J = 11.0, 6.2 Hz, 1H), 3.42 (dd, J = 6.4, 4.4 Hz, 1H), 3.10 – 2.95 (m, 3H), 2.86 –
1
3
2
.77 (m, 3H); C NMR (125 MHz, CDCl ): δ 173.2, 149.7, 148.7, 124.1, 62.8, 62.4,
3
5
2.2, 48.2, 35.8. HRMS (EI-TOF) m/z: [M]+ Calcd for C H N O 225.1239, found
2
1
1
17
3
225.1230.
(S)-Methyl 3-phenyl-2-((2-(pyridin-4-yl)ethyl)amino)propanoate (15). L-Phenyl-alanine
methyl ester hydrochloride (216 mg, 1 mmol, 1 equiv.) and 4-vinylpyridine (105 mg, 1
mmol, 1 equiv.) were dissolved in acetonitrile (3 mL) and stirred at 90 °C for 42 hours.
The reaction was cooled to room temperature. Dichloromethane (3 mL) and saturated
sodium bicarbonate (2 mL) were added and the mixture was stirred for 10 minutes at
room temperature. The mixture was extracted with dichloromethane (2 x 5 mL), washed
with brine, dried over Na SO , and concentrated under vacuum. The residue was purified
2
4
by column chromatography on basic alumina to afford a yellow oil (156 mg, 0.55 mmol,
1
5 %); R = 0.40 (basic alumina; eluent = 1:1 Hexanes/EtOAc); H NMR (500 MHz,
5
f
CDCl ): δ 8.46 (d, J = 4 Hz, 2H), 7.30 - 7.21 (m, 3H), 7.16 - 7.12 (m, 2H), 7.07 - 7.03
3
(m, 2H), 3.67 (s, 3H), 3.53 (t, J = 6.8 Hz, 1H), 3.00 - 2.87 (m, 3H), 2.79 - 2.68 (m, 3H);
1
3
C NMR (125 MHz, CDCl ): δ 174.7, 159.9, 149.2, 137.2, 136.3, 129.2, 128.4, 126.7,
3
1
23.2, 121.2, 63.1, 51.7, 47.6, 39.5, 38.3. HRMS (EI-TOF) m/z: [M]+ Calcd for
C H N O 285.1603, found 285.1602.
21
17
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(
S)-Methyl 4-methyl-2-((2-(pyridin-4-yl)ethyl)amino)pentanoate (16). L-Leucine methyl
ester hydrochloride (182 mg, 1 mmol, 1 equiv.), 4-vinylpyridine (126 mg, 1.2 mmol, 1.2
equiv.), and glacial acetic acid (57 µL, 1 mmol, 1 equiv.) were dissolved in 1 mL
methanol and stirred at 60 °C for 42 hours. The reaction was cooled to room temperature
and diluted with 5 mL of dichloromethane. Saturated sodium bicarbonate (2 mL) was
added and the mixture was stirred for 10 minutes at room temperature. The mixture was
extracted with dichloromethane (2 x 5 mL), washed with brine, dried over Na SO , and
0
1
2
3
4
5
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7
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9
0
1
2
3
4
5
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8
9
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1
2
3
4
5
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8
9
0
1
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
4
concentrated under vacuum. The residue was purified by column chromatography on
basic alumina to afford an orange oil (113 mg, 0.45 mmol, 45 %); R = 0.37 (basic
f
1
alumina, eluent = 5:1 Hexanes/EtOAc); H NMR (300 MHz, CDCl ): δ 8.48 - 8.43 (m,
3
2
H), 7.13 - 7.09 (m, 2H), 3.67 (s, 3H), 3.25 (t, J = 7.3 Hz, 1H), 2.91 - 2.62 (m, 4H), 1.64
(septet, J = 6.7 Hz, 1H), 1.45 - 1.36 (m, 2H), 0.87 (d, J = 6.7 Hz, 3H), 0.84 (d, J = 6.6
1
3
Hz, 3H); C NMR (75 MHz, CDCl ): δ 176.2, 149.6, 149.0, 124.4, 59.9, 51.6, 48.1, 42.6,
3
3
5.8, 24.8, 22.6, 22.3. HRMS (EI-TOF) m/z: [M]+ Calcd for C H N O 251.1760,
14 23 2 2
found 251.1750.
(S)-Methyl 2-((2-(5-ethylpyrimidin-2-yl)ethyl)amino)-3-methylbutanoate (17). L-Valine
methyl ester hydrochloride (167 mg, 1 mmol, 1 equiv.), 5-ethyl-2-vinylpyrimidine (88
mg, 0.66 mmol, 0.66 equiv.), and glacial acetic acid (57 µL, 1 mmol, 1 equiv.) were
dissolved in 1.5 mL methanol and stirred at 60 °C for 42 hours. The reaction was cooled
to room temperature and diluted with 5 mL of dichloromethane. Saturated sodium
bicarbonate (2 mL) was added and the mixture was stirred for 10 minutes at room
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temperature. The mixture was extracted with dichloromethane (2 x 5 mL), washed with
brine, dried over Na SO , and concentrated under vacuum. The residue was purified by
2
4
column chromatography on silica gel to afford an orange oil (122 mg, 0.46 mmol, 70 %);
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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32
33
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35
36
37
38
39
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41
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43
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
R = 0.35 (eluent = 4 % MeOH in EtOAc); H NMR (500 MHz, CDCl ): δ 8.51 (s, 2H),
f
3
3.70 (s, 3H), 3.16 - 3.05 (m, 4H), 2.98 - 2.90 (m, 1H), 2.62 (q, J = 7.7 Hz, 2H), 1.93
1
septet, J = 6.7 Hz, 1H), 1.27 (t, J = 7.7 Hz, 3H), 0.91 (m, 6H); C NMR (125 MHz,
3
(
CDCl ): δ 175.4, 167.1, 156.3, 133.5, 67.5, 51.4, 47.1, 39.1, 31.5, 23.3, 19.0, 18.8, 15.0;
3
HRMS (EI-TOF) m/z: [M]+ Calcd for C H N O 265.1790, found 265.1787.
2
1
4
23
3
(
S)-Methyl 3-methyl-2-((2-(pyrazin-2-yl)ethyl)amino)butanoate (18). L-Valine methyl
ester hydrochloride (66 mg, 0.40 mmol, 1.18 equiv.), vinylpyrazine (36 mg, 0.34 mmol, 1
equiv), and glacial acetic acid (19 µL, 0.34 mmol, 1 equiv.) were dissolved in acetonitrile
(
1.5 mL) and stirred at 65 °C for 40 hours. The reaction was cooled to room temperature
and diluted with 5 mL of dichloromethane. Saturated sodium bicarbonate (2 mL) was
added and the mixture was stirred for 10 minutes at room temperature. The mixture was
extracted with dichloromethane (2 x 5 mL), washed with brine, dried over Na SO , and
2
4
concentrated under vacuum. The residue was purified by column chromatography on
silica gel to afford a brown oil (49 mg, 0.21 mmol, 61 %); R = 0.44 (eluent = 1:4
f
1
Hexanes/EtOAc); H NMR (300 MHz, CDCl ): δ 8.51-8.48 (m, 2H), 8.42 (d, J = 2.5 Hz,
3
1
0
1
H), 2.73 (s, 3H), 3.12 – 2.97 (m, 4H), 2.94-2.82 (m, 1H), 1.94 (septet, J = 6.5 Hz, 1H),
1
3
.92 (d, J = 3.0 Hz, 3H), 0.89 (d, J = 3.0 Hz, 3H); C NMR (75 MHz, CDCl ): δ 175.1,
3
55.9, 145.0, 143.9, 142.4, 67.3, 51.5, 47.6, 35.6, 31.5, 19.0, 18.7. HRMS (EI-TOF) m/z:
[
M]+ Calcd for C H N O 237.1477, found 237.1473.
12 19 3 2
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(
S)-Methyl 3-methyl-2-((2-(4-phenylthiazol-2-yl)ethyl)amino)butanoate (19). L-Valine
methyl ester hydrochloride (70 mg, 0.42 mmol, 1.2 equiv.), 4-phenyl-2-vinylthiazole (66
mg, 0.35 mmol, 1 equiv), and glacial acetic acid (20 µL, 0.35 mmol, 1 equiv.) were
dissolved in acetonitrile (1.5 mL) and stirred at 65 °C for 40 hours. The reaction was
cooled to room temperature and diluted with 5 mL of dichloromethane. Saturated sodium
bicarbonate (2 mL) was added and the mixture was stirred for 10 minutes at room
temperature. The mixture was extracted with dichloromethane (2 x 5 mL), washed with
brine, dried over Na SO , and concentrated under vacuum. The residue was purified by
0
1
2
3
4
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9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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7
8
9
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1
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
4
column chromatography on basic alumina to afford a pale yellow oil (65 mg, 0.20 mmol,
1
58 %); R = 0.4 (eluent = 7:1 Hexanes/EtOAc); H NMR (300 MHz, CDCl ): δ 7.93-7.87
f
3
(m, 2H), 7.46-7.38 (m, 2H), 7.37-7.29 (m, 2H), 3.73 (s, 3H), 3.29-3.05 (m, 4H), 2.95-
2
3
1
.83 (m, 1H), 1.97 (septet, J = 6.7 Hz, 1H), 0.98 (d, J = 6.9 Hz, 3H), 0.97 (d, J = 6.9 Hz,
1
3
H); C NMR (75 MHz, CDCl ): δ 175.2, 168.7, 154.8, 134.6, 128.7, 127.9, 126.3,
3
12.4, 67.5, 51.5, 47.8, 34.1, 31.6, 19.3, 18.7. HRMS (EI-TOF) m/z: Calcd for [M]+
C H N O S 318.1402, found 318.1402.
22
17
2
2
(S)-Methyl 1-(2-(quinoxalin-2-yl)ethyl)pyrrolidine-2-carboxylate (20). L-Proline methyl
ester hydrochloride (97 mg, 0.58 mmol, 1.09 equiv.), 2-vinylquinazoline (84 mg, 0.54
mmol, 1 equiv), and triethylamine (81 µL, 0.58 mmol, 1.09 equiv.) were dissolved in
acetonitrile (1 mL) and stirred at 65 °C for 40 hours. The reaction was cooled to room
temperature and paritioned with 10 mL of diethyl ether and 5 mL of water. The aqueous
was extracted with an additional 10 mL of diethyl ether and the combined extracts were
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washed with brine, dried over Na SO , and concentrated under vacuum. The residue was
2
4
purified by column chromatography on silica gel to afford a yellow-green oil (114 mg,
1
.40 mmol, 74 %); R = 0.38 (eluent = 1:1 Hexanes/EtOAc); H NMR (500 MHz,
0
f
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CDCl ): δ 8.80 (s, 1H), 8.08 (dd, J = 7.8, 1.7 Hz, 1H), 8.03 (dd, J = 7.8, 1.7 Hz, 1H),
3
7.73 (pt, J = 7.9, 1.8 Hz, 2H), 3.67 (s, 3H), 3.41-3.35 (m, 1H), 3.34-3.24 (m, 4H), 3.07-
3
1
.00 (m, 1H), 2.62-2.55 (m, 1H), 2.21-2.10 (m, 1H), 2.02-1.92 (m, 2H). 1.91-1.81 (m,
1
3
H); C NMR (125 MHz, CDCl ): δ 174.1, 155.4, 146.0, 142.1, 141.3, 129.9, 129.2,
3
129.1, 128.8, 65.8, 53.42, 53.38, 51.9, 35.3, 29.3, 23.2. HRMS (EI-TOF) m/z: Calcd for
M]+ C H N O 285.1477, found 285.1472.
[
16
19
3
2
(S)-Methyl 1-(2-(benzo[d]oxazol-2-yl)ethyl)pyrrolidine-2-carboxylate (21). L-Proline
methyl ester hydrochloride (100 mg, 0.6 mmol, 1.03 equiv.), 2-vinylbenzoxazole (84 mg,
0
.58 mmol, 1 equiv), and triethylamine (84 µL, 0.6 mmol, 1.03 equiv.) were dissolved in
acetonitrile (1 mL) and stirred at 65 °C for 40 hours. The reaction was cooled to room
temperature and paritioned with 10 mL of diethyl ether and 5 mL of water. The aqueous
was extracted with an additional 10 mL of diethyl ether and the combined extracts were
washed with brine, dried over Na SO , and concentrated under vacuum. The residue was
2
4
purified by column chromatography on silica gel to afford a pale yellow oil (103 mg,
1
0.38 mmol, 65 %); R = 0.55 (eluent = 1:1 Hexanes/EtOAc); H NMR (500 MHz,
f
CDCl ): δ 7.69-7.65 (m, 1H), 7.50-7.46 (m, 1H), 7.32-7.28 (m, 2H), 3.71 (s, 3H), 3.37-
3
3
.29 (m, 2H). 3.25 (td, J = 7.8, 3.2 Hz, 1H), 3.18 (t, J = 7.18 Hz, 2H), 3.06-3.00 (m, 1H),
1
.54-2.48 (m, 1H), 2.19-2.10 (m, 1H), 2.01-1.90 (m, 2H), 1.89-1.80 (m, 1H); C NMR
3
2
(
125 MHz, CDCl ): δ 174.4, 165.4, 150.7, 141.3, 124.6, 124.1, 119.6, 110.3, 65.7, 53.3,
3
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1.9, 51.4, 29.4, 28.3, 23.3. HRMS (EI-TOF) m/z: [M]+ Calcd for C H N O 274.1318,
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18
3
found 274.1315.
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(
S)-Methyl 5-oxo-1-(2-(pyridin-2-yl)ethyl)pyrrolidine-2-carboxylate (23). L-Glutamic
acid dimethyl ester hydrochloride (212 mg, 1 mmol, 1 equiv.), 2-vinylpyridine (105 mg,
mmol, 1 equiv), and glacial acetic acid (57 µL, 1 mmol, 1 equiv.) were dissolved in
1
methanol (1.5 mL) and stirred at 60 °C for 48 hours. The reaction was cooled to room
temperature and diluted with 5 mL of dichloromethane. Saturated sodium bicarbonate (2
mL) was added and the mixture was stirred for 10 minutes at room temperature. The
mixture was extracted with dichloromethane (2 x 5 mL), washed with brine, dried over
Na SO , and concentrated under vacuum. The residue was purified by column
2
4
chromatography on silica gel to afford a yellow oil (146 mg, 0.59 mmol, 59 %); R = 0.26
f
1
(eluent = 2 % MeOH in EtOAc); H NMR (500 MHz, CDCl ): δ 8.44 (d, J = 4.5 Hz,
3
1
H), 7.54 (dt, J = 7.6, 1.7 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.09 – 7.05 (m, 1H), 4.09 –
.05 (m, 1H), 4.00 (p, J = 7.1 Hz, 1H), 3.66 (s, 3H), 3.32 (p, J = 7.1 Hz, 1H), 3.03 – 2.89
4
1
(m, 2H), 2.41 – 2.31 (m, 1H), 2.25 – 2.12 (m, 2H), 1.99 – 1.91 (m, 1H); C NMR (125
3
MHz, CDCl ): δ 175.2, 172.5, 158.7, 149.1, 136.5, 123.3, 121.6, 59.9, 52.3, 41.6, 35.8,
3
2
9.4, 23.1. HRMS (EI-TOF) m/z: [M]+ Calcd for C H N O 248.1161, found
13 16 2 3
248.1162.
(E)-2-(3,3,3-Trifluoroprop-1-en-1-yl)quinoline (25). 2-Methylquinoline (430 mg, 3
mmol), trifluoroacetaldehyde monohydrate, 75% wt. in H O, (0.60 mL, 3.9 mmol, 1.3
2
equiv.), diethylamine hydrochloride (428 mg, 3.9 mmol, 1.3 equiv.), and triethylamine
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(
21 µL, 0.15 mmol, 0.05 equiv.) were dissolved in 5 mL of 1,4-dioxane and stirred at 90
°
C for 50 hours. The mixture was cooled to room temperature and concentrated under
vacuum. The residue was purified by column chromatography on silica gel to afford a
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light brown solid (304 mg, 1.36 mmol, 45%); R = 0.38 (eluent = 5% EtOAc in Hexanes);
f
1
mp 42 – 44 °C; H NMR (300 MHz, CDCl ): δ 8.21 (d, J = 8.5 Hz, 1H), 8.11 (d, J = 8.7
3
Hz, 1H), 7.84 (d, J =8.2 Hz, 1H), 7.80 - 7.73 (m, 1H), 7.62 - 7.55 (m, 1H), 7.53 (d, J =
1
.5 Hz, 1H), 7.42 (dq, J = 15.9, 6.1 Hz, 1H), 6.91 (dq, J = 15.9, 6.8 Hz, 1H); C NMR
3
8
(75 MHz, CDCl ): δ 152.0, 148.1, 137.6 (q, J = 6.5 Hz), 137.0, 130.2, 129.7, 128.0,
3
19
27.6, 127.4, 123.4 (q, J = 269.5 Hz), 121.2 (q, J = 34.7 Hz), 120.1; F NMR ( MHz,
1
CDCl ): δ -63.8. HRMS (ESI-TOF) m/z: [M+1]+ Calcd for C H NF 224.0687, found
3
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3
224.0673.
(2S)-Ethyl 3-Methyl-2-((1,1,1-trifluoro-3-(quinolin-2-yl)propan-2-yl)amino)butanoate
(26/27). L-Valine ethyl ester (48 mg, 0. 33 mmol, 1 equiv.), 25 (75 mg, 0.33 mmol, 1
equiv.), and glacial acetic acid (19 µL, 0.33 mmol, 1 equiv.) were dissolved in 0.5 mL
acetonitrile and stirred at 60 °C for 42 hours. The reaction was cooled to room
temperature and diluted with 5 mL of dichloromethane. Saturated sodium bicarbonate (2
mL) was added and the mixture was stirred for 10 minutes at room temperature. The
mixture was extracted with dichloromethane (2 x 5 mL), washed with brine, dried over
Na SO , and concentrated under vacuum. The residue was purified by column
2
4
chromatography on silica gel to afford a yellow oil (92 mg, 0.25 mmol, 75 %); R = 0.40
f
1
eluent = 7:1 Hexanes/EtOAc) as a mixture of diastereomers (dr 71:29, determined by F
9
(
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NMR integration). HRMS (EI-TOF) m/z: [M]+ Calcd for C H N O F 368.1712,
2
1
9
23
2 3
found 368.1705.
0
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(
2S)-methyl 3-phenyl-2-((1,1,1-trifluoro-3-(quinolin-2-yl)propan-2-yl)amino)propanoate
(29). L-Phenylalanine methyl ester (58 mg, 0.33 mmol, 1 equiv.), 21 (75 mg, 0.33 mmol,
equiv.), and glacial acetic acid (19 µL, 0.33 mmol, 1 equiv.) were dissolved in 0.5 mL
1
acetonitrile and stirred at 60 °C for 43 hours. The reaction was cooled to room
temperature and diluted with 5 mL of dichloromethane. Saturated sodium bicarbonate (2
mL) was added and the mixture was stirred for 10 minutes at room temperature. The
mixture was extracted with dichloromethane (2 x 5 mL), washed with brine, dried over
Na SO , and concentrated under vacuum. The residue was purified by column
2
4
chromatography on silica gel to afford an orange oil (66 mg, 0.18 mmol, 54 %); R = 0.27
f
(eluent = 20% Et O in Hexane) as a mixture of diastereomers (dr 68:32, determined by
2
1
9
F NMR integration). HRMS (EI-TOF) m/z: [M]+ Calcd for C H N O F 403.1633,
2 3
2
2
22
2
found 403.1627.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications
1
13
website. H and C NMR spectra of new compounds.
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AUTHOR INFORMATION
Corresponding Author
* E-mail: dklumpp@niu.edu
ORCID
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Douglas Klumpp: 0000-0001-5271-699X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Partial support from the U. S. National Science Foundation is gratefully
acknowledged (1300878). We also thank Northern Illinois University for a Research
Opportunity Grant to support this work.
REFERENCES
(
(
(
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Tetrahedron Lett. 2009, 50, 386. (b) Boy, K. M.; Guernon, J. M. Tetrahedron
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12) Silverman, R. B.; Holladay, M. W. The Organic Chemistry of Drug Design and
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