Michael Addition of Amines and Thiols to Dehydroalanine Amides: A Remarkable Rate Acceleration in Water

Article abstract of DOI:10.1021/jo034762z

In water, the rate of Michael addition of amines and thiols to dehydroalanine amides was greatly accelerated, leading to shorter reaction times and higher yields. The scope of the new conditions was tested with a range of amines, thiols, and dehydroalanine amides. The ease and efficiency of this method provides an attractive route to the synthesis of natural and unnatural amino acid derivatives.

Full text of DOI:10.1021/jo034762z

Mich a el Ad d ition of Am in es a n d Th iols to Deh yd r oa la n in e
Am id es: A Rem a r k a ble Ra te Acceler a tion in Wa ter
B. Narasimhulu Naidu,* Margaret E. Sorenson, Timothy P. Connolly, and Yasutsugu Ueda
Discovery Chemistry, The Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway,
Wallingford, Connecticut 06492
Narasimhulu.Naidu@bms.com
Received J une 4, 2003
In water, the rate of Michael addition of amines and thiols to dehydroalanine amides was greatly
accelerated, leading to shorter reaction times and higher yields. The scope of the new conditions
was tested with a range of amines, thiols, and dehydroalanine amides. The ease and efficiency of
this method provides an attractive route to the synthesis of natural and unnatural amino acid
derivatives.
TABLE 1. Op tim iza tion of th e Mich a el Ad d ition w ith
Ben zyla m in ea
In tr od u ction
Dehydroalanine amides are important constituents of
many natural products, such as microcystins,1a lantibio-
tics,1b thiostrepton,1c and nocathiacins.2 It has been
postulated that the dehydroamino acids play an impor-
tant role in defining the three-dimensional structure
required for the biological activities of these agents.3
Moreover, they are versatile synthetic precursors because
dehydroalanine amide moieties can be readily trans-
formed into various natural and unnatural amino acid
derivatives.4 In this paper, we describe our findings of
the Michael addition of amines and thiols to dehydroala-
nine amides in water.
Although the Michael addition is one of the most
powerful and widely used synthetic tools,5 there are only
a handful of reports on the Michael addition of nucleo-
philes to dehydroalanine derivatives.4,6 This may be due
to the fact that these dehydroalanine derivatives are
generally very poor Michael acceptors.6b
entry
amine equiv
solvent
DMF
THF
MeOH
1:1 DMF/H2O
1:1 THF/H2O
1:1 MeOH/H2O
H2O
H2O
H2O
time (h)
yield (%)b
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
10
5
48
48
120
96
120
48
15
0c
0c
77
77
84
75
91
82
76
24
48
2
a
Reactions were run on a 0.5 mmol scale in 5 mL of solvent.
Isolated yields. c No detectable product was formed within this
b
period.
While most Michael additions are performed in organic
solvents, today’s environmental concerns encourage the
development of “greener” conditions where possible.
Although the use of water as a reaction solvent has
received considerable attention in synthetic organic
chemistry,7 Michael additions in water are relatively
scarce.8 Additionally, it may be possible by utilizing the
unique physicochemical properties of water to realize
reactivity and/or selectivity that cannot be attained in
organic solvents.9
(1) (a) Namikoshi, M.; Sivonen, K.; Evans, W. R.; Carmichael, W.
W.; Rouhiainen, L.; Luukkainen, R.; Rinehart, K. L. Chem. Res. Toxicol.
1992, 5, 661-666 and references therein. (b) J ack, R. W.; J ung, G.
Curr. Opin. Chem. Biol. 2000, 4, 310-317. (c) Anderson, B.; Hodgkin,
D. C.; Viswamitra, M. A. Nature 1970, 225, 233-235.
(2) (a) Sasaki, T.; Otani, T.; Matsumoto, H.; Unemi, N.; Hamada,
M.; Takeuchi, T.; Hori, M. J . Antibiot. 1998, 8, 715-721. (b) Leet, J .
E.; Li, W.; Ax, H. A.; Matson, J . A.; Huang, S.; Huang, R.; Cantone, J .
L.; Drexler, D.; Dalterio, R. A.; Lam, K. S. J . Antibiot. 2003, 56, 232-
242.
(3) (a) Palmer, D. E.; Pattaroni, C.; Nunami, K.; Chadha, R. K.;
Goodman, M.; Wakamiya, T.; Fukase, K. J . Am. Chem. Soc. 1992, 114,
5634-5642. (b) Suzen, S. Ankara Univ. Eczacilik Fak. Derg. 1999, 28,
129-141. (c) Nomoto, S.; Sano, A.; Shiba, T. Tetrahedron Lett. 1979,
6, 521-522.
(4) (a) Gulzar, M. S.; Morris, K. B.; Gani, D. J . Chem. Soc., Chem.
Commun. 1995, 1061-1062. (b) Choi, D.; Kohn, H. Tetrahedron Lett.
1995, 36, 7371-7373.
(5) Perlmutter, P. Conjugate Addition Reactions in Organic Syn-
thesis; Pergamon Press: Oxford, England, 1992.
(6) (a) Labia, R.; Morin, C. J . Org. Chem. 1986, 51, 249-251. (b)
Ferreira, P. M. T.; Maia, H. L. S.; Monteiro, L. S.; Sacramento, J . J .
Chem. Soc., Perkin Trans. 1 2001, 3167-3173 and references therein.
(7) (a) Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie
Academic and Professional: London, 1998. (b) Li, C.-J .; Chan, T.-H.
Organic Reactions in Aqueous Media; J ohn Wiley & Sons: New York,
1997.
(8) (a) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl.
1971, 10, 496-497. (b) Larpent, C.; Patin, H. Tetrahedron 1988, 44,
6107-6118. (c) Larpent, C.; Meignan, G.; Patin, H. Tetrahedron 1990,
46, 6381-6398. (d) J enner, G. Tetrahedron 1996, 52, 13557-13568.
(e) Keller, E.; Feringa, B. L. Tetrahedron Lett. 1996, 37, 1879-1882.
(f) Keller, E.; Feringa, B. L. Synlett 1997, 842-843. (g) Mori, Y.;
Kakumoto, K.; Manabe, K.; Kobayashi, S. Tetrahedron Lett. 2000, 41,
3107-3111. (h) Bensa, D.; Brunel, J .-M.; Buono, G.; Rodriguez, J .
Synlett 2001, 715-717.
(9) Manabe, K.; Iimura, S.; Sun, X.-M.; Kobayashi, S. J . Am. Chem.
Soc. 2002, 124, 11971-11978 and references therein.
10.1021/jo034762z CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/27/2003
10098
J . Org. Chem. 2003, 68, 10098-10102

Michael Addition of Amines and Thiols
TABLE 2. Mich a el Ad d ition of Am in es a n d Th iols to Deh yd r oa la n in e Am id es 1a -ca
entry
substrate/product
R1
R2
R3XH
BnNH2
MeNH2
Me2NH
HOCH2CH2NH(Me)
HOCH2CH2NH(Bn)
morpholine
BnNH(OH)
NH3
MeNH2
Me2NH
Me2NH
Me2NCH2CH2SH
H2NCH2CH2SH
HO2CCH2CH2SH
HO3SCH2CH2SH
Me2CHSH
time (h)
yield (%)b
1
2
3
4
5
6
7
8
1a /2a
1a /2b
1a /2c
1a /2d
1a /2e
1a /2f
1a /2g
1a /2h
1b/2i
1b/2j
1c/2k
1a /2l
1a /2m
1a /2n
1a /2o
1a /2p
1b/2q
1c/2r
1c/2s
H
H
H
H
H
H
H
H
H
H
Et
H
H
H
H
H
H
Et
Et
4-HO-PhCH2CH2
4-HO-PhCH2CH2
4-HO-PhCH2CH2
4-HO-PhCH2CH2
4-HO-PhCH2CH2
4-HO-PhCH2CH2
4-HO-PhCH2CH2
4-HO-PhCH2CH2
HO2CCH2
15
5
3
10
192
15
5
168
3
3
36
1
1
1
91
100
99
95
62
100
90
98c
100
100
90d
93
9
10
11
12
13
14
15
16
17
18
19
HO2CCH2
Et
4-HO-PhCH2CH2
4-HO-PhCH2CH2
4-HO-PhCH2CH2
4-HO-PhCH2CH2
4-HO-PhCH2CH2
HO2CCH2
97
88
85
97
100
72e
91e
1
1
1
48
72
Me2CHSH
Me2CHSH
Me2NCH2CH2SH
Et
Et
a
Unless otherwise mentioned, the reactions were conducted in water using 10 equiv of amine or 3 equiv of thiol and 3 equiv of Et3N.
b Isolated yields. c Reaction was carried out in aqueous ammonium hydroxide (28-30% NH3). 20 equiv of amine was used. e These reactions
were conducted using 6 equiv of thiol and 6 equiv of Et3N.
d
Resu lts a n d Discu ssion
Conditions for the Michael addition were optimized
using dehydroalanine amide 1a and benzylamine, and
the results are summarized in Table 1. The reaction was
conducted in anhydrous organic solvents such as DMF,
methanol, and THF for comparison. As shown in Table
1, no detectable Michael adduct was formed in aprotic
organic solvents such as DMF and THF even after 48 h
(entries 1 and 2). As expected, the Michael addition of
benzylamine to 1a did take place in methanol but
required 120 h for completion (entry 3).
F IGURE 1. Dehydroalanine amides.
Because water has been reported to have an unusual
effect on the rate and outcome of many organic reactions,
we decided to examine the effect of added water. To our
surprise, when a mixture of 1a and benzylamine was
stirred in DMF/H2O (1:1) or THF/H2O (1:1), the Michael
reaction occurred smoothly, albeit slowly, and provided
the desired product 2a in good yields (entries 4 and 5).
In 50% aqueous methanol, the reaction was significantly
faster, furnishing the Michael adduct 2a in 75% yield
(entry 6). In water, the addition of benzylamine to 1a was
complete in 15 h and provided the Michael adduct 2a in
91% isolated yield (entry 7). Systematically reducing the
number of equivalents of benzylamine led to somewhat
longer reaction times but still provided very good isolated
yields of the Michael adduct 2a (entries 8 and 9). The
dramatic rate acceleration in water may be attributed
to several factors such as enforced hydrophobic interac-
tions, stabilization of the activated complex through
solvation or hydrogen bonding, and micellar catalysis.
With optimal conditions in hand, we next examined
the generality of these conditions to other substrates
using several amines and thiols. The results are sum-
marized in Table 2. Generally, the Michael addition
between dehydroalanine amides 1a -d (Figure 1) and a
variety of amines proceeded efficiently, furnishing mod-
erate to excellent isolated yields of desired products. With
dehydroalanine amide 1a , additions were usually faster
with hydrophilic amines (entries 2, 3, and 7) but slower
with more sterically hindered amines (entries 5 and 6)
and hydrophobic amines (entries 1 and 5). Thus, the
Michael addition of sterically hindered N-benzylamino-
ethanol to 1a was very slow and provided only a moderate
yield of the product after 192 h. Even though ammonia
is highly polar and sterically uncrowded, addition to 1a
was extremely slow, requiring 168 h for completion. This
may be due to the relatively weaker nucleophilicity of
ammonia compared to alkylamines in protic solvents. The
Michael addition of amines to dehydroalanine amides 1b
and 1c also proceeded smoothly to give the corresponding
products in excellent isolated yields (entries 9-11).
Having obtained excellent results with amines, we then
examined the addition of thiols to dehydroalanine amides
1a -c. Triethylamine was found to be essential to facili-
tate the reaction. The added base may play a dual role
in improving the solubility of the dehydroalanine amides
and acting as a base catalyst for the Michael addition of
thiols. In general, the addition of thiols to dehydroalanine
amides was faster than that of amines. We found that
thiols containing both basic and acidic functional groups
such as tertiary amine, primary amine, carboxylic acid,
J . Org. Chem, Vol. 68, No. 26, 2003 10099

Naidu et al.
TABLE 3. Mich a el Ad d ition of Am in es a n d Th iols to
Deh yd r oa la n in e Am id e 1d a
completion. However, the addition of morpholine to 1e
was slower and required 60 h for completion, but with
excess morpholine the reaction was complete in 26 h and
provided 3c in very good isolated yield. Sodium thio-
methoxide addition to 1e was complete in 1 h and
produced the desired product 3d in an excellent yield.
In conclusion, the Michael addition of amines and
thiols to dehydroalanine amides in the presence of water
is efficient and high yielding. Reaction rates tend to be
faster as the proportion of water in the solvent is
increased. The ease and efficacy of this method provides
an attractive route to the synthesis of natural and
unnatural amino acid derivatives from readily available
dehydroalanine amides. Application of these findings to
the preparation of natural product analogues will be
disclosed elsewhere.10
entry
RXH
MeNH2
Me2NH
pyrrolidine
Me2CHSH
time (h)
product
yield (%)b
1
2
3
4
5
48
192
144
72
2t
96
95
2u
2v
2w
2x
(100)c
97
Me2NCH2CH2SH
48
63
a
Reactions were conducted in a 1:1 MeOH/H2O solvent system
using 50 equiv of the nucleophile. Isolated yields. c Crude yield.
b
TABLE 4. Mich a el Ad d ition of Am in es a n d Th iols to
Deh yd r oa la n in e Am id e 1ea
Exp er im en ta l Section
Gen er a l P r oced u r e for th e Ad d ition of Am in es to
Deh yd r oa la n in e Am id es (1a -e). A mixture of 1 (0.5 mmol)
and amine (5 mmol) in water (5 mL) was stirred at room
temperature until the reaction was complete. The reaction
mixture was then freeze-dried to give the desired product 2.
Alternatively, the reaction mixture was acidified with aq HCl
(1 N, 5 mL) and purified on a C-18 reverse-phase column using
MeOH/water mixtures. Product-containing fractions were
combined, concentrated, and freeze-dried to give 2.
2-Acet yla m in o-3-b en zyla m in o-N-[2-(4-h yd r oxyp h en -
yl)eth yl]p r op ion a m id e (2a ): purified using 10 and 15%
MeOH/water; white powder (0.1826 g, 91%); 1H NMR (500
MHz, DMSO-d6) δ 9.52 (1H, br s), 9.34 (1H, br s), 8.50 (1H, d,
J ) 7.9 Hz), 8.16 (1H, t, J ) 5.6 Hz), 7.59-7.55 (2H, m), 7.45-
7.40 (3H, m), 6.96 (2H, d, J ) 8.2 Hz), 6.68 (2H, d, J ) 8.2
Hz), 4.65-4.60 (1H, m), 4.18-4.13 (2H, m), 3.73 (1H, br s),
3.25-3.17 (3H, m), 3.06-2.99 (1H, m), 2.58 (2H, t, J ) 7.5
Hz), 1.91 (3H, s); 13C NMR (125.77 MHz, DMSO-d6) δ 170.0,
168.4, 155.6, 131.5, 130.1, 129.4, 129.1, 128.9, 128.5, 115.0,
50.0, 49.5, 47.0, 40.7, 34.0, 22.8; HRMS calcd for C20H26N3O3
(M + H) 356.1974, found 356.1969. Anal. Calcd for C20H25N3O3‚
0.31H2O‚1.1HCl: C, 59.89; H, 6.71; N, 10.48; Cl, 9.72. Found:
C, 59.76; H, 6.83; N, 10.58; Cl, 9.96.
2-Acetyla m in o-N-[2-(4-h yd r oxyp h en yl)eth yl]-3-m eth -
yla m in op r op ion a m id e (2b): white powder (0.1402 g, 100%);
1H NMR (500 MHz, DMSO-d6) δ 7.98 (1H, t, J ) 5.5 Hz), 7.86
(1H, d, J ) 7.9 Hz), 6.98 (2H, d, J ) 8.6 Hz), 6.66 (2H, d, J )
8.6 Hz), 4.30-4.26 (1H, m), 3.45-3.13 (4H, m), 2.62-2.55 (4H,
m), 2.22 (3H, s), 1.84 (3H, m); 13C NMR (125.77 MHz, DMSO-
d6) δ 170.6, 169.1, 155.5, 129.4, 129.3, 114.9, 52.8, 52.0, 40.4,
35.4, 34.1, 22.5; HRMS calcd for C14H22N3O3 (M + H) 280.1661,
found 280.1663. Anal. Calcd for C14H21N3O3‚0.2H2O‚0.1CH3-
NH2: C, 59.26; H, 7.57; N, 15.18. Found: C, 59.26; H, 7.51;
N, 15.36.
2-Acetyla m in o-3-d im eth yla m in o-N-[2-(4-h yd r oxyp h en -
yl)eth yl]p r op ion a m id e (2c): white powder (0.1452 g, 99%);
1H NMR (500 MHz, DMSO-d6) δ 9.08 (1H, br s), 8.06 (1H, t,
J ) 5.7 Hz), 7.90 (1H, d, J ) 8.2 Hz), 6.98 (2H, d, J ) 8.2 Hz),
6.66 (2H, d, J ) 8.2 Hz), 4.33-4.29 (1H, m), 3.23-3.16 (2H,
m), 2.57 (2H, t, J ) 7.3 Hz), 2.40-2.36 (1H, m), 2.32-2.28 (1H,
m), 2.12 (6H, s), 1.83 (3H, s); 13C NMR (125.77 MHz, DMSO-
d6) δ 170.6, 168.8, 155.5, 129.4, 129.3, 114.9, 60.6, 50.8, 45.1,
40.4, 34.1, 22.4; HRMS calcd for C15H24N3O3 (M + H) 294.1818,
found 294.1815. Anal. Calcd for C15H23N3O3‚0.1H2O‚0.1(CH3)2-
NH: C, 60.91; H, 7.97; N, 14.49. Found: C, 60.58; H, 8.04; N,
14.35.
entry
RXH
time (h)
product
yield (%)b
1
2
3
4
5
MeNH2
Me2NH
morpholine
morpholine
CH3SNa
6
3
60
26
1
3a
3b
3c
3c
3d
100
99
100
98c
96
a
Unless otherwise mentioned, the reactions were conducted in
a 2:3 MeOH/H2O solvent system using 10 equiv of the nucleophile.
Isolated yields. c 20 equiv of morpholine was used.
b
and sulfonic acid added to 1a very efficiently and
provided excellent isolated yields of Michael adducts
(entries 12-16). Also, treatment of an aqueous solution
of 1b and 1c with thiols produced the desired Michael
adducts in moderate to excellent isolated yields (entries
17-19). Surprisingly, the addition of thiols to 1c was
slower, presumably because of the poor solubility of 1c
in water.
Dehydroalanine amide 1d with two aromatic rings has
very poor water solubility. Consequently, Michael addi-
tions with 1d were carried out in 50% aqueous methanol,
and the results are summarized in Table 3. Perhaps
because of the presence of the extra methyl substituent
on the olefin and reduced hydrophobic effects, the addi-
tion of amines/thiols to 1d was slower, and as a result
excess nucleophile was needed for completion in a
reasonable time. Nevertheless, excellent yields of Michael
adducts (2t-x) were obtained with both amines and
thiols. The addition of nucleophiles to 1d was nonselec-
tive, resulting in inseparable mixtures of diastereomers.
Choi and Kohn5b reported that the Michael addition
of amines and sodium thiomethoxide to 1e in methanol
required an excess of the nucleophile (15-22 equiv) and
1-4 days for completion. Encouraging results with 1a -d
prompted us to examine the effect of water on the rate
of the Michael addition to 1e. The results in Table 4
clearly indicate that the inclusion of water in the reaction
solvent increases the rate of the addition of nucleophiles
to 1e severalfold. For example, in 60% aqueous methanol,
the addition of methylamine to 1e was complete in 6 h,
whereas dimethylamine addition took only 3 h for
(10) Naidu, B. N.; Li, W.; Sorenson, M. E.; Connolly, T. P.; Wich-
towski, J . A.; Zhang, Y.; Kim, O. K.; Matiskella, J . D.; Lam, K. S.;
Bronson, J . J .; Ueda, Y. Tetrahedron Lett. In press.
10100 J . Org. Chem., Vol. 68, No. 26, 2003

Michael Addition of Amines and Thiols
2-Acetyla m in o-3-[(2-h yd r oxyeth yl)m eth yla m in o]-N-[2-
(4-h yd r oxyp h en yl)eth yl]p r op ion a m id e (2d ): purified us-
ing water followed by 5 and 10% MeOH/water; white solid
(3H, s); HRMS calcd for C9H18N3O4 (M + H) 232.1297, found
232.1292. Anal. Calcd for C9H17N3O4‚0.5(CH3)2NH‚0.4H2O: C,
46.02; H, 8.23; N, 18.78. Found: C, 45.82; H, 8.38; N, 18.57.
1
(0.177 g, 95%); H NMR (500 MHz, DMSO-d6) δ 9.43 (1H, br
2-Acetyla m in o-3-d im eth yla m in o-N,N-d ieth ylp r op ion a -
m id e (2k ): purified using 5-20% MeOH/water; white powder
(0.120 g, 90%); 1H NMR (500 MHz, CD3OD) δ 5.19-5.15 (1H,
m), 3.50-3.35 (4H, m), 3.18-3.13 (2H, m), 2.76 (6H, s), 2.04
(3H, s), 1.25 (3H, t, J ) 7.2 Hz), 1.15 (3H, t, J ) 7.2 Hz); 13C
NMR (125.77 MHz, CD3OD) δ 172.2, 168.9, 59.6, 46.4, 44.1,
42.2, 40.9, 21.6, 13.5, 12.0; HRMS calcd for C11H24N3O2 (M +
H) 230.1869, found 230.1865.
N-{1-[2-(4-Hyd r oxyp h en yl)eth ylca r ba m oyl]-2-m eth yl-
a m in op r op yl}ben za m id e (2t). To a suspension of 1d (0.10
g, 0.31 mmol) in MeOH (3 mL) was added methylamine (2.15
mL, 40 wt % in H2O, 15.5 mmol). The resulting solution was
stirred at room temperature for 48 h and concentrated to yield
2t as a green solid (0.108 g, 96%): 1H NMR (300 MHz CDCl3)
δ 8.01 (1H, t, J ) 4.0 Hz), 7.86-7.79 (2H, m), 7.64 (1H, d, J )
5.9 Hz), 7.51-7.39 (4H, m), 7.03 (2H, d, J ) 8.4 Hz), 6.73 (2H,
d, J ) 8.4 Hz), 4.52 (1H, dd, J ) 3.1, 5.7 Hz), 3.54-3.47 (2H,
m), 3.27 (1H, dd, J ) 6.6, 3.30 Hz), 2.74 (2H, t, J ) 6.8 Hz),
2.47 (3H, s), 1.11 (0.9H, d, J ) 6.6 Hz), 0.96 (2.1 H, d, J ) 6.6
Hz); LCMS calcd for C20H26N3O3 (M + H) 356 20, found 356.14.
Anal. Calcd for C20H25N3O3‚0.5H2O: C, 65.91; H, 7.19; N,
11.53. Found: C, 65.99; H, 7.26; N, 11.50.
N-{2-Dim eth yla m in o-1-[2-(4-h yd r oxyp h en yl)eth ylca r -
ba m oyl]p r op yl}ben za m id e (2u ). To a suspension of 1d (0.10
g, 0.31 mmol) in MeOH (2 mL) was added dimethylamine (3.0
mL, 40 wt % in H2O, 15.5 mmol). The resulting solution was
stirred at room temperature for 8 days and concentrated to
yield 2u as a pale brown solid (0.113 g, 95% yield): 1H NMR
(300 MHz CDCl3) δ 7.85-7.79 (2H, m), 7.52-7.38 (4H, m),
7.02-6.95 (2H, m), 6.75-6.69 (2H, m), 6.39-6.33 (1H, m), 4.63
(0.3H, d, J ) 8.4 Hz), 4.47 (0.7H, d, J ) 5.5 Hz), 3.53-3.46
(2H, m), 2.90 (1H, t, J ) 6.4 Hz), 2.75-2.68 (2H, m), 1.00 (0.3H,
d, J ) 6.9 Hz), 0.90 (0.7H, d, J ) 6.6 Hz); HRMS calcd for
s), 9.25 (1H, br s), 8.38 (1H, d, J ) 8.6 Hz), 8.21 (1H, br s),
6.98 (2H, d, J ) 8.2 Hz), 6.68 (2H, d, J ) 8.5 Hz), 5.36 (1H, br
s), 4.74-4.70 (1H, m), 3.74 (2H, t, J ) 4.9 Hz), 3.60-3.11 (6H,
m), 2.81 (3H, s), 2.60 (2H, t, J ) 7.5 Hz), 1.91 (3H, s); 13C NMR
(125.77 MHz, DMSO-d6) δ 170.0, 168.2, 155.7, 129.4, 129.0,
115.1, 58.2, 56.4, 55.0, 47.9, 40.7, 34.0, 22.7; HRMS calcd for
C
15H26N3O4 (M + H) 324.1923, found 324.1927. Anal. Calcd
for C15H25N3O3‚0.5H2O‚1.1HCl: C, 51.59; H, 7.33; N, 11.28;
Cl, 10.47. Found: C, 51.83; H, 7.24; N, 11.27; Cl, 10.61.
2-Acetyla m in o-3-[ben zyl(2-h yd r oxyeth yl)a m in o]-N-[2-
(4-h yd r oxyp h en yl)eth yl]p r op ion a m id e (2e): purified using
10-30% MeOH/water; white solid (0.158 g, 62%); 1H NMR (500
MHz, DMSO-d6) δ 9.15 (1H, s), 8.13 (1H, t, J ) 5.5 Hz), 7.88
(1H, d, J ) 8.2 Hz), 7.30-7.26 (4H, m), 7.24-7.20 (1H, m),
6.99 (2H, d, J ) 8.5 Hz), 6.67 (2H, d, J ) 8.2 Hz), 4.43-4.38
(2H, m), 3.61 (2H, d, J AB ) 13.9 Hz), 3.45-3.39 (2H, m), 3.32
(1H, s), 3.23-3.16 (2H, m), 2.70 (1H, dd, J ) 12.8, 7.3 Hz),
2.61-2.42 (4H, m), 1.84 (3H, s); 13C NMR (125.77 MHz, DMSO-
d6) δ 170.6, 168.9, 155.5, 139.1, 129.34, 129.30, 128.6, 127.9,
126.6, 115.0, 58.7, 58.3, 56.1, 55.4, 51.1, 40.5, 34.1, 22.5; HRMS
calcd for C22H30N3O4 (M + H) 400.2236, found 400.2244. Anal.
Calcd for C22H29N3O4: C, 66.14; H, 7.31; N, 10.51. Found: C,
65.93; H, 7.29; N, 10.27.
2-Acet yla m in o-N-[2-(4-h yd r oxyp h en yl)et h yl]-3-m or -
p h olin -4-ylp r op ion a m id e (2f): white solid (0.1783 g, 100%);
1H NMR (500 MHz, DMSO-d6) δ 9.16 (1H, br s), 8.05 (1H, t,
J ) 5.5 Hz), 7.92 (1H, d, J ) 8.2 Hz), 6.99 (2H, d, J ) 8.6 Hz),
6.66 (2H, d, J ) 8.2 Hz), 4.39-4.35 (1H, m), 3.46-3.42 (5H,
m), 3.29-3.23 (1H, m), 3.20-3.13 (1H, m), 2.66 (1H, t, J ) 4.7
Hz), 2.57 (2H, t, J ) 7.2 Hz), 2.47-2.29 (6H, m), 1.83 (3H, s);
13C NMR (125.77 MHz, DMSO-d6) δ 170.5, 168.9, 155.5, 129.4,
129.3, 114.9, 67.2 (morpholine), 66.0, 59.8, 53.1, 45.9 (mor-
pholine), 49.9, 40.3, 34.1, 22.5; HRMS calcd for C17H24N3O4
(M - H) 334.1767, found 334.1781. Anal. Calcd for C17H25N3O4‚
0.2H2O‚0.25morpholine: C, 59.91; H, 7.61; N, 12.62. Found:
C, 59.53; H, 7.77; N, 12.62.
C
21H28N3O3 (M + H) 370.2131, found 370.2141. Anal. Calcd
for C21H27N3O3‚0.6H2O: C, 66.33; H, 7.47; N, 11.05. Found:
C, 66.23; H, 7.10; N, 11.39.
N-{1-[2-(4-Hyd r oxyp h en yl)eth ylca r ba m oyl]-2-p yr r oli-
d in -1-ylp r op yl}ben za m id e (2v). To a suspension of 1d (0.10
g, 0.31 mmol) in MeOH (2 mL) was added pyrrolidine (1.3 mL,
15.5 mmol) followed by water (2.0 mL). The resulting solution
was stirred at room temperature for 6 days and concentrated
to yield 2v as a white powder (0.122.5 g, 100%, 85-90%
purity): 1H NMR (300 MHz CDCl3) δ 8.61 (1H, t, J ) 4.8 Hz),
7.83-7.78 (2H, m), 7.53-7.39 (4H, m), 7.02-6.96 (2H, m),
6.79-6.71 (3H, m), 4.69 (1H, t, J ) 3.7 Hz), 3.60-3.47 (2H,
m), 3.06-2.97 (1H, m), 2.93 (1H, dd, J ) 6.6, 3.66 Hz), 2.74
(2H, t, J ) 6.6 Hz), 2.67-2.57 (3H, m), 1.68-1.59 (4H, m),
1.05 (0.9H, d, J ) 6.8 Hz), 0.93 (2.1H, d, J ) 6.8 Hz); HRMS
calcd for C23H30N3O3 (M + H) 396.2287, found 396.2287.
Gen er a l P r oced u r e for th e Ad d ition of Th iols to
Deh yd r oa la n in e Am id es 1a -e. A mixture of 1 (0.5 mmol),
thiol (1.5 mmol), and Et3N (1.5 mmol) in water (5 mL) was
stirred at room temperature until the reaction was complete.
The reaction mixture was then freeze-dried to give the desired
product 2. Alternatively, the reaction mixture was acidified
with aq HCl (1 N, 5 mL) and purified on a C-18 reverse phase
column using MeOH/water mixtures. Product-containing frac-
tions were combined, concentrated, and freeze-dried to give
2.
2-Acetyla m in o-3-(2-d im eth yla m in oeth ylsu lfa n yl)-N-[2-
(4-h yd r oxyp h en yl)eth yl]p r op ion a m id e (2l): purified using
water followed by 5% MeOH/water; white solid (0.1861 g, 93%);
1H NMR (500 MHz, DMSO-d6) δ 10.53 (1H, s), 9.16 (1H, br s),
8.26 (1H, t, J ) 5.7 Hz), 8.21 (1H, d, J ) 8.2 Hz), 6.99 (2H, d,
J ) 8.2 Hz), 6.68 (2H, d, J ) 8.2 Hz), 4.42-4.38 (1H, m), 3.27-
3.17 (4H, m), 2.89-2.86 (2H, m), 2.82 (1H, dd, J ) 13.4, 5.2
Hz), 2.75 (6H, s), 2.64-2.58 (3H, m), 1.87 (3H, s); 13C NMR
(125.77 MHz, DMSO-d6) δ 169.7, 169.2, 155.6, 129.4, 129.2,
115.0, 55.5, 52.2, 41.9, 41.7, 40.5, 34.1, 33.5, 25.0, 22.4; HRMS
2-Ace t yla m in o-3-(b e n zylh yd r oxya m in o)-N -[2-(4-h y-
d r oxyp h en yl)eth yl]p r op ion a m id e (2g): acidified with TFA
and purified using 10-50% MeOH/water; white solid (0.2185
1
g, 90%); H NMR (500 MHz, DMSO-d6) δ 9.45-8.55 (2H, br
s), 7.98 (1H, d, J ) 7.9 Hz), 7.89 (1H, t, J ) 5.5 Hz), 7.34-
7.25 (5H, m), 6.99 (2H, d, J ) 8.2 Hz), 6.67 (2H, d, J ) 8.2
Hz), 4.53-4.48 (1H, m), 3.90 (2H, s), 3.25-3.18 (2H, m), 3.02-
2.95 (1H, m), 2.86-2.79 (1H, m), 2.59 (2H, t, J ) 7.5 Hz), 1.86
(3H, s); 13C NMR (125.77 MHz, DMSO-d6) δ 170.1, 169.3,
155.6, 129.4, 129.3, 127.9, 127.1, 115.0, 63.5, 60.7, 50.6, 40.6,
34.2, 22.5; HRMS calcd for C20H26N3O4 (M + H) 372.1923,
found 372.1918.
2-Acetyla m in o-3-a m in o-N-[2-(4-h yd r oxyp h en yl)eth yl]-
1
p r op ion a m id e (2h ): white powder (0.132 g, 98%); H NMR
(500 MHz, DMSO-d6) δ 9.19 (1H, br s), 7.94-7.87 (2H, m), 7.79
(1H, t, J ) 5.6 Hz), 6.99-6.97 (2H, m), 6.68-6.65 (2H, m),
4.12-4.08 (1H, m), 3.29-3.17 (3H, m), 3.03-2.97 (1H, m),
2.70-2.56 (3H, m), 1.86 (1H, s), 1.81 (2H, s); HRMS calcd for
C
13H19N3O3 (M + Na) 288.1324, found 288.1311. Anal. Calcd
for C13H19N3O3‚0.2H2O: C, 58.06; H, 7.27; N, 15.63. Found:
C, 57.72; H, 7.27; N, 15.43.
(2-Acet yla m in o-3-m et h yla m in op r op ion yla m in o)a ce-
tic a cid (2i): white powder (0.12 g, 100%); 1H NMR (300 MHz,
CD3OD) δ 4.63 (1H, dd, J ) 7.02, 5.80 H), 3.77 (2H, br s), 2.98
(2H, m), 2.54 (3H, s), 2.48 (3H, s), 2.05 (3H, s); HRMS calcd
for C8H16N3O4 (M + H) 218.1141, found 218.1135. Anal. Calcd
for C8H15N3O4‚0.25CH3NH2‚0.4H2O: C, 42.68; H, 7.40; N,
19.61. Found: C, 42.70; H, 7.20; N, 19.43.
(2-Acetyla m in o-3-d im eth yla m in op r op ion yla m in o)a c-
1
etic a cid (2j): white powder (0.131 g, 100%); H NMR (300
MHz, CD3OD) δ 4.61 (1H, dd, J ) 8.2, 6.10 Hz), 3.77 (2H, d,
J ) 1.5 Hz), 2.74 (2H, m), 2.69 (6H, s), 2.38 (6H, s), 2.05
J . Org. Chem, Vol. 68, No. 26, 2003 10101

Naidu et al.
calcd for C17H28N3O3S (M + H) 354.1852, found 354.1849. Anal.
Calcd for C17H27N3O3S‚0.3H2O‚1.1HCl: C, 51.18; H, 7.25; N,
10.53; Cl, 9.77; S, 8.04. Found: C, 50.95; H, 7.45; N, 10.48;
Cl, 9.66; S, 8.08.
7.9 Hz), 5.06-5.01 (1H, m), 3.58-3.47 (2H, m), 3.40-3.33 (1H,
m), 3.28-3.21 (1H, m), 2.95-2.83 (2H, m), 2.76 (1H, dd, J )
13.4, 5.8 Hz), 1.98 (3H, s), 1.24-1.20 (9H, m), 1.11 (3H, t, J )
7.0 Hz); HRMS calcd for C12H24N2O2S (M + NH4 + CH3CN)
319.2168, found 319.2168. Anal. Calcd for C12H24N2O2S: C,
55.35; H, 9.29; N, 10.75; S, 12.31. Found: C, 55.43; H, 9.10;
N, 10.69; S, 12.19.
2-Acetyla m in o-3-(2-d im eth yla m in oeth ylsu lfa n yl)-N,N-
d ieth ylp r op ion a m id e (2s): purified using 5-20% MeOH/
water; white solid (0.156 g, 91%); 1H NMR (500 MHz, CD3OD)
δ 4.99-4.94 (1H, m), 3.51-3.33 (6H, m), 3.07-2.90 (3H, m),
2.92 (6H, s), 2.82-2.76 (1H, m), 1.99 (3H, s), 1.24 (3H, t, J )
7.0 Hz), 1.13 (3H, t, J ) 7.0 Hz); 13C NMR (125.77 MHz, CD3-
OD) δ 172.9, 171.2, 58.0, 50.5, 43.7, 43.60, 43.55, 42.2, 34.8,
27.7, 22.5, 14.9, 13.2; HRMS calcd for C13H28N3O2S (M + H)
2-Acet yla m in o-3-(2-a m in oet h ylsu lfa n yl)-N-[2-(4-h y-
d r oxyp h en yl)et h yl]p r op ion a m id e (2m ): purified using
water followed by 5% MeOH/water; white solid (0.1794 g, 97%);
1H NMR (500 MHz, DMSO-d6) δ 9.16 (1H, br s), 8.26 (1H, t,
J ) 5.7 Hz), 8.21 (1H, d, J ) 8.6 Hz), 8.17 (3H, br s), 6.98 (2H,
d, J ) 8.2 Hz), 6.68 (2H, d, J ) 8.5 Hz), 4.41-4.36 (1H, m),
3.26-3.15 (2H, m), 3.00-2.93 (2H, m), 2.83-2.71 (3H, m),
2.61-2.57 (3H, m), 1.86 (3H, s); 13C NMR (125.77 MHz, DMSO-
d6) δ 169.8, 169.3, 155.6, 129.4, 129.2, 115.0, 52.2, 40.6, 38.2,
34.1, 33.4, 28.3, 22.5; HRMS calcd for C15H24N3O3S (M + H)
326.1539, found 326.1538. Anal. Calcd for
C15H23N3O3S‚
0.4H2O‚1.05HCl: C, 48.57; H, 6.75; N, 11.33; Cl, 10.04; S, 8.64.
Found: C, 48.89; H, 6.69; N, 11.36; Cl, 10.38; S, 8.62.
3-{2-Acetyla m in o-2-[2-(4-h yd r oxyp h en yl)eth ylca r ba m -
oyl]eth ylsu lfa n yl}p r op ion ic a cid (2n ): purified using 5 and
290.1902, found 290.1903. Anal. Calcd for
0.4H2O‚1.25HCl: C, 45.63; H, 8.56; N, 12.28; S, 9.37; Cl, 12.95.
Found: C, 45.89; H, 8.25; N, 12.32; S, 9.34; Cl, 12.59.
C13H27N3O2S‚
2-Acetyla m in o-N-[2-(4-h yd r oxyp h en yl)eth yl]-3-isop r o-
p ylsu lfa n ylbu tyr a m id e (2w ). To a suspension of 1d (0.10
g, 0.31 mmol) in MeOH (2.5 mL) was added 2-propanethiol
(1.44 mL, 15.5 mmol) followed by H2O (2.5 mL) and Et3N (2.9
mL, 15.5 mmol). The resulting mixture was stirred at room
temperature for 72 h and then concentrated to give 2w as a
white powder (0.1206 g, 97%, 95% purity): 1H NMR (300 MHz
CDCl3) δ 7.81 (2H, d, J ) 6.9 Hz), 7.52-7.42 (4H, m), 7.09
(2H, d, J ) 8.4 Hz), 6.93 (1H, t, J ) 5.5 Hz), 6.75 (2H, d, J )
8.4 Hz), 4.67 (1H, dd, J ) 6.2, 2.9 Hz), 3.60-3.48 (3H, m),
3.31-3.17 (1H, m), 2.78 (2H, t, J ) 6.9 Hz), 1.39 (3H, d, J )
6.6 Hz), 1.29 (3H, d, J ) 6.9 Hz), 1.14 (3H, d, J ) 6.9 Hz);
1
10% MeOH/water; white solid (0.192 g, 88%); H NMR (500
MHz, DMSO-d6) δ 8.13-8.10 (2H, m), 6.98 (2H, d, J ) 8.2 Hz),
6.66 (2H, d, J ) 8.6 Hz), 4.37-4.33 (1H, m), 3.25-3.14 (2H,
m), 2.74-2.64 (7H, m), 2.61-2.55 (3H, m), 2.40 (2H, t, J ) 7.3
Hz), 1.84 (3H, s), 1.02 (6H, t, J ) 7.3 Hz); 13C NMR (125.77
MHz, DMSO-d6) δ 173.6, 170.0, 169.1, 155.6, 129.4, 129.2,
115.0, 52.4, 45.2, 40.6, 35.3, 34.1, 33.5, 27.0, 22.4, 10.1; HRMS
calcd for C16H23N2O5S (M + H) 355.1328, found 355.1316. Anal.
Calcd for C16H22N2O5S‚0.85H2O‚0.83Et3N: C, 55.54; H, 8.03;
N, 8.74; S, 7.07. Found: C, 55.93; H, 7.92; N, 8.69; S, 7.46.
2-{2-Acetyla m in o-2-[2-(4-h yd r oxyp h en yl)eth ylca r ba m -
oyl]eth ylsu lfa n yl}eth a n esu lfon ic a cid (2o). The reaction
mixture was quenched with aq NaHCO3 (1 M, 3 mL) and
purified using 5% MeOH/water: white solid (0.20 g, 85%); 1H
NMR (500 MHz, DMSO-d6) δ 9.15 (1H, s), 8.90 (1H, br s), 8.11
(1H, t, J ) 5.7 Hz), 8.06 (1H, d, J ) 8.6 Hz), 6.99 (2H, d, J )
8.2 Hz), 6.66 (2H, d, J ) 8.2 Hz), 4.35-4.31 (1H, m), 3.25-
3.15 (2H, m), 3.12-3.07 (3.34H, m), 2.76-2.54 (8H, m), 1.84
(3H, s), 1.17 (5H, t, J ) 7.3 Hz); 13C NMR (125.77 MHz, DMSO-
d6) δ 169.9, 169.1, 155.5, 129.4, 129.3, 115.0, 52.4, 51.7, 45.7,
40.6, 34.1, 33.7, 27.1, 22.4, 8.5; HRMS calcd for C15H21N2O6S2
(M - H) 389.0841, found 389.0841. Anal. Calcd for C15H22N2-
O6S2‚0.4Na‚0.9H2O‚0.6Et3N: C, 46.80; H, 6.94; N, 7.63; S,
13.43; Na, 1.93. Found: C, 46.99; H, 6.79; N, 7.65; S, 13.82;
Na, 1.89.
HRMS calcd for
401.1904.
C22H29N2O3S (M + H) 401.1899, found
2-Acetyla m in o-3-(2-d im eth yla m in oeth ylsu lfa n yl)-N-[2-
(4-h yd r oxyp h en yl)eth yl]bu tyr a m id e (2x). To a suspension
of 1d (0.10 g, 0.31 mmol) in MeOH (2.5 mL) was added
2-dimethylaminoethanethiol hydrochloride (2.19 g, 15.5 mmol)
and Et3N (2.19 mL, 15.5 mmol) followed by water (2.5 mL).
The resulting solution was stirred at room temperature for
48 h. The reaction was then quenched with 1 N aq HCl (15
mL) and purified by C-18 reverse phase chromatography,
eluting with 30-50% CH3CN/H2O containing 0.1% HCl, to give
a solid. This was suspended in H2O and filtered to yield pure
2x as a white solid (0.0857 g, 63%): 1H NMR (300 MHz CDCl3)
δ 8.18 (1H, t, J ) 5.5 Hz), 7.80 (2H, dd, J ) 6.9, 5.1 Hz), 7.54-
7.40 (3H, m), 7.15 (1H, d, J ) 8.8 Hz), 7.08 (1H, d, J ) 8.4
Hz), 7.03 (1H, d, J ) 8.4 Hz), 6.86 (1H, d, J ) 8.4 Hz), 6.77
(1H, d, J ) 8.4 Hz), 5.01 (1H, dd, J ) 8.8, 4.4 Hz), 4.59 (1H,
dd, J ) 6.2, 2.9 Hz), 3.67-3.52 (1H, m), 3.50-3.36 (1H, m),
3.33-3.22 (1H, m), 3.16-3.00 (1H, m), 2.94-2.89 (2H, m),
2.83-2.74 (2H, m), 2.39 (6H, s), 1.15 (3H, dd, J ) 11.0, 7.3
Hz); HRMS calcd for C23H32SN3O3 (M + H) 430.2164, found
430.2163. Anal. Calcd for C23H31N3O3S‚0.02HCl‚0.5H2O: C,
62.88; H, 7.35; N, 9.56; S, 7.30; Cl, 0.16. Found: C, 63.03; H,
7.58; N, 9.55; S, 7.59; Cl, 0.15.
2-Acetyla m in o-N-[2-(4-h yd r oxyp h en yl)eth yl]-3-isop r o-
p ylsu lfa n ylp r op ion a m id e (2p ): white solid (0.158 g, 97%);
1H NMR (500 MHz, DMSO-d6) δ 9.16 (1H, s), 8.11-8.04 (2H,
m), 6.98 (2H, d, J ) 8.2 Hz), 6.66 (2H, d, J ) 8.2 Hz), 4.35-
4.31 (1H, m), 3.26-3.14 (2H, m), 2.98-2.90 (1H, m), 2.74 (1H,
dd, J ) 13.2, 6.1 Hz), 2.61-2.56 (3H, m), 1.84 (3H, s), 1.18
(3H, d, J ) 6.2 Hz), 1.17 (3H, d, J ) 6.2 Hz); 13C NMR (125.77
MHz, DMSO-d6) δ 170.0, 169.0, 155.5, 129.4, 129.3, 114.9, 52.7,
40.5, 34.2, 34.1, 32.2, 23.2, 23.1, 22.4; HRMS calcd for
C
16H25N2O3S (M + H) 325.1586, found 325.1597. Anal. Calcd
for C16H24N2O3S‚0.2H2O: C, 58.58; H, 7.50; N, 8.54; S, 9.77.
Found: C, 58.97; H, 7.73; N, 8.64; S, 9.48.
Ack n ow led gm en t. We thank Dr. Gene Dubowchik
for valuable suggestions in the preparation of this paper.
(2-Acetyla m in o-3-isop r op ylsu lfa n ylp r op ion yla m in o)-
1
a cetic a cid (2q): white powder (0.182, 100%); H NMR (300
MHz, CD3OD) δ 4.57 (1H, dd, J ) 8.6, 4.88 Hz), 3.77 (2H, dd,
J ) 55.2, 17.4 Hz), 3.18 (6H, q, J ) 7.3 Hz), 3.09 (1H, dd, J )
13.7, 5.2 Hz), 3.00 (1H, m), 2.80 (1H, dd, J ) 13.7, 8.8 Hz),
2.05 (3H, s), 1.31 (9H, t, J ) 7.3 Hz), 1.28 (6H, dd, J ) 11.9,
6.7 Hz); HRMS calcd for C10H19N2O4S (M + H) 263.1066, found
263.1059.
2-Acetyla m in o-N,N-d ieth yl-3-isop r op ylsu lfa n ylp r op i-
on a m id e (2r ): purified using 20% MeOH/water; white solid
(0.0931 g, 72%); 1H NMR (500 MHz, CDCl3) δ 6.53 (1H, d, J )
Su p p or tin g In for m a tion Ava ila ble: Description of ex-
perimental procedures and analytical data for dehydroalanine
1
amides (1a -e) and Michael adducts 3a -d , H NMR spectra
for 1b-e, 2g, 2k , 2q, 2v, 2w , and 3a -d , and the 13C NMR
spectrum for 2k . This material is available free of charge via
the Internet at http://pubs.acs.org.
J O034762Z
10102 J . Org. Chem., Vol. 68, No. 26, 2003