Exploration of the Mitsunobu reaction with Tosyl- and Boc-hydrazones as nucleophilic agents

Article abstract of DOI:10.1021/jo061185g

Tosyl- and Boc-hydrazones were found to be effective nucleophiles in the Mitsunobu reaction. Tosyl hydrazones reacted cleanly with primary and secondary alcohols when co-administered to a cooled DBAD/PPh₃ or DEAD/PPh ₃ complex. Boc-h

Full text of DOI:10.1021/jo061185g

Exploration of the Mitsunobu Reaction with
Tosyl- and Boc-Hydrazones as Nucleophilic
Agents
John M. Keith* and Leslie Gomez
Johnson & Johnson Pharmaceutical Research & DeVelopment,
L.L.C., 3210 Merryfield Row, San Diego, California 92121
jkeith@prdus.jnj.com
ReceiVed June 8, 2006
FIGURE 1. Utility of functionalized hydrazones.
We began our studies using the tosyl hydrazone of benzal-
dehyde (2) as our substrate as there is precedent for alkylation
5
of tosyl hydrazones and because sulfonamides are effective
6
nucleophiles for the Mitsunobu reaction. Indeed, when a THF
solution of 2, benzyl alcohol, and Ph3P were treated with di-
7
tert-butyl azodicarboxylate (DBAD) at 0 °C (Method A), the
desired N-benzylated product was formed in good yield (Table
1
, 4). These conditions were inefficient for secondary alcohols,
8
however, giving poor conversions and an interesting tetrazan
side product (3, Figure 2) resulting from Michael-type addition
of the hydrazone onto DBAD yielding a compound with four
Tosyl- and Boc-hydrazones were found to be effective
nucleophiles in the Mitsunobu reaction. Tosyl hydrazones
reacted cleanly with primary and secondary alcohols when
co-administered to a cooled DBAD/PPh or DEAD/PPh
3 3
complex. Boc-hydrazones required electron-withdrawing
substituents to participate in the reaction.
9
contiguous nitrogens. Product 3 was isolable and chro-
matographable, but decomposed vigorously at its melting point
(154 °C). Products such as 3 likely arise when the phosphonium-
alcoxide electrophile reacts sluggishly, thus allowing the highly
electrophilic DBAD to compete for the hydrazone nucleophile.
Formation of 3 could be prevented by premixing DBAD and
PPh3 at 0 °C for 10 min, which results in precipitation of the
DBAD/PPh3 adduct, and then treating the heterogeneous
Hydrazones represent a versatile class of chemical intermedi-
ates capable of acting as both electrophiles and nucleophiles.
10
1
2
mixture dropwise with a solution of alcohol and hydrazone
Their ease of preparation, increased hydrolytic stability relative
to imines, and tendency toward crystallinity are all desirable
characteristics of hydrazones. Despite these positive traits,
hydrazones have been under studied and much of their basic
chemistry unexplored. Our interest in hydrazones was as
nucleophilic partners in the Mitsunobu reaction. There are some
examples in the literature of intramolecular Mitsunobu reactions
(
2
Method B). Method B substantially improved the yield when
-indanol was the substrate (14B), but gave similar results as
Method A with N-Boc-4-piperidinol (16B). Methods A and B
were then reexamined by using diethyl azodicarboxylate (DEAD)
instead of DBAD to give Methods C and D. Of the two, Method
D gave higher yields, suggesting the steric environment sur-
rounding the azodicarboxylate/ triphenylphosphine adduct plays
a large role in reaction progression, and no products of type
3
hydrazone and alcohol with co-addition. Treating the preformed
DEAD/PPh3 adduct sequentially with a solution of hydrazone
followed by a solution of alcohol (Method E) gave nearly
3
with acyl hydrazones, but we wished to extend the reaction to
include tosyl- and Boc-hydrazones for intermolecular substitu-
tions to give products of type 1 (Figure 1). Products of type 1
can in turn be converted into other useful products.4
11
.
We then compared the effect of sequential addition of
(
1) (a) Keith, J. M.; Jacobsen, E. N. Org. Lett. 2004, 6, 153-155. (b)
Berdinskii, I. S.; Posyagina, E. Yu.; Orlova, L. D.; Lyadova, A. A. Zh.
Org. Khim. 1990, 26, 366-370. (c) Ogawa, C.; Konishi, H.; Sugiura, M.;
Kobayashi, S. Org. Biomol. Chem. 2004, 2, 446-448.
(5) (a) Islam, A. M.; Abdel-Halim, A. M.; Salama, M. A. Egypt. J. Chem.
1987, 29, 405-431. (b) Donia, S. G.; Shams, N.; El-Rahman, T. A. Ind. J.
Chem., Sect. B 1988, 27B, 117-120.
(
2) (a) Cacchi, S.; La Torre, F.; Misiti, D. Synthesis 1977, 301-303. (b)
Zhao, G.-L.; Shi, M. Tetrahedron 2005, 61, 7277-7288.
(6) Henry, J. R.; Marcin, L. R.; McIntosh, M. C.; Scola, P. M.; Weinreb,
S. M. Tetrahedron Lett. 1989, 30, 5709-5712.
(7) Mitsunobu, O. Synthesis 1981, 1, 1-28.
(3) (a) Kadow, J. F.; Vyas, D. M.; Doyle, T. W. Tetrahedron Lett. 1989,
3
0, 3299-3302. (b) Curran, W. V.; Ross, A. A.; Lee, V. J. J. Antibiot.
1
988, 41, 1418-1429.
(8) Busch, M.; Muller, H.; Schwarz, E. Ber. Dtsch. Chem. Ges. B 1923,
56, 1600-1612.
(4) (a) Kobayashi, S.; Hirabayashi, R. J. Am. Chem. Soc. 1999, 121,
6
2
942-6943. (b) Benstead, D. J.; Hulme, A. N.; McNab, H.; Wight, P. Synlett
(9) For entry 14 A, Table 1, a 24% yield of this side product was
obtained.
005, 1571-1574. (cC) Buchwald, S. L.; Willoughby, C. A. Catalytic
asymmetric and nonasymmetric reduction of imines and oximines using
metal catalysts. U.S. Cont.-in-part of U.S. Ser. No. 698940, abandoned,
US 5292893, 1994. (d) Schantl, J. G.; Hebeisen, P.; Karpellus, P. Synth.
Commun. 1989, 19, 39-48.
(10) Smith, A. B.; Hale, K. J.; Rivero, R. A. Tetrahedron Lett. 1986,
27, 5813-5816.
(11) We detected the DEAD derived tetrazan using Method C, but did
not attempt to isolate this side product.
1
0.1021/jo061185g CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/05/2006
J. Org. Chem. 2006, 71, 7113-7116
7113

TABLE 1. Mitsunobu Reaction of 2 with Primary and Secondary
Alcohols
FIGURE 2. Tetrazan side product.
With the optimization studies complete, we examined a
variety of primary and secondary alcohols, including allylic,
benzylic, propargyllic, heterobenzylic, and simple alkanols
(Table 1). For ease of TLC monitoring, the hydrazone was used
as the limiting reagent for most of the examples. However, in
those instances where the alcohol is precious, as with the alcohol
precursor to 11, the hydrazone can be used in excess and good
yields obtained. Simple, highly reactive alcohols undergo clean
conversion to the alkylated hydrazone with Method A or B,
but as these methods did not appear to be as effective for
secondary alcohols, we elected to use Method D for all
substrates.
Boc-hydrazones14 were then tested for effectiveness as
nucleophiles in the Mitsunobu reaction with Method D. The
Boc-hydrazone of benzaldehyde proved to be completely
unreactive under all conditions examined, giving only recovered
hydrazone. We were curious if the lack of observed reactivity
1
5
was due to electronic or steric factors. We prepared four
increasingly electron poor and sterically crowded Boc-hydra-
zones and examined them in the Mitsunobu reaction with benzyl
alcohol. We observed a gradual increase in reactivity as electron
deficiency and steric-hindrance increased, suggesting pKa of the
hydrazone, and not steric bulk associated with the Boc group,
was determining reactivity (Table 2). Indeed, the 2,6-dintroben-
zaldehyde derivative gave a quite useful yield of substitution
product (20).
In conclusion, we have extended the utility of the Mitsunobu
reaction to include tosyl- and Boc-hydrazones as nucleophillic
components. Preformation of a DEAD/PPh3 complex prior to
addition of alcohol and hydrazone (Method D) gave superior
results than traditional methods (Method A or C) for secondary
alcohols. Boc-hydrazones were found to be unreactive unless
they possesed pKa lowering substituents.
Experimental Section
Procedure A: To a round-bottomed flask are added the hydra-
zone substrate, alcohol (1.2 equiv), triphenylphosphine (1.4 equiv),
and THF (0.2 M). The mixture is cooled to 0 °C (ice bath) and
treated with DBAD (1.2 equiv) to give a bright yellow solution.
The reaction is monitored by TLC until complete or no longer
a
Reactions typically failed to progress beyond 4 h. b Reactions were run
with 100 mg of hydrazone; all yields are post silica gel column chroma-
tography. Alcohol was the limiting reagent.
c
(12) It remains unclear why this is the case though we have experienced
this phenomenon with other systems as well, e.g. aryl/alkyl ether formation.
Reactions were run under anhydrous conditions and with an inert atmosphere
identical results as co-addition Method D. Reversing the addition
of alcohol and hydrazone (Method F) gave a slight improvement
in yield (Table 1, 16, Methods D-F). While there is a slight
upward trend in yields for 16 with Methods D-F, the differ-
ences are too small to draw any mechanistic conclusions. Further
clouding the mechanistic issue is that the reactions typically
(
N2).
(13) Other phosphines examined: PMe3, PBu3, P(furyl)3, and the arsine
AsPh3.
(14) Boc-hydrazones were prepared by heating a 1:1 mixture of hydrazide
and aldehyde (typically 1 g) in ethanol with 10 drops glacial HOAc at 80
°C for 15 min and then allowing the solution to cool. The hydrazone product
can then be isolated by vacuum filtration.
(15) It is necessary for the nucleuphile to have a pKa e 15 for
intermolecular Mitsunobu reactions: Hughes, D. L. The Mitsunobu Reac-
tion. In Org. Reactions, John Wiley & Sons: New York, 1993, Vol. 42, p
335-656.
12
fail to progress beyond 4 h. Further reaction optimization with
phosphines13 other than PPh3 failed to give product when used
in conjunction with Method D.
7
114 J. Org. Chem., Vol. 71, No. 18, 2006

TABLE 2. Mitsunobu Reaction of Boc-Hydrazones with Benzyl
Alcohol
28.0, 21.5; MS (TOF) m/z 505.0824 [M + H]; HRMS calcd for
S 505.2115, found 505.2093 [M + H].
24 32 6 4
C H O N
1
4
6
: white solid; mp 109-110 °C; H NMR (acetone-d , 600 MHz)
δ 7.94-7.90 (m, 2H), 7.75-7.71 (m, 1H), 7.59-7.55 (m, 2H),
7
5
.48-7.41 (m, 4H), 7.40-7.33 (m, 5H), 7.32-7.26 (m, 1H), 5.04-
.00 (m, 2H), 2.44-2.40 (m, 3H); 13C NMR (acetone-d
, 600 MHz)
6
δ 146.4, 146.2, 138.0, 137.2, 136.3, 131.8, 131.5, 130.6, 130.5,
30.0, 129.4, 128.9, 128.7, 52.9, 22.5; MS (ESI) m/z 365.3 [M +
H]; HRMS calcd for C21 S 365.1318, found 365.1312 [M
H].
6
: white solid; mp 73-74 °C; H NMR (acetone-d , 600 MHz)
1
20 2 2
H N O
+
1
5
δ 8.08 (s, 1H), 7.80 (d, J ) 8.2 Hz, 2H), 7.71-7.66 (m, 2H), 7.42-
7
.38 (m, 3H), 7.30 (d, J ) 8.1 Hz, 2H), 3.54 (d, J ) 6.5 Hz, 2H),
.40 (s, 3H), 1.10-1.01 (m, 1H), 0.59-0.55 (m, 2H), 0.43-0.38
2
(
m, 2H); 13C NMR (acetone-d
, 600 MHz) δ 148.9, 143.7, 134.5,
6
1
34.0, 130.2, 129.3, 128.5, 128.1, 127.4, 52.5, 21.4, 9.3, 4.3; MS
(
ESI) m/z 329.3 [M + H]; HRMS calcd for C18
H
20
N
2
O
2
S 329.1318,
found 329.1305 [M + H].
1
6
3
: white solid; mp 101-103 °C; H NMR (CDCl , 500 MHz) δ
7
7
0
1
.88 (d, J ) 8.3 Hz, 2H), 7.81 (s, 1H), 7.70-7.66 (m, 2H), 7.43-
.38 (m, 3H), 7.28 (d, J ) 8.2 Hz, 2H), 4.68 (s, 2H), 2.39 (s, 3H),
.02 (s, 9H); 13C NMR (CDCl
, 500 MHz) δ 144.9, 144.0, 134.4,
3
33.9, 129.9, 129.3, 128.6, 128.4, 127.2, 96.1, 92.2, 36.6, 21.4,
0.64; MS (ESI) m/z 385.2 [M + H]; HRMS calcd for C20
SSi 385.1400, found 385.1386 [M + H].
-
24 2 2
H N O -
1
7
: white solid; mp 52-55 °C; H NMR (acetone-d
6
, 600 MHz)
δ 8.17 (s, 1H), 7.88 (d, J ) 8.2 Hz, 2H), 7.72-7.69 (m, 2H), 7.45-
a
Reactions were run with 100 mg of hydrazone; all yields are post silica
7
(
(
1
5
.40 (m, 5H), 4.19-4.01 (m, 1H), 3.90-3.73 (m, 4H), 3.70-3.65
m, 1H), 3.46 (td, J ) 2.9, 11.7 Hz, 1H), 3.02-2.67 (m, 2H), 2.40
s, 3H), 1.44 (s, 9H); 13C NMR (acetone-d
, 600 MHz) δ 155.9,
46.0, 136.6, 136.3, 131.9, 131.3, 130.5, 129.2, 80.9, 75.5, 68.1,
gel column chromatography.
6
progressing. Concentrating the reacting mixture to dryness and
chromatographing the residue (EtOAC/Hexanes) gives the pure
product.
Procedure B: To a round-bottomed flask are added triph-
enylphosphine (2.0 equiv) and THF (0.4 M relative to hydrazone
substrate) and the mixture is cooled to 0 °C (ice bath). Once cool,
the solution is treated with DBAD (1.8 equiv) and the mixture
stirred for 10 min, during which time the phosphine-DBAD adduct
precipitates. To the slurry/solid mass is then added, dropwise over
2.3, 48.1, 46.8, 44.8, 43.6, 29.5, 22.4; MS (ESI) m/z 496.3 [M +
Na]; HRMS calcd for C24
H].
H
31
N
3
5
O S 474.2057, found 474.2063 [M
+
1
8
: white solid, mp 103-104 °C; H NMR (CDCl
3
, 600 MHz) δ
8
.31 (s, 1H), 7.69 (d, J ) 8.3 Hz, 4H), 7.46-7.39 (m, 3H), 7.31
(
(
d, J ) 8.0 Hz, 2H), 4.98 (s, 1H), 4.93 (d, J ) 5.9 Hz, 1H), 4.68
d, J ) 5.9 Hz, 1H), 4.30-4.26 (m, 1H), 3.77-3.72 (m, 1H), 3.38-
3
.34 (m, 1H), 3.36 (s, 3H), 2.42 (s, 3H), 1.44 (s, 3H), 1.31 (s, 3H);
1
3
3
C NMR (CDCl , 600 MHz) δ 156.4, 144.3, 133.5, 131.1, 129.6,
10 min, a solution consisting of hydrazone, alcohol (1.5 equiv),
1
28.7, 128.3, 128.1, 112.4, 109.9, 85.1, 83.6, 82.3, 55.2, 52.7, 26.3,
and THF (0.4 M). The resultant mixture is stirred at 0 °C until
reaction is complete or stops progressing.
2
4.8, 21.6; MS (ESI) m/z 483.3 [M + Na]; HRMS calcd for
23 28 2 6
C H N O S 461.1741, found 461.1724 [M + H].
Procedure C: As per procedure A except DEAD was used.
Procedure D: As per procedure B except DEAD was used.
Procedure E: To a round-bottomed flask are added triph-
enylphosphine (2.0 equiv) and THF (0.4 M relative to hydrazone
substrate) and the mixture is cooled to 0 °C (ice bath). Once cool,
the solution is treated with DEAD (1.8 equiv) and the mixture stirred
for 10 min before adding, dropwise over 3 min, a solution consisting
of the hydrazone and THF (0.7 M). After 10 min, a solution
consisting of alcohol (1.5 equiv) and THF (0.7 M relative to
hydrazone) is added dropwise over 3 min. The reaction is then
stirred at 0 °C (ice bath) until complete.
Procedure F: To a round-bottomed flask are added triph-
enylphosphine (2.0 equiv) and THF (0.4 M relative to hydrazone
substrate) and the mixture is cooled to 0 °C (ice bath). Once cool,
the solution is treated with DEAD (1.8 equiv) and the mixture stirred
for 10 min before adding, dropwise over 3 min, a solution consisting
of the alcohol (1.5 equiv) and THF (0.7 M relative to the
hydrazone). After 10 min, a solution consisting of hydrazone and
THF (0.7 M relative to hydrazone) is added dropwise over 3 min.
1
9
: white solid; mp 98-100 °C; H NMR (acetone-d
δ 8.54-8.50 (m, 1H), 8.38-8.35 (m, 1H), 7.78 (d, J ) 8.3 Hz,
H), 7.73 (s, 1H), 7.66-7.63 (m, 1H), 7.50-7.46 (m, 2H), 7.34
d, J ) 8.1 Hz, 2H), 7.25-7.20 (m, 4H), 4.92 (s, 2H), 2.30 (s,
6
, 600 MHz)
2
(
3
1
5
H); 13C NMR (acetone-d
36.8, 136.6, 136.1, 133.6, 132.0, 131.6, 130.6, 130.1, 129.1, 125.4,
6
, 600 MHz) δ 150.8, 150.7, 148.2, 146.4,
0.9, 22.5; MS (ESI) m/z 366.3 [M + H]; HRMS calcd for
20 19 3 2
C H N O S 366.1271, found 366.1265 [M + H].
1
1
0: white solid; mp 105-106 °C; H NMR (CDCl
3
, 600 MHz)
δ 7.85 (d, J ) 8.3 Hz, 2H), 7.73 (s, 1H), 7.61-7.57 (m, 2H), 7.38-
7
(
1
4
.35 (m, 3H), 7.33 (d, J ) 8.4 Hz, 2H), 7.21-7.20 (m, 1H), 4.98
s, 2H), 2.42 (s, 3H); 13C NMR (CDCl
, 600 MHz) δ 151.2, 145.7,
44.4, 136.2, 134.4, 133.8, 130.2, 129.6, 128.6, 128.2, 127.4, 120.5,
7.7, 21.6; MS (ESI) m/z 450.0 [M + H]; HRMS calcd for C18
449.9940, found 449.9930 [M + H].
3
16
H -
3 2 2
BrN O S
1
6
11: white solid; mp 127-128 °C; H NMR (acetone-d , 600
MHz) δ 8.45 (s, 1H), 7.88 (d, J ) 8.3 Hz, 2H), 7.66-7.63 (m,
2H), 7.45 (d, J ) 8.0 Hz, 2H), 7.43-7.40 (m, 3H), 5.02 (s, 2H),
3.89 (s, 3H), 2.43 (s, 3H); 13C NMR (CDCl
The reaction is then stirred at 0 °C (ice bath) until complete.
3
, 600 MHz) δ 150.4,
1
3
: white solid; mp 154-156 °C, vigorous decomposition; H
145.6, 144.2, 135.0 (d, J ) 15.9 Hz), 131.3, 130.6, 129.7, 129.3,
128.4, 115.7, 106.3, 46.5, 33.9, 21.5; MS (ESI) m/z 524.9 [M +
H]; HRMS calcd for C19
NMR (acetone-d
6
, 600 MHz) δ 11.10-11.97 (m, 1H), 9.13-8.93
(
m, 1H), 7.90-7.85 (m, 2H), 7.70-7.63 (m, 2H), 7.45-7.36 (m,
H18Br
2 4 2
N O S 524.9590, found 524.9575
5
H), 2.39 (s, 3H), 1.53-1.50 (m, 4H), 1.47 (s, 7H), 1.35 (s, 7H);
[M + H].
1
3
1
C NMR (acetone-d
6
, 600 MHz) δ 160.2, 153.7, 145.8, 143.4,
12: colorless oil; H NMR (CDCl
3
, 600 MHz) δ 8.62 (s, 1H),
138.4, 134.4, 132.0, 131.4, 130.4, 129.6, 128.5, 84.7, 84.5, 28.3,
7.74-7.71 (m, 2H), 7.70 (d, J ) 8.3 Hz, 2H), 7.45-7.39 (m, 3H),
J. Org. Chem, Vol. 71, No. 18, 2006 7115

7
3
1
2
.27 (d, J ) 8.3 Hz, 2H), 4.50 (heptet, J ) 6.7 Hz, 1H), 2.39 (s,
7.24 (m, 1H), 7.23 (d, J ) 7.4 Hz, 2H), 5.15 (s, 2H), 1.60 (s, 9H);
13
H), 1.08 (d, J ) 6.7 Hz, 6H); 13C NMR (CDCl
, 600 MHz) δ
3
3
C NMR (CDCl , 600 MHz) δ 153.3, 138.4, 135.5, 131.0 (quartet,
59.3, 143.7, 136.1, 134.1, 130.9, 129.6, 128.7, 128.0, 127.9, 53.0,
J ) 32.3 Hz), 128.9, 127.4, 127.1, 126.2, 125.5 (quartet, J ) 3.7
Hz), 124.9, 123.1, 82.4, 48.6, 28.2; MS (ESI) m/z 323.3 [M + H];
1.5, 20.5; MS (ESI) m/z 317.3 [M + H]; HRMS calcd for
C
17
H
20
N
2
O
2
S 317.1318, found 317.1317 [M + H].
HRMS calcd for C20
H].
21 3 2 2
H F N O 379.1628, found 379.1635 [M +
1
3
13: colorless oil; H NMR (CDCl , 600 MHz) δ 8.72 (s, 1H),
7
3
1
.74 (d, J ) 6.8 Hz, 2H), 7.65 (d, J ) 8.3 Hz, 2H), 7.47-7.40 (m,
1
1
6
8: white solid; mp 56-57 °C; H NMR (acetone-d , 600 MHz)
H), 7.27 (d, J ) 8.1 Hz, 2H), 4.54-4.48 (m, 1H), 2.41 (s, 3H),
δ 8.08 (d, J ) 7.9 Hz, 1H), 7.93 (br s, 1H), 7.55-7.48 (m, 2H),
.67-1.61 (m, 2H), 1.59-1.51 (m, 4H), 1.44-1.37 (m, 2H); 13
C
7
2
(
1
8
3
.38 (t, J ) 7.7 Hz, 1H), 7.24-7.20 (m, 2H), 7.16 (d, J ) 7.5 Hz,
NMR (acetone-d
6
, 600 MHz) δ 163.9, 146.0, 137.4, 136.0, 133.1,
13
H), 7.13 (t, J ) 7.3 Hz, 1H), 5.08 (s, 2H), 1.45 (s, 9H); C NMR
, 600 MHz) δ 155.2, 137.8, 137.1, 135.2, 134.2, 130.9,
1
3
3
31.4, 130.7, 130.1, 130.0, 63.7, 31.3, 26.4, 22.5; MS (ESI) m/z
43.3 [M + H]; HRMS calcd for C19
43.1479 [M + H].
acetone-d
6
H
22
2 2
N O S 343.1475, found
30.6, 129.2, 128.6, 128.4, 127.4 (quartet, J ) 5.8 Hz), 127.1, 125.3,
3.3, 50.0, 29.4; HRMS calcd for C20
79.1614 [M + H].
H
21
F N
3 2
O
2
379.1628, found
1
1
4: white solid; mp 143-145 °C; H NMR (CDCl
3
, 600 MHz)
δ 8.57 (s, 1H), 7.71 (d, J ) 8.2 Hz, 2H), 7.58 (d, J ) 7.1 Hz, 2H),
.42-7.39 (m, 1H), 7.37-7.30 (m, 4H), 7.11-7.06 (m, 4H), 5.03
quintet, J ) 8.2 Hz, 1H), 3.09-3.03 (m, 2H), 2.98-2.92 (m, 2H),
1
19: yellow foam; H NMR (acetone-d
6
, 600 MHz) δ 8.28 (br s,
7
1
1
2
2
1
4
H), 8.14 (dd, J ) 1.3, 8.0 Hz, 1H), 7.95 (dd, J ) 1.1, 8.2 Hz,
H), 7.73 (t, J ) 7.4 Hz, 1H), 7.60-7.56 (m, 1H), 7.40-7.35 (m,
H), 7.32 (d, J ) 7.5 Hz, 2H), 7.29 (t, J ) 7.3 Hz, 1H), 5.23 (s,
(
2
1
2
3
.44 (s, 3H); 13C NMR (CDCl
34.9, 133.6, 131.2, 129.6, 128.6, 128.2, 126.5, 124.2, 61.0, 36.1,
1.6; MS (ESI) m/z 391.3 [M + H]; HRMS calcd for C23
3
, 600 MHz) δ 161.7, 144.2, 140.6,
H), 1.59 (s, 9H); 13C NMR (acetone-d
, 600 MHz) δ 155.0, 150.2,
6
22 2 2
H N O S
37.8, 136.7, 134.8, 131.3, 130.5, 129.7, 129.1, 128.5, 126.2, 83.3,
9.8, 29.3; MS (ESI) m/z 378.3 [M + Na]; HRMS calcd for
91.1475, found 391.1467 [M + H].
1
1
5: colorless oil; H NMR (acetone-d
6
, 600 MHz) δ 8.54 (s,
C
19
H
21
N
3
O
4
356.1605, found 356.1593 [M + H].
1
7
1
2
H), 7.83 (d, J ) 7.8 Hz, 2H), 7.75 (d, J ) 6.9 Hz, 2H), 7.51-
.44 (m, 5H), 5.89-5.74 (m, 1H), 5.40-5.25 (m, 1H), 4.90 (br s,
H), 4.01-3.83 (m, 2H), 3.82-3.63 (m, 1H), 3.45-3.30 (m, 1H),
1
20: orange crystalline solid; mp 108-109 °C; H NMR (acetone-
d
6
, 600 MHz) δ 8.20 (d, J ) 7.8 Hz, 2H), 8.47 (br s, 1H), 7.83 (t,
.45 (s, 3H), 1.45-1.36 (m, 9H); 13C NMR (acetone-d
6
, 600 MHz)
J ) 8.4 Hz, 1H), 7.39-7.36 (m, 2H), 7.29-7.26 (m, 3H), 5.18 (s,
2
1
2
H), 1.55 (s, 9H); 13C NMR (acetone-d
37.3, 132.9, 132.2, 130.5, 129.9, 129.1, 128.2, 125.9, 83.7, 49.4,
9.3; MS (ESI) m/z 423.7 [M + Na]; HRMS calcd for C19
423.1281, found 423.1275 [M + Na].
6
, 600 MHz) δ 154.8, 151.5,
δ 155.9, 146.4, 137.8, 136.0, 132.9, 131.7, 130.6, 129.9 (d, J )
19.7 Hz), 81.1, 56.9, 45.2, 43.1, 29.5, 22.5; MS (ESI) m/z 478.3
20 4
H N -
[
4
M + Na]; HRMS calcd for C24
H
29
N
3
O
4
S 456.1952, found
, 600
NaO
6
56.1934 [M + H].
1
1
6: white solid; mp 149-150 °C; H NMR (acetone-d
6
MHz) δ 8.68 (s, 1H), 7.81-7.78 (m, 4H), 7.51-7.43 (m, 5H),
Acknowledgment. We warmly thank D. J. Tognarelli and
Jiejun Wu for their effort in generating some of the analytical
data for this project.
4
(
.33-4.27 (m, 1H), 4.14-3.98 (m, 2H), 2.92-2.69 (m, 2H), 2.43
s, 3H), 1.74-1.66 (m, 2H), 1.57-1.51 (m, 2H), 1.39 (s, 9H); 13
C
NMR (acetone-d
6
, 600 MHz) δ 161.0, 155.9, 146.3, 138.4, 136.1,
133.0, 131.7, 130.7, 129.8, 80.5, 60.8, 31.9, 29.5, 22.5; MS (ESI)
Supporting Information Available: H and 13C NMR data for
all prepared compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
1
m/z 349.2 [M - BOC]; HRMS calcd for C24
found 458.2099 [M + H].
31 3 4
H N O S 458.2108,
1
1
7: colorless oil; H NMR (CDCl
3
, 600 MHz) δ 7.70 (d, J )
8.1 Hz, 2H), 7.56 (d, J ) 8.3 Hz, 2H), 7.36-7.34 (m, 2H), 7.28-
JO061185G
7
116 J. Org. Chem., Vol. 71, No. 18, 2006