Regioselective passerini and passerini-knoevenagel reactions with vic-diketo amides

Article abstract of DOI:10.1002/ejoc.201301548

The Passerini reaction of vic-diketo amides with a variety of isocyanides and carboxylic acids has been examined. α-Acyloxy β-keto carboxamides were formed regioselectively as the major products. For the Passerini reactions with electron-withdrawing-group-substituted acetic acids, a one-pot Passerini-Knoevenagel reaction was accomplished by the addition of triethylamine. vic-Diketo amides react with a variety of isocyanides and carboxylic acids in a regioselective Passerini three-component reaction (P-3CR) to give good to excellent yields of α-acyloxy-β-keto-carboxamides. In the case of Passerini reactions with electron-withdrawing-group-substituted acetic acids, a one-pot Passerini-Knoevenagel reaction was accomplished by the addition of triethylamine. Copyright

Full text of DOI:10.1002/ejoc.201301548

FULL PAPER
DOI: 10.1002/ejoc.201301548
Regioselective Passerini and Passerini–Knoevenagel Reactions with vic-Diketo
Amides
Jan Roßbach,[a] Klaus Harms,[a] and Ulrich Koert*[a]
Keywords: Synthetic methods / Multicomponent reactions / Regioselectivity / Aldol reactions
The Passerini reaction of vic-diketo amides with a variety of
isocyanides and carboxylic acids has been examined.
α-Acyloxy β-keto carboxamides were formed regioselectively
as the major products. For the Passerini reactions with elec-
tron-withdrawing-group-substituted acetic acids, a one-pot
Passerini–Knoevenagel reaction was accomplished by the
addition of triethylamine.
aldehydes,[16–20] 2-oxoacetates and 2-oxoacetamides,[21] α-
keto esters,[22,23] trifluoro-2-oxopropanoates,[24] and 2-oxo-
β-lactams.[25] In these examples, reactivity is a question of
chemoselectivity. Of the α-diketones 5, only symmetrical
starting materials have been used, i.e., benzil,[26–28] butane-
dione,[28] and 1,4-dibromobutanedione.[29] The reaction of
a symmetrical diketone 5 with an acid 2 and an isocyanide 3
leads to an α-acyloxycarboxamide 6. To the best of our
knowledge, the regioselectivity of the Passerini reaction in-
volving α-dicarbonyl compounds has not been investigated.
The symmetrical indan-1,2,3-trione is the only example of a
vic-tricarbonyl compound that has been used in a Passerini
reaction.[30] The potential of α-dicarbonyl Passerini reac-
tions extends to the formation of heterocycles, i.e., ox-
azoles,[17] pyrrolidine-2,4-diones,[29] and butenolides. Cycli-
zation of butenolides has been achieved by Knoevenagel
condensation,[18] Aldol condensation,[19,28] Dieckmann con-
densation,[23] or Horner–Wadsworth–Emmons (HWE) ole-
fination.[20]
Introduction
Multicomponent reactions[1] are useful tools for
medicinal chemistry[2,3] and diversity-oriented synthesis
(DOS).[4–6] Their discovery dates back to the mid-19th cen-
tury. Chronologically, the Strecker reaction (1837,[7] 1850[8])
was followed by Hantzsch dihydropyridine synthesis
(1882),[9] Biginelli reaction (1891),[10] and Mannich reaction
(1903,[11] 1912[12]). The first isocyanide-based multicompo-
nent reaction (IMCR) was discovered by Passerini in
1921.[13] The reaction of an aldehyde 1, a carboxylic acid 2,
and an isocyanide 3 to give an α-acyloxycarboxamide 4 is
called the Passerini three-component reaction (P-3CR)
(Scheme 1). Ugi expanded this reaction by the addition of
an amine to give a four component reaction leading to α-
acylaminocarboxamides.[14] The development of IMCRs
has had a strong impact on combinatorial chemistry.[15]
Vicinal tricarbonyl compounds offer the chance for
multifunctionalization, and if a regioselective functionaliza-
tion can be achieved, they would have considerable poten-
tial as synthetic building blocks. The addition of nucleo-
philes to unsymmetrical acyclic vic-tricarbonyl compounds
has, to date, been limited to O- and N-nucleophiles.[31,32]
Stereoselective additions of C-nucleophiles have only been
investigated with symmetrical vic-tricarbonyl compounds,
in particular diethyl ketomalonate[33–37] or for an intramo-
lecular aldol reaction.[38] Recently, we showed that the re-
gio- and diastereoselective alkylation of diketo amides and
diketo esters is possible by using crotylboration reac-
tions.[39] The reaction of a diketo amide 7 with (E)-crotyl-
boronate 8 resulted in an attack of the nucleophile at the β-
keto group, and the diastereoselective formation of homo-
allylic alcohol 9 (Scheme 2). A Passerini reaction of a diketo
amide 7 could lead to two regioisomeric α-acylamino-carb-
oxamides. An attack at the α-keto group would result in the
Scheme 1. The use of aldehydes and vic-dicarbonyl compounds in
the Passerini reaction.
As well as ketones and aldehydes, the Passerini reaction
has been applied to vic-dicarbonyl compounds, i.e., α-keto
[a] Fachbereich Chemie, Philipps-Universität Marburg,
Hans-Meerwein-Straße 4, 35043 Marburg, Germany
E-mail: koert@chemie.uni-marburg.de
www.uni-marburg.de/fb15/ag-koert
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301548.
Eur. J. Org. Chem. 2014, 993–1006
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
993

J. Roßbach, K. Harms, U. Koert
FULL PAPER
formation of compound 10, while attack at the β-keto Table 1. Passerini three-component reaction of vic-diketo amides 7
with aliphatic carboxylic acids and tert-butyl isocyanide.
group would produce compound 11. In this paper we pres-
ent the results of a study on the Passerini reaction of vic-
tricarbonyl compounds of type 7.
Entry
7
RЈ
Solvent
Time
[h]
14, yield
14/15[b]
[%][a]
1
2
3
4
5
6
7
8
7a
7a
7a
7a
7b
7b
7b
7b
Me
Me
iPr
tBu
Me
Me
iPr
toluene
CH2Cl2
CH2Cl2
CH2Cl2
toluene
CH2Cl2
CH2Cl2
CH2Cl2
2
2
14a, 82[c]
14a, 85[d]
14b, 89[e]
14c, 91[f]
14d, 92
86:14
90:10
91:9
92:8
92:8
94:6
95:5
94:6
16
17
1 h
0.5
3.5
1.7
14d, 92
14e, 81
tBu
14f, 94[g]
[a] Isolated yield of α-Passerini product 14. [b] Determined from
the 1H NMR spectrum of the crude material. [c] 96% of an iso-
meric mixture of 14a and 15a; 85:15 ratio. [d] 95% of an isomeric
mixture of 14a and 15a; 89:11 ratio. [e] 98% of an isomeric mixture
of 14a and 15b; 91:9 ratio. [f] 99% of an isomeric mixture of 14c
and 15c; 92:8 ratio. [g] 99% of an isomeric mixture of 14f and 15f;
95:5 ratio.
Scheme 2. vic-Diketo amides as starting materials for the Passerini
reaction.
Results and Discussion
The synthesis of the vic-diketo amides ideally starts from
the corresponding β-keto amide (i.e., 12; Scheme 3).[30,31]
Reliable procedures for the conversion of the keto amide
into the tricarbonyl compound include the oxidative cleav-
age of α-methylene derivatives,[40] direct oxidation,[41,42] and
the use of α-diazo β-dicarbonyl compounds.[43] In our
hands, this last method gave the best results. For diketo
amides 12, Regitz diazo transfer using p-acetamidobenz-
enesulfonyl azide (p-ABSA) gave α-diazo β-keto amides 13.
Subsequent treatment with tert-butyl hypochlorite in formic
acid led, after distillation, to the desired tricarbonyl com-
pounds (i.e., 7).
Figure 1. X-ray structure of Passerini product 14a.
When vic-diketo amides are used in a Passerini reaction,
the remaining unreacted keto group may undergo further
subsequent transformations. For carboxylic acids bearing
an electron-withdrawing group (EWG), an aldol condensa-
tion of the Knoevenagel type could lead to butenolides as
final products (Scheme 4). In an α-selective Passerini reac-
tion of a vic-diketo amide 7, the initial product (i.e., 16)
could undergo a subsequent aldol condensation to give but-
Scheme 3. Synthesis of vic-diketo amides 7.
Treatment of vic-diketo amides 7 with different aliphatic
carboxylic acids and tert-butyl isocyanide yielded Passerini
products 14 and 15 with a high regioselectivity in favour of
compound 14; compound 14 results from an α-addition to
the α-keto group (Table 1). The structural assignment of
Passerini product 14a was done using an X-ray structure
(Figure 1).[46]
Scheme 4. Passerini reaction and subsequent aldol condensation.
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Passerini Reactions with vic-Diketo Amides
Table 2. Passerini reaction of vic-diketo amides with α-EWG-sub- Knoevenagel-type aldol condensation products 20 and 21
stituted acetic acid derivatives and tert-butyl isocyanide.
were formed under these conditions.
For chloroacetic acid (Table 2, entry 6), the initial Pass-
erini product (i.e., 18d) could be isolated, and this com-
pound was subjected to
a separate aldol reaction
(Scheme 5). Using LiHMDS (lithium hexamethyldisilazide)
as base, chlorohydrin 22 was obtained in an intramolecular
aldol addition. X-ray-structural analysis of compound 22
revealed the cis configuration of the chlorohydrin (see Sup-
porting Information).[46] Attempts to obtain epoxides from
the haloacetic-acid-derived Passerini products in a Darzens-
type reaction were unsuccessful, probably due to the cis
configuration of the halohydrins.
Entry
7
EWG
Solvent
Time
[h]
18, yield 18:19[b]
[%][a]
Scheme 5. Intramolecular aldol addition of Passerini product 18d
to give 22.
1
2
3
4
5
6
7
8
7a CO2Me
7a CO2Me
7a Ts
toluene
CH2Cl2
toluene
CH2Cl2
0.25 18a, 86[c] 98:2
0.5
1.5
1.8
17
17
18
0.7
0.8
0.3
0.5
17
18a, 89[d] 98:2
18b, 97
18b, 99
18c, 75
99:1
99:1
n.d.
To promote the formation of the Knoevenagel-type aldol
condensation products, the addition of base in a one-pot
fashion was examined. Triethylamine was found to promote
the aldol condensation to form butenolides 20 and 21 di-
rectly (Table 3). α-Knoevenagel products 20 were obtained
as the major products when EWG = CO2Me, Ts, and
PO(OEt)2 (Table 3, entries 3–7 and 10–12). The structural
assignment of the Passerini–Knoevenagel product 20f was
done using an X-ray structure (Figure 2).[46] For cyanoace-
tic acid, the addition of a base was not necessary for the
formation of the aldol condensation product (Table 3, en-
tries 1, 2, 8, and 9).
The isocyanide component was varied using several com-
mercially available isocyanides. Keto isocyanide 24 was syn-
thesized by dehydration of amide 23 (Scheme 6).
For vic-diketo amide 7b and acetic acid as the carboxylic
acid, Passerini products 26 were formed with various iso-
cyanides in very good yields and with very good α-selectivi-
7a Ts
7a PO(OEt)2 CH2Cl2
7a Cl
CH2Cl2
CH2Cl2
toluene
CH2Cl2
toluene
CH2Cl2
18d, 85[e] 86:14
7a Br
18e, 87[f]
18f, 64[g]
18f, 84
87:13
88:12
89:11
7b Ts
9
7b Ts
10
11
12
7b CO2Me
7b CO2Me
18g, 60[h] 90:10
18g, 82[i]
18h, 88[j]
91:9
93:7
7b PO(OEt)2 CH2Cl2
[a] Isolated yield of α-Passerini product 18. [b] Determined from
1
the H NMR spectrum of the crude material. [c] 97% of a mixture
of 18a and 20a; 89:11 ratio. [d] 98% of a mixture of 18a and 20a;
91:9 ratio. [e] 99% of an isomeric mixture of 18d and 19d; 86:14
ratio. [f] 99% of an isomeric mixture of 18e and 19e; 87:13 ratio.
[g] 88% of a mixture of 18f and 20f; 73:27 ratio. [h] 87% of a mix-
ture of 18g and 20g; 69:31 ratio. [i] 89% of a mixture of 18g and
20g; 91:9 ratio. [j] Compound 19h was also formed in 4.5% yield.
n.d.: not determined.
enolide 17. The Passerini product resulting from attack at ties (Table 4). No by-products were observed with the more
the β-position could also lead to a related aldol condensa- acidic isocyanides (Table 4, entries 2–4). Aryl isocyanides
tion product.
gave results comparable to those obtained with alkyl iso-
Different EWG-substituted acetic acids were examined in cyanides.
Passerini reactions using tert-butyl isocyanide and various
The successful use of keto isocyanide 24 in a Passerini
vic-diketo amides (Table 2). For EWG = CO2Me and p- reaction is noteworthy. The short 1,4-distance between the
TolSO2 (Ts), Passerini products 18a and 18b were isolated ketone and the isocyanide group prevents an intramolecular
in very good yields and with excellent α-selectivities when α-addition. Only the intermolecular Passerini product (i.e.,
diketodimethylamide 7a was used (Table 2, entries 1–4). 26f) was formed in excellent yield.
The structural assignment of Passerini product 18g was
Passerini–Knoevenagel products 27 were formed in a
done using an X-ray structure (see Supporting Infor- three-component reaction of various isocyanides with vic-
mation).[46] Lower α-selectivities were obtained for the diketo amide 7b and cyanoacetic acid (Table 5). Lower
morpholino diketo amide 7b (Table 2, entries 8–11). With yields were seen with more acidic isocyanides (Table 5, en-
halo-substituted acetic acids, isomeric mixtures were ob- tries 2 and 3), but the formation of by-products was not
served (Table 2, entries 6 and 7). Only minor amounts of observed.
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995

J. Roßbach, K. Harms, U. Koert
FULL PAPER
Figure 2. X-ray structure of Passerini–Knoevenagel product 20f.
Table 4. Passerini three-component reaction of vic-diketo amide 7b
with acetic acid and various isocyanides.
Table 3. The base-promoted Passerini–Knoevenagel reaction of vic-
diketo amides with α-EWG-substituted acetic acid derivatives.
Entry
R
Reaction time Product, isolated yield
[h]
[%]
1
2
3
4
5
6
7
tBu
CH2Ts
CH2CO2Me
CH2PO(OEt)2
2-naphthyl
4-MeO-C6H4
(CH2)2COMe
0.5
24
20
24
21.5
21
14d, 92
26a, 92
26b, 87
26c, 100
26d, 97
26e, 100
26f, 99
Entry
7
EWG
Solvent Time 20, yield
20/21[b]
[h]
[%][a]
16
1[c]
2[c]
3
4
5
7a CN
7a CN
7a CO2Me
7a CO2Me
7a Ts
7a Ts
7a PO(OEt)2 CH2Cl2 24
toluene
CH2Cl2
toluene
CH2Cl2 1.2
toluene
CH2Cl2 2.2
2
2
1
20a, 82[d]
20a, 66[e]
20b, 75[f]
20b, 82[g]
20c, 58[h]
20c, 55[i]
20d, 37[j]
20e, 87
92:8
91:9
75:25
88:12
72:28
72:28
86:14[k]
99:1
Table 5. Passerini–Knoevenagel reaction of vic-diketo amide 7b
with cyanoacetic acid and various isocyanides.
2
6
7
8[c]
9[c]
10
11
12
7b CN
7b CN
7b CO2Me
7b Ts
toluene 1.2
CH2Cl2 0.9
CH2Cl2
20e, 86
99:1
2
20f, 81
90:10
78:22
81:19[k]
CH2Cl2 3.83
20g, 31[l]
20h, 18[m]
7b PO(OEt)2 CH2Cl2 24
[a] Isolated yield of α-Passerini–Knoevenagel product 20. [b] Deter-
1
mined from the H NMR spectrum of the crude material. [c] With
Entry
R
Reaction time Product, isolated yield
cyanoacetic acid, no base was added. [d] 90% of an isomeric mix-
ture of 20a and 21a; 91:9 ratio. [e] 72% of an isomeric mixture of
20a and 21a; 92:8 ratio. [f] Compound 21b was also formed in 17%
yield. [g] Compound 21b was also formed in 12% yield. [h] 78% of
an isomeric mixture of 20c and 21c; 74:26 ratio. [i] 74% of an iso-
meric mixture of 20c and 21c; 74:26 ratio. [j] β-Passerini–HWE
product 28a was also formed in 6% yield. [k] Based on isolated
yields. [l] 36% of the isomeric mixture of 20g/21g 87:13. [m] β-Pass-
erini–HWE product 28b (6%) and α-Passerini–HWE product 29
(7%) were also formed.
[h]
[%]
1
2
3
4
5
6
7
tBu
CH2Ts
CH2CO2Me
CH2PO(OEt)2
2-naphthyl
4-MeO-C6H4
(CH2)2COMe
0.9
24
23
24
23
23
16
20e, 86
27a, 57
27b, 64
27c, 82
27d, 66
27e, 75
27f, 80
Conclusions
In summary, the Passerini reaction of vic-diketo amides
with a variety of isocyanides and carboxylic acids leads to
α-acyloxy-β-keto-carboxamides with high α-regioselectively.
A one-pot Passerini–Knoevenagel reaction is possible if
Scheme 6. Synthesis of keto isocyanide 24.
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Passerini Reactions with vic-Diketo Amides
190.7 (C-3), 161.9 (C-1), 73.4 (C-2), 37.5 [2 C, N(CH3)2], 27.4 (C-
EWG-substituted acetic acids are used as substrates. For
cyanoacetic acid, the aldol condensation occurs spontane-
ously, while for other EWG-substituted acetic acids, the
presence of a base such as triethylamine is necessary. The
α-acyloxy-β-keto-carboxamides and butenolides obtained
by this new method could be used as intermediates in the
synthesis of complex target molecules. Besides vic-diketo
amides, other vic-tricarbonyl compounds should be good
substrates for this type of multicomponent reaction.
4) ppm. FTIR (neat): ν = 2930 (w), 2099 (s), 1623 (s), 1492 (m),
˜
1442 (m), 1385 (s), 1361 (s), 1260 (s), 1227 (s), 1140 (m), 1049 (m),
963 (m), 892 (w), 847 (w), 733 (m), 685 (w), 634 (m), 607 (m),
546 (w), 517 (m), 471 (w), 440 (w) cm–1. HRMS (ESI): calcd. for
C6H9N3O2Na [M + Na]+ 178.0587; found 178.0588.
2-Diazo-1-morpholinobutane-1,3-dione (13b): Following general
procedure A on a 29.2 mmol scale, 13b (5.76 g, 29.2 mmol, quant.)
was obtained as a yellow liquid. TLC (pentane/ethyl acetate, 1:1):
Rf = 0.31. 1H NMR (300 MHz, CDCl3): δ = 3.76–3.70 [m, 4 H,
O(CH2)2], 3.54–3.47 [m, 4 H, N(CH2)2], 2.33 (s, 3 H, 4-H3) ppm.
13C NMR (62.9 MHz, CD3CN): δ = 189.7 (C-3), 161.1 (C-1), 74.2
(C-2), 67.2 [2 C, O(CH2)2], 46.5 [2 C, N(CH2)2], 27.3 (C-4) ppm.
Experimental Section
FTIR (neat): ν = 2968 (w), 2923 (w), 2858 (w), 2105 (s), 1620 (s),
˜
General Remarks: All non-aqueous reactions were carried out using
flame-dried glassware under an argon atmosphere. All solvents
were distilled by rotary evaporation prior to use. Solvents for non-
aqueous reactions were dried as follows before use: dichlorometh-
ane was distilled from CaH2 under an argon atmosphere. Toluene
was distilled from sodium under an argon atmosphere. HPLC-
grade acetonitrile was used as supplied. All commercially available
reagents and reactants were used without purification unless other-
wise noted. Reactions were monitored by thin-layer chromatog-
raphy (TLC) using Merck Silica Gel 60 F245 plates, which were
visualized by fluorescence quenching under UV light. In addition,
TLC plates were stained using cerium sulfate/phosphomolybdic
acid or potassium permanganate stains. Chromatographic purifica-
tion of products was carried out on Machery–Nagel Silica 60 M
(230–400 mesh) unless otherwise noted, using a forced flow of elu-
ent. Concentration under reduced pressure was carried out by ro-
tary evaporation at 40 °C and appropriate pressure, and by expos-
ing to high vacuum at room temperature if necessary. IR spectra
were recorded with a Bruker Alpha FTIR interferometer. The ab-
sorption bands are given in wavenumbers (cm–1), and intensities
are reported as follows: s = strong, m = medium, w = weak, br. =
broad band. NMR spectra were recorded with Bruker DPX-250,
AV-300, DRX-400, DRX-500, AV-500, and AV-600 spectrometers
at ambient temperature. Chemical shifts are reported in ppm, and
the solvent resonance was used as an internal standard (C1HCl3:
δ = 7.26 ppm; C1HD2COCD3: δ = 2.05 ppm; 13CDCl3: δ =
1419 (s), 1361 (m), 1247 (s), 1192 (m), 1111 (s), 1068 (m), 1015 (m),
961 (m), 925 (w), 878 (m), 836 (m), 752 (m), 670 (w), 626 (m),
582 (m), 549 (w), 518 (m), 445 (w) cm–1. HRMS (ESI): calcd. for
C8H11N3O3Na [M + Na]+ 220.0693; found 220.0694.
Preparation of 2,3-Dioxobutanamides 7a and 7b. General Procedure
B: tert-Butyl hypochlorite (1.10 equiv.) was added by syringe to a
solution of the diazo compound (1.00 equiv.) in formic acid (1 mL/
0.3 mmol) at 0 °C. After the bubbling had ceased, the mixture was
allowed to warm to ambient temperature, and the solvent was evap-
orated under reduced pressure. The crude product was purified by
bulb-to-bulb distillation.
N,N-Dimethyl-2,3-dioxobutanamide (7a): Following general pro-
cedure B on a 3.22 mmol scale, 7a (461 mg, 3.22 mmol, quant.) was
1
obtained as a yellow solid. H NMR (300 MHz, CDCl3): δ = 3.03
(s, 3 H, NCH3), 2.95 (s, 3 H, NCH3), 2.46 (s, 3 H, 4-H3) ppm. 13C
NMR (75 MHz, CDCl3): δ = 197.6 (C-3), 184.9 (C-2), 165.6 (C-1),
36.7 (NC H ), 34.2 (NC H ), 24.6 (C-4) ppm. FTIR (neat): ν =
˜
a
3
b
3
2939 (w), 1715 (s), 1645 (s), 1506 (w), 1448 (w), 1405 (m), 1357 (m),
1271 (w), 1164 (w), 1035 (m), 954 (w), 868 (m), 767 (w), 735 (w),
692 (w), 657 (w), 631 (w), 591 (m), 501 (m), 436 (w) cm–1. HRMS
(ESI): calcd. for C6H10NO3 [M + H]+ 144.0655; found 144.0656.
1-Morpholinobutane-1,2,3-trione (7b): Following general procedure
B on a 2.53 mmol scale, 7b (469 mg, 2.53 mmol, quant.) was ob-
tained as a yellow solid. TLC (pentane/ethyl acetate, 1:1): Rf = 0.43.
1H NMR (500 MHz, CDCl3): δ = 3.76–3.73 (m, 2 H, OCH2), 3.71–
3.65 (m, 4 H, OCH2, NCH2), 3.37–3.33 (m, 2 H, NCH2), 2.46 (s,
3 H, 4-H3) ppm. 13C NMR (75 MHz, CDCl3): δ = 197.5 (C-3),
184.6 (C-2), 164.2 (C-1), 66.7 (OCH2), 66.5 (OCH2), 46.1 (NCH2),
77.16 ppm; (CD3)213CO:
δ = δ =
206.26 ppm; CD313CN:
118.26 ppm). Data are reported as follows: s = singlet, d = doublet,
t = triplet, sept = septet, m = multiplet. Mass spectra were recorded
with a Finnigan LTQ-FT or a QStar-Pulsar i instrument (both op-
erated by the mass spectroscopy service of the Philipps University
of Marburg). Melting points were determined by using a capillary
with a Stuart SMP10 device.
42.0 (NCH ), 24.5 (C-4) ppm. FTIR (neat): ν = 2972 (w), 2923 (w),
˜
2
2860 (w), 1716 (m), 1640 (s), 1442 (m), 1358 (m), 1272 (m),
1231 (w), 1193 (w), 1164 (w), 1111 (s), 1071 (m), 1012 (m), 954 (m),
923 (w), 834 (m), 733 (m), 582 (m), 502 (m), 474 (w), 437 (w) cm–1.
HRMS (ESI): calcd. for C8H11NO4Na [M + Na]+ 208.0580; found
208.0578.
Preparation of 2-Diazo-3-oxobutanamides 13a and 13b. General Pro-
cedure A: β-Keto amide (1.00 equiv.) and 4-acetamidobenzenesulf-
onyl azide (1.00 equiv.) were dissolved in acetonitrile (1 mL/
0.3 mmol), and triethylamine (1.10 equiv.) was added. The mixture
was stirred at ambient temperature for 16 h, then the solution was
filtered through a layered pad of sodium sulfate on silica gel, elut-
ing with ethyl acetate. The solvent was removed under reduced
pressure, and the crude product was suspended in dichloromethane.
The suspension was filtered through a layered pad of sodium sulf-
ate on silica gel, eluting with dichloromethane. The solvent was
removed under reduced pressure to give the diazo compound.
General Procedure C, Passerini Reaction: Diketo amide 7a or 7b
(1.00 equiv.) was dissolved in dichloromethane or toluene (final
concentration of 7a/7b: 0.30 m) at room temperature. The carbox-
ylic acid (1.20 equiv.) was added, followed by the isocyanide
(1.20 equiv.). The reaction mixture was stirred at room temperature
for the indicated time, then it was diluted with dichloromethane
(20 mL), and the mixture was washed with sodium hydrogen car-
bonate solution (saturated aq.; 20 mL). The phases were separated,
and the aqueous phase was extracted with dichloromethane (2ϫ
20 mL). The combined organic extracts were dried with sodium
sulfate, and the solvent was evaporated under reduced pressure.
2-Diazo-N,N-dimethyl-3-oxobutanamide (13a): Following general
procedure A on a 38.7 mmol scale, 13a (6.01 g, 38.7 mmol, quant.)
was obtained as a yellow liquid. TLC (pentane/ethyl acetate, 1:1):
1
Rf = 0.24. H NMR (300 MHz, CDCl3): δ = 3.01 [s, 6 H, N(CH3) The crude product was purified by column chromatography on sil-
2], 2.35 (s, 3 H, 4-H3) ppm. 13C NMR (62.9 MHz, CD3CN): δ =
ica (eluent indicated in each case).
Eur. J. Org. Chem. 2014, 993–1006
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
997

J. Roßbach, K. Harms, U. Koert
FULL PAPER
1-(tert-Butylamino)-2-(dimethylcarbamoyl)-1,3-dioxobutan-2-yl
Acetate (14a): Following general procedure C in toluene or dichlo-
romethane on a 0.80 mmol scale using 7a, after a reaction time of
2 h, and using pentane/ethyl acetate, 2:1 as eluent, 14a was isolated
as a mixture of 14a and 15a (in toluene: 220 mg, 0.76 mmol, 96%,
85:15 14a/15a; in dichloromethane: 217 mg, 0.76 mmol, 95%, 89:11
14a/15a) as a colourless solid. TLC (pentane/ethyl acetate, 3:1): Rf
ene: 191 mg, 0.58 mmol, 92 %; dichloromethane: 163 mg,
0.50 mmol, 92%) was isolated as a colourless solid. TLC (pentane/
ethyl acetate, 2:1): Rf = 0.18; m.p. 136 °C (pentane). 1H NMR
(500 MHz, CDCl3): δ = 7.46 (s, 1 H, NH), 4.00–3.32 [m, 8 H,
N(C2H4)2O], 2.31 (s, 3 H, 4-H3), 2.30 (s, 3 H, CH3CO2), 1.40 [s, 9
H, C(CH3)3] ppm. 13C NMR (150 MHz, CDCl3): δ = 197.7 (C-3),
168.8 (CO2), 163.1 [2-CON(C2H4)2O], 161.1 (C-1), 87.9 (C-2), 66.8
(OCH2), 66.6 (OCH2), 52.3 [C(CH3)3], 46.9 (NCH2), 43.8 (NCH2),
1
= 0.12; m.p. 105 °C (ethyl acetate). H NMR (400 MHz, CDCl3):
δ = 7.56 (s, 1 H, NH), 3.04 (s, 3 H, NCH3), 2.96 (s, 3 H, NCH3), 28.5 [3 C, C(CH3)3], 25.9 (C-4), 20.8 (CH3CO2) ppm. FTIR (neat):
2.30 (s, 3 H, 4-H3), 2.28 (s, 3 H, CH3CO2), 1.35 [s, 9 H, C(CH3)3]
ν = 3358 (w), 3328 (w), 2976 (w), 2856 (w), 1772 (w), 1712 (m),
˜
ppm. 13C NMR (100 MHz, CDCl3): δ = 197.9 (C-3), 168.8 (CO2), 1687 (s), 1657 (s), 1586 (w), 1516 (m), 1480 (m), 1430 (m),
164.8 (2-CONMe2), 161.2 (C-1), 88.3 (C-2), 52.3 [C(CH3)3], 37.6 1367 (m), 1298 (m), 1272 (m), 1241 (s), 1202 (s), 1108 (s), 1044 (m),
(NCH3), 37.4 (NCH3), 28.6 [3 C, C(CH3)3], 25.9 (C-4), 20.8 986 (m), 929 (w), 895 (m), 869 (w), 822 (m), 783 (w), 758 (w),
(CH CO ) ppm. FTIR (neat): ν = 3363 (w), 2969 (w), 2934 (w), 729 (w), 667 (w), 609 (s), 589 (m), 532 (m), 461 (m) cm–1. HRMS
˜
3
2
1759 (m), 1732 (m), 1692 (s), 1644 (s), 1527 (m), 1456 (m), (ESI): calcd. for C15H24N2O6Na [M + Na]+ 351.1527; found
1394 (m), 1365 (m), 1218 (s), 1100 (m), 1062 (w), 1029 (w), 991 (w), 351.1524.
897 (w), 847 (w), 823 (w), 753 (s), 666 (w), 603 (w), 574 (w),
1-(tert-Butylamino)-2-(morpholinocarbonyl)-1,3-dioxobutan-2-yl
Isobutyrate (14e): Following general procedure C in dichlorometh-
ane on a 0.57 mmol scale using 7b, after a reaction time of 3.5 h,
531 (m), 461 (w), 430 (w), 405 (w) cm–1. HRMS (ESI): calcd. for
C13H22N2O5Na [M + Na]+ 309.1421; found 309.1422.
1-(tert-Butylamino)-2-(dimethylcarbamoyl)-1,3-dioxobutan-2-yl Iso-
butyrate (14b): Following general procedure C in dichloromethane
on a 0.73 mmol scale using 7a, after a reaction time of 16.2 h, and
using chloroform as eluent, 14b was isolated as a mixture of 14b
and 15b (226 mg, 0.72 mmol, 98%, 91:9 14b/15b) as a colourless
liquid. TLC (pentane/ethyl acetate, 2:1): Rf = 0.31. 1H NMR
(300 MHz, CDCl3): δ = 7.53 (s, 1 H, NH), 3.02 (s, 3 H, NCH3),
and using pentane/ethyl acetate, 2:1 as eluent, 14e (163 mg,
0.46 mmol, 81%) was isolated as a colourless solid. TLC (pentane/
ethyl acetate, 2:1): Rf = 0.27; m.p. 68 °C. 1H NMR (300 MHz,
CDCl3): δ = 7.38 (s, 1 H, NH), 3.99–3.20 [m, 8 H, N(C2H4)2O],
2.71 (sept, J = 7.0 Hz, 1 H, CHCO2), 2.17 (s, 3 H, 4-H3), 1.29 [s,
9 H, C(CH3)3], 1.23 [d, J = 7.0 Hz, 6 H, CH(CH3)2] ppm. 13C
NMR (75 MHz, CDCl3): δ = 197.7 (C-3), 174.5 (CO2), 163.1 [2-
2.93 (s, 3 H, NCH3), 2.76 (sept, J = 7.0 Hz, 1 H, CHCO2), 2.25 (s, CON(C2H4)2O], 161.1 (C-1), 87.3 (C-2), 66.6 [2 C, O(CH2)2], 52.1
3 H, 4-H3), 1.32 [s, 9 H, C(CH3)3], 1.27 [d, J = 7.0 Hz, 6 H, [C(CH3)3], 46.8 (NCH2), 43.7 (NCH2), 33.9 (CHCO2), 28.4 [3 C,
CH(CH3)2] ppm. 13C NMR (75 MHz, CDCl3): δ = 198.0 (C-3), C(CH3)3], 25.7 (C-4), 18.7 (CH3CH), 18.7 (CH3CH) ppm. FTIR
174.6 (CO2), 164.9 (2-CONMe2), 161.2 (C-1), 87.8 (C-2), 52.1 (neat): ν = 3346 (w), 2972 (w), 2929 (w), 2862 (w), 1732 (m),
˜
[C(CH3)3], 37.6 (NCH3), 37.3 (NCH3), 34.0 (CHCO2), 28.5 [3 C,
1693 (s), 1642 (s), 1532 (m), 1436 (m), 1392 (w), 1360 (m), 1300 (w),
C(CH3)3], 25.8 (C-4), 18.9 (CHCH3), 18.8 (CHCH3) ppm. FTIR 1272 (m), 1244 (m), 1192 (m), 1111 (s), 1022 (w), 977 (w), 915 (w),
(neat): ν = 3384 (w), 2973 (w), 2935 (w), 2879 (w), 2114 (w), 848 (w), 805 (w), 733 (m), 646 (w), 586 (m), 538 (w), 458 (w),
˜
1732 (s), 1695 (s), 1644 (s), 1530 (s), 1460 (m), 1392 (m), 1360 (m), 419 (w) cm–1. HRMS (APCI): calcd. for C17H28N2O6Na [M +
1253 (m), 1222 (m), 1184 (s), 1132 (s), 1097 (s), 1056 (m), 989 (w),
915 (w), 883 (w), 854 (w), 820 (w), 737 (w), 681 (w), 651 (w),
581 (w), 538 (m), 461 (w), 415 (w) cm–1. HRMS (APCI): calcd. for
C15H26N2O5Na [M + Na]+ 337.1734; found 337.1725.
Na]+ 379.1840; found 379.1832.
1-(tert-Butylamino)-2-(morpholinocarbonyl)-1,3-dioxobutan-2-yl
Pivalate (14f): Following general procedure C in dichloromethane
on a 0.59 mmol scale using 7b, after a reaction time of 100 min,
and using pentane/ethyl acetate, 3:1 as eluent, 14f was isolated as
a mixture of 14f and 15f (218 mg, 0.59 mmol, 99%, 95:5 14f/15f)
as a colourless liquid. TLC (pentane/ethyl acetate, 3:1): Rf = 0.28.
1H NMR (300 MHz, CDCl3): δ = 7.40 (s, 1 H, NH), 3.95–3.25 [m,
8 H, N(C2H4)2O], 2.14 (s, 3 H, 4-H3), 1.28 [s, 9 H, NHC(CH3)3],
1.25 [s, 9 H, (CH3)3CCO2] ppm. 13C NMR (75 MHz, CDCl3): δ =
197.7 (C-3), 176.0 (CO2), 163.1 [2-CON(C2H4)2O], 161.0 (C-1),
1-(tert-Butylamino)-2-(dimethylcarbamoyl)-1,3-dioxobutan-2-yl Piv-
alate (14c): Following general procedure C in dichloromethane on
a 0.73 mmol scale using 7a, after a reaction time of 16.7 h, and
using chloroform as eluent, 14c was isolated as a mixture of 14c
and 15c (239 mg, 0.73 mmol, 99%, 92:8 14c/15c) as a colourless
solid. TLC (pentane/ethyl acetate, 3:1): Rf = 0.31; m.p. 54 °C (chlo-
1
roform). H NMR (300 MHz, CDCl3): δ = 7.54 (s, 1 H, NH), 3.02
(s, 3 H, NCH3), 2.93 (s, 3 H, NCH3), 2.24 (s, 3 H, 4-H3), 1.31 [s, 9 87.1 (C-2), 66.6 [2 C, O(CH2)2], 52.0 [NHC(CH3)3], 46.8 (NCH2),
H, NHC(CH3)3], 1.31 [s, 9 H, (CH3)3CCO2] ppm. 13C NMR 43.7 (NCH2), 38.8 [(CH3)3CCO2], 28.4 [3 C, NHC(CH3)3], 27.0 [3
(75 MHz, CDCl3): δ = 198.0 (C-3), 176.0 (CO2), 165.0 (2-
CONMe2), 161.2 (C-1), 87.6 (C-2), 52.0 [NHC(CH3)3], 39.0
[(CH3)3CCO2], 37.6 (NCH3), 37.2 (NCH3), 28.5 [3 C, NHC-
C, (CH ) CCO ], 25.6 (C-4) ppm. FTIR (neat): ν = 2970 (w),
˜
3 3 2
2926 (w), 2862 (w), 1738 (m), 1694 (m), 1643 (s), 1534 (m),
1436 (m), 1396 (w), 1362 (m), 1275 (m), 1243 (m), 1193 (w),
1115 (s), 1023 (w), 976 (w), 930 (w), 885 (w), 854 (w), 767 (w),
(CH ) ], 27.2 [3 C, (CH ) CCO ], 25.8 (C-4) ppm. FTIR (neat): ν =
˜
3 3
3 3
2
2971 (w), 2934 (w), 2876 (w), 1737 (m), 1695 (s), 1645 (s), 1532 (m), 733 (m), 692 (w), 648 (w), 589 (m), 541 (w), 452 (w) cm–1. HRMS
1484 (w), 1457 (m), 1394 (m), 1362 (m), 1277 (w), 1222 (w),
1174 (m), 1126 (s), 1062 (w), 1029 (w), 988 (w), 897 (w), 837 (w),
799 (w), 766 (w), 733 (w), 688 (w), 650 (w), 583 (w), 539 (w),
452 (w), 403 (w) cm–1. HRMS (APCI): calcd. for C16H28N2O5Na
[M + Na]+ 351.1890; found 351.1881.
(ESI): calcd. for C18H30N2O6Na [M + Na]+ 393.1996; found
393.1994.
1-(tert-Butylamino)-2-(dimethylcarbamoyl)-1,3-dioxobutan-2-yl
Methyl Malonate (18a): Following general procedure C in toluene
on a 0.68 mmol scale, or in dichloromethane on a 0.65 mmol scale,
1-(tert-Butylamino)-2-(morpholinocarbonyl)-1,3-dioxobutan-2-yl using 7a, after a reaction time of 15 min (toluene) or 30 min
Acetate (14d): Following general procedure C in toluene on a
0.63 mmol scale, or in dichloromethane on a 0.54 mmol scale, using
7b, after a reaction time of 55 min (toluene) or 30 min (dichloro-
methane), and using pentane/ethyl acetate, 2:1 as eluent, 14d (tolu-
(dichloromethane), and using pentane/ethyl acetate, 1:1 as eluent,
18a was isolated as a mixture of 18a and 20a (toluene: 225 mg,
0.66 mmol, 97 %, 89:11 18a/20a; dichloromethane: 218 mg,
0.64 mmol, 98%, 91:9 18a/20a) as a colourless liquid. TLC (pent-
998
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 993–1006

Passerini Reactions with vic-Diketo Amides
1
1
ane/ethyl acetate, 1:1): Rf = 0.28. H NMR (300 MHz, CDCl3): δ
112 °C (pentane). H NMR (600 MHz, CDCl3): δ = 7.45 (s, 1 H,
= 7.46 (s, 1 H, NH), 3.78 (s, 3 H, OCH3), 3.63 (s, 2 H, CH2), 3.01
NH), 4.29 (d, J = 14.8 Hz, 1 H, CH2CO2), 4.26 (d, J = 14.8 Hz, 1
(s, 3 H, NCH3), 2.97 (s, 3 H, NCH3), 2.35 (s, 3 H, 4-H3), 1.35 [s, 9 H, CH2CO2), 3.01 (s, 3 H, NCH3), 2.97 (s, 3 H, NCH3), 2.35 (s, 3
H, C(CH3)3] ppm. 13C NMR (75 MHz, CDCl3): δ = 197.2 (C-3), H, 4-H3), 1.35 [s, 9 H, C(CH3)3] ppm. 13C NMR (150 MHz,
166.5 (CO2), 164.2 (CO2), 163.9 (2-CONMe2), 160.8 (C-1), 89.2 (C-
2), 52.8 (OCH3), 52.3 [C(CH3)3], 41.2 (CH2CO2), 37.4 (NCH3),
CDCl3): δ = 197.0 (C-3), 165.1 (CO2), 164.2 (2-CONMe2), 160.5
(C-1), 89.3 (C-2), 52.5 [C(CH3)3], 40.5 (CH2CO2), 37.6 (NCH3),
37.3 (NCH ), 28.5 [3 C, C(CH ) ], 26.0 (C-4) ppm. FTIR (neat): ν 37.4 (NCH ), 28.5 [3 C, C(CH ) ], 26.0 (C-4) ppm. FTIR (neat): ν
˜
˜
3
3 3
3
3 3
= 3358 (w), 2967 (w), 1776 (m), 1734 (s), 1690 (s), 1648 (s), 1526 (s),
1447 (m), 1397 (m), 1358 (m), 1261 (m), 1213 (s), 1176 (s), 1139 (s), 1528 (m), 1495 (w), 1455 (w), 1401 (m), 1362 (m), 1321 (w),
1096 (s), 1015 (m), 903 (w), 840 (w), 797 (w), 755 (s), 676 (m), 1267 (w), 1218 (m), 1152 (s), 1095 (m), 1064 (w), 1027 (w), 990 (w),
= 3354 (w), 2969 (w), 1778 (m), 1736 (m), 1685 (s), 1639 (s),
582 (m), 531 (m), 460 (m), 402 (m) cm–1. HRMS (ESI): calcd. for 922 (w), 839 (w), 802 (w), 758 (w), 692 (w), 625 (w), 602 (m),
C15H25N2O7 [M + H]+ 345.1656; found 345.1654.
580 (m), 555 (m), 524 (w), 462 (w), 435 (w), 400 (w) cm–1. HRMS
(ESI): calcd. for C13H21ClN2O5Na [M + Na]+ 343.1031; found
343.1034.
1-(tert-Butylamino)-2-(dimethylcarbamoyl)-1,3-dioxobutan-2-yl 2-
Tosylacetate (18b): Following general procedure C in toluene on a
0.61 mmol scale, or in dichloromethane on a 0.68 mmol scale, using
7a, after a reaction time of 90 min (toluene) or 110 min (dichloro-
methane), and using pentane/ethyl acetate, 2:1 as eluent, 18b (tolu-
ene: 260 mg, 0.59 mmol, 97 %; dichloromethane: 296 mg,
0.67 mmol, 99%) was isolated as a colourless solid. TLC (pentane/
ethyl acetate, 1:1): Rf = 0.51; m.p. 58 °C (chloroform). 1H NMR
(300 MHz, CDCl3): δ = 7.82 (d, J = 8.3 Hz, 2 H, 2 Hortho), 7.38 (d,
1-(tert-Butylamino)-2-(dimethylcarbamoyl)-1,3-dioxobutan-2-yl 2-
Bromoacetate (18e): Following general procedure C in dichloro-
methane on a 0.80 mmol scale using 7a, after a reaction time of
18 h, and using chloroform as eluent, 18e was isolated as a mixture
of 18e and 19e (289 mg, 0.79 mmol, 99 %, 87:13 18e/19e) as a
colourless solid. TLC (pentane/ethyl acetate, 2:1): Rf = 0.33; m.p.
82 °C (pentane). 1H NMR (600 MHz, CDCl3): δ = 7.45 (s, 1 H,
br. s, J = 8.0 Hz, 2 H, 1 H, 2 Hmeta, NH), 4.34 (d, J = 14.5 Hz, 1 NH), 4.04 (s, 2 H, CH2CO2), 3.03 (s, 3 H, NCH3), 2.97 (s, 3 H,
H, CH2CO2), 4.20 (d, J = 14.5 Hz, 1 H, CH2CO2), 2.99 (s, 3 H,
NCH3), 2.35 (s, 3 H, 4-H3), 1.35 [s, 9 H, C(CH3)3] ppm. 13C NMR
NCH3), 2.95 (s, 3 H, NCH3), 2.45 (s, 3 H, CH3Ar), 2.41 (s, 3 H, (150 MHz, CDCl3): δ = 197.1 (C-3), 164.9 (CO2), 164.2 (2-
4-H3), 1.35 [s, 9 H, C(CH3)3] ppm. 13C NMR (75 MHz, CDCl3): δ CONMe2), 160.6 (C-1), 89.3 (C-2), 52.4 [C(CH3)3], 37.7 (NCH3),
= 196.4 (C-3), 163.9 (CO2), 160.8 (2-CONMe2), 159.5 (C-1), 146.0
37.3 (NCH3), 28.5 [3 C, C(CH3)3], 26.0 (C-4), 24.9 (CH2CO2) ppm.
(Cipso), 136.0 (Cpara), 130.3 (2 C, 2 Cmeta), 128.3 (2 C, 2 Cortho), 90.4 FTIR (neat): ν = 3403 (w), 2969 (w), 1732 (m), 1693 (s), 1646 (s),
˜
(C-2), 60.7 (CH2CO2), 52.5 [C(CH3)3], 37.4 (NCH3), 36.9 (NCH3), 1523 (s), 1456 (m), 1395 (m), 1363 (m), 1264 (s), 1220 (m), 1177 (s),
28.4 [3 C, C(CH3)3], 26.3 (CH3Ar), 21.8 (C-4) ppm. FTIR (neat):
1097 (s), 1026 (w), 991 (w), 915 (w), 888 (w), 826 (w), 754 (m),
ν = 3364 (w), 2972 (w), 2932 (w), 1769 (m), 1732 (m), 1689 (s), 714 (w), 672 (w), 644 (w), 581 (m), 552 (m), 459 (w), 402 (w) cm–1.
˜
1652 (s), 1598 (w), 1526 (m), 1455 (m), 1397 (m), 1364 (m), HRMS (ESI): calcd. for C13H21BrN2O5Na [M + Na]+ 387.0526;
1325 (s), 1153 (s), 1081 (s), 1024 (w), 995 (w), 919 (w), 893 (w), found 387.0528.
814 (m), 751 (m), 699 (w), 654 (m), 585 (m), 515 (s), 461 (m) cm–1.
1-(tert-Butylamino)-2-(morpholinocarbonyl)-1,3-dioxobutan-2-yl 2-
Tosylacetate (18f): Following general procedure C in toluene or in
dichloromethane on a 0.54 mmol scale using 7b, after a reaction
HRMS (ESI): calcd. for C20H29N2O7S [M + H]+ 441.1690; found
441.1697.
1-(tert-Butylamino)-2-(dimethylcarbamoyl)-1,3-dioxobutan-2-yl 2- time of 40 min (toluene) or 50 min (dichloromethane), and using
(Diethoxyphosphoryl)acetate (18c): Following general procedure C
in dichloromethane on a 0.61 mmol scale using 7a, after a reaction
time of 17 h, and using ethyl acetate as eluent, 18c (194 mg,
0.46 mmol, 75%) was isolated as a colourless liquid.[44] TLC (ethyl
pentane/ethyl acetate, 2:1 as eluent, 18f was isolated as a mixture
of 18f and 20f (toluene: 227 mg, 0.47 mmol, 88%, 73:27 18f/20f)
or as pure 18f (dichloromethane: 219 mg, 0.45 mmol, 84%) as a
colourless solid. TLC (pentane/ethyl acetate, 2:1): Rf = 0.10. 1H
NMR (300 MHz, CDCl3): δ = 7.84 (d, J = 8.3 Hz, 2 H, 2 Hortho),
1
acetate): Rf = 0.32. H NMR (300 MHz, CDCl3): δ = 7.48 (s, 1 H,
NH), 4.17–4.00 [m, 4 H, P(OCH2)2], 3.11 (d, J = 6.0 Hz, 1 H, 7.40 (d, J = 8.1 Hz, 2 H, 2 Hmeta), 7.29 (s, 1 H, NH), 4.35 (d, J =
CH2CO2), 3.04 (d, J = 6.0 Hz, 1 H, CH2CO2), 2.92 (s, 3 H, NCH3), 14.6 Hz, 1 H, CH2CO2), 4.17 (d, J = 14.6 Hz, 1 H, CH2CO2), 3.99–
2.86 (s, 3 H, NCH3), 2.30 (s, 3 H, 4-H3), 1.32–1.21 [m, 6 H, 3.26 [m, 8 H, N(C2H4)2O], 2.47 (s, 3 H, CH3Ar), 2.43 (s, 3 H, 4-
P(OCH2CH3)2], 1.26 [s, 9 H, C(CH3)3] ppm. 13C NMR (75 MHz, H3), 1.36 [s, 9 H, C(CH3)3] ppm. 13C NMR (75 MHz, CDCl3): δ =
CDCl3): δ = 196.6 (C-3), 164.1 (2-CONMe2), 162.8 (d, J = 5.9 Hz, 196.0 (C-3), 162.4 (CO2), 160.8 [2-CON(C2H4)2O], 168.5 (C-1),
CO2), 161.1 (C-1), 89.5 (C-2), 63.0 (d, J = 6.4 Hz, POCH2), 62.6 146.1 (Cipso), 135.9 (Cpara), 130.3 (2 C, 2 Cmeta), 128.2 (2 C, 2 Cortho),
(d, J = 6.5 Hz, POCH2), 52.1 [C(CH3)3], 37.1 (NCH3), 36.8
90.2 (C-2), 66.6 (OCH2), 66.3 (OCH2), 60.5 (CH2CO2), 52.5
(NCH3), 33.8 (d, J = 135.6 Hz, CH2CO2), 28.2 [3 C, C(CH3)3], [C(CH3)3], 46.5 (NCH2), 43.4 (NCH2), 28.3 [3 C, C(CH3)3], 26.2
26.0 (C-4), 16.3 (POCH2CH3), 16.2 (POCH2CH3) ppm. 31P NMR (CH Ar), 21.8 (C-4) ppm. FTIR (neat): ν = 3365 (w), 2971 (w),
˜
3
(101 MHz, CDCl ): δ = 19.4 ppm. FTIR (neat): ν = 3287 (w),
2926 (w), 2864 (w), 1769 (m), 1732 (m), 1688 (s), 1651 (s), 1598 (w),
1526 (m), 1443 (m), 1395 (w), 1363 (m), 1325 (m), 1224 (s),
1154 (s), 1112 (s), 1079 (s), 1018 (w), 981 (m), 913 (m), 815 (m),
˜
3
2977 (w), 2934 (w), 1765 (w), 1733 (m), 1657 (m), 1531 (m),
1454 (w), 1395 (m), 1364 (w), 1252 (s), 1178 (m), 1103 (m), 1021 (s),
968 (s), 864 (w), 787 (w), 733 (m), 699 (w), 637 (w), 591 (w), 766 (w), 731 (s), 652 (m), 587 (s), 541 (m), 514 (s), 460 (m) cm–1
.
533 (w), 466 (w), 401 (w) cm–1 . HRMS (ESI): calcd. for
C17H31N2O8PNa [M + Na]+ 445.1710; found 445.1717.
HRMS (ESI): calcd. for C22H31N2O8S [M + H]+ 483.1796; found
483.1791.
1-(tert-Butylamino)-2-(dimethylcarbamoyl)-1,3-dioxobutan-2-yl 2- 1-(tert-Butylamino)-2-(morpholinocarbonyl)-1,3-dioxobutan-2-yl
Chloroacetate (18d): Following general procedure C in dichloro-
methane on a 0.85 mmol scale using 7a, after a reaction time of
17 h, and using chloroform as eluent, 18d was isolated as a mixture
Methyl Malonate (18g): Following general procedure C in toluene
on a 0.58 mmol scale, or in dichloromethane on a 0.59 mmol scale,
using 7b, after a reaction time of 20 min (toluene) or 30 min
of 18d and 19d (272 mg, 0.85 mmol, 99 %, 86:14 18d/19d) as a (dichloromethane), and using pentane/ethyl acetate, 2:1 as eluent,
colourless solid. TLC (pentane/ethyl acetate, 2:1): Rf = 0.16; m.p. 18g was isolated as a mixture of 18g and 20g (toluene: 192 mg,
Eur. J. Org. Chem. 2014, 993–1006
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
999

J. Roßbach, K. Harms, U. Koert
0.50 mmol, 87 %, 69:31 18g/20g; dichloromethane: 204 mg, toluene (final concentration of 7a/7b: 0.30 m) at room temperature.
FULL PAPER
0.53 mmol, 89%, 91:9 18g/20g) as a colourless solid. TLC (pentane/
The carboxylic acid (1.20 equiv.) was added, followed by the iso-
ethyl acetate, 1:1): Rf = 0.28; m.p. 84 °C (chloroform). 1H NMR cyanide (1.20 equiv.). The reaction mixture was stirred at room
(300 MHz, CDCl3): δ = 7.27 (s, 1 H, NH), 3.82–3.33 [m, 8 H, temperature for the indicated time, then triethylamine (2.50 equiv.)
N(C2H4)2O], 3.77 (s, 3 H, OCH3), 3.59 (s, 2 H, CH2CO2), 2.30 (s,
was added. The reaction mixture was stirred at room temperature
3 H, 4-H3), 1.33 [s, 9 H, C(CH3)3] ppm. 13C NMR (75 MHz, for the indicated time, then it was diluted with dichloromethane
CDCl3): δ = 197.1 (C-3), 166.4 (CO2), 164.0 (CO2), 162.7 [2-
CON(C2H4)2O], 160.8 (C-1), 88.9 (C-2), 66.7 [2 C, O(CH2)2], 52.9
(20 mL), and the mixture was washed with ammonium chloride
solution (saturated aq.; 20 mL). The phases were separated, and
(OCH3), 52.5 [C(CH3)3], 46.8 (NCH2), 43.8 (NCH2), 41.2 the aqueous phase was extracted with dichloromethane (2 ϫ
(CH CO ), 28.5 [3 C, C(CH ) ], 26.0 (C-4) ppm. FTIR (neat): ν =
3324 (w), 2966 (w), 2860 (w), 1792 (m), 1769 (m), 1737 (s),
20 mL). The combined organic extracts were dried with sodium
sulfate, and the solvent was evaporated under reduced pressure.
˜
2
2
3 3
1686 (m), 1637 (s), 1541 (m), 1441 (m), 1340 (m), 1278 (m), The crude product was purified by column chromatography on sil-
1248 (m), 1195 (m), 1145 (s), 1106 (s), 1067 (m), 1008 (m), 951 (w), ica (eluent indicated in each case).
909 (w), 854 (w), 830 (w), 795 (w), 731 (w), 685 (w), 656 (w),
N-tert-Butyl-4-cyano-N,N,3-trimethyl-5-oxofuran-2,2(5H)-dicarbox-
amide (20a): Following general procedure C in toluene on a
0.76 mmol scale, or in dichloromethane on a 0.71 mmol scale, using
588 (m), 526 (w), 458 (m), 396 (w) cm–1. HRMS (ESI): calcd. for
C17H27N2O8 [M + H]+ 387.1762; found 387.1760.
1-(tert-Butylamino)-2-(morpholinocarbonyl)-1,3-dioxobutan-2-yl 2- 7a, after a reaction time of 2 h, and using pentane/ethyl acetate, 2:1
(Diethoxyphosphoryl)acetate (18h): Following general procedure C
in dichloromethane on a 0.49 mmol scale using 7b, after a reaction
time of 17 h, and using ethyl acetate as eluent, 18h was isolated as
as eluent, 20a was isolated as a mixture of 20a and 21a (toluene:
202 mg, 0.69 mmol, 90%, 91:9 20a/21a; dichloromethane: 150 mg,
0.51 mmol, 72%, 92:8 20a/21a) as a colourless solid. TLC (pentane/
a mixture of 18h and 19h (206 mg, 0.44 mmol, 91%, 97:3 18h/19h) ethyl acetate, 1:1): Rf = 0.46; m.p. 169 °C (pentane). 1H NMR
1
as a colourless liquid.[44] TLC (ethyl acetate): Rf = 0.34. H NMR
(500 MHz, CDCl3): δ = 6.29 (s, 1 H, NH), 3.05 (s, 3 H, NCH3),
(300 MHz, CDCl3): δ = 7.44 (s, 1 H, NH), 4.22–4.06 [m, 4 H, 2.97 (s, 3 H, NCH3), 2.59 (s, 3 H, 3-CH3), 1.35 [s, 9 H, C(CH3)3]
P(OCH2)2], 3.80–3.35 [m, 8 H, N(C2H4)2O], 3.15 (dd, J = 20.8, J
= 15.0 Hz, 1 H, CH2CO2), 3.07 (dd, J = 21.1, J = 15.0 Hz, 1 H,
ppm. 13C NMR (125 MHz, CDCl3): δ = 181.5 (C-3), 165.5 (C-5),
162.5 (2-CONMe2), 161.1 (2-CONHtBu), 109.9 (4-CN), 104.8 (C-
CH2CO2), 2.34 (s, 3 H, 4-H3), 1.38–1.27 [m, 6 H, P(OCH2CH3)2], 4), 91.3 (C-2), 53.3 [C(CH3)3], 37.2 (NCH3), 36.9 (NCH3), 28.4 [3
1.32 [s, 9 H, C(CH3)3] ppm. 13C NMR (75 MHz, CDCl3): δ = 196.9
(C-3), 163.1 (d, J = 5.9 Hz, CO2), 162.7 [2-CON(C2H4)2O], 161.2
(C-1), 88.4 (C-2), 66.6 (OCH2), 66.4 (OCH2), 63.2 (d, J = 6.5 Hz,
POCH2), 62.8 (d, J = 6.6 Hz, POCH2), 52.3 [C(CH3)3], 46.6
C, C(CH ) ], 16.9 (3-CH ) ppm. FTIR (neat): ν = 3369 (m),
˜
3 3 3
2969 (w), 2938 (w), 2243 (w), 1777 (s), 1691 (s), 1663 (s), 1527 (s),
1454 (m), 1401 (m), 1370 (m), 1315 (w), 1281 (m), 1215 (m),
1172 (m), 1055 (s), 1014 (m), 939 (w), 907 (w), 841 (w), 756 (m),
(NCH2), 43.5 (NCH2), 34.0 (d, J = 135.5 Hz, CH2CO2), 28.4 [3 C, 698 (w), 649 (m), 624 (w), 565 (m), 493 (m), 469 (w), 433 (w),
C(CH3)3], 26.2 (C-4), 16.4 (POCH2CH3), 16.4 (POCH2CH3) ppm. 403 (w) cm–1. HRMS (ESI): calcd. for C14H19N3O4Na [M + Na]+
31P NMR (101 MHz, CDCl ): δ = 19.2 ppm. FTIR (neat): ν =
316.1268; found 316.1266.
˜
3
3287 (w), 2975 (w), 2923 (w), 2864 (w), 1766 (m), 1733 (m),
1686 (m), 1657 (m), 1531 (m), 1441 (m), 1395 (w), 1363 (w),
1249 (s), 1111 (m), 1020 (s), 971 (s), 861 (w), 819 (w), 787 (w),
754 (w), 677 (w), 591 (m), 531 (w), 462 (m) cm–1. HRMS (ESI):
calcd. for C19H33N2O9PNa [M + Na]+ 487.1816; found 487.1814.
Methyl 5-(tert-Butylcarbamoyl)-5-(dimethylcarbamoyl)-4-methyl-2-
oxo-2,5-dihydrofuran-3-carboxylate (20b): Following general pro-
cedure D in toluene on a 0.66 mmol scale, or in dichloromethane
on a 0.59 mmol scale, using 7a, after a reaction time of 30 min,
triethylamine was added, and the mixture was stirred for a further
30 min (toluene) or 40 min (dichloromethane). Pentane/ethyl acet-
ate, 1:1 was used as eluent. Compound 20b (toluene: 161 mg,
0.49 mmol, 75%; dichloromethane: 159 mg, 0.49 mmol, 82%) was
isolated as a colourless colourless solid. TLC (pentane/ethyl acet-
ate, 1:1): Rf = 0.42; m.p. 184 °C. 1H NMR (300 MHz, CDCl3): δ =
6.45 (s, 1 H, NH), 3.85 (s, 3 H, OCH3), 3.04 (s, 3 H, NCH3), 2.93
1-(tert-Butylamino)-2-methyl-4-morpholino-1,3,4-trioxobutan-2-yl
2-(Diethoxyphosphoryl)acetate (19h): From the reaction described
above, a small amount of pure 19h (10 mg, 0.02 mmol, 4.5%) was
1
isolated as a colourless liquid. TLC (ethyl acetate): Rf = 0.40. H
NMR (500 MHz, CDCl3): δ = 7.04 (s, 1 H, NH), 4.26–4.19 [m, 4
H, P(OCH2)2], 3.77–3.68 [m, 5 H, O(CH2)2, NCH2], 3.60–3.53 (m,
2 H, NCH2, NCH2), 3.47 (dt, J = 13.6, J = 4.7 Hz, 1 H, NCH2), (s, 3 H, NCH3), 2.60 (s, 3 H, 4-CH3), 1.35 [s, 9 H, C(CH3)3] ppm.
3.11 (dd, J = 21.5, J = 14.6 Hz, 1 H, CH2CO2), 3.05 (dd, J = 20.8,
J = 14.5 Hz, 1 H, CH2CO2), 1.89 (s, 3 H, 2-CH3), 1.42–1.38 [m, 6
13C NMR (150 MHz, CDCl3): δ = 178.0 (C-4), 166.9 (C-2), 163.2
(5-CONMe2), 162.3 (5-CONHtBu), 161.1 (3-CO2Me), 117.7 (C-3),
H, P(OCH2CH3)2], 1.41 [s, 9 H, C(CH3)3] ppm. 13C NMR 89.2 (C-5), 52.7 (OCH3), 52.4 [C(CH3)3], 37.1 (NCH3), 36.7
(125 MHz, CDCl3): δ = 192.2 (C-3), 165.7 (C-1), 164.8 (d, J = (NCH ), 28.3 [3 C, C(CH ) ], 16.2 (4-CH ) ppm. FTIR (neat): ν =
˜
3
3 3
3
6.4 Hz, CO2), 163.3 (C-4), 86.3 (C-2), 66.7 (OCH2), 66.5 (OCH2), 3347 (m), 2975 (w), 1785 (s), 1720 (m), 1675 (s), 1651 (s), 1533 (m),
63.2 (d, J = 6.3 Hz, POCH2), 63.1 (d, J = 6.4 Hz, POCH2), 51.9 1439 (m), 1353 (s), 1286 (m), 1220 (s), 1166 (m), 1108 (m), 1044 (s),
[C(CH3)3], 46.3 (NCH2), 42.1 (NCH2), 34.4 (d, J = 133.2 Hz, 1015 (s), 939 (w), 904 (w), 836 (w), 798 (m), 759 (w), 694 (w),
CH2CO2), 28.6 [3 C, C(CH3)3], 22.4 (2-CH3), 16.5 (d, J = 3.7 Hz,
659 (w), 582 (m), 529 (w), 503 (w), 460 (w), 410 (w) cm–1. HRMS
(ESI): calcd. for C15H23N2O6 [M + H]+ 327.1551; found 327.1553.
POCH2CH3), 16.5 (d, J = 3.7 Hz, POCH2CH3) ppm. 31P NMR
(101 MHz, CDCl ): δ = 19.5 ppm. FTIR (neat): ν = 3333 (w),
˜
3
Methyl 5-(tert-Butylcarbamoyl)-4-(dimethylcarbamoyl)-5-methyl-2-
oxo-2,5-dihydrofuran-3-carboxylate (21b): From the reaction de-
scribed above, 21b (toluene: 36 mg, 0.11 mmol, 17%; dichlorometh-
ane: 24 mg, 0.07 mmol, 12%) was isolated as a colourless liquid.
2973 (w), 2927 (w), 2864 (w), 1737 (m), 1679 (m), 1646 (s),
1530 (m), 1448 (m), 1394 (w), 1366 (w), 1264 (s), 1160 (w),
1112 (m), 1021 (s), 969 (s), 819 (w), 788 (w), 654 (w), 624 (w),
584 (w), 550 (w), 488 (w) cm–1 . HRMS (ESI): calcd. for
C19H33N2O9PNa [M + Na]+ 487.1816; found 487.1816.
1
TLC (pentane/ethyl acetate, 1:1): Rf = 0.17. H NMR (500 MHz,
CDCl3): δ = 6.32 (s, 1 H, NH), 3.83 (s, 3 H, OCH3), 3.06 (s, 3 H,
NCH3), 2.76 (s, 3 H, NCH3), 1.84 (s, 3 H, 5-CH3), 1.31 [s, 9 H,
C(CH3)3] ppm. 13C NMR (125 MHz, CDCl3): δ = 169.5 (C-4),
General Procedure D, Passerini–Knoevenagel Reaction: Diketo
amide 7a or 7b (1.00 equiv.) was dissolved in dichloromethane or
1000
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Passerini Reactions with vic-Diketo Amides
165.2 (C-2), 165.1 (5-CONHtBu), 161.5 (4-CONMe2), 159.8 (3-
2970 (w), 2933 (w), 1772 (s), 1668 (s), 1630 (s), 1452 (m), 1404 (m),
CO2Me), 118.0 (C-3), 87.3 (C-5), 53.0 (OCH3), 52.2 [C(CH3)3], 37.7 1363 (m), 1283 (m), 1226 (s), 1160 (m), 1108 (m), 1060 (w),
(NCH3), 34.3 (NCH3), 28.4 [3 C, C(CH3)3], 24.6 (5-CH3) ppm. 1026 (m), 962 (m), 907 (m), 861 (m), 814 (w), 787 (w), 758 (w),
HRMS (ESI): calcd. for C15H23N2O6 [M + H]+ 327.1551; found
327.1554.
721 (w), 680 (w), 644 (w), 596 (m), 535 (w), 460 (w) cm–1. HRMS
(ESI): calcd. for C13H20N2O4Na [M + Na]+ 291.1315; found
291.1315.
N-tert-Butyl-N,N,3-trimethyl-5-oxo-4-tosylfuran-2,2(5H)-dicarb-
oxamide (20c): Following general procedure D in toluene or dichlo-
romethane on a 0.59 mmol scale using 7a, after a reaction time of
60 min, triethylamine was added, and the mixture was stirred for a
further 60 min (toluene) or 70 min (dichloromethane). Pentane/
N-tert-Butyl-4-cyano-3-methyl-2-(morpholinocarbonyl)-5-oxo-2,5-di-
hydrofuran-2-carboxamide (20e): Following general procedure C in
toluene on a 0.55 mmol scale, or in dichloromethane on a
0.54 mmol scale, using 7b, after a reaction time of 70 min (toluene)
ethyl acetate, 1:1 was used as eluent. Compound 20c was isolated or 40 min (dichloromethane), and using pentane/ethyl acetate, 2:1
as a mixture of 20c and 21c (toluene: 196 mg, 0.46 mmol, 78%,
74:26 20c/21c; dichloromethane: 186 mg, 0.44 mmol, 74%, 74:26
20c/21c) as a colourless solid. TLC (pentane/ethyl acetate, 1:1): Rf
= 0.51; m.p. 156 °C (pentane). H NMR (500 MHz, CDCl3): δ =
7.92 (d, J = 8.4 Hz, 2 H, 2 Hortho), 7.35 (d, J = 8.1 Hz, 2 H, 2
as eluent, 20e (toluene: 160 mg, 0.48 mmol, 87%; dichloromethane:
156 mg, 0.47 mmol, 86%) was isolated as a colourless solid. TLC
(pentane/ethyl acetate, 2:1): Rf = 0.46; m.p. 148 °C (pentane). 1H
NMR (500 MHz, CDCl3): δ = 6.30 (s, 1 H, NH), 3.79–3.39 [m, 8
H, N(C2H4)2O], 2.60 (s, 3 H, 3-CH3), 1.37 [s, 9 H, C(CH3)3] ppm.
1
Hmeta), 5.97 (s, 1 H, NH), 2.97 (s, 3 H, NCH3), 2.89 (s, 3 H, NCH3), 13C NMR (125 MHz, CDCl3): δ = 181.2 (C-3), 165.9 (C-5), 161.3
2.76 (s, 3 H, 3-CH3), 2.43 (s, 3 H, CH3Ar), 1.34 [s, 9 H, C(CH3)3] [2-CON(C2H4)2O], 161.0 (2-CONHtBu), 110.0 (4-CN), 104.9 (C-
ppm. 13C NMR (125 MHz, CDCl3): δ = 176.1 (C-3), 164.7 (C-5),
162.8 (2-CONMe2), 161.7 (2-CONHtBu), 146.0 (Cipso), 136.3
4), 91.4 (C-2), 66.5 (OCH2), 66.2 (OCH2), 53.4 [C(CH3)3], 46.5
(NCH2), 43.4 (NCH2), 28.3 [3 C, C(CH3)3], 16.9 (3-CH3) ppm.
(Cpara), 130.1 (2 C, 2 Cmeta), 128.6 (2 C, 2 Cortho), 126.8 (C-4), 89.5 FTIR (neat): ν = 3368 (w), 2973 (w), 2927 (w), 2864 (w), 2243 (w),
˜
(C-2), 53.1 [C(CH3)3], 37.1 (NCH3), 36.8 (NCH3), 28.4 [3 C, 1786 (s), 1690 (s), 1656 (s), 1520 (s), 1437 (m), 1368 (m), 1274 (s),
C(CH ) ], 21.9 (CH Ar), 15.6 (3-CH ) ppm. FTIR (neat): ν = 1249 (m), 1215 (s), 1114 (s), 1070 (m), 1017 (s), 936 (w), 909 (w),
˜
3
3
3
3
3350 (w), 2976 (w), 2933 (w), 1775 (m), 1684 (m), 1655 (m),
885 (w), 850 (w), 823 (m), 754 (m), 696 (w), 665 (w), 823 (m),
1618 (m), 1517 (m), 1455 (w), 1395 (m), 1362 (m), 1331 (m), 754 (m), 696 (w), 665 (w), 588 (m), 541 (m), 490 (m), 449 (w) cm–1.
1260 (m), 1207 (m), 1156 (s), 1108 (m), 1051 (m), 987 (m), 901 (w), HRMS (APCI): calcd. for C16H22N3O5 [M + H]+ 336.1554; found
814 (w), 756 (m), 704 (w), 660 (s), 609 (m), 558 (s), 516 (m), 492 (m)
cm–1. HRMS (ESI): calcd. for C20H27N2O6S [M + H]+ 423.1584;
found 423.1576.
336.1551.
Methyl 5-(tert-Butylcarbamoyl)-4-methyl-5-(morpholinocarbonyl)-2-
oxo-2,5-dihydrofuran-3-carboxylate (20f): Following general pro-
cedure D in dichloromethane on a 0.59 mmol scale using 7b, after
a reaction time of 95 min, triethylamine was added, and the mix-
ture was stirred for a further 20 min. Pentane/ethyl acetate, 2:1 was
used as eluent. Compound 20f (178 mg, 0.48 mmol, 81%) was iso-
lated as a colourless solid. TLC (pentane/ethyl acetate, 2:1): Rf =
Diethyl 5-(tert-Butylcarbamoyl)-5-(dimethylcarbamoyl)-4-methyl-2-
oxo-2,5-dihydrofuran-3-ylphosphonate (20d): Following general pro-
cedure D in dichloromethane on a 0.63 mmol scale using 7a, after
a reaction time of 16.5 h, triethylamine was added, and the mixture
was stirred for a further 7 h. tert-Butyl methyl ether was used as
eluent. Compound 20d (96 mg, 0.24 mmol, 37%) was isolated as a
colourless solid. TLC (ethyl acetate): Rf = 0.49; m.p. 175 °C (pent-
ane). 1H NMR (500 MHz, CDCl3): δ = 6.07 (s, 1 H, NH), 4.34–
4.15 [m, 4 H, P(OCH2)2], 3.07 (s, 3 H, NCH3), 2.99 (s, 3 H, NCH3),
1
0.30; m.p. 190 °C. H NMR (500 MHz, CDCl3): δ = 6.17 (s, 1 H,
NH), 3.88 (s, 3 H, OCH3), 3.79–3.38 [m, 8 H, N(C2H4)2O], 2.62 (s,
3 H, 4-CH3), 1.34 [s, 9 H, C(CH3)3] ppm. 13C NMR (125 MHz,
CDCl3): δ = 177.6 (C-4), 166.8 [5-CON(C2H4)2O], 162.4 (C-2),
2.66 (d, J = 2.8 Hz, 3 H, 3-CH3), 1.42–1.37 [m, 6 H, P(OCH2- 162.2 (5-CONHtBu), 161.1 (3-CO2Me), 118.0 (C-3), 89.2 (C-5),
CH3)2], 1.38 [s, 9 H, C(CH3)3] ppm. 13C NMR (125 MHz, CDCl3): 66.6 (OCH2), 66.2 (OCH2), 52.9 [C(CH3)3], 52.6 (OCH3), 46.5
δ = 181.6 (d, J = 13.2 Hz, C-4), 168.9 (d, J = 20.9 Hz, C-2), 163.4
(5-CONMe2), 162.6 (5-CONHtBu), 117.0 (d, J = 204.4 Hz, C-3),
(NCH2), 43.3 (NCH2), 28.4 [3 C, C(CH3)3], 16.3 (4-CH3) ppm.
FTIR (neat): ν = 3341 (m), 2970 (w), 2864 (w), 1784 (s), 1722 (m),
˜
90.8 (d, J = 17.2 Hz, C-5), 63.5 (d, J = 6.0 Hz, POCH2), 63.2 (d, J 1680 (s), 1648 (s), 1529 (m), 1443 (m), 1360 (m), 1336 (m),
= 5.7 Hz, POCH2), 52.8 [C(CH3)3], 37.2 (NCH3), 36.9 (NCH3), 1277 (m), 1237 (m), 1209 (s), 1110 (m), 1059 (m), 1020 (s), 933 (w),
28.5 [3 C, C(CH3)3], 16.5 (d, J = 6.0 Hz, POCH2CH3), 16.4 (d, J
884 (w), 845 (w), 797 (m), 761 (w), 683 (w), 655 (w), 589 (m),
= 6.4 Hz, POCH2CH3), 16.9 (d, J = 1.5 Hz, 4-CH3) ppm. 31P NMR 526 (w), 503 (w), 456 (w) cm–1 . HRMS (ESI): calcd. for
(202 MHz, CDCl ): δ = 6.81 ppm. FTIR (neat): ν = 3313 (w),
C17H25N2O7 [M + H]+ 369.1656; found 369.1660.
˜
3
2971 (w), 2932 (w), 1769 (s), 1653 (s), 1620 (m), 1533 (m), 1452 (w),
1397 (m), 1367 (m), 1259 (s), 1220 (m), 1165 (m), 1103 (w),
1011 (s), 965 (s), 817 (w), 763 (m), 694 (w), 654 (w), 614 (m),
545 (m), 489 (m) cm–1. HRMS (ESI): calcd. for C17H29N2O7PNa
[M + Na]+ 427.1605; found 427.1606.
N-tert-Butyl-3-methyl-2-(morpholinocarbonyl)-5-oxo-4-tosyl-2,5-
dihydrofuran-2-carboxamide (20g): Following general procedure D
in dichloromethane on a 0.54 mmol scale using 7b, after a reaction
time of 3.2 h, triethylamine was added, and the mixture was stirred
for a further 40 min. Diethyl ether was used as eluent. Compound
N2-tert-Butyl-N3,N3,2-trimethyl-5-oxo-2,5-dihydrofuran-2,3-di- 20g was isolated as a mixture of 20g and 21g (90 mg, 0.20 mmol,
carboxamide (28a): From the reaction described above, 28a (10 mg,
0.04 mmol, 6%) was isolated as a colourless solid. TLC (ethyl acet-
ate): Rf = 0.55; m.p. 134 °C (pentane). 1H NMR (400 MHz,
36%, 87:13 20g/21g) as a colourless solid. TLC (pentane/ethyl acet-
ate, 2:1): Rf = 0.47; m.p. 192 °C (pentane). 1H NMR (500 MHz,
CDCl3): δ = 7.97 (d, J = 8.4 Hz, 2 H, 2 Hortho), 7.40 (d, J = 8.1 Hz,
CDCl3): δ = 6.25 (s, 1 H, NH), 5.92 (s, 1 H, 4-H), 3.05 (s, 3 H, 2 H, 2 Hmeta), 5.92 (s, 1 H, NH), 3.93–3.36 [m, 8 H, N(C2H4)2O],
NCH3), 2.86 (s, 3 H, NCH3), 1.87 (s, 3 H, 2-CH3), 1.33 [s, 9 H,
C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δ = 169.8 (C-5),
166.7 (2-CONHtBu), 163.8 (C-3), 163.0 (3-CONMe2), 116.4 (C-4),
89.7 (C-2), 51.9 [C(CH3)3], 38.4 (NCH3), 34.6 (NCH3), 28.6 [3 C,
2.80 (s, 3 H, 3-CH3), 2.47 (s, 3 H, CH3Ar), 1.38 [s, 9 H, C(CH3)3]
ppm. 13C NMR (125 MHz, CDCl3): δ = 175.7 (C-3), 164.5 (C-5),
161.7 [2-CON(C2H4)2O], 161.6 (2-CONHtBu), 146.1 (Cipso), 136.2
(Cpara), 130.2 (2 C, 2 Cmeta), 128.7 (2 C, 2 Cortho), 127.0 (C-4), 89.3
(C-2), 66.6 (OCH2), 66.1 (OCH2), 53.2 [C(CH3)3], 46.4 (NCH2),
C(CH ) ], 24.5 (2-CH ) ppm. FTIR (neat): ν = 3371 (w), 3098 (w),
˜
3 3
3
Eur. J. Org. Chem. 2014, 993–1006
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1001

J. Roßbach, K. Harms, U. Koert
FULL PAPER
43.3 (NCH2), 28.4 [3 C, C(CH3)3], 21.9 (CH3Ar), 15.5 (3-CH3)
170.5 (C-3), 163.6 (2-CONHtBu), 162.7 [3-CON(C2H4)2O], 115.9
ppm. FTIR (neat): ν = 3424 (w), 2975 (w), 2928 (w), 2865 (w), (C-4), 90.5 (C-2), 66.7 (OCH2), 66.3 (OCH2), 52.5 [C(CH3)3], 46.5
˜
1795 (s), 1685 (m), 1647 (s), 1600 (w), 1515 (m), 1452 (m), 1397 (w),
1364 (w), 1325 (m), 1301 (w), 1274 (m), 1222 (s), 1149 (s), 1110 (m),
1065 (w), 1003 (s), 956 (w), 927 (w), 884 (w), 857 (w), 815 (m),
791 (w), 755 (m), 732 (w), 703 (w), 660 (s), 588 (s), 522 (s), 485 (w),
459 (w), 409 (w) cm–1. HRMS (ESI): calcd. for C22H28N2O7SNa
[M + Na]+ 487.1509; found 487.1505.
(NCH2), 43.3 (NCH2), 28.5 [3 C, C(CH3)3], 15.7 (3-CH3) ppm.
FTIR (neat): ν = 3341 (w), 2971 (w), 2925 (w), 2862 (w), 1767 (s),
˜
1653 (s), 1522 (m), 1439 (m), 1367 (m), 1275 (m), 1248 (m),
1200 (m), 1110 (s), 1072 (w), 1030 (m), 995 (m), 911 (m), 849 (m),
753 (m), 656 (w), 588 (m), 509 (w), 454 (w) cm–1. HRMS (ESI):
calcd. for C15H23N2O5 [M + H]+ 311.1601; found 311.1610.
Diethyl 5-(tert-Butylcarbamoyl)-4-methyl-5-(morpholinocarbonyl)-2-
oxo-2,5-dihydrofuran-3-ylphosphonate (20h): Following general pro-
cedure D in dichloromethane on a 0.51 mmol scale using 7b, after
a reaction time of 16.5 h, triethylamine was added, and the mixture
was stirred for a further 7 h. tert-Butyl methyl ether/ethyl acetate
was used as eluent. Compound 20h (41 mg, 0.09 mmol, 18%) was
isolated as a colourless solid. TLC (ethyl acetate): Rf = 0.47; m.p.
166 °C (CDCl3). 1H NMR (500 MHz, CDCl3): δ = 5.96 (s, 1 H,
(2R*,3S*,4S*)-N-tert-Butyl-4-chloro-3-hydroxy-N,N,3-trimethyl-
5-oxodihydrofuran-2,2(3H)-dicarboxamide (22): Chloroacetate 18d
(50 mg, 0.16 mmol) was dissolved in tetrahydrofuran (2 mL), and
the solution was cooled to –78 °C. Lithium hexamethyldisilazide
(1 m in tert-butyl methyl ether; 0.17 mL, 0.17 mmol) was added,
and the reaction mixture was stirred for 6 h at –78 °C. Then, the
reaction mixture was poured into ammonium chloride solution
(saturated aq.; 20 mL), and the mixture was extracted with dichlo-
NH), 4.31–4.12 [m, 4 H, P(OCH2)2], 3.80–3.36 [m, 8 H, romethane (3ϫ 20 mL). The combined organic extracts were dried
N(C2H4)2O], 2.62 (d, J = 2.8 Hz, 3 H, 3-CH3), 1.36 (d, J = 7.1 Hz,
3 H, POCH2CH3), 1.36 (d, J = 7.1 Hz, 3 H, POCH2CH3), 1.34 [s,
9 H, C(CH3)3] ppm. 13C NMR (125 MHz, CDCl3): δ = 181.0 (d, J
= 13.3 Hz, C-4), 168.7 (d, J = 20.8 Hz, C-2), 162.5 (5-CONHtBu),
162.2 [5-CON(C2H4)2O], 117.3 (d, J = 204.8 Hz, C-3), 90.6 (d, J =
17.4 Hz, C-5), 66.6 (OCH2), 66.2 (OCH2), 63.6 (d, J = 5.9 Hz,
POCH2), 63.2 (d, J = 5.8 Hz, POCH2), 52.8 [C(CH3)3], 46.5
(NCH2), 43.3 (NCH2), 28.4 [3 C, C(CH3)3], 16.5 (d, J = 6.0 Hz,
with sodium sulfate, and the solvent was evaporated under reduced
pressure. The crude product was purified by flash column
chromatography on silica (pentane/ethyl acetate, 2:1). Aldol ad-
dition product 22 (10.5 mg, 0.033 mmol, 21%) was obtained as a
colourless solid. TLC (pentane/ethyl acetate, 2:1): Rf = 0.32; m.p.
1
144 °C (chloroform). H NMR (500 MHz, CDCl3): δ = 6.50 (s, 1
H, NH), 4.73 (s, 1 H, 4-H), 3.99 (s, 1 H, OH), 3.13 (s, 3 H, NCH3),
3.05 (s, 3 H, NCH3 ), 1.64 (s, 3 H, 3-CH3 ), 1.37 [s, 9 H,
POCH2CH3), 16.4 (d, J = 6.4 Hz, POCH2CH3), 16.9 (d, J = C(CH3)3] ppm. 13C NMR (125 MHz, CDCl3): δ = 169.1 (C-5),
1.8 Hz, 4-CH3) ppm. 31P NMR (202 MHz, CDCl3): δ = 6.70 ppm.
FTIR (neat): ν = 3285 (w), 2984 (w), 2914 (w), 2862 (w), 1775 (s),
167.5 (2-CONMe2), 163.3 (2-CONHtBu), 89.6 (C-2), 80.4 (C-3),
59.7 (C-4), 52.9 [C(CH3)3], 38.6 (NCH3), 37.8 (NCH3), 28.5 [3 C,
˜
1677 (m), 1655 (s), 1623 (m), 1539 (m), 1444 (m), 1391 (w), C(CH ) ], 22.2 (3-CH ) ppm. FTIR (neat): ν = 3478 (w), 3389 (w),
˜
3 3
3
1366 (m), 1265 (s), 1221 (m), 1196 (m), 1111 (m), 1063 (w), 2961 (w), 2921 (m), 2852 (w), 1804 (s), 1737 (w), 1683 (m), 1636 (s),
1006 (s), 970 (s), 848 (w), 821 (w), 768 (m), 689 (w), 656 (w), 1517 (m), 1456 (m), 1375 (m), 1262 (m), 1207 (m), 1174 (s),
618 (m), 589 (m), 548 (m), 501 (w), 461 (w), 433 (w) cm–1. HRMS 1116 (m), 1062 (m), 1028 (m), 1000 (w), 956 (s), 894 (w), 834 (w),
(ESI): calcd. for C19H31N2O8PNa [M + Na]+ 469.1710; found 793 (w), 732 (w), 673 (m), 649 (w), 529 (s), 483 (m), 405 (m) cm–1.
469.1717.
HRMS (ESI): calcd. for C13H21ClN2O5Na [M + Na]+ 343.1031;
found 343.1032.
N-tert-Butyl-2-methyl-3-(morpholinocarbonyl)-5-oxo-2,5-dihydro-
furan-2-carboxamide (28b): From the reaction described above, 28b
(9 mg, 0.03 mmol, 6 %) was isolated as a colourless solid. TLC
4-Isocyanobutan-2-one (24): In a flame-dried flask under an inert
gas atmosphere, dichloromethane (123 mL) was cooled to 0 °C, and
(ethyl acetate): Rf = 0.60; m.p. 144 °C (CDCl3). 1H NMR triethylamine (18.1 mL, 130 mmol) was added. N-(3-Oxobutyl)-
(500 MHz, CDCl3): δ = 6.23 (s, 1 H, NH), 5.91 (s, 1 H, 4-H), 3.93 formamide 23 (5.0 g, 43.4 mmol; prepared according to Brederek
(dt, J = 13.4, J = 4.1 Hz, 1 H, NCH2), 3.77–3.73 (m, 2 H, 2 OCH2),
et al.[45]) was added in one portion, and then phosphoryl chloride
3.72–3.66 (m, 1 H, OCH2), 3.59 (ddd, J = 11.5, J = 5.5, J = 3.3 Hz, (4.0 mL, 43.4 mmol) was added dropwise by syringe. The reaction
1 H, OCH2), 3.53 (ddd, J = 13.4, J = 6.5, J = 4.6 Hz, 1 H, NCH2), mixture was stirred for 40 min at 0 °C. The reaction mixture was
3.30 (ddd, J = 13.2, J = 7.5, J = 3.2 Hz, 1 H, NCH2), 3.20 (ddd, J
allowed to warm to room temperature, then it was stirred for
= 13.3, J = 4.8, J = 3.1 Hz, 1 H, NCH2), 1.88 (s, 3 H, 2-CH3), 1.32 30 min at room temperature. The reaction mixture was poured into
[s, 9 H, C(CH3)3] ppm. 13C NMR (125 MHz, CDCl3): δ = 169.4 ammonium chloride solution (saturated aq.; 150 mL), and the
(C-5), 166.6 (2-CONHtBu), 162.9 (C-3), 161.7 [3-CON(C2H4)2O], phases were separated. The aqueous phase was extracted with
116.7 (C-4), 89.7 (C-2), 66.6 (OCH2), 66.5 (OCH2), 52.0 dichloromethane (3ϫ 150 mL), and the combined organic extracts
[C(CH3)3], 47.3 (NCH2), 41.9 (NCH2), 28.6 [3 C, C(CH3)3], 24.5 were dried with sodium sulfate. The solvent was evaporated under
(2-CH ) ppm. FTIR (neat): ν = 3355 (m), 3111 (w), 2974 (w),
reduced pressure with the temperature kept below 18 °C. Vacuum
distillation (45 °C, 1.3 mbar) gave keto-isocyanide 24 (2.16 g,
22.3 mmol, 51%) as a colourless liquid. TLC (pentane/ethyl acet-
ate, 2:1): Rf = 0.38. b.p. 45 °C (1.3 mbar). 1H NMR (300 MHz,
˜
3
2918 (w), 2864 (w), 1762 (s), 1667 (s), 1643 (s), 1617 (s), 1523 (s),
1549 (m), 1435 (s), 1397 (w), 1366 (m), 1300 (m), 1227 (s),
1143 (m), 1107 (s), 1063 (m), 999 (m), 962 (m), 912 (m), 872 (m),
837 (m), 807 (w), 773 (w), 737 (w), 624 (m), 589 (m), 555 (w), CDCl3): δ = 3.63 (tt, J = 6.8, J = 2.0 Hz, 2 H, 4-H2), 2.86 (tt, J =
520 (w), 457 (w), 410 (w) cm–1 . HRMS (ESI): calcd. for
C15H22N2O5Na [M + Na]+ 333.1421; found 333.1419.
6.7, J = 1.8 Hz, 2 H, 3-H2), 2.20 (s, 3 H, 1-H3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 203.7 (C-2), 157.1 (t, J = 5.2 Hz, NC), 42.6
(C-3), 36.1 (t, J = 7.2 Hz, C-4), 30.1 (C-1) ppm. FTIR (neat): ν =
˜
N-tert-Butyl-3-methyl-2-(morpholinocarbonyl)-5-oxo-2,5-dihydro-
furan-2-carboxamide (29): From the reaction described above, 29
(11 mg, 0.04 mmol, 7%) was isolated as a colourless liquid. TLC
(ethyl acetate): Rf = 0.74. H NMR (500 MHz, CDCl3): δ = 5.99
(s, 1 H, NH), 5.86 (q, J = 1.5 Hz, 1 H, 4-H), 3.78–3.40 [m, 8 H,
2958 (w), 2153 (m), 1716 (s), 1440 (w), 1412 (w), 1369 (m),
1270 (w), 1169 (m), 1075 (w), 1036 (w), 993 (w), 952 (w), 792 (w),
748 (w), 583 (w), 493 (m) cm–1 . HRMS (ESI): calcd. for
C5H7NONa [M + Na]+ 120.0420; found 120.0421.
1
N(C2H4)2O], 2.34 (d, J = 1.5 Hz, 3 H, 3-CH3), 1.34 [s, 9 H, 2-(Morpholinocarbonyl)-1,3-dioxo-1-(tosylmethylamino)butan-2-yl
C(CH3)3] ppm. 13C NMR (125 MHz, CDCl3): δ = 171.1 (C-5),
Acetate (26a): Following general procedure C in dichloromethane
1002
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 993–1006

Passerini Reactions with vic-Diketo Amides
on a 0.54 mmol scale using 7b, after a reaction time of 24 h, and
using tert-butyl methyl ether as eluent, 26a (219 mg, 0.50 mmol,
92%) was isolated as a colourless solid. TLC (tert-butyl methyl
2-(Morpholinocarbonyl)-1-(naphthalen-2-ylamino)-1,3-dioxobutan-
2-yl Acetate (26d): Following general procedure C in dichlorometh-
ane on a 0.54 mmol scale using 7b, after a reaction time of 21.5 h,
ether): Rf = 0.18; m.p. 75 °C (chloroform). 1H NMR (400 MHz, and using diethyl ether as eluent, 26d (209 mg, 0.52 mmol, 97%)
CDCl3): δ = 8.58 (br. s, 1 H, NH), 7.73 (d, J = 8.3 Hz, 2 H, 2
Hortho), 7.35 (d, J = 8.2 Hz, 2 H, 2 Hmeta), 4.75 (dd, J = 14.1, J = m.p. 74 °C (chloroform). H NMR (500 MHz, CDCl3): δ = 10.14
was isolated as a pale yellow solid. TLC (diethyl ether): Rf = 0.31;
1
7.0 Hz, 1 H, NHCH2), 4.62 (dd, J = 14.1, J = 6.6 Hz, 1 H,
NHCH2), 3.82–3.39 [m, 8 H, N(C2H4)2O], 2.44 (s, 3 H, CH3Ar),
(s, 1 H, NH), 8.21 (d, J = 2.0 Hz, 1 H, 1Ј-H), 7.82–7.76 (m, 3 H,
4Ј-H, 5Ј-H, 8Ј-H), 7.49 (dd, J = 8.8, J = 2.2 Hz, 1 H, 3Ј-H), 7.46
2.24 (s, 3 H, CH3CO2), 2.19 (s, 3 H, 4-H3) ppm. 13C NMR (ddd, J = 7.8, J = 7.1, J = 1.5 Hz, 1 H, 7Ј-H), 7.42 (ddd, J = 7.9,
(75 MHz, CDCl3): δ = 197.1 (C-3), 168.6 (CO2), 163.1 (C-1), 162.3
J = 7.0, J = 1.6 Hz, 1 H, 6Ј-H), 3.99–3.49 [m, 8 H, N(C2H4)2O],
[2-CON(C2H4)2O], 145.5 (Cipso), 134.3 (Cpara), 130.2 (2 C, 2 Cmeta), 2.37 (s, 3 H, 4-H3), 2.34 (s, 3 H, CH3CO2) ppm. 13C NMR
128.9 (2 C, 2 Cortho), 87.3 (C-2), 66.5 (2 C, 2 OCH2), 60.6 (NHCH2), (75 MHz, CDCl3): δ = 198.0 (C-3), 168.9 (CH3CO2), 163.1 [2-
47.1 (NCH2), 44.2 (NCH2), 25.5 (C-4), 21.8 (CH3Ar), 20.6
CON(C2H4)2O], 160.5 (C-1), 134.6 (C-2Ј), 133.9 (C-8aЈ), 131.2 (C-
(CH CO ) ppm. FTIR (neat): ν = 3336 (w), 3935 (w), 3858 (w), 4aЈ), 129.0, 127.9, 127.7, 126.8 (C-7Ј), 125.5 (C-6Ј), 120.3 (C-3Ј),
˜
3
2
2120 (w), 1759 (m), 1733 (m), 1699 (s), 1643 (s), 1598 (w), 1516 (m),
117.5 (C-1Ј), 87.5 (C-2), 66.8 (2 C, 2 OCH2), 47.2 (NCH2), 44.2
1435 (m), 1365 (w), 1321 (m), 1294 (m), 1215 (s), 1141 (s), 1113 (s), (NCH ), 25.8 (C-4), 20.7 (CH CO ) ppm. FTIR (neat): ν =
˜
2
3
2
1083 (m), 1020 (w), 975 (m), 933 (w), 886 (w), 857 (w), 817 (m),
752 (m), 668 (w), 565 (s), 511 (s), 455 (m), 411 (w) cm–1. HRMS
(ESI): calcd. for C19H24N2O8SNa [M + Na]+ 463.1146; found
463.1147.
3316 (w), 3054 (w), 2966 (w), 2922 (w), 2856 (w), 1759 (m),
1731 (m), 1694 (s), 1640 (s), 1594 (m), 1543 (s), 1502 (m), 1431 (s),
1359 (s), 1299 (w), 1216 (s), 1109 (s), 1019 (m), 973 (m), 933 (w),
888 (m), 854 (m), 813 (m), 749 (m), 703 (w), 662 (w), 594 (m),
521 (w), 474 (m), 427 (w) cm–1 . HRMS (ESI): calcd. for
C21H22N2O6Na [M + Na]+ 421.1370; found 421.1372.
Methyl 2-[2-Acetoxy-2-(morpholinocarbonyl)-3-oxobutanamido]-
acetate (26b): Following general procedure C in dichloromethane
on a 0.54 mmol scale using 7b, after a reaction time of 20 h, and
using tert-butyl methyl ether as eluent, 26b (162 mg, 0.47 mmol,
87%) was isolated as a colourless solid. TLC (ethyl acetate): Rf =
1-(4-Methoxyphenylamino)-2-(morpholinocarbonyl)-1,3-dioxobutan-
2-yl Acetate (26e): Following general procedure C in dichlorometh-
ane on a 0.54 mmol scale using 7b, after a reaction time of 21 h,
and using tert-butyl methyl ether as eluent, 26e (205 mg,
0.54 mmol, 100%) was isolated as an orange solid. TLC (tert-butyl
methyl ether): Rf = 0.29; m.p. 154 °C (chloroform). 1H NMR
(500 MHz, CDCl3): δ = 9.73 (s, 1 H, NH), 7.46–7.41 (m, 2 H, 2
Hortho), 6.88–6.84 (m, 2 H, 2 Hmeta), 3.96–3.44 [m, 8 H, N(C2H4)
2O], 3.79 (s, 3 H, OCH3), 2.33 (s, 3 H, 4-H3), 2.31 (s, 3 H, CH3CO2)
ppm. 13C NMR (125 MHz, CDCl3): δ = 198.1 (C-3), 169.0
(CH3CO2), 163.0 [2-CON(C2H4)2O], 160.1 (C-1), 157.1 (Cpara),
130.3 (Cipso), 122.1 (2 C, 2 Cortho), 114.3 (2 C, 2 Cmeta), 87.4 (C-2),
66.7 (2 C, 2 OCH2), 55.6 (OCH3), 47.2 (NCH2), 44.2 (NCH2), 25.9
1
0.51; m.p. 105 °C. H NMR (400 MHz, CDCl3): δ = 8.02 (br. s, 1
H, NH), 4.10 (dd, J = 17.9, J = 5.6 Hz, 1 H, NHCH2), 4.04
(dd, J = 18.0, J = 5.7 Hz, 1 H, NHCH2), 3.92–3.40 [m, 8 H,
N(C2H4)2O], 3.75 (s, 3 H, OCH3), 2.31 (s, 3 H, 4-H3), 2.28 (s, 3 H,
CH3CO2) ppm. 13C NMR (100 MHz, CDCl3): δ = 196.8 (C-3),
169.2 (CO2Me), 168.8 (CH3CO2), 163.2 (C-1), 162.6 [2-
CON(C2H4)2O], 87.9 (C-2), 66.7 (2 C, 2 OCH2), 52.6 (OCH3), 47.0
(NCH2), 44.0 (NCH2), 41.8 (NHCH2), 25.9 (C-4), 20.7 (CH3CO2)
ppm. FTIR (neat): ν = 3304 (w), 2926 (w), 2863 (w), 1742 (s),
˜
1678 (m), 1645 (s), 1511 (m), 1438 (m), 1367 (m), 1304 (w),
1258 (m), 1204 (s), 1170 (s), 1108 (s), 1066 (w), 1019 (w), 978 (m),
933 (w), 892 (w), 865 (w), 804 (w), 713 (m), 687 (w), 657 (w),
588 (m), 528 (m), 467 (m) cm–1. HRMS (ESI): calcd. for
C14H20N2O8Na [M + Na]+ 367.1112; found 367.1112.
(C-4), 20.7 (CH CO ) ppm. FTIR (neat): ν = 3318 (w), 2926 (w),
˜
3
2
2855 (w), 1760 (m), 1731 (m), 1690 (s), 1643 (s), 1600 (m), 1512 (s),
1437 (m), 1363 (m), 1302 (w), 1219 (s), 1177 (s), 1108 (s), 1026 (s),
976 (m), 935 (w), 900 (w), 828 (s), 753 (m), 664 (w), 596 (m),
517 (m), 452 (m) cm–1. HRMS (ESI): calcd. for C18H23N2O7 [M +
H]+ 379.1500; found 379.1505.
1-[(Diethoxyphosphoryl)methylamino]-2-(morpholinocarbonyl)-
1,3-dioxobutan-2-yl Acetate (26c): Following general procedure C
in dichloromethane on a 0.54 mmol scale using 7b, after a reaction
time of 24 h, and using chloroform/methanol, 20:1 as eluent, 26c
(228 mg, 0.54 mmol, 100 %) was isolated as a colourless liquid.
TLC (chloroform/methanol, 20:1): Rf = 0.36. 1H NMR (300 MHz,
CDCl3): δ = 8.06 (br. s, 1 H, NH), 4.15 (ddd, J = 8.1, J = 7.0, J =
6.0 Hz, 2 H, POCH2), 4.11 (ddd, J = 8.1, J = 7.1, J = 5.9 Hz, 2 H,
POCH2), 3.79 (ddd, J = 15.8, J = 12.4, J = 6.3 Hz, 1 H, NHCH2),
3.69 (ddd, J = 15.8, J = 12.2, J = 5.8 Hz, 1 H, NHCH2), 3.71–3.44
[m, 8 H, N(C2H4)2O], 2.28 (s, 3 H, 4-H3), 2.27 (s, 3 H, CH3CO2)
1.32 [dt, J = 6.9, J = 5.8 Hz, 6 H, P(OCH2CH3)2] ppm. 13C NMR
(75 MHz, CDCl3): δ = 196.9 (C-3), 168.7 (CH3CO2), 162.8 (d, J =
5.9 Hz, C-1), 162.8 [2-CON(C2H4)2O], 87.6 (C-2), 66.6 (2 C, 2
OCH2), 62.8 [d, J = 6.5 Hz, 2 C, P(OCH2)2], 47.0 (NCH2), 44.0
(NCH2), 35.7 (d, J = 156.8 Hz, NHCH2), 25.7 (C-4), 20.7
(CH3CO2), 16.5 (d, J = 5.1 Hz, POCH2CH3), 16.5 (d, J = 5.0 Hz,
POCH2CH3) ppm. 31P NMR (202 MHz, CDCl3): δ = 21.5 ppm.
2-(Morpholinocarbonyl)-1,3-dioxo-1-(3-oxobutylamino)butan-2-yl
Acetate (26f): Following general procedure C in dichloromethane
on a 0.62 mmol scale using 7b, after a reaction time of 16 h, and
using ethyl acetate as eluent, 26f (210 mg, 0.61 mmol, 99%) was
1
isolated as a colourless liquid. TLC (ethyl acetate): Rf = 0.29. H
NMR (400 MHz, CDCl3): δ = 7.82 (br. s, 1 H, NH), 3.78–3.45 [m,
10 H, N(C2H4)2O, 1Ј-H2], 2.69 (dt, J = 6.2, J = 3.2 Hz, 2 H, 2Ј-
H2), 2.27 (s, 3 H, 4-H3), 2.26 (s, 3 H, CH3CO2), 2.15 (s, 3 H, 4Ј-
H3) ppm. 13C NMR (75 MHz, CDCl3): δ = 207.0 (C-3Ј), 197.2 (C-
3), 168.8 (CH3CO2), 162.9 [2-CON(C2H4)2O], 162.8 (C-1), 87.8 (C-
2), 66.7 (2 C, 2 OCH2), 46.9 (NCH2), 44.0 (NCH2), 42.6 (C-2Ј),
35.2 (C-1Ј), 30.2 (C-4Ј), 25.9 (C-4), 20.8 (CH3CO2) ppm. FTIR
(neat): ν = 3599 (w), 3348 (w), 2926 (w), 2860 (w), 1761 (m),
˜
1683 (s), 1644 (s), 1522 (m), 1433 (m), 1363 (m), 1302 (w), 1215 (s),
1174 (s), 1111 (s), 1020 (m), 976 (m), 932 (w), 891 (w), 858 (w),
833 (w), 803 (w), 754 (w), 662 (w), 598 (m), 523 (m), 453 (m),
410 (w) cm–1. HRMS (ESI): calcd. for C15H22N2O7Na [M + Na]+
365.1319; found 365.1318.
FTIR (neat): ν = 3547 (w), 2984 (w), 2927 (w), 2862 (w), 2152 (w),
˜
1765 (w), 1734 (m), 1689 (m), 1648 (m), 1526 (w), 1437 (m),
1369 (w), 1367 (w), 1302 (w), 1215 (s), 1111 (m), 1018 (s), 970 (s),
857 (w), 823 (w), 791 (w), 702 (w), 658 (w), 599 (w), 533 (m), 4-Cyano-3-methyl-2-(morpholinocarbonyl)-5-oxo-N-(tosylmethyl)-
453 (w) cm–1. HRMS (ESI): calcd. for C16H27N2O9PNa [M +
Na]+ 445.1346; found 445.1347.
2,5-dihydrofuran-2-carboxamide (27a): Following general procedure
C in dichloromethane on a 0.54 mmol scale using 7b, after a reac-
Eur. J. Org. Chem. 2014, 993–1006
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1003

J. Roßbach, K. Harms, U. Koert
FULL PAPER
tion time of 24 h, and using diethyl ether as eluent, 27a (139 mg,
0.31 mmol, 27%) was isolated as a colourless solid. TLC (tert-butyl
methyl ether): Rf = 0.36; m.p. 180 °C (chloroform, decomp.). 1H
4-Cyano-3-methyl-2-(morpholinocarbonyl)-N-(naphthalen-2-yl)-5-
oxo-2,5-dihydrofuran-2-carboxamide (27d): Following general pro-
cedure C in dichloromethane on a 0.54 mmol scale using 7b, after
NMR (500 MHz, CDCl3): δ = 7.75 (d, J = 8.3 Hz, 2 H, 2 Hortho), a reaction time of 19 h, and using pentane/ethyl acetate, 3:1 as elu-
7.43 (d, J = 8.0 Hz, 2 H, 2 Hmeta), 7.39 (t, J = 6.5 Hz, 1 H, NH),
4.67 (dd, J = 14.2, J = 6.7 Hz, 1 H, NHCH2), 4.64 (dd, J = 14.5,
J = 6.8 Hz, 1 H, NHCH2), 3.78–3.31 [m, 8 H, N(C2H4)2O], 2.49
(s, 3 H, CH3Ar), 2.39 (s, 3 H, 3-CH3) ppm. 13C NMR (125 MHz,
ent, 27d (145 mg, 0.36 mmol, 66%) was isolated as a brown oil.
TLC (pentane/ethyl acetate, 3:1): Rf = 0.20. H NMR (500 MHz,
CDCl3): δ = 8.54 (s, 1 H, NH), 8.25 (d, J = 2.1 Hz, 1 H, 1Ј-H),
7.90–7.80 (m, 3 H, 4Ј-H, 5Ј-H, 8Ј-H), 7.57–7.45 (m, 3 H, 3Ј-H, 6Ј-
1
CDCl3): δ = 180.0 (C-3), 164.3 (C-5), 162.7 [2-CON(C2H4)2O], H, 7Ј-H), 3.90–3.47 [m, 8 H, N(C2H4)2O], 2.72 (s, 3 H, 3-CH3)
160.3 (2-CONH), 146.6 (Cipso), 133.6 (Cpara), 130.6 (2 C, 2 Cmeta), ppm. 13C NMR (125 MHz, CDCl3): δ = 181.0 (C-3), 165.7 (C-5),
128.7 (2 C, 2 Cortho), 109.4 (4-CN), 105.5 (C-4), 90.3 (C-2), 66.5
(2 C, 2 OCH2), 59.9 (NHCH2), 46.7 (NCH2), 43.6 (NCH2), 21.9 8aЈ), 131.6 (C-4aЈ), 129.6, 128.0, 127.9, 127.3 (C-7Ј), 126.3 (C-6Ј),
(CH Ar), 16.8 (3-CH ) ppm. FTIR (neat): ν = 3298 (w), 2925 (w), 119.4 (C-3Ј), 118.0 (C-1Ј), 109.7 (4-CN), 105.5 (C-4), 91.2 (C-2),
2868 (w), 2238 (w), 1795 (s), 1695 (s), 1653 (s), 1597 (w), 1534 (m), 66.6 (OCH2), 66.2 (OCH2), 46.6 (NCH2), 43.7 (NCH2), 17.2 (3-
161.0 [2-CON(C2H4)2O], 169.9 (2-CONH), 133.6 (C-2Ј), 133.1 (C-
˜
3
3
1509 (m), 1438 (m), 1398 (w), 1374 (w), 1315 (m), 1266 (m),
1216 (m), 1112 (s), 1077 (s), 1029 (s), 927 (m), 873 (w), 844 (w),
CH ) ppm. FTIR (neat): ν = 3341 (w), 3059 (w), 2970 (w),
2924 (w), 2861 (w), 2249 (w), 1793 (m), 1692 (m), 1651 (s),
˜
3
812 (m), 751 (m), 713 (w), 658 (m), 597 (s), 559 (m), 506 (s), 1597 (w), 1541 (m), 1502 (m), 1434 (m), 1361 (m), 1310 (w),
436 (m), 408 (w) cm–1. HRMS (ESI): calcd. for C20H21N3O7SNa 1268 (m), 1242 (m), 1113 (m), 1056 (w), 1020 (m), 961 (w), 909 (m),
[M + Na]+ 470.0992; found 470.0997.
856 (w), 814 (m), 728 (s), 646 (m), 590 (m), 501 (w), 473 (m),
429 (w) cm–1. HRMS (ESI): calcd. for C22H19N3O5Na [M + Na]+
428.1217; found 428.1222.
Methyl 2-[4-Cyano-3-methyl-2-(morpholinocarbonyl)-5-oxo-2,5-di-
hydrofuran-2-carboxamido]acetate (27b): Following general pro-
cedure C in dichloromethane on a 0.59 mmol scale using 7b, after
a reaction time of 19 h, and using chloroform/tert-butyl methyl
ether as eluent, 27b (133 mg, 0.38 mmol, 64%) was isolated as a
colourless solid. TLC (pentane/ethyl acetate, 1:1): Rf = 0.31; m.p.
4-Cyano-N-(4-methoxyphenyl)-3-methyl-2-(morpholinocarbonyl)-5-
oxo-2,5-dihydrofuran-2-carboxamide (27e): Following general pro-
cedure C in dichloromethane on a 0.54 mmol scale using 7b, after
a reaction time of 19 h, and using pentane/ethyl acetate, 2:1 as elu-
ent, 27e (156 mg, 0.41 mmol, 75%) was isolated as an off-white
solid. TLC (pentane/ethyl acetate, 2:1): Rf = 0.25; m.p. 84 °C
(CDCl3). 1H NMR (500 MHz, CDCl3): δ = 8.36 (s, 1 H, NH),
7.51–7.45 (m, 2 H, 2 Hortho), 6.93–6.88 (m, 2 H, 2 Hmeta), 3.81 (s,
3 H, OCH3), 3.78–3.46 [m, 8 H, N(C2H4)2O], 2.67 (s, 3 H, 3-CH3)
ppm. 13C NMR (125 MHz, CDCl3): δ = 181.2 (C-3), 165.9 (C-
5), 161.0 [2-CON(C2H4)2O], 159.4 (2-CONH), 157.9 (Cpara), 128.7
(Cipso), 122.1 (2 C, 2 Cortho), 114.7 (2 C, 2 Cmeta), 109.7 (4-CN),
105.3 (C-4), 91.2 (C-2), 66.5 (OCH2), 66.2 (OCH2), 55.7 (OCH3),
1
206 °C (acetone). H NMR [500 MHz, (CD3)2CO]: δ = 8.56 (br. s,
1 H, NH), 4.14 (dd, J = 17.4, J = 6.6 Hz, 1 H, CH2NH), 3.93 (dd,
J = 17.4, J = 5.6 Hz, 1 H, CH2NH), 3.71 (s, 3 H, OCH3), 3.69–
3.41 [m, 8 H, N(C2H4)2O], 2.56 (s, 3 H, 3-CH3) ppm. 13C NMR
[125 MHz, (CD3)2CO]: δ = 180.9 (C-3), 170.3 (CO2Me), 165.7 (C-
5), 164.1 (2-CONH), 162.0 [2-CON(C2H4)2O], 111.0 (4-CN), 105.8
(C-4), 91.9 (C-2), 67.1 (OCH2), 67.0 (OCH2), 52.7 (OCH3), 47.6
(NCH2), 44.0 (NCH2), 41.8 (NHCH2), 16.9 (3-CH3) ppm. FTIR
(neat): ν = 3506 (w), 3353 (w), 2926 (w), 2861 (w), 2235 (w),
˜
46.6 (NCH ), 43.6 (NCH ), 17.2 (3-CH ) ppm. FTIR (neat): ν =
˜
2
2
3
1799 (s), 1751 (w), 1691 (s), 1656 (s), 1531 (w), 1439 (m), 1370 (m),
1251 (m), 1212 (s), 1142 (m), 1115 (m), 1015 (s), 932 (w), 877 (w),
848 (w), 817 (w), 760 (w), 703 (w), 668 (w), 591 (m), 548 (w),
502 (w), 436 (w) cm–1. HRMS (ESI): calcd. for C15H17N3O7Na [M
+ Na]+ 374.0959; found 374–0967.
3312 (w), 2966 (w), 2925 (w), 2860 (w), 2245 (w), 1795 (s), 1688 (s),
1647 (s), 1605 (w), 1512 (s), 1439 (m), 1368 (w), 1305 (w), 1241 (s),
1178 (w), 1112 (s), 1060 (m), 1023 (s), 901 (w), 824 (m), 761 (w),
731 (m), 689 (w), 644 (w), 589 (m), 526 (m), 482 (w), 441 (w) cm–1.
HRMS (ESI): calcd. for C19H19N3O6Na [M + Na]+ 408.1166;
found 408.1169.
Diethyl [4-Cyano-3-methyl-2-(morpholinocarbonyl)-5-oxo-2,5-dihy-
drofuran-2-carboxamido]methylphosphonate (27c): Following gene-
ral procedure C in dichloromethane on a 0.54 mmol scale using 7b,
after a reaction time of 24 h, and using ethyl acetate as eluent, 27c
(190 mg, 0.44 mmol, 82%) was isolated as a colourless solid. TLC
(ethyl acetate): Rf = 0.22; m.p. 180 °C (chloroform). 1H NMR
(500 MHz, CDCl3): δ = 7.42 (t, J = 5.4 Hz, 1 H, NH), 4.19–4.10
[m, 4 H, P(OCH2)2], 3.81 (ddd, J = 15.7, J = 12.5, J = 6.7 Hz, 1
H, NHCH2), 3.77–3.35 [m, 8 H, N(C2H4)2O], 3.55 (ddd, J = 13.5,
J = 5.8, J = 3.9 Hz, 1 H, NHCH2), 2.59 (s, 3 H, 3-CH3), 1.35 [dt, J
= 7.1, J = 3.2 Hz, 6 H, P(OCH2CH3)2] ppm. 13C NMR (125 MHz,
CDCl3): δ = 179.9 (C-3), 164.7 (C-5), 162.4 (d, J = 3.8 Hz, 2-
CONH), 161.0 [2-CON(C2H4)2O], 109.7 (4-CN), 105.5 (C-4), 90.7
(C-2), 66.6 (OCH2), 66.4 (OCH2), 63.3 (d, J = 6.5 Hz, POCH2),
63.2 (d, J = 6.6 Hz, POCH2), 46.7 (NCH2), 43.5 (NCH2), 35.5 (d,
J = 157.3 Hz, NHCH2), 16.9 (3-CH3), 16.6 [d, J = 5.6 Hz, 2 C,
4-Cyano-3-methyl-2-(morpholinocarbonyl)-5-oxo-N-(3-oxobutyl)-
2,5-dihydrofuran-2-carboxamide (27f): Following general procedure
C in dichloromethane on a 0.54 mmol scale using 7b, after a reac-
tion time of 16 h, and using ethyl acetate as eluent, 27f (150 mg,
0.43 mmol, 80 %) was isolated as a colourless solid. TLC (ethyl
acetate): Rf = 0.45; m.p. 114 °C (chloroform). 1H NMR (500 MHz,
CDCl3): δ = 6.98 (t, J = 5.6 Hz, 1 H, NH), 3.85–3.19 [m, 10 H, 1Ј-
H2, N(C2H4)2O], 2.75 (ddd, J = 18.6, J = 7.0, J = 4.8 Hz, 1 H, 2Ј-
H2), 2.68 (ddd, J = 18.6, J = 7.0, J = 4.9 Hz, 1 H, 2Ј-H2), 2.60 (s,
3 H, 3-CH3), 2.18 (s, 3 H, 4Ј-H3) ppm. 13C NMR (125 MHz,
CDCl3): δ = 207.3 (C-3Ј), 180.6 (C-3), 164.8 (C-5), 162.1 (2-
CONH), 161.0 [2-CON(C2H4)2O], 109.7 (4-CN), 105.2 (C-4), 90.7
(C-2), 66.6 (OCH2), 66.2 (OCH2), 46.5 (NCH2), 43.5 (NCH2), 41.8
(C-2Ј), 35.2 (C-1Ј), 30.2 (C-4Ј), 17.1 (3-CH ) ppm. FTIR (neat): ν =
˜
3
3343 (w), 2925 (w), 2862 (w), 2244 (w), 1793 (s), 1683 (s), 1649 (s),
1525 (m), 1437 (m), 1368 (m), 1309 (w), 1269 (m), 1249 (m),
1218 (m), 1170 (w), 1112 (m), 1070 (m), 1020 (m), 880 (w), 849 (w),
817 (w), 754 (s), 696 (w), 667 (w), 588 (m), 484 (w), 441 (w), 408 (w)
cm–1. HRMS (ESI): calcd. for C16H19N3O6Na [M + Na]+
372.1166; found 372.1168.
P(OCH CH ) ] ppm. FTIR (neat): ν = 3207 (w), 3045 (w),
˜
2
3 2
2983 (w), 2928 (w), 2872 (w), 2239 (w), 1788 (m), 1688 (m),
1653 (s), 1543 (w), 1438 (m), 1397 (w), 1372 (w), 1308 (w),
1267 (m), 1205 (s), 971 (m), 909 (m), 870 (w), 843 (w), 813 (w),
753 (m), 659 (w), 600 (m), 543 (w), 486 (m), 411 (w) cm–1. HRMS
(ESI): calcd. for C17H24N3O8PNa [M + Na]+ 452.1193; found 1-(tert-Butylamino)-3-(dimethylamino)-1,3-dioxopropan-2-yl 2-(Di-
452.1194.
ethoxyphosphoryl)acetate (30a): After an undocumented time
1004
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 993–1006

Passerini Reactions with vic-Diketo Amides
[5]
[6]
[7]
J. E. Biggs-Houck, A. Younai, J. T. Shaw, Curr. Opin. Chem.
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standing in CDCl3, a small amount of 30a was isolated as a colour-
less liquid. TLC (ethyl acetate): Rf = 0.20. 1H NMR (500 MHz,
CDCl3): δ = 6.99 (s, 1 H, NH), 5.78 (s, 1 H, 2-H), 4.26–4.08 [m, 4
H, P(OCH2)2], 3.25 (s, 3 H, NCH3), 3.17 (dd, J = 21.9, J = 14.7 Hz,
1 H, CH2CO2), 2.98 (s, 3 H, NCH3), 2.98 (dd, J = 20.0, J =
14.7 Hz, 1 H, CH2CO2), 1.38–1.32 [m, 6 H, P(OCH2CH3)2], 1.36
[s, 9 H, C(CH3)3] ppm. 13C NMR (125 MHz, CDCl3): δ = 165.1
(C-3), 164.0 (d, J = 6.1 Hz, CO2), 163.8 (C-1), 71.0 (C-2), 63.2 (d,
J = 6.4 Hz, POCH2), 63.0 (d, J = 6.4 Hz, POCH2), 52.0 [C(CH3)
3], 37.9 (NCH3), 36.4 (NCH3), 34.1 (d, J = 133.7 Hz, CH2CO2),
28.7 [3 C, C(CH3)3], 16.5 [d, J = 6.0 Hz, 2 C, P(OCH2CH3)2] ppm.
E. Ruijter, R. Scheffelaar, R. V. A. Orru, Angew. Chem. 2011,
123, 6358–6371; Angew. Chem. Int. Ed. 2011, 50, 6234–6246.
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of four sections in the article on pp. 136–213); b) A. Laurent,
Ann. Pharm. 1837, 21, 130–134; A. Laurent, Ann. Pharm. 1838,
28, 265–269.
a) A. Strecker, Ann. Chem. Pharm. 1850, 75, 27–45; b) A.
Strecker, Ann. Chem. Pharm. 1854, 91, 349–351.
A. Hantzsch, Justus Liebig’s Ann. Chem. 1882, 215, 1–82.
a) P. Biginelli, Ber. Dtsch. Chem. Ges. 1891, 24, 1317–1319; b)
P. Biginelli, Ber. Dtsch. Chem. Ges. 1891, 24, 2962–2967; c) P.
Biginelli, Gazz. Chim. Ital. 1893, 23, 360–416; d) L. Banfi, R.
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(Ed.: L. Overman), Wiley, Hoboken, New Jersey (USA), 2005,
pp. 1–140.
[8]
[9]
[10]
31P NMR (101 MHz, CDCl ): δ = 19.7 ppm. FTIR (neat): ν =
˜
3
3315 (w), 2975 (w), 2934 (w), 1749 (m), 1659 (s), 1536 (w),
1454 (w), 1398 (w), 1366 (w), 1251 (s), 1156 (w), 1112 (w), 1018 (s),
969 (s), 866 (w), 817 (w), 786 (w), 714 (w), 624 (w), 575 (w),
529 (w), 473 (m) cm–1. HRMS (ESI): calcd. for C15H29N2O7PNa
[M + Na]+ 403.1605; found 403.1603.
[11]
C. M. van Marle, B. Tollens, Ber. Dtsch. Chem. Ges. 1903, 36,
1351–1357.
1-(tert-Butylamino)-3-morpholino-1,3-dioxopropan-2-yl 2-(Di- [12]
ethoxyphosphoryl)acetate (30b): After an undocumented time
standing in CDCl3, a small amount of 30b was isolated as a colour-
a) C. Mannich, W. Krösche, Arch. Pharm. 1912, 250, 647–667;
b) C. Mannich, J. Chem. Soc. Abstr. 1917, 112, 634–635; c) C.
Mannich, Arch. Pharm. 1917, 255, 261–276.
a) M. Passerini, L. Simone, Gazz. Chim. Ital. 1921, 51, 126–
129; b) M. Passerini, Gazz. Chim. Ital. 1921, 51, 181–189.
a) I. Ugi, R. Meyr, U. Fetzer, C. Steinbrückner, Angew. Chem.
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less liquid. TLC (ethyl acetate): Rf = 0.22. 1H NMR (500 MHz,
[13]
CDCl3): δ = 6.99 (s, 1 H, NH), 5.74 (s, 1 H, 2-H), 4.27–4.08 [m, 4
H, P(OCH2)2], 3.91 (ddd, J = 13.1, J = 4.2, J = 4.2 Hz, 1 H,
[14]
NCH2), 3.79 (ddd, J = 13.3, J = 5.4, J = 3.1 Hz, 1 H, NCH2),
3.77–3.74 (m, 2 H, 2 OCH2), 3.71 (ddd, J = 11.5, J = 5.5, J =
3.4 Hz, 1 H, OCH2), 3.67–3.60 (m, 2 H, NCH2, OCH2), 3.51 (ddd,
J = 13.2, J = 7.4, J = 3.2 Hz, 1 H, NCH2), 3.18 (dd, J = 21.9, J =
[15]
A. Dömling, I. Ugi, Angew. Chem. 2000, 112, 3300–3344; An-
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14.7 Hz, 1 H, CH2CO2), 3.00 (dd, J = 20.1, J = 14.7 Hz, 1 H,
CH2CO2), 1.39–1.32 [m, 6 H, P(OCH2CH3)2], 1.37 [s, 9 H,
C(CH3)3] ppm. 13C NMR (125 MHz, CDCl3): δ = 163.9 (d, J =
6.0 Hz, CO2), 163.5 (C-3), 163.5 (C-1), 71.0 (C-2), 66.8 (OCH2),
66.8 (OCH2), 63.3 (d, J = 6.4 Hz, POCH2), 63.1 (d, J = 6.5 Hz,
POCH2), 52.1 [C(CH3)3], 47.0 (NCH2), 43.2 (NCH2), 34.1 (d, J =
133.7 Hz, CH2CO2), 28.7 [3 C, C(CH3)3], 16.5 [d, J = 6.0 Hz, 2 C,
P(OCH2CH3)2] ppm. 31P NMR (101 MHz, CDCl3): δ = 19.6 ppm.
[16]
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A. G. Neo, J. Delgado, C. Polo, S. Marcaccini, C. F. Marcos,
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[18]
FTIR (neat): ν = 3315 (w), 2974 (w), 2926 (w), 2864 (w), 2244 (w),
˜
1750 (m), 1659 (s), 1536 (w), 1450 (m), 1395 (w), 1365 (w), 1251 (s),
1162 (w), 1112 (m), 1019 (s), 968 (s), 866 (w), 836 (w), 786 (w),
731 (m), 567 (w), 531 (w), 480 (m), 428 (w) cm–1. HRMS (ESI):
calcd. for C17H31N2O8PNa [M + Na]+ 445.1710; found 445.1706.
[19]
[20]
[21]
[22]
[23]
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H, 13C, and 31P NMR spectra for all com-
pounds; X-ray structures of compounds 18g and 22.
Acknowledgments
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Financial support by the Deutsche Forschungsgemeinschaft
(DFG) and Fonds der Chemischen Industrie is gratefully acknowl-
edged.
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product
2-acetyl-N1-tert-butyl-2-hydroxy-N3,N3-dimethyl-
malonamide) contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Received: October 12, 2013
Published Online: December 6, 2013
1006
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