Aziridine-2-carboxaldehyde dimers undergo homo-Ugi 4-component-5-center reactions

Article abstract of DOI:10.1055/s-0030-1260261

Dimeric α-aziridine aldehydes have been used as the aldehyde component in Ugi and Passerini reactions. The highly reactive mixed anhydride intermediate is subject to nucleophilic attack by the aziridine, leading to homo-Ugi' β-acylaziridinyl-α-aminoamides. The products can be readily transformed into substituted lactones. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0030-1260261

SPECIAL TOPIC
▌2851
sApezciialrtiodpicine-2-carboxaldehyde Dimers Undergo Homo-Ugi 4-Component-
5-center Reactions
Homo-Ugi 4-Component-5-center Reactions
Benjamin H. Rotstein, Andrei K. Yudin*
Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON, M5S 3H6, Canada
Fax +1(416)9467676; E-mail: ayudin@chem.utoronto.ca
Received: 18.04.2012; Accepted: 11.05.2012
Though aziridines have been synthesized during the
Abstract: Dimeric α-aziridine aldehydes have been used as the al-
course of an Ugi multicomponent reaction,7 and have
dehyde component in Ugi and Passerini reactions. The highly reac-
been used simultaneously as amine and ketone surrogates
tive mixed anhydride intermediate is subject to nucleophilic attack
by the aziridine, leading to ‘homo-Ugi’ β-acylaziridinyl-α-amino-
in a three component coupling,8 until recently, no aziri-
amides. The products can be readily transformed into substituted dine had been reported to intercept the Ugi reaction. Two
lactones.
years ago, our lab introduced peptide macrocyclization
through an intercepted Ugi reaction.9 Using a reversibly
Key words: aziridines, aldehydes, multicomponent reactions, het-
erocycles, amphoteric molecules
autoprotected aziridine aldehyde as the oxo component,
the putative formimino anhydride intermediate is subject
to nucleophilic attack from the pendant NH-aziridine. In
the case of peptide macrocyclization, this preference for
aziridine attack over attack from the secondary amine is
explained by the significant ring-strain the latter process
would engender. The source of the high diastereoselectiv-
ity observed, unusual for Ugi reactions, is likely related to
the dimeric and homochiral nature of the aldehyde com-
ponent. Our lab has observed and reported several exam-
ples of aziridine aldehydes disrupting and templating
mechanisms of common reactions.9,10
Multicomponent reactions (MCRs) with high functional
group tolerance are instrumental in efforts to transform
simple and readily available starting materials into com-
plex molecules. At first, MCRs were limited to only a few
backbones. For example, the Ugi four-component reac-
tion produces the α-acylaminoamide scaffold (Figure
1a).1 Diversity within the products was realized using
building block arrays or by post-condensation modifica-
tions.2 In recent times, a great many variants of MCRs that
produce novel scaffolds have been reported.3
Aware that aziridine aldehyde-induced peptide macrocy-
clization functions through an Ugi-type 3-component 5-
centered process, we sought to apply this class of reagents
to 4-component-5-centered reactions. We envisioned that
the aziridine could intercept the formimino anhydride in-
termediate to give products based around an unusual β-
(acylaziridinyl)-α-aminoamide core (Figure 1b). The
‘homo-U-4CR’ reaction – which would produce β-(acyl-
amino)amides – has proven elusive.8,11 With the goal of
revealing useful scaffolds derived from aziridine alde-
hydes, we set out to study intercepted Ugi reactions using
untethered carboxylic acid and amine components.
R3
O
R3
O
a)
b)
H
N
R1
N
R4
R1
N
R4
N
H
R2
O
O
N
R2
R2'
Ugi α-acylaminoamide
β-(acylaziridinyl)-α-aminoamide
Figure 1 The scaffolds accessible by (a) the original Ugi 4CR, and
(b) the modified MCR described herein
Interception of the mixed anhydride intermediates of iso-
cyanide-based multicomponent reactions has led to the
development of several new processes. The Ugi–Smiles
reaction elaborates heterocycles by substitution of phe-
nols or aromatic thiols for carboxylic acids.4 Oxazoles
synthesized from isocyanoacetates and imines are stable
analogues of formylimino anhydrides, and have been
transformed in situ using a variety of pericyclic reactions.5
In the absence of an oxo-component, carboxylic acids
have been reacted with isocyanides to produce formimi-
date carboxylate mixed anhydrides, which function both
as strong acylating agents, and are able to rearrange to sta-
ble N-formyl amides.6
Mechanistically, α-aziridine aldehyde dimers are believed
to engage reactants without monomerization.10b,12 Imini-
um ion formation is followed by the α-addition of carbox-
ylate to the isocyanide, generating a formimino anhydride
(Scheme 1). Aziridine attack on this reactive acylating
species leads to the formation of the two amide bonds
found in the desired homo-Ugi product. One cannot envi-
sion such a process with other secondary amines, since
iminium formation would be unselective in those systems.
This process is mechanistically similar to aziridine alde-
hyde induced peptide macrocyclization. Insights into each
of these mechanisms could facilitate a deeper understand-
ing of peptide ring-closure kinetics.13
In a trial reaction, an equimolar mixture of serine-derived
aziridine-2-carboxaldehyde dimer, morpholine, tert-butyl
isocyanide, and 4-hydroxyphenylacetic acid were mixed
SYNTHESIS 2012, 44, 2851–2858
Advanced online publication: 11.07.2012
DOI: 10.1055/s-0030-1260261; Art ID: SS-2012-C0355-ST
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

2852
B. H. Rotstein, A. K. Yudin
SPECIAL TOPIC
reaction, there is less preorganization involved in iminium
activation.
R2'
OH
Cyclic secondary amines such as morpholine and pyrro-
lidine afforded the best yields due to increased rate of im-
inium ion formation. Dibenzylamine also performed well
in the reaction, but aliphatic secondary amines, such as di-
ethylamine, were not tolerated. This mirrors our findings
in peptide macrocyclization, where a proline-terminated
peptide is the ideal amine component. When isopropyl-
amine was used, a complex mixture was formed, from
which no desired product could be isolated. Benzylamine,
however, did participate in the reaction (Scheme 2). Inter-
estingly, isolation and characterization revealed that the
aziridine amide was not present in the product 1. Rather,
the product of an uninterrupted Ugi reaction was formed.
This stands in contrast to the analogous reaction with pri-
mary amino acids, which give stable cyclic products that
contain both the activated aziridine amide and a secondary
amine.9 In those cases, aziridine attack on the formimido
anhydride intermediate is kinetically favored. These ob-
servations have been attributed both to the high nucleo-
philicity of NH-aziridines, as well to ring strain
preventing amine attack. It is not currently known wheth-
er the aziridine amide is an intermediate in the present re-
action.
O
N
R2
NH
OH
R3
N
NH
– H2O
C
R3
N
R3
N
R4
O
R3
R1
R2'
HN
O
R1
OH
C
R2
O
N
R4
NH
–
R3
O
R3
R4
O
R2'
N
O
H
N
R2
R1
N
R4
∗
∗
N
O
H
NH
O
N
R1
R2
R2'
R3
Scheme 1 Proposed mechanism of ‘intercepted Ugi’ reaction
in 2,2,2-trifluoroethanol (TFE) at room temperature. The
desired intercepted-Ugi product was formed in 70% yield
(anti/syn = 1.15:1). By conducting the reaction in different
classes of solvents it was found that the process would
also take place in water, dichloromethane, N,N-dimethyl-
formamide, or methanol. Toluene did not facilitate the re-
action, presumably due to poor solubility of the
carboxylic acid. While the isolated yields from each suit-
able reaction solvent were comparable, product formation
was fastest in TFE. Addition of excess components did
not influence the reaction efficiency. The reaction appears
to reach completion within four hours. The optimal order
of addition was combination of the aldehyde and amine,
followed by sequential addition of the isocyanide and acid
components.
O
OH
O
OH
NH
N
TFE (0.2 M)
r.t., 4 h
b
N
H
O
N
O
Ph
∗
NC
a
Ph
Ph
NH2
NH
path b
path a
O
NH
The intercepted Ugi reaction was then tested with a vari-
ety of differentially functionalized inputs (Table 1).
Yields ranged from moderate to excellent, while diastere-
oselectivity was modest in most cases. Aromatic and ali-
phatic carboxylic acids were well tolerated. Heterocycles,
phenols, nitro groups, aryl halides, and even an aniline did
not interfere with the reaction course. A variety of isocy-
anides were tested, and all were compatible with the reac-
tion. Of particular note are the fluorescent isocyanide14
(entry 5) and thioester isocyanides15 (entries 6 and 16). As
well, both substituted and unsubstituted aziridine alde-
hydes performed similarly under these conditions.
O
H
N
Ph
N
∗
Ph
N
N
H
O
1
O
HN
Ph
(64 %, 1.3:1 dr)
Ph
Scheme 2 Reaction of aziridine-2-carboxaldehyde, benzoic acid,
benzylamine, and tert-butyl isocyanide, and possible mechanistic
pathways
In a few cases when using aliphatic carboxylic acids, mi-
nor products were observed after flash chromatography.
These products were characterized as lactones 2 and 3,
and are believed to form via intramolecular amide O-at-
tack on the activated aziridine (Scheme 3). The relative
stereochemistry of 2 was established using 1H NMR cou-
pling constant analysis and 2D NMR spectra. The struc-
ture of this compound was confirmed unambiguously by
X-ray crystallography (Scheme 3). We screened Lewis
acids to initiate this rearrangement in solution, but were
fruitless in this search. Heating the aziridine amide in di-
chloromethane in the presence of silica gel, however, did
Save for a few examples with poor selectivity, in each
case the anti-isomer was preferred. This was established
by comparison of JH,H coupling constants of the newly
formed stereocenter. Previous studies have found that the
carboxylate directly facilitates isocyanide addition to im-
inium ions.16 In peptide macrocyclization, the high facial
selectivity of isocyanide addition can be rationalized by
the presence of a tethered carboxylate, which could pre-
dispose the imine toward selective attack. In the present
3
Synthesis 2012, 44, 2851–2858
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Homo-Ugi 4-Component-5-center Reactions
2853
afford the desired lactone in synthetically useful yield. N- the observed lactones. This unanticipated transformation
Acylaziridines are typically subject to rearrangement to demonstrates the value of exploration into novel molecu-
oxazolines in the presence of acid.17 In our case, however, lar scaffolds, as well as the bountiful reactivity accessible
attack from the auxiliary tert-butylamide is faster. Ring from aziridine aldehydes.
substitution is followed by imidate hydrolysis to construct
Table 1 Intercepted Ugi Reactions with Aziridine Aldehyde Dimersa
Entry R1
R2, R2′
R3 (R/S)b
R4
Yield (%)c anti/syn drd
1
-CH2CH2OCH2CH2-
H (-,S)
t-Bu
70
80
1.2:1
2:1
HO
2
-CH2(CH2)2CH2-
H (-,S)
t-Bu
HO
3
4
Bn, Bn
Et, Et
H (-,S)
H (-,S)
t-Bu
t-Bu
89
0
3:1
n/a
HO
3-pyridyl
O
N
5
3-pyridyl
Ph
-CH2(CH2)2CH2-
H (-,S)
91
3:1
Me2N
O
O
6
-CH2CH2OCH2CH2-
H (-,S)
72
3.5:1
EtS
7
8
Et
-CH2CH2CHPhCH2CH2-
-CH2CH2OCH2CH2-
H (-,S)
H (-,S)
t-Bu
t-Bu
80
94
1.2:1
1:1
4-(NO2)C6H4
9
10
11
-CH2(CH2)2CH2-
-CH2(CH2)2CH2-
-CH2CH2OCH2CH2-
i-Pr (S,R)
Me (S,R)
i-Pr (S,R)
t-Bu
t-Bu
t-Bu
85
79
83
2.6:1
3.6:1
0.6:1
HO
HO
12
13
14
Ph
-CH2(CH2)2CH2-
-CH2CH2OCH2CH2-
Bn, Bn
i-Pr (S,R)
i-Pr (S,R)
i-Pr (S,R)
t-Bu
t-Bu
t-Bu
63
81
90
1.1:1
4:1
Et
3-pyridyl
1.8:1
15
16
-CH2(CH2)2CH2-
-CH2(CH2)2CH2-
i-Pr (S,R)
i-Pr (S,R)
t-Bu
82
59
0.9:1
1.1:1
S
O
2-BrC6H4
EtS
F
17
-CH2CH2OCH2CH2-
i-Pr (S,R)
t-Bu
72
3:1
F
NH2
a Reaction conditions: acid (0.1 mmol), amine (0.1 mmol), aziridine aldehyde dimer (0.05 mmol), isocyanide (0.1 mmol), TFE (0.2 M), 23 °C,
4 h
b Assignments refer to: (R3 substituent position, α-aldehyde position).
c Determined by recovery of starting material (b.r.s.m.).
d Determined by inspection of crude 1H NMR analysis.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2851–2858

2854
B. H. Rotstein, A. K. Yudin
SPECIAL TOPIC
Scheme 3 Lactones synthesized by aziridine ring opening on silica gel and crystal structure of 2
Finally, another surprising observation was made during
the course of these studies. The Ugi reaction is often che-
moselective due to the reversibility of the elementary
steps leading up to isocyanide attack on an activated im-
O
O
H
H
N
N
N
N
N
H
H
O
OH
O
OH
inium ion. Indeed, the barrier to isocyanide attack is great
enough that recent studies suggest the requirement for
general acid activation of the imine prior to isocyanide at-
tack.16 This also explains why Passerini products are sel-
dom observed during Ugi reactions. Surprisingly, the
formation of Passerini products was observed during a
few of our reactions. When we replicated these examples
in the absence of amine, we were further surprised that the
intercepted Passerini products were formed rapidly, near-
ly at a comparable rate to the Ugi products (Figure 2). In
the course of our investigations into peptide macrocycli-
zation, we have been trying to explain the high rate of re-
activity of aziridine aldehyde-induced macrocyclization.
This result seems to suggest that an aziridine aldehyde is
similarly susceptible to isocyanide attack as an aziridine
imine may be, and parallels some of our findings in reduc-
tive amination.10a In addition, the Passerini β-(acylaziridi-
nyl)-α-hydroxyamides contain a core scaffold entirely
unreported in the literature.
4 (73% b.r.s.m., 2.1:1 d.r)
5 (44% b.r.s.m., 3:1 d.r.)
Figure 2 Products of intercepted Passerini reaction
ed in the literature, and display rich and potentially useful
reactivity. This study has also produced findings that will
help to reveal the nature of aziridine aldehyde reactivity,
including macrocyclization applications.
All reactions were carried out under an atmosphere of air unless oth-
erwise stated. Reagents were used as obtained from commercial
suppliers or purified according to standard procedures. Aziridine-2-
carboxaldehyde was synthesized according to literature proce-
dure.9b THF was distilled from sodium benzophenone ketyl under
N2. TFE and 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) were pur-
chased from Oakwood Products (West Columbia, SC). Anhyd tolu-
ene and Et2O were obtained using the method described by
Grubbs.18 Flash chromatography was performed using SiliaFlash
P60 40–63 μm silica gel. TLC was performed on EMD silica gel 60
F
254 TLC glass plates and visualized with UV light, and I2 on silica
or permanganate stain. All 1H and 13C NMR spectra were recorded
using a Bruker 400 MHz and Varian 200, 300 or 400 MHz spec-
trometers and were internally referenced to residual protiosolvent.
2D (COSY, HSQC) NMR spectroscopy was used where appropri-
ate to assist the assignment of signals in the 1H and 13C NMR spec-
tra. LC-MS (ESI) was recorded on an Agilent 1200 Series
quadrupole spectrometer.
In summary, we have reported an application of unpro-
tected aziridine aldehyde dimers in isocyanide-based mul-
ticomponent reactions. The Ugi and Passerini reactions
are disrupted from their normal course by the presence of
a pendant aziridine. The products formed are unrepresent-
Synthesis 2012, 44, 2851–2858
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Homo-Ugi 4-Component-5-center Reactions
2855
(S)-Boc-Valinol
The product was extracted with EtOAc (3 × 100 mL), and the com-
bined organic extracts were dried (Na2SO4), filtered, and concen-
trated. The product was purified by vacuum distillation (47 °C/5
Torr); yield: 3.55 g (76%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 2.22 (dd, J = 7.3, 2.5 Hz, 1 H),
1.94 (ddd, J = 10.0, 7.6, 2.5 Hz, 1 H), 1.47 (s, 9 H), 1.31 (dd,
J = 13.9, 7.0 Hz, 1 H), 0.99 (dd, J = 18.5, 6.8 Hz, 6 H).
Boc-valine (50 g, 0.23 mol) was loaded into a round-bottomed
flask. THF (230 mL) was added, and the resulting solution was
cooled to –10 °C. i-Pr2EtN (40 mL, 0.23 mol) was added, followed
by isobutyl chloroformate (30 mL, 0.23 mol). The mixture was
stirred for 15 min and vacuum filtered into a 500 mL round-bot-
tomed flask. The filtrate was cooled to –10 °C. NaBH4 (13.05 g,
0.345 mmol) was dissolved in H2O (108 mL) and added using an
addition funnel over 5 min (CAUTION: Gas evolution! Rapid ad-
dition will lead to product loss.) After the addition is complete, the
reaction is diluted with H2O (100 mL) and extracted with EtOAc (3
× 200 mL). The combined organic extracts were dried (Na2SO4), fil-
tered, and concentrated to yield the title compound; yield: 45.1 g
(96%); colorless oil.
13C NMR (100 MHz, CDCl3): δ = 172.2, 81.9, 45.7, 35.4, 31.4, 28.2,
20.1, 19.7.
(2R,3S)-tert-Butyl 3-Methylaziridine-2-carboxylate20
The title compound was prepared in an analogous method to the iso-
propyl derivative described above; yield: 0.8 g (20%); pale yellow
oil.
1H NMR (400 MHz, CDCl3): δ = 2.23–2.16 (m, 1 H), 2.16–2.12 (m,
1 H), 1.47 (s, 9 H), 1.21 (d, J = 5.5 Hz, 3 H).
1H NMR (400 MHz, CDCl3): δ = 4.71 (d, J = 7.9 Hz, 1 H), 3.63
(ddd, J = 17.4, 11.1, 4.9 Hz, 2 H), 3.39 (d, J = 6.5 Hz, 1 H), 1.89–
1.69 (m, 1 H), 1.43 (s, 9 H), 0.97–0.87 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 172.0, 82.0, 37.2, 34.4, 28.2, 18.2.
13C NMR (100 MHz, CDCl3): δ = 171.3, 157.0, 79.6, 69.8, 64.2,
60.5, 58.2, 28.5, 19.6, 19.0, 18.6, 14.3.
(2S,4S,5R,6S)-6-Isopropyl-2-[(2R,3S)-3-isopropylaziridin-2-yl]-
3-oxa-1-azabicyclo[3.1.0]hexan-4-ol
(S)-Boc-Alaninol
The title compound was prepared in an analogous method to the iso-
To a flame-dried Schlenk flask equipped with a stir bar and a rubber
septum under N2 was cannulated (2R,3S)-tert-butyl 3-isopro-
pylaziridine-2-carboxylate (1.5 g, 8.1 mmol, 1.0 equiv) in toluene
(27 mL). The flask was cooled to –78 °C with stirring before
DIBAL-H (1.0 M, 16.2 mL, 16.2 mmol, 2.0 equiv) was added over
20 min by cannulation. After 2 h, the reaction was judged to be com-
plete by TLC (eluent: 25% EtOAc–hexanes), and MeOH (0.51 mL,
12.2 mmol, 1.5 equiv) was added over 10 min. The flask was
warmed to r.t., after which sat. aq Na2SO4 (2 mL) was added to in-
duce precipitation of aluminum salts. The salts were removed by fil-
tration and washing with EtOAc (15 mL). The filtrate was diluted
with H2O (15 mL), and extracted with EtOAc (3 × 20 mL). The
combined organic layers were dried (Na2SO4), filtered, and concen-
trated. The product was purified by flash chromatography (EtOAc–1%
Et3N–MeOH, 9:1); yield: 545 mg (60%); colorless solid; Rf = 0.14
(EtOAc–MeOH, 9:1).
propyl derivative described above; yield: 12.9 g (70%); colorless
oil.
1H NMR (399 MHz, CDCl3): δ = 4.73 (s, 1 H), 3.73 (d, J = 4.2 Hz,
1 H), 3.60 (dd, J = 11.0, 3.9 Hz, 1 H), 3.48 (dd, J = 11.0, 6.1 Hz, 1
H), 3.38 (d, J = 6.5 Hz, 1 H), 1.42 (s, 9 H), 1.12 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 156.5, 69.8, 30.9, 28.5, 19.0.
(S)-tert-Butyl 2-Isopropylaziridine-1-carboxylate19
Boc-valinol (15.2 g, 75 mmol) and TsCl (17.2 g, 90 mmol) were dis-
solved in anhyd Et2O (1.5 L). Fresh, finely powdered KOH (16.8 g,
300 mmol) was added to the flask. (Important: KOH pellets, not
flakes, should be used.) The mixture was heated to reflux until com-
pletion, as detected by TLC (~16 h). The mixture was then poured
into a separatory funnel containing ice and H2O. The organic layer
was separated, washed with brine (250 mL), dried (MgSO4), fil-
tered, and concentrated. The title compound was isolated by vacu-
um distillation (42 °C/2 Torr); yield: 7.2 g (52%); colorless oil.
1H NMR (CDCl3, 400 MHz): δ = 5.25 (s, 1 H), 4.90 (s, 1 H), 2.46
(d, J = 2.9 Hz, 1 H), 2.19 (br s, 1 H), 1.84 (br s, 1 H), 1.28 (m, 3 H),
1.16 (dd, J = 8.2, 2.9 Hz, 1 H), 1.03–0.98 (m, 12 H), 0.94 (d, J = 6.8
Hz, 3 H).
13C NMR (CDCl3, 100 MHz): δ = 96.6, 94.8, 49.9, 45.9, 40.6, 37.6,
32.3, 30.4, 20.3, 20.3, 20.2, 19.8.
1H NMR (400 MHz, CDCl3): δ = 2.21 (d, J = 6.2 Hz, 1 H), 2.12
(ddd, J = 7.4, 6.2, 3.9 Hz, 1 H), 1.93 (d, J = 3.8 Hz, 1 H), 1.44 (s, 9
H), 1.39 (dd, J = 13.7, 6.9 Hz, 1 H), 1.05 (d, J = 6.7 Hz, 3 H), 0.95
(d, J = 6.8 Hz, 3 H).
MS (ESI): m/z = 227.2 [M + H].
13C NMR (100 MHz, CDCl3): δ = 163.0, 80.9, 44.5, 31.1, 30.8, 28.0,
19.9, 19.2.
(2S,4S,5R,6S)-6-Methyl-2-[(2R,3S)-3-methylaziridin-2-yl]-3-
oxa-1-azabicyclo[3.1.0]hexan-4-ol
The title compound was prepared in an analogous method to the iso-
propyl derivative described above; yield: 205 mg (48%); pale yel-
low semi-solid; Rf < 0.1 (EtOAc–MeOH, 9:1).
1H NMR (400 MHz, CDCl3): δ = 5.24 (s, 1 H), 4.94 (s, 1 H), 2.39
(d, J = 2.9 Hz, 1 H), 2.12 (d, J = 2.6 Hz, 1 H), 2.07–1.95 (m, 1 H),
1.51–1.42 (m, 1 H), 1.29 (d, J = 5.6 Hz, 3 H), 1.17 (d, J = 5.6 Hz, 3
H).
(S)-tert-Butyl 2-Methylaziridine-1-carboxylate19
The title compound was prepared in an analogous method to the iso-
propyl derivative described above. Vacuum distillation: 30 °C/5
Torr; yield: 6.9 g (59%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 2.48–2.39 (m, 1 H), 2.23 (d,
J = 5.9 Hz, 1 H), 1.87 (d, J = 3.8 Hz, 1 H), 1.45 (s, 9 H), 1.26 (d,
J = 5.5 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 162.6, 81.0, 69.9, 33.7, 32.6, 28.1,
19.0, 17.5.
13C NMR (100 MHz, CDCl3): δ = 96.4, 94.2, 51.3, 39.7, 34.3, 29.6,
18.7, 16.5.
(2R,3S)-tert-Butyl 3-Isopropylaziridine-2-carboxylate20
MS (ESI): m/z = 171.1 [M + H].
A flame-dried flask with a stir bar was cooled to r.t. under N2. THF
(76 mL) and 2,2,6,6-tetramethylpiperidine (188 mL, 75.3 mmol)
were added by syringe. The contents were cooled to –78 °C. n-BuLi
(1.6 M in hexanes, 47.1 mL, 75.3 mmol) was added dropwise to the
flask by cannulation. The flask was then warmed at r.t. for 30 min,
then cooled again to –78 °C. (S)-tert-Butyl 2-isopropylaziridine-1-
carboxylate (4.65 g, 25.1 mmol) was dissolved in THF (76 mL), and
added to the flask by cannulation over 30 min. The reaction mixture
was stirred at –78 °C for 2 h or until completion. Sat. aq NH4Cl (100
mL) was added slowly to the flask, which was then warmed to r.t.
Multicomponent Reactions; General Procedure
A solution of aziridine aldehyde dimer (0.05 mmol, 0.5 equiv) and
amine (0.1 mmol, 1.0 equiv) in TFE (to make a 0.4 M solution of
the dimer) was mixed at r.t. for 5 min. Sequentially, isocyanide (0.1
mmol, 1.0 equiv) and carboxylic acid (0.1 mmol, 1.0 equiv) were
added. The reaction mixture was then stirred for 4 h, monitoring by
TLC (eluent: 50% EtOAc–hexanes) and LCMS. The reaction mix-
ture was then diluted with CH2Cl2 (10 mL) and washed with H2O (4
mL). The aqueous layer was extracted with CH2Cl2 (2 × 10 mL). If
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2851–2858

2856
B. H. Rotstein, A. K. Yudin
SPECIAL TOPIC
an emulsion formed, this was broken up by addition of brine. The
combined organic layers were dried (Na2SO4), filtered and concen-
trated. The crude residue was purified by flash chromatography us-
ing hexanes and EtOAc.
6.0 Hz, 2 H), 3.01–2.92 (br m, 3 H), 2.89 (dd, J = 14.8, 7.4 Hz, 2 H),
2.79 (t, J = 5.9 Hz, 2 H), 2.69–2.58 (m, 4 H), 2.36 (d, J = 6.6 Hz, 1
H), 1.24 (t, J = 7.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 198.4, 178.7, 170.5, 133.2, 132.4,
129.2, 128.6, 73.0, 67.2, 51.3, 43.3, 35.2, 35.2, 31.7, 23.5, 14.8.
(S)-N-(tert-Butyl)-2-{(S)-1-[2-(4-hydroxyphenyl)acetyl]aziri-
din-2-yl}-2-morpholinoacetamide (Table 1, entry 1)
Yield: 70 mg (70%); dr = 1.2:1; yellow semi-solid.
MS (ESI): m/z = 406.2 [M + 1].
(S)-N-(tert-Butyl)-2-(4-phenylpiperidin-1-yl)-2-[(S)-1-propio-
nylaziridin-2-yl]acetamide (Table 1, entry 7)
1H NMR (400 MHz, CDCl3): δ = 7.11 (br s, 1 H), 7.08 (d, J = 8.5
Hz, 2 H), 6.76 (d, J = 8.5 Hz, 2 H), 3.73–3.67 (m, 4 H), 3.64 (d,
J = 6.2 Hz, 2 H), 2.94–2.83 (m, 2 H), 2.61 (ddd, J = 11.2, 7.0, 3.8
Hz, 3 H), 2.35 (d, J = 8.8 Hz, 1 H), 2.32 (d, J = 3.1 Hz, 1 H), 2.20
(d, J = 6.4 Hz, 1 H), 1.34 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 184.2, 169.6, 155.8, 130.6, 125.4,
115.7, 73.3, 67.3, 51.1, 43.2, 35.5, 29.4, 28.8, 19.2.
Yield: 18.6 mg (80%); dr = 1.2:1; pale solid.
1H NMR (400 MHz, CDCl3): δ = 7.34–7.28 (m, 2 H), 7.22 (dd,
J = 7.8, 2.9 Hz, 3 H), 6.64 (s, 1 H), 4.96 (dd, J = 12.5, 6.2 Hz, 1 H),
4.86 (ddd, J = 10.4, 8.1, 4.4 Hz, 1 H), 4.02 (dd, J = 14.3, 8.1 Hz, 1
H), 3.94–3.85 (m, 1 H), 3.10 (d, J = 11.3 Hz, 1 H), 2.90 (d, J = 4.4
Hz, 1 H), 2.44 (ddd, J = 9.6, 7.9, 5.4 Hz, 2 H), 2.31 (d, J = 7.6 Hz,
1 H), 2.29–2.23 (m, 2 H), 1.95–1.82 (m, 2 H), 1.80–1.62 (m, 2 H),
1.37 (d, J = 3.8 Hz, 3 H), 1.35 (s, 9 H).
MS (ESI): m/z = 376.5 [M + H].
(S)-N-(tert-Butyl)-2-{(S)-1-[2-(4-hydroxyphenyl)acetyl]aziri-
din-2-yl}-2-(pyrrolidin-1-yl)acetamide (Table 1, entry 2)
Yield: 100.6 mg (80%); dr = 2:1; colorless wax.
13C NMR (100 MHz, CDCl3): δ = 178.1, 168.6, 146.0, 128.6, 126.9,
126.4, 76.3, 72.3, 57.4, 52.8, 50.6, 42.4, 34.0, 28.9, 22.1, 21.7.
1H NMR (400 MHz, CDCl3): δ = 7.08 (d, J = 8.5 Hz, 2 H), 7.01 (s,
1 H), 6.78 – 6.73 (d, J = 8.5 Hz, 2 H), 3.64 (d, J = 3.6 Hz, 2 H), 2.83
(dd, J = 6.9, 2.4 Hz, 2 H), 2.73–2.64 (m, 3 H), 2.36 (d, J = 8.6 Hz,
1 H), 2.33 (d, J = 3.2 Hz, 1 H), 2.15 (d, J = 6.5 Hz, 1 H), 2.04 (s, 1
H), 1.77 (s, 4 H), 1.34 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 184.0, 170.0, 155.5, 130.6, 125.8,
115.7, 72.2, 51.5, 51.0, 43.3, 37.2, 29.1, 28.8, 23.5.
MS (ESI): m/z = 372.7 [M + 1].
(S)-N-(tert-Butyl)-2-morpholino-2-[(S)-1-(4-nitrobenzoyl)aziri-
din-2-yl]acetamide (Table 1, entry 8)
Yield: 12.2 mg (94%); dr = 1:1; yellow oil.
1H NMR (400 MHz, CDCl3): δ = 8.26 (tt, J = 12.7, 7.7 Hz, 4 H),
6.50 (s, 1 H), 5.02–4.93 (m, 2 H), 3.79–3.74 (m, 2 H), 3.01–2.92 (m,
1 H), 2.71 (d, J = 3.4 Hz, 1 H), 2.61 (d, J = 8.9 Hz, 1 H), 2.43 (d,
J = 6.5 Hz, 1 H), 1.25 (s, 9 H).
MS (ESI): m/z = 360.3 [M + H].
MS (ESI): m/z = 391.2 [M + 1].
(S)-N-(tert-Butyl)-2-(dibenzylamino)-2-{(S)-1-[2-(4-hydroxy-
phenyl)acetyl]aziridin-2-yl}acetamide (Table 1, entry 3)
Yield: 22.5 mg (89%); dr = 3:1; colorless solid.
1H NMR (400 MHz, CDCl3): δ = 7.36 (s, 1 H), 7.33–7.24 (m, 10 H),
7.13 (d, J = 8.5 Hz, 2 H), 6.79 (d, J = 8.5 Hz, 2 H), 3.98 (d, J = 13.3
Hz, 2 H), 3.86–3.79 (m, 3 H), 3.70 (d, J = 6.3 Hz, 2 H), 2.97–2.90
(m, 1 H), 2.82 (d, J = 8.8 Hz, 1 H), 2.38 (d, J = 6.4 Hz, 1 H), 2.13
(d, J = 3.0 Hz, 1 H), 1.32 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 183.8, 170.5, 155.7, 138.9, 130.5,
129.0, 128.6, 128.6, 128.4, 127.4, 127.2, 125.9, 115.8, 63.9, 54.4,
53.2, 51.1, 43.5, 33.1, 29.9, 28.8.
(R)-N-(tert-Butyl)-2-{(2R,3S)-1-[2-(4-hydroxyphenyl)acetyl]-3-
isopropylaziridin-2-yl}-2-(pyrrolidin-1-yl)acetamide (Table 1,
entry 9)
Yield: 26 mg (94%); dr = 1:1; colorless solid.
1H NMR (400 MHz, CDCl3): δ = 9.37 (s, 1 H), 7.12 (d, J = 8.5 Hz,
2 H), 6.85 (s, 1 H), 6.76 (d, J = 8.6 Hz, 2 H), 3.64 (dd, J = 51.7, 15.6
Hz, 2 H), 2.73 (dd, J = 6.9, 3.2 Hz, 4 H), 2.67 (m, 1 H), 2.51 (dd,
J = 8.1, 3.2 Hz, 1 H), 2.33 (d, J = 7.9 Hz, 1 H), 1.73 (t, J = 2.9 Hz,
4 H), 1.58–1.49 (m, 1 H), 1.35 (s, 9 H), 1.16 (d, J = 6.7 Hz, 3 H),
0.89 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 181.9, 170.5, 154.9, 130.7, 126.8,
115.6, 72.2, 51.7, 50.8, 48.5, 44.0, 41.7, 29.8, 28.9, 23.6, 21.6, 19.8.
MS (ESI): m/z = 486.7 [M + H].
N-{2-[6-(Dimethylamino)-1,3-dioxo-1H-benzo[de]isoquinolin-
2(3H)-yl]ethyl}-2-(1-nicotinoylaziridin-2-yl)-2-(pyrrolidin-1-
yl)acetamide (Table 1, entry 5)
MS (ESI): m/z = 402.7 [M + 1].
N-(tert-Butyl)-2-{1-[2-(4-hydroxyphenyl)acetyl]-3-methylaziri-
din-2-yl}-2-(pyrrolidin-1-yl)acetamide (Table 1, entry 10)
Yield: 34 mg (85%); dr = 2.6:1; pale oil.
1H NMR (400 MHz, CDCl3): δ = 7.32 (dd, J = 8.0, 6.4 Hz, 2 H),
7.24–7.20 (m, 2 H), 6.76 (s, 1 H), 3.45 (s, 1 H), 3.27 (dd, J = 3.7,
1.8 Hz, 1 H), 3.23 (d, J = 3.5 Hz, 1 H), 2.53 (dd, J = 14.4, 10.4 Hz,
1 H), 2.23 (ddd, J = 6.8, 5.8, 3.6 Hz, 1 H), 1.86 (dd, J = 13.6, 6.8 Hz,
2 H), 1.77 (s, 2 H), 1.56 (dt, J = 13.2, 5.3 Hz, 2 H), 1.44 (dd, J = 7.6,
5.9 Hz, 2 H), 1.03 (s, 9 H), 1.01 (dd, J = 6.7, 3.7 Hz, 3 H).
Yield: 39 mg (91%); dr = 3:1; orange solid.
1H NMR (400 MHz, CDCl3): δ = 9.08 (d, J = 1.4 Hz, 1 H), 8.64 (dd,
J = 4.9, 1.6 Hz, 1 H), 8.46 (dd, J = 7.3, 1.1 Hz, 1 H), 8.35 (d, J = 8.2
Hz, 1 H), 8.27 (dd, J = 8.5, 1.1 Hz, 1 H), 8.16 (d, J = 8.0 Hz, 1 H),
7.53 (dd, J = 8.5, 7.3 Hz, 1 H), 7.25 (dd, J = 7.7, 5.1 Hz, 1 H), 6.97
(d, J = 8.3 Hz, 1 H), 4.40–4.32 (m, 1 H), 3.73–3.67 (m, 2 H), 3.61–
3.54 (m, 2 H), 3.05 (s, 3 H), 2.99 (s, 3 H), 2.86 (m, 4 H), 2.77 (d,
J = 8.7 Hz, 1 H), 2.55 (d, J = 3.3 Hz, 1 H), 2.14 (d, J = 6.6 Hz, 1 H),
1.81 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 184.6, 176.7, 170.9, 170.0, 133.3,
133.1, 133.1, 132.3, 130.1, 130.1, 130.0, 129.2, 129.1, 128.6, 128.5,
128.5, 128.4, 128.3, 127.1, 72.9, 67.1, 50.7, 43.2, 35.2, 35.0, 34.2,
23.4, 14.7.
13C NMR (100 MHz, CDCl3): δ = 184.6, 172.0, 150.1, 130.1, 126.4,
118.9, 57.3, 53.2, 43.4, 41.0, 40.5, 35.1, 28.5, 26.6, 22.4.
MS (ESI): m/z = 374.1 [M + 1].
(R)-N-(tert-Butyl)-2-[(2R,3S)-3-isopropyl-1-(3-phenylpropano-
yl)aziridin-2-yl]-2-morpholinoacetamide (Table 1, entry 11)
Yield: 31 mg (79%); dr = 3.6:1; crystalline colorless solid.
1H NMR (400 MHz, CDCl3): δ = 7.26 (t, J = 3.5 Hz, 2 H), 7.20 (dd,
J = 7.5, 2.7 Hz, 2 H), 6.37 (s, 1 H), 4.43 (dd, J = 6.6, 4.4 Hz, 1 H),
4.06 (t, J = 6.1 Hz, 1 H), 3.71 (t, J = 4.5 Hz, 4 H), 3.65–3.57 (m, 1
H), 2.94 (dd, J = 12.2, 4.9 Hz, 2 H), 2.66–2.51 (m, 6 H), 1.75–1.65
(m, 1 H), 1.34–1.31 (m, 9 H), 0.88 (dd, J = 10.8, 6.8 Hz, 6 H).
MS (ESI): m/z = 541.8 [M + 1].
S-Ethyl 3-{(S)-2-[(S)-1-Benzoylaziridin-2-yl]-2-morpholino-
acetamido}propanethioate (Table 1, entry 6)
Yield: 54.1 mg (72%); dr = 3.2:1; pale yellow oil.
1H NMR (400 MHz, CDCl3): δ = 8.03 (dd, J = 5.1, 3.3 Hz, 2 H),
7.63 (t, J = 6.0 Hz, 1 H), 7.54 (ddd, J = 6.9, 4.0, 1.2 Hz, 1 H), 7.44
(t, J = 7.6 Hz, 2 H), 3.74 (dt, J = 5.7, 3.7 Hz, 4 H), 3.58 (dd, J = 9.8,
Synthesis 2012, 44, 2851–2858
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Homo-Ugi 4-Component-5-center Reactions
2857
13C NMR (100 MHz, CDCl3): δ = 179.2, 167.7, 165.1, 140.8, 128.6,
128.5, 126.3, 74.1, 73.2, 67.3, 51.3, 51.1, 32.7, 32.4, 30.0, 28.9,
18.5, 18.3.
S-Ethyl 2-{2-[1-(2-Bromobenzoyl)-3-isopropylaziridin-2-yl]-2-
(pyrrolidin-1-yl)acetamido}-2-methylpropanethioate (Table 1,
entry 16)
Yield: 14.7 mg (82%); dr = 1.1:1; pale oil.
MS (ESI): m/z = 416.6 [M + 1].
1H NMR (300 MHz, CDCl3): δ = 7.80–7.75 (m, 1 H), 7.64 (dd,
J = 3.6, 2.4 Hz, 1 H), 7.30–7.28 (m, 2 H), 4.63 (dd, J = 8.0, 3.4 Hz,
1 H), 4.31 (dd, J = 8.0, 5.9 Hz, 1 H), 2.93–2.88 (m, 3 H), 2.84 (dd,
J = 7.4, 5.1 Hz, 7 H), 1.82 (dd, J = 8.4, 5.4 Hz, 8 H), 1.47 (s, 6 H),
1.40 (s, 5 H), 1.26–1.19 (m, 11 H), 1.04–0.99 (m, 8 H).
13C NMR (100 MHz, CDCl3): δ = 193.5, 169.1, 161.1, 134.1, 132.0,
131.8, 131.7, 127.4, 127.1, 81.1, 74.2, 71.6, 62.4, 51.8, 32.9, 26.2,
24.7, 23.6, 18.7, 14.6.
2-[(2R,3S)-1-Benzoyl-3-isopropylaziridin-2-yl]-N-(tert-butyl)-2-
(pyrrolidin-1-yl)acetamide (Table 1, entry 12)
Yield: 12.4 mg (83%); dr = 1.6:1; colorless solid.
1H NMR (400 MHz, CDCl3): δ (major isomer) = 8.06–8.01 (m, 2
H), 7.42 (ddd, J = 12.6, 5.6, 2.0 Hz, 3 H), 6.96 (s, 1 H), 4.61 (dd,
J = 6.4, 3.0 Hz, 1 H), 4.28 (t, J = 6.2 Hz, 1 H), 2.70–2.62 (m, 4 H),
2.35 (dd, J = 13.2, 5.7 Hz, 1 H), 1.79–1.72 (m, 4 H), 1.37 (s, 9 H),
1.25 (d, J = 6.8 Hz, 1 H), 0.80 (d, J = 6.8 Hz, 3 H), 0.63 (d, J = 6.6
Hz, 3 H); δ (minor isomer) = 7.98 (dd, J = 8.3, 1.3 Hz, 2 H), 7.53
(dd, J = 4.9, 3.6 Hz, 2 H), 6.45 (s, 1 H), 3.95 (t, J = 5.2 Hz, 1 H),
3.65 (t, J = 7.0 Hz, 1 H), 3.42 (t, J = 6.6 Hz, 1 H), 2.84–2.80 (m, 4
H), 1.83 (t, J = 6.3 Hz, 4 H), 1.17 (s, 1 H), 1.08 (s, 9 H), 1.02–0.99
(m, 3 H), 0.94 (dd, J = 6.8, 2.7 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ (both isomers) = 178.1, 170.2,
168.4, 162.0, 134.9, 132.9, 131.3, 130.0, 129.4, 128.5, 128.4, 128.4,
80.5, 74.5, 73.7, 73.6, 52.0, 51.8, 51.6, 50.8, 50.6, 41.0, 33.0, 29.5,
28.9, 28.4, 23.6, 23.5, 21.0, 20.4, 18.6, 18.2.
MS (ESI): m/z = 525.4, 527.4 [M + 1].
2-[1-(2-Amino-4,5-difluorobenzoyl)-3-isopropylaziridin-2-yl]-
N-(tert-butyl)-2-morpholinoacetamide (Table 1, entry 17)
Yield: 14.4 mg (72%); dr = 3:1; pale brown solid.
1H NMR (400 MHz, MeOD): δ = 7.39 (ddd, J = 11.7, 9.0, 5.5 Hz, 1
H), 6.58 (ddd, J = 17.8, 12.9, 6.8 Hz, 1 H), 4.34 (d, J = 5.5 Hz, 1 H),
3.68 (dd, J = 10.2, 5.6 Hz, 2 H), 3.16 (dd, J = 5.5, 3.1 Hz, 1 H),
2.97–2.86 (m, 2 H), 2.69–2.58 (m, 4 H), 2.33 (dd, J = 7.3, 3.0 Hz, 1
H), 1.61 (dt, J = 13.6, 6.8 Hz, 1 H), 1.28–1.25 (m, 9 H), 1.11–1.01
(m, 6 H).
13C NMR (100 MHz, MeOD): δ = 173.9, 170.3, 145.8, 119.7, 116.8,
106.0, 105.8, 105.5, 85.30, 68.1, 54.8, 46.9, 45.0, 31.3, 28.8, 20.2,
19.4.
19F NMR (377 MHz, MeOD): δ = –135.8 (ddd, J = 21.9, 12.7, 8.8
Hz), –136.7 (ddd, J = 22.2, 12.7, 9.2 Hz).
MS (ESI): m/z = 372.3 [M + 1].
(R)-N-(tert-Butyl)-2-[(2R,3S)-3-isopropyl-1-propionylaziridin-
2-yl]-2-morpholinoacetamide (Table 1, entry 13)
Yield: 9.6 mg (63%); dr = 1.1:1; colorless oil.
1H NMR (400 MHz, CDCl3): δ = 6.44 (s, 1 H), 4.43 (dd, J = 6.6, 4.2
Hz, 1 H), 4.06 (t, J = 6.2 Hz, 1 H), 3.73 (dd, J = 6.5, 2.7 Hz, 3 H),
2.70–2.56 (m, 5 H), 2.26 (qd, J = 7.6, 1.1 Hz, 2 H), 1.74 (dd,
J = 12.7, 6.7 Hz, 1 H), 1.33 (s, 9 H), 1.17 (t, J = 7.6 Hz, 3 H), 0.91
(dd, J = 16.2, 6.8 Hz, 6 H).
MS (ESI): m/z = 439.3 [M + 1].
N-{(S)-1-[(S)-Aziridin-2-yl]-2-(tert-butylamino)-2-oxoethyl}-N-
benzylbenzamide (1)
The title compound was prepared using benzylamine as the amine
component according to the general procedure; yield: 29 mg (64%);
dr = 1.3:1; colorless oil.
13C NMR (100 MHz, CDCl3): δ = 167.8, 166.8, 74.0, 73.5, 67.3,
51.4, 51.0, 32.7, 28.9, 21.8, 18.5, 18.2, 10.7.
MS (ESI): m/z = 340.5 [M + 1].
1H NMR (400 MHz, CDCl3): δ = 8.10–8.06 (m, 1 H), 7.93–7.89 (m,
1 H), 7.55 (t, J = 7.4 Hz, 1 H), 7.50–7.38 (m, 2 H), 7.36–7.28 (m, 2
H), 7.14 (d, J = 6.7 Hz, 1 H), 4.92–4.84 (m, 1 H), 4.11 (dd, J = 8.5,
7.2 Hz, 1 H), 3.79 (dd, J = 35.3, 13.3 Hz, 2 H), 3.21 (d, J = 6.6 Hz,
1 H), 1.33 (s, 9 H), 1.27 (s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 170.7, 169.5, 132.8, 131.7, 130.1,
128.8, 128.6, 128.4, 128.3, 127.6, 80.2, 65.9, 57.6, 52.6, 50.8, 28.7.
(R)-N-(tert-Butyl)-2-(dibenzylamino)-2-[(2R,3S)-3-isopropyl-1-
nicotinoylaziridin-2-yl]acetamide (Table 1, entry 14)
Yield: 19.1 mg (81%); dr = 4:1; pale solid.
1H NMR (400 MHz, CDCl3): δ = 9.07 (d, J = 1.4 Hz, 1 H), 8.66 (dd,
J = 4.8, 1.7 Hz, 1 H), 8.20 (dt, J = 8.0, 1.9 Hz, 1 H), 7.43–7.30 (m,
11 H), 6.38 (s, 1 H), 4.86 (dd, J = 6.2, 5.4 Hz, 1 H), 4.38 (dd, J = 6.3,
5.1 Hz, 1 H), 3.95–3.83 (m, 4 H), 3.15 (d, J = 5.2 Hz, 1 H), 1.95–
1.81 (m, 1 H), 1.36 (s, 9 H), 1.07 (d, J = 6.8 Hz, 3 H), 0.94 (d,
J = 6.8 Hz, 3 H).
MS (ESI): m/z = 366.6 [M + 1].
N-(2-Isopropyl-4-morpholino-5-oxotetrahydrofuran-3-yl)-3-
phenylpropanamide (2)
13C NMR (75 MHz, CDCl3): δ = 178.1, 172.2, 168.4, 160.1, 151.9,
149.4, 138.7, 135.8, 129.1, 128.9, 128.6, 128.5, 127.7, 124.2, 123.2,
79.3, 76.0, 66.2, 55.4, 53.3, 51.4, 33.0, 29.0, 19.1, 17.7.
The substrate (from Table 1, entry 11; 26 mg, 0.065 mmol) was dis-
solved in CH2Cl2 (2 mL) and added to a vial containing silica gel
(200 mg). The vial was heated to 40 °C for 2 h. The reaction mixture
was then loaded onto a silica gel column, and the product was eluted
by flash chromatography using hexanes and EtOAc; yield: 16.1 mg
(72%); colorless solid.
MS (ESI): m/z = 499.9 [M + 1].
(R)-N-Benzyl-2-{(2R,3S)-3-isopropyl-1-[2-(thiophen-3-yl)ace-
tyl]aziridin-2-yl}-2-(piperidin-1-yl)acetamide (Table 1, entry
15)
1H NMR (400 MHz, CDCl3): δ = 7.29 (dd, J = 9.4, 3.3 Hz, 2 H),
7.23–7.17 (m, 3 H), 5.55 (d, J = 9.0 Hz, 1 H), 4.58 (dd, J = 18.6, 8.9
Hz, 1 H), 3.79 (dd, J = 8.5, 5.0 Hz, 1 H), 3.66 (dd, J = 10.8, 6.1 Hz,
4 H), 3.49 (d, J = 10.0 Hz, 1 H), 2.98 (td, J = 7.2, 2.6 Hz, 2 H), 2.84–
2.76 (m, 2 H), 2.57–2.50 (m, 4 H), 1.83 (td, J = 6.9, 5.0 Hz, 1 H),
0.95 (dd, J = 6.8, 4.8 Hz, 6 H).
Yield: 15.3 mg (90%); dr = 1.8:1; yellow solid.
1H NMR (300 MHz, CDCl3): δ = 7.33–7.30 (m, 2 H), 7.25 (d,
J = 1.8 Hz, 1 H), 7.20–7.15 (m, 2 H), 7.10–7.08 (m, 1 H), 6.99 (ddd,
J = 8.1, 4.9, 1.3 Hz, 2 H), 6.72 (s, 1 H), 4.64 (d, J = 10.0 Hz, 1 H),
4.53 (dd, J = 6.5, 4.8 Hz, 1 H), 4.37 (d, J = 6.1 Hz, 1 H), 4.28 (d,
J = 5.8 Hz, 1 H), 4.16–4.10 (m, 2 H), 4.07 (d, J = 6.4 Hz, 1 H), 3.78
(dd, J = 8.7, 5.3 Hz, 1 H), 2.79 (d, J = 4.8 Hz, 1 H), 2.68 (dd,
J = 10.4, 5.6 Hz, 2 H), 2.53 (d, J = 7.5 Hz, 4 H), 1.80–1.72 (m, 1 H),
1.26 (t, J = 7.1 Hz, 2 H), 0.94–0.89 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 171.8, 171.7, 140.4, 128.8, 128.5,
126.7, 67.1, 49.6, 49.0, 38.4, 31.4, 30.6, 28.9, 18.5, 16.6.
MS (ESI): m/z = 361.6 [M + 1].
13C NMR (100 MHz, CDCl3): δ = 172.2, 169.2, 138.6, 135.3, 128.8,
128.6, 127.9, 127.5, 125.5, 122.5, 78.3, 74.8, 52.1, 50.5, 48.7, 43.2,
38.5, 32.7, 31.0, 29.7, 26.5, 24.3.
N-(2-Isopropyl-4-morpholino-5-oxotetrahydrofuran-3-yl)pro-
pionamide (3)
The substrate (from Table 1, entry 7; 12 mg, 0.035 mmol) was dis-
solved in CH2Cl2 (1 mL) and added to a vial containing silica gel
MS (ESI): m/z = 440.3 [M + 1].
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2851–2858

2858
B. H. Rotstein, A. K. Yudin
SPECIAL TOPIC
(0.1 g). The vial was heated to 40 °C for 2 h. The reaction mixture
was then loaded onto a silica gel column, and the product was eluted
by flash chromatography using hexanes and EtOAc; yield: 7.0 mg
(70%); pale yellow solid.
1H NMR (400 MHz, CDCl3): δ = 5.47 (d, J = 8.9 Hz, 1 H), 4.65 (dd,
J = 18.8, 8.9 Hz, 1 H), 3.93 (dd, J = 8.6, 5.1 Hz, 1 H), 3.71 (t, J = 4.7
Hz, 4 H), 3.58 (d, J = 10.1 Hz, 1 H), 2.96–2.87 (m, 2 H), 2.69–2.61
(m, 2 H), 2.24 (q, J = 7.7 Hz, 2 H), 2.03–1.92 (m, 1 H), 1.17 (t,
J = 7.6 Hz, 3 H), 1.02 (dd, J = 6.8, 1.5 Hz, 6 H).
References
(1) Ugi, I.; Steinbrückner, C. Angew. Chem. 1960, 72, 267.
(2) Marcaccini, S.; Torroba, T. Post-condensation
Modifications of the Passerini and Ugi Reactions, In
Multicomponent Reactions; Zhu, J.; Bienaymé, H., Eds.;
Wiley-VCH: Weinheim, 2005.
(3) Dömling, A. Curr. Opin. Chem. Biol. 2002, 6, 306.
(4) El Kaïm, L.; Gizolme, M.; Grimaud, L.; Oble, J. Org. Lett.
2006, 8, 4019.
(5) Gulevich, A. V.; Zhdanko, A. G.; Orru, R. V. A.;
Nenajdenko, V. G. Chem. Rev. 2010, 110, 5235.
(6) Wilson, R. M.; Stockdill, J. L.; Wu, X.; Li, X.; Vadola, P. A.;
Park, P. K.; Wang, P.; Danishefsky, S. J. Angew. Chem. Int.
Ed. 2012, 51, 2834.
(7) Ugi, I.; Schmid, T. J. Prakt. Chem. 1997, 339, 652.
(8) (a) Kern, O. T.; Motherwell, W. B. Chem. Commun. 2003,
2988. (b) Kern, O. T.; Motherwell, W. B. Chem. Commun.
2005, 1787.
13C NMR (100 MHz, CDCl3): δ = 173.4, 171.7, 67.2, 49.7, 49.2,
30.9, 30.0, 18.4, 16.9, 9.7.
MS (ESI): m/z = 285.1 [M + 1].
(S)-2-[(2R,3S)-1-Benzoyl-3-isopropylaziridin-2-yl]-N-(tert-bu-
tyl)-2-hydroxyacetamide (4)
The title compound was prepared from the starting materials used
for the product from Table 1, entry 12 according to the general pro-
cedure for multicomponent reactions, with the omission of amine.
The reaction was monitored by TLC (eluent: EtOAc) and LCMS.
Aqueous workup was performed after a 16 h reaction time; yield:
13.7 mg (73%); dr = 2.1:1; colorless oil.
(9) (a) Hili, R.; Rai, V.; Yudin, A. K. J. Am. Chem. Soc. 2010,
132, 2889. (b) Rotstein, B. H.; Rai, V.; Hili, R.; Yudin, A. K.
Nat. Protoc. 2010, 5, 1813.
1H NMR (400 MHz, CDCl3): δ = 8.13–8.10 (m, 1 H), 8.00–7.97 (m,
1 H), 7.59 (d, J = 7.4 Hz, 1 H), 7.44 (dd, J = 10.7, 4.3 Hz, 2 H), 6.40
(s, 1 H), 4.49 (t, J = 5.8 Hz, 1 H), 4.32 (t, J = 5.5 Hz, 1 H), 4.17 (d,
J = 5.1 Hz, 1 H), 1.87 (dd, J = 12.9, 6.7 Hz, 1 H), 1.17 (s, 9 H), 0.99
(dd, J = 6.8, 4.7 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 170.0, 166.4, 132.3, 130.2, 128.7,
128.6, 86.4, 71.5, 71.3, 51.4, 32.7, 28.5, 17.8, 16.9.
(10) (a) Hili, R.; Yudin, A. K. J. Am. Chem. Soc. 2006, 128,
14772. (b) Hili, R.; Yudin, A. K. J. Am. Chem. Soc. 2009,
131, 16404. (c) Cheung, L. L. W.; He, Z.; Decker, S. M.;
Yudin, A. K. Angew. Chem. Int. Ed. 2011, 50, 11798.
(11) (a) Dömling, A. Chem. Rev. 2006, 106, 17. (b) Homo-P-
3CR and U-4CR products were reported previously, but the
structural assignment of the homo-P-3CR products has since
been revised (see ref. 8b).
(12) (a) Hili, R.; Yudin, A. K. Angew. Chem. Int. Ed. 2008, 47,
4188. (b) Li, X.; Yudin, A. K. J. Am. Chem. Soc. 2007, 129,
14152.
(13) Kolano, C.; Helbing, J.; Kozinski, M.; Sander, W.; Hamm,
P. Nature 2006, 444, 469.
(14) Rotstein, B. H.; Mourtada, R.; Kelley, S. O.; Yudin, A. K.
Chem.–Eur. J. 2011, 17, 12257.
(15) Rotstein, B. H.; Winternheimer, D. J.; Yin, L. M.; Deber, C.
M.; Yudin, A. K. Chem. Commun. 2012, 48, 3775.
(16) Chéron, N.; Ramozzi, R.; El Kaïm, L.; Grimaud, L.; Fleurat-
Lessard, P. J. Org. Chem. 2012, 77, 1361.
(17) Zhou, P.; Chen, B.-C.; Davis, F. A. Asymmetric Syntheses
with Aziridinecarboxylate and Aziridine-phosphonate
Building Blocks, In Aziridines and Epoxides in Organic
Synthesis; Yudin, A. K., Ed.; Wiley-VCH: Weinheim, 2006.
(18) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R.
K.; Timmers, F. J. Organometallics 1996, 15, 1518.
(19) Wessig, P.; Schwarz, J. Synlett 1997, 893.
(20) Hodgson, D. M.; Humphreys, P. G.; Xu, Z.; Ward, J. G.
Angew. Chem. Int. Ed. 2007, 46, 2245.
MS (ESI): m/z = 319.4 [M + 1].
(S)-N-(tert-Butyl)-2-hydroxy-2-[(2R,3S)-3-isopropyl-1-nicoti-
noylaziridin-2-yl]acetamide (5)
The title compound was prepared from the starting materials used
for the product from Table 1, entry 14 according to the general pro-
cedure for multicomponent reactions, with the omission of amine.
The reaction was monitored by TLC (eluent: EtOAc) and LCMS.
Aqueous workup was performed after a 16 h reaction time; yield:
9.1 mg (44%); dr = 3:1; pale oil.
1H NMR (400 MHz, CDCl3): δ = 8.83–8.78 (m, 1 H), 8.37–8.31 (m,
1 H), 8.22–8.17 (m, 1 H), 7.45–7.36 (m, 2 H), 5.86 (s, 1 H), 4.93 (d,
J = 7.5 Hz, 1 H), 3.29 (dd, J = 7.5, 3.3 Hz, 1 H), 2.84 (dd, J = 7.3,
3.2 Hz, 1 H), 1.87–1.80 (m, 1 H), 1.38 (s, 9 H), 1.04–0.99 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 175.7, 163.9, 154.3, 151.2, 137.5,
136.5, 123.5, 75.0, 52.1, 48.2, 42.3, 30.0, 28.7, 20.4.
MS (ESI): m/z = 320.6 [M + 1].
Acknowledgment
We thank NSERC for financial support. We also thank Dr. Alan
Lough for X-ray crystal structure analysis of 2.
Synthesis 2012, 44, 2851–2858
© Georg Thieme Verlag Stuttgart · New York