Diversity-oriented synthesis of cyclopropyl peptides from Ugi-derived dehydroalanines

Article abstract of DOI:10.1016/j.tet.2017.09.005

A three-step synthesis of cyclopropyl peptides is reported. The protocol involves a consecutive Ugi-4CR/elimination reaction to prepare dehydroalanines followed by a Corey-Chaykovsky cyclopropanation reaction. Peptide-like molecules that resemble some pharmacologically active compounds with a variety of substituents in the cyclopropane ring were prepared. When (2-ethoxy-2-oxoethyl) dimethyl sulfonium ylide was used the reaction exclusively gives the cis-diastereoisomer cyclopropanes in good yields from readily prepared starting materials. A collection of 26 highly substituted cyclopropyl peptides were obtained.

Full text of DOI:10.1016/j.tet.2017.09.005

Accepted Manuscript
Diversity-oriented synthesis of cyclopropyl peptides from Ugi-derived dehydroalanines
David A. Contreras-Cruz, Miguel A. Sánchez-Carmona, Fabio A. Vengoechea-
Gómez, Daniel Peña-Ortíz, Luis D. Miranda
PII:
S0040-4020(17)30918-3
10.1016/j.tet.2017.09.005
TET 28956
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 13 June 2017
Revised Date: 4 September 2017
Accepted Date: 6 September 2017
Please cite this article as: Contreras-Cruz DA, Sánchez-Carmona MA, Vengoechea-Gómez FA,
Peña-Ortíz D, Miranda LD, Diversity-oriented synthesis of cyclopropyl peptides from Ugi-derived
dehydroalanines, Tetrahedron (2017), doi: 10.1016/j.tet.2017.09.005.
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Diversity-oriented synthesis of cyclopropyl
peptides from Ugi-derived dehydroalanines
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David A. Contreras-Cruz, Miguel A. Sánchez-Carmona, Fabio A. Vengoechea-Gómez, Daniel Peña-Ortíz and
Luis D. Miranda
Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria,
Coyoacán, Ciudad de México, 04510, México

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Diversity-oriented synthesis of cyclopropyl peptides from Ugi-derived
dehydroalanines
David A. Contreras-Cruza , Miguel A. Sánchez-Carmona,a Fabio A. Vengoechea-Gómez,a Daniel Peña-
Ortíza and Luis D. Mirandaa
a Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, Coyoacán, Ciudad de México, 04510, México.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A three-step synthesis of cyclopropyl peptides is reported. The protocol involves a consecutive
Ugi-4CR/elimination reaction to prepare dehydroalanines followed by a Corey-Chaykovsky
cyclopropanation reaction. Peptide-like molecules that resemble some pharmacologically active
compounds with a variety of substituents in the cyclopropane ring were prepared. When (2-
ethoxy-2-oxoethyl) dimethyl sulfonium ylide was used the reaction exclusively gives the cis-
diastereoisomer cyclopropanes in good yields from readily prepared starting materials. A
collection of 26 highly substituted cyclopropyl peptides were obtained.
Available online
Keywords:
cyclopropyl peptides
dehydroalanine
2017 Elsevier Ltd. All rights reserved
.
Ugi reaction
Corey-Chaykovsky reaction
———
Corresponding author. Tel.: +0-000-000-0000; fax: +0-000-000-0000; e-mail: lmiranda@unam.mx

2
Tetrahedron
ACCEPTED MANUSCRIPT
Cyclopropyl amino acids and peptides are important
carbonyl compound and an isonitrile.17 Remarkably, when this
synthetic targets, some of which display significant
pharmacological properties. Leading examples are eglumegad 1
(Figure 1) that offers significant potential for the treatment of
anxiety disorders1 and MK-0686 2 that shows considerable
promise for the treatment of chronic pain;2 indeed, both
molecules are currently in clinical trials. Additionally, belactosin
A (3) is a natural product that shows significant antitumor effects
and contains a cyclopropyl peptide framework.3 Interestingly, the
parent scaffold 1-aminocyclopropanecarboxylic acid (ACC) 4
possesses herbicidal activity and influences plant growth by
itself.4 Besides, ACC and their derivatives are the expected
starting materials for the synthesis of a variety of biologically
active cyclopropyl peptides through step-wise long peptide
coupling reactions.5 It is worth mentioning that the presence of
the cyclopropyl ring into a peptide backbone could increase
stability against metabolic degradation, as well as restriction of
conformational flexibility.6 Therefore, the development of
practical methodologies for the rapid construction of libraries of
peptide-like molecules containing a cyclopropane ring is highly
desirable. In this context, approaches for the synthesis of
reaction is combined with subsequent post-condensation
reactions, libraries of chemically diverse peptide-like scaffolds
can be rapidly assembled in a few reaction steps. Along this line,
we have shown that diversely substituted dehydroalanines
scaffolds could be accessed in a modular fashion through an Ugi-
4CR followed by an elimination process, from readily accessible
starting materials.18 Based on this work, we envisioned that the
application of a cyclopropanation reaction to these later Ugi-
derived dehydroalanines might compile an attractive three-step
protocol for the rapid construction of a library of cyclopropyl
peptides. At the outset, it was clear that such a protocol might
allow access to highly substituted cyclopropyl peptides, just by
taking advantage of the three diversification vectors produced by
the variation of the isonitrile, amine, and carboxylic acid in the
original four-component set of the Ugi reaction (Table 1). Thus,
in the present work, dehydroalanines obtained by an
Ugi/elimination protocol were cyclopropanated using Corey-
Chaykovsky conditions to construct a small cyclopropyl peptide
library. This report is part of our ongoing work toward the
development
of
novel
applications
of
Ugi-derived
cyclopropyl
derivatives
peptidomimetics
include the
involving
of
dehydroalanine
Corey-Chaykovsky
dehydroalanines.19
use
Accordingly, our work commenced with the synthesis of a
collection of differently substituted dehydroalanines using the
previously reported Ugi-4C microwave-assisted reaction between
the benzoyloxyacetaldehyde 5 with tert-butyl isonitrile 6 and
cyclopropanation conditions, in which α,β-dehydrolactone
adducts,7 didehydroalanine methyl esters,8 or Cbz-protected
enones9 are reacted with sulfur ylides.
various primary amines
7
and carboxylic acids 8.
COOH
H
H
Benzoyloxyacetaldehyde 5 was used as the aldehyde in the four-
component input set in all Ugi reactions because the benzoyl
group is essential to shape the dehydroalanine double bond in the
elimination step. Due to its accessibility, we chose the tert-butyl
isocyanide 6 for this study, although one cyclohexyl derivative
was also utilized in the further cyclopropanation process (see
Table 2, 11r). As shown in Table 1, all the Ugi adducts were
obtained in moderate to good yields, just by mixing the four
components in methanol under microwave irradiation at 100 ºC
for 2-3 h. As some decomposition of the product was observed in
some experiments, selected examples were performed at 50 ºC,
giving similar results, but with a cleaner profile (verified only by
TLC). We also observed that the reaction can be carried out in
refluxing methanol with similar yields, although over a longer
reaction time (12 h).
O
H2N
HOOC
O
O
CO2H
H2N
H
N
N
H
Eglumegad (1)
Metabotropic glutamate
receptor (mGluR2/3) antagonist
H
O
Belactosin A (3)
Activity against pancreome
and colon cancer
O
CF3
NH
COOH
NH2
O
N
CO2CH3
Cl
H
ACC (4)
F
Direct precursor of the
plant hormone ethylene
MK-0686 (2)
Bradiquinin receptor
(B1) antagonist
Figure 1. Biologically active cyclopropyl peptides.
With Ugi adducts 9a-q in hand, the elimination process was
implemented
employing
KOH
as
the
base
and
tetrabutylammonium iodide (TBAI) as a phase transfer catalyst.
Under these conditions, dehydroalanines 10a-q were obtained in
moderate to good yields (Table 1). In some cases, heating to 50
°C was required to accelerate the reaction (entries 3 and 5-17).
As expected, using the (S)-(−)-α-methylbenzylamine as the
amine input in the Ugi reaction (entry 8) gave an inseparable
diastereomeric mixture of 9h (1.7:1). However, this issue was
inconsequential since one chiral center was further removed after
the elimination process (10h), a reaction which unexpectedly
On the other hand, the 1,3-cycloaddition of diazo compounds
to dehydroamino acid derivatives has also been used to
synthesize cyclopropane amino acids. Diazomethane or
diazoalkanes react with a dehydroamino acid derivative to
furnish a pyrazoline, followed by extrusion of nitrogen gas which
produces
a
cyclopropane. Chiral 1,4-oxazinones,10 chiral
azlactone,11 chiral diketopiperazine,12 dehydroamino acid
acetonide,13 and didehydroalanine methyl esters8 have been used.
However, diazo compounds exhibit high toxicity and are
potentially explosive, which limits their utility.14 Some reports
have solved this problem by generating diazo compounds in situ
from the corresponding tosylhydrazone salt.15 Catalytic system
involving tosylhydrazone salts, rhodium tetraacetate, and chiral
sulfides to generate cyclopropanate α-amino acrylates has also
been reported.16 It is worth noting that in most of these methods
the amide links are created through classic reagents and using
time-consuming step-wise peptide coupling protocols.
gave only 11% yield. Similarly,
a low yield of the
dehydroalanine 10s was observed in the elimination step when
isopropylamine was used (9s, exp. 18). Furthermore, when
bulkier tert-butylamine was used in the Ugi adduct 9t, its total
decomposition was observed under the elimination conditions
and the dehydroalanine 10t was not observed (Table 1, exp 19).
These observations suggest that a bulky amine vector is
deleterious to the efficiency of the elimination process
(dehydroalanines 10h, 10s, 10t).
The Ugi four component reaction (4-CR) is a process in which
a dipeptide backbone is straightforwardly created using a single
experimental setup, starting from an amine, a carboxylic acid, a

3
Table 2. Synthesis of unsubstitued cyclopropanes
ACCEPTED MANUSCRIPT
Table 1. Synthesis of dehydroalanines.
O
S
O
N
O
N
I
R3
R3
(1.5 eq)
R2
O
R2
O
NaH (1.5 eq.)
DMSO r.t.
2-5 h
NH
t-Bu
HN
t-Bu
11
10
I
N
O
O
N
O
N
O
O
exp
1
R2
R3
Ph-
Product yield (%)f
O
MeO
MeO
MeO
4-MeO-Bn-
4-MeO-Bn-
4-MeO-Bn-
Bn-
9a (83)a
9b (74)a
9c (56)a
9d (32)b
9e (49)b
9f (63)b
9g (69)c
10a (73)d
NHtBu
NHtBu
NHtBu
11c (59 %)
11a (73 %)
11b (66 %)
2
2-I-Ph-
CH3-
Ph-
10b (60)d
10c (71)e
10d (81)d
10e (65)e
10f (23)e
10g (43)e
3
I
OMe
4
N
O
O
N
O
O
N
O
O
5
Bn-
2-I-Ph-
Ph-
6
2-MeO-Bn-
2-MeO-Bn-
NHtBu
11e (37 %)
NHtBu
NHtBu
11f (75 %)
11d (24 %)
7
2-I-Ph-
9h (41)c
8
Ph-
10h (11)e
Ph
(d.r. 1.7:1)
I
OMe
N
N
O
O
N
O
O
O
O
9
Ph-CH2-CH2-
Ph-CH2-CH2-
Ph-CH2-CH2-
Ph-
2-I-Ph-
4-MeO-Ph-
Ph-
9i (35)c
9j (69)c
9k (47)c
9l (84)c
10i (67)e
10j (87)e
10k (67)e
10l (74)e
10
11
12
NHtBu
NHtBu
NHtBu
11h (18 %)
OMe
11i (82 %)
11g (63 %)
4-MeO-Ph-CH2-
CH2-
I
MeO
9m (68)c
9n (32)c
10m (80)e
10n (53)e
N
O
O
13
14
4-MeO-Ph-CH2-
CH2-
2-I-Ph-
N
O
O
N
O
O
NHtBu
4-MeO-Ph-
(CH2)2-
4-MeO-Ph
NHtBu
11j (82 %)
NHtBu
11l (38 %)
11k (88 %)
15
16
17
18
19
2-Br-Ph-(CH2)2-
2-Br-Ph-(CH2)2-
2-Br-Bn-
iPr-
Ph-
2-I-Ph-
CH3-
Ph-
9o (56)c
9p (44)c
9q (39)c
9s (72)c
9t (38)e
10o (78)e
10p (84)e
10q (68)e
10s (35)d
10t (0)d
OMe
MeO
I
MeO
N
O
O
N
O
O
Br
N
O
O
NHtBu
NHtBu
11o (78 %)
tBu-
Ph-
11m (54 %)
NHtBu
11n (66 %)
Conditions: a) MeOH, 50 °C, MW. b) 100 °C, MW. c) reflux, MeOH. d)
KOH, 50%, TBAI, C6H6:H2O, 1:1, r.t., or e) 50 ºC.
Br
I
I
N
O
O
N
O
O
N
O
O
f) Isolated yield after column chromatography.
Br
NHtBu
HN
11q (82 %)
NHtBu
11p (89 %)
11r (59 %)*
N
O
O
NHtBu
11s (14 %)
*See supporting information. Isolated yields after column chromatography.
The next task involved defining suitable conditions to carry
out the cyclopropanation process. Fortunately, cyclopropane 11a
was easily obtained under Corey-Chaykovsky modified
conditions applied to dehydroalanine 10a.20 Commercially
available trimethylsulfoxonium iodide proved to be an efficient
ylide source, and sodium hydride was used as the base; the
reactions proceeded smoothly in anhydrous DMSO. Then we

4
Tetrahedron
ACCEPTED MANUSCRIPT
prepared a series of cyclopropanes using dehydroalanines 10
Table 4. Synthesis of substitued cyclopropanes.
(Table 2). In all cases, a slight excess of trimethylsulfoxonium
iodide and sodium hydride were required to ensure the complete
consumption of dehydroalanines 10. Under these conditions,
regular to good yields were obtained in general, except for the
cyclopropanes 11h and 11s which were obtained in low yields,
probably by the influence of the bulky amine moiety (vide
supra). It is worth noting that cyclopropane 11r, bearing a
cyclohexyl moiety (from cyclohexylisocyanide, obtained
previously by our group),19a was also obtained, demonstrating
that dehydroalanines derived from a different isocyanide source
can be cyclopropanated with good results.
N
O
MeO
CONHtBu
CO2Et
13a (56%)
I
I
N
O
N
O
N
O
To extend the scope of the protocol, then we envisioned the
variation of the ylide source to obtain three-substituted
cyclopropanes. Thus, readily accessible (2-ethoxy-2-oxoethyl)
dimethylsulfonium bromide 12 was tested as the ylide precursor
and its sulfonium ylide was generated in situ under basic
conditions from 12. A short screening was carried out to optimize
the process using dehydroalanine 10a as a model substrate (Table
3). Under standard conditions, in which DMF was used as
solvent, no conversion of dehydroalanine 10a was observed
(entries 1, 2). Likewise, solvents such as 1,2-DCE and
chloroform (entries 3, 4) gave low yields. A slight increase in the
yield was observed when a THF/chloroform mixture was used
(entry 5), but the best yield was obtained using anhydrous THF
and sodium hydride as the base (entry 7, 8). Potassium tert-
butoxide gave poor results when used as the base in the same
solvent (entry 6). Heating to reflux was necesary to shorten the
reaction time and to improve the yield. Three equivalents of the
sulfonium bromide and the base were required to reach complete
consumption of starting material. Under these optimized
conditions, cyclopropane 13a was obtained in 56% yield (entry
8). Notably, exclusively cis diastereomer 13a (with the N-
benzylbenzamido group as reference)21 was isolated after flash
column chromatography and unambiguously characterized by
single crystal X-Ray analysis (Table 4) and 1H RMN
spectroscopy.
CONHtBu
CONHtBu
MeO
CONHtBu
CO2Et
13b (84%)
CO2Et
CO2Et
13d (41%)
13e (56%)
MeO
MeO
I
I
N
O
N
O
O
N
O
CONHtBu
CO2Et
CONHtBu
HN
EtO2C
CO2Et
13l (16%)
13m (46%)
13r (57%)*
*See supporting information. Isolated yields after column chromatography.
Then, selected dehydroalanines 10 were submitted to the
optimized conditions to obtain a series of seven three-substituted
cyclopropyl peptides 13a-r (Table 4). In general, moderate to
good yields were obtained in the cyclopropanation process. It
should be noted that higher temperatures and longer times were
required to carry out cyclopropanation using sulfonium bromide
12
in
comparison
with
cyclopropanation
using
trimethylsulfoxonium iodide. As expected, all further examples
showed cis diastereoselectivity, as verified by the X-ray analysis
of 13d, 13e, and 13m.22 Interestingly, dehydroalanines 10f, 10g,
10h and 10s were unreactive under these conditions (see 11f, g,
h, s for reference). Apparently, the presence of a methyl or o-
methoxy group near the double bond of the dehydroalanine
Table 3. Optimization screening to obtain 13a.
moiety, exerts
a certain steric hindrance for the ylide
approximation, although this is only a speculation and the actual
effect remains unknown.
Br
EtO2C
S
O
N
O
N
R3
12
R3
Diastereoselectivity can be rationalized in the following way:
the sulfonium ylide could react with dehydroalanine 10 in two
orientations, generating the zwitterionic intermediates A or B
(Scheme 1). Then, unfavorable dipole-dipole interaction between
ester and amide carbonyl groups in transition state I of the
cyclopropanation step might be expected to prevent the formation
of th trans-diastereoisomer. Conversely, in the transition state II
this interaction is avoided, and might be responsible for the
exclusively observed cis diastereoselectivity. Interestingly, in the
transition sate II the carbonyl group of the ester faces the amine
moiety, an interaction that might be responsible for the failure of
the cyclopropanation process in dehydroalanines 10f, g, h, s
which bear relatively bulkier residues as the R2 substituent.
R2
O
(3 eq.)
R2
O
base
NH
t-Bu
HN
t-Bu
10
CO2Et
13
entry
solvent
base (eq.)
T (°C)
time (h)
yield
(%)
1
2
3
4
5
6
7
8
DMF
DMF
NaH (3)
tBuOK (3)
DBU (2)
DBU (1.5)
NaH (2)
25
25
24
48
24
144
24
8
n.r
n.r
3
1,2 DCE
CHCl3
reflux
25
17
30
9
In summary, a practical linear three-step synthesis of highly
substituted cyclopropanes using the sequence Ugi-
4CR/elimination/Corey-Chaykovsky reaction is reported. Using
this strategy, a series of 1,1-two- substituted and 1,1,2-cis-three-
substituted cyclopropanes were synthesized. The substitution
pattern of the cyclopropanes could be diversely tuned in the
multicomponent Ugi reaction and then in the Corey-Chaykovsky
cyclopropanation process. Due to the important pharmacological
properties of the peptidomimetic cyclopropanes, we believe that
THF/CHCl3 1:1
THF
25
tBuOK (3)
NaH (3)
reflux
25
THF
24
14
51
56
THF
NaH (3)
reflux

5
this protocol might be useful for the synthesis of libraries of such
scaffolds in medicinal chemistry programs.
removed under vacuum to get a crude oil which was purified by
ACCEPTED MANUSCRIPT
flash chromatography eluting with a hexane/ethyl acetate solvent
system.
For method C. In a round-bottom flask under argon
atmosphere, 2-oxoethyl benzoate 5 (0.98 g, 6 mmol, 1.5 eq.) was
dissolved in 14 mL of methanol. Then amine 7 (4 mmol, 1 eq.)
was added and stirred to room temperature for fifteen minutes,
and then carboxylic acid 8 (4 mmol, 1 eq.) was added. After
stirring fifteen minutes, t-butyl isocyanide 6 (0.46 mL, 4 mmol, 1
eq.) was added and stirred for fifteen minutes. Heating to reflux
was started and maintained for 12 h. After cooling to room
temperature, the organic solvent was removed under vacuum to
S
CO2Et
+
10
R1
O
R1
O
HN
HN
N
R2
N
R2
O
O
O
O
H
B
A
H
O
get a crude oil which was purified by flash column
S
S
O
chromatography eluting with a hexane/ethyl acetate solvent
system.
See supporting information for characterization details of the Ugi
adducts.
R1
O
R1
O
HN
HN
N
R2
O
N
R2
O
O
General procedure for the synthesis of dehydroalanines 10.
In a round-bottom flask under argon, the Ugi adduct 9 (1.35
mmol, 1 eq.) was taken in 11 mL of benzene, then
tetrabutylammoniun iodide (0.15 g, 0.4 mmol, 0.3 eq.) was
added. Later, 11 mL of 50% aqueous KOH solution were added,
and the mixture was stirred at room temperature (Method D) or
with heating to 50 °C (Method E) until the starting material was
consumed. Benzene was removed under vacuum, and the product
was extracted with 10 mL of dichloromethane(3x10ml). The
combined dichloromethane extracts were dried over sodium
sulfate and concentrated under vacuum to furnish a brown oil.
The residue was purified by flash column chromatography on
silica gel eluting with hexane/ethyl acetate solvent system.
O
O
H
I
H
II
O
S
S
X
R1
O
R1
O
HN
HN
R2
O
N
N
O
R2
O
O
O
H
O
H
13-trans
13-cis
N-(3-(tert-butylamino)-3-oxoprop-1-en-2-yl)-N-(4-
methoxybenzyl)benzamide (10a).
Ugi adduct 9a (1.0 eq.) was reacted with KOH solution according
to the general procedure (Method D) stirring for 3.5 hours. The
resulting oil was purified by flash column chromatography
eluting with a hexane/ethyl acetate (7:3) solvent system to
provide 10a as a light yellow solid (73%) Mp: 82-84 °C. 1HNMR
(CDCl3, 400 MHz, 25 °C) δ = 1.03 (s, 9H), 3.79 (s, 3H), 4.90 (s,
2H), 5.24 (s, 2H), 5.88 (s, 1H), 6.87 (d, J = 8.7 Hz, 2H), 7.20-
7.42 (m, 5H), 7.47-7.60 (m, 2H); 13C NMR (CDCl3,100 MHz) δ
= 28.1, 51.1, 52.8, 55.3, 114.2, 128.0, 128.5, 129.3, 130.3, 130.5,
135.4, 145.0, 159.4, 162.8, 170.6; IR (Sol CHCl3) 789, 1237,
1512, 1607, 1663, 3065 cm-1; HRMS (ESI+) m/z calcd for
C22H27N2O3 [M+H]+ 367.2021, found 367.2024.
Scheme 1. Rationalization of the cis selectivity
1. Experimental section
1.1 General methods.
Unless otherwise noted, all reagents were obtained commercially
and used without further purification. 1H and 13C spectra were
recorded on Jeol Eclipse-300 MHz, Bruker Avance III-400 MHz
and Varian Unity Inova-500 MHz model spectrometers. Mass
spectra were recorded on a Jeol JMS-700 spectrometer or on a
Jeol JMS-T100LC spectrometer. Infrared spectra were obtained
with a Bruker Tensor 27 FT-IR spectrometer. Optical rotation
was measured on Perkin Elmer Model 343 polarimeter with
sodium lamp. Column chromatography was performed with silica
gel (200-300 mesh).
N-(3-(tert-butylamino)-3-oxoprop-1-en-2-yl)-2-iodo-N-(4-
methoxybenzyl)benzamide (10b).
Ugi adduct 9b (1.0 eq.) was reacted with KOH solution
according to the general procedure (Method D) stirring for 4
hours. The resulting oil was purified by flash column
chromatography eluting with a hexane/ethyl acetate (7:3) solvent
system to provide 10b as a yellow solid (60%) Mp: 81-86 °C. 1H
NMR (CDCl3, 400 MHz, 25 °C) δ = 1.03 (s, 2H), 1.17 (s, 6H)*,
1.33 (s, 1H), 3.80 (s, 3H), 4.90 (s, 2H), 5.34 (s, 1H), 5.45 (s, 1H),
5.82 (s, 1H), 6.85- 6.90 (m, 2H), 7.22-7.77 (m, 5H), 7.74-7.76
(m, 1H) (*Rotamers can be observed at 25°C); 13C NMR (CDCl3,
100 MHz) δ = 28.0, 28.3, 51.1, 51.4, 51.6, 52.8, 55.3, 94.1,
114.1, 114.2, 121.5, 127.6, 127.9, 128.0, 128.4, 128.9, 129.3,
130.2, 130.4, 130.5, 130.8, 135.4, 139.3, 141.3, 142.6, 145.0,
159.4, 159.5, 162.5, 169.7; IR (Sol CHCl3) 1626, 1664, 2968,
3269 cm-1; HRMS (ESI+) m/z calcd for C22H26I1N2O3 [M+H]+
493.0988, found 493.0997.
General procedures for the synthesis of Ugi adducts 9.
For method A and method B: In a microwave tube under
argon, 2-oxoethyl benzoate 5 (0.98 g, 6 mmol, 1.5 eq.) was
dissolved in 14 mL of methanol. Then amine 7 (4 mmol, 1 eq.)
was added and stirred for five minutes, and then carboxylic acid
8 (4 mmol, 1 eq.) was added. After five minutes, t-butyl
isocyanide 6 (0.46 mL, 4 mmol, 1 eq.) was added and stirred for
5 minutes. The tube was sealed with a pressure cap and heated to
50 °C (Method A) or 100 °C (Method B) for 3 h, under
microwave irradiation in a Biotage Initiator+ microwave reactor.
After cooling to room temperature, the organic solvent was

6
Tetrahedron
ACCEPTED MANUSCRIPT
N-tert-butyl-2-(N-(4-methoxybenzyl)acetamido)acrylamide
eluting with a hexane/ethyl acetate (7:3) solvent system to
1
(10c).
provide 10g as a white solid (43 %) Mp: 108-110°C. H NMR
(CDCl3, 400 MHz, 25 °C) δ =1.17 (s, 9H), 3.81 (s, 3H), 5.05 (s,
2H), 5.49 (s, 1H), 5.59 (s, 1H), 5.87 (s, 1H), 6.83-7.02 (m, 3H),
7.20-7.32 (m, 3H), 7.53 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 8.0 Hz,
1H); 13C NMR(CDCl3, 100 MHz) δ = 28.3, 46.2, 51.2, 55.6, 94.1,
110.7, 121.0, 121.2, 124.6, 127.5, 128.0, 129.5, 130.3, 131.7,
139.4, 141.4, 142.5, 157.8, 162.4, 169.8; IR (Sol CHCl3) 742,
1404, 1616, 1664, 2978, 3349 cm-1; HRMS (ESI+) m/z calcd for
C22H26I1N2O3 [M+H]+ 493.0988, found 493.0998.
Ugi adduct 9c (1.0 eq.) was reacted with KOH solution according
to the general procedure (Method E) stirring for 1.5 hours. The
resulting oil was purified by flash column chromatography
eluting with a hexane/ethyl acetate (65:35) solvent system to
1
provide 10c as a light orange solid (71%) Mp: 99-101 °C. H
NMR (CDCl3, 400 MHz, 25 °C) δ = 1.14 (s, 9H), 2.00 (s, 3H),
3.79 (s, 3H), 4.69 (s, 2H), 5.40 (s, 2H), 6.37 (s, 1H), 6.86 (d, J =
8.7 Hz, 2H), 7.28 (d, J = 8.6 Hz, 2H); 13C NMR (CDCl3, 100
MHz) δ = 22.2, 28.1, 51.1, 51.9, 55.2, 114.3, 122.4, 129.2, 130.6,
143.8, 159.5, 162.2, 170.3; IR (Sol CHCl3) 1621, 1667, 2965,
3351 cm-1; HRMS (ESI+) m/z calcd for C17H25N2O3 [M+H]+
305.1865, found 305.1868.
(R)-N-(3-(tert-butylamino)-3-oxoprop-1-en-2-yl)-N-(1-
phenylethyl)benzamide (10h).
Ugi adduct 9h (1.0 eq.) was reacted with KOH solution
according to the general procedure (Method E) stirring for 2.5
hours. The resulting oil was purified by flash column
chromatography eluting with a hexane/ethyl acetate (7:3) solvent
system to provide 10h as a yellow oil (11 %). [α]D 25 = -0.47 (c =
N-benzyl-N-(3-(tert-butylamino)-3-oxoprop-1-en-2-
yl)benzamide (10d).
Ugi adduct 9d (1.0 eq.) was reacted with KOH solution
according to the general procedure (Method D) stirring for 24
hours. The resulting oil was purified by flash column
chromatography eluting with a hexane/ethyl acetate (7:3) solvent
system to provide 10d as a colorless solid (81%) Mp: 55-59 °C.
1H RMN (CDCl3, 300 MHz, 25 °C) δ = 1.01 (s, 9H), 4.97 (s, 2H),
5.26 (s, 2H), 5.86 (br, 1H), 7.29-7.46 (m, 8H), 7.55-7.59 (m, 2H);
13C RMN (CDCl3, 75 MHz) δ = 28.1, 51.3, 53.6, 128.1, 128.2,
128.6, 128.9, 129.0, 130.8, 135.4, 137.3, 145.3, 162.9, 177.7. IR
(Sol CHCl3) 1613, 1664, 2974, 3353 cm-1; HRMS (ESI+) m/z
calcd for C21H25N2O2 [M+H]+ 337.1916, found 337.1917.
1
0.63, CHCl3); H NMR (CDCl3, 400 MHz, 25 °C) δ =0.99 (s,
9H), 1.67 (d, J = 7.1 Hz, 3H), 5.19 (br, 2H), 6.16 (br, 1H), 7.15-
7.40 (m, 6H), 7.40-7.62 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ
=27.9, 28.5, 51.0, 54.2, 126.8, 128.0, 128.2, 128.5, 128.7, 128.8,
129.6, 130.2, 133.2, 136.2, 163.0, 171.0; IR (Sol CHCl3) 697,
1612, 1667, 2969, 3341 cm-1; HRMS (ESI+) m/z calcd for
C22H27N2O2 [M+H]+ 351.2072, found 351.2079.
N-(3-(tert-butylamino)-3-oxoprop-1-en-2-yl)-N-
phenethylbenzamide (10i).
Ugi adduct 9i (1.0 eq.) was reacted with KOH solution according
to the general procedure (Method E) stirring for 4 hours. The
resulting oil was purified by flash column chromatography
eluting with a hexane/ethyl acetate (7:3) solvent system to
N-benzyl-N-(3-(tert-butylamino)-3-oxoprop-1-en-2-yl)-2-
iodobenzamide (10e).
Ugi adduct 9e (1.0 eq.) was reacted with KOH solution according
to the general procedure (Method E) stirring for 21 hours. The
resulting oil was purified by flash column chromatography
eluting with a hexane/ethyl acetate (7:3) solvent system to
1
provide 10i as a light yellow solid (67 %) Mp: 117-120°C. H
NMR (CDCl3, 300 MHz, 25 °C) δ =1.16 (s, 4H)*, 1.39 (s, 5H),
2.94 (t, J = 6.9 Hz, 1H), 3.01-3.09 (m, 1H), 3.73 (td, J = 6.9, 5.9
Hz, 1H), 3.86-3.98 (m, 1H), 5.01 (s, 0.5H)*, 5.50 (s, 0.5H), 5.69
(d, J = 0.8 Hz, 0.5H)*, 6.13 (s, 0.5H), 6.81 (s, 0.5H), 7.19-7.57
(m, 9H), 7.69 (dd, J = 8.3, 1.4 Hz, 1H) (*Rotamers can be
observed at 25°C); 13C NMR (CDCl3, 75 MHz) δ = 23.9, 28.2,
33.7, 35.7, 41.1, 51.2, 51.4, 51.5, 126.5, 126.7, 128.1, 128.3,
128.5, 128.6, 128.7, 128.8, 128.9, 130.5, 131.3, 134.6, 135.6,
138.7, 138.8, 145.3, 159.3, 163.1, 163.2, 167.4, 170.8; IR (Sol
CHCl3) 694, 1312, 1518, 1632, 2931, 2972, 3332 cm-1; HRMS
(ESI+) m/z calcd for C22H27N2O2 [M+H]+ 351.2072, found
351.2068.
1
provide 10e as a yellow solid (65 %) Mp: 104-107 °. H NMR
(CDCl3, 400 MHz, 25 °C) δ = 1.15 (s, 9H), 4.93 (s, 2H), 5.42 (s,
2H), 5.74 (s, 1H), 6.75-7.44 (m, 9H); 13C NMR (CDCl3, 100
MHz) δ = 28.3, 51.4, 52.0, 94.2, 121.1, 127.6, 128.0, 128.0,
128.8, 129.3, 130.4, 136.8, 139.3, 141.2, 142.6, 162.6, 169.7; IR
(Sol CHCl3) 730, 1188,1619, 1664, 2970, 3332 cm-1; HRMS
(ESI+) m/z calcd for C21H24I1N2O2 [M+H]+ 463.0882, found
463.0871.
N-(3-(tert-butylamino)-3-oxoprop-1-en-2-yl)-N-(2-
methoxybenzyl)benzamide (10f).
Ugi adduct 9f (1.0 eq.) was reacted with KOH solution according
to the general procedure (Method E) stirring for 55 hours. The
resulting oil was purified by flash column chromatography
eluting with a hexane/ethyl acetate (8:2) solvent system to
provide 10f as a light yellow solid (23 %) Mp: 95-98 °C. 1HNMR
(CDCl3, 400 MHz, 25 °C) δ = 1.07 (s, 9H), 3.79 (s, 3H), 5.02 (s,
2H), 5.20 (s, 1H), 5.59 (s, 1H), 5.85 (s, 1H), 6.86 (d, J = 8.0 Hz,
1H), 6.96 (td, J = 7.5, 1.0 Hz, 1H), 7.24-7.41 (m, 4H), 7.48 (dd, J
= 7.5, 1.6 Hz, 1H), 7.53-7.60 (m, 2H); 13C NMR(CDCl3, 100
MHz) δ = 28.1, 47.8, 51.0, 55.4, 110.6, 120.9, 125.0, 127.2,
128.0, 128.3, 129.1, 130.3, 130.5, 135.7, 144.7, 157.5, 162.8,
170.8; IR (Sol CHCl3) 753, 1240, 1608, 1664, 2962, 3344 cm-1;
HRMS (ESI+) m/z calcd for C22H27N2O3 [M+H]+ 367.2021,
found 367.2013.
N-(3-(tert-butylamino)-3-oxoprop-1-en-2-yl)-2-iodo-N-
phenethylbenzamide (10j).
Ugi adduct 9j (1.0 eq.) was reacted with KOH solution according
to the general procedure (Method E) stirring for 7 hours. The
resulting oil was purified by flash column chromatography
eluting with a hexane/ethyl acetate (7:3) solvent system to
1
provide 10j as a white solid (87 %) Mp: 117-119°C. H NMR
(CDCl3, 400 MHz, 25 °C) δ = 1.29 (s, 5H)*, 1.38 (s, 2H), 1.43 (s,
2H), 2.97 (t, J = 6.9 Hz, 0.5H), 3.09 (t, J = 7.8 Hz, 1H), 3.51 (s,
0.5H), 3.69-3.79 (m, 0.5H), 3.71- 3.77 (m, 0.5H), 3.91 (s, 1H),
5.41 (s, 0.5H), 5.56 (s, 1H), 5.73 (s, 0.5H), 6.75-7.47 (m, 8H),
7.81 (dd, J = 20.4, 7.9 Hz, 1H) (*Rotamers can be observed at
25°C);13C NMR (CDCl3, 100 MHz) δ = 23.9, 28.2, 28.5, 28.7,
33.7, 35.4, 41.1, 49.7, 51.7, 92.4, 94.2, 126.5, 126.6, 127.4,
127.7, 128.1, 128.1, 128.3, 128.6, 128.7, 128.8, 129.0, 130.3,
130.7, 131.0, 138.4, 139.4, 139.8, 141.5, 143.0, 162.7, 169.9; IR
(Sol CHCl3) 499, 646, 696, 744, 1010, 1191, 1321, 1394, 1449,
1514, 1618, 1643, 1674, 2962, 3024, 3060, 3348 cm-1; HRMS
(ESI+) m/z calcd for C22H26I1N2O2 [M+H]+ 477.1038, found
477.1035.
N-(3-(tert-butylamino)-3-oxoprop-1-en-2-yl)-2-iodo-N-(2-
methoxybenzyl)benzamide (10g).
Ugi adduct 9g (1.0 eq.) was reacted with KOH solution according
to the general procedure (Method E) stirring for 5.5 hours. The
resulting oil was purified by flash column chromatography

7
1H), 3.78-3.81 (m, 4H)*, 3.83 (s, 2H), 3.85-3.92 (m, 1H), 5.02
ACCEPTED MANUSCRIPT
N-(3-(tert-butylamino)-3-oxoprop-1-en-2-yl)-4-methoxy-N-
phenethylbenzamide (10k).
(s, 1H), 5.73 (d, J = 0.5 Hz, 1H), 6.05 (s, 1H), 6.72- 6.94 (m,
4H), 7.07-7.21 (m, 2H), 7.52 (d, J = 8.9 Hz, 1H), 7.66 (d, J = 8.9
Hz, 1H) (*Rotamers can be observed at 25°C); 13C NMR (CDCl3,
100 MHz) δ = 23.9, 28.2, 28.3, 32.8, 34.8, 41.2, 51.2, 51.3, 51.7,
55.2, 55.3, 113.3, 113.7, 114.0, 114.1, 115.9, 127.0, 127.8, 128.5,
129.7, 129.9, 130.4, 130.7, 130.9, 158.3, 159.3, 161.5, 162.1,
163.3, 166.9, 170.4; IR (Sol CHCl3) = 83, 1031, 1245,1510,
1604, 1663, 2925, 2966, 3330 cm-1; HRMS (ESI+) m/z calcd for
C24H31N2O4 [M+H]+ 411.2283, found 411.2285.
Ugi adduct 9k (1.0 eq.) was reacted with KOH solution
according to the general procedure (Method E) stirring for 5
hours. The resulting oil was purified by flash column
chromatography eluting with a hexane/ethyl acetate (7:3) solvent
system to provide 10k as a white solid (67 %) Mp: 142-145 °C.
1H NMR (CDCl3, 400 MHz, 25 °C) δ = 1.17 (s, 6H), 1.38 (s,
3H)*, 2.93 (t, J = 6.9 Hz, 1H), 3.00-3.11 (m, 1H), 3.66-3.73 (m,
1H), 3.81 (s, 2H), 3.83 (s, 1H)*, 3.88-3.97 (m, 1H), 5.02 (s, 1H),
5.53 (s, 1H), 5.72 (d, J = 0.7 Hz, 1H), 6.83 (d, J = 9.0 Hz, 1H),
6.89 (d, J = 9.0 Hz, 1H), 7.21-7.37 (m, 5H), 7.52 (d, J = 9.0 Hz,
1H), 7.66 (d, J = 9.0 Hz, 1H) (*Rotamers can be observed at
25°C); 13C NMR (CDCl3, 100 MHz) δ = 23.9, 28.2, 28.3, 33.7,
35.8, 41.0, 51.2, 51.4, 51.6, 55.3, 113.3, 113.7, 115.9, 120.0,
126.5, 126.9, 127.8, 128.5, 128.6, 128.7, 128.8, 129.0, 130.4,
138.8, 139.0, 145.6, 159.3, 161.5, 162.1, 163.3, 166.9, 170.4; IR
(Sol CHCl3) 698, 1254, 1520, 1617, 2967, 3317 cm-1; HRMS
(ESI+) m/z calcd for C23H29N2O3 [M+H]+ 381.2178, found
381.2160.
N-(2-bromophenethyl)-N-(3-(tert-butylamino)-3-oxoprop-1-
en-2-yl)benzamide (10o).
Ugi adduct 9o (1.0 eq.) was reacted with KOH solution according
to the general procedure (Method E) stirring for 5 hours. The
resulting oil was purified by flash column chromatography
eluting with a hexane/ethyl acetate (7:3) solvent system to
1
provide 10o as a colorless solid (78 %) Mp: 127-130 °C. H
NMR (CDCl3, 400 MHz, 25 °C) δ = 1.20 (s, 9H), 3.10-3.36 (m,
2H), 3.81-4.04 (m, 2H), 5.02 (s, 1H), 5.55 (s, 1H), 5.51 (s, 1H),
7.10 (td, J = 7.8, 1.8 Hz, 1H), 7.18-7.45 (m, 5H), 7.54 (dd, J =
6.9, 1.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ = 28.4, 34.2,
49.6, 51.5, 115.8, 124.6, 127.7, 128.1, 128.3, 130.5, 131.4, 132.8,
135.6, 138.2, 145.5, 163.4, 171.0; IR (Sol CHCl3) = 664, 719,
761, 1520, 1623, 1639, 1923, 2956, 3332 cm-1; HRMS (ESI+)
m/z calcd for C22H2679Br1N2O2 [M+H]+ 429.1177, found
429.1180.
N-(3-(tert-butylamino)-3-oxoprop-1-en-2-yl)-N-(4-
methoxyphenethyl)benzamide (10l).
Ugi adduct 9l (1.0 eq.) was reacted with KOH solution according
to the general procedure (Method E) stirring for 3.5 hours. The
resulting oil was purified by flash column chromatography
eluting with a hexane/ethyl acetate (7:3) solvent system to
1
provide 10l as a light yellow solid (74 %) Mp: 105-108°C. H
N-(2-bromophenethyl)-N-(3-(tert-butylamino)-3-oxoprop-1-
en-2-yl)-2-iodobenzamide (10p).
NMR (CDCl3, 300 MHz, 25 °C) δ = 1.16 (s, 9H), 2.84-3.15 (m,
2H), 3.79 (s, 3H), 3.82-3.98 (m, 2H), 5.02 (s, 1H), 5.53 (s, 1H),
5.69 (d, J = 0.7 Hz, 1H), 6.85 (d, J = 8.7 Hz, 2H), 7.17 (d, J = 8.5
Hz, 2H), 7.36 (dd, J = 13.0, 7.1 Hz, 3H), 7.51 (dd, J = 8.1, 1.6
Hz, 2H); 13C NMR (CDCl3, 75 MHz) δ = 28.2, 28.5, 29.6, 32.7,
51.4, 51.6, 55.2, 114.0, 116.3, 126.8, 128.1, 128.3, 128.5, 129.7,
129.9, 130.4, 130.6, 131.3, 135.6, 145.2, 158.2, 163.2, 170.8; IR
(Sol CHCl3) = 702, 1240, 1612, 1664, 2966, 3337 cm-1; HRMS
(ESI+) m/z calcd for C23H29N2O3 [M+H]+ 381.2178, found
381.2167.
Ugi adduct 9p (1.0 eq.) was reacted with KOH solution
according to the general procedure (Method E) stirring for 5.5
hours. The resulting oil was purified by flash column
chromatography eluting with a hexane/ethyl acetate (8:2) solvent
system to provide 10p as a light yellow solid (84 %) Mp: 158-
1
160 °C. H NMR (CDCl3, 400 MHz, 25 °C) δ = 1.30 (s, 5H)*,
1.38 (s, 1H), 1.44 (s, 3H), 2.92-3.25 (m, 2H), 3.47-3.99 (m, 2H),
5.25-5.76 (m, 2H), 5.89-6.19 (m, 1H), 6.98-7.63 (m, 7H), 7.70-
7.89 (m, 1H) (*Rotamers can be observed at 25°C); 13C NMR
(CDCl3, 100 MHz) δ = 28.2, 28.6, 28.7, 34.1, 35.1, 35.6, 39.7,
47.8, 50.2, 51.7, 94.2, 116.3, 119.3, 124.6, 127.7, 127.9, 128.1,
128.1, 128.4, 130.4, 130.6, 131.0, 131.1, 131.5, 132.8, 132.9,
133.0, 137.8, 139.0, 139.4, 139.9, 141.4, 143.2, 162.8, 170.0; IR
(Sol CHCl3) = 665, 735, 920, 1323, 1405, 1527, 1627, 1662,
2868, 2961, 3332 cm-1; HRMS (ESI+) m/z calcd for
C22H2579Br1I1N2O2 [M+H]+ 555.0144, found 555.0141.
N-(3-(tert-butylamino)-3-oxoprop-1-en-2-yl)-2-iodo-N-(4-
methoxyphenethyl)benzamide (10m).
Ugi adduct 9m (1.0 eq.) was reacted with KOH solution
according to the general procedure (Method E) stirring for 3.5
hours. The resulting oil was purified by flash column
chromatography eluting with a hexane/ethyl acetate (7:3) solvent
system to provide 10m as a light yellow solid (80 %) Mp: 162-
164°C. 1H NMR (CDCl3, 400 MHz, 25 °C) δ = 1.29 (s, 9H), 3.02
(t, J = 7.8 Hz, 2H), 3.79 (s, 3H), 3.87 (br, 2H), 5.42 (s, 1H), 5.59
(s, 1H), 5.75 (s, 1H), 6.63-6.92 (m, 3H), 7.10-7.33 (m, 4H), 7.72-
7.82 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ = 28.5, 32.7, 49.9,
51.7, 55.2, 94.1, 114.0, 117.1, 120.1, 127.7, 129.6, 129.9, 130.3,
139.4, 141.5, 142.9, 158.3, 162.6, 169.9; IR (Sol CHCl3) = 702,
1032, 1240,1335, 1612, 1664, 2924, 2966, 3337 cm-1; HRMS
(ESI+) m/z calcd for C23H28I1N2O3 [M+H]+ 507.1144, found
507.1151.
2-(N-(2-bromobenzyl)acetamido)-N-tert-butylacrylamide
(10q).
Ugi adduct 9q (1.0 eq.) was reacted with KOH solution
according to the general procedure (Method E) stirring for 5
hours. The resulting oil was purified by flash column
chromatography eluting with a hexane/ethyl acetate (6:4) solvent
1
system to provide 10q as yellow solid (68 %) Mp: 70-73 °C. H
NMR (CDCl3, 300 MHz, 25 °C) δ = 1.19 (s, 9H), 2.06 (s, 3H),
4.94 (s, 2H), 5.47 (s, 1H), 5.68 (s, 1H), 6.37 (s, 1H), 7.18 (td, J =
7.7, 1.8 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.39-7.46 (m, 1H), 7.56
(dd, J = 7.9, 1.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ = 22.3,
28.3, 51.5, 100.0, 122.7, 124.7, 128.1, 129.8, 132.2, 133.1, 136.0,
143.5, 162.2, 170.8; IR (Sol CHCl3) = 746, 1206, 1231, 1391,
1535, 1627, 1664, 2924, 2970, 3306 cm-1; HRMS (ESI+) m/z
calcd for C16H2279Br1N2O2 [M+H]+ 353.0864, found 353.0853.
N-(3-(tert-butylamino)-3-oxoprop-1-en-2-yl)-4-methoxy-N-(4-
methoxyphenethyl)benzamide (10n).
Ugi adduct 9n (1.0 eq.) was reacted with KOH solution
according to the general procedure (Method E) stirring for 5
hours. The resulting oil was purified by flash column
chromatography eluting with a hexane/ethyl acetate (7:3) solvent
system to provide 10n as a white solid (53 %) Mp: 126-128°C.
1H NMR (CDCl3, 400 MHz, 25 °C) δ = 1.17 (s, 4H), 1.38 (s,
5H)*, 2.86 (t, J = 6.9 Hz, 1H), 2.92-3.01 (m, 1H), 3.62-3.70 (m,
N-benzyl-N-(3-(cyclohexylamino)-3-oxoprop-1-en-2-yl)-2-
iodobenzamide (10r).

8
Tetrahedron
This compound was prepared according to the method reported
N-tert-butyl-1-(N-(4-
ACCEPTED MANUSCRIPT
by Miranda.2 Spectral data matched well with previously
reported.
methoxybenzyl)acetamido)cyclopropanecarboxamide (11c).
Dehydroalanine 10c (1 eq.) was reacted with
trimethylsulfoxonium iodide and NaH 60% according to the
general procedure, stirring for 2 hours. The resulting oil was
purified by flash column chromatography eluting with ethyl
N-(3-(tert-butylamino)-3-oxoprop-1-en-2-yl)-N-
isopropylbenzamide (10s). Purified by flash column
chromatography eluting with a hexane/ethyl acetate (7:3) solvent
system to provide 10s as pale yellow solid (35%), M.p. 63-66 °C.
1H NMR (CDCl3, 300 MHz, 25 °C) δ = 1.28-1.31 (m, 15H),
4.63-4.67 (m, 1H), 5.27 (s, 1H), 5.84 (br, 1H), 6.06 (s, 1H), 7.28-
7.36 (m, 3H), 7.45-7.48 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ =
20.4, 28.4, 49.7, 51.4, 99.9, 121.5, 127.8, 128.0, 129.9, 136.5,
141.9, 163.6, 171.0; IR (thin film) 713, 792, 1128, 1245, 1365,
1453, 1527, 1618, 1670, 2929, 2971, 3333, 3436 cm-1; HRMS
(ESI+) m/z calcd for C17H25N2O2 [M+H]+ 289.19160, found
289.19156.
1
acetate solvent to provide 11c as a clear oil (59 %). H NMR
(CDCl3, 400 MHz, 25 °C) δ = 1.39 (s, 9H), 1.88-2.10 (m, 2H),
2.12 (s, 3H), 3.21-3.30 (m, 1H), 3.45 (td, J = 9.4, 2.8 Hz, 1H),
3.81 (s, 3H), 4.53 (q, J = 17.0 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H),
7.19 (d, J = 8.7 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ = 22.2,
23.2, 27.4, 42.3, 52.0, 54.4, 55.3, 59.4, 113.8, 127.7, 129.2,
159.0, 171.3, 171.6; IR (Sol CHCl3) = 728, 1030, 1243, 1289,
1407, 1644, 1685, 2965, 3461 cm-1; HRMS (ESI+) m/z calcd for
C18H27N2O3 [M+H]+ 319.2021, found 319.2011.
General procedure for the synthesis of cyclopropanes 11 with
trimethylsulfoxonium iodide.
N-benzyl-N-(1-(tert-
butylcarbamoyl)cyclopropyl)benzamide (11d).
In a round-bottom flask under argon, dehydroalanine 10 (0.15
mmol, 1 eq.) was taken in 3 mL of dry DMSO. Then
trimethylsulfoxonium iodide (52 mg, 0.23 mmol, 1.5 eq.) and
NaH 60% (9 mg, 0.23 mmol, 1.5 eq.) were added and the
reaction mixture was stirred at room temperature until the starting
material was consumed. The reaction was quenched with 5 mL of
water and extracted with 5 mL of ethyl acetate for three times;
the combined organic extracts were dried over sodium sulfate and
concentrated under vacuum to furnish a brown oil. This material
was purified by flash column chromatography on silica gel
eluting with hexane/ethyl acetate solvent system.
Dehydroalanine 10d (1 eq.) was reacted with
trimethylsulfoxonium iodide and NaH 60% according to the
general procedure, stirring for 5 hours. The resulting oil was
purified by flash column chromatography eluting with a
hexane/ethyl acetate (8:2→7:3) solvent system to provide 11d as
a cloudy oil (24 %). 1H NMR (CDCl3, 300 MHz, 25 °C) δ = 1.42
(s, 9H), 2.05-2.17 (m, 2H), 3.08-3.69 (m, 2H), 3.91-4.22 (m, 1H),
4.47-4.83 (m, 2H), 7.28 -7.59 (m, 10H); 13C NMR (CDCl3, 75
MHz) δ = 22.9, 27.4, 42.7, 54.6, 59.8, 127.0, 127.5, 128.4, 128.8,
129.8, 136.0, 137.3, 171.2, 172.2; IR (Sol CHCl3) = 697, 732,
1287, 1400, 1646, 1684, 2922, 2970, 3057 cm-1; HRMS (ESI+)
m/z calcd for C22H27N2O2 [M+H]+ 351.2072, found 351.2070.
N-(1-(tert-butylcarbamoyl)cyclopropyl)-N-(4-
methoxybenzyl)benzamide (11a).
N-benzyl-N-(1-(tert-butylcarbamoyl)cyclopropyl)-2-
iodobenzamide (11e).
Dehydroalanine 10a (1 eq.) was reacted with trimethyl
sulfoxonium iodide and NaH 60 % according to the general
procedure, stirring for 2 hours. The resulting oil was purified by
flash column chromatography eluting with a hexane/ethyl acetate
Dehydroalanine 10e (1 eq.) was reacted with
trimethylsulfoxonium iodide and NaH 60% according to the
general procedure, stirring for 2 hour. The resulting oil was
purified by flash column chromatography eluting with a
hexane/ethyl acetate (6:4) solvent system to provide 11e as a
1
(6:4) solvent system to provide 11a as a yellow oil (73 %). H
NMR (CDCl3, 400 MHz, 25 °C) δ = 1.42 (s, 9H), 1.70-2.48 (m,
2H), 2.97-3.65 (m, 2H), 3.79 (s, 3H), 3.89-4.27 (m, 1H), 4.35 –
4.69 (m, 2H), 6.88 (d, J = 8.5 Hz, 2H), 7.07-7.75 (m, 7H); 13C
NMR (CDCl3, 100 MHz) δ = 22.9, 27.4, 42.7, 54.0, 55.3, 59.6,
114.1, 127.0, 128.4, 129.0, 129.7, 136.1, 159.0, 171.3, 171.9; IR
(Sol CHCl3) = 720, 1038, 1248, 1399, 1516, 1630, 1656, 2931,
2964, 3322 cm-1; HRMS (ESI+) m/z calcd for C23H29N2O3
[M+H]+ 381.2178, found 381.2166.
1
yellow solid (37 %) Mp: 47-50 °C. H NMR (CDCl3, 500 MHz,
25 °C) δ = 1.35 (s, 2H), 1.42 (s, 7H)*, 1.80-2.45 (m, 2H), 3.05-
3.64 (m, 2H), 3.87-4.54 (m, 2H), 6.98-7.10 (m, 1H), 7.18-7.59
(m, 7H), 7.77-7.86 (m, 1H) (*Rotamers can be observed at
25°C); 13C NMR (CDCl3, 125 MHz) δ = 22.4, 23.7, 27.4, 27.5,
41.7, 42.9, 46.9, 54.6, 59.5, 61.8, 92.2, 92.5, 127.0, 127.7, 127.8,
127.9, 128.2, 128.4, 128.5, 128.7, 129.0, 130.2, 130.2, 139.1,
151.7, 170.8; IR (Sol CHCl3) = 697, 1290, 1407, 1640, 1686,
2922, 2956 cm-1; HRMS (ESI+) m/z calcd for C22H26I1N2O2
[M+H]+ 477.1038, found 477.1033.
N-(1-(tert-butylcarbamoyl)cyclopropyl)-2-iodo-N-(4-
methoxybenzyl)benzamide (11b).
Dehydroalanine 10b (1 eq.) was reacted with trimethyl
sulfoxonium iodide and NaH 60 % according to the general
procedure, stirring for 2 hours. The resulting oil was purified by
flash column chromatography eluting with a hexane/ethyl acetate
N-(1-(tert-butylcarbamoyl)cyclopropyl)-N-(2-
methoxybenzyl)benzamide (11f).
1
(6:4) solvent system to provide 11b as a yellow oil (66 %). H
Dehydroalanine 10f (1 eq.) was reacted with
trimethylsulfoxonium iodide and NaH 60% according to the
general procedure, stirring for 2 hour. The resulting oil was
purified by flash column chromatography eluting with a
hexane/ethyl acetate (6:4) solvent system to provide 11f as a pale
yellow solid (75 %) Mp: 124-126°C. 1H NMR (CDCl3, 300 MHz,
25 °C) δ = 1.42 (s, 9H), 1.86-2.17 (m, 2H), 3.22-3.57 (m, 2H),
3.72 (s, 3H), 4.61 (q, J = 16.6 Hz, 2H), 6.79-7.01 (m, 2H), 7.24-
7.62 (m, 7H); 13C NMR (CDCl3, 75 MHz) δ = 14.3, 21.1, 22.7,
27.5, 42.8, 50.7, 54.4, 55.1, 60.0, 60.4, 110.1, 120.7, 125.4,
127.3, 128.2, 128.8, 128.9, 129.8, 136.4, 157.4, 171.4, 172.4; IR
(Sol CHCl3) = 723, 1235, 1398, 1633, 1686, 2933, 2967 cm-1;
NMR (CDCl3, 400 MHz, 25 °C) δ = 1.26 (s, 1H), 1.35 (s, 2H),
1.42 (s, 6H)*, 1.81-2.48 (m, 2H), 3.02-3.37 (m, 1H), 3.50-3.70
(m, 1H), 3.79 (d, 3H)*, 3.86-4.68 (m, 3H), 6.76-6.92 (m, 2H),
6.99-7.91 (m, 6H) (*Rotamers can be observed at 25°C); 13C
NMR (CDCl3, 100 MHz) δ = 14.1, 21.0, 22.3, 22.9, 23.5, 27.3,
27.4, 29.6, 41.6, 42.9, 46.1, 54.0, 54.4, 54.7, 55.2, 59.2, 59.6,
60.3, 61.7, 92.1, 92.5, 113.7, 114.0, 126.9, 127.7, 127.9, 128.2,
128.4, 128.4, 128.8, 129.1, 129.3, 129.7, 130.1, 130.1, 130.4,
139.0, 141.7, 142.3, 158.7, 159.1, 170.2, 170.8, 172.0; IR (Sol
CHCl3) = 727, 1244, 1638, 1685, 2240, 2927, 2960, 3056 cm-1.
HRMS (ESI+) m/z calcd for C23H28I1N2O3 [M+H]+ 507.1144,
found 507.1146.

9
HRMS (ESI+) m/z calcd for C23H29N2O3 [M+H]+ 381.2178,
found 381.2195.
(s, 3H), 1.45 (s, 6H)*, 2.24-3.47 (m, 6H), 3.62-3.78 (m, 1H),
ACCEPTED MANUSCRIPT
3.96-4.18 (m, 1H), 5.28 (s, 1H), 6.78-7.49 (m, 8H), 7.77-7.88 (m,
1H) (*Rotamers can be observed at 25°C); 13C NMR (CDCl3, 75
MHz) δ = 14.2, 22.1, 23.2, 23.5, 24.0, 27.3, 27.4, 29.6, 34.0,
34.4, 36.0, 36.3, 41.3, 41.7, 42.7, 43.3, 45.8, 47.0, 50.3, 53.3,
53.4, 54.5, 54.7, 58.3, 60.3, 61.0, 61.5, 62.4, 92.2, 92.4, 92.8,
93.2, 126.2, 126.3, 126.4, 126.5, 127.6, 127.9, 128.1, 128.2,
128.4, 128.5, 128.6, 128.9, 129.0, 130.1, 138.0, 138.2, 138.9,
139.0, 139.1, 139.6, 139.7, 140.1, 141.7, 142.0, 142.4, 169.3,
170.0, 170.3, 170.8, 171.2, 171.5; IR (Sol CHCl3) = 699, 746,
1290, 1408, 1636, 1685, 2923, 2959, 3439 cm-1; HRMS (ESI+)
m/z calcd for C23H28IN2O2 [M+H]+ 491.1195, found 491.1202.
N-(1-(tert-butylcarbamoyl)cyclopropyl)-2-iodo-N-(2-
methoxybenzyl)benzamide (11g).
Dehydroalanine 10g (1 eq.) was reacted with
trimethylsulfoxonium iodide and NaH 60% according to the
general procedure, stirring for 3.5 hours. The resulting oil was
purified by flash column chromatography eluting with a
hexane/ethyl acetate (65:35) solvent system to provide 11g as a
white solid (63 %) Mp: 143-147 °C. 1H NMR (CDCl3, 300 MHz,
25 °C) δ = 1.33 (s, 3H), 1.42 (s, 6H)*, 2.13 (s, 0H), 1.82-2.20 (m,
2H), 3.05-3.64 (m, 2H), 3.73 (s, 2H)*, 3.84 (s, 1H), 3.97-4.52 (m,
3H), 6.76-7.10 (m, 3H), 7.20-7.43 (m, 3H), 7.59-7.89 (m, 2H)
(*Rotamers can be observed at 25°C); 13C NMR (CDCl3, 75
MHz) δ = 22.5, 23.3, 27.3, 29.6, 41.2, 41.6, 42.9, 49.1, 54.3,
54.5, 55.0, 59.8, 61.7, 92.1, 92.8, 109.8, 120.4, 120.6, 124.2,
126.2, 127.6, 127.8, 127.9, 128.4, 128.6, 128.7, 129.1, 130.0,
138.9, 141.6, 142.4, 156.2, 156.9, 170.4, 170.8, 172.0; IR (Sol
CHCl3) = 751, 1239, 1399, 1644, 1681, 2926, 2961 cm-1; HRMS
(ESI+) m/z calcd for C23H28I1N2O3 [M+H]+ 507.1144, found
507.1148.
N-(1-(tert-butylcarbamoyl)cyclopropyl)-4-methoxy-N-
phenethylbenzamide (11k).
Dehydroalanine 10k (1 eq.) was reacted with
trimethylsulfoxonium iodide and NaH 60% according to the
general procedure, stirring for 2 hours. The resulting oil was
purified by flash column chromatography eluting with a
hexane/ethyl acetate (7:3) solvent system to provide 11k as a
white oil (88 %). 1H NMR (CDCl3, 400 MHz, 50 °C) δ = 1.27 (s,
1H), 1.41 (s, 9H), 1.63-2.11 (m, 2H), 2.91-3.66 (m, 5H), 3.82 (s,
3H), 4.36 (br, 1H), 6.89 (d, J = 8.8 Hz, 2H), 7.07-7.47 (m, 7H);
13C NMR (CDCl3, 100 MHz) δ = 23.3, 27.4, 29.7, 34.4, 36.3,
41.6, 42.9, 46.4, 52.7, 54.6, 55.3, 60.3, 62.2, 113.7, 126.3, 128.5,
128.7, 128.8, 160.6, 171.1, 172.0; IR (Sol CHCl3) = 700, 838,
1249, 1631, 1679, 2924, 2965 cm-1; HRMS (ESI+) m/z calcd for
C24H31N2O3 [M+H]+ 395.2334, found 395.2320.
(R)-N-(1-(tert-butylcarbamoyl)cyclopropyl)-N-(1-
phenylethyl)benzamide (11h).
Dehydroalanine 10h (1 eq) was reacted with
trimethylsulfoxonium iodide and NaH 60% according to the
general procedure, stirring for 2 hours. The resulting oil was
purified by flash column chromatography eluting with a
hexane/ethyl acetate (7:3) solvent system to provide 11h as a
N-(1-(tert-butylcarbamoyl)cyclopropyl)-N-(4-
methoxyphenethyl)benzamide (11l).
25
clear oil (18 %). [α]D = +93.86 (c = 0.57, CHCl3); 1H NMR
(CDCl3, 300 MHz, 25 °C) δ = 1.39 (s, 9H), 1.42-1.61 (m, 1H),
1.69 (d, J = 6.9 Hz, 3H), 1.97-2.18 (m, 1H), 3.20 (td, J = 8.9, 6.1
Hz, 1H), 3.56 (td, J = 10.0, 9.2, 6.2 Hz, 2H), 5.05 (q, J = 6.7 Hz,
1H), 7.22-7.44 (m, 8H), 7.50-7.57 (m, 2H); 13C NMR (CDCl3,
100 MHz) δ = 17.7, 22.8, 27.4, 43.0, 54.4, 56.3, 56.9, 126.4,
127.3, 127.4, 127.8, 128.7, 129.4, 136.9, 171.5; IR (Sol CHCl3) =
698, 728, 1289, 1427, 1632, 1688, 2238, 2927, 2973, 3059 cm-1;
HRMS (ESI+) m/z calcd for C23H29N2O2 [M+H]+ 365.2229,
found 365.2232.
Dehydroalanine 10l (1
eq.) was reacted with
trimethylsulfoxonium iodide and NaH 60% according to the
general procedure, stirring for 2 hours. The resulting oil was
purified by flash column chromatography eluting with a
hexane/ethyl acetate (6:4) solvent system to provide 11l as a
white oil (38 %). 1H NMR (CDCl3, 400 MHz, 50 °C) δ = 1.41 (s,
9H), 1.89-2.20 (m, 2H), 2.77-3.57 (m, 6H), 3.75 (s, 3H), 4.32 (br,
1H), 6.79-7.41 (m, 9H); 13C NMR (CDCl3, 100 MHz) δ = 23.2,
23.3, 27.3, 29.6, 33.4, 35.4, 41.4, 42.8, 46.4, 52.6, 54.5, 55.2,
60.1, 62.1, 113.8, 126.5, 127.1, 128.3, 128.4, 129.3, 129.5, 129.9,
132.0, 136.5, 158.1, 170.6, 171.2, 171.8, 172.5; IR (Sol CHCl3) =
702, 1030, 1244, 1632, 1686, 2925, 2958, 3475 cm-1; HRMS
(ESI+) m/z calcd for C24H31N2O3 [M+H]+ 395.2334, found
395.2350.
N-(1-(tert-butylcarbamoyl)cyclopropyl)-N-
phenethylbenzamide (11i).
Dehydroalanine 10i (1 eq.) was reacted with
trimethylsulfoxonium iodide and NaH 60% according to the
general procedure, stirring for 2 hours. The resulting oil was
purified by flash column chromatography eluting with a
hexane/ethyl acetate (6:4) solvent system to provide 11i as a
N-(1-(tert-butylcarbamoyl)cyclopropyl)-2-iodo-N-(4-
methoxyphenethyl)benzamide (11m)
1
yellow oil (82 %). H NMR (CDCl3, 400 MHz, 25 °C) δ = 1.37-
Dehydroalanine 10m (1 eq.) was reacted with
trimethylsulfoxonium iodide and NaH 60% according to the
general procedure, stirring for 3 hours. The resulting oil was
purified by flash column chromatography eluting with a
hexane/ethyl acetate (6:4) solvent system to provide 11m as a
1.44 (m, 9H)*, 1.69-2.25 (m, 2H), 2.82-3.65 (m, 6H), 4.27-4.41
(m, 1H), 6.91 (br, 1H), 7.20-7.51 (m, 9H) (*Rotamers can be
observed at 25°C); 13C NMR (CDCl3, 100 MHz) δ = 23.1, 23.3,
27.3, 34.3, 36.3, 41.4, 42.8, 46.2, 52.4, 54.5, 60.1, 62.0, 126.2,
126.4, 127.1, 128.4, 128.6, 128.9, 129.3, 129.4, 136.4, 137.9,
139.9, 170.6, 171.1, 171.7, 172.5; IR (Sol CHCl3) = 699, 1290,
1406, 1632, 1686, 2970, 3473 cm-1; HRMS (ESI+) m/z calcd for
C23H29N2O2 [M+H]+ 365.2229, found 365.2212.
1
yellow oil (54 %). H NMR (CDCl3, 300 MHz, 25 °C) δ = 1.36
(s, 3H), 1.46 (s, 6H)*, 1.88-2.62 (m, 2H), 2.72-3.67 (m, 5H), 3.74
(s, 2H)*, 3.79 (s, 1H), 3.95-4.18 (m, 1H), 5.29 (s, 1H), 6.71-6.89
(m, 3H), 7.04-7.49 (m, 4H), 7.77-7.89 (m, 1H) (*Rotamers can
be observed at 25°C); 13C NMR (CDCl3, 75 MHz) δ = 22.1, 23.2,
23.5, 24.0, 27.3, 27.4, 29.6, 33.1, 33.5, 35.0, 35.4, 41.3, 41.6,
42.7, 43.3, 46.0, 47.2, 50.5, 53.4, 54.5, 54.6, 55.2, 58.2, 60.9,
61.5, 62.4, 92.2, 92.3, 113.8, 113.9, 126.5, 127.6, 127.8, 128.0,
128.2, 128.4, 128.5, 129.6, 129.8, 130.0, 130.1, 131.6, 132.1,
138.8, 138.9, 139.1, 139.7, 141.7, 142.4, 158.0, 158.1, 170.0,
170.3, 170.8, 171.2, 171.4; IR (Sol CHCl3) = 746, 1031, 1243,
1636, 1686, 2930, 2960, 3474 cm-1; HRMS (ESI+) m/z calcd for
C24H30IN2O3 [M+H]+ 521.1301, found 521.1298.
N-(1-(tert-butylcarbamoyl)cyclopropyl)-2-iodo-N-
phenethylbenzamide (11j).
Dehydroalanine 10j (1 eq.) was reacted with
trimethylsulfoxonium iodide and NaH 60% according to the
general procedure, stirring for 2 hours. The resulting oil was
purified by flash column chromatography eluting with a
hexane/ethyl acetate (6:4) solvent system to provide 11j as a
1
brown oil (82 %). H NMR (CDCl3, 300 MHz, 25 °C) δ = 1.36

10
Tetrahedron
N-(1-(tert-butylcarbamoyl)cyclopropyl)-4-methoxy-N-
MHz) δ = 18.0, 21.9, 23.1, 27.4, 28.2, 29.6, 41.7, 42.3, 49.5,
ACCEPTED MANUSCRIPT
(4-methoxyphenethyl)benzamide (11n).
51.2, 53.0, 54.4, 59.8, 61.1, 122.3, 127.5, 127.9, 128.0, 128.1,
128.3, 128.5, 129.0, 129.5, 130.7, 132.4, 132.9, 133.0, 136.1,
171.2, 171.5; IR (Sol CHCl3) 750, 1023, 1291, 1403, 1648, 1686,
2922, 2963, 3489 cm-1; HRMS (ESI+) m/z calcd for
C17H2479Br1N2O2 [M+H]+ 367.1021, found 367.1014.
Dehydroalanine 10n (1 eq.) was reacted with
trimethylsulfoxonium iodide and NaH 60% according to the
general procedure, stirring for 2.5 hours. The resulting oil was
purified by flash column chromatography eluting with a
hexane/ethyl acetate (7:3) solvent system to provide 11n as a
clear oil (66 %). 1H NMR (CDCl3, 400 MHz, 25 °C) δ = 1.41 (s,
9H), 1.57-2.22 (m, 3H), 2.81-3.64 (m, 6H), 3.77 (s, 3H), 3.83 (s,
3H), 6.79-7.41 (m, 8H); 13C NMR (CDCl3, 100 MHz) δ = 23.3,
27.4, 29.7, 54.6, 55.2, 55.3, 113.7, 113.9, 128.7, 129.7, 158.2,
160.6, 171.2, 172.0.; IR (Sol CHCl3) = 837, 1028, 1244, 1608,
1686, 2924, 3484 cm-1; HRMS (ESI+) m/z calcd for C25H33N2O4
[M+H]+ 425.2440, found 425.2441.
N-benzyl-N-(1-(cyclohexylcarbamoyl)cyclopropyl)-2-
iodobenzamide (11r).
Dehydroalanine 10r (1.0 eq.) was reacted with
trimethylsulfoxonium iodide and NaH 60% according to the
general procedure, stirring for 2 hours. The resulting oil was
purified by flash column chromatography eluting with a
hexane/ethyl acetate (6:4) solvent system to provide 11r as a
1
yellow solid (59 %) Mp: 105-108 °C. H NMR (CDCl3, 400
N-(2-bromophenethyl)-N-(1-(tert-
butylcarbamoyl)cyclopropyl)benzamide (11o).
MHz, 25 °C) δ = 1.07-1.42 (m, 5H), 1.56-1.91 (m, 5H), 2.15-2.49
(m, 2H), 2.96-3.52 (m, 2H), 3.88-4.47 (m, 3H), 7.00-7.57 (m,
8H), 7.79-7.89 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ = 22.3,
23.5, 24.8, 24.8, 24.9, 25.0, 25.1, 28.9, 29.6, 29.7, 38.8, 39.9,
46.4, 50.9, 53.9, 58.4, 60.6, 91.7, 92.0, 126.6, 127.1, 127.2,
127.3, 127.8, 127.9, 128.1, 128.1, 128.3, 129.7, 135.6, 137.8,
138.5, 138.6, 141.1, 141.7, 168.9, 169.4, 170.2, 171.6; IR (Sol
CHCl3) 748, 1432, 1645, 1687, 2854, 2931, 3060 cm-1; HRMS
(ESI+) m/z calcd for C24H28I1N2O2 [M+H]+ 503.1195, found
503.1198.
Dehydroalanine 10o (1 eq.) was reacted with
trimethylsulfoxonium iodide and NaH 60% according to the
general procedure, stirring for 4 hours. The resulting oil was
purified by flash column chromatography eluting with a
hexane/ethyl acetate (6:4) solvent system to provide 11o as a
clear oil (78 %). 1H NMR (CDCl3, 400 MHz, 25 °C) δ = 1.41 (s,
4H), 1.50 (s, 5H)*, 1.86-2.04 (m, 1H), 2.37 (dd, J = 17.0, 7.8 Hz,
1H), 2.99-3.82 (m, 6H), 4.45 (s, 1H), 6.97-7.60 (m, 9H)
(*Rotamers can be observed at 25°C); 13C NMR (CDCl3, 100
MHz) δ = 21.0, 23.2, 23.4, 27.4, 28.7, 29.7, 34.6, 36.6, 41.5,
42.9, 44.1, 50.4, 54.6, 54.7, 60.1, 62.2, 124.4, 126.6, 127.2,
127.7, 128.2, 128.3, 128.4, 128.5, 129.4, 129.6, 131.0, 131.8,
132.7, 132.8, 136.4, 136.5, 137.4, 139.2, 170.5, 171.2, 171.9,
172.8; HRMS (ESI+) m/z calcd for C23H2879Br1N2O2 [M+H]+
443.1334, found 443.1320.
N-(1-(tert-butylcarbamoyl)cyclopropyl)-N-
isopropylbenzamide (11s). Purified by flash column
chromatography eluting with a hexane/ethyl acetate (7:3) solvent
system to provide 11s as white solid (14%), M.p. 145-151 °C. 1H
NMR (CDCl3, 300 MHz, 25 °C) δ = 1.42-1.58 (m, 19H), 3.99 (q,
J= 6 Hz, 1H), 6.70 (br, 1H), 7.37-7.46 (m, 5H); 13C NMR
(CDCl3, 75 MHz) δ = 20.9, 22.2, 28.7, 29.7, 51.4, 54.1, 100.0,
126.7, 128.2, 129.9, 171.5; IR (thin film) 675, 694, 1133, 1364,
1395, 1525, 1621, 1656, 2923, 2976, 3326 cm-1; HRMS (ESI+)
m/z calcd for C18H27N2O2 [M+H]+ 303.20725, found 303.20745.
N-(2-bromophenethyl)-N-(1-(tert-
butylcarbamoyl)cyclopropyl)-2-iodobenzamide (11p).
Dehydroalanine 10p (1 eq.) was reacted with
trimethylsulfoxonium iodide and NaH 60% according to the
general procedure, stirring for 5 hours. The resulting oil was
purified by flash column chromatography eluting with a
hexane/ethyl acetate (6:4) solvent system to provide 11p as a
General procedure for the synthesis of cyclopropanes 13 with
sulfonium bromide 12.
In a round-bottom flask under argon, dehydroalanine 10 (0.28
mmol, 1 eq.) was taken in 5 mL of dry THF. Then sulfonium
bromide 12 (0.19 g, 0.84 mmol, 3 eq.) and NaH 60% (34 mg,
0.84 mmol, 3 eq.) were added and the reaction mixture was
stirred at room temperature for 10 min and then refluxed until
dehydroalanine was consumed. The reaction was quenched with
5 mL of water and extracted with 5 mL of CH2Cl2 for three times;
the combined dichloromethane extracts were dried over sodium
sulfate and concentrated under vacuum. This material was
purified by column chromatography on silica gel eluting with
hexane/ethyl acetate solvent system.
1
brown oil (89 %). H NMR (CDCl3, 400 MHz, 50 °C) δ = 1.27
(s, 1H), 1.36 (s, 3H), 1.46 (s, 5H)*, 2.14-2.39 (m, 2H), 2.94 –
3.87 (m, 6H), 6.99-7.54 (m, 7H), 7.78-7.84 (m, 1H) (*Rotamers
can be observed even at 50°C); 13C NMR (CDCl3, 100 MHz) δ =
14.0, 14.1, 21.0, 22.1, 22.6, 23.1, 23.3, 24.0, 27.3, 27.4, 28.8,
29.6, 31.8, 34.3, 34.7, 36.3, 36.5, 41.2, 41.6, 42.5, 43.3, 43.8,
44.7, 48.0, 51.1, 54.5, 54.7, 58.2, 60.3, 60.9, 61.5, 62.5, 70.5,
92.1, 92.5, 124.2, 124.3, 127.6, 127.8, 127.8, 128.1, 128.2, 128.5,
130.1, 131.2, 131.6, 132.5, 132.7, 137.3, 137.8, 138.8, 138.9,
139.2, 139.8, 141.6, 142.3, 170.1, 170.2, 170.7, 171.6; IR (Sol
CHCl3) 748,1016, 1290, 1408, 1637, 1685, 2922, 2958, 3459 cm-
1; HRMS (ESI+) m/z calcd for C23H2779Br1I1N2O2 [M+H]+
569.0300, found 569.0308.
Ethyl
2-(tert-butylcarbamoyl)-2-(N-(4-
methoxybenzyl)benzamido)cyclopropanecarboxylate (13a).
Dehydroalanine 10a (1 eq.) was reacted with sulfonium
bromide 12 and NaH 60 % according to the general procedure,
refluxing for 14 hours. The resulting mixture was purified by
flash column chromatography eluting with a hexane/ethyl acetate
(8:2) solvent system to provide 13a as a colorless solid (51 %)
Mp: 112-117°C. 1H NMR (CDCl3, 500 MHz, 25 °C) δ = 1.09 (s,
9H), 1.21 (t, J= 7 Hz, 3H), 1.79 (dd, J= 7 Hz, 1H), 2.14 (dd, J = 5
Hz, 1H), 2.68 (dd, J = 7 Hz, 1H), 3.75 (s, 3H), 4.1 (c, J= 7 Hz,
2H), 4.43 (dd, J = 15 Hz, 2H), 6.34 (br, 1H), 6.9 (dd, J= 8.5 Hz,
4H), 7.45 (m, 5H); 13C NMR (CDCl3, 125 MHz) δ = 14.1, 19.5,
28.2, 30.7, 48.0, 50.7, 53.7, 55.2, 61.1, 114.3, 126.8, 127.9,
128.6, 129.8, 130.2, 136.3, 159.5, 167.1, 170.5, 173.8; IR (Sol
CHCl3) 1240.6, 1658, 2922, 2963, 3429 cm-1; HRMS (ESI+) m/z
calcd for C26H33N2O5 [M+H]+ 453.2389, found 453.2402.
1-(N-(2-bromobenzyl)acetamido)-N-tert-
butylcyclopropanecarboxamide (11q).
Dehydroalanine 10q (1 eq.) was reacted with
trimethylsulfoxonium iodide and NaH 60% according to the
general procedure, stirring for 5 hours. The resulting oil was
purified by flash column chromatography eluting with ethyl
1
acetate to provide 11q as a yellow oil (82 %). H NMR (CDCl3,
400 MHz, 25 °C) δ = 1.11 (s, 2H), 1.40 (s, 7H)*, 1.95 (d, J =
62.2 Hz, 0H), 1.76- 2.03 (m, 2H), 2.07 (s, 2H)*, 2.23-2.29 (m,
1H), 3.25-3.53 (m, 1H), 4.41-4.73 (m, 2H), 7.16-7.58 (m , 4H)
(*Rotamers can be observed at 25°C); 13C NMR (CDCl3, 100

11
Ethyl
2-(tert-butylcarbamoyl)-2-(2-iodo-N-(4-
Hz, 2H), 6.74 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H),
ACCEPTED MANUSCRIPT
methoxybenzyl)benzamido)cyclopropanecarboxylate (13b).
7.17 (s, 1H), 7.32-7.47 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ =
14.0, 18.0, 28.5, 30.2, 34.2, 48.2, 51.2, 52.6, 55.2, 61.2, 113.9,
126.5, 128.5, 129.4, 129.6, 129.8, 135.9, 158.3, 168.2, 170.0,
174.6; IR (Sol CHCl3) 700, 1180, 1244, 1512, 1629, 1674, 1722,
2963, 3290 cm-1; HRMS (ESI+) m/z calcd for C27H35N2O5
[M+H]+ 467.2546, found 467.2551.
Dehydroalanine 10b (1 eq.) was reacted with sulfonium
bromide 12 and NaH 60 % according to the general procedure,
refluxing for 8 hours. The resulting mixture was purified by flash
column chromatography eluting with a hexane/ethyl acetate (8:2)
solvent system to provide 13b as a colorless solid (84 %) Mp:
148-153°C. 1H NMR (CDCl3, 500 MHz, 25 °C) δ = 1.15 (s, 9H),
1.23 (t, J = 7 Hz, 3H), 1.77 (dd, J = 5 Hz, 1H), 2.14 (dd, J = 5
Hz, 1H), 2.7 (dd, J = 7 Hz, 1H), 3.77 (s, 3H), 4.12 (m, 2H), 4.28
(dd, J = 14.5 Hz, 2H), 6.5 (br, 1H), 6.78- 7.89 (m, 8H); 13C NMR
(CDCl3, 125 MHz) δ = 14.0, 20.2, 28.2, 28.6, 30.8, 51.6, 54.2,
55.3, 61.2, 114.1, 126.8, 128.4, 128.6, 130.2, 130.6, 131.3, 139.4,
141.7, 159.6, 166.8, 170.9, 172.7; IR (Sol CHCl3) 1247, 1653,
2854, 2924, 3416 cm-1; HRMS (ESI+) m/z calcd for
C26H32I1N2O5 [M+H]+ 579.1355, found 579.1360.
Ethyl
2-(tert-butylcarbamoyl)-2-(2-iodo-N-(4-
methoxyphenethyl)benzamido)cyclopropanecarboxylate
(13m).
Dehydroalanine 10m (1 eq.) was reacted with sulfonium
bromide 12 and NaH 60 % according to the general procedure,
refluxing for 20 hours. The resulting mixture was purified by
flash column chromatography eluting with a hexane/ethyl acetate
(8:2) solvent system to provide 13m as colorless solid (46 %)
1
Mp: 138-142 °C. H NMR (CDCl3, 300 MHz, 25 °C) δ = 1.26 (t,
Ethyl
2-(N-benzylbenzamido)-2-(tert-
J = 7.1 Hz, 3H), 1.42 (s, 9H), 1.68 (dd, J = 6.9, 5.0 Hz, 1H), 2.27
(dd, J = 9.0, 5.0 Hz, 1H), 2.68 (dd, J = 9.0, 7.0 Hz, 1H), 2.96 (dd,
J = 9.4, 7.8 Hz, 2H), 3.10-3.24 (m, 1H), 3.40 (ddd, J = 13.9, 9.7,
7.9 Hz, 1H), 3.74 (s, 3H), 4.05-4.22 (m, 2H), 6.77 (d, J = 8.7 Hz,
2H), 6.92 (d, J = 8.7 Hz, 2H), 7.10 (ddd, J = 8.0, 6.2, 3.0 Hz,
1H), 7.22 (br, 1H), 7.34-7.41 (m, 2H), 7.85 (d, J = 8.1 Hz, 1H);
13C NMR (CDCl3, 100 MHz) δ = 14.1, 18.4, 29.0, 30.5, 34.4,
47.3, 52.0, 52.9, 55.2, 61.2, 92.1, 114.0, 128.1, 128.6, 129.5,
129.7, 130.6, 138.8, 142.1, 158.3, 167.8, 170.3, 173.3; IR (Sol
CHCl3) 763, 1025, 1211, 1243, 1511, 1634, 1669, 1714, 2967,
3310 cm-1; HRMS (ESI+) m/z calcd for C27H34I1N2O5 [M+H]+
593.1512, found 593.1521.
butylcarbamoyl)cyclopropanecarboxylate (13d).
Dehydroalanine 10d (1 eq.) was reacted with sulfonium
bromide 12 and NaH 60 % according to the general procedure,
refluxing for 6 hours. The resulting mixture was purified by flash
column chromatography eluting with a hexane/ethyl acetate (8:2)
solvent system to provide 13d as colorless solid (41 %) Mp: 150-
153°C. 1H NMR (CDCl3, 400 MHz, 25 °C) δ = 1.08 (s, 9H), 1.21
(t, J = 7.2 Hz, 3H), 1.80 (dd, J = 5 Hz, 1H), 2.14 (dd, J = 5 Hz),
2.68 (dd, J = 7 Hz, 1H), 4.11 (m, 2H), 4.49 (dd, J = 14.8 Hz, 2H),
6.39 (br, 1H), 7.09-7.46 (m, 10H); 13C NMR (CDCl3, 100 MHz)
δ = 14.1, 19.5, 28.2, 30.7, 48.1, 50.8, 54.4, 61.2, 126.8, 128.3,
128.7, 128.9, 129.0, 129.8, 135.8, 136.2, 167.0, 170.5, 174.0; IR
(Sol CHCl3) 447, 698, 1154, 1180, 1206, 1237, 1387, 1518,
1652, 1715, 2976, 3059, 3440 cm-1 ; HRMS (ESI+) m/z calcd for
C25H31N2O4 [M+H]+ 423.2283, found 423.2281.
Ethyl
2-(N-benzyl-2-iodobenzamido)-2-
(cyclohexylcarbamoyl)cyclopropanecarboxylate (13r).
Dehydroalanine 10r (1 eq.) was reacted with sulfonium
bromide 12 and NaH 60 % according to the general procedure,
refluxing for 24 hours. The resulting mixture was purified by
flash column chromatography eluting with a hexane/ethyl acetate
(7:3) solvent system to provide 13s as a white solid (57 %) Mp:
Ethyl
2-(N-benzyl-2-iodobenzamido)-2-(tert-
butylcarbamoyl)cyclopropanecarboxylate (13e).
Dehydroalanine 10e (1 eq.) was reacted with sulfonium
bromide 12 and NaH 60 % according to the general procedure,
refluxing for 24 hours. The resulting mixture was purified by
flash column chromatography eluting with a hexane/ethyl acetate
(8:2) solvent system to provide 13e as colorless solid (56 %) Mp:
169-173°C. 1H NMR (CDCl3, 400 MHz, 25 °C) δ = 1.14 (s, 9H),
1.23 (t, J = 7 Hz, 3H), 1.79 (dd, J = 4.8 Hz, 1H), 2.13 (dd, J = 4.8
Hz, 1H), 2.71 (dd, J = 6.8 Hz, 1H), 4.13 (m, 2H), 4.34 (dd, J= 15
Hz, 2H), 6.54 (br, 1H), 7.11-7.89 (m, 9H); 13C NMR (CDCl3, 100
MHz) δ = 14.1, 20.2, 28.6, 30.9, 47.4, 51.6, 54.9, 61.2, 93.3,
126.8, 128.4, 128.7, 128.7, 130.0, 130.7, 134.7, 139.4, 141.6,
166.8, 170.9, 172.8; IR (Sol CHCl3) 460, 698, 744, 1157, 1182,
1203, 1233, 1383, 1653, 1708, 2924, 2968, 3061, 3418 cm-1;
HRMS (ESI+) m/z calcd for C25H30I1N2O4 [M+H]+ 549.1250,
found 549.1252.
1
100-102°C. H NMR (CDCl3, 400 MHz, 25 °C) δ = 0.78 (m,
1H), 1.05 (m, 3H), 1.24 (t, J = 7.2 Hz, 3H), 1.6 (m, 5H), 1.82 (dd,
J = 5.0 Hz, 1H), 1.92 (m, 1H), 2.13 (dd, J = 5.0 Hz, 1H), 2.77
(dd, J = 7 Hz, 1H), 3.51 (m, 1H), 4.12 (m, 2H), 4.34 (dd, J = 14.8
Hz, 2H), 6.55 (d, J = 7.6 Hz, 1H), 7.11-7.89 (m, 9H); 13C NMR
(CDCl3, 100 MHz) δ = 14.1, 20.6, 25.1, 25.1, 25.6, 31.1, 33.0,
33.2, 46.9, 49.6, 54.9, 61.2, 93.2, 128.3, 128.4, 128.5, 128.7,
130.0, 130.7, 134.6, 139.3, 141.7, 166.9, 171.0, 172.8; IR (Sol
CHCl3) 694, 745, 1158, 1182, 1235, 1383, 1652, 1714, 2852,
2923, 3423 cm-1; HRMS (FAB+) m/z calcd for C27H32I1N2O4
[M+H]+ 575.1407, found 575.1409.
Acknowledgments
D. A. C. thanks CONACYT for PhD scholarship (Grant No.
271165). Financial support from ‘‘Marcos Moshinsky
Foundation” is gratefully acknowledged. We also thank R.
Patiño, E. García-Ríos, A. Peña, E. Huerta, I. Chavez, R. Gaviño,
Ma. C. García-González, L. Velasco and J. Pérez for technical
support. The authors show gratitude to Simón Hernandez-Ortega
for X-ray crystallography.
Ethyl
2-(tert-butylcarbamoyl)-2-(N-(4-
methoxyphenethyl)benzamido)cyclopropanecarboxylate
(13l).
Dehydroalanine 10l (1 eq.) was reacted with sulfonium
bromide 12 and NaH 60 % according to the general procedure,
refluxing for 24 hours. The resulting mixture was purified by
flash column chromatography eluting with a hexane/ethyl acetate
References and notes
1
(85:15) solvent system to provide 13l as colorless oil (16 %). H
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12
Tetrahedron
ACCEPTED MANUSCRIPT
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Supplementary data
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