Amination of Carbenium Ions Generated by Directed Protonolysis of Cyclopropane

Article abstract of DOI:10.1021/acs.joc.8b02576

Directed intramolecular protonolyis of the cyclopropane C-C bond is demonstrated as a strategy to generate carbenium ions. This intermediate can be subjected to amination with nitriles under Ritter reaction conditions. Directing groups such as carbamate, carboxamide, urea, ester, and ketone were found to be efficient for regioselective anti-Markovnikov cleavage of cyclopropane. Depending on the directing group, the amination provided orthogonally protected 1,4-diamine, ?-amino carboxylic, and ?-amino ketone derivatives.

Full text of DOI:10.1021/acs.joc.8b02576

Subscriber access provided by ECU Libraries
Article
Amination of Carbenium Ions Generated
by Directed Protonolysis of Cyclopropane
Marija Skvorcova, Lukass T. Lukasevics, and Aigars Jirgensons
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02576 • Publication Date (Web): 11 Mar 2019
Downloaded from http://pubs.acs.org on March 11, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 41
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Amination of Carbenium Ions Generated by Directed Protonolysis of Cyclopropane
Marija Skvorcova,a,† Lukass T. Lukasevics,a,† and Aigars Jirgensons a,*
aLatvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia
*Corresponding author; phone: +371 67014948; e-mail: aigars@osi.lv
† These authors contributed equally to the manuscript
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
Y
R1
R2
RCN
R3
N
R3
HN
R1
R2
R
X
X
O
O
O
=
TFA, AcOH
Y
Y
Y
H
amide, carbamate, urea, ester, ketone
C-C bond
cleavage
R1
R2
R1
H
X
O
R2
24 examples, yield 32-92%
H
O
X
Y
Y
ABSTRACT: Directed intramolecular protonolyis of cyclopropane C-C bond is
demonstrated as a strategy to generate carbenium ion. This intermediate can be
subjected to amination with nitriles under Ritter reaction conditions. Directing groups
such as carbamate, carboxamide, urea, ester and ketone were found efficient for
regioselective anti-Markovnikov cleavage of cyclopropane. Depending on the directing
group, the amination provided orthogonally protected 1,4-diamine, amino carboxylic,
and -amino ketone derivatives.
Introduction
Functionalization of the C-C bond has received increased attention in recent years as a
strategy to provide access to useful compounds from readily available starting
materials.1 However, such transformations are challenging due to the relative inertness
of the C-C sigma bond. In cyclopropane, the overlap of C-C bond forming electrons is
less efficient which makes the character of the molecular orbital more similar to a -
bond.2 Rich chemistry has been developed with cyclopropanes activated with donor
and/or acceptor groups enabling relatively mild conditions and predictable
regioselectivity.3,4 The reactivity of non-activated cyclopropanes has been relatively less
explored. Nevertheless, there is a range of examples for metal promoted reactions5 and
reactions with electrophiles such as halogens,6 hypervalent iodine,7 Lewis8 and Brønsted
acids.9 Typically, the regioselectivity of electrophilic cleavage of non-activated
cyclopropane is high except for protonolysis. A modified anti-Markovnikov rule has
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 41
1
2
3
4
5
6
7
8
been proposed to predict the protolytic C-C bond cleavage between the most substituted
and the least substituted carbons of cyclopropane, however, with few exceptions, the
selectivity is moderate.9 Recently, we reported that the C-C bond of N-acylated
aminomethyl cyclopropanes can be regioselectively cleaved in anti-Markovnikov
fashion between the two most substituted carbons (Scheme 1).10 In this transformation,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
protonated amide 1-H+ (DG:
NH(C=O)R3) served as a directing group for
intramolecular proton transfer to the C-C bond via “edge” trajectory leading to
carbenium ion 2 formation. Intramolecular trapping of the carbenium ion 2 with amide
function provided pyrrolidines 3 in good yields.
Our previous work:
R1
N
R2
DG: NH(C=O)R3
R3
R1
R1
R2
O
H
2
3
R1
R2
H
n
R2
DG
n
n
O
DG
DG
This work:
H
1-H+
HN
R1
R2
R
RCN
1
DG
intermolecular
amination
"edge" protonation trajectory
n
4
Scheme 1. Amination of cyclopropane via protonolysis of the C-C bond
To extend the application of regioselective cleavage of cyclopropane 1, we explored the
Ritter-type11,12 intermolecular amination of intermediate carbenium ions 2. In the
context of this reaction, we also investigated the scope of directing groups for selective
cyclopropane C-C bond protonolysis.
Results and Discussion
To examine the intermolecular amination of carbenium ion 2, cyclopropane derivatives
5a,b were subjected to a reaction with nitriles using TFA which gave the highest
selectivity of protonolyis in our previous study,10 with no additional solvent (Table 1).
The reaction of carbamate 5a with acetonitrile provided the desired product 6a,
although in low yield (Table 1, entry 1). Expectedly, a significant amount of pyrrolidine
3 (Scheme 1) was produced from substrate 5a. To suppress the cyclization reaction, the
carbamate nitrogen was blocked by introduction of a methyl group. Consequently, the
reaction of N-methylated analogue 5b with acetonitrile provided diamine derivative 6b
in medium yield (Table 1, entry 2). Increasing the temperature was detrimental to the
yield of diamine 6b (Table 1, entry 3). However, the addition of AcOH, as a preferred
solvent for the Ritter reaction,11b and increased temperature were beneficial in
ACS Paragon Plus Environment

Page 3 of 41
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
improving the yield of product 6b (Table 1, entry 4). Chloroacetonitrile13 and
benzonitrile were also found as suitable amino components for the transformation of
substrate 5b to diamine derivatives 6c and 6d (Table 1, entries 5 and 6).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Optimization of Ritter-type Aminationa
O
CO2Et
HN
R
CO2Et
TFA / RCN / AcOH
24 h, rt or 60 o
N
N
R1
R1
C
, R1 = H;
, R1 = Me
5a
5b
6a-d
ratio of
product,
yield (%)
6a, 9
entry R1
RCN
temp.
TFA / RCN / AcOH
4 / 1 / 0
1
2
3
4
5
6
H
MeCN
MeCN
MeCN
MeCN
rt
Me
Me
Me
rt
4 / 1 / 0
6b, 62
6b, 44
6b, 84
6c, 84
60
60
60
60
4 / 1 / 0
1 / 1 / 1
Me ClCH2CN
Me PhCN
1 / 1 / 1
1 / 1 / 1
6d, 77
a)
Reactions were performed on a 0.22 – 0.47 mmol scale, c = 0.1 M (in a mixture of
TFA/ RCN/AcOH). Isolated yields are given.
With efficient amination conditions in hand, the scope of the carbamate N-substituents
was examined (Table 2). In the reaction with chloroacetonitrile, substrates 7a-d bearing
different types of N-substituents gave the desired amination products 8a-d in good
yields (Table 2, entries 1-4). Interestingly, N-paramethoxybenzyl (PMB) substituted
carbamate 7e provided N-acetylated product 9 (Table 2, entry 5). Such a product can be
explained by the formation of acylium ions from acetic acid which presumably attacks
the carbamate function after the cleavage of PMB group in acidic conditions.
Table 2. Scope of the Carbamate N-Substituenta
O
O
Cl
Cl
CO2Et
HN
CO2Et
Me
ClCH2CN / TFA / AcOH
1 / 1 / 1
HN
CO2Et
N
R
N
N
R
24 h, 60 o
C
O
7a-e
8a-d
9
entry
substrate, R
7a, Bn
product, yield (%)
8a, 63
1
2
7b, allyl
8b, 90
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 41
1
2
3
4
5
6
7
8
3
4
5
7c, propargyl
7d, Ph
8c, 88
8d, 74
9, 87
7e, PMB
9
aReactions were performed on a 0.15 – 0.48 mmol scale, c = 0.1 M. Isolated yields are
given.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The scope of cyclopropane substitution was investigated for substrates 10a-e in the
Ritter reaction with chloroacetonitrile (Table 3). 2,2-Me,Ph-substituted cyclopropane
10a gave product 11a in lower yield (Table 3, entry 1) compared to 2,2-dialkyl
substituted analogues 5b and 7a-e (Tables 1, 2).
Table 3. Scope of cyclopropane substitutiona
O
R4
R5
R3
Cl
TFA / ClCH2CN / AcOH
1 / 1 / 1
NH R5
CO2Et
R2
R1
10a-e
CO2Et
R6
R1
R2
N
R6
N
24 h, 60 o
C
R4
11a-e
R3
entry
1
substrate
product (yield %)
O
Cl
CO2Et
NH
CO2Et
Me
Ph
N
Me
Ph
N
Bn
Bn
10a
11a
(45)
O
Cl
CO Et
NH Me CO2Et
Me
2
2
3
N
N
Me
Me
11b
10b
(55)
O
Me
Me
Cl
CO2Et
NH
CO2Et
N
Me
Me
N
Me
Me
Me
Me
10c
cis-
10c
11c
10c
32 from trans-
(41 from cis-
and
10c)
trans-
O
Me
Me
Me
Me
Cl
NH
Bn
Bn
N
Me
Me
N
4
5
CO2Et
CO2Et
Me Me
b
10d
11d
(0 )
O
Me
N
Cl
NH
Me
CO2Et
Ph
N
Ph
CO2Et
c
10e
11e
(0 )
a) Reactions were performed on a 0.12 - 0.25 mmol scale, c = 0.1 M. Isolated yields are
b)
given.
Ionization of substrate 10d was observed leading to ethyl
acetyl(benzyl)carbamate as the main product; c) No reaction of substrate 10e.
ACS Paragon Plus Environment

Page 5 of 41
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
The introduction of an additional substituent at the 2,2-dialkyl cyclopropane ring
(substrates 10b,c) led to a drop in the yields of products 11b,c (Table 3, entries 2,3).
2,2,3,3-Tetrasubstituted cyclopropane 10d failed to give amide 11d, instead, a
significant amount of C-N bond ionization product was isolated (Table 3, entry 4). No
reaction was observed with the substrate 10e bearing phenyl group as carbenium ion
stabilizing substituent (Table 3, entry 5). Such a result is in accordance with our
previous observation10 that phenyl group does not facilitate the protonolysis of
cyclopropane despite its carbenium ion stabilizing effect.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Next, the directing groups for intramolecular proton transfer in substrates 12a-i were
explored to generate the carbenium ions for the Ritter-type amination (Table 4). The
reaction of chloroacetonitrile with N-methylbenzamide 12a provided the desired
diamine derivative 13a in a high yield (Table 4, entry 1). Phthalimide and urea in
substrates 12b,c were less efficient directing groups leading to a lower yield of
amination products 13b,d due to side product formation (Table 4, entries 2,3).
The reaction of acetonitrile with substrate 12d containing a trichloroacetamido group
gave a considerably improved yield of diamine 13d (Table 4, entry 4) compared to
analogues ethoxycarbamate 5a (Table 1). This can be attributed to weaker
nucleophilicity of trichloroacetamide preventing the intermolecular amination pathway.
Carboxamide, ester and keto groups in substrates 12e-h were found as very efficient
directing groups for the protolysis of cyclopropane leading to amination products 13e-h
in the reaction with chloroacetonitrile (Table 4, entries 5-8). An amino acid motif
containing substrate 12i gave the expected product 13i with a significantly reduced yield
together with N-acylated by-product 13j (Table 4, entry 9).
A notable difference in the reactivity was observed for α,-unsaturated amide isomers
Z-12k and E-12k (Scheme 2). Isomer Z-12k gave the desired product Z-13k smoothly,
while the other isomer E-12k was unreactive. Such a result is in accordance with
intramolecular proton transfer to the C-C bond of cyclopropane in isomer Z-12k which
is not possible for isomer E-12k. This result, together with good reactivity of amide
12e, esters 12f,g and ketone 12h strongly indicates that the oxygen atom is involved in
intramolecular proton transfer to cyclopropane.
Both isomers of unsaturated amino acid Z-12l and E-12l were transformed to
chloroacetamide Z-13l (Scheme 2). A significantly better yield compared to substrate
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 41
1
2
3
4
5
6
7
8
13i amination was obtained likely due to the reduced nucleophilicity of the carbamate
function in unsaturated analogues Z- and E-12l. The product Z-13l formation as a single
isomer from both substrates Z- and E-12l can be explained by the isomerization of the
double bond either in the substrate or product to form a thermodynamically more stable
cis-isomer.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 4. Scope of Directing Groupsa
Y
R1
R1
TFA / RCN / AcOH
R1
R1
O
1 / 1 / 1
X
X
Y
24 h, 60 o
C
HN
R
O
12a-i
13a-j
O
entry
substrate
product (yield %)
O
Me
N
Me
Me
Me
Ph
N
Ph
Me
Me
1
2
3
4
HN
Cl
O
12a
O
13a
(92)
O
Me
Me
O
N
N
Me
Me
HN
Me
O
O
O
12b
13b
(47)
O
Me
Me
Ph
Me Me
N
N
Me
Me
N
N
HN
Me Me
Ph
Cl
O
O
13c
12c
(44)
O
N
H
CCl3
H
N
CCl3
HN
Me
Me
O
12db,c
O
13d
(58)
O
Me
NEt2
Me
NEt2
HN
5
6
7
Me
Cl
13e
O
O
O
O
12ed
12f
(63)
Me
Me
CO2Et
Me
Me
HN
CO2Et
Cl
13f
(93)
CO2Me
CO2Me
CO2Me
HN
Cl
CO2Me
13g
12g
(81)
O
Me
Me
O
8
HN
Cl
O
12h
13h
(79)
ACS Paragon Plus Environment

Page 7 of 41
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Me
Me
CO2Me
CO2Et
CO2Et
HN
HN
Cl
O
N
Me
Me
R
9
CO2Me
13i
13j
, R = H (22)
, R = Ac (21)
12i
a) Reactions were performed on 0.08 – 0.47 mmol scale, c = 0.1 M. Isolated yields are
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
given. Reaction conditions: 25% TFA in MeCN, rt; c) An addition of AcOH reduces
b)
the yield; d) The reaction was performed at rt;
Me
O
NEt2
CO2Me
NHCO2Et
CO2Me
Me
a
a
Me
HN
NHCO2Et
HN
NEt2
O
Cl
Me
Cl
O
O
12l
12l
Z-
E-
13l
Z-
12k
12k
Z-
E-
13k
Z-
13k
12k
)
12k)
(80% from Z-
(no reaction of E-
12l
(84% from Z-
(82% from E-
)
E-
12l
)
Conditions a: ClCH2CN, AcOH, TFA, 60oC
Scheme 2 The effect of unsaturated linker
Me
CF3
Me
Me
CF3
O
a
Me
Me
+ 2 regioisomers
O
HN
71%
Cl
13m
O
12m
Conditions a: ClCH2CN, AcOH, TFA, 60 o
C
Scheme 3 Nonselective cyclopropane protonolysis
An additional evidence for the crucial role of the directing group in the selective proton
transfer was obtained from the Ritter reaction with substrate 12m bearing substituted
phenyloxy group (Scheme 3). This substrate provided an inseparable mixture of three
regioisomers according to 1H, 13C, and 19F NMR data (in ratio 4:1.7:1, see Supporting
Information) with amide 13m as the major product. Such an outcome can be explained
by considerable extent of intermolecular cyclopropane protonolysis which
predominantly leads to the cleavage of the bond between the most and the less
substituted carbons.9
Conclusion
Several functional groups such as carbamate carboxamide, urea, ester and ketone
efficiently direct regioselective protonolytic cleavage of the cyclopropane C-C bond.
Carbenium ions generated by the directed protonolysis of cyclopropane can be
intermoleculary aminated under Ritter-type reaction conditions. This provides a
relatively short synthesis route to orthogonally protected 1,4-diamine, amino
carboxylic, and -amino ketone derivatives.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 41
1
2
3
4
5
6
Experimental Section
7
8
9
All procedures were performed under an argon atmosphere unless otherwise noted.
Reagents and starting materials were obtained from commercial sources and used as
received. Solvents were purified and dried by standard procedures prior to use. Flash
column chromatography was carried out using silica gel (230 − 400 mesh). Thin layer
chromatography (TLC) was performed on silica gel and was visualized with a UV lamp
or staining with KMnO4. NMR spectra were recorded on 300, 400, 600 MHz
spectrometers with chemical shift values (δ) in parts per million using the residual
chloroform, dimethylsulfoxide or acetone signal as an internal standard. HRMS
analyses were performed on a hybrid quadrupole time-of-flight mass spectrometer
equipped with an electrospray ion source.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General procedures for the Ritter reaction
Method A: cyclopropane (0.1 mmol) was dissolved in a mixture of TFA / RCN in ratio
4 / 1 (1 mL) and stirred in ambient temperature until either full consumption of the
product or no changes in conversion were observed (24 h). The reaction mixture was
evaporated to dryness under reduced pressure. The crude product was re-dissolved in
Et2O, evaporated to dryness repeatedly (2 × 3 mL), and purified by column
chromatography on silica gel using an appropriate eluent.
Method B: cyclopropane (0.1 mmol) was dissolved in a mixture of TFA / RCN / AcOH
o
in a ratio of 1 / 1 / 1 (1 mL) and stirred at 60 C until either full consumption of the
product or no changes in conversion were observed (24 h). Reaction mixture was
evaporated to dryness under reduced pressure. The crude product was re-dissolved in
Et2O and evaporated to dryness repeatedly (2 × 3 mL) and purified by column
chromatography on silica gel using an appropriate eluent.
Ethyl (3-(1-acetamidocyclohexyl)propyl)carbamate (6a). Prepared by method A from
cyclopropane 5a (50 mg, 0.23 mmol), MeCN (460 µL), TFA (1.84 mL). Purification by
column chromatography (eluent EtOAc) gave product 6a (6 mg, 9%) as a colourless
oil.1H NMR (300 MHz, CDCl3, ppm) δ 5.02 (b. s, 1H), 4.74 (b. s, 1H), 4.09 (q, J = 6.9
Hz, 2H), 3.14 (q, J = 6.5 Hz, 2H), 2.03 - 1.95 (m, 3H), 1.83 – 1.75 (m, 2H), 1.60 – 1.16
13
(m, 13H, overlaps with H2O signal). C{1H} NMR (101 MHz, CDCl3, ppm) δ 169.9,
ACS Paragon Plus Environment

Page 9 of 41
The Journal of Organic Chemistry
1
2
3
4
5
6
7
156.8, 60.7, 55.9, 41.3, 35.0, 25.8, 24.5, 23.8, 21.8, 14.7. HR-MS (ESI-TOF) m/z:
Calcd. for C14H27N2O3 271.2022; found 271.2024 [M+H]+.
8
9
Ethyl (3-(1-acetamidocyclohexyl)propyl)(methyl)carbamate (6b). Prepared by
method A from cyclopropane 5b (60 mg, 0.26 mmol), MeCN (0.53 mL), TFA (2.10
mL) or method B from cyclopropane 5b (100 mg, 0.44 mmol), MeCN (1.46 mL), TFA
(1.46 mL), AcOH (1.46 mL). Purification by column chromatography (eluent EtOAc) in
both cases gave product 6b (39 mg, 62% by method A; 106 mg, 84% by method B) as a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
colourless oil. H NMR (300 MHz, CDCl3, ppm) δ 5.13 (s, 1H), 4.07 (q, J = 7.1 Hz,
2H), 3.17 (t, J = 6.7 Hz, 2H), 2.82 (s, 3H), 2.04 – 1.87 (m, 5H), 1.74 – 1.63 (m, 2H),
1.59 – 1.14 (m, 13H). 13C{1H} NMR (101 MHz, CDCl3, ppm) δ 169.5, 156.6, 61.1,
55.8, 53.5, 49.4, 49.0, 34.8, 25.8, 24.5, 21.8, 14.8, 1.9. HR-MS (ESI-TOF) m/z: calcd.
for C15H29N2O3 285.2178, found 285.2186 [M+H]+.
Ethyl (3-(1-(2-chloroacetamido)cyclohexyl)propyl) (methyl)carbamate (6c).
Prepared by method B from cyclopropane 5b (54 mg, 0.24 mmol) ClCH2CN (0.80 mL),
TFA (0.80 mL), AcOH (0.80 mL). Purification by column chromatography (eluent
EtOAc) gave product 6c (64 mg, 84%) as a colourless oil. 1H NMR (400 MHz, CDCl3,
ppm) δ 6.18 (s, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.95 (s, 2H), 3.18 (t, J = 7.2 Hz, 2H), 2.84
(s, 3H), 2.09 – 1.99 (m, 2H), 1.77 – 1.66 (m, 2H), 1.62 – 1.18 (m, 13H, overlaps with
H2O). 13C{1H} NMR (101 MHz, CDCl3, ppm) δ 164.6, 156.4, 61.0, 56.2, 49.1, 48.7,
42.9, 34.8, 34.5, 25.5, 21.6, 14.7. HR-MS (ESI-TOF) m/z: Calcd. for C15H28N2O3Cl
319.1788, found 319.1799 [M+H]+.
Ethyl (3-(1-benzamidocyclohexyl)propyl)(methyl) carbamate (6d). Prepared by
method B from cyclopropane 5b (50 mg, 0.22 mmol), PhCN (0.73 mL), TFA (0.73
mL), AcOH (0.73 mL). Purification by column chromatography (eluent EtOAc) gave
product 6d (59 mg, 77%) as a colourless oil. 1H NMR (400 MHz, CDCl3,ppm) δ 7.75 –
7.63 (m, 2H), 7.50 – 7.32 (m, 3H), 5.74 (s, 1H), 4.05 (qd, J = 7.1, 1.2 Hz, 2H), 3.21 (s,
2H), 2.81 (s, 3H), 2.15 (m, 2H), 1.92 – 1.74 (m, 2H), 1.68 – 1.09 (m, 13H, overlaps with
H2O signal). 13C{1H} NMR (101 MHz, CDCl3, ppm) δ 166.9, 156.5, 136.0, 131.2,
128.6, 126.6, 61.0, 56.1, 49.2, 40.0, 35.0, 29.7, 25.8, 21.9, 14.7.HR-MS (ESI-TOF) m/z:
Calcd. for C20H31N2O3 347.2335, found 347.2336 [M+H]+.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 41
1
2
3
4
5
6
7
8
Ethyl benzyl(3-(1-(2-chloroacetamido)cyclohexyl) propyl)carbamate (8a). Prepared
by method B from cyclopropane 7a (50 mg, 0.16 mmol) ClCH2CN (0.80 mL), TFA
(0.80 mL), AcOH (0.80 mL). Purification by column chromatography (eluent EtOAc)
9
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
gave product 8a (41 mg, 63%) as a colourless oil. H NMR (400 MHz, CDCl3, ppm) δ
7.35 – 7.17 (m, 5H), 6.13 (b. s, 1H), 4.45 (b. s, 2H), 4.17 (q, J = 6.9 Hz, 2H), 3.93 (s,
2H), 3.17 (b. s, 2H), 2.06 – 1.97 (m, 2H), 1.71 – 1.63 (m, 2H), 1.62 – 1.17 (m, 13H,
13
overlaps with H2O signal). C{1H} NMR (101 MHz, CDCl3, ppm) δ 164.7, 156.9,
138.3, 128.6, 127.9, 127.4, 61.4, 56.4, 50.6, 47.6, 46.8, 43.1, 35.1, 34.6, 25.7, 21.8,
14.8. HR-MS (ESI-TOF) m/z: Calcd. for C21H32ClN2O3 395.2101; found: 395.2104
[M+H]+.
Ethyl allyl(3-(1-(2-chloroacetamido)cyclohexyl)propyl) carbamate (8b). Prepared by
method B from cyclopropane 7b (122 mg, 0.48 mmol) ClCH2CN (1.60 mL), TFA (1.60
mL), AcOH (1.60 mL). Purification by column chromatography (eluent hexanes/EtOAc
1
2.5:1) gave product 8b (151 mg, 90%) as a colourless oil. H NMR (400 MHz, CDCl3,
ppm) δ 6.16 (s, 1H), 5.81 – 5.65 (m, 1H), 5.09 (d, J = 11.3 Hz, 2H), 4.10 (q, J = 7.1 Hz,
2H), 3.94 (b. s, 2H), 3.81 (b. s, 2H), 3.15 (t, J = 7.7 Hz, 2H), 2.11 – 1.98 (m, 2H), 1.76 –
1.66 (m, 2H), 1.63 – 1.15 (m, 13H). 13C{1H} NMR (101 MHz, CDCl3, ppm) δ 164.6,
156.2, 134.0, 116.2, 61.1, 56.2, 49.6, 47.3, 46.6, 42.9, 34.9, 34.5, 25.5, 21.6, 14.7.HR-
MS (ESI-TOF) m/z: Calcd. for C17H30ClN2O3 345.1945; found: 345.1940 [M+H]+.
Ethyl (3-(1-(2-chloroacetamido)cyclohexyl)propyl) (prop-2-yn-1-yl)carbamate (8c).
Prepared by method B from cyclopropane 7c (51 mg, 0.20 mmol) ClCH2CN (0.40 mL),
TFA (0.40 mL), AcOH (0.40 mL). Purification by column chromatography (eluent
hexanes/EtOAc 2.7:1) gave product 8c (61 mg, 88%) as a colourless oil.1H NMR (400
MHz, CDCl3, ppm) δ 6.19 (s, 1H), 4.15 (q, J = 7.1 Hz, 2H), 4.06 (b. s, 2H), 3.97 (s,
2H), 3.32 (t, J = 7.4 Hz, 2H), 2.20 (t, J = 2.4 Hz, 1H), 2.12 – 2.00 (m, 2H), 1.80 – 1.72
(m, 2H), 1.65 – 1.46 (m, 5H), 1.45 – 1.30 (m, 5H), 1.25 (t, J = 7.1 Hz, 3H). 13C{1H}
NMR (101 MHz, CDCl3, ppm) δ 164.7, 155.9, 79.5, 71.5, 61.6, 56.3, 47.1, 46.7, 42.9,
36.3, 34.9, 34.5, 25.5, 21.7, 14.6. HR-MS (ESI-TOF) m/z: Calcd. for
C17H28ClN2O3 343.1788; found: 343.1790 [M+H]+.
Ethyl (3-(1-(2-chloroacetamido)cyclohexyl)propyl) phenyl)carbamate (8d).
Prepared by method B from cyclopropane 7d (40 mg, 0.14 mmol) ClCH2CN (0.30 mL),
TFA (0.30 mL), AcOH (0.30 mL). Purification by column chromatography (eluent
ACS Paragon Plus Environment

Page 11 of 41
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
hexanes/EtOAc 2.5:1) gave product 8d (39 mg, 74%) as a colourless oil. 1H NMR (400
MHz, CDCl3, ppm) δ 7.38 – 7.28 (m, 2H), 7.25 – 7.11 (m, 3H), 6.12 (b. s, 1H), 4.13 (q,
J = 7.0 Hz, 2H), 3.90 (s, 2H), 3.64 (t, J = 7.3 Hz, 2H), 2.08 – 1.97 (m, 2H), 1.83 – 1.72
(m, 2H), 1.64 – 1.12 (m, 13H). 13C{1H} NMR (101 MHz, CDCl3, ppm) δ 164.6, 155.6,
141.9, 128.8, 127.2, 126.4, 61.5, 56.3, 50.4, 42.9, 34.8, 34.5, 25.5, 22.0, 21.6, 14.5. HR-
MS (ESI-TOF) m/z: Calcd. for C20H30ClN2O3 381.1945; found: 381.1944 [M+H]+.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl acetyl(3-(1-(2-chloroacetamido)cyclohexyl) propyl)carbamate (9). Prepared
by method B from cyclopropane 7e (50 mg, 0.15 mmol) ClCH2CN (0.30 mL), TFA
(0.30 mL), AcOH (0.30 mL). Purification by column chromatography (eluent
hexanes/EtOAc 2.5 : 1) gave product 9 (46 mg, 87%) as a colourless oil. 1H NMR (400
MHz, CDCl3, ppm) δ 6.14 (b. s, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.95 (s, 2H), 3.70 – 3.61
(m, 2H), 2.47 (s, 3H), 2.07 – 1.95 (m, 2H), 1.79 – 1.69 (m, 2H), 1.62 – 1.18 (m, 13H).
13C{1H} NMR (101 MHz, CDCl3, ppm) δ 172.9, 164.6, 154.6, 62.7, 56.2, 44.2, 42.9,
34.5, 26.8, 25.5, 22.4, 21.6, 14.2. HR-MS (ESI-TOF) m/z: Calcd. for
C16H28ClN2O4 347.1738; found: 347.1728 [M+H]+.
Ethyl benzyl(4-(2-chloroacetamido)-4-phenylpentyl) carbamate (11a). Prepared by
method B from cyclopropane 10a (50 mg, 0.15 mmol) ClCH2CN (0.40 mL), TFA
(0.40 mL), AcOH (0.40 mL). Purification by column chromatography (eluent
hexanes/EtOAc 1:1) gave product 11a (29 mg, 45%) as a colourless oil.1H NMR (400
MHz, CDCl3, ppm) δ 7.38 – 7.09 (m, 10H), 6.79 (m, 1H), 4.36 (b. s, 2H), 4.16 (q, J =
6.9 Hz, 2H), 4.03 – 3.91 (m, 2H), 3.15 (m, 2H), 2.01 (td, J = 12.9, 4.8 Hz, 1H), 1.87 (td,
13
J = 12.6, 4.9 Hz, 1H), 1.71 (s, 3H), 1.46 – 1.12 (m, 6H). C{1H} NMR (101 MHz,
cdcl3) δ 164.8, 144.7, 138.0, 128.7, 128.0, 127.5, 127.13, 125.1, 61.5, 59.2, 50.6, 50.2,
46.8, 46.3, 43.1, 38.4, 29.8, 25.4, 22.9, 14.8. HR-MS (ESI-TOF) m/z: Calcd. for
C23H30ClN2O3 417.1945; found: 417.1954 [M+H]+.
Ethyl
(3-(1-(2-chloroacetamido)cyclohexyl)-2-methyl-propyl)(methyl)carbamate
(11b). Prepared by method B from cyclopropane 10b (60 mg, 0.25 mmol) ClCH2CN
(0.90 mL), TFA (0.90 mL), AcOH (0.90 mL). Purification by column chromatography
(gradient hexanes/EtOAc 5:1 to 1:1) gave product 11b (45 mg, 55%) as a colourless oil.
1H NMR (400 MHz, CDCl3, ppm) δ 6.25 (s, 1H), 4.12 (q, J = 7.1 Hz, 2H), 4.04 – 3.90
(m, 2H), 3.21 – 3.04 (m, 1H), 3.03 – 2.81 (m, 4H), 2.20 – 2.05 (m, 2H), 1.92 (b. s, 1H),
1.78 – 1.18 (m, 13H, overlaps with H2O signal), 0.90 (d, J = 5.4 Hz, 3H). 13C{1H} NMR
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 41
1
2
3
4
5
6
7
8
(101 MHz, CDCl3, ppm) δ 164.7, 156.9, 61.2, 56.8, 56.0, 43.2, 41.9, 35.6, 35.2, 34.95,
27.8, 25.6, 21.8, 19.9, 19.5, 14.9. HR-MS (ESI-TOF) m/z: Calcd. for
C16H30ClN2O3 333.1945; found: 333.1937 [M+H]+.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl (4-(2-chloroacetamido)-3,4-dimethylpentyl) (methyl)carbamate (11c).
Prepared by method B from cyclopropane trans-10c (25 mg, 0.12 mmol), ClCH2CN
(0.42 mL), TFA (0.42 mL), AcOH (0.42 mL) or cis-10c (50 mg, 0.25 mmol), ClCH2CN
(0.80 mL), TFA (0.80 mL), AcOH (0.80 mL). Purification by column chromatography
(gradient hexanes/ EtOAc 5:1 to 1:1) in both cases gave product 11c (11 mg, 32% from
1
trans-10c; 31 mg, 41% from cis-10c) as a colourless oil. H NMR (400 MHz, CDCl3,
ppm) δ 6.31 (b. s, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.94 (s, 2H), 3.38 – 3.15 (m, 2H), 2.88
(s, 3H), 2.05 (dqd, J = 10.7, 6.8, 2.2 Hz, 1H), 1.81 – 1.70 (m, 1H), 1.31 (d, J = 2.3 Hz,
6H), 1.25 (t, J = 7.1 Hz, 3H), 1.21 – 1.08 (m, 1H), 0.97 – 0.89 (m, 3H). 13C{1H} NMR
(101 MHz, CDCl3, ppm) δ 164.8, 156.6, 61.3, 57.6, 47.9, 43.2, 37.5, 34.7, 29.8, 23.9,
23.4, 14.9, 14.3. HR-MS (ESI-TOF) m/z: Calcd. for C12H23ClNaN2O3 301.1295; found:
301.1281 [M+Na]+.
N-(4-(2-Chloroacetamido)-4-methylpentyl)-N-methyl benzamide (13a). Prepared by
method B from cyclopropane 12a (50 mg, 0.23 mmol), ClCH2CN (0.70 mL), TFA
(0.70 mL), AcOH (0.70 mL). Purification by column chromatography (eluent
hexanes/acetone 1:1) gave product 13a (66 mg, 92%) as a colourless oil. 1H NMR (400
MHz, CDCl3, ppm) δ 7.38 ( b.s, 5H), 6.29 (d, J = 57.7 Hz, 1H, rotamer), 3.91 (d, J =
15.3 Hz, 2H, rotamer), 3.52 and 3.21 (b. s, together 2H, rotamers), 3.09 – 2.84 (m, 3H,
rotamer), 1.81 (b. s, 1H), 1.73 – 1.41 (m, 3H), 1.39 – 1.16 (m, 6H). 13C{1H} NMR (101
MHz, CDCl3, ppm) δ 165.0, 136.8, 129.4, 128.5, 126.9, 126.6, 54.2, 54.0, 51.4, 47.6,
43.0, 37.7, 36.7, 36.3, 32.9, 26.9, 23.2, 21.8. HR-MS (ESI-TOF) m/z: Calcd. for C16H24
ClN2O2 311.1526; found: 311.1517 [M+H]+.
N-(5-(1,3-Dioxoisoindolin-2-yl)-2-methylpentan-2-yl) acetamide (13b). Prepared by
method B from cyclopropane 12b (50 mg, 0.21 mmol), MeCN (1.40 mL), TFA
(1.40 mL), AcOH (1.40 mL). Purification by column chromatography (eluent EtOAc)
1
gave product 13b (30 mg, 47%) as a colourless crystalline solid. H NMR (300 MHz,
CDCl3, ppm) δ 7.86 – 7.80 (m, 2H), 7.74 – 7.67 (m, 2H), 5.19 (b. s, 1H), 3.68 (t, J = 6.9
13
Hz, 2H), 1.89 (s, 3H), 1.80 – 1.59 (m, 4H), 1.31 – 1.21 (m, 6H). C{1H} NMR (101
MHz, CDCl3, ppm) δ 169.5, 168.5, 134.0, 132.2, 123.3, 53.5, 38.3, 36.9, 27.1, 24.5,
ACS Paragon Plus Environment

Page 13 of 41
The Journal of Organic Chemistry
1
2
3
4
5
6
7
23.5. HR-MS (ESI-TOF) m/z: Calcd. for C16H21N2O3 289.1552; found: 289.1566
[M+H]+.
8
9
2-Chloro-N-(5-(1,3-dimethyl-3-phenylureido)-2-methyl
pentan-2-yl)acetamide
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(13c). Prepared by method B from cyclopropane 12c (38 mg, 0.15 mmol), ClCH2CN
(0.50 mL), TFA (0.50 mL), AcOH (0.50 mL). Purification by column chromatography
1
(eluent CH2Cl2/Tol/MTBE 1:1:2) gave product 13c (23 mg, 44%) as a colorless oil. H
NMR (400 MHz, CDCl3, ppm) δ 7.32 (d, J = 0.9 Hz, 2H), 7.06 (dd, J = 8.5, 1.1 Hz,
3H), 6.26 (s, 1H), 3.93 (s, 2H), 3.18 (s, 3H), 3.14 – 3.09 (m, 2H), 2.57 (s, 3H), 1.64 –
1.55 (m, 2H), 1.43 – 1.33 (m, 2H), 1.31 (s, 6H). 13C{1H} NMR (101 MHz, CDCl3, ppm)
δ 164.9, 162.0, 147.2, 129.5, 124.6, 124.1, 54.1, 50.3, 43.0, 40.0, 37.1, 36.2, 26.8, 22.1.
HR-MS (ESI-TOF) m/z: Calcd. for C17H27ClN3O2 340.1792; found: 340.1785 [M+H]+.
N-(3-(1-Acetamidocyclohexyl)propyl)-2,2,2-trichloro-acetamide (13d). Prepared by
method B from cyclopropane 12d (100 mg, 0.47 mmol), MeCN (1.20 mL), TFA (1.20
mL), AcOH (1.20 mL). Purification by column chromatography (eluent EtOAc) gave
product 13d (35 mg, 58%) as a colourless crystalline solid.1H NMR (300 MHz, CDCl3,
ppm) δ 6.92 (b. s, 1H), 5.06 (b. s, 1H), 3.34 (m, 2H), 2.01 – 1.81 (m, 7H), 1.64 – 1.20
13
(m, 11H, overlaps with H2O signal). C{1H} NMR (101 MHz, CDCl3, ppm) δ 169.8,
o
162.2, 92.8, 55.7, 41.9, 35.1, 34.8, 25.7, 24.6, 22.7, 21.8. Tm.p.=144-147 C. Anal.
Calcd. for C13H21Cl3N2O2: C, 45.43; H, 6.16; N, 8,15; found C, 45.31; H, 6.24; N, 8.00.
6-(2-Chloroacetamido)-N,N-diethyl-6-methylheptan- amide (13e). Prepared by
method B from cyclopropane 12e (30 mg, 0.41 mmol) ClCH2CN (0.50 mL), TFA
(0.50 mL), AcOH (0.50 mL). Purification by column chromatography (eluent
Hexanes/EtOAc 2:1) gave product 13e (28 mg, 63%) as a yellowish oil.1H NMR (400
MHz, CDCl3, ppm) δ 6.33 (b. s, 1H), 3.93 (s, 2H), 3.33 (dq, J = 26.8, 7.1 Hz, 4H), 2.34
– 2.25 (m, 2H), 1.76 – 1.59 (m, 4H), 1.34 (s, 8H), 1.16 (d, J = 7.2 Hz, 3H), 1.10 (t, J =
13
7.1 Hz, 3H). C{1H} NMR (101 MHz, CDCl3, ppm) δ 172.0, 164.9, 54.4, 43.1, 42.1,
40.2, 40.1, 33.0, 26.7, 25.7, 23.9, 14.5, 13.2. HR-MS (ESI-TOF) m/z: Calcd. for
C14H28ClN2O2 291.1839; found: 291.1850 [M+H]+.
Ethyl 6-(2-chloroacetamido)-6-methylheptanoate (13f). Prepared by method B from
cyclopropane 12f (70 mg, 0.41 mmol) ClCH2CN (1.36 mL), TFA (1.36 mL), AcOH
(1.36 mL). Purification by column chromatography (eluent Hexanes/EtOAc 1:1) gave
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 41
1
2
3
4
5
6
7
8
9
product 13f (101 mg, 93%) as a colourless oil.1H NMR (400 MHz, CDCl3, ppm)δ 6.26
(b. s, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.92 (s, 2H), 2.29 (t, J = 7.4 Hz, 2H), 1.75 – 1.68
(m, 2H), 1.61 (quintet, J = 7.5 Hz, 2H), 1.34 – 1.19 (m, 11H). 13C{1H} NMR (101 MHz,
CDCl3, ppm) δ 173.6, 164.9, 60.3, 54.3, 43.0, 39.7, 34.3, 26.7, 25.2, 23.6, 14.3. HR-MS
(ESI-TOF) m/z: Calcd. for C12H22ClNaNO3 286.1186; found 286.1190 [M+Na]+.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Dimethyl 2-(3-(1-(2-chloroacetamido)cyclohexyl)prop-yl)malonate (13g). Prepared
by method B from cyclopropane 12g (79.5 mg, 0.31 mmol) in ClCH2CN (0.90 mL),
TFA (0.90 mL), AcOH (0.90 mL). Purification by column chromatography (eluent
1
hexanes/EtOAc 2:1) gave product 13g (88 mg, 81%) as a colourless oil. H NMR (400
MHz, CDCl3, ppm) δ 6.16 (b. s, 1H), 3.96 (s, 2H), 3.72 (s, 6H), 3.36 (t, J = 7.5 Hz, 1H),
2.11 – 1.99 (m, 2H), 1.87 (q, J = 7.6 Hz, 2H), 1.85 – 1.75 (m, 2H), 1.70 – 1.45 (m, 3H),
1.46 – 1.18 (m, 7H). 13C{1H} NMR (101 MHz, CDCl3, ppm) δ 169.8, 164.6, 56.3, 52.4,
51.4, 42.9, 37.2, 34.5, 28.9, 25.5, 21.6, 20.9. HR-MS (ESI-TOF) m/z: Calcd. for
C16H27ClNO5348.1578; found: 348.1581 [M+H]+.
2-Chloro-N-(1-(5-oxohexyl)cyclohexyl)acetamide (13h). Prepared by method B from
cyclopropane 12h (15 mg, 0.08 mmol) in ClCH2CN (0.20 mL), TFA (0.20 mL), AcOH
(0.20 mL). Purification by column chromatography (eluent hexanes/EtOAc 2:1) gave
product 13h (18 mg, 79%) as a yellowish oil.1H NMR (400 MHz, CDCl3, ppm) δ 6.17
(s, 1H), 3.97 (s, 2H), 2.42 (t, J = 7.4 Hz, 2H), 2.12 (s, 3H), 2.05 (dd, J = 11.2, 3.9 Hz,
2H), 1.82 – 1.72 (m, 2H), 1.66 – 1.50 (m, 5H), 1.45 – 1.16 (m, 7H). 13C{1H} NMR (101
MHz, CDCl3, ppm) δ 209.1, 164.6, 56.4, 43.5, 43.0, 37.6, 34.5, 29.8, 25.6, 23.9, 22.5,
21.7. HR-MS (ESI-TOF) m/z: Calcd. for C14H25ClNO2 274.1574; found: 274.1563
[M+H]+.
Methyl 6-(2-chloroacetamido)-2-((ethoxycarbonyl) amino)-6-methylheptanoate
(13i). Prepared by method B from cyclopropane 12i (33 mg, 0.13 mmol) ClCH2CN
(0.45 mL), TFA (0.45 mL), AcOH (0.45 mL). Purification by column chromatography
(eluent MTBE/CH2Cl2 1:6) gave product 13i (10 mg, 22%) as a colourless oil. 1H NMR
(400 MHz, CDCl3, ppm) δ 6.29 (s, 1H), 5.17 (d, J = 8.5 Hz, 1H), 4.40 – 4.27 (m, 1H),
4.12 (q, J = 7.1 Hz, 2H), 3.94 (s, 2H), 3.74 (s, 3H), 1.86 – 1.70 (m, 4H), 1.64 (td, J =
14.2, 8.1 Hz, 2H), 1.33 (s, 8H), 1.25 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz,
CDCl3, ppm) δ 173.1, 165.1, 156.3, 61.3, 54.2, 53.5, 52.5, 52.5, 43.0, 39.4, 33.1, 26.8,
ACS Paragon Plus Environment

Page 15 of 41
The Journal of Organic Chemistry
1
2
3
4
5
6
7
26.6, 19.9, 14.6. HR-MS (ESI-TOF) m/z: Calcd. for C16H27ClNaN2O6 401.1455; found:
401.1469 [M+Na]+.
8
9
Methyl
6-(2-chloroacetamido)-2-(N-(ethoxycarbonyl)
acetamido)-6-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
methylheptanoate (13j). Isolated as by-product in Ritter reaction of cyclopropane 12i
(33 mg, 0.13 mmol) in ClCH2CN (0.45 mL), TFA (0.45 mL) and AcOH (0.45 mL).
Purification by column chromatography (eluent CH2Cl2/Tol/MTBE 1:1:2) gave by-
product 13j (11 mg, 21%) as a colourless oil. 1H NMR (400 MHz, CDCl3, ppm) δ 6.24
(s, 1H), 5.24 (dd, J = 9.0, 5.3 Hz, 1H), 4.35 – 4.17 (m, 2H), 3.93 (d, J = 0.7 Hz, 2H),
3.68 (s, 3H), 2.55 (s, 3H), 2.22 – 2.10 (m, 1H), 1.83 (dtd, J = 14.5, 9.1, 5.6 Hz, 1H),
1.73 (dd, J = 9.2, 7.7 Hz, 2H), 1.34 – 1.27 (m, 11H). 13C{1H} NMR (101 MHz, CDCl3,
ppm) δ 172.8, 171.0, 165.0, 153.9, 63.4, 55.7, 54.2, 52.4, 43.0, 39.6, 30.0, 26.7, 26.7,
26.6, 21.0, 14.1. HR-MS (ESI-TOF) m/z: Calcd. for C16H28ClN2O6 379.1636; found:
379.1631 [M+H]+.
(Z)-5-(1-(2-Chloroacetamido)cyclohexyl)-N,N-diethyl-pent-2-enamide
(cis-13k).
Prepared by method B from cyclopropane cis-12k (70 mg, 0.41 mmol) ClCH2CN (0.30
1
mL), TFA (0.30 mL), AcOH (0.30 mL). Yield of cis-13k was 80% (determined by H
1
NMR using 1,3-bis(trichloromethyl)benzene as an internal standard). H NMR (400
MHz, CDCl3, ppm) δ 6.45 (b. s, 1H), 6.03 – 5.81 (m, 2H), 3.95 (s, 2H), 3.41 (q, J = 7.1
Hz, 2H), 3.32 (q, J = 7.1 Hz, 2H), 2.39 – 2.31 (m, 2H), 2.21 – 2.12 (m, 2H), 1.93 – 1.86
(m, 2H), 1.64 – 1.23 (m, 8H, overlaps with H2O signal), 1.14 (td, J = 7.1, 1.8 Hz, 6H).
13C{1H} NMR (101 MHz, CDCl3, ppm) δ 167.2, 165.2, 141.9, 121.8, 56.6, 43.3, 42.6,
39.7, 36.8, 34.5, 29.8, 25.7, 23.6, 21.8, 14.4, 13.3. HR-MS (ESI-TOF) m/z: Calcd. for
C17H30ClN2O2 329.1996; found: 329.1994 [M+H]+.
Methyl (Z)-6-(2-chloroacetamido)-2-((ethoxycarbonyl) amino)-6-methylhept-2-
enoate (cis-13l). Prepared by method B from cyclopropane cis-12l (77 mg, 0.31 mmol)
ClCH2CN (1.00 mL), TFA (1.00 mL), AcOH (1.00 mL) or trans-12l (48
mg, 0.20 mmol), ClCH2CN (0.60 mL), TFA (0.60 mL), AcOH (0.60 mL). Purification
by column chromatography (eluent EtOAc). Both cis- and trans-isomers of 12l gave
product cis-13l as a single isomer. In case of cis-12l yield was 84% and trans-12l 82%.
1H NMR (400 MHz, CDCl3, ppm) δ 6.60 (t, J = 7.6 Hz, 1H), 6.37 (b. s, 1H), 6.22 (b. s,
1H), 4.16 (q, J = 7.1 Hz, 2H), 3.94 (s, 2H), 3.77 (s, 3H), 2.27 – 2.14 (m, 2H), 2.01 –
13
1.85 (m, 2H), 1.35 (s, 6H), 1.27 (t, J = 7.1 Hz, 3H). C{1H} NMR (101 MHz, CDCl3,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 41
1
2
3
4
5
6
7
ppm) δ 165.2, 165.0, 154.4, 136.9, 125.5, 61.6, 54.1, 52.3, 42.9, 37.8, 26.7, 23.5, 14.4.
HR-MS (ESI-TOF) m/z: Calcd. for C16H28ClN2O4 347.1738; found: 347.1728 [M+H]+.
8
9
3-(2,2-Dimethylcyclopropyl)propan-1-ol (12n).
A
solution of ester 12f
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(1.1 g, 6.46 mmol) in dry Et2O (5 mL) was added to suspension of LiAlH4
(270 mg, 7.1 mmol) in Et2O (24 mL) at -10 oC and stirred for 30 min. Reaction mixture
was carefully quenched with H2O until formation of gas ceased then filtered. The filtrate
was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude
product was purified by column chromatography (eluent hexanes/EtOAc 10:1) to yield
alcohol 12n (404 mg, 49%) as a colorless oil. 1H NMR (400 MHz, CDCl3, ppm) δ 3.67
(t, J = 6.6 Hz, 2H), 1.70 – 1.61 (m, 2H), 1.48 – 1.22 (m, 3H), 1.02 (d, J = 5.0 Hz, 6H),
0.47 (dtd, J = 8.3, 7.0, 5.3 Hz, 1H), 0.37 (dd, J = 8.5, 4.0 Hz, 1H), -0.09 – -0.15 (m,
13
1H). C{H} NMR (101 MHz, CDCl3, ppm) δ 63.1, 33.4, 27.7, 26.1, 24.5, 20.0, 19.8,
15.5. Unstable under the conditions of HRMS. GC-MS m/z = 128.1 [M]+
1-(3-(2,2-Dimethylcyclopropyl)propoxy)-2-(trifluoromethyl)benzene (12m). To a
solution of alcohol 12n (100 mg, 0.78 mmol) in dry THF (24 mL) t-BuOK
o
(96 mg, 0.85 mmol) was added in a single portion and heated at 80 C for 15 min
followed by addition of 1-fluoro-2-(trifluoromethyl)benzene (100 µL, 0.78 mmol) and
stirred overnight. Reaction mixture was quenched with H2O (25 mL) and diluted with
EtOAc (25 mL). Aqueous phase was separated and extracted with EtOAc (2×20 mL).
Organic extracts were combined, dried over Na2SO4, filtered and concentrated under
reduced pressure. The crude product was purified by column chromatography (eluent
hexanes/EtOAc 15:1) to yield ether 12m (120 mg, 57%) as a colorless oil. 1H NMR
(400 MHz, CDCl3, ppm) δ 7.58 – 7.53 (m, 1H), 7.50 – 7.41 (m, 1H), 7.00 – 6.94 (m,
2H), 4.08 (t, J = 6.3 Hz, 2H), 1.96 – 1.85 (m, 2H), 1.61 – 1.41 (m, 2H, overlaps with
H2O signal), 1.04 (d, J = 4.0 Hz, 6H), 0.55 – 0.47 (m, 1H), 0.39 (dd, J = 8.5, 4.0 Hz,
13
1H), -0.06 – -0.12 (m, 1H). C{1H} NMR (101 MHz, CDCl3) δ 157.2, 133.2, 127.2
(q, JC-F = 5.3 Hz), 123.9 (q, JC-F = 272.2 Hz), 119.7, 119.0 (q, JC-F = 30.7 Hz), 112.7,
68.4, 29.7, 27.7, 26.0, 24.3, 19.9, 19.8, 15.5. 19F NMR (376 MHz, CDCl3, ppm) δ -
62.42. HR-MS (ESI-TOF) m/z: Calcd. for C15H18F3O 271.1310; found: 271.1309 [M-
H]-.
2-Cyclohexylideneacetonitrile (16a).14 A solution of phosphonate 15 (14.51 g, 89.66
mmol) in Et2O (25 mL) at 0 oC was added dropwise to the suspension of NaH (3.58 g,
ACS Paragon Plus Environment

Page 17 of 41
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
89.66 mmol; 60% dispersion in mineral oil) in Et2O (150 mL) and stirred for 15 min.
Then cyclohexanone (14a) (8.43 mL, 89.66 mmol) was added dropwise over 10 min.
The reaction mixture was allowed to warm up to room temperature and stirred
9
o
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
overnight. The reaction mixture was cooled to 0 C and quenched with H2O (250 mL).
Phases were separated, aqueous phase was extracted with CH2Cl2 (3×50 mL). Organic
extracts were combined and dried (Na2SO4), filtered and concentrated under reduced
pressure. The crude product was purified by column chromatography (eluent
hexanes/EtOAc 4:1) to yield nitrile 16a (9.63 g, 97%) as a colorless oil. This compound
1
is known in the literature15. H NMR (400 MHz, CDCl3, ppm) δ 5.04 – 5.01 (m, 1H),
2.50 – 2.44 (m, 2H), 2.24 (t, J = 6.1 Hz, 2H), 1.71 – 1.52 (m, 6H, overlaps with H2O
signal).
(E)-3-Phenylbut-2-enenitrile (16b).14 Nitrile 16b was prepared by an analogy to nitrile
14b from acetophenone (1.00 g, 8.32 mmol), NaH (366 mg, 9.15 mmol; 60% dispersion
in mineral oil), phosphonate 15 (1.62 g, 9.15 mmol), Et2O (100 mL). Purification by
column chromatography (eluent hexanes /EtOAc 4:1) yielded nitrile 16b (1.12 g, 95 %)
as a colorless oil. This compound is known in the literature.16 1H NMR (300 MHz,
CDCl3) δ 7.51 – 7.33 (m, 5H), 5.62 (s, 1H), 2.48 (s, 3H).
Ethyl (2-cyclohexylideneethyl)carbamate (17a)14. To the suspension of AlCl3 (716
mg, 5.36 mmol) in Et2O (45 mL) at 0 oC LiAlH4 (640 mg, 16.87mmol) was added
portionwise. The reaction mixture was allowed to warm up to room temperature and
stirred for 1 h. The reaction mixture was cooled again to 0 oC and solution of nitrile 16a
(619 mg, 5.11 mmol) was added dropwise over 10 min and stirred for 1 h. Then sat. aq.
NaHCO3 was slowly added until formation of gas ceased. To this biphasic solution
ethylchloroformate (1.83 g, 16.87 mmol) was added dropwise and the reaction mixture
was stirred overnight at room temperature. The reaction mixture was cooled in ice bath,
and then diluted with 1 M aq. HCl (25mL) and EtOAc (25 mL). The reaction mixture
was filtered and the phases were separated. Aqueous phase was extracted with EtOAc
(2×15 mL). Organic extracts were combined, dried (Na2SO4) and concentrated under
reduced pressure. The crude product was purified by column chromatography (eluent
1
petrolether/EtOAc 6:1) to afford carbamate 17a (741 mg, 66%) as a colorless oil. H-
NMR (400 MHz, CDCl3, ppm) δ 5.14 (t, J = 7.1 Hz, 1H), 4.52 (b. s, 1H), 4.11 (q, J =
6.7 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H), 2.15 (t, J = 5.7 Hz, 2H), 2.08 (t, J = 5.8 Hz, 2H),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 41
1
2
3
4
5
6
7
8
9
1.57 – 1.46 (m, 6H), 1.23 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz CDCl3, ppm) δ
156.5, 143.8, 117.1, 60.5, 37.9, 36.8, 28.7, 28.3, 27.7, 26.6, 14.6. HR-MS (ESI-TOF)
m/z: Calcd. for C11H20NO2 198.1494; found: 198.1497 [M+H]+.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl (E)-(3-phenylbut-2-en-1-yl)carbamate (17b).14 Carbamate 17b was prepared by
an analogy to carbamate 17a from nitrile 16b (814 mg, 5.68 mmol), LiAlH4 (712
mg, 18.76 mmol), AlCl3 (796 mg, 5.96 mmol), ethyl chloroformate (1.63 mL, 17.05
mmol) in Et2O (25 mL). Purification by column chromatography (eluent
hexanes/EtOAc 3:1) afforded carbamate 17b (667 mg, 59%) as a colorless oil. 1H NMR
(400 MHz, CDCl3, ppm) δ 7.39 – 7.35 (m, 2H), 7.34 – 7.28 (m, 2H), 7.27 – 7.22 (m,
1H), 5.81 – 5.70 (m, 1H), 4.73 (b. s, 1H), 4.14 (q, J = 6.9 Hz, 2H), 3.98 (t, J = 5.7 Hz,
2H), 2.08 (d, J = 1.2 Hz, 3H), 1.25 (td, J = 7.1, 2.6 Hz, 3H). 13C{1H} NMR (101 MHz,
CDCl3, ppm) δ 156.7, 142.9, 138.1, 128.3, 127.3, 125.8, 124.0, 61.0, 39.5, 16.1, 14.8.
HR-MS (ESI-TOF) m/z: Calcd. for C13H18NO2 220.1338; found: 220.1338 [M+H]+.
Ethyl (spiro[2.5]octan-1-ylmethyl)carbamate (5a)14. To a solution of Et2Zn
o
(1 mL, 1 mmol; 1 M solution in hexane) in dry CH2Cl2 (3 mL) at -78 C CH2I2
(0.16 mL, 2 mmol) was added dropwise. The reaction mixture was allowed to warm up
o
to 0 C and stirred for 15 min. Solution of alkene 17a (99 mg, 0.5 mmol) in CH2Cl2 (3
mL) was added dropwise to the reaction mixture, then allowed to warm up to room
temperature and stirred overnight. The reaction mixture was quenched with saturated
NH4Cl aq. (20 mL) and stirred for 15 min. Phases were separated, aqueous phase was
extracted with CH2Cl2 (2×15 mL). Organic extracts were combined and dried (Na2SO4),
filtered and concentrated under reduced pressure. Purification by column
chromatography (eluent hexanes/EtOAc 8:1) yielded cyclopropane 5a (91 mg, 86%) as
a colorless oil. This compound is known in the literature.10 1H NMR (300 MHz, CDCl3,
ppm) δ 4.62 (b. s, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.24 – 3.11 (m, 2H), 1.56 – 1.08 (m,
13H), 0.73 (qd, J = 7.8, 5.3 Hz, 1H), 0.42 (dd, J = 8.4, 4.5 Hz, 1H), 0.07 (t, J = 4.8 Hz,
1H).
Ethyl (((1S*,2S*)-2-methyl-2-phenylcyclopropyl)methyl)carbamate (18).14 To the
solution of Et2Zn (7.50 mL, 6.75 mmol; 1 M solution in hexanes,) in dry CH2Cl2 (15
mL) at -78 oC CH2I2 (0.42 mL, 5.17 mmol) was added dropwise. Reaction mixture was
allowed to warm up to 0 oC and stirred for 15 min. In a separate flask, to the solution of
alkene 16b (741 mg, 3.37 mmol) and DIPEA (437 mg, 3.37 mmol) in dry CH2Cl2
ACS Paragon Plus Environment

Page 19 of 41
The Journal of Organic Chemistry
1
2
3
4
5
o
(15 mL) at -78 C, TMSOTf (751 mg, 3.37 mmol) was slowly added and resulting
solution was stirred for additional 15 min. Contents of the second flask was then slowly
added to the solution of Et2Zn and CH2I2 and allowed to warm up to room temperature
and stirred overnight. The reaction mixture was quenched with saturated NH4Cl aq.
(20 mL) and stirred for 15 min. Phases were separated, aqueous phase was extracted
with CH2Cl2 (2×20 mL). Organic extracts were combined and dried (Na2SO4), filtered
and concentrated in vacuo. Purification by column chromatography (eluent
hexanes/EtOAc 5:1) yielded cyclopropane 18 (412 mg, 52%) as a colorless oil. This
compound is known in the literature.18 1H NMR (400 MHz, CDCl3, ppm) δ 7.39 – 7.35
(m, 2H), 7.34 – 7.28 (m, 2H), 7.27 – 7.22 (m, 1H, overlaps with CDCl3 signal), δ 4.76
(s, 1H), 4.20 – 4.12 (m, 2H), 3.51 (dt, J = 13.1, 6.4 Hz, 1H), 3.27 (dt, J = 13.3, 7.5 Hz,
1H), 1.45 (s, 3H), 1.28 (q, J = 7.1 Hz, 4H), 1.14 (dd, J = 8.9, 4.8 Hz, 1H), 0.59 (t, J =
5.2 Hz, 1H).
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-Cyclohexylideneethan-1-amine (19).14 To the suspension of AlCl3 (2.32 g, 17.40
o
mmol) in Et2O (70 mL) at 0 C LiAlH4 (2.09 g, 55.25 mmol) was added portionwise.
The reaction mixture was allowed to warm up to room temperature and stirred for 1 h.
o
Reaction mixture was cooled again to 0 C and solution of nitrile 16a (2.02 g, 16.64
mmol) in Et2O (15 mL) was added dropwise. The reaction mixture was quenched with
water and filtered (to remove inorganic solids). The filtrate was dried over KOH pellets,
filtered and concentrated under reduced pressure to obtain amine 19 (2.03 g, 98%) as a
pale yellow oil. This compound is known in the literature.18 1H NMR (300 MHz, CDCl3,
ppm) δ 5.20 (t, J = 7.0 Hz, 1H), 3.27 (d, J = 7.0 Hz, 2H), 2.19 – 2.00 (m, 4H), 1.79 (b. s,
2H), 1.50 (d, J = 14.2 Hz, 6H).
2,2,2-Trichloro-N-(2-cyclohexylideneethyl)acetamide (20).14 Trichloroacetyl chloride
(726 mg, 3.99 mmol) was added dropwise to a cooled (0 °C) solution of amine 19 (500
mg, 3.99 mmol) and Et3N (1.21 g, 11.97 mmol) in CH2Cl2 (5 mL) and reaction mixture
was stirred for 4 h. The reaction mixture was diluted with 1 M aq. HCl and stirred for 5
min. Phases were separated, organic phase was washed with 1 M aq. HCl (10 mL),
dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by
column chromatography (eluent hexanes/EtOAc 10:1, rf = 0.5) to afford amide 20 (956
mg, 88%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 6.55 (b. s, 1H), 5.24 – 5.15
(m, 1H), 3.95 (dd, J = 7.2, 5.3 Hz, 2H), 2.23 – 2.05 (m, 4H), 1.64 – 1.44 (m, 6H).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 41
1
2
3
4
5
6
7
8
9
13C{1H} NMR (101 MHz, CDCl3, ppm) δ 161.6, 146.9, 114.8, 92.8, 38.7, 37.0, 29.1,
28.5, 27.9, 26.7. HR-MS (ESI-TOF) m/z: Calcd. for C10H15Cl3NO 270.0219; found:
270.0207 [M+H]+.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2,2,2-Trichloro-N-(spiro[2.5]octan-1-ylmethyl)acetamide (12d).14 To a solution of
Et2Zn (2.58 mL, 2.21mmol; 1 M solution in hexanes) in dry CH2Cl2 (20 mL) at – 78 oC
CH2I2 (0.42 mL, 5.17 mmol) was added dropwise. The reaction mixture was allowed to
o
warm up to 0 C and stirred for 15 min. Solution of alkene 20 (350 mg, 1.29 mmol) in
CH2Cl2 (15 mL) was added dropwise to the reaction mixture, then allowed to warm up
to room temperature and stirred overnight. The reaction mixture was quenched with
saturated NH4Cl aq. (20 mL) and stirred for 15 min. Phases were separated, aqueous
phase was extracted with CH2Cl2 (2×20 mL). Organic extracts were combined and dried
(Na2SO4), filtered and concentrated under reduced pressure. Purification by column
chromatography (eluent hexanes/EtOAc 8:1, rf = 0.7) yielded cyclopropane 12d (261
1
mg, 71%) as a colorless oil. H NMR (400 MHz, CDCl3, ppm) δ 6.67 (b. s, 1H), 3.38
(dd, J = 7.8, 5.3 Hz, 2H), 1.60 – 1.17 (m, 10H, overlaps with H2O signal), 0.84 (qd, J =
7.9, 5.2 Hz, 1H), 0.53 (dd, J = 8.4, 4.6 Hz, 1H), 0.18 (t, J = 4.9 Hz, 1H). 13C{1H} NMR
(101 MHz, CDCl3, ppm.) δ 162.0, 93.2, 42.5, 37.9, 31.0, 26.7, 26.3, 26.1, 24.3, 23.1,
17.6. HR-MS (ESI-TOF) m/z: Calcd. for C11H17Cl3NO 284.0376; found: 284.0376
[M+H]+.
2-(3-Methylbut-2-en-1-yl)isoindoline-1,3-dione (22).14 Prenyl bromide (1.00 g, 6.70
mmol) was added to a mixture of potassium phtalimide (21) (1.49 g, 8.05 mmol) in
DMF (10 mL). After heating at 120 oC for 1 h, the reaction mixture was refluxed at 160
oC for 9 h. Then mixture was diluted with CH2Cl2 (30 mL) and water (30 mL). Phases
were separated, organic phase was washed with H2O (3 × 30 mL), dried (Na2SO4),
filtered and concentrated under reduced pressure. The crude product was purified by
column chromatography (gradient petrolether/EtOAc 1:4 to 1:2) to afford phtalimide 22
(1.22 g, 85%) as a colorless crystalline solid. This compound is known in the
literature.19 1H NMR (400 MHz, CDCl3, ppm) δ 7.86 – 7.78 (m, 2H), 7.73 – 7.64 (m,
2H), 5.27 (tdt, J = 7.2, 2.8, 1.4 Hz, 1H), 4.28 – 4.23 (m, 2H), 1.82 (s, 3H), 1.70 (s, 3H).
2-((2,2-Dimethylcyclopropyl)methyl)isoindoline-1,3-dione (12b).14 Obtained by an
analogy to cyclopropane 12 from alkene 22 (300 mg, 1.39 mmol), Et2Zn
(6.64 mL, 4.64 mmol; 1 M solution in hexane), CH2I2 (0.67 mL, 8.36 mmol) in CH2Cl2
ACS Paragon Plus Environment

Page 21 of 41
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
(15 mL). Purification by column chromatography (eluent petrolether/EtOAc 5:1)
yielded cyclopropane 12b (270 mg, 84%) as a colorless crystalline solid. 1H NMR (400
MHz, CDCl3, ppm) δ 7.84 (dd, J = 5.4, 3.1 Hz, 2H), 7.70 (dd, J = 5.5, 3.0 Hz, 2H), 3.80
(dd, J = 14.2, 6.6 Hz, 1H), 3.57 (dd, J = 14.2, 8.4 Hz, 1H), 1.19 (s, 3H), 1.12 – 0.98 (m,
4H), 0.44 (dd, J = 8.6, 4.5 Hz, 1H), 0.27 (t, J = 4.9 Hz, 1H). 13C{1H} NMR (101 MHz,
CDCl3, ppm) δ 168.5, 133.9, 132.4, 123.2, 38.9, 27.1, 23.3, 20.3, 19.1, 16.6. Tmelt. = 50
oC. Anal. Calcd. for C14H15NO2: C, 73.34; H, 6.59; N, 6.11; found C, 73.29; H, 6.57; N,
6.12.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-Cyclohexylidenepropanenitrile (23).14 To a solution of diisopropylamine (906 mg,
o
8.95 mmol) in dry THF (10 mL) at -78 C n-BuLi (6.98 mL, 8.66 mmol; 1.24 M
solution in hexane) was added dropwise and stirred for 15 min. Then solution of nitrile
16a (0.70 g, 5.77 mmol) in THF (10 mL) was slowly added and stirred for additional 15
min, followed by addition of MeI (820 mg, 5.77 mmol). The reaction mixture was
allowed to warm up to room temperature and stirred overnight. After full consumption
of starting material (TLC), the reaction mixture was quenched with saturated aq. NH4Cl
(15 mL). Phases were separated, aqueous phase was extracted with CH2Cl2 (2×15 mL).
Organic extracts were combined, dried (Na2SO4), filtered and concentrated in vacuo.
The crude product was purified by column chromatography (eluent hexanes/EtOAc 8:1,
rf = 0.55) to afford nitrile 23 (537 mg, 69 %) as a colorless oil. This compound is
known.20 1H NMR (300 MHz, CDCl3, ppm) δ 2.52 – 2.41 (m, 2H), 2.22 (d, J = 5.4 Hz,
2H), 1.89 – 1.79 (m, 3H), 1.70 – 1.48 (m, 6H).
Ethyl (2-cyclohexylidenepropyl)carbamate (24).14 Carbamate 24 was prepared by an
analogy to carbamate 17a from nitrile 23 (497 mg, 3.67 mmol), LiAlH4 (460 mg, 12.13
mmol), AlCl3 (515 mg, 3.85 mmol), ethyl chloroformate (1.20 g, 11.02 mmol) in Et2O
(50 mL). Purification by column chromatography (eluent hexanes/EtOAc = 1:1)
1
afforded carbamate 24 (519 mg, 67%) as a colorless oil. H NMR (400 MHz, CDCl3,
ppm) δ 4.44 (b. s, 1H), 4.11 (q, J = 7.0 Hz, 2H), 3.78 (d, J = 5.2 Hz, 2H), 2.17 (dt, J =
13
21.2, 5.6 Hz, 4H), 1.69 (s, 3H), 1.58 – 1.45 (m, 6H), 1.24 (t, J = 7.0 Hz, 3H). C{1H}
NMR (101 MHz, CDCl3, ppm) δ 156.9, 137.9, 121.2, 60.8, 43.3, 30.8, 30.4, 28.5, 27.9,
26.9, 16.8, 14.8. HR-MS (ESI-TOF) m/z : Calcd. for C12H22NO2 212.1651; found:
212.1659 [M+H]+.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 41
1
2
3
4
5
6
7
8
9
Ethyl ((1-methylspiro[2.5]octan-1-yl)methyl)carbamate (25).14 Synthesized by an
analogy to cyclopropane 5a from alkene 24 (400 mg, 1.89 mmol), Et2Zn (3.78 mL, 3.78
mmol; 1M solution in hexane), CH2I2 (0.61 mL, 7.57mmol) in CH2Cl2 (20 mL).
Purification by column chromatography (eluent petrolether/EtOAc 8:1) yielded
cyclopropane 25 (313 mg, 73%) as a colorless oil.1H NMR (400 MHz, CDCl3, ppm) δ
4.57 (b. s, 1H), 4.18 – 4.00 (m, 2H), 3.33 (dd, J = 13.6, 6.1 Hz, 1H), 3.09 (dd, J = 13.6,
4.9 Hz, 1H), 1.61 – 1.17 (m, 13H, overlaps with H2O), 1.11 (s, J = 2.1 Hz, 3H), 0.30 –
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
0.23 (m, J = 4.4 Hz, 1H), 0.13 (d, J = 4.5 Hz, 1H). C{1H} NMR (101 MHz, CDCl3,
ppm) δ 156.9, 60.8, 47.1, 32.5, 32.2, 27.8, 26.6, 26.2, 26.2, 24.5, 23.7, 17.7, 14.8. HR-
MS (ESI-TOF) m/z : Calcd. for C13H24NO2 226.1807; found: 226.1802 [M+H]+.
N-((2,2 - Dimethylcyclopropyl)methyl)benzamide (28a).14 Benzoyl chloride (85 µL,
0.74 mmol) was added dropwise to a cooled (0 °C) solution of amine 26 (100 mg, 0.74
mmol) and Et3N (0.23 mL, 1.62 mmol) in CH2Cl2 (6 mL) and reaction mixture was
stirred at room temperature overnight. Concentration in vacuum followed by
purification by flash column chromatography (eluent hexanes/EtOAc 2.5:1) afforded
28a (135 mg, 90%) as a colorless oil. This compound is known in the literature.10 1
H
NMR (300 MHz, CDCl3, ppm) δ 7.80 – 7.72 (m, 2H), 7.53 – 7.39 (m, 3H), 6.08 ( b. s,
1H), 3.56 – 3.33 (m, 2H), 1.15 (s, 3H), 1.09 (s, 3H), 0.88 (qd, J = 7.8, 5.3 Hz, 1H), 0.53
(dd, J = 8.5, 4.5 Hz, 1H), 0.19 (t, J = 4.9 Hz, 1H).
Ethyl ((2,2,3,3-tetramethylcyclopropyl)methyl)carbamate (28b).14 Carbamate 28b
was synthesized by an analogy to carbamate 17a from amine salt 27 (0.20 g, 1.22
mmol), TEA (0.51 mL, 3.66 mmol), ethyl chloroformate (0.11 mL, 1.22 mL) in CH2Cl2
(25 mL). Purification by column chromatography yielded carbamate 28b (207 mg,
85%) as a colorless oil. This compound is known in the literature.10 1H NMR (300 MHz,
CDCl3, ppm) δ 4.48 (b. s, 1H), 4.11 (q, J = 7.0 Hz, 2H), 3.21 – 3.09 (m, 2H), 1.24 (t, J =
7.1 Hz, 3H), 1.07 (s, 6H), 0.98 (s, 6H), 0.39 (t, J = 7.7 Hz, 1H).
1-((2,2-Dimethylcyclopropyl)methyl)-3-phenylurea (28c).14 Phenyl isocyanate (36
µL, 0.33 mmol, 1.0 equiv) was added dropwise to a cooled (0 °C) solution of 26 (45
mg, 0.33 mmol) and Et3N (55 µL, 0.40 mmol) in CH2Cl2 (5 mL) and reaction mixture
was stirred at room temperature overnight. Concentration in vacuum followed by
ACS Paragon Plus Environment

Page 23 of 41
The Journal of Organic Chemistry
1
2
3
4
5
6
7
purification by flash column chromatography (eluent hexanes/EtOAc = 2:1) afforded
urea 28c (68 mg, 94%) as a colorless oil. This compound is known in the literature.10
8
9
Ethyl 2,2,3-trimethylcyclopropanecarboxylate (30).14 To a solution of alkene 29
(4.18 mL, 39.51 mol) and Rh2(OAc)4 (25 mg, 0.05 mmol) in dry CH2Cl2 (40 mL) ethyl
diazoacetate (1.38 mL, 11.43 mmol) was added dropwise over 6 h. The reaction mixture
was evaporated to dryness. The crude product was purified by column chromatography
(eluent hexanes/CH2Cl2 2:1) to obtain ester 30 (1.23 g, 69%) as inseparable mixture of
diastereomers. This compound is known in the literature.21 1H NMR (300 MHz, CDCl3,
ppm) δ 4.18 – 3.99 (m, 2H), 1.43 – 1.30 (m, 1H), 1.30 – 1.02 (m,13H).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2,2,3-Trimethylcyclopropane-1-carboxamide (31).14 To solution of ester 30 (1.23 g,
7.87 mmol) in MeOH (20 mL) at 0 oC solution of KOH (4.33 g, 78.7 mmol) in H2O (15
mL) was added and stirred at room temperature overnight. Then methanol was
evaporated under reduced pressure and remaining solution was acidified with 1 M aq.
HCl until pH = 2 followed by extraction with Et2O (2 × 20 mL). Organic extracts were
combined, dried (Na2SO4), filtered and concentrated in vacuo to obtain crude product as
colorless oil. The crude product was used in the next step without further purification.
To the solution of crude carboxylic acid (866 mg, 6.75 mmol) in dry THF (10 mL) at 0
oC triethylamine (1.03 mL, 7.43 mmol) and ethyl chloroformate (0.71 mL, 7.43 mmol)
were added dropwise and stirred for 1 h. Excess of NH3 in THF was added then stirred
at room temperature overnight. Reaction mixture was quenched with 1 M aq. HCl (20
mL). Phases were separated, aqueous phase was extracted with CH2Cl2 (2×20 mL).
Organic extracts were combined, dried (Na2SO4), filtered and concentrated in vacuo to
obtain crude product as colorless oil. The crude amide 31 was used in next step without
further purification.
Ethyl (((1R*,3S*)-2,2,3-trimethylcyclopropyl)methyl)carbamate (32).14 To the crude
o
amide 31 (271 mg, 2.13 mmol) in dry THF (20 mL) at 0 C LiAlH4 (162 mg, 4.26
mmol) was added portionwise. The reaction mixture was refluxed for 30 min, then
allowed to cool down to room temperature. Saturated aq. NaHCO3 was slowly added
until formation of gas ceased. Ethyl chloroformate (0.61 mL, 6.39 mmol) was dropwise
added to reaction mixture and stirred overnight at room temperature. Reaction mixture
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 41
1
2
3
4
5
6
7
8
was diluted with 1 M aq. HCl (20 mL). The precipitate was filtered and aqueous phase
was separated, extracted with EtOAc (2×20 mL). Organic extracts were combined,
dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product
was purified by column chromatography (eluent hexanes/EtOAc = 5:1) to obtain
diastereomers cis-32 (170 mg, 43%) and trans-32 (44 mg, 11%) as colorless oils. Cis-
isomer (cis-32): 1H NMR (400 MHz, CDCl3) δ 4.51 (b. s, 1H), 4.11 (q, J = 7.0 Hz, 2H),
3.24 – 3.05 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H), 1.06 – 1.00 (m, 3H), 0.98 – 0.92 (m, 6H),
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
0.68 – 0.58 (m, 2H). C{1H} NMR (101 MHz, CDCl3) δ 156.6, 77.1, 60.7, 37.8, 28.9,
25.7, 20.4, 17.6, 14.8, 14.5, 8.4. HR-MS (ESI-TOF) m/z : Calcd. for C10H20NO2 ,
1
186.1494; found: 186.1490 [M+H]+. Trans- isomer (trans-32): H NMR (400 MHz,
CDCl3) δ 4.56 (b. s, 1H), 4.09 (q, J = 7.0 Hz, 2H), 3.33 – 3.20 (m, 1H), 3.01 (m, 1H),
1.22 (t, J = 7.1 Hz, 3H), δ 1.04 – 0.97 (m, 9H), 0.38 – 0.29 (m, 2H). 13C{1H} NMR (101
MHz, CDCl3) δ 156.4, 60.5, 41.8, 30.9, 23.4, 21.5, 21.2, 19.1, 14.6, 13.3. HR-MS (ESI-
TOF) m/z : Calcd. for C10H20NO2 186.1494; found: 186.1503 [M+H]+.
Ethyl (2-cyclohexylideneethyl)(methyl)carbamate (5b).14 To the suspension of NaH
(66 mg, 1.65 mmol; 60 wt% in mineral oil) in DMF (6 mL) at 0 oC solution of
carbamate 5a (233 mg, 1.65 mmol) in DMF (5 mL) was added dropwise and stirred for
30 min at room temperature. Then MeI (103 L, 1.10 mmol) was slowly added and
stirred for additional 2 h. The reaction mixture was quenched with sat. aq. NH4Cl
(11 mL) and stirred for 5 min. The phases were separated, aqueous phase was extracted
with CH2Cl2 (2×10 mL). Organic extracts were combined, dried (Na2SO4), filtered and
concentrated under reduced pressure. The crude product was purified by column
chromatography (eluent hexanes/EtOAc = 5:1) to obtain product 5b (177 mg, 71%) as a
1
colorless oil. H NMR (400 MHz, CDCl3, ppm) δ 4.11 (q, J = 7.1 Hz, 2H), 3.41 (pl. s.,
1H), 3.20 (dd, J = 14.4, 7.7 Hz, 1H), 2.92 (s, 3H), 1.54 – 1.28 (m, 9H), 1.25 (t, J = 7.1
Hz, 3H), 1.12 (m, 1H), 0.74 (ddd, J = 14.3, 7.6, 5.5 Hz, 1H), 0.43 (dd, J = 8.5, 4.4 Hz,
13
1H), 0.11 (s, 1H). C{1H} NMR (101 MHz, CDCl3, ppm) δ 156.7, 61.2, 55.9, 34.9,
29.8, 25.8, 24.4, 21.8, 14.8. HR-MS (ESI-TOF) m/z: Calcd. for C13H24NO2 226.1807;
found: 226.1817 [M+H]+.
Ethyl benzyl(spiro[2.5]octan-1-ylmethyl)carbamate (7a).14 Synthesized by an
analogy to 5b from carbamate 5a (299 mg, 1.41 mmol), NaH (363 mg, 2.12 mmol; 60
ACS Paragon Plus Environment

Page 25 of 41
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
wt% in mineral oil), benzyl bromide (0.25 mL, 2.12 mmol) in DMF (10 mL).
Purification by column chromatography (eluent hexanes/EtOAc = 8:1) afforded product
7a (0.32 g, 75%) as a colorless oil. 1H NMR (400 MHz, CDCl3, ppm) δ 7.36 – 7.28 (m,
2H), 7.29 – 7.20 (m, 3H, overlaps with CDCl3 signal), 4.57 (b. s, 2H), 4.18 (q, J = 6.8
Hz, 2H), 3.55 – 3.33 (m, 1H), 3.14 (b. s, 1H), 1.56 – 1.19 (m, 12H), 1.11 – 1.00 (m,
1H), 0.75 (s, 1H), 0.40 (dd, J = 8.4, 4.4 Hz, 1H), 0.07 (s, 1H). 13C{1H} NMR (101 MHz,
CDCl3, ppm) δ 156.6, 138.3, 128.5, 127.8, 127.1, 61.4, 49.5, 46.0, 45.5, 37.7, 30.9,
26.5, 26.0, 25.7, 23.5, 22.6, 17.6, 14.8. HR-MS (ESI-TOF) m/z: Calcd. for C19H28NO2
302.2120; found: 302.2115 [M+H]+.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl allyl(spiro[2.5]octan-1-ylmethyl)carbamate (7b).14 Synthesized by an analogy
to 5b from carbamate 5a (0.20 g, 0.95 mmol, NaH (0.06 g, 1.43 mmol; 60 wt% in
mineral oil), allyl bromide (0.12 mL, 1.43 mmol) in THF (6 mL). Purification by
column chromatography on silica gel (eluent hexanes/EtOAc 10:1) afforded product 7b
(0.23 g, 96%) as a colorless oil. 1H NMR (400 MHz, CDCl3, ppm) δ 5.78 (ddt, J = 16.1,
10.6, 5.7 Hz, 1H), 5.26 – 5.00 (m, 2H), 4.13 (q, J = 7.5 Hz, 2H), 3.93 (b. s, 2H), 3.44
(bs, 1H), 3.15 (dd, J = 14.5, 7.9 Hz, 1H), 1.78 – 1.28 (m, 9H), 1.24 (td, J = 7.1, 2.0 Hz,
3H), 1.13 – 1.04 (m, 1H), 0.82 – 0.65 (m, 1H), 0.42 (dd, J = 8.4, 4.4 Hz, 1H), 0.10 (t, J
= 5.0 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3, ppm) δ 156.3, 134.2, 115.9, 61.1,
48.5, 45.4, 37.6, 30.9, 26.4, 25.9, 25.6, 23.4, 22.8, 17.5, 14.7. HR-MS (ESI-TOF) m/z:
calcd. for C15H26NO2 252.1964; found: 252.1970 [M+H]+.
Ethyl prop-2-yn-1-yl(spiro[2.5]octan-1-ylmethyl)carbamate (7c).14 Synthesized by
an analogy to 5b from carbamate 5a (201 mg, 0.95 mmol), NaH (43 mg, 1.14 mmol; 60
wt% in mineral oil), propargyl bromide (0.16 mL, 1.42 mmol) in DMF (5 mL).
Purification by column chromatography on silica gel (eluent hexanes/EtOAc = 10:1)
afforded product 7c (207 g, 87%) as a colorless oil. 1H NMR (400 MHz, CDCl3, ppm) δ
4.15 (q, J = 6.8 Hz, 4H), 3.55 (b. s, 1H), 3.30 (dd, J = 14.6, 7.9 Hz, 1H), 2.19 (t, J = 2.5
Hz, 1H), 1.61 – 1.31 (m, 9H), 1.26 (t, J = 7.1 Hz, 3H), 1.14 – 1.04 (m, 1H), 0.76 (tdd, J
= 8.1, 6.6, 5.3 Hz, 1H), 0.45 (dd, J = 8.5, 4.5 Hz, 1H), 0.15 (t, J = 4.8 Hz, 1H). 13C{1H}
NMR (101 MHz, CDCl3, ppm) δ 155.9, 79.6, 71.3, 61.5, 45.5, 37.5, 35.3, 30.8, 26.4,
25.9, 25.6, 23.5, 22.3, 17.3, 14.6. HR-MS (ESI-TOF) m/z: Calcd. for
C15H24NO2 250.1807; found: 250.1810 [M+H]+.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 41
1
2
3
4
5
6
7
8
9
Ethyl (4-methoxybenzyl)(spiro[2.5]octan-1-ylmethyl)carbamate (7e).14 Synthesized
by an analogy to 5b from carbamate 5a (0.21 g, 0.99 mmol), NaH (44 mg, 1.09 mmol;
60 wt% in mineral oil), 4-metoxybenzyl chloride (0.14 mL, 1.09 mmol), TBAI (18 mg,
0.05 mmol) in DMF (5 mL). Purification by column chromatography (eluent
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
hexanes/EtOAc 10:1) afforded product 7e (222 mg, 68%) as a colorless oil. H NMR
(400 MHz, CDCl3, ppm) δ 7.16 (b. s, 2H), 6.90 – 6.76 (m, 2H), 4.50 (b. s, 2H), 4.18
(qd, J = 7.1, 0.8 Hz, 2H), 3.79 (s, 3H), 3.57 – 3.30 (m, 1H), 3.10 (bs, 1H), 1.55 – 1.15
(m, 12H), 1.15 – 0.98 (m, 1H), 0.80 – 0.67 (m, 1H), 0.40 (dd, J = 8.5, 4.4 Hz, 1H), 0.07
(bs, 1H). C{1H} NMR (101 MHz, CDCl3, ppm) δ 158.7, 156.6, 130.3, 128.8, 113.8,
13
61.2, 55.2, 48.7, 45.6, 37.6, 30.9, 26.4, 25.9, 25.6, 23.4, 22.6, 17.6, 14.7. HR-MS (ESI-
TOF) m/z: Calcd. for C20H30NO3 332.2226; found: 332.2230 [M+H]+.
14
Ethyl benzyl(((1S*,2S*)-2-methyl-2-phenylcyclopropyl)methyl)carbamate (10a).
Synthesized by an analogy to 5a from carbamate 18 (390 mg, 0.85 mmol), NaH (100
mg, 2.50 mmol; 60 wt% in mineral oil), benzyl bromide (0.29 mol, 2.50 mmol) in DMF
(10 mL). Purification by column chromatography (eluent hexanes/EtOAc 6:1) afforded
product 10a (467 mg, 86%) as a colorless oil. 1H NMR (400 MHz, CDCl3, ppm) δ 7.37
– 7.13 (m, 10H, overlaps with CDCl3), 4.75 – 4.52 (m, 2H), 4.29 – 4.15 (m, 2H), 3.61 –
3.29 (m, 2H), 1.39 (s, 3H), 1.35 – 1.19 (m, 4H), 1.11 (dd, J = 9.0, 4.8 Hz, 1H), 0.54 (b.
s, 1H). 13C{1H} NMR (101 MHz, CDCl3, ppm) δ 156.9, 147.6, 138.1, 128.6, 128.4,
127.8, 127.3, 127.0, 125.8, 61.5, 49.9, 49.7, 46.3, 45.8, 24.7, 20.9, 19.7, 14.8. HR-MS
(ESI-TOF) m/z: calcd. for C21H26NO2 324.1964; found: 324.1956 [M+H]+.
Ethyl methyl((1-methylspiro[2.5]octan-1-yl)methyl)carbamate (10b).14 Synthesized
by an analogy to 5a from carbamate 25 (303 mg, 1.34 mmol), NaH (81 mg, 2.01 mmol;
60 wt% in mineral oil), MeI (125 µL, 2.01 mmol) in DMF (6 mL). Purification by
column chromatography (eluent hexanes/EtOAc 5:1) afforded product 10b (262 mg,
1
81%) as a colorless oil. H NMR (400 MHz, CDCl3, ppm) δ 4.13 (q, J = 7.1 Hz, 2H),
3.54 (dd, J = 42.1, 14.0 Hz, 1H), 3.16 (d, J = 14.2 Hz, 1H), 2.88 (s, 3H), 1.61 – 1.29 (m,
10H), 1.25 (t, J = 7.1 Hz, 3H), 0.99 (s, 3H), 0.27 (s, 1H), 0.19 (d, J = 4.5 Hz, 1H).
13C{1H} NMR (101 MHz, CDCl3, ppm) δ 157.1, 61.2, 52.3, 32.2, 26.6, 26.1, 26.1, 24.3,
22.7, 16.7, 14.9. HR-MS (ESI-TOF) m/z: calcd. For C14H26NO2 240.1964; found:
240.1954 [M+H]+.
ACS Paragon Plus Environment

Page 27 of 41
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Ethyl methyl(((1S*,3S*)-2,2,3-trimethylcyclopropyl)methyl)carbamate (trans-
10c)14. Synthesized by an analogy to 5b from carbamate trans-32 (44 mg, 0.23 mmol),
NaH (14 mg, 0.35 mmol; 60 wt% in mineral oil), MeI (51 mg, 0.35 mmol) in DMF
(4 mL). Purification by column chromatography (eluent hexanes/EtOAc 10:1) afforded
product trans-10c (45 mg, 95%) as a colorless oil. 1H NMR (400 MHz, CDCl3, ppm) δ
4.12 (q, J = 7.1 Hz, 2H), 3.41 – 3.15 (m, 2H), 2.90 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H), 1.06
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
– 0.98 (m, 9H), 0.39 – 0.26 (m, 2H). C{1H} NMR (101 MHz, CDCl3, ppm) δ 156.6,
61.1, 48.5, 30.0, 23.6, 22.0, 21.3, 21.2, 19.3, 19.3, 14.9, 14.8, 13.5.
Ethyl methyl(((1R*,3S*)-2,2,3-trimethylcyclopropyl)methyl)carbamate (cis-10c).14
Synthesized by an analogy to 5b from carbamate cis-32 (159 mg, 0.85 mmol), NaH (52
mg, 1.28 mmol; 60 wt% in mineral oil), MeI (183 mg, 1.28 mmol) in DMF (6 mL).
Purification by column chromatography (eluent hexanes/EtOAc 10:1) afforded product
cis-10c (142 mg, 83%) as a colorless oil. 1H NMR (400 MHz, CDCl3, ppm) δ 4.12 (q, J
= 7.1 Hz, 2H), 3.34 – 3.15 (m, 2H), 2.88 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H), 1.03 (s, 3H),
13
0.96 – 0.92 (m, 6H), 0.68 – 0.54 (m, 2H). C{1H} NMR (101 MHz, CDCl3, ppm) δ
156.6, 61.2, 44.3, 28.9, 24.4, 20.3, 17.2, 14.9, 14.7, 8.6. HR-MS (ESI-TOF) m/z: calcd.
For C11H22NO2 200.1651; found: 200.1647 [M+H]+.
Ethyl
benzyl((2,2,3,3-tetramethylcyclopropyl)methyl)carbamate
(10d).14
Synthesized by an analogy to 5a from carbamate 28b (0.20 g, 1.03 mmol), NaH (62 mg,
1.55 mmol; 60 wt% in mineral oil), benzyl bromide (0.18 mL, 1.55 mmol) in DMF (10
mL). Purification by column chromatography (eluent hexanes/EtOAc = 4:1) afforded
product 10d (243 mg, 81%) as a colorless oil. 1H NMR (400 MHz, CDCl3, ppm) δ 7.40
– 7.15 (m, 5H), 4.51 (b. s, 2H), 4.28 – 4.08 (m, 2H), 3.38 – 3.15 (m, 2H), 1.35 – 1.15
13
(m, 3H), 1.01 (s, 6H), 0.90 (s, 6H), 0.36 (b. s, 1H). C{1H} NMR (101 MHz, CDCl3,
ppm) δ 156.6, 138.4, 128.5, 127.4, 127.0, 61.4, 49.5 and 49.10, 43.5 and 43.0, 31.8,
23.5, 21.3, 17.1, 14.8. HR-MS (ESI-TOF) m/z: Calcd. for C18H28NO2 290.2120; found:
290.2114 [M+H]+.
Ethyl
methyl(((1S*,2S*)-2-phenylcyclopropyl)methyl)carbamate
(10e).14
Synthesized
by an analogy to 5b from ethyl methyl(((1S,2S)-2-
phenylcyclopropyl)methyl)carbamate (35 mg, 0.16 mmol), NaH (10 mg, 0.24 mmol; 60
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 41
1
2
3
4
5
6
7
wt% in mineral oil), MeI (15 µL, 0.24 mmol) in DMF (3 mL). Purification by column
chromatography (eluent hexanes/EtOAc 2:1) afforded product 10e (22 mg, 59%) as a
8
9
1
colorless oil. H NMR (400 MHz, CDCl3, ppm) δ 7.30 – 7.21 (m, 2H, overlaps with
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CDCl3 signal), 7.17 – 7.12 (m, 1H), 7.07 – 7.01 (m, 2H), 4.17 – 4.06 (m, 2H), 3.38 (m,
1H), 3.24 (dd, J = 14.3, 6.8 Hz, 1H), 2.97 (b. s, 3H), 1.82 (b. s, 1H), 1.27 (m, J = 7.1
Hz, 4H), 0.99 – 0.88 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 156.6, 142.6, 128.4,
125.9, 125.7, 61.3, 52.5, 34.7, 22.2, 21.9, 14.9, 14.2. HR-MS (ESI-TOF) m/z: Calcd. for
C14H20NO2 234.1494; found: 234.1487 [M+H]+.
N-((2,2-dimethylcyclopropyl)methyl)-N-methylbenzamide (12a).14 Synthesized by
an analogy to 5a from carbamate 28a (200 mg, 0.98 mmol), NaH (59 mg, 1.47 mmol;
60 wt% in mineral oil), MeI (209 mg, 1.47 mmol) in DMF (5 mL). Purification by
column chromatography (eluent hexanes/EtOAc 2:1) afforded product 12a (163 mg,
1
76%) as a colorless oil. H NMR (400 MHz, (CD3)2CO, ppm) δ 7.45 – 7.35 (m, 5H),
3.65 – 3.21 (m, 2H), 3.02 (b. s, 3H), 1.25 – 0.68 (m, 7H), 0.49 (b. s, 1H), 0.29 – -0.12
13
(m, 1H). C{1H} NMR (101 MHz, (CD3)2CO, ppm) 138.7, 130.0, 129.2, 127.9, 27.4,
20.5, 19.3, 16.6. HR-MS (ESI-TOF) m/z: calcd. for C14H20NO 218.1545; found:
218.1552 [M+H]+.
1-((2,2-Dimethylcyclopropyl)methyl)-1,3-dimethyl-3-phenylurea
(12c).14
Synthesized by an analogy to 5a from carbamate 28c (133 mg, 0.60 mmol), NaH
(73mg, 1.82 mmol; 60 wt% in mineral oil), MeI (259 mg, 1.82 mmol) and DMF (8 mL).
Purification by column chromatography (eluent hexanes/EtOAc = 4:1) afforded product
1
12c (89 mg, 59%) as a colorless oil. H NMR (400 MHz, CDCl3, ppm) δ 7.34 – 7.28
(m, 2H), 7.10 – 7.04 (m, 3H), 3.27 – 3.11 (m, 5H), 2.62 (s, 3H), 1.02 (d, J = 2.6 Hz,
6H), 0.66 (dtd, J = 8.7, 7.0, 5.5 Hz, 1H), 0.43 (dd, J = 8.7, 4.4 Hz, 1H), 0.04 – -0.00 (m,
1H). 13C{1H} NMR (101 MHz, CDCl3, ppm) δ 161.8, 147.2, 129.4, 124.1, 123.6, 50.0,
39.6, 35.8, 27.1, 22.6, 20.2, 18.8, 15.7. HR-MS (ESI-TOF) m/z: Calcd. for
C15H23N2O 247.1810; found: 247.1808 [M+H]+.
Ethyl phenyl(spiro[2.5]octan-1-ylmethyl)carbamate (7d)14. In pressure tube, under
continuous stream of argon, carbamate 5a (329 mg, 1.55 mmol), iodobenzene (318 mg,
1.55 mmol), Pd2(dba)3 (3.6 mg, 15.6 µmol, 0.01 equiv), Xanthpos (27 mg, 46.70 µmol,
ACS Paragon Plus Environment

Page 29 of 41
The Journal of Organic Chemistry
1
2
3
4
5
6
7
0.03 equiv), Cs2CO3 (710 mg, 2.17 mmol) were dissolved in dry, degassed 1,4-dioxane
o
(2 mL). Reaction vessel was sealed and temperature was rised to 110 C. The reaction
8
9
mixture was stirred for 48 h, then was diluted with brine (10 mL) and EtOAc (10 mL).
Phases were separated, organic phase was washed with brine (10 mL), dried over
Na2SO4, filtered and concentrated in vacuo. Purification by column chromatography
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
(eluent hexanes/EtOAc 2:1) afforded product 7d (40 mg, 9%) as a yellowish oil. H
NMR (400 MHz, CDCl3, ppm) δ 7.41 – 7.29 (m, 2H), 7.29 – 7.16 (m, 3H), 4.14 (q, J =
7.1 Hz, 2H), 3.76 (dd, J = 14.4, 7.0 Hz, 1H), 3.68 (dd, J = 14.4, 7.4 Hz, 1H), 1.51 – 1.18
(m, 12H), 1.07 – 0.94 (m, 1H), 0.73 (dtd, J = 8.6, 7.3, 5.4 Hz, 1H), 0.36 (dd, J = 8.6, 4.5
13
Hz, 1H), 0.06 – 0.02 (m, 1H). C{1H} NMR (101 MHz, CDCl3, ppm) δ 155.7, 141.9,
128.7, 127.8, 126.5, 61.4, 49.8, 37.4, 30.6, 26.4, 25.8, 25.5, 23.8, 23.2, 17.1, 14.6. HR-
MS (ESI-TOF) m/z: Calcd. for C18H26NO2 288.1964; found: 288.1976 [M+H]+.
Ethyl spiro[2.5]octane-1-carboxylate (34).14 To a suspension of NaH (1.09 g, 27.36
o
mmol; 60 wt% in mineral oil) in dry DMSO (30 mL) at 0 C trimethylsulfoxonium
idoide (6.02 g, 27.36 mmol) was added portionwise. The reaction mixture was allowed
to warm up to room temperature and ester 33 (3.83 g, 22.80 mmol) was added, then
stirred overnight. The reaction mixture was diluted with H2O (20 mL) and EtOAc (20
mL). The phases were separated, aqueous phase was extracted with EtOAc (2×20 mL).
Organic extracts were combined, washed with brine, dried over Na2SO4, filtered and
concentrated under reduced pressure. The crude product was dissolved in CH2Cl2 (30
mL) and cooled to -78 oC. Stream of ozone was introduced through needle until reaction
mixture turned blue. Stream of ozone was replaced with stream of argon and bubbled
trough the solution for 20 min to get rid of the remaining ozone gas. Reaction mixture
was warmed up to room temperature and diluted with H2O (30 mL). Excess of thiourea
was added and stirred for 30 min. Phases were separated, aqueous phase was extracted
with CH2Cl2 (2×20 mL). Organic extracts were combined, dried over Na2SO4, filtered
and concentrated under reduced pressure. The crude product was purified by column
chromatography (eluent hexanes/EtOAc 10:1) afforded product 34 (2.18 g, 52 %) as a
colorless oil. This compound is known in the literature.22 1H NMR (300 MHz, CDCl3,
ppm) δ 4.12 (q, J = 7.1 Hz, 2H), 1.63 – 1.19 (m, 13H, overlaps with H2O signal), 1.09 –
1.03 (m, 1H), 0.90 – 0.76 (m, 2H).
ACS Paragon Plus Environment