The synthesis of α,α-disubstituted α-amino acids via ichikawa rearrangement

Article abstract of DOI:10.1021/acs.joc.5b02628

An approach to α,α-disubstituted α-amino acids is reported. The key step is allyl cyanate-to-isocyanate rearrangement. As demonstrated, the resultant allyl isocyanates can be directly trapped with various nucleophiles, for instance, alcohols, amines, and organometallic reagents, to provide a broad range of N-functionalized allylamines. The developed method has been successfully applied in the synthesis of two bioactive peptides: 2-aminoadamantane-2-carboxylic acid derived P2X₇-evoked glutamate release inhibitor and 4-amino-tetrahydropyranyl-4-carboxylic acid derived dipeptide GSK-2793660, which is currently in clinical trials as cathepsin C inhibitor for the treatment of cystic fibrosis, noncystic fibrosis bronchiectasis, ANCA-associated vasculitis and bronchiectasis.

Full text of DOI:10.1021/acs.joc.5b02628

Subscriber access provided by GAZI UNIV
Article
The synthesis of alpha,alpha-disubsituted
alpha-amino acids via Ichikawa rearrangement
Piotr Szcze#niak, Micha# Pieczykolan, and Sebastian Stecko
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02628 • Publication Date (Web): 04 Jan 2016
Downloaded from http://pubs.acs.org on January 11, 2016
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 free 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 accessible to all
readers and 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.
The Journal of Organic Chemistry 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 71
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
The synthesis of α,αꢀdisubsituted αꢀamino acids via Ichikawa rearrangement
Piotr Szcześniak, Michał Pieczykolan and Sebastian Stecko*
Institute of Organic Chemistry, Polish Academy of Sciences
Kasprzaka 44/52, 01ꢀ224 Warsaw, Poland
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
eꢀmail: sebastian.stecko@icho.edu.pl
Graphical abstract:
Abstract:
An approach to α,αꢀdisubstitutedꢀαꢀamino acids is reported. The key step is
allyl cyanateꢀtoꢀisocyanate rearrangement. As demonstrated the resulted allyl
isocyanates can be directly trapped with various nucleophiles, for instance alcohols,
amines, organometallic reagents, to provide a broad range of Nꢀfunctionalized
allylamines. The developed method has been successfully applied in the synthesis of
two bioactive peptides: 2ꢀaminoadamantaneꢀ2ꢀcarboxylic acidꢀderived P2X ꢀevoked
7
glutamate release inhibitor and 4ꢀaminoꢀtetrahydropyranylꢀ4ꢀcarboxylic acidꢀderived
dipeptide GSKꢀ2793660 which is currently in phase I of clinical trials as cathepsin C
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 71
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
inhibitor for the treatment of cystic fibrosis, nonꢀcystic fibrosis bronchiectasis, ANCAꢀ
associated vasculitis and bronchiectasis.
Keywords: amino acids, sigmatropic rearrangements, quaternary amino acids
Introduction
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
α,αꢀDisubstitutedꢀαꢀamino acids (ααAA) are an important class of nonꢀnatural
1,2
amino acids. Their incorporation into the peptide structure results frequently in
conformational distortions and increased rigidity that lead to enhanced resistance
2,3
toward proteolytic enzymes.
These conformational restrictions are particularly
significant when the α,αꢀdisubstitutedꢀαꢀamino acid moiety is incorporated into a
4
cyclic structure that results in the modulation of conformational preferences and
biological activity of such peptides. Therefore, α,αꢀAAs play an important role in the
design of novel peptides and peptidomimetics with enhanced biological properties
and this area of study is of profound interest to leading academic and industrial
2,5
laboratories.
Geminally disubstituted αꢀamino acids, particularly α,αꢀcycloalkylꢀsubstituted
αꢀamino acids, have also been found as medicines or potential drug candidates. For
example,
4ꢀaminopiperidineꢀ4ꢀcarboxylic
acidꢀderived
remifentanil
®
6
(1)(GlaxoSmithKline: Ultiva ) is a shortꢀacting synthetic opioid analgesic drug (an
analogue of fentanyl), which is given to patients during surgery to relieve pain and as
7
an adjunct to an anesthetic. It has approx. 100ꢀ200 times higher potency than
8
morphine. Even more active are its analogues: sufentanil (2) and carfentanil (3). The
last one exhibits potency ca. 10,000 times that of morphine, and therefore is intended
for large animal use only since its extreme potency makes it inappropriate for use in
8
humans.
2
ACS Paragon Plus Environment

Page 3 of 71
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Another interesting example is 4ꢀaminoꢀtetrahydropyranylꢀ4ꢀcarboxylic acidꢀ
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
9
,6
derived dipeptide 4 (GSKꢀ2793660), which is currently in phase I of clinical trials as
cathepsin C (also known as dipeptidyl peptidase I enzyme) inhibitor for the treatment
10
of cystic fibrosis, nonꢀcystic fibrosis bronchiectasis, ANCAꢀassociated vasculitis and
11,12,13,14,15,16,17
bronchiectasis.
1c,1dꢀf, 18,19
The typical methodologies to prepare ααAAs
involve the use of cyclic
compounds as the starting materials, and the most common methods of their
20,21
22,23
preparation include the BuchererꢀBergs
and the Strecker reactions.
Other
2
4
18f,25
attractive methods are the addition to αꢀiminoesters,
alkylations,,
26
27
cycloadditions and enolate amination. Among them the strategies based on
28,29,30,31,32
rearrangement reactions, for instance [3,3]ꢀ
or [2,3]ꢀsigmatropic
33,34
rearrangements,
are particularly attractive. Due to concerted mechanism of such
rearrangements, that proceeds through a wellꢀdefined cyclic transition state, they
show a high degree of stereospecificity and/or stereoselectivity. Thanks to their
nature, such rearrangements are highly atomꢀeconomic processes which is
consistent with the current trends for efficient modern synthetic methods.
29b, 29c, 35,30,36
Very recently, we demonstrated that the Ichikawa rearrangement
36b
is a useful tool for the preparation of functionalized βꢀ and γꢀhydroxyꢀαꢀamino acids
36c
as well as βꢀaryl alanines. It was also used as a key step in the total synthesis of
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 71
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
6a
lacosamide, a serineꢀderived anticonvulsant drug for epilepsy treatment.
Herein,
we present our extended studies on the synthesis of unnatural amino acids via
sigmatropic rearrangement. In particular, we focused our attention on the synthesis
ααAAs as outlined in Scheme 1.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 1
Results and discussion
We began our investigation with the preparation of a series of allyl carbamates
of type 5. These compounds can be easily synthesized starting from simple acyclic
and cyclic ketones via an olefination, reduction and carbamate formation sequence
(Scheme 2).
Scheme 2
4
ACS Paragon Plus Environment

Page 5 of 71
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
With a library of type 5 carbamates in hand we began the studies on their
transformation into the corresponding allylamines. The treatment of carbamate 5a
with 2 eq. of TFAA in the presence of Et
cyanate (6) which subsequently rearranged to the corresponding allyl isocyanate (7)
Scheme 3). Intermediate 7 can be easily trapped by direct reaction with an excess of
MeOH in the presence of 10 mol% of Bu SnOMe to afford α,αꢀgemꢀsubstituted
allylamine 8a in 79% overall yield (after 3 steps). Since the double bond in compound
is more substituted, its rearrangement is slower with respect to less substituted allyl
3
N (6 eq.) resulted in its dehydration to allyl
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
(
3
6
36
carbamates investigated previously; therefore the reaction time had to be extended
36
from 20ꢀ30 min (previous studies ) to 1ꢀ1.5 h in this case. Isocyanate 7 can be also
trapped with MeOLi. However, in this case the formation of byꢀproduct 9 was noticed
which plausibly originated from Et N addition to 7 followed by elimination as depicted
3
in Scheme 4.
Scheme 3
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 71
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 5
Next, the substrate scope of different carbamates 5aꢀj was investigated. As
shown in Scheme 5, the above method enables the synthesis of both acyclic (8aꢀc)
and cyclic allylamines (8dꢀj) with high overall yield. The key advantages of the
protocol presented in Scheme 5 are mild reaction conditions and no need for any
metal catalysts or high temperatures to induce the rearrangement process.
At this stage of studies the low yield of the desired product was observed only
in the case of the cyclopropanoneꢀderived allyl carbamate (15ꢀ20%). However, it was
a result of problems with product isolation. Fortunately, the change of MeOH to
BnOLi as the nucleophile let us obtain the corresponding NꢀCbz derivative 8d in 67%
overall yield.
Another advantage of the presented rearrangement is the possibility of using
various nucleophilic reagents which allows preparing a broad range of differently Nꢀ
6
ACS Paragon Plus Environment

Page 7 of 71
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
protected geminallyꢀsubstituted allylamines (Table 1). For example, the replacement
of MeOH with other alcohols, for instance tꢀBuOH or BnOH, led to the formation of
the corresponding Nꢀprotected allylamines, namely NꢀBoc or NꢀCbz derivatives (8k
and 8l). It was done by treatment of intermediate isocyanate either by lithium alkoxide
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
(
e.g. tꢀBuOLi or BnOLi, Table 1, ent. 3 and 4) or by ROH in the presence of catalytic
amount of DMAP (Table 1, entry 5). Interestingly, in case of carbamate of 5g the
formation of analogue of compound 9 was not observed even when MeOLi was
4
applied. The use of NaBH , as the nucleophile source, furnished formamide 10.
Finally, the use of nitrogen nucleophiles such as ammonia, nꢀdibutylamine or
benzylamine led to the formation of the corresponding ureas 11a, 11b and 11c,
respectively. As summarized in Table 1, all of these products were formed in
excellent overall yield after 3 steps.
Table 1. Nucleophile scope in
rearrangement/addition sequence for
carbamate 5g.
Ent.
1
Nucleophile
R
Yield
a
[%]
MeOH/Bu
3
SnOMe OMe
8g)
OMe
8g)
OtꢀBu
87
82
88
(
2
MeOLi
(
3
tꢀBuOLi
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 71
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(8k)
4
5
6
7
BnOLi
OBn (8l)
OBn (8l)
H (10)
66
63
62
60
b
BnOH
NaBH
NH
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
NH
2
(11a)
8
9
BnNH2
BnNH
85
90
(
11b)
nꢀBu
(11c)
nꢀBu
2
NH
2
N
10
MeMgBr
PhMgBr
Me (12a)
Ph (12b)
64
65
11
a
b
isolated yield, overall after 3 steps; in the
presence of 10 mol% of DMAP.
As can be seen from entries 8 and 9, the use of Grignard reagents as the
nucleophilic species allowed also the preparation of Nꢀacyl disubstituted allylamines
1
2a and 12b. It is worth to stress that oxidative cleavage of the double bond in 12a
and 12b should provide the corresponding Nꢀacyl disubstituted amino acids. Such
hindered compounds are not easy to prepare by typical dehydrative coupling of
37
amines and carboxylic acids in the presence of a coupling reagent. The essential
problem is the low rate of the reaction of the amine on the activated carboxylic acid. It
is even more complicated when sterically hindered carboxylic acids (or their
derivatives, e.g. acyl chlorides) are used. Recently, Bode and coꢀworkers
8
ACS Paragon Plus Environment

Page 9 of 71
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
3
8
39
demonstrated that isocyanates and Nꢀcarboxyanhydrides can be an interesting
solution for the formation of sterically hindered amides and amino acids.
Encouraged by these reports and our initial work, we decided to examine
whether other structurally different Grignard reagents, including bulky ones, can be
applied for our dehydration/rearrangement/addition sequence.
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
As exemplified in Scheme 6, the investigated transformations proceed
efficiently not only for simple methylꢀ or phenylmagnesium bromide but also for more
sterically demanding reagents such as isopropyl or tꢀbutyl Grignard reagent. Good
results were also obtained in the case of 2ꢀmethoxyphenylmagnesium bromide or 1ꢀ
naphthylmagnesium bromide. Quite good yield was also obtained in the case of the
addition of the sterically hindered mesitylmagnesium bromide.
Scheme 6
The addition of organolithium reagents to the allyl isocyanate generated in situ
also proceeded smoothly and the desired products were obtained in moderate yields
(
Scheme 7). In addition, this approach enabled the synthesis of several interesting
heterocyclic allyl amides (e.g. 15a, 15b) in good yield as well (Scheme 7).
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 71
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 7
Finally, selected disubstituted allylamine derivatives were converted into the
corresponding amino esters. Initially, we planned to perform this transformation by
the ozonolysis of the double bond in the presence of 2M NaOH in MeOH (Marshall
40
36
protocol ), which approach we used successfully in our previous works.
Surprisingly, this approach proceeded poorly in the case of investigated α,αꢀ
geminally substituted allylamines (yields ca. 30ꢀ50%) probably, due to side
decarboxylation process and some problems with an isolation of polar amino acids.
Thus, the target amino acids or aminoesters were obtained by sequential
41
ozonolysis/PinnickꢀLindgren oxidation eventually followed by the esterification of
the resulting amino acid as presented in Scheme 8.
10
ACS Paragon Plus Environment

Page 11 of 71
The Journal of Organic Chemistry
1
2
3
4
5
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
Scheme 8
Having explored the scope of the oneꢀpot dehydration/rearrangement/addition
process, in the next step the synthetic utility of α,αꢀdisubstituted allylamines for the
preparation of biologically active compounds was investigated.
We decided to apply the above approach in the formal synthesis of
GSK2793660 (4), a dipeptide which, as already mentioned, is currently in phase I of
clinical trials as cathepsin C inhibitor for the treatment of cystic fibrosis, nonꢀcystic
fibrosis
bronchiectasis,
ANCAꢀassociated
This molecule was planned to be synthesized according to the
retrosynthetic scheme outlined in Scheme 9.
vasculitis
and
bronchiectasis.
6,11,12,13,14,15,16,17
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 71
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
O
O
O
OH
O
RHN
O
O
N
H
N
H2N
part A
N
+
O
part B
O
O
P
O
O
H2N
+
RHN
4
EtO
EtO
N
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
7
18
Scheme 9. Retrosynthesis of compound 4.
Part A of 4 was prepared from carbamate 5h obtained from tetrahydroꢀ4Hꢀ
pyranꢀ4ꢀone. As presented in Scheme 10, upon treatment with TFAA/Et N carbamate
h underwent dehydration/rearrangement to provide an isocyanate intermediate
3
5
which was trapped directly with tꢀBuOLi to provide product 19 in 80% yield after 3
steps. The oxidation of the double bond using ozonolysis/PinnickꢀLindgren oxidation
gave NꢀBoc protected amino acid 20 in 65%.
Scheme 10. Reagents and conditions: a) i. TFAA, Et
BuOH, LiHMDS, THF, rt, 5 h, 80 % (3 steps); b) i. O
NaH PO , 2ꢀmethylꢀ2ꢀbutene, tꢀBuOH/H O, 62% (2 steps).
3
N, THF, –10 °C then rt, 1h; ii. tꢀ
3
, CH Cl , –78 °C, ii. NaClO
2
2
2
,
2
4
2
Fragment B of compound 4 was planned to be prepared via HWE olefination
of aldehyde 18 with phosphonate 17 (Scheme 9). Phosphonate 17 was obtained
from diethylphosphonoacetic acid by its activation with (COCl) and treatment with
2
42
indoline (21) according to the procedure reported by Webber et al. (Scheme 11).
1
2
ACS Paragon Plus Environment

Page 13 of 71
The Journal of Organic Chemistry
1
2
3
4
5
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
Scheme 11. Reagents and conditions: a) (COCl)
6%; b) 2ꢀbromoacetyl bromide, Et N, CH Cl , –10 °C then rt, 65%; c) i. Ph
reflux, 24h, ii. Et N, CHCl , 4 h, 67% (2 steps).
2
, diethylphosphonoacetic acid,
7
3
2
2
3
P, PhMe,
3
3
Chiral aldehyde 26 was prepared starting with Lꢀ2ꢀaminobutyric acid (Scheme
12). After Nꢀprotection with Boc
2
O (24), this compound was converted into Weinreb
9b
4
amide 25 according to Neipp et al. Upon treatment with LiAlH amide 25 was
selectively reduced to aldehyde 26. Compound 26, after aqueous workꢀup, was
directly subjected to the olefination reaction by its addition to a solution of 17
pretreated with LiHMDS. Unfortunately, the desired product 27 was obtained in
moderate 64% yield. Close results were obtained when the olefination was performed
43
under MasamuneꢀRoush conditions by treatment with phosphonate 17 in the
presence of LiCl/DBU in MeCN (68%). The highest yield was obtained when 27 was
44
prepared via Wittig reaction with ylide 23 (75%). Compound 23 was prepared as
presented in Scheme 11.
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 71
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 12. Reagents and conditions: a) Boc
2
O, aq. NaOH, 93%; b) i. CDI, THF; iii.
MeNHOMeꢁHCl, iꢀPr NEt, CH Cl , rt, 93%; c) LiAlH , THF, –20 °C then rt; d) ylide 23,
2
2
2
4
PhMe, 40 °C, 75%; e) 4M HCl, dioxane; f) amino acid 20, coupling agent.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Deprotection of 27 with TFA, according to a procedure described by Neipp et
9b
al., provided the corresponding amine 28 in low yield and with poor purity. Much
more effective was deprotection of 27 by the treatment with 4M HCl in dioxane at rt.
After the removal of the solvent the resulting amine hydrochloride 28 was directly
subjected to the coupling reaction with amino acid 20.
®10
Initially, coupling of 20 with 28 was performed in the presence of T3P
in
9b
AcOEt according to a procedure reported by Neipp et al. However, only traces of
the desired product 29 were obtained. Poor results were also obtained when other
10
coupling agents were applied (e.g. HATU, DCC, EDCl, HOBt, ClCOOiꢀBu). LCꢀMS
analysis showed the presence of the desired molecular peak predominantly (458
+
[
M+H] ), however, NMR spectra indicated the presence of a complicated reaction
mixture. Deeper analysis of the NMR spectra indicated that the desired compound 29
was formed along with byproducts. The key observation from the analysis of NMR
spectra was that these additional products plausibly do not contain a double bond,
which suggested that amine 29 undergoes partially unwanted cyclization to isomeric
aziridines via intramolecular Michael reaction (at the coupling or the deprotection
stage). None of these compounds were isolated in pure form due to their similar
polarity. The attempts to separate them by either column chromatography or
preparative TLC failed.
Due to the failure of our initial synthetic strategy, an alternative pathway of the
formal synthesis of 4 was designed (Scheme 13). Now, amino acid 20 was coupled
14
ACS Paragon Plus Environment

Page 15 of 71
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
4
5
with methyl (S)ꢀ2ꢀaminobutanoate
in the presence of HATU and Nꢀ
methylmorpholine (NMM). The resulting peptide 30 was reduced to the amino alcohol
which was directly oxidized to the aldehyde with DessꢀMarin periodinane (DMP).
After aqueous workꢀup, this aldehyde was directly treated with ylide 23 to afford the
desired product 29 in 95% yield after 3 steps. The final deprotection has been
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
9b
already described by Neipp et al.
Scheme 13. Reactants and conditions: a) methyl (S)ꢀ2ꢀaminobutanoate
hydrochloride, HATU, NMM, THF, rt, 75%; b) i. LiAlH , Et O; ii. DMP, CH Cl ; iii. ylide
4
2
2
2
2 2
23, CH Cl , 40 °C, 95% (3 steps).
The adamantyl moiety is an important structural element of numerous
46
biologically active compounds,
including several currently used drugs (e.g.
46a,47
46
amantadine (antiviral, Parkinson’s disease),
menantadine (Alzeimer’s disease),
46,48
46,49
46,49,50
tromantadine (antiviral)
and antidiabetics vidagliptin
and saxagliptin.
An
interesting example is unnatural amino acid 31 (2ꢀaminoadamantaneꢀ2ꢀcarboxylic
acid), which has been reported to possess interesting biological activity as a transport
51,52
mediator.
2ꢀAminoadamantanecarboxylic residue has been also recognized as a
53
54
key structural element of SR 48692 (32, Meclinertant) and SR 142948A (33)
55
responsible for key interactions allowing the selective recognition of neurotensins,
sevenꢀtransmembrane G proteinꢀcoupled receptors acting as neurotransmitters and
5
6,57
neuromodulators demonstrating a range of biological activity.
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 71
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5
8
Recently, Ley and coꢀworkers reported the synthesis of 31 and its derivative
3
4 which demonstrated excellent in vivo analgesic properties in the mouse abdominal
58b
constriction test.
7
Further experiments indicated that 34 inhibits also the P2X ꢀ
58b
7
evoked glutamate release. P2X receptors have been associated with chronic pain
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
and arthritis, which makes them potential targets for future drug discovery, especially
in the case of neurodegenerative diseases such as multiple sclerosis, Alzheimer’s
59
and Huntington’s diseases, or amyotrophic lateral sclerosis.
5
8
Inspired by the report of Ley and coꢀworkers we decided to apply our method
for the preparation of adamantylꢀderived diamide 34 as outlined in Scheme 14. The
reaction sequence began with HWE olefination of 2ꢀadamantanone (35) followed by
ester reduction and carbamate formation by the treatment of allyl alcohol 36 with
trichloroacetyl isocyanate and basic hydrolysis. The obtained carbamate 37 was
subjected to a dehydration/rearrangement cascade reaction to provide the
isocyanate which was directly treated with PhMgBr and resulted in the formation of
benzamide 38 in 74% yield after 3 steps. Interestingly, an oxidation of the double
bond with RuCl
results were obtained when ozonolysis/PinnickꢀLindgren oxidation was applied
62%).
3 4
/NaIO provided carboxylic acid 39 in 60% yield. The comparible
(
Finally, carboxylic acid 39 was subjected to a coupling reaction with
cyclopropylamine to provide the target diamide 34. Initially, acid 39 was activated
with (COCl) and the resulting acid chloride was reacted with CyNH . However, the
2
2
16
ACS Paragon Plus Environment

Page 17 of 71
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
desired product 34 was obtained in poor yield (20%) and with low purity. The same
low efficiency was achieved in the case of the mixed anhydride strategy (i.e. either
with methyl chloroformate or sꢀbutyl chloroformate). The best results were obtained
again when HATU was used as the acid activator. The final product 34 was obtained
in 62% yield after chromatographic purification.
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
Scheme 14: Synthesis of 34. Reagents and conditions: a) i. (EtO) P(O)CH COOEt,
2
2
NaH, THF, rt, overnight, yield 79%; ii. DIBALꢀH, CH
TCAꢀNCO, CH Cl , 0 °C then rt, 1 h; ii. aq. K CO
steps); c) i. TFAA, Et N, THF, –10 °C then rt, 1 h; ii. PhMgBr, THF, –30 °C then rt,
overnight, yield 74% (overall after 3 steps); d) RuCl ꢁxH O, NaIO , acetone/H O 9:1,
2
Cl
2
, –70 °C, 2 h, yield 75%; b)
2
2
2
3
, MeOH, rt, 2 h, yield 63 % (2
3
3
2
4
2
rt, 60%; e) cyclopropylamine, HATU, NMM, THF, rt, 62%.
Conclusions
In summary, novel approach to α,αꢀdisubstitutedꢀαꢀamino acids has been
developed. The key step of reported method is cyanateꢀtoꢀisocyanate rearrangement.
Important advantages of this reaction over other [3,3]ꢀsigmatropic rearrangements,
for instance Overman reaction, are mild reaction conditions (~0 °C to rt, short
reaction time ca. 1 h) and no need to use any metal catalyst. In addition, generated
allyl isocyanates can be directly trapped by various nucleophilic species, for example
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 71
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
alcohols, amines, organometallic reagents. In result, this approach enables synthesis
a broad range of Nꢀfunctionalized allylamines.
The developed method has been successfully applied in the synthesis of two
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
bioactive peptides: 2ꢀaminoadamantaneꢀ2ꢀcarboxylic acidꢀderived P2X ꢀevoked
glutamate release inhibitor and 4ꢀaminoꢀtetrahydropyranylꢀ4ꢀcarboxylic acidꢀderived
dipeptide GSKꢀ2793660 which is currently in phase I of clinical trials as cathepsin C
inhibitor for the treatment of cystic fibrosis, nonꢀcystic fibrosis bronchiectasis, ANCAꢀ
associated vasculitis and bronchiectasis.
Experimental section:
Synthesis of unsaturated esters. General procedure: Neat triethyl
phosphonoacetate (10 mmol) was added to a suspension of NaH (10 mmol) in dry
THF (50 mL). After 30 min a solution of ketone (8 mmol) in dry THF (10 mL) was
added and the resulting mixture was stirred overnight. The progress of the reaction
was followed by TLC. The reaction was quenched by the addition of water (50 mL).
The organic layer was separated and the aqueous one was extracted with ether
(
3×50 mL). The combined organic solutions were dried over anhydr. Na SO and
2 4
then the solvents were removed under diminished pressure and the residue was
purified by column chromatography.
Ethyl 3,3ꢀdiphenylacrylate: colorless oil; yield 3.78 g (91%) staring from 3 g (16.46
60 1
mmol) of benzophenone; Spectral data in agreement with literature data. H NMR
(
400 MHz, CDCl ) δ: 7.40–7.26 (m, 8H), 7.24ꢀ7.15 (m, 2H), 6.34 (s, 1H), 4.02 (q, J
3
13
7.1 Hz, 2H), 1.10 (t, J 7.1 Hz, 3H); C NMR (100 MHz, CDCl3) δ: 166.1, 156.4,
18
ACS Paragon Plus Environment

Page 19 of 71
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
140.8, 139.0, 129.5, 129.1, 128.3, 128.1, 128.0, 127.7, 117.3, 60.3, 14.1; Anal. calcd
16 2
for C17H O : C 80.93, H 6.39; Found C 81.04, H 6.32.
Ethyl 3ꢀethylpentꢀ2ꢀenoate: colorless oil, yield 5.66 (52%) starting from 6 g (69.55
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
mmol) of 3ꢀpentanone; b.p. 64ꢀ68 °C/5 Torr; Spectral data in agreement with
61 1
literature data. H NMR (400 MHz, CDCl
3
) δ: 5.46 (s, 1H), 4.01 (q, J 7.1 Hz, 2H),
13
2.40 (q, J 6.8 Hz, 2H), 2.07 (q, J 6.7 Hz, 2H), 1.09 (t, J 7.1, 3H), 0.90 (2×t, 6H);
C
3
NMR (100 MHz, CDCl ) δ: 168.1, 165.3, 113.5, 61.2, 30.9, 25.7, 13.2, 12.5; IR (film)
ꢀ1
v: 1734, 1638 cm ; Anal. calcd for C H O : C 69.19, H 10.32; Found: C 69.26, H
9
16
2
10.25.
Ethyl
4ꢀ((tꢀbutyldimethylsilyl)oxy)ꢀ3ꢀ(((tꢀbutyldimethylsilyl)oxy)methyl)butꢀ2ꢀ
62
enoate: pale yellow oil; yield 2.02 g (83%) starting from 2 g (6.28 mmol) of O,Oꢀ
TBSꢀdihydroxyacetone; purification by chromatography on silica gel (3% AcOEt in
62 1
hexanes); Spectral data in agreement with literature data.
CDCl ) δ: 5.90 (t, J 1.9 Hz, 1H), 4.87ꢀ4.85 (m, 2H), 4.45ꢀ4.41 (m, 2H), 4.10 (q, J 7.1
Hz, 2H), 1.21 (t, J 7.1 Hz, 3H), 0.95 (s, 18H), 0.09 (s, 6H), 0.06 (s, 6H); IR (film) v:
H NMR (400 MHz,
3
ꢀ
1
1730, 1633 cm ; Anal. calcd for C19
40 4 2
H O Si : C 58.71, H 10.37; Found: C 58.79, H
10.29.
Ethyl 2ꢀcyclopropylideneacetate: prepared following the procedure reported by
63
Arai et al. ; colorless oil; yield 1.72 g (70%) starting from 3.4 g (19.51 mmol) of (1ꢀ
63
ethoxycyclopropoxy)trimetylsilane; Spectral data in agreement with literature data.
1
3
H NMR (500 MHz, CDCl ) δ: 6.24–6.21 (m, 1H), 4.21 (q, J 7.1 Hz, 2H), 1.48–1.42
13
(m, 2H), 1.30 (t, J 7.1 Hz, 3H), 1.25–1.19 (m, 2H); C NMR (126 MHz, CDCl ) δ:
3
ꢀ
1
1
66.2, 144.8, 111.0, 60.1, 14.3, 4.5, 2.0; IR (film) v: 1720, 1266, 1181 cm ; MS (ESIꢀ
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 71
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
TOF) m/z 149 [M+Na ]; Anal. calcd for C
7 10 2
H O : C 66.65, H 7.99; Found: C 66.72, H
7.85.
Ethyl 2ꢀcyclobutylideneacetate: yield 1.54 g (86%) starting from 0.93 g (12.74
mmol) of cyclobutanone; purification by column chromatography on silica gel (5%
then 10% AcOEt in hexanes); colorless oil. Spectral data in agreement with literature
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
64 1
data. H NMR (500 MHz, CDCl
3
) δ: 5.57 (p, J 2.3 Hz, 1H), 4.14 (q, J 7.1 Hz, 2H),
3
.16–3.07 (m, 2H), 2.83 (t, J 7.9 Hz, 2H), 2.14–2.01 (m, 2H), 1.26 (t, J 7.1 Hz, 3H);
13
3
C NMR (126 MHz, CDCl ) δ: 167.5, 166.6, 112.4, 59.5, 33.7, 32.3, 17.7, 14.3; IR
ꢀ1
(
8 12 2
film) v: 1718, 1676, 1335, 1189 cm ; HRMS (ESIꢀTOF) m/z calcd for C H O Na
+
[M+Na ] 163.0735; Found 163.0732.
Ethyl 2ꢀcyclopentylideneacetate: yield 6.01 g (82%) staring from 4 g (47.55 mmol)
of cyclopentanone; purification by column chromatography on silica gel (5% then
1
1
0% AcOEt in hexanes); colorless oil; H NMR (400 MHz, CDCl
3
) δ: 5.81 (s, 1H),
4
.13 (q, J 7.1 Hz, 2H), 2.77 (t, J 7.2 Hz, 2H), 2.45 (t, 6.9 Hz, 2H), 1.78ꢀ1.64 (m, 4H),
13
3
1.25 (t, J 7.1, 3H); C NMR (100 MHz, CDCl ) δ: 169.4, 167.4, 111.8, 59.61, 36.1,
ꢀ
1
3
2.8, 26.7, 25.6, 14.5; IR (film) v: 1721, 1271, 1200, 1031 cm ; MS (ESIꢀTOF) m/z
+
1
77 [M+Na ]; Anal. Calcd for C H O : C 70.10, H 9.15; Found: C 70.21, H 9.08.
9
14
2
Ethyl 2ꢀcyclohexylideneacetate: yield 22.63 g (88%) starting from 15 g (152.84
mmol) of cyclohexanone; purification by column chromatography on silica gel (5%
1
then 10% AcOEt in hexanes); colorless oil; H NMR (400 MHz, CDCl
3
) δ: 5.63 (s,
1
H), 4.12 (q, J 7.1 Hz, 2H), 2.85ꢀ2.82 (m, 2H), 2.23ꢀ2.18 (m, 2H), 1.74ꢀ1.56 (m, 6H),
13
1
.26 (t, J 7.1 Hz, 3H); C NMR (100 MHz, CDCl ) δ: 166.8, 163.4, 112.9, 59.4, 37.9,
3
ꢀ
1
29.7, 28.6, 27.7, 26.2, 14.3; IR (film) v: 1724, 1270, 1205, 1032 cm ; MS (ESIꢀTOF)
+
m/z 191 [M+Na ]; Anal. calcd for C10
H
16
O
2
: C 71.39, H 9.59; Found: C 71.28, H 9.51.
20
ACS Paragon Plus Environment

Page 21 of 71
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Ethyl 2ꢀ(tetrahydroꢀ4Hꢀpyranꢀ4ꢀylidene)acetate: yield 3.03 g (90%) starting from 2
g (19.8 mmol) of tetrahydroꢀ4Hꢀpyranꢀ4ꢀone, purification by column chromatography
1
on silica gel (15% then 20% AcOEt in hexanes); yellow oil; H NMR (500 MHz,
CDCl
H), 3.00 (t, J 5.6 Hz, 2H), 2.32 (t, J 5.5 Hz, 2H), 1.27 (t, J 7.1 Hz, 3H); C NMR
(126 MHz, CDCl ) δ: 166.4, 157.1, 114.5, 69.0, 68.5, 59.7, 37.5, 31.0, 14.3; IR (film)
3
) δ: 5.67 (s, 1H), 4.15 (q, J 7.1 Hz, 2H), 3.76 (t, J 5.5 Hz, 2H), 3.73 (t, J 5.6 Hz,
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
2
3
v: 2977, 2909, 2847, 1712, 1651, 1386, 1251, 1201, 1177, 1147, 1097, 1039, 1009,
ꢀ1
8
64, 850, 683 cm ; HRMS (EI) m/z calcd for C
9
H
14
O
3
[M] 170.0943; Found
170.0938.
NꢀBoc 4ꢀ(2ꢀethoxyꢀ2ꢀoxoethylidene)piperidine: Yield 2.67 g (79%) starting from
2.5 g (12.55 mmol) of Nꢀtꢀbutoxycarbonylꢀpiperidinꢀ4ꢀone; purification by column
1
chromatography on silica gel (10% AcOEt in hexanes); colorless oil; H NMR (400
MHz, CDCl
H), 2.19 (s, 2H), 1.38 (s, 9H), 1.18 (t, J 7.1 Hz, 3H); C NMR (101 MHz, CDCl
166.1, 157.7, 154.4, 115.2, 79.7, 59.6, 36.3, 29.4, 28.3, 14.2; IR (film) v: 1698, 1421,
3
) δ: 5.62 (s, 1H), 4.06 (q, J 7.0 Hz, 2H), 3.52–3.32 (m, 4H), 2.98–2.76 (m,
13
2
3
) δ:
ꢀ
1
1
254, 1167 cm ; HRMS (ESIꢀTOF) m/z calcd for C14
4
H23NO Na 292.1525; Found
292.1523.
Ethyl 2ꢀcycloheptylideneacetate: yield 5 g (62%) starting from 5 g (44.58 mmol) of
cycloheptanone; purification by flash column chromatography on silica gel (3%
1
AcOEt in hexanes); colorless oil; H NMR (400 MHz, CDCl
3
) δ: 5.67 (t, J 1.5 Hz, 1H),
4.16 (q, J 7.5 Hz, 2H), 2.88 (dt, J 6.5, 1.5 Hz, 2H), 2.37 (dt, J 6.5, 1.5 Hz, 2H), 1.72–
13
1
.62 (m, 4H), 1.58–1.50 (m, 4H), 1.28 (t, J 7.5 Hz, 3H); C NMR (100 MHz, CDCl3)
δ: 166.6, 115.6, 59.0, 38.9, 32.0, 29.8, 29.0, 28.0, 26.6, 14.3; IR (film) v: 2990, 2926,
ꢀ1
18 2
1714, 1635, 1445, 1147, 1038 cm ; HRMS (EI) m/z calcd for C11H O [M] 182.1307;
Found 182.1314.
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 71
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Synthesis of allyl carbamates 5. General procedure: To a cooled (–70 °C)
2 2
solution of the unsaturated ester (8 mmol) in CH Cl (50 mL) a 1M soln. of DIBALꢀH
in hexanes (20 mL, 20 mmol) was added. The progress of the reduction was followed
by TLC. When the reduction was complete, the reaction was quenched by the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2 4
addition of sat. aq. Na SO (4.4 mL). When a precipitate appeared, the mixture was
diluted with Et O and stirred for 1 h. Solids were filtered off and washed with Et O.
2
2
After drying over anhydr. Na
2
SO
4
the solvent was removed under diminished
pressure and the crude alcohol was used in the next step.
To a solution of allyl alcohol (8 mmol) in CH
TCAꢀNCO (10.4 mmol) was added. After 1 h the solvent was removed under
diminished pressure and the residue was dissolved in a mixture of MeOH/H O (50
mL, 4:1 v/v) and K CO (4 g) was added in one portion. After 1.5 h MeOH was
2 2
Cl (50 mL) cooled to –10 °C
2
2
3
removed and the aqueous residue was extracted with CH
2 2
Cl (4×50 mL). The
combined organic extracts were dried over MgSO , filtered through a silica gel pad
4
and the solvent was removed under diminished pressure. The residue was
chromatographed on silica gel to afford the corresponding allyl carbamate 5.
3,3ꢀdiphenylallyl carbamate (5a): yield 0.57 g (73%) starting from 0.65 g (3.09
mmol) of ethyl 3,3ꢀdiphenylacrylate; purification by column chromatography on silica
1
gel (5% AcOEt in hexanes); colorless crystals; m.p. 111.0ꢀ111.6 °C; H NMR (500
3
MHz, CDCl ) δ: 7.41–7.16 (m, 10H), 6.19 (t, J 7.0 Hz, 1H), 4.65 (d, J 7.0 Hz, 2H),
13
4
.59 (s, 2H); C NMR (126 MHz, CDCl ) δ: 146.2, 141.5, 138.7, 129.7, 128.3, 128.2,
3
ꢀ1
1
27.8, 127.7, 127.6, 122.7, 63.2; FTIR (film) v: 3439, 3328, 3262, 3224, 1688 cm ;
+
HRMS (ESIꢀTOF) m/z calcd for C16
H15NO
2
Na [M+Na ] 276.1000. Found 276.1003.
22
ACS Paragon Plus Environment

Page 23 of 71
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
3ꢀEthylpentꢀ2ꢀenꢀ1ꢀyl carbamate (5b): yield 1.3 g (63%) starting from 1.5 g (13.14
mmol) of ethyl 3ꢀethylpentꢀ2ꢀenoate; purification by column chromatography on silica
1
gel (15% AcOEt in hexanes); colorless oil; H NMR (400 MHz, CDCl
3
) δ: 5.29 (t, J 7.1
Hz, 1H), 4.71 (s, 2H), 4.60 (d, J 7.1 Hz, 2H), 2.15–2.01 (m, 4H), 1.04–0.97 (m, 6H);
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
3
3
C NMR (101 MHz, CDCl ) δ: 149.8, 137.1, 116.6, 61.7, 29.1, 23.7, 13.5, 12.3; FTIR
ꢀ
1
(film) v: 3464, 3348, 1710, 1602, 1405, 1330, 1073, 1045 cm ; MS (ESIꢀTOF) m/z
+
1
9
4
80 [M+Na ], Anal. calcd for C H NO : C 61.12, H 9.62, N 8.91; Found C 61.08, H
8
15
2
.68, N 8.75.
ꢀ(tꢀbutyldimethylsilyloxy)ꢀ3ꢀ(tꢀbutyldimethylsilyloxymethyl)butꢀ2ꢀenꢀ1ꢀyl
carbamate (5c): yield 1.43 g (72%, 3 steps); purification by column chromatography
1
on silica gel (2% to 5% AcOEt in hexanes); white solid; m.p. 41ꢀ42 °C; H NMR (500
MHz, CDCl ) δ: 5.67 (t, J 7.0 Hz, 1H), 4.69 (d, J 7.0 Hz, 2H), 4.63 (br s, 2H), 4.24 (s,
3
13
2
H), 4.20 (s, 2H), 0.91 (s, 9H), 0.89 (s, 9H), 0.07 (s, 6H), 0.06 (s, 6H); C NMR (126
MHz, CDCl ) δ: 156.7, 142.9, 119.4, 64.1, 61.1, 59.1, 25.9, 25.8, 18.4, 18.2, –5.4;
FTIR (film) v: 3510, 3356, 3279, 3200, 2954, 2929, 2857, 1726, 1254, 1107, 1052,
3
ꢀ
1
+
8
37, 777 cm ; HRMS (ESIꢀTOF) m/z calcd for C18
4 2
H39NO Si Na [M+Na ] 412.2315;
Found 412.2317.
2
ꢀCyclopropylideneethyl carbamate (5d): yield 396 mg (80%) starting from 490 mg
1
(3.88 mmol) of ethyl 2ꢀcyclopropylideneacetate; white solid; m.p. 42ꢀ42.5 °C; H NMR
(400 MHz, CDCl
3
) δ: 5.98–5.92 (m, 1H), 4.73 (s, 2H), 4.70 (ddt, J 6.6, 2.4, 1.1 Hz,
13
2
3
H), 1.12 (dt, J 2.0, 1.2 Hz, 4H); C NMR (101 MHz, CDCl ) δ: 149.4, 130.0, 112.8,
ꢀ
1
6
5.3, 27.9, 19.0; FTIR (film) v: 3475, 3348, 1709, 1602, 1403, 1341, 1051 cm ; MS
+
(ESIꢀTOF) m/z 150 [M+Na ]; Anal. calcd for C
6
H
9
NO
2
: C 56.68, H 7.14, N 11.02;
Found C 56.59, H 7.20, N 10.58.
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 71
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2ꢀCyclobutylideneethyl carbamate (5e): yield 0.96 g (60%) starting from 1.6 g
(11.4 mmol) of ethyl 2ꢀcyclobutylideneacetate; purification by flash chromategraphy
on silica gel (from 10% to 20% AcOEt in hexanes); colorless crystals; m.p. 47ꢀ48 °C;
1
3
H NMR (400 MHz, CDCl ) δ: 5.31–5.23 (m, 1H), 4.73 (br s, 2H), 4.43 (dp, J 7.2, 1.1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
Hz, 2H), 2.79–2.64 (m, 4H), 2.05–1.92 (m, 2H); C NMR (101 MHz, CDCl
3
) δ: 156.9,
148.2, 114.5, 61.9, 31.1, 29.4, 17.0; FTIR (film) v: 3433, 3330, 3266, 3211, 1684,
ꢀ
1
+
1
1
2
612, 1414, 1347, 1041 cm ; HRMS (ESIꢀTOF) m/z calcd for C H NO Na [M+Na ]
7 11 2
64.0687; Found 164.0689.
ꢀCyclopentylideneethyl carbamate (5f): yield 2.36 g (78%) starting from 3 g
(19.45 mmol) of ethyl 2ꢀcyclopentylideneacetate; purification by flash
chromatography on silica gel (from 10% to 20% AcOEt in hexanes); colorless
1
crystals; m.p. 62ꢀ64 °C ; H NMR (500 MHz, CDCl ) δ: 5.49–5.38 (m, 1H), 4.78 (s,
3
2H), 4.54 (d, J 7.1 Hz, 2H), 2.36–2.23 (m, 4H), 1.68 (p, J 6.8 Hz, 2H), 1.61 (p, J 6.7
13
Hz, 2H); C NMR (125 MHz, CDCl
3
) δ: 157.1, 150.5, 114.2, 63.4, 33.8, 28.7, 26.2,
26.0; FTIR (film) v: 3451, 3333, 3268, 3199, 2952, 1705, 1607, 1356, 1330, 1046,
ꢀ
1
+
7
1
2
8 2
83 cm ; HRMS (ESIꢀTOF) m/z calcd for C H13NO Na [M+Na ] 178.0844; Found
78.0845.
ꢀCyclohexylideneethyl carbamate (5g): yield 4.23 g (84%) starting from 5 g (29.72
mmol) of ethyl 2ꢀcyclohexylideneacetate; purification by column chromatography on
1
silica gel (20% AcOEt in hexanes); white solid, m.p. 84.0ꢀ84.5 °C; H NMR (500
3
MHz, CDCl ) δ: 5.30 (t, J 7.1 Hz, 1H), 4.62 (s, 2H), 4.58 (d, J 7.2 Hz, 2H), 2.23–2.18
13
(
m, 2H), 2.16–2.10 (m, 2H), 1.60–1.51 (m, 6H); C NMR (126 MHz, CDCl ) δ 156.9,
3
146.9, 115.4, 61.2, 37.0, 29.0, 28.3, 27.7, 26.6; FTIR (film) v: 3497, 3447, 3335,
ꢀ1
3266, 3798, 1712, 1605, 1331, 1044, 739 cm ; HRMS (ESIꢀTOF) m/z calcd for
+
C
9
H
15NO
2
Na [M+Na ] 192.1002. Found 192.1000.
24
ACS Paragon Plus Environment

Page 25 of 71
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2ꢀ(Tetrahydroꢀ4Hꢀpyranꢀ4ꢀylidene)ethyl carbamate (5h): yield 3.34 g (83%)
starting from 4 g (23.50 mmol) of Ethyl 2ꢀ(tetrahydroꢀ4Hꢀpyranꢀ4ꢀylidene)acetate; the
crude carbamate was dissolved in a small amount of AcOEt and hexane was added
1
to precipitate compound 5h as colorless crystals; m.p. 84.5–85.5 °C; H NMR (500
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
3 2
MHz, CDCl ) δ: 5.40 (t, J 7.3 Hz, 1H), 4.68 (s, 2H, NH ), 4.58 (d, J 7.3 Hz, 2H), 3.74–
13
3.65 (m, 4H), 2.35 (t, J 5.2 Hz, 2H), 2.25 (t, J 5.5 Hz, 2H); C NMR (126 MHz,
CDCl ) δ: 156.9, 141.4, 117.5, 69.4, 68.7, 60.8, 36.9, 30.1; FTIR (film) v: 3424, 3322,
3
ꢀ1
+
3
260, 3208, 1680, 1055 cm ; HRMS (ESIꢀTOF) m/z calcd for C
8
H
13NO
3
Na [M+Na ]
194.0793. Found 194.0790.
tꢀButyl 4ꢀ(2ꢀ(carbamoyloxy)ethylidene)piperidineꢀ1ꢀcarboxylate (5i): yield 0.873
(88%) starting from 0.873 (3.68 mmol) of NꢀBoc 4ꢀ(2ꢀethoxyꢀ2ꢀ
g
g
oxoethylidene)piperidine; purification by column chromatography on silica gel
1
(
hexanes/AcOEt 2:1); colorless crystals; m.p. 150.5–151.5 °C; H NMR (500 MHz,
3
CDCl ) δ: 5.43 (t, J 7.1 Hz, 1H), 4.66ꢀ4.61 (br s, 2H, NH), 4.59 (d, J 7.1 Hz, 2H),
13
3.52–3.34 (m, 4H), 2.33–2.25 (m, 2H), 2.23–2.13 (m, 2H), 1.46 (s, 9H); C NMR
(126 MHz, CDCl
3
) δ: 156.7, 154.7, 141.9, 118.1, 97.3, 79.6, 60.7, 35.7, 28.4; FTIR
ꢀ1
(
film) v: 3406, 3260, 3196, 1722, 1685 cm ; HRMS (ESIꢀTOF) m/z calcd for
+
C
13
H
22
N
2
O
4
Na [M+Na ] 293.1477. Found 293.1480.
2ꢀCycloheptylideneethyl carbamate (5j): yield 1.96 g (83%) starting from 1.8 g
(12.84 mmol) of ethyl 2ꢀcycloheptylideneacetate; purification by column
1
chromatography on silica gel (hexanes/AcOEt 4:1); white solid; m.p. 49ꢀ50 °C; H
NMR (400 MHz, CDCl ) δ: 5.30 (t, J 7.0 Hz, 1H), 5.00 (s, 2H), 4.52 (d, J 7.0 Hz, 2H),
3
13
2.34–2.17 (m, 4H), 1.61–1.38 (m, 8H); C NMR (101 MHz, CDCl
3
) δ: 157.4, 148.0,
118.9, 61.7, 37.7, 30.0, 29.7, 28.9, 28.6, 27.2; FTIR (film) v: 3450, 3333, 3266, 3202,
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 71
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
ꢀ
1
2920, 2849, 1702, 1606, 1335, 1058 cm ; HRMS (ESIꢀTOF) m/z calcd for
+
C H NO Na [M+Na ] 206.1157; Found 206.1157.
10
17
2
Rearrangement of carbamates 5 to carbamates 8. General procedure: To a
solution of allyl carbamate 5 (0.74 mmol) and Et N (450 mg, 620 ꢂL, 4.44 mmol) in
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
dry THF (10 mL) cooled to 0 °C, TFAA (311 mg, 200 ꢂL, 1.48 mmol) was added, and
the resulting mixture was warmed to room temperature slowly. After 1 h dry MeOH (5
mL) and Bu SnOMe (0.1 mmol, 32 mg, 30 ꢂL) were added and the reaction mixture
3
stirred overnight. After the removal of the solvents, the crude product was supported
on silica gel and chromatographed on silica gel to afford the methoxy carbamate 8.
Methyl (1,1ꢀdiphenylallyl)carbamate (8a): yield 127 mg (79%) starting from 150 mg
1
(0.59 mmol) of carbamate 5a; waxy solid; H NMR (500 MHz, CDCl
3
) δ: 7.38–7.21
(
m, 10H), 6.88–6.72 (m, 1H), 5.63 (br s, 1H), 5.38 (d, J 10.7 Hz, 1H), 4.86 (d, J 17.4
13
Hz, 1H), 3.61 (br s, 3H); C NMR (126 MHz, CDCl ) δ: 143.5, 140.8, 128.2, 127.7,
3
1
27.3, 116.2, 67.1, 51.9; FTIR (film) v: 3412, 3342, 1737, 1493, 1447, 1246, 1190,
ꢀ
1
+
2
1037, 766, 701 cm ; HRMS (ESIꢀTOF) m/z calcd for C17H17NO Na [M+Na ]
290.1157; Found 290.1147.
Methyl (3ꢀethylpentꢀ1ꢀenꢀ3ꢀyl)carbamate (8b): yield 95 mg (63%) starting from 150
1
mg (0.76 mmol) of carbamate 5b; colorless oil; H NMR (500 MHz, CDCl
3
) δ: 5.69
(
dd, J 17.6, 11.0 Hz, 1H), 5.16 (d, J 11.0 Hz, 1H), 5.02 (d, J 17.6 Hz, 1H), 4.61 (s,
13
1H), 3.62 (s, 3H), 1.73–1.53 (m, 4H), 0.79 (t, J 7.4 Hz, 6H); C NMR (126 MHz,
CDCl ) δ: 155.2, 142.0, 113.0, 59.8, 51.5, 27.7, 15.6; FTIR (film) v: 3451, 2968, 2937,
3
ꢀ1
+
1
719, 1246, 1102 cm ; HRMS (ESIꢀTOF) m/z calcd for C H NO Na [M+Na ]
9 17 2
194.1157; Found 194.1153.
Methyl
(2,2,3,3,9,9,10,10ꢀoctamethylꢀ6ꢀvinylꢀ4,8ꢀdioxaꢀ3,9ꢀdisilaundecanꢀ6ꢀ
yl)carbamate (8c): yield 114 mg (73%) starting from 150 mg (0.386 mmol) of
26
ACS Paragon Plus Environment

Page 27 of 71
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
carbamate 5c; column chromatography on silica gel (2% AcOEt in hexanes);
1
colorless oil; H NMR (500 MHz, CDCl ) δ: 6.00 (dd, J 17.6, 11.0 Hz, 1H), 5.25–5.18
3
13
(
m, 2H), 3.61 (s, 4H), 0.89 (s, 18H), 0.06 (s, 6H), 0.05 (s, 6H); C NMR (126 MHz,
3
CDCl ) δ: 165.1, 136.8, 115.2, 63.9, 60.5, 52.3, 51.6, 25.8, 18.2, –5.5; FTIR (film) v:
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
3
434, 3354, 1739, 1498, 1254, 1084, 838, 777 cm ; HRMS (ESIꢀTOF) m/z calcd for
+
C
19 4 2
H41NO Si Na [M+Na ] 426.2472. Found 426.2476.
Benzyl (1ꢀvinylcyclopropyl)carbamate (8d): yield 114 mg (67%) starting from 100
mg (0.786 mmol) of carbamate 5d; purification by column chromatography on silica
1
gel (10% AcOEt in hexanes); colorless crystals; m.p. 85ꢀ86 °C; H NMR (400 MHz,
CDCl
3
) δ 7.38–7.30 (m, 5H), 5.46 (dd, J 17.0, 10.5 Hz, 1H), 5.26 (s, 1H), 5.10 (s, 2H),
5
2
6
1
.06 (d, J 17.0 Hz, 1H), 5.00 (d, J 10.5 Hz, 1H), 1.16–1.05 (m, 2H), 0.98–0.90 (m,
13
H); C NMR (101 MHz, CDCl ) δ: 155.9, 140.4, 136.5, 128.5, 128.2, 128.1, 110.9,
3
6.61, 34.8, 16.5; FTIR (film) v: 3442, 3329, 3088, 3013, 2551, 2924, 2898, 1693,
ꢀ
1
661, 1637, 1520, 1258, 1090, 897, 747, 699 cm ; HRMS (ESIꢀTOF) m/z calcd for
+
C
13
H
15NO
2
Na [M+Na ] 240.1000; Found 240.1004
Methyl (1ꢀvinylcyclobutyl)carbamate (8e): yield 171 mg (78%) starting from 200
mg (1.42 mmol) of carbamate 5e; column chromatography on silica gel (15% AcOEt
1
in hexanes); colorless oil; H NMR (500 MHz, CDCl
3
) δ: 6.09 (dd, J 17.2, 10.5 Hz,
1
H), 5.16 (d, J 17.2 Hz, 1H), 5.08 (d, J 10.5 Hz, 1H), 4.93 (s, 1H), 3.63 (s, 3H), 2.35–
13
2.16 (m, 4H), 1.97–1.88 (m, 2H), 1.86–1.76 (m, 2H); C NMR (126 MHz, CDCl
3
) δ:
1
1
1
55.2, 141.3, 111.6, 57.3, 51.7, 33.0, 14.7; FTIR (film) v: 3327, 2216, 1705, 1522,
ꢀ1
+
257, 1085, 915 cm ; HRMS (ESIꢀTOF) m/z calcd for C H NO Na [M+Na ]
8
13
2
78.0844. Found 178.0846.
Methyl (1ꢀvinylcyclopentyl)carbamate (8f): yield 75%; colorless oil; column
1
chromatography on silica gel (15% AcOEt in hexanes); H NMR (400 MHz, CDCl
3
) δ:
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 71
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5.94 (dd, J 17.3, 10.6 Hz, 1H), 5.09 (dd, J 17.3, 0.8 Hz, 1H), 5.03 (d, J 10.6 Hz, 1H),
13
4
.74 (s, 1H), 3.61 (s, 3H), 2.02–1.88 (m, 2H), 1.82–1.64 (m, 6H); C NMR (101 MHz,
CDCl ) δ: 155.5, 154.6, 141.9, 111.8, 64.5, 51.6, 38.1, 23.1; FTIR (film) v: 3340,
933, 1721, 1525, 1250, 1100 cm ; HRMS (ESIꢀTOF) m/z calcd for C
3
ꢀ1
2
9 2
H15NO Na
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
[
M+Na ] 192.1000. Found 192.1006.
Methyl 1ꢀvinylcyclohexylcarbamate (8g): yield 282 mg (87%) starting from 300 mg
(1.77 mmol) of carbamate 5g; yellowish oil; column chromatography on silica gel
1
(
20% AcOEt in hexanes); H NMR (500 MHz, CDCl
3
) δ: 5.92 (dd, J 17.5, 10.7 Hz,
1H), 5.12 (d, J 17.5 Hz, 1H), 5.07 (d, J 10.7 Hz, 1H), 4.60 (s, 1H), 3.62 (s, 3H), 2.00
13
(m, 2H), 1.70–1.19 (m, 8H); C NMR (125 MHz, CDCl
3
) δ: 155.2, 143.6, 112.3, 55.6,
ꢀ
1
5
1.5, 35.1, 25.5, 21.6; FTIR (film) v: 3343, 2933, 1719, 1526, 1251, 1105 cm ;
+
HRMS (ESIꢀTOF) m/z calcd for C H NO Na [M+Na ] 206.1157; Found 206.1160.
10
17
2
Methyl (4ꢀvinyltetrahydroꢀ2Hꢀpyranꢀ4ꢀyl)carbamate (8h): yield 292 mg (90%)
starting from 300 mg (1.75 mmol) of carbamate 5h; colorless crystals; m.p. 56.5ꢀ57.5
1
°C; H NMR (500 MHz, CDCl
3
) δ: 5.93 (dd, J 17.4, 10.7 Hz, 1H), 5.21–5.08 (m, 2H),
4
1
3
.67 (s, 1H), 3.79–3.65 (m, 4H), 3.63 (s, 3H), 1.99 (br d, J 14.0 Hz, 2H), 1.85 (ddd, J
13
4.0, 9.8, 4.4 Hz, 2H); C NMR (126 MHz, CDCl ) δ: 142.1, 113.4, 63.4, 53.4, 51.7,
3
ꢀ
1
5.3; FTIR (film) v: 3519, 3325, 1712, 1532, 1262, 1104 cm ; HRMS (ESIꢀTOF) m/z
+
calcd for C
9
H15NO
3
Na [M+Na ] 208.0950. Found 208.0944.
tꢀButyl 4ꢀ((methoxycarbonyl)amino)ꢀ4ꢀvinylpiperidineꢀ1ꢀcarboxylate (8i): yield
1
1
91 mg (90%) starting from 200 mg (0.74 mmol) of carbamate 5i; colorless oil; H
NMR (500 MHz, CDCl ) δ: 5.90 (dd, J 17.4, 10.7 Hz, 1H), 5.19–5.11 (m, 2H), 4.64 (s,
3
1H), 3.80–3.66 (m, 2H), 3.62 (s, 3H), 3.20–3.09 (m, 2H), 2.10–1.93 (m, 2H), 1.77–
13
1.63 (m, 2H), 1.45 (s, 9H); C NMR (126 MHz, CDCl
3
) δ: 154.7, 141.9, 113.5, 79.6,
54.3, 51.7, 39.5, 34.5, 28.4, 26.9; FTIR (film) v: 3330, 1732, 1697, 1674, 1250, 1162
28
ACS Paragon Plus Environment

Page 29 of 71
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
ꢀ
1
+
cm ; HRMS (ESIꢀTOF) m/z calcd for C14
24 2 4
H N O Na [M+Na ] 307.1634. Found
3
07.1633.
Methyl (1ꢀvinylcycloheptyl)carbamate (8j): yield 155 mg (90%) starting from 200
1
mg (0.87 mmol) of carbamate 5j; yellowish oil; H NMR (400 MHz, CDCl
3
) δ: 5.90
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
(
dd, J 17.4, 10.7 Hz, 1H), 5.03 (d, J 17.4 Hz, 1H), 4.97 (d, J 10.7 Hz, 1H), 4.75 (s,
13
1H), 3.56 (s, 3H), 1.92–1.36 (m, 12H); C NMR (101 MHz, CDCl
3
) δ: 155.2, 144.1,
ꢀ
1
1
11.2, 59.3, 51.4, 38.4, 29.1, 22.1; FTIR (film) v: 3342, 2925, 1713, 1525, 1242 cm ;
+
HRMS (ESIꢀTOF) m/z calcd for C H NO Na [M+Na ] 220.1313; Found 220.1313.
11
19
2
tꢀButyl (1ꢀvinylcyclohexyl)carbamate (8k): To a solution of allyl carbamate 5g (150
mg, 0.89 mmol) and Et N (538 mg, 740 ꢂL, 5.32 mmol) in dry THF (10 mL) cooled to
3
0 °C, TFAA (373 mg, 246 ꢂL, 1.77 mmol) was added and the resulting mixture was
warmed to room temperature slowly. In a separate flask a 1M soln. of LiHMDS (5.3
mL, 5.32 mmol) was added to a solution of tꢀBuOH (1 mL) in dry THF (10 mL). After
1
h the solution of tꢀBuOLi was added to the generated allyl isocyanate and the
reaction mixture was stirred for 2 h. Then the volatiles were removed under
diminished pressure. The residue was purified by flash chromatography on silica gel
1
(7% AcOEt in hexanes) to afford 172 mg of compound 8k (88%) as a waxy solid; H
3
NMR (400 MHz, CDCl ) δ: 5.87 (dd, J 17.4, 10.7 Hz, 1H), 5.05 (dd, J 17.5, 1.0 Hz,
13
1
H), 5.00 (dd, J 10.7, 0.9 Hz, 1H), 4.44 (s, 1H), 1.55–1.42 (m, 10H), 1.38 (s, 9H); C
NMR (101 MHz, CDCl
3
) δ: 144.0, 128.3, 128.2, 111.8, 55.5, 35.2, 28.40, 28.39, 25.5,
+
2
2
1
1.6; HRMS (ESIꢀTOF) m/z calcd for C13
H23NO
2
Na [M+Na ] 248.1629 Found
48.1636; FTIR (film) v: 3449, 3358, 3277, 2977, 2931, 2858, 1725, 1694, 1494,
ꢀ
1
451, 1389, 1365, 1247, 1170, 1088, 967, 906, 778 cm .
Benzyl (1ꢀvinylcyclohexyl)carbamate (8l): To a solution of allyl carbamate 5g (150
mg, 0.89 mmol) and Et N (538 mg, 740 ꢂL, 5.32 mmol) in dry THF (10 mL) cooled to
3
29
ACS Paragon Plus Environment