1,3-Dioxa-[3,3]-sigmatropic Oxo-Rearrangement of Substituted Allylic Carbamates: Scope and Mechanistic Studies

Article abstract of DOI:10.1021/acs.joc.8b01320

An unexpected 1,3-dioxa-[3,3]-sigmatropic rearrangement during the treatment of aryl- and alkenyl-substituted allylic alcohols with activated isocyanates is reported. The reorganization of bonds is highly dependent on the electron density of the aromatic

Full text of DOI:10.1021/acs.joc.8b01320

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Article
1,3-Dioxa-[3,3]-Sigmatropic Oxo-Rearrangement of Substituted
Allylic Carbamates: Scope and Mechanistic Studies
Maddalen Agirre, Sylvain HENRION, Iván Rivilla, Jose Ignacio Miranda, Fernando
P. Cossio, Bertrand Carboni, Jose M. Villalgordo, and François Carreaux
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01320 • Publication Date (Web): 20 Nov 2018
Downloaded from http://pubs.acs.org on November 23, 2018
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1,3-DIOXA-[3,3]-SIGMATROPIC
OXO-REARRANGEMENT
CARBAMATES: SCOPE
OF
SUBSTITUTED
ALLYLIC
AND
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MECHANISTIC STUDIES
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Maddalen Agirre,† Sylvain Henrion,‡ Ivan Rivilla,† José I. Miranda,¶ Fernando
P. Cossío,*† Bertrand Carboni,‡ José M. Villalgordo,§ and François Carreaux*‡
† Departamento de Química Orgánica I and Centro de Innovación en Química Avanzada
(ORFEO-CINQA), Facultad de Química, Universidad del País Vasco/Euskal Herriko
Unibertsitatea (UPV/EHU) and Donostia International Physics Center (DIPC), Pº Manuel
Lardizabal 3, 20018 San Sebastián/Donostia, Spain. ¶ SGIker NMR Facility, Universidad del
País Vasco/Euskal Herriko Unibertsitatea (UPV/ EHU), Avda. Tolosa 72, E-20018 San
Sebastián/Donostia, Spain. ‡ Univ Rennes, CNRS, ISCR (Institut des Sciences Chimiques de
Rennes)-UMR 6226, 263, avenue du Général Leclerc, Campus de Beaulieu, F-35000 Rennes,
§
France. VillaPharma Research, Parque Tecnológico de Fuente Alamo, Ctra. El Estrecho-
Lobosillo, Av. Azul, 30320 Murcia, Spain.
NHR3
R3NCO
110 ºC
OH
O
O
R1
R2
R1
R2
rt
R1 = aryl, alkenyl
R2 = H, alkyl
R3 = EWG
25 examples
32
R3HN
O

NHR3
Concerted
Asynchronous
O
R2
O
O
[3,3]s

Chair
TS
R1
R2
R1
ABSTRACT: An unexpected 1,3-dioxa-[3,3]-sigmatropic rearrangement during the treatment
of aryl- and alkenyl-substituted allylic alcohols with activated isocyanates is reported. The
reorganization of bonds is highly dependent on the electron density of the aromatic ring and
the nature of isocyanate used. This metal-free tandem reaction from branched allyl alcohols
initiated by a carbamoylation reaction and followed by a sigmatropic rearrangement thus
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offers a new access to (E)-cinnamyl and conjugated (E,E)-diene carbamates such as N-acyl
and N-sulfonyl derivatives. A computational study was conducted in order to rationalize this
phenomenon as well as a rearrangement progress kinetic analysis was performed.
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INTRODUCTION
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Among the plethora of tools at the disposal of synthetic organic chemists, the [3,3]-
sigmatropic rearrangements represent very useful methods for the regio and stereoselective
formation of carbon-carbon or carbon-heteroatom bonds.1 Among the C-N bond forming
reactions, the sigmatropic rearrangement of allylic trichloroacetimidates, namely the Overman
rearrangement,2 occupies a place of choice as shown by the number of total synthesis
involving this method.3 The decarboxylative [3,3]-rearrangement of allylic carbamates
represents also a very useful strategy for the preparation of protected allylic amines from
allylic alcohols with an excellent regio-and stereoselectivity.4,5 Initially reported by Holm et
al. in 1970,6 the allyl cyanate/isocyanate rearrangement can be now considered as an attractive
alternative method to those above-mentioned, due to the fact that the transposition occurs at or
below ambient temperature, under metal-free conditions and with a complete transfer of
chirality.7 The first step of this process is the formation of the transient allyl cyanate from a
carbamate-type B, under dehydration conditions, followed by a spontaneous [3,3]-sigmatropic
bond reorganization to afford the corresponding allyl isocyanate C (Figure 1). This domino
dehydration/rearrangement sequence was successfully applied on a wide variety of
carbamates coming from alkyl-substituted allylic alcohols such as A.8 As a continuation of
our studies on the use of this methodology for the synthesis of new reagents or original
compounds,9 we envisaged the formation of branched substituted carbamates of B-type in
which R would be an aryl group since they have never been employed to date in this kind of
rearrangement.7b However, as preliminary result, we observed that treatment of 1-(4-
methoxyphenyl)prop-2-en-1-ol with trichloroacetyl isocyanate followed by a basic hydrolysis
following a standard sequential process did not provide the expected branched compound
(Figure 1). The only product formed was a primary carbamate 4a with a well-defined
stereochemistry of the double bond (E). In view of previous works concerning the thermal
rearrangement of allylic esters,10,11 we envisioned at this stage that the formation of 4a could
be the outcome of a rapid 1,3-dioxa-[3,3]-sigmatropic rearrangement12 from the branched
trichloroacetyl carbamate intermediate before hydrolysis.
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OH
4
5
R
A
6
7
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9
1) Cl3CCONCO, rt,
CH2Cl2, 1 h
2) K2CO3, MeOH/H2O
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R = Alkyl
(Ref. 8)
R = 4-methoxyphenyl
O
O
O
NH2
H2N
O
R
B
4a
MeO
Dehydration/Allyl Cyanate-to-Isocyanate
Rearrangement Sequence
O
N
R
C
Figure 1. Observation of the uncatalyzed 1,3-dioxa-[3,3]-sigmatropic rearrangement.
Surprisingly, this rearrangement does not require any metal catalyst and takes place
under neutral conditions.13 Indeed, the scarce examples described in literature require catalytic
methods based on palladium (II) or mercury (II) salts.14 Taking into account the important
role of molecules bearing a carbamate group as synthetic intermediates15 as well as in modern
drug discovery,16 and that this one-pot process starting from 2-alken-1-ols (A, R = aryl or
alkenyl) could constitute a valuable access to linear allyl carbamates (Figure 2),17 we decided
to further explore the substrate scope and limitations of this methodology in order to offer a
rationalization of this phenomenon.
R1 R2
N
R1 R2
N
Catalyzed oxo-sigmatropic
rearrangement
ref. 14
O
O
O
O
1
R
R
Metal-Free rearrangement
This work
R = aryl, alkenyl
Figure 2. Proposed 1,3-dioxa-[3,3]-sigmatropic rearrangement of O-allyl carbamates.
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In this paper, we report the results of our study. We show that the rate of the 1,3-
dioxa-[3,3] sigmatropic rearrangement depends mainly on the electron density of the aromatic
ring. These experimental observations have been confirmed by a kinetic study establishing
that the rearrangement is of first kinetic order. The nature of the isocyanate used is also
important for the transposition to occur. Activated reagents such as trichloroacetyl or p-
toluenesulfonyl isocyanates were required. Other substrates, in which an aryl group at the
allylic position (C1) was replaced by an alkenyl group, were also examined with success. In
addition, a computational study of the mechanism has also been carried out in order to seed
some light on the nature of this stereoselective thermal rearrangement.
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RESULTS AND DISCUSSION
Experimental studies. First of all, we carefully examined the reaction of 1-(4-
methoxyphenyl)prop-2-en-1-ol 1a with trichloroacetyl isocyanate by monitoring the
1
carbamoylation over time by H NMR (Scheme 1). At room temperature, the reaction is
complete after 15 minutes in favor of the formation of 3a, product which may result of a [3,3]
sigmatropic rearrangement from intermediate 2a. At no moment during this NMR study was
the branched carbamate 2a detected indicating the short-lived nature of this reaction
intermediate even at lower temperature (-70 °C). In all cases only the linear carbamate 3a was
formed, with (E)-stereochemistry of the internal double bond. After evaporation of solvent,18
3a could be isolated from the reaction medium by trituration techniques or used without
further purification. Treatment of crude mixture under basic conditions in the presence of
K2CO3 afforded the expected compound 4a with 73% overall yield from 1a and 62% from 4-
methoxybenzaldehyde. It is noteworthy that this new compound 4a was also prepared from
the same starting material, according to a conventional longer strategy (four steps instead of
three) and a poorer overall yield (52%).19
Scheme 1. Synthesis of 4a Using a Rearrangement/Hydrolysis Sequence.
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CCl3
4
5
6
7
O
NH
OH
O
O
O
O
TCA-NCO
O
N
CCl3
H
8
9
CDCl3
rt
O
O
O
3a
1a
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Conv. >99% after 15 min.
2a
, not observed
62% overall yield
K2CO3,
MgBr
85%
1a
73% from
MeOH/H2O
rt, 16 h
THF, 0 °C,
16 h
1) (C2H5O)2POCH2CO2C2H5, LiCl
DBU, CH3CN, rt, 16 h, 86%
2) DIBAL-H, toluene, -78° C, 1 h, 87%
O
O
H
O
NH2
3) TCA-NCO, CH2Cl2, rt, 2 h
4) K2CO3, H2O/MeOH, 0° C, 3 h
70% for two steps
O
O
4a
52% overall yield
In order to determine the main factors that influence this sigmatropic rearrangement,
different secondary allylic alcohols bearing both electron withdrawing and electron donating
groups at para position on the aromatic ring were tested in the presence of trichloroacetyl
isocyanate (TCA-NCO). As summarized in Table 1, the bond reorganization is highly
dependent on the nature of the substituent. Except when the mesomeric effect is positive (+
M, R = OMe, entry 1), heating the reaction mixture was required for all other cases (entries 2-
4). During the NMR study, the formation of intermediates 2b-d was clearly identified as
being the first step before rearrangement can occur. The results obtained confirmed that the
rate of this reaction is much slower with electron-deficient aromatic rings. Indeed, conversion
of 2c into 3c (R = Cl, -I and +M effects) was complete after 20 h at 90 °C (entry 3) while with
R = NO2 (-I and -M effects), the time of reaction was increased sixfold to reach only 50%
conversion to 3d (entry 4). These results suggest a significant electron-deficient character for
the allyl moiety along this sigmatropic process. After evaporation of solvent and hydrolysis
under basic conditions, all linear carbamates 4 were obtained as single stereoisomer (E) and
with moderate to good yields.
Table 1. Synthesis of Linear Carbamates 4 from Allyl Alcohols 1 Using Trichloroacetyl
Iscocyanate.
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CCl3
NH
O
Cl3CCONCO,
solvent, T,
time
OH
O
O
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R
R
2a-d
(Not Isolated)
1a-d
a
b
c
d
: R = MeO
: R = H
: R = Cl
: R = NO2
K2CO3,
[3,3]s
CCl3
NH2
O
O
NH
O
O
O
MeOH/H2O,
rt, 16 h
R
R
3a-d
4a-d
Entry
R
Solvent
T (° C)
Time (h)a
Product
(Yield, %)b
4a, 73
4b, 92
4c, 50
1
2
3
4
MeO
H
Cl
CH2Cl2
Toluene
Toluene
Toluene
r.t.
90
90
90
0.25
16
20
NO2
120c
4d, 43
a Reaction was monitored by 1H-NMR until total consumption of starting material
using a deuterated solvent. Isolated yield of pure product. 50% conversion
observed.
b
c
Considering the potential importance of dienyl carbamates in the synthesis of natural
products,20 the carbamoylation/rearrangement/hydrolysis sequence was also extended to other
substrates such as C3-alkenyl-substituted allylic alcohols 5. The results indicated in Table 2
led to similar conclusions regarding the electronic effects that promote the rearrangement.
More the aromatic ring was electron-rich, faster was the sigmatropic process. The difference
of reaction rate between starting materials 1 and 5, both of them possessing the same
substitution pattern on the aromatic ring can be in part explained by the generation of a
conjugated diene unit acting as the driving force due to the higher stability of products 6. For
instance, the rearrangement took place from 5c in the presence of trichloroacetyl isocyanate
(Table 2, entry 3) without heating, whereas a temperature of 90 ºC was required for starting
alcohol 1c (Table 1, entry 3). In the case of nitro group (entry 4, Table 2), the rearranged
product 6d was not observed by NMR analysis even after 7 days of reaction at 90 ºC, most
likely due to the instability of the corresponding reaction intermediates at this temperature. In
all other cases, the linear conjugated diene carbamates 7 were obtained after basic hydrolysis
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in good yields, except for R = OMe (Table 2, entry 1), for which the purification on silica gel
led to lose of product.
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Table 2. Carbamoylation/Rearrangement/Hydrolysis Sequence of C3-Alkenyl-
Substituted Allyl Alcohols 5.
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CCl3
O
NH
Cl3CCONCO
CDCl3, rt,
time
OH
O
O
3
5a-d
6a-d
(Not Isolated)
R
R
NH2
K2CO3,
a
b
c
d
: R = MeO
: R = H
: R = Cl
: R = NO2
MeOH/H2O,
rt, 16 h
O
O
7a-d
R
Entry
R
Time (h)a
Product
(Yield, %)b
7a, 24(65)e
7b, 65
1
2
3
MeO
H
Cl
2
4
4
7c, 75
4c
NO2
178d
-
Reactions were monitored by 1H-NMR until total
a
consumption of starting material. b Isolated yield of pure
c
d
product. Reaction carried out in toluene-d8 at 90 °C.
No formation of desired product was observed.
e
Determined by 1H-NMR using 1,3,5-trimethoxybenzene
as internal reference.
In order to bring to light the utility of this new process, the synthetic interest of linear
carbamates such as 4a was evaluated through a [3,3]-allyl cyanate rearrangement.21 Treatment
of 4a with trifluoroacetic anhydride (TFAA, 1.5 equiv) in the presence of a large excess of
Et3N at 0 °C for 30 min. led to the complete formation of isocyanate which can be quenched
with various nucleophiles to afford compounds 8, 9 and 10 in unoptimized yields (Scheme 2).
When benzyl alcohol was used as nucleophile, a catalytic amount of Ti(Ot-Bu)4 was
required.22
Scheme 2. Selected In Situ Transformations of Rearranged Carbamate 4a.
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N
NH2
O
HN
O
O
7
8
9
(50%)
4a
8
MeO
MeO
10
11
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(CF3CO)2O, NEt3,
CH2Cl2, 0 ºC, 30 min
N-Diethylamine,
CH2Cl2, rt, 3 h
N
O
N
O
[3,3]s
MeO
MeO
(Not Isolated)
BnOH, Ti(Ot-Bu)4,
CH2Cl2, rt,16 h
N-Benzylallylamine,
CH2Cl2, rt, 3 h
O
Ph
N
Ph
HN
O
HN
O
(45%)
(55%)
10
9
MeO
MeO
In our quest to determine the parameters influencing this 1,3-dioxa-[3,3]-sigmatropic
rearrangement, the nature of the reagent was afterwards examined using deactivated
isocyanates. As expected, treatment of 1a with aliphatic or aromatic isocyanates in the
presence of Et3N and a catalytic amount of DMAP gave rise to the corresponding branched
carbamates 11 (R = Ph) and 12 (R = i-Pr) with no trace of linear rearranged carbamates, as
revealed by NMR analysis of the corresponding crude reaction mixtures (Scheme 3).23,24
When the phenyl isocyanate was used, the conversion was incomplete, which justifies the low
yield obtained for the isolated compound 11 (30%). From these last results, the presence of
the N-trichloroacetyl group in carbamates, such as 2a, appears to be critical for the
implementation of the rearrangement, likely by making the NH group less basic.
Scheme 3. No Rearrangement Observed with Deactivated Isocyanates During The
Carbamoylation Reaction
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O
RNCO, Et3N,
DMAP (cat.), CH2Cl2,
reflux, 16 h
O
NHR
1a
No Rearrangement
MeO
11
12
: R=Ph (30%)
: R=i-Pr (65%)
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In order to validate our hypothesis that the reorganization of branched aryl allyl
carbamates could be reliant on the acidity of the carbamate NH, we tried the reaction between
the allyl alcohol 1a and p-toluenesulfonyl isocyanate. After 15 minutes at room temperature
in CH2Cl2, the conversion into linear N-tosyl carbamate 14a was complete leading exclusively
the (E)-isomer. In these conditions, the product was obtained after purification with an
excellent yield (90%) from 1a (Table 3). The one-pot reaction was extended to other aryl allyl
alcohols 1 with good to high yields of purified products 14, except for 14h and 14i because of
their weak stability on silica gel. For substrates with electron-poor aromatic rings (1b, 1c, 1d,
1e), heating in toluene solution was required. In all cases, the exclusive E-isomer formation of
the internal double bond was maintained. Structure of 14e was determined by X-ray
crystallography.
Table 3. 1,3-dioxa-[3,3]-Sigmatropic Rearrangement Using p-Toluenesulfonyl
Isocyanate as Reagent.
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O
O
S
NH
O
O
OH
O
O
O
Tos-NCO
S
Ar
O
N
Ar
Ar
solvent, T,
time
H
13
14
1
O
10
11
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O
O
O
O
NHTos
O
NHTos
NHTos
Cl
MeO
14c
, Toluene, 90 °C,
20 h, 70%
14a,
14b,
CH2Cl2, rt,
15 min., 90%
Toluene, 90 °C,
6 h, 95%
O
O
O
NHTos
O
NHTos
O2N
14e
14e,
Toluene, 90 °C,
6 h, 70%
14d
, Toluene, 90 °C,
4 days, 40%
O
OMe
O
O
O
NHTos
O
NHTos
O
NHTos
O
BnO
14f,
14g,
16 h, 85%
CH2Cl2, rt,
15 min., 74%
CH2Cl2, rt,
14h,
CH2Cl2, rt,
1 h, 36% (85%)a
O
O
O
MeO
MeO
BnO
MeO
O
O
O
NHTos
O
NHTos
O
NHTos
14k,
CH2Cl2, rt,
14j,
CH2Cl2, rt,
45 min., 54%
14i,
CH2Cl2, rt,
45 min., 32% (80%)a
3 h, 84%
a Determined by 1H-NMR using 1,3,5-trimethoxybenzene as internal reference.
Benzoyl isocyanate was also successfully employed to yield the rearranged product 15
from 1a (Scheme 4). After 30 minutes in CDCl3, the starting material was completely
consumed and the primary carbamate 15 was obtained in 63% yield after purification.
Scheme 4. Carbamoylation/Rearrangement Sequence Using Benzoyl Isocyanate.
O
O
PhCONCO, CDCl3,
rt, 30 min.
O
N
Ph
1a
H
MeO
15
(63%)
In the same way, the one-pot process using tosyl isocyanate reagent was carried out
successfully from C3-alkenyl-substituted allyl alcohols 5 to afford the corresponding (E,E)-
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conjugated linear carbamates 16 (Table 4). Nevertheless, compound 16d (R = NO2, Table 4,
5
6
entry 4) was obtained in moderate yield after separation of the unreacted starting material.
7
8
9
Table 4. Carbamoylation/Rearrangement Sequence Using Tosyl Isocyanate From C3-
Alkenyl-Substituted Allyl Alcohols 5.
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
NHTos
Tos-NCO,
CD2Cl2, rt,
time
OH
O
O
a
: R = MeO
5a-d
16a-d
R
R
b
: R = H
c
: R = Cl
d
: R = NO2
Entry
R
Time (h)a
Product
(Yield, %)b
16a, 25(85)e
16b, 75
1
2
MeO
H
0.5
4
3
Cl
4
16c, 68
16d, 36
4c
NO2
120d
Reactions were monitored by 1H-NMR until total
consumption of starting material. Isolated yield of pure
product. c Reaction carried out in toluene-d8 at 90 °C. d 50
% conversion was observed. Determined by H-NMR
using 1,3,5-trimethoxybenzene as internal reference.
a
b
e
1
In order to test whether the carbamoylation reaction could be followed by a sequential
double sigmatropic oxo-rearrangement in a one-pot process, 1-aryl-2,4-butadien-1-ols 17 as a
mixture of stereoisomers were prepared from hexanedial according to a described procedure
(Scheme 5).25 Treatment of 17 with tosyl and benzoyl isocyanates led to the formation of the
corresponding rearranged products 18ab, 18ba and 18bb respectively. The reactions took
place at room temperature with a complete conversion after 2 h in CH2Cl2, but unfortunately
the purification of these compounds is difficult due to their instability on silica gel (see
Experimental Section). It should be noted, however, that even in the presence of a deactivating
group on the aromatic ring, these substrates are prone to undergo this consecutive double
rearrangement under mild conditions, as demonstrated with alcohol 17b.
Scheme 5. Consecutive [3,3]-Sigmatropic Rearrangements from Starting Alcohols 17.
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5
NHR1
O
OH
O
R1NCO, CH2Cl2, rt, 2 h
complete conversion
6
7
8
R
R
partially purified
1
9
17a
17b
18ab
18ba
18bb
: R = H
: R = Cl
: R = H; R = COPh
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
: R = Cl; R = Tos
1
: R = Cl; R = COPh
[3,3]s
NHR1
NHR1
O
NHR1
O
O
O
O
O
[3,3]s
R
R
R
Finally, we studied the stereoselectivity of the rearrangement in terms of the transfer
of chirality when a chiral allyl alcohol is used as starting reactant. To this end, we analyzed
the behavior of racemic (E)-1-phenylbut-2-en-1-ol 20 and its (S)-enantiomer (Figure 3).26
This latter starting alcohol was separated from a racemic mixture by HPLC using a chiral
stationary phase (see the Experimental Section). After this chromatographic separation, (S)-20
was obtained with an enantiomeric excess of 98%. Both racemic and (S)-20 were transformed
into carbamates 21 (not isolated, see Figure 3) by reaction with (R)-[1-(4-fluoro-
phenyl)ethyl]isocyanate (R)-19 in the presence of triethylamine. After two days of reaction at
110 ºC in toluene the corresponding rearranged products 22 was obtained. The HPLC profile
of the diastereomeric mixture of (S,R)+(R,R) carbamates 22 showed two well-defined peaks
compatible, within the experimental error, with that would be expected for the reaction
product stemming from racemic 20. In the case of the product formed using (S)-20 as reactant,
formation of (S,R)-22 was observed with 95% diastereomeric excess, according to the HPLC
profile. These results, show that, within the experimental error, most of –if not all– the
observed rearrangement takes place via a symmetry allowed concerted supra-supra
mechanism, with virtually complete 1,3-transfer of the chiral information contained in the
starting alcohol, together with retention of configuration of the double bond. The mechanistic
aspects derived from this observation shall be discussed in the following section.
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O
N
F
5
6
7
8
9
( )-
R 19
NEt3 (40 mol%)
Toluene, 90 ºC, 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
OH
OH
HPLC
Ph
Ph
[( )+( )]-
( )-
S 20
S
R 20
(ee = 98%)
97.32%
)-
F
F
(
S,R 22
HN
HN
)-
2.68%
( , )-
R R 22
O
O
O
O
Ph
[(
Ph
)+(
)]-
(
S,R R,R 21
S,R 21
Toluene,
110 ºC, 2d
Toluene,
110 ºC, 2d
(42%)
(39%)
52.86%
( , )-
R R 22
F
F
47.14%
)-
(
S,R 22
HN
HN
O
O
O
O
Ph
Ph
[(
(min)
time
(
)-
S,R 22
)+(
)]-
S,R R,R 22
(de = 95%)
Figure 3. Assessment of the chirality transfer in the reaction between isocyanate (R)-19 and
alcohol 20. The HPLC chromatograms are also shown.
Mechanistic studies. Conversion of alcohols 1b,c (R=H, Cl, respectively) into the rearranged
products 14b,c in the presence of p-toluenesulfonyl isocyanate was monitored by 1H-NMR in
deuterated toluene at 90 ºC. A selected ensemble of spectra recorded at different reaction
times is gathered in Figure 4. These data indicate that alcohol 1c is immediately converted
into carbamate 13c, as it can be appreciated by comparison of both spectra. This intermediate
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carbamate evolves towards the rearranged product 14c with no detectable intermediate
5
6
species. Using these NMR data and applying first-order kinetics in eq 1
7
8
(1)
ln[ퟏퟑ풄]푡 ―ln[ퟏퟑ풄]0 = ― 푘표푏푠
t
9
푘
표푏푠 = 1.08( ± 0.04) 푥 10 ―4
s—1. A similar study for alcohol 1b (R=H) led to a
we obtained
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
푘
표푏푠 = 1.62( ± 0.06) 푥 10 ―4
s—1 (see the Supporting Information).
measured kinetic constant of
These results were confirmed in a combined experiment using a 1:1 mixture of 1b and 1c, to which a
50 % of p-toluenesulfonyl isocyanate was added. After 5 min. of reaction at room temperature,
1
the H-NMR analysis revealed that ca. 50 % of both alcohols remained unreacted, whereas
carbamates 13b and 13c were observed in a 1.0:1.2 ratio. After 6h of reaction at 90 ºC, a
complete 13b 14b (R=H) conversion was observed, whereas for the 13c 14c (R=Cl)
→
→
rearrangement the conversion was of ca. 40 %. These results showed that the fast formation of
carbamates 13 from alcohols 1 is not selective and that the subsequent dioxa-[3,3]-
sigmatropic rearrangements occur through a kinetically independent process, not related to the
formation of the starting carbamate. In the case of alcohol 1a (R=OMe) the reaction was too
fast to obtain a reliable first-order kinetic under the same experimental conditions used for 1b
and 1c. However, we could measure the first-order reaction rate until 15 min of reaction at
푘
표푏푠 = 1.63( ± 0.05) 푥 10 ―3
s—1, one order of magnitude faster
room temperature and obtained
than in the preceding cases. Similar experiments with 1d (R=NO2) were not possible because
the reaction was too slow. We also examined the efficiency of the reaction in the presence of
polar solvents. When alcohol 1b and tosyl isocyanate were allowed to react in DMSO or
DMF no reaction was observed, whereas in acetonitrile only 35 % conversion was observed
after three days of reaction at 90 ºC. These results are in agreement with those reported in
Table 3 (vide supra). We concluded from these data that electron withdrawing groups at the
aryl moiety of the starting alcohols result in lower reactivity. On the contrary, electron
releasing groups such as methoxy accelerate the sigmatropic rearrangement. This conclusion
is compatible with an electron deficient character of the allyl moiety at the corresponding
transition state, an aspect (among others) that was analyzed by DFT calculations.
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8
9
NHTos
O
NHTos
O
H
O
O
H
a’’
d’
d’’
[3,3]s
Cl
TosNCO, 90 ºC
C6D5CD3
H
1c
c’
c’’
H
H
a’
H
b’’
b’
H
H
Cl
14c
13c
c’’, d’’
b’’
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
27
18
)
s
3
0
1
x
(
e
m
i
t
9
0
a’
d’
c’
b’
6.2 6.0
5.8 5.6 5.4 5.2 5.0 4.8 4.6 4.4

(ppm)
d
OH
H
d
a
c
c
H
a
H
b
H
b
Cl
1c
6.2 6.0
5.8 5.6 5.4 5.2 5.0 4.8 4.6 4.4
(ppm)

Figure 4. 1H-NMR plots (500 MHz) corresponding to the reaction of 1-(4-chlorophenyl)prop-
2-en-1-ol 1c with of N-tosyl isocyanate at 90 ºC to yield rearranged carbamate 14c via
intermediate 13c. The succesive spectra, recorded at different reaction times, show the
evolution of the allylic hydrogens of both carbamates. The spectrum of the allylic region of 1c
is also shown.
1
Since the H-NMR showed that the formation of 1-arylallyl tosylcarbamates 13b,c from
alcohols 1b,c was not kinetically relevant, we carried out DFT calculations on these
transformations. These calculations were performed at the B3LYP-D3(PCM)/6-
311G++G(d,p) level of theory. Toluene was used as solvent and the Gibbs energies were
calculated at 90 ºC (363.15 K).
Previous work on the rearrangement of allyl esters10a,b suggested that both [3,3] and
[1,3] mechanisms could occur (Scheme 6). In addition, Birney,11,27 Duncan28 and respective
co-workers have indicated that in esters and acetimidates both pericyclic and pseudopericyclic
mechanisms can compete. In order to elucidate the preference for the [1.3] or [3,3] topologies
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9
associated with these 1,3-dioxa-sigmatropic rearrangements, we studied computationally the
degenerate rearrangement of allyl tosylcarbamate 23 via [1,3] or [3,3] sigmatropic shifts. In
turn, within the [3,3] reaction path, we considered chair and boat geometries for the
corresponding saddle points (Scheme 6) as well as the possible occurrence of
pseudopericyclic mechanisms.
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 6. Possible [3,3] and [1,3] Mechanisms for the 1,3-Dioxa Rearrangement of Allyl
Tosylcarbamate 23.
The chief geometric and energetic features of transition structures chair-TS(3,3), boat-
TS(3,3) and TS(1,3) are gathered in Figure 5. Our calculations indicate that the dioxa-[3,3]-
sigmatropic mechanism is clearly preferred with respect to the [1,3] rearrangement involving
only one of the oxygen atoms of the carboxylate moiety. Within the [3,3] mechanism, the
chair geometry of the corresponding transition state is 4.6 kcal/mol less energetic than that
associated with the boat analogue. These results are in agreement with the empirical
observations reported by Lewis and Hill,10 who established that the [1,3] mechanism is
substantially more energetic than the [3,3] reaction path. On the other hand, the dihedral
angles calculated for the three transition structures shown in Figure 5 indicate 
interactions between both reactants, with dihedral angles  of 85-110 deg. Since the
participation of the lone pairs (orbitally disconnected to the C=O orbitals) of one or two
oxygen atoms should lead to  values close to 180 deg. (vide infra), we concluded that both
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[1,3] and [3,3] geometries shown in Figure 5 correspond to pericyclic and not to
pseudopericyclic processes. In addition, these 1,3-dioxa-[3,3]-sigmatropic rearrangements
take place via chair geometries and symmetry allowed29 supra-supra topologies.
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
a
a
1.23
b
b
1.27
2.58
1.25
1.26
2.21
1.25
2.68
1.26
2.23
1.38
c
2.18
c
1.38
2.23
d
1.38
1.38
1.38
1.38
d
=−100.7
=−110.6
=−85.5
b
b
b
a
c
a
a
c



c
d
d
d
chair-TS(3,3)
boat-TS(3,3)
TS(1,3)
(+15.0)
(0.0)
(+4.6)
Figure 5. Optimized structures (B3LYP-D3(PCM=toluene)/6-311++G(d,p) level of theory) of
transition structures chair-TS(3,3), boat-TS(3,3) and TS(1,3) depicted in Scheme 6. Bond
distances are in Å. Dihedral angle  (in deg.) is defined by the a-b-c-d atoms. Numbers in
parenthesis are the relative energies, in kcal/mol.
We also performed isotope labeling NMR experiments in order to verify the
previously discussed computational results. These experiments were carried out by using a
17
18
16
mixture of 11.1% H2 O, 29.7% H2 O and 59.2% H2 O. Conversion of
(trichloromethyl)benzene 24 into doubly labeled benzoic acid 25 under microwave
irradiation30 permitted two synthetic routes (Figure 6A). In the first one, we prepared diester
26 following a described procedure.31 The 17O-NMR spectrum is shown in Figure 6B. In this
spectrum two well separated signals at 340 and 136 ppm can be observed, associated with the
sp2 and sp3-hybrydized 17O nuclei, respectively. This process permitted us to calibrate the
17
performance of O-NMR to distinguish the starting and final resonances associated with the
[17O ]13b [17O ]14b transformation.
→
1
1
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9
A
B
Ph
Microwaves, 150 W,
6 bar, 135 ºC, 30 min
*O
b
Ph CCl3
17O
Ph
17O
(93 %)
*OH
H2*O
a
340
24
O
136
[*O2]25
(17O)=245
OEt
17O2]26
a
b
e
M
1
[
h
,
h
P
2
,
)
2
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
f
T
,
C
º
O
(
0
LiAlH4, THF
r. t., 16 h
u
(85 %)
8
C
)
A
360
300
240
180
120
D
%
E
7
Ph
8
(17O) (ppm)
(
b
*O
a
*
OH
*O
c’’
c’
C
H
SO2PhMe
H
SO2PhMe
O
N
N
Ph
17O
b’
a’
[*O]27
b’’
17O
OEt
O
O
(17O)=0
a’’
[*O2]26
a(17O)=340
b(17O)=136
Ph
Ph
[17O1]13b
[
17O1]14b
1. ClOCCOCl, DMSO
2. TEA, -84 ºC, 2h
(65 %)
a’’
c’+c’’
120 min
100 min
BrMg-CH=CH2
THF, r. t., 4h
*
OH
*O
129
(54 %)
Ph
Ph
[*O]1b
[*O]28
80 min
60 min
40 min
20 min
(17O)=31
(17O)=554
Tos-N=C=O
PhMe, rt
264
c’+c’’
NHTos
NHTos
PhMe, 90 ºC, 6 h
(86 %)
150
*
O
*O
O
O
c’
b’
Ph
Ph
0 min
0
[*O1]13b
[*O1]14b
(17O)=264
250
200
150
300
100
50
(17O)=150
(17O) (ppm)
Figure 6. (A) Synthesis of labelled allyl tosylcarbamates [*O1]13b and [*O1]14b, and diester
[*O2]26. The [17O]-labeled compounds were synthesized from a mixture of 11.1% H2 O,
17
together with 29.7% H2 O and 59.2% H2 O. The (17O) chemical shifts of the [17O]-labelled
18
16
compounds are given in ppm. (B) O-NMR spectrum of diester [17O2]26, in which the sp2
17
and sp3-hybridized oxygen atoms can be distinguished. (C) 17O-NMR spectra of the [17O1]13b
[17O ]14b transformation recorded in d8-PhMe at different reaction times. The signals of
→
1
sulfone oxygen atoms (c’ and c’’, natural abundances) are also given.
The second synthetic route of labeling experiments consisted of the conversion of
labeled benzoic acid 25 into allyl alcohol 1b via a sequence of reduction, oxidation and
addition reactions involving O-labeled benzyl alcohol 27 and benzaldehyde 28, whose
diagnostic (17O) chemical shifts are gathered in Figure 6A (see the Supporting Information
for further details). Reaction of labeled 1b with tosyl isocyanate led almost immediately (vide
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supra) to labeled 13b. The 17O-NMR spectrum of labeled [17O1]13b showed a very broad
signal at 150 ppm, partially superimposed to the signal associated with the sulfone moiety
(natural abundance, see the Supporting Information for further details). Heating of [17O1]13b
led us to observe a new signal at 264 ppm (Figure 6C), which was interpreted as associated
with the sp2-hybrydized 17O nucleus of [17O1]14b on the basis of the related signal of [17O2]26
shown in Figure 6B. The emergent signal of [17O1]14b was coincident with the decrease of
the broad signal of [17O1]13b, the broad signals of the SO2 groups of both tosyl carbamates
being of similar chemical shift.32 These results, together with the above described calculations
and experiments involving chiral species, led us to the conclusion that, as suggested by Lewis
and Hill,10 the conversion of carbamates 13 into their regioisomers 14 takes place via
concerted pericyclic 1,3-dioxa-[3,3]-sigmatropic rearrangements.
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
‡
G363 (exp.)  22.4 kcal·mol-1
(+25.9)
1.55
1.23
TSb’
‡
G363= +4.2
(+21.7)
1.50
1.24
2.64
0.07
1.35
1.27
1.67
1.36
TSb
q(TosNHCO2) = -0.67
2.28
0.20
2.56
0.10
1.39
1.26
q(TosNHCO2) = -0.71
1.42
1.30
0.17
2.34
1.36
1.63
(boat)
1.41
1.33
Sy = 0.72
(chair)
Sy = 0.75
(0.0)
13b
(-5.5)
(-5.5)
q(TosNHCO2) = -0.37
14b
14b
1.67
1.03
1.35
1.46
1.68
1.21
1.05
1.33
q(TosNHCO2) = -0.36
1.21
0.82
0.81
1.46
1.34
1.84
1.97
1.33
1.51
1.01
1.49
1.04
Figure 7. Reaction profiles of the thermal rearrangement of 1-phenylallyl tosylcarbamate 13b
to yield cinnamyl tosylcarbamate 14b. All stationary points were calculated at the B3LYP-
D3(PCM,solvent=toluene)/6-311++G(d,p) level of theory. Numbers in parentheses are the
relative free energies, in kcal/mol, calculated at 363.15 K with respect to 13b. The
experimental Gibbs activation energy, estimated at the same temperature, is also provided.
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Bond distances are given in Å. q(CO2) values, displayed in red, correspond to the natural
charges of the carboxy moieties and are given in a. u. Numbers in blue correspond to the
respective bond orders. The Sy parameter stands for the synchronicity of each elementary
process via TSb and TSb’. For a perfectly synchronous transformation, Sy=1 (see text).
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The reaction coordinate associated with the [3,3] sigmatropic rearrangement of 1-
phenylallyl tosylcarbamate 13b to yield cinnamyl tosylcarbamate 14b (R=H) was analyzed
first. The chief features of this reaction are gathered in Figure 7. We found two transition
structures TSb and TSb’ corresponding to chair and boat geometries, respectively. The
former saddle point was found to be ca. 4.2 kcal/mol less energetic than its boat congener,
which indicates that only the 13b TSb 14b reaction coordinate is kinetically relevant. The
theoretical activation energy was calculated to be 21.7 kcal/mol. From the 1H-NMR data (vide
supra), the experimental Gibbs activation energy at 363.15 K was estimated from the Eyring
equation (eq.2) associated with kobs:
퐺3‡63(푒푥푝)
푘표푏푠 = 휅푘 ·363.15푒푥푝 ― Δ
퐵
(2)
[
]
ℎ
푅·363.15
Assuming  1, the estimated activation energy was calculated to be 22.4 kcal/mol, in good
agreement with the computational value. In addition, using the bond orders associated with
the suprafacial [3,3] sigmatropic shift, we computed the earliness of the reaction path via TSb
as the average of the degree of advancement BAV of both saddle points, according to the
following expression (eq.3):
퐵푇푖 푆 ― 퐵푅푖
1
6
6
푖 = 1
6
푖 = 1
∑
∑
(3)
훿퐵퐴푉
=
훿퐵푖 = 1
푃
푅
6
퐵푖 ― 퐵푖
where Bi is the bond order of the i-th bond involved in the pericyclic reaction at the reactant
(R) 13b, transition state (TS) TSb and product (P) 14b. For the 13b TSb 14b
transformation it was found that BAV =0.42. Since for an exactly midway transition structure
BAV=0.5, this result indicates an slightly early saddle point, with Grxn=-5.5 kcal/mol. We
also calculated the synchronicity Sy of the reaction as
|
|
훿퐵푖 ― 훿퐵퐴푉
훿퐵퐴푉
1
6
푖 = 1
∑
(4)
푆푦 = 1 ― 10
According to this expression (eq.4), for a perfectly synchronous [3,3] sigmatropic reaction,
|
|
Bi=BAV for any i=1,2, … ,6 and therefore
and Sy=1. In our case, we
훿퐵푖 ― 훿퐵퐴푉 = 0
obtained Sy=0.75 for the 13b 14b reaction mediated by TSb, which suggests a noticeable
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asynchronicity. When the same reaction is mediated by TSb’, the reaction was computed to
be slightly more asynchronous (see Figure 7). These results are in line with the geometries
obtained for both saddle points, with two C···O distances associated with the bonds being
broken and formed (see Figure 7). This partially asynchronous but still concerted character of
the reaction mechanism agrees with the preservation of the chiral information contained in the
starting enantiopure allyl alcohol (see Figure 3). Finally, the charge analysis of the
carboxylate moiety along the reaction coordinate showed that this charge was ca. 0.2 e higher
in the transition structures than in the reactant and product (Figure 7). This result points to
relatively polar transition structures, with an associated positive charge delocalized in the allyl
moiety. As a consequence, electron-withdrawing groups in the starting allyl alcohol should
destabilize this partial cationic character, thus leading to higher activation energies. Likewise,
electron releasing substituents should accelerate the sigmatropic rearrangement, in good
agreement with our experimental results (see Tables 1-4).
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We also performed the above described DFT study with tosylcarbamate 13c (R=Cl) to
yield 4-chlorocynnamyl tosylcarbamate 14c (see the Supporting Information for further
details). The computed reaction profile for this series was similar to that found for R=H case.
As expected, the activation energy computed for the 13c 14c reaction via TSc was
calculated to be 22.6 kcal/mol, a value slightly higher than that found for the parent 13b
14b reaction. The excellent agreement between this latter computational value and the
corresponding experimental estimate (22.7 kcal/mol, see the Supporting Information) reflects
the reliability of our calculations and reproduces correctly the lower reaction rate with respect
to the parent reaction (R=H) for allyl alcohols when R=Cl.
In order to analyze the reasons for the preference for the chair conformation in TSb,
we considered applying the distortion/interaction-activation strain model33 to both saddle
points. However, the intramolecular nature of the sigmatropic rearrangement hampered the
analysis in terms of interacting molecules. Therefore, we decomposed the activation energy
E‡ as the sum of the deformation (FDEF) and interaction (FINT) terms between two
carboxylic (C) and allylic (A) fragments at transition structure TSb:
∆퐸 ‡ = ∆퐸퐹‡퐷퐸퐹 + ∆퐸퐹‡퐼푁푇
(5)
The deformation of both fragments can be envisaged as the sum of the zwitterionic (ZW) and
diradical (DR) contributions of both fragments:
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∆퐸퐹‡퐷퐸퐹 = 푋푍푊∆퐸푍‡푊 +(1 ― 푋푍푊)∆퐸퐷‡푅
(6)
5
6
where
is the weight of the zwitterionic contribution, the corresponding diradical
푋푍푊
7
8
coefficient
satisfying the relation
. Since for the DR structures the charges
푋푍푊 + 푋퐷푅 = 1
푋퐷푅
9
of both fragments are zero, we approximated the contribution of the ZW form as
,
푋푍푊 = 훿
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namely the NBO charge of the allylic fragment A in TSb (Figure 8).
∆퐸푍‡푊
The
term was computed as the sum of the single-point energies of isolated
carboxylate (C-) and allyl cation (A+) fragments at the geometry of TSb, with respect to the
energy E0 of the reactant 13b:
‡
‡
‡
(
)
(7)
∆퐸푍푊 = ∆퐸퐶 ― + ∆퐸퐴 + ― 퐸0
∆퐸퐷‡푅
The
term was computed in a similar way, but considering the contributions of the
carboxy (C·) and allyl (A·) isolated radical fragments, also computed at the geometries of the
transition state TSb:
‡
‡
‡
(
)
(8)
∆퐸퐷푅 = ∆퐸퐶· + ∆퐸퐴· ― 퐸0
Our results indicate that both in the chair and boat conformations of TSb the
contributions of the ZW forms are ca. 1 kcal/mol larger than those associated with the DR
‡
‡
forms. Thus, in chair-TSb the respective values are
kcal/mol and
∆퐸푍푊 = 73.3
∆퐸퐷푅 = 72.3
∆퐸푍‡푊 = 78.4
kcal/mol, whereas the corresponding values for boat-TSb are
kcal/mol and
‡
‡
‡
‡
kcal/mol. The computed total values of
,
and
terms of eq.
∆퐸퐷푅 = 77.6
∆퐸 ∆퐸퐹퐷퐸퐹
∆퐸퐹퐼푁푇
(1) are shown in Figure 8. Our calculations indicate that the fragment deformation term
‡
‡
is 5.1 kcal/mol higher in boat-TSb than in chair-TSb, the difference in
퐹퐼푁푇 being
∆퐸
∆퐸퐹퐷퐸퐹
of only 1.2 kcal/mol in favor of boat-TSb. Therefore, in the boat geometry both the
deformation (destabilizing) and interaction (stabilizing) terms between the C and A fragments
are higher in magnitude because of closer steric, Coulombic and electronic contacts in boat-
∆퐸퐹‡퐷퐸퐹
TSb with respect to its chair congener. We conclude that
is responsible for the
preference for the chair conformation in these pericyclic transition structures, since the more
congested boat geometry induces a larger departure of the C and A fragments from their
respective optimal geometries.
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A
q=−1
singlet
q=0
doublet
C
C
5
6
7
8
NHTos
NHTos
NHTos
O
O
O
O
O
O


+
9
Ph
Ph
Ph
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q=+1
q=0
=0.71 (chair)
=0.67 (boat)
A
A
singlet
doublet
DR
ZW
TSb
B
78.1
80
60
40
73.0
r
i
t
a
a
34.1
o
b
h
c
30.2
y
g
r
t
a
r
i
20
0
e
n
a
o
b
h
c
E
EF‡INT
e
v
i
t
EF‡DEF
a
l
E‡
e
R
c
h
b
o
a
a
t
i
r
−42.8
−44.0
Figure 8. (A) Fragment deformation/interaction analysis (see text) of TSb in terms of
resonant zwitterionic (ZW) and diradical (DR) contributions between carboxy (C) and allyl
(A) fragments. q is the formal charge of the corresponding fragment. The expected
2
〈 〉
푆
values, in atomic units (a.u.) are also given. The sum of NBO charges of each fragment at
chair- and boat-TSb, in a.u., are denoted as . (B) Calculated activation  ‡ ), deformation (
∆퐸
‡
‡
) and interaction energies ( 퐹퐼푁푇) for the chair and boat conformations of TSb, in
∆퐸퐹퐷퐸퐹 ∆퐸
kcal/mol.
In order to assess whether this relatively polar character of the sigmatropic shift can be
extended to other para-substituted allyl alcohol derivatives, we computed at the B3LYP-
D3(SCRF,solvent=toluene)/6-311++G(d,p) level the activation free energies associated with
different reactants and we plotted these energies with respect to the combined Hammett
parameter34
of the corresponding substituents in the form
〈휎〉
〈휎〉 = 푍푊·휎푝+ + 1 ― 푍푊 휎푝
(
)
(8)
휎푝+
휎푝
where
is the Taft resonance parameter for positive charges and
is the Hammett
parameter for a para-substituent (Figure 9). Our results show a moderate linear correlation
between the Gibbs activation energies and the combined polar Hammett-Taft parameter
.
〈휎〉
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However, there is no linear correlation between the Ga and Grxn values,35 as it is shown in
Figure 9B. This result does not follow the behavior observed for other pericyclic reactions
such as 1,4-dihydrogenations and [4+2] cycloadditions of aromatic molecules,36 thus
suggesting that the relationship between activation and reaction energies is not reducible to
Marcus-Hammond models. In our opinion, this supports our conclusion that the transition
structures of these sigmatropic rearrangements follow a polar-radical carboxy/allyl model not
directly connected to the reactants or products. Within this context, it is interesting to note that
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Houk and Ess37 have shown a departure from the Marcus-Hammond framework in 1,3-dipolar
‡
reactions, in which the nature of the different dipoles generates different
푟푥푛 plots.
∆퐻 /∆퐻
NHTos
O
NHTos
O
O
O
e
a
b
c
: R=Me
R=F
: R=CN
: R=OMe
: R=H
: R=Cl
Ga
l
:
Grxn
m
d
: R=NO2
R
R
14
13
B
A
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25
23
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19
NO2
NO2
Cl
22.5
20
Cl
H
H
CN
CN
F
F
Me
17.5
15
Me
17
15
r2=0.742
OMe
OMe
-5
-4
-3
-7
-6
0
0.8
0.4
-0.8
-0.4
Grxn (kcal/mol)
Figure 9. (A) Correlation between the calculated (B3LYP-D3(SCRF, solvent=toluene)/6-
311++G(d,p) level of theory) activation energies (Ga) for different para-substituents of allyl
alcohol derivatives and the composite Hammett parameter
(see text). (B) Plot of the
〈휎〉
calculated activation (Ga) and reaction (Grxn) free energies (computed at 363.15 K) for the
substituents indicated in (A).
Finally, we explored computationally the conversion of alcohols 17a,b into
carbamates 18ab-bb (Scheme 5). As a model case, we chose the thermal transformation of
(Z)-buta-1,3-dien-1-yl formate 29a into (E)- or (Z)-31a (Figure 10A). From the s-trans
conformation of (Z)-29a, the 1,3-dioxa-[3,3]-sigmatropic rearrangement gives rise to
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intermediate 30a via saddle point TS1a. This latter intermediate has a novel terminal C=C
bond and yields diene (E)-31a via TS2a, which in this model case is identical to TS1a. In
turn, as we have seen in the previous cases, this model transition structure can adopt chair and
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boat geometries. Another possibility consists of a degenerate pseudopericyclic reaction27,28
—
not subjected to the Woodward-Hoffmann29 rules for thermal sigmatropic rearrangements—
involving the s-cis conformation of (Z)-29a to yield again (Z)-31a (Figure 10A). This latter
process should occur via Cs-symmetric transition structure TS3 by through interconversion
between C-O bonds, C-C bonds and one of the lone pairs of one oxygen of the carboxy
group.
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a
X
b
c
A
a
B
X
X
X
1.25 1.27
b
O
O
O
2.52
O
[3,3]s
R1
R1
(Z)
2.36
TS1
R2
R2
1.35
c
1.36
s-trans 29a,b
30a,b
1.43
1.41
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
(X-a-b-c)=102.1
chair-TS1,2a (0.0)
X
[3,3]s TS2
X
a
a
b
1.26
X
1.26
X
b
2.40
1.43
1.34
O
O
R1
O
O
2.41
R1
1.40
R2
c
R2
(E)
1.37
c
(E)-31a
(E)-18ab
s-cis 29a,b

(X-a-b-c)=123.2
boat-TS1,2a (−0.6)
a: X=R1=R2=H
X
X
ab: X=NHCOPh; R1=Ph;
R2=Me
1.26
1.26
a
b
a
b
X
X
2.21
O
O
2.21
O
O
R1
[3,5]ps
R1
c
TS3
R2
R2
1.38
1.40
(Z)
1.40
1.38
c
s-cis 29’a,b
(Z)-31a
(Z)-18ab
TS3a (0.0)

(X-a-b-c)=178.4
C
chair-TS1b
boat-TS1b
(+1.7 kcal/mol)
(0.0)
(X-a-b-c)=102.4
(X-a-b-c)=139.6
1.24
X
1.27
X
a
1.25
1.27
b
a
2.51
b
2.26
2.40
2.28
c
1.38
c
1.39
1.40
1.39
Figure 10. (A) Sequential vs. one-step (3,3) and (3,5) dioxa-rearrangements of model esters
(Z)-29a,b to yield (E)- 31a,b and (Z)-31a,b. (B) Optimized geometries (B3LYP-
D3(PCM=CHCl3)/6-311++G(d,p) level of theory) and relative energies of transition structures
chair-TS1,2a, boat-TS1,2a and TS3a. (C) Chief geometric and energetic features (B3LYP-
D3(PCM=CHCl3)/6-311++G(d,p)/B3LYP/6-31G(d) level of theory) of transition structures
chair-TS1b and boat-TS1b. Bond distances are given in Å. Numbers in parentheses are the
relative energies, in kcal/mol. The dihedral angle  (in deg.) is defined by the X-a-b-c atoms.
Our calculations showed that, in effect, chair-TS12,a, boat-TS1,2a and TS3a are
practically isoenergetic. In particular, the [3,3] transition structures correspond to pericyclic
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supra,supra topologies, as indicated by the corresponding dihedral angles  (Figure 10B). On
the contrary, TS3a eludes the geometrically demanding supra, antara pericyclic topology by
adopting a pseudopericyclic [3,5] geometry reflected by a  value of ca. 180 deg. Next, we
computed the realistic case associated with the conversion of alcohol (E,Z)-17a into
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carbamate (E)-18ab (Scheme 5) through analysis of the (Z)-29b (E/Z)-18ab transformation.
→
In this case, the [3,5] pseudopericyclic mechanism disappeared from the potential energy
hypersurface and only the pericyclic [3,3] mechanism survived. In addition, saddle point boat-
TS1b was calculated to lie 1.7 kcal/mol above its congener chair-TS1b (Figure 10C). These
computational permitted us to conclude that, although the pseudopericyclic [3,5] mechanism
is conceivable, in this particular case the conversion of (Z)-29b into (E)-18ab via two
consecutive suprafacial [3,3] processes is the only accessible mechanism. These results agree
with the experimental findings summarized in Scheme 5, since a hypothetical
pseudopericyclic [3,5] mechanism should preserve the Z-stereochemistry of the starting
alcohol (Z)-17a.
CONCLUSIONS
In this paper, we have described a tandem reaction from 1-arylallyl alcohols involving
an initial carbamoylation reaction followed by an unexpected metal-free 1,3-dioxa-[3,3]-
sigmatropic rearrangement for a non-conventional access to linear allyl carbamates. Scope
and limitations of this one-pot process were carried out showing the crucial importance of the
electron density from aromatic ring as well as the nature of the isocyanate used. The synthetic
interest of this methodology is all greater given that this kind of sigmatropic rearrangement
can occur rapidly under mild reaction conditions (room temperature) and with a complete
transfer of chiral information.
The mechanism of these [3,3] sigmatropic reactions has been investigated both
1
experimentally and computationally. H-NMR studies show the very fast conversion of
starting alcohols 1b,c to give rise to intermediate tosylcarbamates 13b,c whose [3,3]
sigmatropic rearrangements yielded cinnamyl tosylcarbamates 14b,c without any noticeable
reaction intermediate. The corresponding first-order reaction rates showed a relative reactivity
following the order H>Cl. Computational DFT studies showed asynchronous, but concerted,
suprafacial processes mediated by chair transition structures, in agreement with the observed
stereoselectivities with an enantiopure substrate and NMR experiments with a 17O labeled
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substrate. These latter saddle points reflect correctly the relative reaction rates and activation
energies and show a polar character, in which the carboxy moiety bears a significant negative
charge.
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EXPERIMENTAL SECTION
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General Information and Materials. Tetrahydrofuran (THF) was distilled over
sodium/benzophenone and dichloromethane (DCM) was distilled over P2O5. All other commercially available
1
chemicals were used without further purification. NMR spectra were recorded at 300, 400 or 500 MHz for H
and 75, 101 or 126 MHz for 13C. Chemical shifts of 1H were referenced to Me4Si as internal reference. Data are
represented as follows: chemical shift (ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, br s = broad singlet), coupling constant J (Hz) and integration. Assignments were done with the aid of
DEPT 135, COSY and HSQC experiments. High-resolution mass spectra (HRMS) were recorded on a Micro-
Tof-Q II or on a Q-Tof 2 using positive ion electrospray. Purifications on silica gel were carried out on silica gel
0.006-0.200 mm, 60 Ǻ. Infrared spectra were recorded on a FT-IR spectrometer equipped with a diamond
detection and an ATR unit or a single reflection ATR module; wavenumbers are given in cm-1. Analytical thin
layer chromatography was performed on Silica gel 60 F254 plates. Optical rotations were measured using 10-cm
cell at 22 °C (sodium D-line: 589 nm), and the concentration is expressed in g/dL. Melting points were measured
without correction on a digital melting point apparatus. All analytical high-performance liquid chromatography
(HPLC) were performed, using Daicel Chiralpak IB column. 1-(Phenyl)prop-2-en-1-ol (1b) is a commercialy
available compound. The [17O] labelled H2O (11.1% H217O, 29.7% H218O and 59.2% H216O) was purchased from
Cortecnet. NMR spectra were recorded at 68 MHz for 17O.
General procedure for the synthesis of allylic alcohols 1, 5 and 20. To a solution of
aldehyde (1.50 mmol) in THF (10 mL) was slowly added at 0° C a solution of vinyl or phenylmagnesium
bromide in THF (1.80 mmol, 1 M). The reaction mixture was stirred at room temperature for 16 hours after
which a saturated NH4Cl solution (5 mL) was added. The aqueous layer was extracted with Et2O (4 x 10 mL).
The organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel to afford the corresponding product.
1-(4-Methoxyphenyl)prop-2-en-1-ol (1a).38 Prepared from 4-methoxybenzaldehyde and vinyl
magnesium bromide. Purified using a hexane/ethyl acetate mixture (80/20, Rf 0.25) as eluent. The product was
isolated as a yellow oil (210 mg) in 85% yield. 1H NMR (400 MHz, CDCl3)  7.30 (d, J = 8.2 Hz, 2H), 6.89 (d,
J = 8.2 Hz, 2H), 6.05 (ddd, J = 17.2, 10.3, 5.9 Hz, 1H), 5.34 (dd, J = 17.2, 1.7 Hz, 1H), 5.22–5.12 (m, 2H), 3.81
(s, 3H), 1.89–1.86 (br s, 1H).
1-(4-Chlorophenyl)prop-2-en-1-ol (1c).39 Prepared from 4-chlorobenzaldehyde and vinyl magnesium
bromide. Purified using a hexane/ethyl acetate mixture (85/15, Rf 0.30) as eluent. The product was isolated as a
pale yellow oil (187 mg) in 74% yield. 1H NMR (300 MHz, CDCl3):  7.33–7.31 (m, 4H), 6.01 (ddd, J = 17.0,
10.1, 6.1 Hz, 1H), 5.34 (dt, J = 17.0, 1.2 Hz, 1H), 5.25–5.15 (m, 2H), 1.95 (d, J = 3.7 Hz, 1H).
1-(4-Nitrophenyl)prop-2-en-1-ol (1d).40 Prepared from 4-nitrobenzaldehyde and vinyl magnesium
bromide. Purified using a hexane/ethyl acetate mixture (80/20, Rf 0.20) as eluent. The product was isolated as an
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The Journal of Organic Chemistry
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orange oil (81 mg) in 30% yield. 1H NMR (400 MHz, CDCl3):  8.15 (d, J = 8.7 Hz, 2H), 7.52 (d, J = 8.7 Hz,
2H), 5.96 (ddd, J = 17.1, 10.2, 6.4 Hz, 1H), 5.36 (ddd, J = 17.1, 1.2, 1.2 Hz, 1H), 5.28 (d, J = 6.4 Hz, 1H), 5.23
(ddd, J = 10.3, 1.1, 1.1 Hz, 1H), 2.67–2.65 (br s, 1H).
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1-(4-Methylphenyl)prop-2-en-1-ol (1e).41 Prepared from 4-methylbenzaldehyde and vinyl magnesium
bromide. Purified using a hexane/ethyl acetate mixture (80/20, Rf 0.32) as eluent. The product was isolated as a
yellow oil (218 mg) in 98% yield. 1H NMR (400 MHz, CDCl3):   d, J = 7.5 Hz, 2H), 7.18 (d, J = 7.5 Hz,
2H), 6.05 (ddd, J = 17.1, 10.2, 6.0 Hz, 1H), 5.35 (d, J = 17.1 Hz, 1H), 5.21–5.17 (m, 2H), 2.35 (s, 3H), 1.93 (d, J
= 6.0 Hz, 1H).
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1-(4-Benzyloxyphenyl)prop-2-en-1-ol (1f).42 Prepared from 4-benzyloxybenzaldehyde and vinyl
magnesium bromide. Purified using a hexane/ethyl acetate mixture (75/25, Rf 0.30) as eluent. The product was
isolated as
a
colorless oil (284 mg) in 79% yield. 1H NMR (400 MHz, CDCl3):
  m   m 2H  d J = 8.3 Hz 2H 6.05 (ddd, J = 17.1, 10.3, 5.9 Hz, 1H), 5.34
(d, J = 17.1 Hz, 1H), 5.21–5.15 (m, 2H), 5.07 (s, 2H), 1.86 (d, J = 3.4 Hz, 1H).
1-(2-Methoxyphenyl)prop-2-en-1-ol (1g).43 Prepared from 2-methoxybenzaldehyde and vinyl
magnesium bromide. Purified using a hexane/ethyl acetate mixture (85/15, Rf 0.44) as eluent. The product was
isolated as a colorless oil (172 mg) in 70% yield. 1H NMR (400 MHz, CDCl3):  7.32–7.25 (m, 2H), 7.01–6.94
(m, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.14 (ddd, J = 17.2, 10.4, 5.6 Hz, 1H), 5.41 (dd, J = 5.6, 5.6 Hz, 1H), 5.31 (dd,
J = 17.2, 4.4 Hz, 1H), 5.17 (dd, J = 10.4, 4.4 Hz, 1H), 3.87 (s, 3H), 2.77 (dd, J = 4.5, 3.8 Hz, 1H).
1-(2,3-Dihydrobenzofuran-5-yl)prop-2-en-1-ol (1h).44 Prepared from 2,3-dihydrobenzofuran-5-
carboxaldehyde and vinyl magnesium bromide. Purified using a hexane/ethyl acetate mixture (80/20, Rf 0.33) as
eluent. The product was isolated as a colorless oil (259 mg) in 98% yield. 1H NMR (400 MHz, CDCl3):  7.32–
7.29 (m, 1H), 7.16 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 6.10 (ddd, J = 16.7, 10.3, 5.8 Hz, 1H), 5.34
(ddd, J = 17.1, 1.4, 1.4 Hz, 1H), 5.24 (ddd, J = 10.4, 1.4, 1.4 Hz, 1H), 5.19 (d, J = 5.8 Hz, 1H), 4.63 (t, J = 8.7
Hz, 2H), 3.26 (t, J = 8.7 Hz, 2H), 1.92–1.86 (br s, 1H).
1-(3,4-Dimethoxyphenyl)prop-2-en-1-ol (1i).45 Prepared from 3,4-dimethoxybenzaldehyde and vinyl
magnesium bromide. Purified using a hexane/ethyl acetate mixture (70/30, Rf 0.27) as eluent. The product was
isolated as a pale yellow oil (117 mg) in 40% yield. 1H NMR (400 MHz, CDCl3):  6.94–6.89 (m, 2H), 6.85 (d,
J = 7.8 Hz, 1H), 6.05 (ddd, J = 17.1, 10.4, 5.9 Hz, 1H), 5.36 (d, J = 17.1 Hz, 1H), 5.20 (d, J = 10.4 Hz, 1H), 5.17
(d, J = 5.9 Hz, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 1.96–1.90 (br s, 1H).
1-(3-(Benzyloxy)-4-methoxyphenyl)prop-2-en-1-ol
(1j).
Prepared
from
3-benzyloxy-4-
methoxybenzaldehyde and vinyl magnesium bromide. Purified using a hexane/ethyl acetate mixture (80/20, Rf
1
0.21) as eluent. The product was isolated as a pale yellow oil (324 mg) in 80% yield. H NMR (400 MHz,
CDCl3):  7.45 (d, J = 7.5 Hz, 2H), 7.36 (dd, J = 7.4, 7.4 Hz, 2H), 7.31 (d, J = 7.2 Hz, 1H), 6.96 (s, 1H), 6.94–
6.90 (m, 1H), 6.87 (d, J = 8.2 Hz, 1H), 5.99 (ddd, J = 17.2, 10.3, 5.7 Hz, 1H), 5.30 (d, J = 17.2 Hz, 1H), 5.19–
5.16 (m, 1H), 5.14 (s, 2H), 5.12–5.10 (m, 1H), 3.87 (s, 3H), 1.87 (d, J = 3.8 Hz, 1H). 13C{1H} NMR (101 MHz,
CDCl3):  149.1, 148.1, 140.3, 136.9, 135.3, 128.4, 127.7, 127.4, 119.2, 114.6, 112.3 (d, J = 5.7 Hz), 111.6 (d, J
= 4.6 Hz), 74.6, 70.9, 55.9. IR (cm-1) 3488, 3054, 1511, 1263, 1157, 1135, 1021, 730, 698. HRMS (ESI): m/z
calcd. for C17H19O3 [M+H]+ 271.1334; found: 271.1335.
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